From c888018780ae352f4765ec7f2d1d01ee0ce7558c Mon Sep 17 00:00:00 2001 From: 97harsh Date: Fri, 3 Jul 2020 02:30:28 +0530 Subject: [PATCH] Updated the claims code --- .../notebooks/2T.4.5 Claim extraction.ipynb | 2341 +---------------- 1 file changed, 95 insertions(+), 2246 deletions(-) diff --git a/contradictory_claims/notebooks/2T.4.5 Claim extraction.ipynb b/contradictory_claims/notebooks/2T.4.5 Claim extraction.ipynb index 0df6c5e..211dd80 100644 --- a/contradictory_claims/notebooks/2T.4.5 Claim extraction.ipynb +++ b/contradictory_claims/notebooks/2T.4.5 Claim extraction.ipynb @@ -11,7 +11,7 @@ }, { "cell_type": "code", - "execution_count": 1, + "execution_count": null, "metadata": {}, "outputs": [], "source": [ @@ -57,20 +57,9 @@ }, { "cell_type": "code", - "execution_count": 2, + "execution_count": null, "metadata": {}, - "outputs": [ - { - "data": { - "text/plain": [ - "55" - ] - }, - "execution_count": 2, - "metadata": {}, - "output_type": "execute_result" - } - ], + "outputs": [], "source": [ "import gc\n", "gc.collect()" @@ -78,7 +67,7 @@ }, { "cell_type": "code", - "execution_count": 3, + "execution_count": null, "metadata": {}, "outputs": [], "source": [ @@ -87,7 +76,7 @@ " Predictor wrapper for the AcademicPaperClassifier\n", " \"\"\"\n", " def _json_to_instance(self, json_dict: JsonDict) -> Instance:\n", - " print(json_dict)\n", + "# print(json_dict)\n", " sentences = json_dict['sentences']\n", " instance = self._dataset_reader.text_to_instance(sents=sentences)\n", " return instance\n" @@ -102,28 +91,9 @@ }, { "cell_type": "code", - "execution_count": 4, + "execution_count": null, "metadata": {}, - "outputs": [ - { - "name": "stderr", - "output_type": "stream", - "text": [ - "/home/harsh/anaconda3/envs/Coronawhy/lib/python3.8/site-packages/torch/nn/modules/rnn.py:47: UserWarning: dropout option adds dropout after all but last recurrent layer, so non-zero dropout expects num_layers greater than 1, but got dropout=0.2 and num_layers=1\n", - " warnings.warn(\"dropout option adds dropout after all but last \"\n" - ] - }, - { - "data": { - "text/plain": [ - "31" - ] - }, - "execution_count": 4, - "metadata": {}, - "output_type": "execute_result" - } - ], + "outputs": [], "source": [ "archive = load_archive(\"./model_crf.tar.gz\") ## available at github\n", "predictor = Predictor.from_archive(archive, 'discourse_crf_predictor')\n", @@ -134,11 +104,12 @@ }, { "cell_type": "code", - "execution_count": 21, + "execution_count": 5, "metadata": {}, "outputs": [], "source": [ - "WEIGHT_PATH=\"https://s3-us-west-2.amazonaws.com/pubmed-rct/model_crf_tf.th\"\n", + "# WEIGHT_PATH=\"https://s3-us-west-2.amazonaws.com/pubmed-rct/model_crf_tf.th\"\n", + "WEIGHT_PATH=\"./model_crf_tf.th\"\n", "model = predictor._model\n", "for param in list(model.parameters()):\n", " param.requires_grad = False ## not train weights\n", @@ -154,16 +125,18 @@ }, { "cell_type": "code", - "execution_count": 29, + "execution_count": 6, "metadata": {}, "outputs": [], "source": [ - "text_input=\"The present world is facing a devastating reality as drug abuse prevails in every corner of a society. The progress of a country is obstructed due to the excessive practice of taking drugs by the young generation. Like other countries, Bangladesh is also facing this dreadful situation. The multiple use of drug substances leads an individual to a sorrowful destination and for this reason, the natural behavior of human mind is disrupted. An addicted individual may regain his normal life by proper monitoring and treatment. The objective of this study is to analyze a mathematical model on the dynamics of drug abuse in the perspective of Bangladesh and reduce the harmful consequences with effective control policies using the idea of optimal control theory. The model has been solved analytically introducing a specific optimal goal. Numerical simulations have also been performed to review the behaviors of analytical findings. The analytical results have been verified with the numerical simulations. The analysis of this paper shows that it is possible to control drug addiction if there is less interaction among general people with the addicted individuals. Family based care, proper medical treatment, awareness and educational programs can be the most effective ways to reduce the adverse effects of drug addiction in a shortest possible time.\"" + "%%capture\n", + "text_input=\"The present world is facing a devastating reality as drug abuse prevails in every corner of a society. The progress of a country is obstructed due to the excessive practice of taking drugs by the young generation. Like other countries, Bangladesh is also facing this dreadful situation. The multiple use of drug substances leads an individual to a sorrowful destination and for this reason, the natural behavior of human mind is disrupted. An addicted individual may regain his normal life by proper monitoring and treatment. The objective of this study is to analyze a mathematical model on the dynamics of drug abuse in the perspective of Bangladesh and reduce the harmful consequences with effective control policies using the idea of optimal control theory. The model has been solved analytically introducing a specific optimal goal. Numerical simulations have also been performed to review the behaviors of analytical findings. The analytical results have been verified with the numerical simulations. The analysis of this paper shows that it is possible to control drug addiction if there is less interaction among general people with the addicted individuals. Family based care, proper medical treatment, awareness and educational programs can be the most effective ways to reduce the adverse effects of drug addiction in a shortest possible time.\"\n", + "print(text_input)" ] }, { "cell_type": "code", - "execution_count": 30, + "execution_count": 7, "metadata": {}, "outputs": [], "source": [ @@ -178,7 +151,7 @@ }, { "cell_type": "code", - "execution_count": 31, + "execution_count": 8, "metadata": {}, "outputs": [ { @@ -187,7 +160,7 @@ "'The present world is facing a devastating reality as drug abuse prevails in every corner of a society. The progress of a country is obstructed due to the excessive practice of taking drugs by the young generation. Like other countries, Bangladesh is also facing this dreadful situation. The multiple use of drug substances leads an individual to a sorrowful destination and for this reason, the natural behavior of human mind is disrupted. An addicted individual may regain his normal life by proper monitoring and treatment. The objective of this study is to analyze a mathematical model on the dynamics of drug abuse in the perspective of Bangladesh and reduce the harmful consequences with effective control policies using the idea of optimal control theory. The model has been solved analytically introducing a specific optimal goal. Numerical simulations have also been performed to review the behaviors of analytical findings. The analytical results have been verified with the numerical simulations. The analysis of this paper shows that it is possible to control drug addiction if there is less interaction among general people with the addicted individuals. Family based care, proper medical treatment, awareness and educational programs can be the most effective ways to reduce the adverse effects of drug addiction in a shortest possible time.'" ] }, - "execution_count": 31, + "execution_count": 8, "metadata": {}, "output_type": "execute_result" } @@ -198,18 +171,11 @@ }, { "cell_type": "code", - "execution_count": 33, + "execution_count": 10, "metadata": {}, - "outputs": [ - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['The present world is facing a devastating reality as drug abuse prevails in every corner of a society.', 'The progress of a country is obstructed due to the excessive practice of taking drugs by the young generation.', 'Like other countries, Bangladesh is also facing this dreadful situation.', 'The multiple use of drug substances leads an individual to a sorrowful destination and for this reason, the natural behavior of human mind is disrupted.', 'An addicted individual may regain his normal life by proper monitoring and treatment.', 'The objective of this study is to analyze a mathematical model on the dynamics of drug abuse in the perspective of Bangladesh and reduce the harmful consequences with effective control policies using the idea of optimal control theory.', 'The model has been solved analytically introducing a specific optimal goal.', 'Numerical simulations have also been performed to review the behaviors of analytical findings.', 'The analytical results have been verified with the numerical simulations.', 'The analysis of this paper shows that it is possible to control drug addiction if there is less interaction among general people with the addicted individuals.', 'Family based care, proper medical treatment, awareness and educational programs can be the most effective ways to reduce the adverse effects of drug addiction in a shortest possible time.']}\n" - ] - } - ], + "outputs": [], "source": [ + "%%capture\n", "discourse_output = discourse_predictor.predict_json({'abstract': abstract})\n", "labels = discourse_output['labels']\n", "pred = claim_predictor.predict_json({'sentences': sentences})\n", @@ -221,7 +187,7 @@ }, { "cell_type": "code", - "execution_count": 34, + "execution_count": 11, "metadata": {}, "outputs": [], "source": [ @@ -236,7 +202,7 @@ }, { "cell_type": "code", - "execution_count": 35, + "execution_count": 12, "metadata": {}, "outputs": [ { @@ -245,7 +211,7 @@ "[0, 0, 0, 0, 0, 0, 0, 0, 0, 100, 100]" ] }, - "execution_count": 35, + "execution_count": 12, "metadata": {}, "output_type": "execute_result" } @@ -256,17 +222,18 @@ }, { "cell_type": "code", - "execution_count": 332, + "execution_count": 13, "metadata": {}, "outputs": [], "source": [ "# df=pd.read_csv(\"../Data/cord_titles_abstracts_conclusions.csv\")\n", - "df=pd.read_csv(\"../Data/section_sent_texts_with_drug_mentions_ann_200504.csv\").drop('Unnamed: 0',axis=1)" + "df=pd.read_csv(\"../Data/section_text_with_drug_mentions_ann_200620.csv\").drop('Unnamed: 0',axis=1)\n", + "df=df.drop_duplicates([\"cord_uid\",\"text\"]).reset_index(drop=True)" ] }, { "cell_type": "code", - "execution_count": 333, + "execution_count": 14, "metadata": {}, "outputs": [ { @@ -291,94 +258,75 @@ " \n", " \n", " cord_uid\n", - " sentence_id\n", " section\n", - " sentence\n", - " w2vVector\n", + " text\n", " drug_terms_used\n", " \n", " \n", " \n", " \n", " 0\n", - " fjmchbew\n", - " fjmchbew032256\n", - " title\n", - " The Author's Response: Case of the Index Patie...\n", - " [0.00944858, -0.05984148, 0.01565553, -0.02196...\n", - " lopinavir,ritonavir,lopinavir,ritonavir\n", + " 019rcbpg\n", + " Potential biological mechanisms of SARS-CoV-2 ...\n", + " there are indications in the literature of a n...\n", + " ifn-gamma\n", " \n", " \n", " 1\n", - " ba6v30jg\n", - " ba6v30jg1633000\n", - " Clinical features and outcomes of the patients\n", - " The clinical features and laboratory test resu...\n", - " [-0.0305434912, -0.0297232307, 0.147603706, 0....\n", - " alanine,creatine\n", + " 01es0zv4\n", + " Abstract\n", + " coronavirus disease 2019 has become a global p...\n", + " chloroquine,lopinavir,remdesivir,ritonavir,azi...\n", " \n", " \n", " 2\n", - " ba6v30jg\n", - " ba6v30jg1633001\n", - " Clinical features and outcomes of the patients\n", - " Fever, cough, and dyspnea were the most common...\n", - " [-0.01814028, 0.09488559, 0.08022365, -0.07600...\n", - " alanine,creatine\n", + " 01es0zv4\n", + " CONCLUSION\n", + " covid-19 is a pandemic with high morbidity and...\n", + " chloroquine,lopinavir,remdesivir,ritonavir,azi...\n", " \n", " \n", " 3\n", - " ba6v30jg\n", - " ba6v30jg1633002\n", - " Clinical features and outcomes of the patients\n", - " The white blood cell counts varied among these...\n", - " [-0.02238245, -0.02396372, 0.09787606, -0.0587...\n", - " alanine,creatine\n", + " 01es0zv4\n", + " CONCLUSION:\n", + " covid-19 is a pandemic with high morbidity and...\n", + " chloroquine,lopinavir,remdesivir,ritonavir,azi...\n", " \n", " \n", " 4\n", - " ba6v30jg\n", - " ba6v30jg1633003\n", - " Clinical features and outcomes of the patients\n", - " The alanine aminotransferase and serum creatin...\n", - " [0.0692584217, 0.131579965, 0.0442873463, 0.04...\n", - " alanine,creatine\n", + " 01lyavy2\n", + " Abstract\n", + " then, the really positive treatment could be t...\n", + " protein s\n", " \n", " \n", "\n", "" ], "text/plain": [ - " cord_uid sentence_id section \\\n", - "0 fjmchbew fjmchbew032256 title \n", - "1 ba6v30jg ba6v30jg1633000 Clinical features and outcomes of the patients \n", - "2 ba6v30jg ba6v30jg1633001 Clinical features and outcomes of the patients \n", - "3 ba6v30jg ba6v30jg1633002 Clinical features and outcomes of the patients \n", - "4 ba6v30jg ba6v30jg1633003 Clinical features and outcomes of the patients \n", + " cord_uid section \\\n", + "0 019rcbpg Potential biological mechanisms of SARS-CoV-2 ... \n", + "1 01es0zv4 Abstract \n", + "2 01es0zv4 CONCLUSION \n", + "3 01es0zv4 CONCLUSION: \n", + "4 01lyavy2 Abstract \n", "\n", - " sentence \\\n", - "0 The Author's Response: Case of the Index Patie... \n", - "1 The clinical features and laboratory test resu... \n", - "2 Fever, cough, and dyspnea were the most common... \n", - "3 The white blood cell counts varied among these... \n", - "4 The alanine aminotransferase and serum creatin... \n", + " text \\\n", + "0 there are indications in the literature of a n... \n", + "1 coronavirus disease 2019 has become a global p... \n", + "2 covid-19 is a pandemic with high morbidity and... \n", + "3 covid-19 is a pandemic with high morbidity and... \n", + "4 then, the really positive treatment could be t... \n", "\n", - " w2vVector \\\n", - "0 [0.00944858, -0.05984148, 0.01565553, -0.02196... \n", - "1 [-0.0305434912, -0.0297232307, 0.147603706, 0.... \n", - "2 [-0.01814028, 0.09488559, 0.08022365, -0.07600... \n", - "3 [-0.02238245, -0.02396372, 0.09787606, -0.0587... \n", - "4 [0.0692584217, 0.131579965, 0.0442873463, 0.04... \n", - "\n", - " drug_terms_used \n", - "0 lopinavir,ritonavir,lopinavir,ritonavir \n", - "1 alanine,creatine \n", - "2 alanine,creatine \n", - "3 alanine,creatine \n", - "4 alanine,creatine " + " drug_terms_used \n", + "0 ifn-gamma \n", + "1 chloroquine,lopinavir,remdesivir,ritonavir,azi... \n", + "2 chloroquine,lopinavir,remdesivir,ritonavir,azi... \n", + "3 chloroquine,lopinavir,remdesivir,ritonavir,azi... \n", + "4 protein s " ] }, - "execution_count": 333, + "execution_count": 14, "metadata": {}, "output_type": "execute_result" } @@ -389,1604 +337,44 @@ }, { "cell_type": "code", - "execution_count": 334, + "execution_count": 15, "metadata": {}, "outputs": [], "source": [ - "df=df.sort_values(by=['cord_uid','section','sentence_id']).reset_index(drop=True)\n", - "df_agg=df.groupby(['cord_uid']).agg({\"sentence\":list,\"sentence_id\":list})\n", - "\n", - "df_agg=df_agg.reset_index().rename(columns={\"sentence\":\"sentences\"})\n", + "df_abs=df.rename(columns={\"text\":\"sentences\"}).copy()\n", "\n", - "df_abs=df_agg" + "df_abs['sentences'] = df_abs.sentences.apply(sent_tokenize)\n", + "# labels = []" ] }, { "cell_type": "code", - "execution_count": 335, + "execution_count": 16, "metadata": {}, "outputs": [ { "data": { "text/plain": [ - "(558, 3)" + "Index(['cord_uid', 'section', 'sentences', 'drug_terms_used'], dtype='object')" ] }, - "execution_count": 335, + "execution_count": 16, "metadata": {}, "output_type": "execute_result" } ], "source": [ - "df_abs.shape" + "df_abs.columns" ] }, { "cell_type": "code", - "execution_count": 336, + "execution_count": 18, "metadata": {}, "outputs": [], "source": [ - "# df_abs['discourse_output'] = df_abs.abstract.apply(lambda x:discourse_predictor.predict_json({'abstract': x}))\n", - "\n", - "# df_abs['labels'] = df_abs['discourse_output'].apply(lambda x:x['labels'])" - ] - }, - { - "cell_type": "code", - "execution_count": 337, - "metadata": {}, - "outputs": [ - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Conclusion-The significance of the study stems mainly from the demonstration that the SARS-CoV-2 macro X domain binds ADP ribose.', 'This is the first step needed to justify screens for potential antivirals that bind in place of ADP ribose.', 'More work needs to be done, however, to understand the antiviral potential of such compounds because the biological role for ADP-ribose binding is still not fully understood.', 'Some work with alpha coronaviruses suggest that ADP-ribose binding by the macro X domain is not needed for viral replication.', '13 However, studies with other (+)RNA viruses suggest that macrodomains are essential for virulence.', '14 This work is also noteworthy because the synthetic codon-optimized plasmid reported here produces up to 100 mg of soluble macro X domain protein per liter of E. coli culture, and this protein retains a high affinity for ADP ribose.', 'The protein could be used for structural studies and screening campaigns.', 'Screening assays with the SARS-CoV-2 protein might actually be more efficient, since the SARS-CoV-2 protein binds ADP-ribose somewhat more tightly (Kd = 10 µM) than the SARS-CoV-1 protein (Kd = 24 µM).', 'The recombinant protein reported here, together with the detailed structural information, might also be useful to others developing SARS-CoV-2 diagnostics and/or therapeutics.', 'Hypervariability in the nsp3 Macro X domain-The structures of most of the soluble portions of the SARS-CoV-1 nsp proteins have been examined at atomic resolution to help understand coronavirus replication and facilitate antiviral drug discovery.', 'The amino acid sequences of each of these proteins were compared with the homologous regions of the rep 1ab protein encoded by SARS-CoV-2 (GenPept Accession YP_009724389).', 'The most similar proteins were the RNA helicases (nsp13) which are identical in all but one of their 603 amino acids: a conservative Val to Ile substitution near their C-termini.', 'The RNA-dependent RNA polymerases (nsp12) are also well-conserved, sharing all but 34 of 955 amino acids.', 'The primary protease that cleaves the polyprotein (nsp5) is also similar in SARS-CoV-1 and SARS-CoV-2, with only 13 amino acids that differ among 306 (4.2% different) (Fig. 1 ).', 'At the other end of the spectrum are the nsp3 proteins, which are notably more different in the two SARS viruses.', 'Nsp3 is a large multidomain membrane-bound protein, 6 and its clearest role in viral replication is cleaving the rep polyprotein.', 'Over 17% of the amino acids in the nsp3 protease domain differ between SARS-CoV-1 and SARS-CoV-2.', 'Other parts of nsp3 are even more variable, like the macrodomains that lie N-terminal to the nsp3 protease domain.', 'Macrodomains consist of four helices that surround a mixed beta sheet.', 'A ligand-binding pocket that typically binds ADP-ribose or related compounds lies between the helices and the sheet.', '7 SARS-CoV-1 has three macrodomains in tandem, but only the first binds ADP ribose.', 'The amino acid sequences of this macro X domain differ by 26% between SARS-CoV-1 and SARS-CoV-2 ( Fig. 1) .', 'Many of the 47 variant residues in the 180 amino acid long SARS macro X domain are clustered near its N-terminus in a region that is particularly variable in the three Coronaviridae genera (Fig. 2) .', 'Macro X domains from coronaviruses that cause the common cold (alpha coronaviruses) 5 and the beta coronaviruses like SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV', \"Nucleotide Binding by the SARS-CoV-2 Macro X domain-Repeated ITC experiments revealed that the purified recombinant protein bound ADP-ribose ( Fig. 3C ) with a dissociation constant of 10 ± 4 µM (uncertainty is the standard deviation of Kd's from independent titrations).\", 'To examine binding specificity, similar titrations were repeated with related nucleotides.', 'The SARS-CoV-2 protein bound ADP, cAMP, ATP and ADP-glucose (Fig. 3D ).', 'All nucleotides lacking the ribose moiety bound with similar high affinities, but none bound with an enthalpy change like that seen with ADP-ribose, suggesting specific contacts form between ADP ribose the SARS-CoV-2 protein.', 'Based on what is seen in the SARS-CoV-2 structures below, these contacts likely occur with the conserved D226 and N244 (positions 30 and 43 in the numbering above the alignment in Fig. 2) .', 'None of the other nucleotides bind with an entropic penalty as seen with ADP-ribose, either, suggesting that the ribose moiety becomes structured when bound to the macrodomain.', 'The energetics of ADP-ribose binding to the SARS-CoV protein are similar to those seen with the same protein from SARS-CoV-1, 9 MERS-CoV. 8 Enthalpy and entropy of binding were also very similar for all three protein (Fig. 3D ).', 'Unlike what is seen with the macro X protein from an alpha coronavirus, 5 enthalpy appears to drive ADP-ribose binding to the macro X domains of the three beta coronaviruses.', 'Structure of the SARS-CoV-2 Macro X Domain-The SARS CoV-2 macro X domain (NSP3 residues 207 to 277) crystallized in space group P212121 with 1 molecule per asymmetric unit.', 'These crystals had a solvent content of 43% and diffracted extremely well.', 'The final resolution limit of the data was set at 0.95 Å ( Table 1 ).', 'The quality of the electron density maps is correspondingly excellent (Fig. 4A ).', 'The section of the structure depicted in this image is located on the surface of the protein and the B-factors of these residues are close to the average B-factor of the protein (7.2 vs 10.2 Å 2 ), indicating that this sample accurately represents the overall quality of the maps.', 'The final model contains the entire sequence from V207 to S377 of nsp3, an N-terminal glycine residue that was left from the TEV-protease cleavage, and 374 solvent molecules.', 'The Rcryst and Rfree values of the final model were 0.119 and 0.137, respectively ( Table 1) .', 'The tertiary structure, as expected, ranges from nearly identical to very similar to those of other coronavirus macro domains, including: SARS CoV-1 (2FAV 9 ; 74.7% sequence identity) with a root mean square deviation (RMSD) value for 162 of 172 Cα atoms of 0.6 Å; MERS CoV (5DUS 8 ; 42.2% identical) with a 1.2 Å RMSD for 161 of 172 Cα atoms; human alpha coronavirus 229E (3EWR 10 ; 32.5% identical) with a 1.5 Å RMSD for 154 of 172 Cα atoms; feline coronavirus (FCoV; 3JZT 11 26.8% identical) with a 1.5 Å RMSD for 153 of 172 Cα atoms; and the gamma CoV infectious bronchitis virus (IBV; 3EWP 10 26.7% identical) with a 2.1 Å RMSD', 'At the time of writing, we discovered that Michalska et al. of the Center for Structural Genomics of Infectious Diseases (Center for Structural Genomics of Infectious Diseases) deposited coordinates for a very similar construct of the SARS-CoV-2 macro X domain including from E206 to E275 of the nsp3 protein, plus an additional 4 residues at the N-terminus (6VSX; unpublished).', 'Their crystals also allowed binding of ADP-ribose (6W02) and AMP (6W6Y), while ours seemed to be packed too tightly to permit ligands to access the binding site (data not shown).', 'We compared our ultra-high-resolution model of the unliganded protein to the ADP-ribosebound form.', 'The RMSD values for the fitting, done by secondary structure matching (SSM']}\n", - "{'sentences': ['Chloroquine as prophylactic agent against COVID-19?']}\n", - "{'sentences': ['The predominant pathological features of COVID-19 infection largely mimic those previously reported for SARS-CoV-1 infection.', 'They include dry cough, persistent fever, progressive dyspnea, and in some cases acute exacerbation of lung function with bilateral pneumonia (30).', 'Major lung lesions include several pathological signs, such as diffuse alveolar damage, inflammatory exudation in the alveoli and interstitial tissue, hyperplasia of fibrous tissue, and eventually lung fibrosis (43) (44) (45) .', 'It has been shown by fluorescence in situ hybridization technique that SARS-CoV-1 RNA locates to the alveolar pneumocytes and alveolar space (46, 47) .', 'Considering all these facts, it is not surprising that most histopathological analyses have been focused on distal parts of the respiratory airways, while the regions other than the alveolus have been less systematically studied.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.13.038752 doi: bioRxiv preprint intermediate cells between goblet, ciliated, and club cells.', 'If SARS-coronaviruses predominantly attack these cells, locating along the airway segments including the trachea, bronchi, and bronchioles until the last segment that is the respiratory bronchioles, it would be obvious that physiological protective mechanisms are severely affected.', 'Defective mucosal protection and inefficient removal of pathogens due to viral infection may contribute to onset of severe bilateral pneumonia that is common for SARS-diseases (51) .', 'This pathogenic mechanism is supported by previous findings, showing that early disease is manifested as a bronchiolar disease with respiratory epithelial cell necrosis, loss of cilia, squamous cell metaplasia, and intrabronchiolar fibrin deposits When we initiated the present study, we hypothesized that understanding better the transcriptional regulation of the ACE2 gene might help to explain the peculiar distribution pattern of ACE2 in tissues.', 'Since upregulation of ACE2 would reflect an increased number of SARS-coronavirus receptors on cell surfaces, it could possibly help us to understand the mechanisms why certain patients (males more than females, old more than young, smokers more than non-smokers) are more susceptible for the most detrimental effects of the COVID-19 infection.', 'In our study, the signals for ACE2 mRNA in the lung specimens did not vary much in different age groups nor did they show significant differences between males and females, which is in line with the previous findings (48) .', 'Therefore, different expression levels of lung ACE2 may not explain the variable outcome of the disease concerning age groups and genders.', 'To investigate the transcriptional regulation of ACE2 gene we made predictions for the binding sites of transcription factors within the proximal promoter region of the intestine-specific and lungspecific human ACE2 transcript promoters.', 'Our findings introduced several putative binding sites in the ACE2 promoter for known transcription factors, which showed high levels of coexpression with ACE2 in several tissues including the ileum, colon, and kidney.', 'The identified transcription factors .', 'CC-BY 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.13.038752 doi: bioRxiv preprint could represent potential candidate target molecules which regulate ACE2 expression.', 'Two of our predictions, for HNF1A and HNF1B have been previously identified experimentally to drive ACE2 expression in pancreatic islet cells and insulinoma cells, respectively (36).', 'Later work by the same group has shown that our prediction of FOXA binding sites in the ACE2 promoter are also likely correct (54) .', 'It is of interest that ACE2 might be regulated by oxygen status.', 'Zhang and coworkers previously demonstrated that ACE2 mRNA and protein levels increased during the early stages of hypoxia and decreased to near-baseline levels at later stages after hypoxia inducible factor (HIF)-1α accumulation (55) .', 'Based on these findings ACE2 has been listed as a HIF1α-target gene (56), although it does not follow the typical HIF1α regulated expression pattern, nor is there any predicted HIF1α binding site in our analyses.', 'The regulation of ACE2 expression remains an enigma and there may be multiple factors involved.', 'There has been a concern that the use of ACE inhibitors and angiotensin receptor blockers could increase the expression of ACE2 and increase patient susceptibility to viral host cell entry (57) .', 'Previous studies have suggested that both ACE inhibitor and angiotensin II receptor type I antagonist therapies increase ACE2 mRNA expression in the rat heart (58) .', 'There has also been some evidence in humans showing increased expression of ACE2 in the heart, brain, and even in urine after treatment with angiotensin receptor blockers (57) .', 'Since these drugs are widely used for treatment of hypertension and heart failure, it would be important to determine in COVID-19 patients whether these medications have any significant effects on symptoms or outcome of the disease.', 'Gene ontology investigations revealed interesting novel data on potential physiological roles of ACE2.', 'The five most significant gene ontology terms included angiogenesis, blood vessel morphogenesis, vasculature development, cardiovascular system development, and blood vessel development.', 'Our analysis of single cell RNA-Seq data suggested that ACE2 is positively, though weakly, expressed in the endothelial cells.', 'In another study, ACE2 expression was previously detected in blood vessels (25), and a recent study showed that SARS-CoV-2 is capable of directly infecting blood vessel cells (11) .', 'Based on the present finding angiogenesis/blood vessel morphogenesis may be considered a putative function for ACE2 in addition to its classical role as the key angiotensin-(1-7) forming enzyme (59) .', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.13.038752 doi: bioRxiv preprint dataset we studied included neither the AT2 nor secretory3 cells that have been recently shown positive for ACE2 (48) .', 'The results suggest that SARS-CoV infection may target the cell types that are important for the protection of airway mucosa and their damage may lead to deterioration of epithelial cell function, finally leading to a more severe lung disease with accumulation of alveolar exudate and inflammatory cells and lung edema, the signs of pneumonia recently described in the lung specimens of two patients with COVID-19 infection (60) .', 'Gene ontology analysis suggested that ACE2 is involved in angiogenesis/blood vessel morphogenesis processes in addition to its classical function in renin-angiotensin system.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.13.038752 doi: bioRxiv preprint Figure 2 .', 'Immunohistochemical localization of ACE2 protein in selected human tissues.', 'In the duodenum (A), the protein is most strongly localized to the apical plasma membrane of absorptive enterocytes (arrows).', 'The goblet cells (arrowheads) show weaker apical staining.', 'Intracellular staining is confined to the absorptive enterocytes.', 'In the kidney (B), ACE2 shows prominent apical staining in the epithelial cells of the proximal convoluted tubules (arrows) and Bowman´s capsule epithelium (arrowheads).', 'The distal convoluted tubules are negative (asterisk).', 'The testis specimen (C) shows strong immunostaining in the seminiferous tubules (arrows) and interstitial cells (arrowheads).', 'The lung sample (D) is negative.', 'In the nasopharyngeal mucosa (E), ACE2 signal is very weak and only occasional epithelial cells show weak signals (arrows).', 'Immunostained specimens were from Protein Expression Atlas (https://www.proteinatlas.org/).', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.13.038752 doi: bioRxiv preprint Figure 3 .', 'Single cell RNA-Seq analysis of different cell types from the respiratory tract (mouse tracheal epithelium), derived from data from GEO dataset GSE103354 (37).', 'Cell types were determined using markers as defined in the CellMarker database, as collected from the literature.', 'ACE2 mRNA expression is shown for comparison in upper panel.', 'UMAP dimensionality reduction plot was computed and visualized in ScanPy (40).', 'CC-BY 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.13.038752 doi: bioRxiv preprint The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.13.038752 doi: bioRxiv preprint Figure 5 .', 'Effect of age on ACE2 mRNA expression levels.', 'Data is extracted from the GTEx dataset as TPM.', 'In these organs, ANOVA revealed significant differences between age categories in tibial nerve (p=8.58 x 10 -6 ), minor salivary gland (p=0.002), and whole blood (p=0.005).', 'In other tissues, the differences did not reach statistical significance.', 'The highest TPM values are seen the small intestine, testis, and kidney.', 'CC-BY 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.13.038752 doi: bioRxiv preprint Figure 6 .', 'Effect of gender on ACE2 mRNA expression levels.', 'Data is extracted from the GTEx dataset as TPM.', 'The expression levels in males and females overlap in all tissue categories.', 'Statistically significant differences studied by ANOVA analysis were determined in esophagusgastroesophageal junction (p=0.024) and whole blood (p=0.0002).', 'The ACE2 mRNA expression levels in testis specimens are shown here for comparison.', 'CC-BY 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.13.038752 doi: bioRxiv preprint Figure 7 .', 'Prediction of transcription factor binding sites in the human ACE2 gene promoter regions of Ensembl transcripts ENST00000252519 and ENST00000427411 using TFBSfootprinter.', 'A) Promoter region of the intestine specific ACE2 transcript.', 'The results show putative binding sites for several transcription factors which have a strong correlation of expression with ACE2 in colon, kidney, and ileum.', 'The predicted binding sites overlap regions of conservation in mammal species (Ensembl GERP), and cluster within 400 base pairs (bp) of the transcription start site.', 'B) Promoter region of the lung specific ACE2 transcript.', 'The predicted binding sites cluster within 200 bp', 'CC-BY 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.13.038752 doi: bioRxiv preprint Figure 8 .', 'Expression of ACE2 highly correlated other genes in single cell datasets of trachea and intestinal epithelia.', 'Trachea expression data is taken from GSE103354 (37) and intestinal epithelia data is derived from GSE92332 (61) .', 'Visualized in ScanPy (40).', 'Table 2 .', 'Gene ontology annotation results for the processes associated with genes strongly coexpressed (≥0.5) with ACE2 across all tissues in GTEx dataset.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': [\"The term 'flatten the curve', originating from the Centers for Disease Control and Prevention [28] , has been used widely to describe the impact of social distancing interventions.\", 'Here, we used a mathematical model to quantify this term by measuring the short-term number of cases, hospitalization, and deaths averted over the first 100 days under four different social distancing interventions and assuming different levels of compliance in the adult population.', 'When looking at the shortterm impact (here considered to be over the first 100 days) of social distancing interventions started early on in the epidemic, our models suggest that only a social distancing intervention involving all the age groups in the population would considerably decrease the number of cases and delay the epidemic the most.', 'However, with as little as 25% reduction in the contact rates in the adult population (combined with 95% in the older adults), one could reduce the number of hospitalizations and deaths by over 90%.', 'Furthermore, reducing the contact rates of adults over 60 alone can have a considerable impact, reducing hospitalizations and deaths by over 30%, in agreement with what others have found [29] .', 'It is important to interpret our results with caution.', 'As any model, we have made important assumptions that could overestimate the effect of the interventions (see limitations below).', 'Quantifying the short-term impact of an intervention is very important since it allows decision makers to estimate the immediate number of resources needed and to plan for further resources in the long term.', 'However, our simulations suggest that even in the more optimistic scenario, where all the age groups reduce their contact rates over 85%, the epidemic is set to rebound once the social distancing interventions are lifted.', 'Our results suggest that social distancing interventions can \"buy us\" several weeks that could prove to be essential to strengthen our health systems and restock medical supplies, but will fail to mitigate the current pandemic.', 'This is in agreement with other modeling results which suggested that very long periods of social distancing would be needed to control transmission [20] .', 'Yet, sustaining social distancing interventions over a period of several months might not be feasible, both economically and socially.', 'A combination of social distancing interventions with testing, isolation and contact tracing of new cases is needed to suppress transmission of SARS-CoV-2 [30] .', 'Further, these interventions need to happen in synchrony around the world, as a new imported case could spark a new outbreak in any given region.', 'Furthermore, our results highlight the importance of the timing of social distancing interventions 8 .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'relative to the epidemic curve.', 'If the intervention is put in place (and lifted) early on in the epidemic, it results in a delay of the epidemic, but if the intervention occurs later on, then it results in flattening the curve.', 'Indeed, the effectiveness of the intervention will depend on the ratio of the number of susceptible, infected and recovered people in the population at the beginning of the intervention.', 'There is evidence that recovered individuals will have immunity to COVID-19 [31] but it is unclear at this point how long this immunity will last.', 'Recovered individuals would be able to re-enter the work force and help the most vulnerable groups.', 'It is then of paramount importance to have an accurate estimate of the number of current and recovered cases to evaluate possible interventions.', 'As of March 12, 2020, the US had tested fewer than 15,000 CDC samples (in contrast to over 200,000 tests performed in South Korea by mid-March) [32] .', 'It is imperative to expand the testing capabilities in all countries affected.', 'Our results suggest that the infectious period is a key parameter that has an extraordinary influence in the modeled speed of an epidemic and hence in the effectiveness of the interventions considered.', 'However, current estimates of the infectious period range from 5.5 days [18] to as long as 20 days [27] .', 'We urgently need to perform studies to have a better understanding of the duration of infectiousness of SARS-CoV-2.', 'Our work has several limitations and has to be interpreted accordingly.', 'First, deterministic mathematical models tend to overestimate the final size of an epidemic.', 'Further, deterministic models will always predict a rebound in the epidemic once the intervention is lifted provided that the number of infected people (exposed or infectious) is positive.', 'To avoid that problem, we forced our infected compartments to be zero if they had less than one person infected at any given time.', 'Second, we considered the latent period to be equal to the incubation period, but it has been suggested that pre-symptomatic transmission is occurring [22] , and the virus SARS-CoV-2 is shed for a prolonged time after symptoms end [33] .', 'It is unclear at this point however, if virus shed by convalescent individuals can infect others.', 'Further, we considered that mild and severe cases would be equally infectious.', 'In this sense, our results are conservative.', 'We used mortality and hospitalizations data from China to assess hospitalizations and deaths rates, but these rates will presumably be country-dependent.', 'New information about the epidemiological characteristics of SARS-CoV-2 is continuously arising, and incorporating such information in mathematical models such as ours is key to provide public health officials with the best tools to make decisions in uncertain times.', 'Taken together, our results suggest that more aggressive approaches need to be taken to mitigate the transmission of SARS-CoV-2.', 'Social distancing interventions need to occur in tandem with testing and contact tracing to minimize the burden of COVID-19.', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'Here, we assumed that adults over 60 will reduce their contact by 95%, children by 85% and adults by 75%.', 'The dotted lines represent the beginning and end of the social distancing intervention, at 50 and 92 days respectively.', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'Here, we assumed that adults over 60 will reduce their contacts by 95%, children by 85% and adults by 95%.', 'The dotted lines represent the beginning and end of the social distancing intervention, at 50 and 92 days respectively.']}\n", - "{'sentences': ['The 2019 coronavirus (SARS-CoV-2) surface protein (Spike) S1 Receptor Binding Domain undergoes conformational change upon heparin binding', \"[{'text': 'Many pathogens take advantage of the dependence of the host on the interaction of hundreds of extracellular proteins with the glycosaminoglycans heparan sulfate to regulate homeostasis and use heparan sulfate as a means to adhere and gain access to cells.\", 'Moreover, mucosal epithelia such as that of the respiratory tract are protected by a layer of mucin polysaccharides, which are usually sulfated.', 'Consequently, the polydisperse, natural products of heparan sulfate and the allied polysaccharide, heparin have been found to be involved and prevent infection by a range of viruses including S-associated coronavirus strain HSR1.', 'Here we use surface plasmon resonance and circular dichroism to measure the interaction between the SARS-CoV-2 Spike S1 protein receptor binding domain (Spike S1 protein receptor binding domain', 'The rapid spread of SARS-CoV-2 represents a significant challenge to global health authorities and, as there are no currently approved drugs to treat, prevent and/or mitigate its effects, repurposing existing drugs is both a timely and appealing strategy.', 'Heparin, a well tolerated anticoagulant drug, has been used successfully for over 80 years with limited and manageable side effects.', 'Furthermore, heparin belongs to a unique class of pharmaceuticals that has effective antidotes available, which makes its use safer.', 'Studying SARS-CoV-2 Spike protein structure and behaviour in solution is a vital step for the development of effective therapeutics against SARS-CoV-2.', 'Here, the ability of the SARS-CoV-2 S1 RBD to bind pharmaceutical heparin has been studied using spectroscopic techniques in concert with molecular modelling.', 'The data show that SARS-CoV-2 S1 RBD binds to heparin and that upon binding, a significant structural change is induced.', 'Moreover, moieties of basic amino acid residues, known to constitute heparin binding domains, are solvent accessible on the SARS-CoV-2 S1 RBD surface and form a continuous patch that is suitable for heparin binding.', 'Glycosaminoglycans are ubiquitously present on almost all mammalian cells and this class of carbohydrates are central to the strategy employed by coronaviridae to attach to host cells.', 'Heparin has previously been shown to inhibit SARS-associated coronavirus strain HSR1 cell invasion 2, 18 and this, in concert with the data presented within this study, supports the utilisation of glycosaminoglycan-derived pharmaceuticals against SARS-associated coronavirus.', 'Furthermore, this study strongly supports the repurposing of heparin and its derivatives as antiviral agents, providing a rapid countermeasure against the current SARS-CoV-2 outbreak.', 'It is noteworthy that even pharmaceutical-grade heparin preparations remain a polydisperse mixture of natural products, containing both anticoagulant and nonanticoagulant saccharide structures.', 'The latter may prove to be an invaluable resource for next-generation, biologically active, antiviral agents that display negligible anticoagulant potential, whilst the former remains tractable to facile, chemical (and enzymatic) engineering strategies to ablate their anticoagulation activities.', 'The subfractionation of existing heparin preparations against anticoagulant activities (with proven low-toxicity profiles, good bioavailability and industrial-scale manufacturing) for off-label pathologies, provides an attractive strategy for quickly and effectively responding to COVID-19 and for the development of next generation heparin-based therapeutics.', 'Such drugs will be amenable to routine parenteral administration through currently established routes and additionally, direct to the respiratory tract via nasal administration, using nebulised heparin, which would be unlikely to gain significant access to the circulation.', 'Thus, the anticoagulant activity of heparin, which can in any event be engineered out, would not pose a problem.', 'Importantly, such a route of administration would not only be suitable for prophylaxis, but also for patients under mechanical ventilation 19 .', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.02.29.971093 doi: bioRxiv preprint']}\n", - "{'sentences': ['In the follow-up period, the complications of COVID-19 were assessed , including acute 297 respiratory distress syndrome (ARDS) (38.3%), cardiac injury (21.7%), liver dysfunction (19.3%), 298 acute kidney injury (17.3%), bacteremia (7.7%), diffuse intravascular coagulation), diffuse intravascular coagulation (7.7%), diffuse intravascular coagulation', \"in Nanshan Zhong's study (38.8% vs. 15.1%, respectively).\", 'The time from December 1, 2019 to 343 the onset of most patients was longer than 50 days.', 'During mid-January to early February, Wuhan 344 experienced the highest peak of COVID-19 outbreak, with a family cluster and high prevalence of 345 COVID-19 in older adults.', 'Longer wait for access to medical care was observed in severe cases 346 compared with that in nonsevere cases.', 'More than half of the patients experienced at least two 347 hospital visits, which may increase the risk of nosocomial transmission events.', 'Diagnosis and 348 treatment may be delayed due to the long wait for access to medical care.', 'Severe COVID-19 349 patients would likely develop ARDS and died of respiratory failure.', 'Although there are currently 350 no effective antiviral drugs for SARS-CoV-2, prompt identification and early respiratory support 351 would relieve severe cases and reduce mortality.', 'The severity of disease in patients with initial 352 positive nucleic acid test was similar to that of all COVID-19 patients.', 'We thus propose that 353 urgent timely diagnosis is crucial, and that early intervention should not be delayed based on 354 nucleic acid test.', 'proinflammatory cytokine levels (INF-γ, IL-1β, IL-6, IL-8, IL-12, and TNF-α) and were 362 associated with the development of ARDS.', '11-13 In our study, severe COVID-19 patients had (0.9%) in our study was markedly lower than that reported in the adult population of Wuhan 366 (6.4%).', '14- 16 We thus speculate that Th2 immune response in asthmatic patients may counter the 367 inflammation process induced by SARS-CoV-2 infection.', 'Further studies are required to 368 characterize the immune response and inflammation features of The majority of severe patients showed rapid progression and multiple organ dysfunction.', 'The to onset in critically ill cases than that in severely ill cases may reflect a higher virulence of 378 SARS-Cov-2, or earlier onset of The risk factors for severity identified in this study included age, high LDH level, and high 380 d-dimer level, consistent with those in previous reports.', '15, 20 However, different from the findings 381 of previous studies 21 , hypertension was the only comorbidity associated with the severity of 382 COVID-19 after adjustment for age, sex and smoking status.', 'The distinct features of pneumonia 383 and high severity in patients with COVID-19 in this study may lead to this difference from 384 previous reports.', 'ACE2, a gateway to SARS, was reported to be a protective factor against 385 SARS-CoV-induced lung injury.', '22, 23 The association between ACE2 expression and hypertension 386 was confirmed in a previous study.', '24 This fact may partly explain the high prevalence of severe 387 COVID-19 in patients with hypertension.', 'LDH has been recognized as a marker for severe 388 prognosis in various diseases, including cancer and infection.', '25 The high LDH level in COVID-19 389 in severe cases suggested that LDH may be associated with lung injury and tissue damage, 390', 'warranting an investigation for the potential mechanism.', 'This study evaluated pre-admission medications for patients with severe COVID-19.', 'Although the 392 proportion of nonsevere cases in patients receiving oseltamivir was higher than that in patients 393 without oseltamivir use, stratification analysis showed that there was no significant difference in case subgroup.', 'Therefore, oseltamivir use may just be an indicator of disease severity.', 'The 396 patients receiving umifenovir were younger than those without umifenovir use, indicating that 397 younger patients may have easier access to drugs or prefer umifenovir.', 'Older age, leukocytosis and high LDH level were reported to be risk factors associated with 399 in-hospital death in previous studies.', '20, 26, 27 The present study also revealed that hyperglycemia 400 was related with increased mortality in COVID-19 patients.', 'The prevalence of hyperglycemia may 401 be associated with underlying diabetes and corticosteroid therapy.', 'However, the localization of 402 ACE2 expression in the pancreas in SARS was reported to damage islets, resulting in 403 hyperglycemia 19 ; this finding suggested that hyperglycemia may also be an indicator of severe 404']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['At the time of writing this commentary (February 2020), the coronavirus COVID-19 epidemic has already resulted in more fatalities compared with the SARS and MERS coronavirus epidemics combined.', 'Therapeutics that may assist to contain its rapid spread and reduce its high mortality rates are urgently needed.', 'Developing vaccines against the SARS-CoV-2 virus may take many months.', 'Moreover, vaccines based on viral-encoded peptides may not be effective against future coronavirus epidemics, as virus mutations could make them futile.', 'Indeed, new Influenza virus strains emerge every year, requiring new immunizations.', 'A tentative suggestion based on existing therapeutics, which would likely be resistant to new coronavirus mutations, is to use available angiotensin receptor 1 (AT1R) blockers, such as losartan, as therapeutics for reducing the aggressiveness and mortality from SARS-CoV-2 virus infections.', 'This idea is based on observations that the angiotensin-converting enzyme 2 (ACE2']}\n", - "{'sentences': ['The world is now experiencing an exponential increase in the COVID-19 infected people, and a significant proportion of them are pregnant women.', 'We summarized the symptoms following COVID-19 infection among pregnant women, and the treatments are commonly provided to them and the outcomes of the pregnancy.', 'A total of nine studies were included in this review, in which 101 infected pregnant women data were analyzed, and the majority of them were in the third trimester of pregnancy.', 'All included studies were conducted in China.', 'Symptoms reported by pregnant women following COVID-19 infection were slightly different from the common symptoms in general infected people, but fever and cough were common.', 'Oxygen and antibiotic therapy were given as treatments for most infected pregnant women.', 'Of the sample analyzed in the eight studies included, 56 of them gave babies following the infection occurred.', 'Approximately 84% of the infected pregnant women had gone through the C-section; around 30% of women had given premature birth, and a total of 18% of these babies were born with LBW.', 'These summary findings will assist healthcare personnel for the better management of pregnant women who have been infected with .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'This study revealed that most infected pregnant women were given symptomatic and supportive treatments considering pregnancy, although anti-inflammatory and antiviral treatments have been used in some cases [30, 31] .', 'Significantly, this study summarized the commonly given antiviral treatments to the infected pregnant women were oseltamivir, lopinavir (400mg), and ritonavir (100mg), which are different from usually recommended medicines to treat COVID-19 in the general population [26] .', 'Therefore, healthcare providers may have to be careful about given antiviral treatments to infected pregnant women.', 'Additionally, oxygen therapy and antibiotic therapy (e.g., cefoperazone sodium) have been used in some cases [31, 32] .', 'Notably, further cautious measures are needed to choose the medicine from previous experience with SARS and its treatments, which is considered like COVID-19 infection, and there are many similarities in treatments given for these infections.', 'For instance, oxygen and antiviral therapy (drugs, including ribavirin, ritonavir, and lopinavir) are used in both SARS and COVID-19 [33].', 'However, corticosteroids were not used to treat COVID-19, although it was used to treat SARS among pregnant women.', 'There is evidence that the use of corticosteroids during pregnancy increases the risk of preterm birth, low birth weight, and preeclampsia [34] .', 'Additional important findings of this study were the higher occurrence of adverse maternal newborn outcomes among COVID-19 infected mothers.', \"For example, as this study reported, around 84% of the infected mothers had birth reported use of the C-section; a rate that is significantly higher than the usual WHO's recommendation of 1-5% use of C-section to avoid death and severe morbidity in mothers and newborns [35, 36] .\", 'Getting COVID-19 infection increases complex viral infection among women in pregnancy; therefore, C-section is recommended to reduce perinatal and neonatal adverse outcomes [37] .', 'We also confirm the evidence of the higher occurrence of preterm birth and LBW among the COVID-19 infected .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.03.31.20049304 doi: medRxiv preprint mothers than their counterparts.', 'These associations are unique, as the previous round of viral infection, such as SARS, did not find any evidence of the association between infection during pregnancy and occurrence of LBW and preterm birth [38] [39] [40] [41] .', 'Viral infection affects pregnancy and fetal growth by gaining access to the placenta and decidua via hematogenous transmission or the lower reproductive tract, leading to the occurrence of such adverse outcomes [42] .', 'However, effects can vary across cell types, gestational age, and changes in the uterine environment and maternal immunity [42] .', 'Therefore, earlier preparedness of the healthcare sectors to handle these adverse consequences would be helpful to reduce further adverse outcomes, including maternal and perinatal mortality.', 'This study has several strengths and limitations.', 'This is the first study of its kind that highlight the symptoms, treatments, and pregnancy outcomes among women who have been infected with COVID-19.', 'These findings may help healthcare providers to take proper initiatives.', 'We did not set any time and study design restrictions that allowed us to include a higher number of studies.', 'However, the major limitation is generalizability because all included studies were conducted in China.', 'Different treatments may be used to treat COVID-19 during pregnancy in other countries.', \"Moreover, none of the included studies reported quantitative data that restrict us to conduct a narrative synthesis of the selected study's findings rather than given any pool estimates.\", 'Despite these limitations, this study has enough merits, which will make healthcare providers informed about the symptoms, treatments, and possible outcomes in pregnant women detected with COVID-19.', 'This study confirms that fever, cough, and breathing difficulties are the major symptoms of COVID-19 infection among pregnant women, which are similar to general infected patients.', 'However, some additional symptoms among pregnant women are postpartum fever and .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'Recommended treatments such as chloroquine and hydroxychloroquine for the infected people are not applicable for pregnant women because of their potential adverse effects on the fetus and newborn; therefore, supportive and symptomatic treatments are given to them.', 'COVID-19 infection during pregnancy also increases the risk of several adverse outcomes, including higher rates of cesarean delivery, low birth weight, and preterm birth.', 'Healthcare providers may consider these for effective management of COVID-19 infected pregnant women, which would reduce pregnancy-related adverse consequences, including maternal and newborn morbidity and mortality.', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint . .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'Traditional Chinese medicine was also used; c two patients were treated with a single antibiotic and five patients were given combination therapy .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', '17 articles were assessed for eligibility 8 full-text articles were excluded because of the following reasons -', '• Different outcomes (4) • Wrong study design (2) • In other language (2) 3 additional articles were identified through checking references in selected articles and selected journals 2918 articles were identified through database searching after duplicates were removed 9 articles were selected for this study', '• All articles reported patients perspectives • 4 articles were retrospective study • 2 study were cross-sectional study • 1 study was case report 112 articles were assessed for eligibility 95 articles were excluded due to those were not related to pregnant women or newborns .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Role of Chloroquine and Hydroxychloroquine in the Treatment of COVID-19 Infection- A Systematic Literature Review', 'Background: Coronavirus pandemic is currently a global public health emergency.', 'At present, no pharmacological treatment is known to treat this condition, and there is a need to review the available treatments.', 'Objective: While there have been studies to describe the role of chloroquine and hydroxychloroquine in various viral conditions, there is limited information about the use of them in COVID-19.', 'This systematic review aims to summarize the available evidence regarding the role of chloroquine in treating coronavirus infection.', 'The preferred reporting items for systematic reviews and meta-analyses (preferred reporting items for systematic reviews and meta-analyses', 'were pre-prints (not yet peer-reviewed) articles) in this systematic review.', 'All the articles mentioned about the role of chloroquine and /or hydroxychloroquine in limiting the infection with SARS-CoV-2 (the virus causing COVID-19).', 'Conclusions: There is theoretical, experimental, preclinical and clinical evidence of the effectiveness of chloroquine in patients affected with COVID-19.', 'There is adequate evidence of drug safety from the long-time clinical use of chloroquine and hydroxychloroquine in other indications.', 'More data from ongoing and future trials will add more insight into the role of chloroquine and hydroxychloroquine in COVID-19 infection.', 'Hydroxychloroquine sulfate ( HCQ', 'The data on the kinetics of chloroquine uptake indicated the drug attained near-maximum intracellular concentrations in 1 hr and a drug level of 60 μg/ml produced a decrement in the cellular biosynthesis of protein, RNA, or DNA.', 'Herpes simplex replication was found to be sensitive to this drug as the level of progeny virus production was depressed by 95% in 24 hr.', '32 CQ also affects viral replication by inhibiting viral gene expression.', 'CQ has an ability to change the pattern of glycosylation in HIV-1 gp120 envelope during In vitro and in vivo tests.', 'CQ also inhibits the replication of the HIV virus in CD4 + T cells 33 .', 'Both CQ and HCQ are weakly alkaline bases and All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', '24 and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', '24.20042366 doi: medRxiv preprint CQ has been found to be effective in inhibiting the infection and spread of SARS CoV in cell culture.', \"CQ inhibits the virus replication by reducing the terminal glycosylation of angiotensin-converting enzyme 2 (ACE2) receptors on the Vero E6 cells' surface and interfering with the binding of SARS-CoV to the ACE2 receptors.\", 'CQ had a significant inhibitory antiviral effect when the susceptible cells were treated either before or after infection, suggesting a possible prophylactic and therapeutic use.', \"5 CQ interferes with COVID-19's attempt to acidify the lysosomes & probably inhibits cathepsins, which needs a low pH for optimal cleavage of COVID-19 spike protein, a requirement for the formation of the autophagosome.\", '18 The Wuhan CoV (COVID-19) S-protein shares an almost identical 3-D structure in its RBD domain with SARS-CoV S-protein.', 'Although relatively weaker than SARS-CoV, the Wuhan CoV S-protein has a strong binding affinity to human ACE2', 'In a study, CQ has been found out to be the potential inhibitor of viral PLpro.', 'The effect of chloroquine during post-entry stages could be manifested via its inhibition of the crucial viral protein, PLpro.', '23 All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', '24.20042366 doi: medRxiv preprint The suggested regimen by Dutch CDC in adults includes an initial dose of 600 mg of chloroquine base followed by 300 mg after 12 h on the first day, followed by 300 mg twice daily on days second to fifth.', 'This document also emphasizes the need for stopping the treatment at day 5 to reduce the risk of side effects, as CQ has a long half-life of 30 hours.', 'There is also a need to differentiate between treatment based on chloroquine phosphate and chloroquine base since 500 mg of chloroquine phosphate is equivalent to 300 mg of chloroquine base.', 'Another set of guidelines by the Italian Society of Infectious and Tropical disease (Lombardy section) suggests the use of CQ 500 mg twice daily or HCQ 200 mg once daily for ten days with treatment duration varying between 5 to 20 days based on clinical severity.', 'The suggested target group of patients ranged from patients with mild respiratory symptoms having comorbidities to patients with severe respiratory failure.', '11 CQ has been recommended for 18-65 years of COVID-19 infected adults at a dose of 500mg twice daily for seven days.', 'For BW ≤ 50 kg patients, the CQ dose should be decreased to 500 once daily during day third to seventh of the treatment cycle ( Table 1 ).', 'There has been no dose recommendation of CQ in COVID-19 infected children so far; hence extreme caution should be followed while prescribing it for children.', 'Acute poisoning of CQ is usually fatal with a dose of 50 mg/kg, and CQ concentration > 25 μ mol/L is a fatal predictor.', '12 In Nigerian children with acute uncomplicated malaria, chloroquine absorption appeared reliable as peak chloroquine concentrations were achieved within 0.5 hours, and its concentration decline slowly, with an elimination half-life of 20 to 60 days.', 'CQ can be detected in urine months after a single dose.', '40 In accordance with the \"New Coronavirus Pneumonia Diagnosis and Treatment Program (Trial Version 6)\" issued by the National Health and Health Commission in China, the recommended dosage of Chloroquine phosphate tablets is 500 mg BID daily for ten days 9 .', 'In case of severe gastrointestinal symptoms, the dose of CQ can be reduced to 500 mg once daily, or can even be discontinued.', 'During the course of CQ treatment, if the throat swab becomes negative and stays negative for three days, the drug withdrawal can be considered.', 'However, the minimum course of CQ treatment needs to be at least five days 13 .', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', '24.20042366 doi: medRxiv preprint So far, results of more than 100 patients treated with CQ has shown that chloroquine phosphate is superior to the control treatment as it inhibits the worsening of pneumonia, improves the lung imaging findings, promotes a virus-negative conversion, and shortens the course of the disease.', 'Severe adverse reactions to CQ were not seen in these patients.', \"The drug has been recommended for inclusion in the next version of the Guidelines for the Prevention, Diagnosis, and Treatment of Pneumonia Caused by COVID-19, issued by the National Health Commission of the People's Republic of China.\", 'This would be the first successful use of CQ in humans for treating acute viral disease.', 'However, this information should be carefully considered before drawing any definitive conclusion as no supporting clinical data has been released yet.', 'As of 23rd February 2020, seven clinical trial registries have been found in the Chinese Clinical Trial Registry for using HCQ to COVID-19 treatment.', 'It has been reported that the safe dosage of HCQ (6-6.5 mg/kg per day) could reach serum levels of 1.4-1.5 μ M in humans.', 'In animals, CQ and HCQ share similar tissue distribution, with concentrations in the liver, spleen, kidney, and lung reaching levels, which are 200-700 times higher than those in the plasma.', 'Therefore a very high concentration in the above tissues is likely to be achieved with the safe dosage of HCQ for inhibiting SARS-CoV-2 infection.', 'This possibility, however, awaits confirmation by clinical trials.', '15 In patients with COVID-19 infection, CQ can interact with lopinavir/ritonavir, Causing QT interval prolongation.', 'Hence HCQ can be considered instead of CQ when the latter is not available for COVID-19 treatment 17 .', 'HCQ has been found to be more potent than CQ at inhibiting SARS-CoV-2 in vitro.', 'HCQ Sulfate 400 mg twice daily for one day, followed by 200 mg twice daily for four more days, has been recommended for treating COVID-19 infection.', \"19 Based on CQ's antiviral mechanisms, its laboratory activity against COVID-19, as well as CQ's pharmacokinetics based on its use for malaria and autoimmune diseases, safe and potentially efficacious dose regimens have been recommended for protection against COVID-19.\", 'This protocol has pre-exposure prophylaxis of 250-500mg CQ daily and post-exposure prophylaxis at 8mg/kg/day CQ for three days.', '24 All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', '24.20042366 doi: medRxiv preprint In a recent trial using HCQ as a single drug and HCQ in combination with azithromycin, the proportion of patients with negative PCR results in nasopharyngeal samples had a significant difference between the two groups.', 'At day six post-treatment, 100% of patients treated with HCQ and azithromycin combination had been virologically cured compared to 57.1% in patients treated with only HCQ and 12.5% in control group.', '21 Contraindications and relative contraindications include NOT to use CQ in people below 18 years and above 65 years, pregnant women, persons allergic to 4-aminoquinoline, patients with hematological disorders or G6PD deficiency, patients with chronic liver or kidney disease, patients with arrhythmia and chronic heart disease, patients with a history of retinal disease or hearing loss, patients known to have a mental illness, Skin diseases like a rash, dermatitis, psoriasis.', 'CQ is known to have drug interactions with various drugs, and expert medical opinion, regarding its interaction with the medicines already taken by patients, is a MUST.', 'There are some mild side effects of CQ while treating malaria, including headache, dizziness, loss of appetite, etc.', 'The primary adverse reaction of CQ at higher doses is ocular toxicity, which could affect the vision.', 'If the discomfort in the eye or visual abnormality occurs, CQ should be discontinued immediately.', 'Other side effects of CQ include cardiac arrhythmia, drug-induced psychosis, leukopenia, etc.', 'Combining CQ with heparin could increase the risk of bleeding.', 'In patients taking Digitalis, CQ could cause a cardiac block.', '13 For decades, most Europeans visiting malaria-endemic areas have been receiving chloroquine prophylaxis, and they would continue it for two months after their return.', 'The use of CQ for the treatment of malaria has also been in use for long, and HCQ has been used at much higher doses of up to 600 mg/day to treat autoimmune diseases.', 'It is quite difficult to find a product having a betterestablished safety profile than CQ at such a low cost.', '10 CQ, and its derivatives have shown early promise to treat COVID-19 infection and should be explored as a potential drug in the preventive and therapeutic role to turn the tide in this rapidly evolving pandemic.', '25 Disorderly clinical trials of All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', '24.20042366 doi: medRxiv preprint COVID-19 using traditional Chinese medicine and Western medicine are ongoing but may not be able to give high-quality clinical evidence.', 'In order to death with the health emergency create by COVID-19, the national administration of scientific research should improve management and coordination for improving the study quality based on clinical trial guidelines.', 'It is also recommended to further research on the role of CQ for COVID-19 prevention.', 'It has also been urged in an article that the above CQ regimens be investigated in parallel with the mass deployment of this drug, without unnecessary regulatory delays, in an attempt to contain the global pandemic as the benefits of CQ far outweigh the risks or costs.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['(methylprednisolone 40-120 mg per day) was given as a combined regimen if severe community-acquired pneumonia was diagnosed by physicians at the designated hospital.', 'Oxygen support (eg, nasal cannula and invasive mechanical ventilation) was administered to patients according to the severity of hypoxaemia.', 'Repeated tests for 2019-nCoV were done in patients confirmed to have 2019-nCoV infection to show viral clearance before hospital discharge or discontinuation of isolation.', 'We report here a cohort of 41 patients with laboratoryconfirmed 2019-nCoV infection.', 'Patients had serious, sometimes fatal, pneumonia and were admitted to the designated hospital in Wuhan, China, by Jan 2, 2020.', 'Clinical presentations greatly resemble SARS-CoV. Patients with severe illness developed ARDS and required ICU admission and oxygen therapy.', 'The time between hospital admission and ARDS was as short as 2 days.', 'At this stage, the mortality rate is high for 2019-nCoV, because six (15%) of 41 patients in this cohort died.', 'The number of deaths is rising quickly.', 'As of Jan 24, 2020, 835 laboratory-confirmed 2019-nCoV infec tions were reported in China, with 25 fatal cases.', 'Reports have been released of exported cases in many provinces in China, and in other countries; See Online for appendix some health-care workers have also been infected in Wuhan.', 'Taken together, evidence so far indicates human transmission for 2019-nCoV. We are concerned that 2019-nCoV could have acquired the ability for efficient human trans mission.', '19 Airborne precautions, such as a fit-tested N95 respirator, and other personal protective equipment are strongly recommended.', 'To prevent further spread of the disease in health-care settings that are caring for patients infected with 2019-nCoV, onset of fever and respiratory symptoms should be closely moni tored among health-care workers.', 'Testing of respiratory specimens should be done immediately once a diagnosis is suspected.', 'Serum antibodies should be tested among health-care workers before and after their exposure to 2019-nCoV for identification of asymp tomatic infections.', 'Similarities of clinical features between 2019-nCoV and previous betacoronavirus infections have been noted.', 'In this cohort, most patients presented with fever, dry cough, dyspnoea, and bilateral ground-glass opacities on chest CT scans.', 'These features of 2019-nCoV infection bear some resemblance to SARS-CoV and MERS-CoV infections.', '20, 21 However, few patients with 2019-nCoV infection had prominent upper respiratory tract signs and symptoms (eg, rhinorrhoea, sneezing, or sore throat), indicating that the target cells might be located in the lower airway.', 'Furthermore, 2019-nCoV patients rarely developed intestinal signs and symptoms (eg, diarrhoea), whereas about 20-25% of patients with MERS-CoV or SARS-CoV infection had diarrhoea.', '21 Faecal and urine samples should be tested to exclude a potential alternative route of transmission that is unknown at this stage.', 'The pathophysiology of unusually high pathogenicity for SARS-CoV or MERS-CoV has not been completely understood.', 'Early studies have shown that increased amounts of proinflammatory cytokines in serum (eg, IL1B, IL6, IL12, IFNγ, IP10, and MCP1) were associated with pulmonary inflammation and extensive lung damage in SARS patients.', '22 MERS-CoV infection was also reported to induce increased concentrations of proinflammatory cytokines (IFNγ, TNFα, IL15, and IL17).', '23 We noted that patients infected with 2019-nCoV also had high amounts of IL1B, IFNγ, IP10, and MCP1, probably leading to activated T-helper-1 (Th1) cell responses.', 'Moreover, patients requiring ICU admission had higher concentrations of GCSF, IP10, MCP1, MIP1A, and TNFα than did those not requiring ICU admission, suggesting that the cytokine storm was associated with disease severity.', 'However, 2019-nCoV infection also initiated increased secretion of T-helper-2 (Th2) cytokines (eg, IL4 and IL10) that suppress inflammation, which differs from SARS-CoV infection.', '22 Further studies are necessary to characterise the Th1 and Th2', 'In view of the high amount of cytokines induced by SARS-CoV, 22, 24 MERS-CoV, 25, 26 and 2019-nCoV infections, corticosteroids were used frequently for treatment of patients with severe illness, for possible benefit by reducing inflammatory-induced lung injury.', 'However, current evidence in patients with SARS and MERS suggests that receiving corticosteroids did not have an effect on mortality, but rather delayed viral clearance.', '[27] [28] [29] Therefore, corticosteroids should not be routinely given systemically, according to WHO interim guidance.', '30 Among our cohort of 41 laboratory-confirmed patients with 2019-nCoV infection, corticosteroids were given to very few non-ICU cases, and low-to-moderate dose of corticosteroids were given to less than half of severely ill patients with ARDS.', 'Further evidence is urgently needed to assess whether systematic corticosteroid treatment is beneficial or harmful for patients infected with 2019-nCoV.', 'No antiviral treatment for coronavirus infection has been proven to be effective.', 'In a historical control study, 31 the combination of lopinavir and ritonavir among SARS-CoV patients was associated with substantial clinical benefit (fewer adverse clinical outcomes).', 'Arabi and colleagues initiated a placebo-controlled trial of interferon beta-1b, lopinavir, and ritonavir among patients with MERS infection in Saudi Arabia.', '32 Preclinical evidence showed the potent efficacy of remdesivir (a broad-spectrum antiviral nucleotide prodrug) to treat MERS-CoV and SARS-CoV infections.', '33, 34 As 2019-nCoV is an emerging virus, an effective treatment has not been developed for disease resulting from this virus.', 'Since the combination of lopinavir and ritonavir was already available in the designated hospital, a randomised controlled trial has been initiated quickly to assess the efficacy and safety of combined use of lopinavir and ritonavir in patients hospitalised with 2019-nCoV infection.', 'Our study has some limitations.', 'First, for most of the 41 patients, the diagnosis was confirmed with lower respiratory tract specimens and no paired nasopharyngeal swabs were obtained to investigate the difference in the viral RNA detection rate between upper and lower respiratory tract specimens.', 'Serological detection was not done to look for 2019-nCoV antibody rises in 18 patients with undetectable viral RNA.', 'Second, with the limited number of cases, it is difficult to assess host risk factors for disease severity and mortality with multivariableadjusted methods.', 'This is a modest-sized case series of patients admitted to hospital; collection of standardised data for a larger cohort would help to further define the clinical presentation, natural history, and risk factors.', 'Further studies in outpatient, primary care, or community settings are needed to get a full picture of the spectrum of clinical severity.', 'At the same time, finding of statistical tests and p values should be interpreted with caution, and non-significant p values do not necessarily rule out difference between ICU and non-ICU patients.', 'Third, since the causative pathogen has just been identified, kinetics of viral load and antibody titres were not available.', 'Finally, the potential exposure bias in our study might account for why no paediatric or adolescent patients were reported in this cohort.', 'More effort should be made to answer these questions in future studies.', 'Both SARS-CoV and MERS-CoV were believed to originate in bats, and these infections were transmitted directly to humans from market civets and dromedary camels, respectively.', '35 Extensive research on SARS-CoV and MERS-CoV has driven the discovery of many SARS-like and MERS-like coronaviruses in bats.', 'In 2013, Ge and colleagues 36 reported the whole genome sequence of a SARS-like coronavirus in bats with that ability to use human ACE2 as a receptor, thus having replication potentials in human cells.', '37 2019-nCoV still needs to be studied deeply in case it becomes a global health threat.', 'Reliable quick pathogen tests and feasible differential diagnosis based on clinical description are crucial for clinicians in their first contact with suspected patients.', 'Because of the pandemic potential of 2019-nCoV, careful surveillance is essential to monitor its future host adaption, viral evolution, infectivity, transmissibility, and pathogenicity.', 'We report the epidemiological, clinical, laboratory, and radiological characteristics, treatment, and clinical outcomes of 41 laboratory-confirmed cases infected with 2019-nCoV.', '27 (66%) of 41 patients had a history of direct exposure to the Huanan seafood market.', 'The median age of patients was 49·0 years (IQR 41·0-58·0), and 13 (32%) patients had underlying disease.', 'All patients had pneumonia.', 'A third of patients were admitted to intensive care units, and six died.', 'High concentrations of cytokines were recorded in plasma of critically ill patients infected with 2019-nCoV.', 'Implications of all the available evidence 2019-nCoV caused clusters of fatal pneumonia with clinical presentation greatly resembling SARS-CoV. Patients infected with 2019-nCoV might develop acute respiratory distress syndrome, have a high likelihood of admission to intensive care, and might die.', 'The cytokine storm could be associated with disease severity.', 'More efforts should be made to know the whole spectrum and pathophysiology of the new disease.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Tropism is determined by an ensemble of different factors, including the mechanism of viral entry to the host, the immune responses to the infection, or the viral hijacking of the cellular machinery in the interest of replication and propagation.', 'In this article, we study the latter by focusing on the translational adaptation of viral genomes to the host.', 'While previous studies on the base composition and codon usage of both DNA and RNA viruses 11, 30 have attributed most of the codon usage variability to the mutational pressure of viral genomes, our analysis proposes tropism as an important driving force.', 'By systematically interrogating all human-infecting viruses, we uncover that tissue tropism explains changes in their codon usage more than other viral properties such as type or family.', 'Therefore, as mutational pressure would act more similarly within phylogenetically closer species, such tropism-related differences in codon usage suggests that tissue-specific tRNA expression could be driving a translational selection on viral genomes.', 'Although high-throughput sequencing of tRNAs has been only recently developed, cases of natural selection of codon usage towards the host have been previously proposed.', 'For instance, codon usage of Parvovirus has been progressively adapted from dogs to cats after the host jump 43 .', 'Influenzaviruses show a similar adaptation over time of viral isolation, deviating from the codon usage of avian hosts 44, 45 .', 'However, whether these progressive changes in codon usage over time are directly driven by translational selection has remained elusive.', 'With the advent of tissue-wide datasets of tRNAs and their translational efficiencies 2 , we can now compute the Supply-to-Demand Adaptation (SDA) of all viral proteomes in different tissues.', 'From there, we then created a random forest model that predicts with high accuracy the viral tropism of proteins based on their profile of adaptation to human tissues.', 'In consequence, the tRNA-based adaptation profile of a protein is descriptive of their viral tropism, indicating that translational selection could indeed drive tropism differences of codon usage.', 'It is important to remark that viruses could still have a good SDA', 'Specifically, we therefore focus our analysis on the new SARS-CoV-2 coronavirus, causative of the current COVID-19 pandemic.', 'As has been recently suggested based on the expression of their entry receptor 21, 22 , SARS-CoV-2 is also translationally adapted to the upper respiratory airways, as well as the lung parenchyma.', 'This upper tract tropism has indeed been linked to the higher transmissibility of the strain 21 .', 'The novel coronavirus showcases the highest SDA among all studied coronaviruses, including lung but also other tissues such as the digestive system and brain.', 'Interestingly, recent reports have shown that COVID-19 patients very frequently have problems in the digestive tract 24,46,47 as well as in neural tissue 23 One major open question in the field still persists: how much natural selection before or after zoonosis shapes the current coronavirus 50 .', 'On the one hand, viruses tend to gradually change their codon usage after a zoonotic jump 43, 45 .', 'On the other hand, given the similarity of SARS-CoV-2 SDA with the phylogenetically closest bat coronavirus, it seems that a translational selection to increase SDA would have acted before the putative zoonosis from bats or other intermediate hosts.', 'Furthermore, in agreement with the highest translational potential of SARS-CoV-2 in their target tissues, a recent model of viral tropism suggested that a tradeoff exists between the efficiency of viral translation and the translational load on the host, indicating that an improved codon usage can make the difference between symptomatic and natural hosts 51 .', 'On the other hand, it is known that host tRNA pools undergo reprogramming upon viral infection of HIV-1, vaccinia virus, and influenza A virus 17, 52 .', 'In this context, differences in codon usage between early and late viral genes have been previously reported, but the directionality of such changes remained unclear 10, 53 .', 'Based on our concept of tissue-specific adaptation, we therefore validate that early replication-related proteins are better adapted to the tissue of infection.', 'Upon infection, we then unveil that changes in tRNA abundance switch the adaptation towards the expression of late structural proteins, confirming a general trend that had previously only been observed in HIV-1 17 .', 'Overall, this is the first systematic analysis establishing a link between the codon usage of human viruses and the translational efficiency of their tissue of infection.', 'This correspondence is particularly observed in early viral proteins, while late counterparts benefit from the tRNA reprogramming that underlies the process of infection.', 'We therefore envision the development of ad hoc gene therapies specifically targeting the tissue of interest.', 'Table 2 for full TCGA cancer type names.', 'See also Extended Data Fig. 1 .', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.06.027557 doi: bioRxiv preprint influenza A virus.', 'Center values within the violin plot represent the median.', 'Using a two-tailed Wilcoxon rank-sum test, only significant differences between viruses are shown: * (p <= 0.05), ** (p <= 0.01), *** (p <= 0.001), **** (p <= 0.0001).', '(B) Average RSEM expression of the corresponding entry receptors of the viruses: MERS-CoV binds to DPP4 35 , SARS-CoV and SARS-CoV-2 bind to ACE2 or BSG with priming by the protease TMPRSS2 36,37 , influenza A virus binds to sialic acids, which are synthesised by the enzymes ST3GAL4 and ST6GAL1 34 .', 'RSEM receptor expression is re-scaled between 0 and 1 among all tissues, being 1 the tissue with highest expression.', 'Refer to Sup.', 'Table 3 Table 6 ).', 'Center values within the violin plot represent the median.', 'Using a two-tailed Wilcoxon rank-sum test, only significant differences are shown: * (p <= 0.05), ** (p <= 0.01), *** (p <= 0.001), **** (p <= 0.0001).']}\n", - "{'sentences': ['COVID-19 and treatment with NSAIDs and corticosteroids: should we be limiting their use in the clinical setting?', 'Given the current SARS-CoV-2 (COVID-19) pandemic, the availability of reliable information for clinicians and patients is paramount.', 'There have been a number of reports stating that non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids may exacerbate symptoms in COVID-19 patients.', 'Therefore, this review aimed to collate information available in published articles to identify any evidence behind these claims with the aim of advising clinicians on how best to treat patients.', 'This review found no published evidence for or against the use of NSAIDs in COVID-19 patients.', 'Meanwhile, there appeared to be some evidence that corticosteroids may be beneficial if utilised in the early acute phase of infection, however, conflicting evidence from the World Health Organisation surrounding corticosteroid use in certain viral infections means this evidence is not conclusive.', 'Given the current availability of literature, caution should be exercised until further evidence emerges surrounding the use of NSAIDs', 'In conclusion, the existing literature does not currently provide conclusive evidence for or against the use of NSAIDs in the treatment of COVID-19 patients, though there appears to be some evidence that corticosteroids may be beneficial if utilised in the early acute phase of infection [14].', 'However, it is important to note this is not specific to COVID-19.', 'Indeed, one review stated that the WHO does not currently recommend corticosteroids in other viral diseases, like Dengue as the ‘glucocorticoid-mediated stimulation of the hypothalamic-pituitaryadrenal axis can also drive lymphocytopenia, or it may promote exaggerated pro-inflammatory responses that eventually cause a worsening of the pathogenic condition’.', 'These are unprecedented times for the medical community and although evidence suggests a potential role for the use of NSAIDs and corticosteroids in COVID-19 treatment, caution should be exercised until further evidence, specific to this infection strain, emerges.', 'The same guidance stands for cancer patients who are not advised to change their medication routine unless told otherwise by their doctor.']}\n", - "{'sentences': ['[Image: see text] Eighteen active substances, including 17 organosulfur compounds found in garlic essential oil (T), were identified by GC–MS analysis.', 'For the first time, using the molecular docking technique, we report the inhibitory effect of the considered compounds on the host receptor angiotensin-converting enzyme 2 (ACE2) protein in the human body that leads to a crucial foundation about coronavirus resistance of individual compounds on the main protease (PDB6LU7) protein of SARS-CoV-2.', 'The results show that the 17 organosulfur compounds, accounting for 99.4% contents of the garlic essential oil, have strong interactions with the amino acids of the ACE2 protein and the main protease PDB6LU7 of SARS-CoV-2.', 'The strongest anticoronavirus activity is expressed in allyl disulfide and allyl trisulfide, which account for the highest content in the garlic essential oil (51.3%).', 'Interestingly, docking results indicate the synergistic interactions of the 17 substances, which exhibit good inhibition of the ACE2', 'The model describing the docking molecules of 18 substances in the garlic essential oil\\ninto the complex structure of the PDB6LU7 protein was constructed using MOE 2015.10 software.', 'The docking was\\nsuccessful in 17 compounds of T1-SARS-CoV-2 to T17-SARS-CoV-2.\\n', 'The DS energy and RMSD values between ligands and proteins shown through hydrogen bonds,\\ncation−π bonds, π–π bonds, and ionic interactions, as\\nwell as the interaction distance between amino acids and the active sites in the title\\nmolecules are presented in Table 3 and Figures 4 and S2 (Supporting Information).', 'The anti-SARS-CoV-2 activity of the garlic essential oil composition into the\\nPDB6LU7 protein of SARS-CoV-2\\nwas found in the following order: T2 = T1 > T5 > T4 > T11 > T15 >\\nT8 > T16 >', 'T9 > T12 > T13 >', 'T3 > T6 > T7 > T10 > T14 >\\nT17.', 'The compounds T1 and T2 indicated the highest\\ncontent in the garlic essential oil (51.3%) and gave the best anti-SARS-CoV-2 activity,\\nfollowed by the three compounds T5, T4, and T11.\\n', 'These five substances account for 65.83% composition of the garlic essential oil (Figure 4).', 'The results demonstrated that these 17\\ncompounds have a stronger inhibition on PDB6LU7 of SARS-CoV-2 than that on the ACE2 protein in the human body.', 'The DS\\nenergy was negative, in the range of −15.32 to −11.68\\nkcal·mol–1.', 'Interactions with amino acid included Pro 565, Gln\\n102, Glu 208, Asn 210, Gly 205, Gln 98, Trp 566, Lys 94, Val 209, Gln 101, Asp 206, Asn\\n103, Ser 563, Ala 396, and Lys 562.', 'The total content of 17 out of 18 compounds in the\\ngarlic essential oil exhibiting inhibition ability toward the PDB6LU7 protein of SARS-CoV-2 is 99.4%.', 'The\\ndocking simulation results are excellent evidence of the anti-SARS-CoV-2 activity of the\\ngarlic essential oil.', 'The simultaneous interaction of 17 out of 18 compounds in the garlic essential oil with\\nthe ACE2 protein and the PDB6LU7\\nprotein is described in Figure 5.', 'Hydrogen\\nbonds, cation−π bonds, π–π bonds, and ionic interactions\\nof 17 compounds with the amino acids of the ACE2 protein included Trp 566, Asn 103, Gly\\n205, Lys 94, Asp 206, Glu 208, Val 209, Pro 565, Asn 210, Ser 563, Gln 98, Gln 102, Gln\\n101, Ala 396, Lys 562, and Ala 396, and those with the amino acids of the PDB6LU7 protein included Gly 143, Glu 166,\\nAsn 142, Leu 141, Cys 145, Ser 144, His 163, and Met 165.', 'Based on the percentage of\\neach compound in the garlic essential oil (shown by GC–MS) and docking score (DS)\\nenergy of each compound, the average DS']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['2020 received treatment according to the fifth edition of the Ministry of Health guidelines [8] [9] : 1.', 'Bed rest and supportive treatment; 2.', 'Regular examination on blood routine, CRP, biochemistry, coagulation function, myocardial enzymes, lung CT; 3.', 'Oxygen therapy, including nasal catheter oxygen, transposal high-flow oxygen therapy, ventilator; 4.', 'Antiviral therapy, including Lopinavir/Ritonavir tablets, Arbidol Hydrochloride Tablets, etc.', 'If the patient maintained a normal body temperature for at least three days, and tested negative with COVID-19 (including throat swab, stool, and sputum) at least twice and 24+ hours apart, as well as showing significant improvement in lung CT, the patient would be considered recovered and discharged from the hospital.', 'The discharged patients were transported by the Chinese government using designated vehicles and they were further isolated for at least two weeks.']}\n", - "{'sentences': ['The SARS-CoV-2 infection in Wuhan is a serious global health problem and has been declared a pandemic by the WHO.', 'Based on data G. Li, et al.', 'Journal of Autoimmunity xxx (xxxx) xxxx from the first 41 patients, a reduction of lymphocytes was a prominent feature of the disease.', 'The main symptoms of patients with COVID-19 infection were interstitial changes in the lung as demonstrated by chest CT.', 'Severe pulmonary interstitial disease leads to hypoxemia and type I respiratory distress, which is related to the prognosis of patients.', 'SARS-CoV-2 invades the lungs through the respiratory tract and causes severe pneumonia, which is the most frequent presentation.', 'It has been found that SARS-CoV-2 is able to bind to the ACE2 receptor on the surface of epithelial cells.', 'Zhou et al. further confirmed that ACE2 is necessary for infection of cells by SARS-CoV-2 [2] .', 'We accessed and analyzed six independent studies (GSE37768, GSE73395, GSE89809, GSE63127, GSE97010, and GSE17400), covering a healthy We showed that ACE2 was found in all of the samples including the healthy population and patients with chronic airway diseases.', 'Thus, there may be no significant difference in the susceptibility to SARS-CoV-2 infection between a healthy population and patients with chronic respiratory diseases.', 'In contrast, current limited data on COVID-19 suggests that patients with underlying lung conditions may be at greater risk for severe chronic airway disease or death.', 'Previous studies found that ACE2 is related to the severity of acute respiratory syndrome induced by the SARS-CoV infection, and mediates the production of cytokines associated with acute respiratory distress syndrome [15, 16] (Fig. 4) .', 'Moreover, ACE2 is also related to adaptive immune responses [17] .', 'In this current study, GSEA analysis showed that the high expression of ACE2 was related to innate immune responses, adaptive immune responses, B cell regulation and cytokine secretion, as well as an enhanced inflammatory response induced by IL-1, IL-10, IL-6, IL-8.', 'We speculate that the immune system dysfunction involved in the high expression of ACE2 is related to the symptoms of a cytokine storm.', 'A clinical study in Wuhan pointed out that the levels of IL-1β, IL-10 and IL-8 were significantly increased in critically ill patients with new coronavirus infection, indicating that the pathologic process may involve an exaggerated pro-inflammatory cytokine response [1] .', 'This may be related to pyroptosis, which has been suggested as another pathogenic mechanism involved in COVID-19 infection.', 'Pyroptosis is an inflammatory form of apoptosis.', 'The fact that tissue injury and death may be related to a pro-inflammatory process resulting from the viral infection suggests that the use of IL-1β blockers or IL-18 blockers may have some benefit in COVID-19 patients.', 'Our results also showed that the high expression of ACE2 increased the expression of genes involved in viral replication, which may enhance the ability of the virus to enter the host cells.', 'Our calculations support the hypothesis that the transcriptome of epithelial cells is altered after infection by SARS-CoV-2 through increased ACE2 expression, which is beneficial to the replication and assembly of virus, and also to the entry of virus into host cells.', 'T cell activation and inflammatory responses mediated by T cell factors are also significantly induced by the altered of transcriptome.', 'It has been speculated that the increased levels of IL1β, IFN-γ, IP10, and MCP1 in patients infected with SARS-CoV-2 are linked to the activation of T-helper-1 (Th1) cell responses [1] .', 'However, there is a lack of pathological data of lung tissue infected with SARS-CoV-2.', 'Through ssGSEA analysis, we found that high expression of ACE2 in lung tissue induced a cytotoxic reaction, neutrophil inflammation and a Th2dominated immune response.', 'Moreover, the expression of ACE2 varies in a time-dependent manner after SARS-CoV infection.', 'ACE2 also mediates the activation of neutrophils, NK cells, Th17 cells, Th2 cells, Th1', 'Graph-based biological networks models capture the topology of the functional relationships between molecular entities such as gene, protein and small compounds, and achieve a finer grain representation of the bioentities and their relationships.', 'In order to further analyze the core genes involved in viral replication and inflammatory responses mediated by ACE2, we constructed a protein-protein interaction network by using BisoGenet.', 'It was found that RPS3 played a key role in viral replication, and SRC non-receptor protein kinase was the hub gene in the inflammatory response.', 'It has been shown that RPS3 plays an important role in cell mitosis by interacting with α-tubulin.', 'When cells are infected with HIV-1, HIV-1 Tat protein can interact with RPS3 and disturb its localization on the spindle, and ultimately inhibit cell proliferation [18] .', 'Moreover, the function of RPS3 depends on its own nuclear translocation, which is regulated by protein kinases such as SRC [19] .', 'We speculate that the increased expression of ACE2 affects RPS3 and SRC, which were the two hub genes involved in viral replication and the inflammatory response.', 'In view of the role of the ACE2 receptor in the ability of SARS-CoV-2 to enter host cells [20] , the question arises as to the effect of ACE inhibitors and angiotensin-receptor blockers (ARBs) in the pathogenesis of COVID-19.', 'This turns out to be a very complex relationship and is currently still very controversial.', 'On the one hand, it has been found that in animal models, ACE inhibitors [21] and ARBs can increase the expression of ACE2 receptors [22] , which theoretically can increase the ability of SARS-CoV-2 to enter cells.', 'However, the data on this is inconsistent, and may in fact be tissue dependent, dosage dependent and may vary among different ARBs', 'In addition, with SARS-CoV, it was discovered that infection with SARS-CoV led to downregulation of the ACE2 receptor [24] .', 'From a physiologic standpoint, the ACE2 receptor serves as a negative regulator of severe lung edema and lung injury by decreasing Ang2 levels [25] .', 'Ang2 induced vascular permeability and lung injury is facilitated by binding to the Angiotensin-2 receptor type 1 (AT1R) [26] .', 'In a mouse model, SARS-CoV induced lung injury can be attenuated by blocking AT1R [27] .', 'If SARS-CoV (and SARS-CoV-2) binding to ACE2 leads to a downregulation of ACE2, this could result in higher Ang2 levels and increased lung injury.', 'Multiple ACE2 knockout mouse models have demonstrated the protective effects of ACE2 from lung injury and vascular inflammation [28, 29] .', 'Since ACE inhibitors do not bind the ACE2, but instead bind to ACE1, they theoretically should have no beneficial effect of blocking SARS-CoV-2 from entering cells.', 'In fact, ACE inhibitors such as lisinopril and captopril have been shown to have no effect on activity of ACE2 [30, 31] .', 'At present there is no strong evidence to discontinue ACE inhibitors or ARBs in patients with COVID-19, nor conversely, to use these drugs as treatment for COVID-19.', 'It is perhaps significant to note that ACE2 is also a significant negative regulator of the renin-angiotensin system (RAS', 'Incidentally, besides the ACE2 receptor, the TMPRSS2 serine protease has been implicated in S protein priming, and it has been proposed as a potential therapeutic target.', 'Additionally, DPP-4 was found to be an entry receptor for MERS, but this has not yet been shown in SARS-CoV-2.', 'A further consideration and potential target for treatment may relate to the role of ADAM-17.', 'While ACE2 is a membrane bound protein, it is cleaved by ADAM-17 leading to shedding to form soluble ACE2.', 'ADAM-17 therefore may lead to a decrease in membrane bound ACE2, reducing its regulatory activity.', 'AT1R upregulates ADAM-17, so use of an ARB may potentially block shedding and reduction of membrane bound ACE2.', 'However, it is believed that the majority of ACE2 is membrane bound and that the decrease resulting from shedding would not significantly affect ACE2 activity to begin with [33] .', 'In conclusion, COVID-19 is a global pandemic that has already caused over 110,000 deaths worldwide so far.', 'Due to human-human transmission of the virus, cases have easily spread across borders and has led to the need to implement disruptive quarantine procedures.', 'Our current study found that there was no significant difference in ACE2 expression between a healthy population and patients with chronic airway disease.', 'The activation of neutrophils, NK cells, Th17 cells, Th2 cells, Th1 cells, dendritic cells, TNFα secreting cells can be induced by overexpression of ACE2 leading to a severe inflammatory response.', 'A schematic model is showed in Fig. 4 .', 'These findings may help clinicians and researchers gain more insight into the pathogenesis and use this to design therapeutic strategies for COVID-19.', 'Note that all results in this study are based on data mining and basic science and translational studies are required to confirm these models.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': [\"[{'text': 'This paper concerns study of the genome of the Wuhan Seafood Market isolate believed to represent the causative agent of the disease COVID-19.\", 'This is to find a short section or sections of viral protein sequence suitable for preliminary design proposal for a peptide synthetic vaccine and a peptidomimetic therapeutic, and to explore some design possibilities.', 'The project was originally directed towards a use case for the Q-UEL language and its implementation in a knowledge management and automated inference system for medicine called the BioIngine, but focus here remains mostly on the virus itself.', 'However, using Q-UEL systems to access relevant and emerging literature, and to interact with standard publically available bioinformatics tools on the Internet, did help quickly identify sequences of amino acids that are well conserved across many coronaviruses including 2019-nCoV. KRSFIEDLLFNKV was found to be particularly well conserved in this study and corresponds to the region around one of the known cleavage sites of the SARS virus that are believed to be required for virus activation for cell entry.', 'This sequence motif and surrounding variations formed the basis for proposing a specific synthetic vaccine epitope and peptidomimetic agent.', 'The work can, nonetheless, be described in traditional bioinformatics terms, and readily reproduced by others, albeit with the caveat that new data and research into 2019-nCoV is emerging and evolving at an explosive pace.', \"Preliminary studies using molecular modeling and docking, and in that context the potential value of certain known herbal extracts, are also described.', 'cite_spans': [], 'ref_spans': [], 'section': 'Abstract'}]\"]}\n", - "{'sentences': ['Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial', 'No clinically proven effective antiviral strategy exists for the epidemic Coronavirus Disease 2019 .', 'We conducted a prospective, randomized, controlled, open-label multicenter trial involving adult patients with COVID-19.', 'Patients were randomly assigned in a 1:1 ratio to receive conventional therapy plus Umifenovir (Arbidol) (200mg*3/day) or Favipiravir (1600mg*2/first day followed by 600mg*2/day) for 10 days.', 'The primary outcome was clinical recovery rate of Day 7.', 'Latency to relief for pyrexia and cough, the rate of auxiliary oxygen therapy (AOT) or noninvasive mechanical ventilation (NMV', 'We conducted a prospective, multicenter, open-labeled, randomized superiority clinical trial and hypothesized that Favipiravir would be superior to Arbidol in terms of efficacy for moderate symptoms, and would accelerate the clinical recovery of pyrexia, cough, and breathing difficulties compared with Arbidol.', 'The combination of traditional Chinese medicine and antiviral drugs is more common in China, which is due to the traditional medical culture background of the treatment All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.17.20037432 doi: medRxiv preprint of choice.', 'Also, anti-infection and immune regulation play an important role in the treatment of the COVID-19.', 'Ancillary treatments, such as traditional Chinese medicine, anti-infection and immunomodulatory drugs, were without statistical difference between groups (Table S2) .', 'Our trial has several limitations.', 'Firstly, for COVID-19, there is no clinically proven effective antiviral drug to serve as the control arm.', 'Although Chinese guideline had recommended several options including Arbidol, 11 no RCT results on these drugs were reported.', 'Arbidol was widely used by Chinese doctors in the beginning stage of this epidemic of COVID-19 (Jan. 1-30, 2020) based on in vitro evidence.', '12 For ethical reasons, we chose Arbidol for the control arm.', 'Secondly, observation time frame was limited due to the urgency of this epidemic.', 'For the same reason, no relapse (including nucleic acid conversion, pyrexia, cough, or pneumonia progress by radiology) tracking were performed for the discharged patients.', 'Thirdly, in the inclusion criteria, we did not force positive nucleic acid test as a necessity.', 'The accuracy of nucleic acid assay was limited, which might due to multiple reasons including previous treatment, latency of onset, sampling method, biological specimen characteristics.', 'This particular accuracy problem was a known issue among clinical practitioners across the world.', 'It was estimated that the assay might have at most 30%-50% of sensitivity for patients in early stage of the disease, whilst contact history, clinical manifestations, radiology evidences, and lab results including leukopenia and lymphopenia could be confirmatory for these nucleic-acid-negative pneumonia patients.', 'In the Chinese guideline, 11 patients meeting these criteria were considered as All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.17.20037432 doi: medRxiv preprint with clinically confirmed COVID-19.', 'In this trial, 46.55% patients in Favipiravir group and 38.33% in Arbidol group were nucleic-acid-positive at enrollment.', 'Considering the population incidence of COVID-19 infection at the time of this trial in Wuhan, we consider the probability for mis-identifying patients of pneumonia disease other than COVID-19 into this trial is low.', 'Fourthly, the protocol does not prespecify clinical classification as a stratification factor.', 'Ethical concerns arose against completely excluding severe/critical cases from potential beneficial treatment.', 'Additionally, because of the complexity of the disease, progression from moderate to severe/critical is possible.', 'Terminating trial treatment to such patients from the study was considered unacceptable.', 'Post-hoc analysis showed that both treatment and clinical classification contributed significantly to the primary outcome of clinical recovery rate at Day 7.', 'Difference of the frequency of severe/critical patients between groups reached a marginal significance, which made an important impact on the trial outcome.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.17.20037432 doi: medRxiv preprint', 'Compared to Arbidol, Favipiravir does not significantly improve clinical recovery rate of Day 7.', 'Favipiravir is associated with significantly shortened latency to relief for pyrexia and cough.', 'Antiviral-associated adverse effects of Favipiravir are mild and manageable.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.17.20037432 doi: medRxiv preprint author/funder, who has granted medRxiv a license to display the preprint in perpetuity.']}\n", - "{'sentences': ['The rapid detection of pathogenic bacteria is vital for the prevention of outbreaks of infectious diseases, including infections by the common foodborne bacteria E.coli and Salmonella Carbohydrate microarrays have been developed as a powerful method to investigate carbohydrate-protein interaction with only very small amounts of glycans, which show great potential for detect the carbohydrate mediated interaction with pathogens.', 'Here, different mannose-coated microarrays were constructed and tested with E.coli (K−12 and BL−21) and Salmonella enterica strains (ATCC9184 and ATCC31685) exhibiting different mannose binding affinities.', 'The optimized carbohydrate microarray was then applied to test the binding of 12 Salmonella enterica and 9 E.coli isolates from local patients for the first time and showed strong binding with certain serovars or subtypes.', 'The results showed that microarray probed with the single mannose structure is not enough for the detection of bacteria with various serovars or subtypes, which contain a high degree of allelic variation in adhesin.', 'We suggest that a complex carbohydrate microarray containing different glycan conformation may be needed for detection of different bacteria isolates.', '[KEY WORDS] Carbohydrate microarray; Mannose; FimH; Adhesin [CLC Number] R965 [Document code] A [Article ID]', 'The glycan ligands can be immobilized on the surface through the various chemical approaches, resulting in their unique spatial arrangement, which is essential for successful fabrication of carbohydrate chips.', 'It has been reported that mannose with ethanolamine linker spotted onto glass slides with the amine-reactive linker can be well used for detect E.coli strains [24] .', 'Similarly, we have found that mannose with ethanolamine linker exhibited stronger binding affinity to Salmonella strains than mannose with aromatic amine linker by microarray, although mannosides with an aromatic aglycon have been reported to bind with FimH protein in a better manner and thus be significant inhibitors of Type 1 fimbriaemediated bacterial adhesion [27, [29] [30] The linker containing phenyl structure may have lower rigidity and thus change the spatial arrangement of the glycan ligands on the surface.', 'In order to test the detection performance, we prepared mannose and aliphatic chain linkers with different lengths and activated the glass slides into N-hydroxy-succinamide-coated glass slides (NHS slides) and thiol-coated glass slides (SH slides', 'To test the specificity, response sensitivity and performance of the arrays, two Salmonella enterica strains (S. gal-linarum, ATCC9184 and S. abortusovis, ATCC31685) and two E.coli strains (E.coli K-12 and E.coli BL-21) were used, among which S. abortusovis ATCC316865 and E.coli K-12 have strong attach ability to mannose derivatives on eukaryotic cells surface, while S.gallinarum ATCC9184 and E.coli BL-21 are not mannose-sensitive due to the deficiency of the FimH protein [36] .', 'The slides were hybridized with bacteria cells stained with SYTO TM 63 Red fluorescent nucleic acid stain, washed and scanned according to modified procedure [25, 35, 37] .', 'All the slides were first hybridized with 10 8 Salmonella and E. coli bacteria cells and results (Fig. 2) show that the microspots that contained a little longer linker (Man-H) exhibited a little higher fluorescence intensities than that with shorter linker (Man-E) on NHS slides with both ATCC316865 and K-12 strains.', 'The NHS slides showed weak binding affinity for E. coli strains.', 'Mannosides (Man-E and Man-H) were also probed on thiol-activated slides (SH slides) with different linkers (L1-L3) to further test the effect of linker length on the detection performance.', 'Interestingly, Fig. 3A and B show that the fluorescence intensities of the microspots are related to the length of linkers between glycans and the glass surface.', 'The results show the microspots of Man-E/L3 on SH-reactive slides exhibited strongest fluorescent signals.', 'However, the microspots probed with Man-H/L2 on SH slides showed the stronger signals than those with Man-H-L1 and Man-H-L3.', 'Since the linker length of Man-E on NHS slides, Man-E-L3, Man-H-L2 on SH slides are roughly similar, it seemed that the binding efficiency of bacteria cells with the glycans are positively correlated with the linkers length within a certain range.', 'The binding between the immobilized mannose and FimH protein may be interfered when the linker is too long, which could result unsuitable stereo-direction of the glycans on the glass slides surface.', 'An efficient immobilization of carbohydrates on the surface is essential for successful fabrication of carbohydrate chips.', 'Comparing with NHS slides, the mannosides can be more efficiently immobilized onto the slides by the coupling of thiol group and maleimide group through the click chemistry reaction, which then showed relatively better performance.', 'Thus, we chose Man-E-L3 probed SH slides for further bacteria detection.', 'The effect of immobilized mannosides amount for detection was also determined.', 'The results show that Man-E-L3 can be probed in a less amount on SH slides to present stronger fluorescent intensities, which are consistent with the above binding tendencies.', 'Since the results showed that the immobilization of 30 mmol·L It shows the similar sensitivity as previous report of the detection of E. coli strains [24] , which needs a bacterial enrichment step prior to detection.', 'In order to test whether the bacteria strains can be detected by this mannose microarray, over 10 7 cells were utilized in the following tests for good detection effect.', 'This detection limit may be improved by immobilization of multivalent glyco-macroligands, such as glycodendrimers [38] [39] , glycopolymers [40] [41] , glycoliposomes [42] [43] , and glyconanoparticles [23, 44] to well control the multivalence, density and orientation of the mannosides on the surface.', 'We then first tested the binding of several Salmonella strains isolated from local patients on this Man-E-L3/SH microarray, including 12 Salmonella isolates in 8 seratypes, such as S. Thomson, S. Enteritidis, S. London, S. Allerton, etc, which are all commonly detected as foodborne bacteria in food market [45] .', 'It is found that most Salmonella isolates can be detected ([S/N] > 5) with the carbohydrate microarray and 9 isolates presented very strong binding affinity ([S/N] >= 10, Table 1 ).', 'It is found this carbohydrate microarray presented positive binding results for 8 Salmonella isolates (Table 1) .', 'Interestingly, the binding affinities of Salmonella varied with the serotypes.', 'Especially, S. London, S. Allerton and S. Senftenberg isolates can be detected by the microarray effectively.', 'The weak binding of other serovars with this mannose microarray ([S/N] <= 5) are probably due to the low binding affinity between the Salmonella serovar and monomannose residue on the surface, for example, FimH adhesin of Salmonella serovar Typhimurium bind strongly to high-mannose oligosaccharides [46] Furthermore, the isolates of the same Salmonella serovar exhibited different binding affinity with the microarray, since the same serovar also contain high-and low-adhesive allelic variants of FimH adhesin, such as S. Typhimurium and S. Enteritidis [47] .', 'We further tested 9 diarrheagenic E. coli isolates from diarrheal patients in 4 categories including enteropathogenic E. coli (EPEC), enteroaggregative E. coli (EAEC), enterotoxigenic E. coli (ETEC) and enterohemorrhagic E. coli (EHEC']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['The QT Interval in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine/Azithromycin', 'We report the change in the QT interval in 84 adult patients with SARS-CoV-2 infection treated with Hydroxychloroquine/Azithromycin combination.', 'QTc prolonged maximally from baseline between days 3 and 4. in 30% of patients QTc increased by greater than 40ms.', 'In 11% of patients QTc increased to >500 ms, representing high risk group for arrhythmia.', 'The development of acute renal failure but not baseline QTc was a strong predictor of extreme QTc prolongation.']}\n", - "{'sentences': ['The ongoing epidemics of coronavirus disease 2019 have caused serious concerns about its potential adverse effects on pregnancy.', 'There are limited data on maternal and neonatal outcomes of pregnant women with COVID-19 pneumonia.', 'We conducted a case-control study to compare clinical characteristics, maternal and neonatal outcomes of pregnant women with and without COVID-19 pneumonia.', 'During January 24 to February 29, 2020, there were sixteen pregnant women with confirmed COVID-19 pneumonia and eighteen suspected cases who were admitted to labor in the third trimester.', 'Two had vaginal delivery and the rest took cesarean section.', 'Few patients presented respiratory symptoms (fever and cough) on admission, but most had typical chest CT images of COVID-19 pneumonia.', 'Compared to the controls, COVID-19 pneumonia patients had lower counts of white blood cells (WBC), neutrophils, C-reactive protein (CRP), and alanine aminotransferase (ALT) on admission.', 'Increased levels of WBC, neutrophils, eosinophils, and CRP', 'COVID-19 infection was not found in the newborns and none developed severe neonatal complications.', 'All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.']}\n", - "{'sentences': ['Remdesivir as a possible therapeutic option for the COVID-19']}\n", - "{'sentences': ['Objectives: To use human genetic variants that proxy angiotensin-converting enzyme (ACE', 'Design: Two-sample Mendelian randomization (MR', 'Setting: Summary-level genetic association data.', 'Participants: Participants were predominantly of European ancestry.', 'Variants that proxy ACE inhibitor drug effects and cardiometabolic risk factors (body mass index, chronic obstructive pulmonary disease, lifetime smoking index, low-density lipoprotein cholesterol, systolic blood pressure and type 2 diabetes mellitus) were selected from publicly available genome-wide association study data (sample sizes ranging from 188,577 to 898,130 participants).', 'Genetic association estimates for lung expression of ACE2 and TMPRSS2 were obtained from the Gene-Tissue Expression (GTEx', 'Main outcomes and measures: Lung ACE2 and TMPRSS2 expression and plasma ACE2 levels.', 'Results: There were no association of genetically proxied ACE inhibition with any of the outcomes considered here.', 'There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in GTEx (p = 4x10 -4 ) and with circulating plasma ACE2 levels in INTERVAL (p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study (p = 0.68).', 'There were no associations between genetically predicted levels of the other cardiometabolic traits with the outcomes.', 'Conclusions: This study does not provide evidence to support that ACE inhibitor antihypertensive drugs affect lung ACE2 and TMPRSS2 expression or plasma ACE2 levels.', 'In the current COVID-19 pandemic, our findings do not support a change in ACE inhibitor medication use without clinical justification.']}\n", - "{'sentences': ['The novel coronavirus originated from the Hunan seafood market at Wuhan, China where bats, snakes, raccoon dogs, palm civets, and other animals are sold, and rapidly spread up to 109 countries.', 'The zoonotic source of SARS-CoV-2 is not confirmed, however, sequence-based analysis suggested bats as the key reservoir.', 'DNA recombination was found to be involved at spike glycoprotein which assorted SARS-CoV (CoVZXC21 or CoVZC45) with the RBD of another Beta CoV, thus could be the reason for cross-species transmission and rapid infection.', 'According to phylogenetic trees, SARS-CoV is closer to SARS-like bat CoVs.', 'Until now, no promising clinical treatments or prevention strategies have been developed against human coronaviruses.', 'However, the researchers are working to develop efficient therapeutic strategies to cope with the novel coronaviruses.', 'Various broad-spectrum antivirals previously used against influenza, SARS and MERS coronaviruses have been evaluated either alone or in combinations to treat COVID-19 patients, mice models, and clinical isolates.', 'Remdesivir, Lopinavir, Ritonavir, and Oseltamivir significantly blocked the COVID-19 infection in infected patients.', 'It can be cocluded that the homologus recombination event at the S protein of RBD region enhanced the transmission ability of the virus.', 'While the decision of bring back the nationals from infected area by various countries and poor screening of passengers, become the leading cause of spreading virus in others countries.', 'Most importantly, human coronaviruses targeting vaccines and antiviral drugs should be designed that could be used against the current as well as future epidemics.', 'There are many companies working for the development of effective SARS-CoV-2 vaccines, such as Moderna Therapeutics, Inovio Pharmaceuticals, Novavax, Vir Biotechnology, Stermirna Therapeutics, Johnson & Johnson, VIDO-InterVac, GeoVax-BravoVax, Clover Biopharmaceuticals, CureVac, and Codagenix.', 'But there is a need for rapid human and animal-based trails as these vaccines still require 3–10 months for commercialization.', 'There must be a complete ban on utilizing wild animals and birds as a source of food.', 'Beside the development of most efficient drug, a strategy to rapidly diagnose SARS-CoV-2 in suspected patient is also required.', 'The signs and symptoms of SARS-CoV-2 induced COVID-19 are a bit similar to influenza and seasonal allergies (pollen allergies).', 'Person suffering from influenza or seasonal allergy may also exhibit temprature which can be detected by thermo-scanners, hence the person will become suspected.', 'Therefore, an accurate and rapid diagnostic kit or meter for detection of SARS-CoV-2 in suspected patients is required, as the PCR based testing is expensive and time consuming.', 'Different teams of Chinese doctors should immediately sent to Eurpean and other countries, especially spain and Italy to control the over spread of COVID-19, because Chinese doctors have efficiently controlled the outbreak in china and limited the mortality rate to less than 3% only.', 'The therapeutic strategies used by Chinese, should also be followed by other countries.']}\n", - "{'sentences': ['The recent outbreak of coronavirus disease 2019 caused by SARS-CoV-2 in 2 December 2019 raised global health concerns.', 'The viral 3-chymotrypsin-like cysteine protease 3 (3CL pro ) enzyme controls coronavirus replication and is essential for its life cycle.', '3CL pro is a 4 proven drug discovery target in the case of severe acute respiratory syndrome coronavirus 5 (SARS-CoV) and middle east respiratory syndrome coronavirus (MERS-CoV', 'Therefore, herein, we analysed the 3CL pro sequence, constructed its 3D homology model, and 8 screened it against a medicinal plant library containing 32,297 potential anti-viral 9 phytochemicals/traditional Chinese medicinal compounds.', 'Our analyses revealed that the top 10 nine hits might serve as potential anti-SARS-CoV-2 lead molecules for further optimisation and 11 drug development process to combat COVID-19.']}\n", - "{'sentences': ['is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.01.20049478 doi: medRxiv preprint mitigate infection effects or protect healthcare workers and the elderly population against the SARS-CoV-2 disease 20 .', 'Several other determinants related to host, viral and environmental factors may be ascribed to these mortality differences.', 'Prevalence of comorbidities such as diabetes, cardiovascular disease, chronic respiratory disease and cancer are rising in LMICs, and in some settings have overtaken HIC.', 'In 2019 non-insulin dependant diabetes mellitus prevalence among adults was reported to be 11% in Asian countries and 6% in Europe 21 .', 'The World Health Organization estimates higher cardiovascular disease risk in Asian regions than in European and North American regions 22 .', 'Since we had no access to comprehensive nationally representative comorbidity data, the contribution of disease comorbidity as a population level risk factor for COVID-19-attributable mortality remains unclear.', 'Genetic risk factors associated with susceptibility to SARS-CoV-2 (in CCL2, mannose binding lectin, CXCL10/IP-10 or ACE2 receptor) are currently under evaluation, and as more evidence accumulates, the role played by these factors may become evident 23, 24 .', 'Variations in SARS-CoV2 receptor binding domain of the spike protein or nucleocapsid protein could alter disease severity 25 , 26 , although this is more likely to occur in an endemic setting rather than during a pandemic.', 'Temperature and relative humidity may be inversely associated with viral transmissibility.', 'but the association has been modest and inconsistent 27, 28 .', 'Early disease models that used assumptions based on CFRs from China and Italy predicted higher mortality in LMICs, which led to countries adopting severe lockdown measures 29 .', 'Ongoing containment measures are critical for infection transmission mitigation.', 'These measures should be balanced against predicted increases in non-COVID-19 mortality arising directly from economic shutdowns and distancing measures.', 'Severe trade restrictions and lowered productivity can increase poverty and food insecurity globally 30 .', 'Major and prolonged disruptions in crucial health service delivery such as immunization programs or access to emergency obstetric and newborn care can result in a direct increase in preventable deaths, as occurred during and after ebolavirus epidemics 31 .', 'Balancing transmission mitigation against sustaining basic health and nutrition access is a difficult but urgent task.', 'The limitations in our analyses are important to consider.', 'Deaths lag behind symptomatic infection by 2-8 weeks, and when compared with concurrent incidence cases may underestimate the CFR, although this is less likely to influence cumulative crude mortality 32 .', 'Health system preparedness of each country and the institution of control measures such as social distancing and lockdowns can also determine the cases and mortality numbers.', 'Our data are not meant to falsely reassure countries that their use of BCG may lead to lower mortality.', 'Indeed, our analysis is ecological, does not take into account present BCG coverage, nor timing of BCG .', 'CC-BY-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.01.20049478 doi: medRxiv preprint vaccine introduction into national schedules, and is not based on a randomized comparison.', 'By far the most important source of unmeasured confounding in our analysis relates to differential testing and reporting.', 'Limited laboratory surveillance availability and access to facility-based care is common in countries using BCG.', 'Substantial case underascertainment or under-reporting of deaths can magnify any association between mortality and BCG use.', 'In exponential functions, small iterations in time result in substantial changes in outcome.', 'Our findings need to be interpreted with caution; given vulnerable health systems and high levels of comorbidities in LMICs, if an exponential rise of cases followed by deaths were to occur in ensuing weeks, this would alter the epidemiological predictions in this report.', 'Despite all these caveats, the inverse relationship between country economic status and COVID-19-attributable mortality, and the strong ecological association with BCG vaccination are intriguing.', 'The findings warrant deeper epidemiological scrutiny and prospective evaluation in individually randomized trials.', 'Importantly the findings in this report illustrate the pivotal role that continuous systematic laboratory surveillance will have in improving our understanding of the pandemic, particularly in LMICs.', 'Such data lead to informed policy making that are beneficial to health and economic outcomes.', 'The direct association between COVID-19-attributable mortality and country-level economic status observed in this analysis is starkly counterintuitive.', 'Prior global disease burden assessments have suggested that deaths from acute respiratory illness are typically higher in low-income settings due to multiple socio-demographic and economic risk factors 16, 17 .', 'Among observed COVID-19-attributable risk factors for disease severity and death, age over 65 years has been identified as a significant factor 4,18 , while it is inferred that LMICs which typically have a younger population structure would potentially experience fewer overall deaths.', 'Another potential confounder was the time lag in deaths following detection of cases.', 'We selected countries with at least 100 reported cases and adjusted for time since this sentinel event.', 'After adjusting for country economic status, proportion of older population and aligning the epidemic trajectories of the highest hit countries, the intriguing observation of a significant association between BCG use and lower COVID-19-attributable mortality remained discernable.', 'Recent non-peer reviewed work reported a similar negative association between BCG use and COVID-19 mortality 19 .', 'Unlike our report, their findings did not account for potential confounding effects of income status, age structure of the population or timing of the epidemic, and included only 5 BCG non-using countries, making reliable inference challenging.', 'Currently, BCG vaccine is being considered for clinical trials in different settings to test its ability to .', 'CC-BY-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['From the beginning of 2002 and 2012, severe respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) crossed the species barriers to infect humans caused thousands of infections and hundreds of deaths, respectively.', 'Currently, a novel coronavirus (SARS-CoV-2) causes the outbreaks of Coronavirus Disease 2019 (COVID-19) was discovered.', 'Until February 18, 2020, there are 72533 confirmed COVID-19 cases (including 10644 severe cases) and 1872 deaths in China.', 'SARS-CoV-2 is surging in the public and caused substantial burdens due to its human-to-human transmission.', 'However, the intermediate host of SARS-CoV-2 is still unclear.', 'Finding the possible intermediate host of SARS-CoV-2 is imperative to prevent further spread of the epidemic.', 'In this study, we used systematic comparison and analysis to predict the interaction between the receptor binding domain (RBD) of coronavirus spike protein and the host receptor, Angiotensin Converting Enzyme 2 (ACE2).', 'The interaction between the key amino acids of S protein RBD and ACE2']}\n", - "{'sentences': ['Background: Severe patients with 2019 novel coronavirus (2019-nCoV', 'Methods: Forty-six hospitalized patients with severe COVID-19 pneumonia hospitalized at Wuhan Union Hospital from January 20 to February 25, 2020, were retrospectively reviewed.', 'The patients were divided into two groups based on whether they received corticosteroid treatment.', 'The clinical symptoms and chest computed tomography(CT) results were compared.', ': A total of 26 patients received intravenous administration of methylprednisolone with a dosage of 1-2mg/kg/d for 5-7 days, while the remaining patients not.', 'There was no significant difference in age, sex, comorbidities, clinical or laboratory parameters between the two groups on admission.', 'The average number of days for body temperature back to the normal range was significantly shorter in patients with administration of methylprednisolone when compared to those without administration of methylprednisolone (2.06±0.28 vs. 5.29±0.70, P=0.010).', 'The patients with administration of methylprednisolone had a faster improvement of SpO2, while patients without administration of methylprednisolone had a significantly longer interval of using supplemental oxygen therapy (8.2days[IQR 7.0-10.3] vs. 13.5days(IQR 10.3-16); P<0.001).', 'In terms of chest CT, the absorption degree of the focus was significantly better in patients with administration of methylprednisolone.', 'Our data indicate that in patients with severe COVID-19 pneumonia, early, lowdose and short-term application of corticosteroid was associated with a faster improvement of clinical symptoms and absorption of lung focus.', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'The pathological process of severe COVID-19 pneumonia is the inflammation reaction characterized by destruction of deep airway and alveolar [6] .', 'It is currently considered that the lung injury is not only associated with direct virus-induced injury, but also COVID-19 invasion triggers the immune responses that lead to the activation of immune cells(monocyte, macrophage, T and B-lymphocyte) to release a large number of pro-and anti-inflammatory cytokines including TNF, IL-1β, IL-6 and so on.', 'Overwhelming secretion of cytokines causes severe lung damage, which manifest as extensive damage of pulmonary vascular endothelial and alveolar epithelial cells as well as increased pulmonary vascular permeability, leading to the pulmonary edema and hyaline membrane formation [11, 12] .', 'Histologic examination has shown diffuse alveolar damage and mucinous exudate, which similar to acute respiratory distress syndrome [6] .', 'For the patients of severe COVID-19 pneumonia, aggravation of symptoms always occurs during 5-7 days after onset [13] .', 'Therefore, it is important to strengthen the treatment for suppression of pro-inflammatory response and control of cytokine storm at this stage.', 'A majority of patients can survival and recover if they overcome this period.', 'Corticosteroid are the classical immunosuppressive drugs, which are important to stop or delay the progression of the pneumonia and have been proved to be effective for treatment of ARDS [14, 15] .', 'In addition to immunosuppressive activities, corticosteroid have an anti-inflammatory role to reduce systemic inflammatory, decrease exudative fluid in the lung tissue, promote absorption of inflammasome and prevent further diffuse alveolar damage, which can relieve hypoxemia and effectively protect the lung to prevent further progression of respiratory insufficiency [16] .', 'Meanwhile, corticosteroid can induce a decrease in body temperature and help alleviate the poisoning symptom caused by hyperthermia.', 'In the present study, the patients with severe COVID-19 pneumonia had markedly increased inflammatory markers such as CRP, IL-6 and FER, which signified occurrence of the inflammatory reaction phase.', 'Meanwhile, most patients developed fever, cough, dyspnea and markedly decline in oxygen saturation, which are the early clinical manifestations of ARDS.', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'Based on these, we believed there was the indictor for corticosteroid admission to treat these patients.', 'Judging from the results, early application of low-dose corticosteroid could improve the treatment effect, presenting as improvement of hypoxia and fever symptom, shorten the disease course, and accelerating focus absorption.', 'Benefited from condition monitoring and refined management, no serious complications caused by corticosteroid happened in these patients.', 'In addition to the timing of treatment, it is also important to master the treatment duration and choose appropriate corticosteroid formulations and dosage.', 'The basic principles of corticosteroid formulations selection lie in the following two aspects: a short half-life and strong penetrating ability.', 'The corticosteroid formulation used in our cohort was methylprednisolone, a median effect corticosteroid with a half-life of 12-36, which has been proved to be associated with a better intensity of immunosuppression [17] .', 'In our experience, the dosage, duration and route of methylprednisolone administration was 1-2mg/kg/d for 5-7 days via intravenous injection.', 'Nevertheless, the specific dosage and duration for individual patient was determined on the clinical manifestations, leucocyte and lymphocyte count, inflammatory index and lesion range.', 'Corticosteroid treatment-induced complications is the other main concern.', 'The most common complication caused by corticosteroid is secondary infection(fungi and bacteria) [18] .', 'In our experience, once the secondary infection occurs in patients with severe COVID-19 pneumonia, sensitive and full-dose antibacterial drugs should be immediately added.', 'The majority of patients are prone to secondary bacterial infection due to exudate accumulation in the lungs, that push the prophylactic use of antibiotics such as moxifloxacin, levofloxacin and cephalosporins.', 'Secondly, the use of immune regulators(human immunoglobulin) can enhance the immune function of the patients.', 'In our experience, human immunoglobulin was usually used in the critical patients with a dosage of 10-20 g/d for 7-10 days as the pulse therapy.', 'Thirdly, thymosin secreted by thymic epithelial cells can promote the maturation of Tlymphocytes and regulate function of cellular immunity.', 'We suggest using thymosin during hospitalization and the course of treatment can be determined according to the results of lymphocyte test.', 'Fourthly, ensure adequate caloric, protein and vitamins intake and maintain .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.03.06.20032342 doi: medRxiv preprint the electrolyte and acid-base balance.', 'The other common complication is hyperglycemia [19] ; therefore, continual blood glucose monitoring is recommended, and antidiabetic agents should be used when necessary.', 'The uncommon complications caused by corticosteroid are gastrointestinal bleeding, hypertension, venous thrombosis, hypokalemia and so on, all of these should be paid attention by us [20] .', 'The prudent use of corticosteroid and preventive measure are essential to prevent deterioration in elder patients with these comorbidities.', 'This study has several limitations.', 'First, the study was a retrospective single center observational research with a small size and no external validation cohort, therefore, unmeasured confounders may influence the accuracy of the results.', 'Secondly, the study has not included the mid-and long-term outcome of the cohort after discharge, and continued followup observation was needed.', 'In conclusion, our data indicate that in patients with severe COVID-19 pneumonia, early, low-dose and short-term application of corticosteroid was associated with a faster improvement of clinical symptoms and absorption of lung focus. .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint . .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.03.06.20032342 doi: medRxiv preprint .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.03.06.20032342 doi: medRxiv preprint Figure 3 Images of chest CT scan on day 1, 7 and 14 after hospitalization in severe COVID-19 pneumonia patients with and without methylprednisolone treatment .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.03.06.20032342 doi: medRxiv preprint']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['BARICITINIB - A JANUASE KINASE INHIBITOR - NOT AN IDEAL OPTION FOR MANAGEMENT OF COVID 19']}\n", - "{'sentences': ['Coronavirus disease 2019 , caused by SARS-CoV-2, has rapidly spread throughout China, but the clinical characteristics of Tibetan patients living in the Qinghai-Tibetan plateau are unknown.', 'We aimed to investigate the epidemiological, clinical, laboratory and radiological characteristics of these patients.', 'We included 67', 'Tibetan patients with confirmed SARS-CoV-2 infection.', 'The patients were divided into two groups based on the presence of clinical symptoms at admission, with 31 and 36 patients in the symptomatic and asymptomatic groups, respectively.', 'The epidemiological, clinical, laboratory and radiological characteristics were extracted and All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.09.20033126 doi: medRxiv preprint analysed.', 'No patient had a history of exposure to COVID-19 patients from Wuhan or had travelled to Wuhan.', 'The mean age of Tibetan patients was 39.3 years and 59% of the patients were male.', 'Seven patients presented with fever on admission and lymphocytopenia was present in 20 patients.', '47 patients had abnormal chest CTs at admission instead of stating that 20 were unchanged.', 'Lactate dehydrogenase levels were increased in 31 patients.', 'Seven patients progressed to severe COVID-19; however, after treatment, their condition was stable.', 'No patients died.', 'Of the 36 asymptomatic patients, the mean age was younger than the symptomatic group (34.4±17.3vs 44.9±18.1 years, P=0.02).', 'Lymphocyte count and prealbumin levels were higher in the asymptomatic group than the group with clinical symptoms (1.6±0.5 vs 1.3±0.6 and 241.8±68.2 vs 191.9±60.3, respectively; P<0.05).', 'Imported cases of COVID-19 in', 'Tibetan patients were generally mild in this high-altitude area.', 'Absence of fever or radiologic abnormalities on initial presentation were common.']}\n", - "{'sentences': ['Chloroquine for the 2019 novel coronavirus SARS-CoV-2']}\n", - "{'sentences': ['Objective To investigate the interference factors causing false-positive result of novel coronavirus IgM antibody (SARS-CoV-2 IgM) detected by gold immunochromatography assay (GICA) and enzyme-linked immunosorbent assay (ELISA).', 'Methods A total of 71 serum from different pathogen infections and related chronic diseases patients were collected from the Affiliated Hospital of North Sichuan Medical College from January 25, 2020 to February 15, 2020.', 'GICA and ELISA were used to detect 2019-nCoV IgM in 71 serum, including 5 influenza A virus (Flu A) IgM positive serum, 5 influenza B virus (Flu B) IgM positive serum, 5 Mycoplasma pneumonia (MP) IgM positive serum, 5 Legionella pneumophila (LP) IgM positive serum, 29 rheumatoid factor (RF) IgM positive serum, 5 hypertension patients serum, 5 diabetes mellitus patients serum, 6 human immunodeficiency virus (HIV) infection patients serum and 6 Corona Virus Disease 2019 (COVID-19) patients serum.', 'The interference factors causing false positive results of the two methods were analyzed, and urea dissociation test was employed to dissociate the 2019-nCoV IgM positive serum using the best dissociation concentration.', 'Statistical analyses were performed by SPSS, version 19.0.', 'Result s 2019-nCoV IgM was positive in 18 cases of middle-high level RF-IgM positive serum and 6 cases of 2019-nCoV-infected serum detected by two methods, and the other 47 serum were negative.', 'When the dissociation concentration of urea was 6 mol/L, 2019-nCoV IgM was negative in 17 cases of middle-high level RF-IgM positive serum and positive in 6 cases of 2019-nCoV-infected serum detected by GICA.', 'When the urea dissociation concentration was 4 mol/L, dissociation time was 10 min and the avidity index<0.46 was set as negative, 2019-nCoV IgM was negative in 15 cases of middle-high level RF-IgM positive serum and positive in 6 cases of 2019-nCoV-infected serum detected by ELISA.', 'Conclusion The middle-high level of RF-IgM could cause false positive results of SARS-CoV-2 IgM detected by GICA and ELISA']}\n", - "{'sentences': ['Safety of hydroxychloroquine, alone and in combination with azithromycin, in light of rapid wide-spread use for COVID-19: a multinational, network cohort and self-controlled case series study', 'Background Hydroxychloroquine has recently received Emergency Use Authorization by the FDA and is currently prescribed in combination with azithromycin for COVID-19 pneumonia.', 'We studied the safety of hydroxychloroquine, alone and in combination with azithromycin.', 'Methods New user cohort studies were conducted including 16 severe adverse events (SAEs', 'Rheumatoid arthritis patients aged 18+ and initiating hydroxychloroquine were compared to those initiating sulfasalazine and followed up over 30 days.', 'Self-controlled case series (SCCS', 'Propensity score stratification and calibration using negative control outcomes were used to address confounding.', 'Cox models were fitted to estimate calibrated hazard ratios (CalHRs', 'Overall, 956,374 and 310,350 users of hydroxychloroquine and sulfasalazine, and 323,122 and 351,956 users of hydroxychloroquine-azithromycin and hydroxychloroquine-amoxicillin were included.', 'No excess risk of SAEs was identified when 30-day hydroxychloroquine and sulfasalazine use were compared.', 'SCCS confirmed these findings.', 'However, when azithromycin was added to hydroxychloroquine, we observed an increased risk of 30-day cardiovascular mortality (CalHR2.19 [1.22-3.94]), chest pain/angina (CalHR 1.15 [95% CI 1.05-1.26]), and heart failure (CalHR 1.22 [95% CI 1.02-1.45])', 'We report here (Table 2 ) on database-specific counts and rates of key outcomes (cardiovascular mortality, chest pain/angina and heart failure) observed in the proposed 30-day intention-to-treat analysis.', 'CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.08.20054551 doi: medRxiv preprint Database-specific counts, incidence rates (IR) of all study outcomes stratified by drug use are detailed in full in Supplementary Table S7 .', 'Least common outcomes included bradycardia (e.g. IR', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.08.20054551 doi: medRxiv preprint person-years (py) amongst HCQ users in CCAE) and end-stage renal disease (e.g. IR <0.92/1,000 py amongst HCQ users in CCAE), whilst most common ones were chest pain/angina (e.g. IR 82.41/1,000 py amongst HCQ users in CCAE) and composite cardiovascular events (e.g. IR 17.96/1,000 py amongst HCQ users in CCAE).', 'As expected, most IRs appeared higher in data sources which included older populations (e.g. IR of composite cardiovascular events in HCQ users in MDCR of 91.39/1,000 py).', 'Mortality rates ranged from 4.81/1,000 person-years in HCQ users in Optum to 17.13/1,000 py amongst HCQ users in VA, with cardiovascular-specific mortality ranging from IR 3.43/1,000 py', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.08.20054551 doi: medRxiv preprint .', 'CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.08.20054551 doi: medRxiv preprint Figure 2 .', 'Meta-analytic risk estimates for hydroxychloroquine vs sulfasalazine and azithromycin vs amoxicillin new users during on-treatment during 30-day and on-treatment follow-up HCQ=hydroxychloroquine; SSZ=sulfasalazine; AZM=azithromycin (plus concurrent hydroxychloroquine exposure); AMX=amoxicillin (plus concurrent hydroxychloroquine exposure); CalHR=calibrated hazard ratio; CI=confidence interval; I2=estimate heterogeneity statistic.', 'CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.08.20054551 doi: medRxiv preprint Consistent findings were seen with the long-term (on treatment) use of HCQ vs SSZ (Figure 3) , with the exception of cardiovascular mortality, which appeared inconsistent in the available databases, but overall increased in the HCQ group when meta-analysed: pooled CalHR 1.65 (1.12-2.44).', 'Similar results were obtained in SCCS analyses, which looked at the effect of HCQ use (on-vs offtreatment) on all outcomes except mortality regardless of indication, and therefore included non-RA patients (Tables S10.1 to 10.6 for database-specific results).', 'All the obtained database-and outcome-specific calHRs for the association between short-term (1 month) use HCQ+AZM vs HCQ+AMX are depicted in the form of Forest plots in Supplementary Figure .', 'CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint (Figure 1 ).', 'Despite a lack of evidence on efficacy, HCQ and HCQ+AZM have become the most popular treatment/s for COVID-19.', 'This is the largest ever analysis of the safety of such treatments worldwide, examining over 900,000 HCQ and more than 300,000 HCQ+AZM users respectively.', 'The results on the risk of SAEs associated with short-term (1 month) HCQ treatment as proposed for COVID-19 therapy are reassuring, with no excess risk of any of the considered safety outcomes compared to an equivalent therapy (SSZ).', 'However, long-term treatment with HCQ as used for RA is associated with a 65% increase in cardiovascular mortality.', 'Worryingly, significant risks are identified for combination users of HCQ+AZM even in the short-term as proposed for COVID19 management, with a 15-20% increased risk of angina/chest pain and heart failure, and a two-fold risk of cardiovascular mortality in the first month of treatment.', 'A systematic review of the cardiac side effects of chloroquine and HCQ identified 86 articles reporting short series or individual cases.', '39 In the 127 included patients, cardiac side effects occurred in mainly women (65.4%) who had a median age of 56 years.', 'Conduction disorders were the main side effect reported (85%), with heart failure (26.8%), ventricular hypertrophy (22%), hypokinesia (9.4%), valvular dysfunction (7.1%) and pulmonary arterial hypertension (3.9%) being the other reported side effects.', 'When drugs were withdrawn, 44.9% of patients recovered normal cardiac function; 12.9% sustained irreversible damage, and 30% died.', 'It should be noted that cardiac toxicity was induced by a high cumulative dose of chloroquine or HCQ in most patients, although some studies identified by this .', 'CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint Our results suggest that long-term use of HCQ leads to an increased risk of cardiovascular mortality, with no observable excess risk of major cardiovascular events or diagnosed bradycardia.', 'Considering the current evidence, this may relate to cumulative effects of HCQ leading to an increased risk of QT lengthening or relate to the moderately increased risk of angina and heart failure seen.', 'However, as the strong association observed with cardiovascular death is not observed with diagnosed arrhythmia or bradycardia in this study, sudden cardiovascular death here is more likely due to QT lengthening and undetected and/or sudden torsade-de-pointes.', 'Although long-term treatment with HCQ is not expected for the management of COVID-19, some research suggests that higher doses as prescribed for COVID-19', 'can, even in the short-term, lead to equivalent side effects given the long half-life of HCQ.', '49 QT lengthening is a known effect of all macrolides including AZM and physicians already use caution when prescribing macrolides concurrently with other medications that can also increase the QT interval.', '[32] [33] [34] In this study, the elevated risk of cardiovascular death with combined HCQ +AZM therapy may arise through their synergistic effects of inducing lethal arrhythmia.', 'CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.08.20054551 doi: medRxiv preprint As with all observational data, this study is limited by its ability to appropriately identify exposure and outcome.', 'Due to the nature of sudden cardiac death, capturing the true cause of cardiovascular related mortality is difficult.', 'We therefore have explored cardiovascular related outcomes other than mortality to determine if deterioration in these pathophysiological processes led to increased mortality.', 'Since this is not seen, and sudden cardiac death in association with prolonged QT interval is described in the literature, our conclusions are drawn from these assumptions.', 'It should be acknowledged that misclassification can occur due to non-adherence or non-compliance with exposure medication, and incomplete lack of recording of SAEs may lead to underestimation of these outcomes.', 'Another potential limitation in this study is the potential for patients to be included in more than one dataset in the US.', 'Whilst we ran meta-analysis, which assume populations are independent, we wish to highlight we are likely to under-estimate variance in our meta-analytic estimates.', 'The comparative new user cohort studies are anchored in patients using HCQ for RA, who therefore are likely to be using HCQ at a lower dose than is currently being proposed for use in the treatment of COVID-19.', 'We have taken into consideration that patients with RA taking HCQ may also have further auto-immune conditions such as systemic lupus erythematosus (SLE) and therefore generate the potential for confounding by indication.', 'We therefore ensured that when investigating covariate balance after propensity score stratification and matching and before unblinding study results, that we did not see unbalanced proportions of patients with a diagnosis of SLE', 'Whilst patients with RA may have greater levels of comorbidities than the general population, the age and demographic profile of patients developing cardiovascular complications described in both the systematic review and FAERS database suggests that complications are not only restricted to those with .', 'CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.08.20054551 doi: medRxiv preprint multimorbidity.', '48 However, absolute risk in our study should be interpreted cautiously since patients with RA are likely different from those with COVID-19.', 'As the world awaits the results of clinical trials for the anti-viral efficacy of HCQ in the treatment of SARS-Cov2 infection, this large scale, international real-world data network study enables us to consider the safety of the most popular drugs under consideration.', 'HCQ appears to be largely safe in both direct and comparative analysis for short term use, but when used in combination with AZM this therapy carries double the risk of cardiovascular death in patients with RA.', 'Whereas we used the collective experience of a million patients to build our confidence in the evidence around the safety profile, the current evidence around efficacy of HCQ+AZI in the treatment of covid-19 is quite limited and controversial.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['The Coronavirus disease 19 pandemic has led to widespread concerns about the risk of infection in patients with rheumatic diseases (RD) receiving disease modifying antrheumatic drugs (DMARDs) and other immunosuppressants (IS', 'A SurveyMonkey® based electronic survey was conducted amongst members of the Indian Rheumatology Association to understand the need for changes in prevailing practices.', 'Of the 861 invitees, 221 responded.', 'In the wake of the pandemic, 47.5% would reduce biological DMARDs (bDMARDs', 'Hydroxychloroquine was the preferred choice (81.9%) for the treatment of COVID-19 followed by protease inhibitors (22.1%) and intravenous immunoglobulin (8.1%).', 'Chloroquine was less preferred (19%).', 'More than two-thirds (70.5%) believed that COVID-19 might trigger macrophage activation syndrome.', 'Social distancing (98.1%) and hand hygiene (74.6%) were recommended by majority.', '62.8% would avoid touch for clinical examination whenever feasible.', 'Most rheumatologists perceived the need to change treatment of RDs during the COVID-19 pandemic; reduce immunosuppression and defer the usage of rituximab and bDMARDs.', 'Due to the COVID-19 pandemic, rheumatologists were hesitant in the usage of bDMARDs (especially RTX followed by anti-TNFs), targeted synthetic (tsDMARDs) and CYC and more inclined to prescribe HCQ for treatment of RDs whereas csDMARDs were perceived as safe.', 'There was lack of consensus on continuing IS infusions.', 'IVIG usage was favoured by a minority however, it still merits consideration.', 'Reasonable risk of viral activation has previously been described with RTX and JAKinibs, and thus the hesitation in prescribing various bDMARDs as well as JAKinibs is not unfounded.', 'However, currently, no data are available on the specific risk of respiratory viral infections due to JAKinibs.', 'While some have advocated the use of JAKinibs to inhibit viral entry through AP-2 associated kinase 1 (AAK1', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.03.20048389 doi: medRxiv preprint however, patients with RDs are likely to have heightened risk, as has been seen in the elderly and those with other co-morbid cardiac or lung disease.', '[9] Disease flares can potentially be induced by the COVID-19, as seen in RDs by most endogenous retroviruses as well as acquired viral infections.', '[8] Previously higher risk of infections has been reported in those with higher disease activity, and vice versa.', '[8] While most rheumatologists believed that COVID-19 may trigger MAS, it might be difficult to distinguish cytopenia and hyperferritinemia due to increased disease activity.', 'The consensus was on the use of Tocilizumab in MAS, possibly backed by a case series, which remains to be confirmed in ongoing trials.', '[10] The feasibility of screening for SARS-CoV-2 before initiation of bDMARDs needs to be explored as previously suggested.', '[11] There was unanimous agreement on use of HCQ for treatment of COVID-19, with more than two-thirds weighing towards initiating it in patients with otherwise low evidence diseasespecific indications.', 'This may be attributed to less toxic nature, fewer interactions, a wider therapeutic index, greater in-vitro efficacy against the COVID-19 and years of experience of rheumatologists.', '[12] A prominent national regulatory body has issued an advisory favouring prophylaxis with hydroxychloroquine for healthcare workers and close contacts of patients with COVID-19 [13] However, caution is needed as reports of toxicity have emerged with the use of prophylaxis.', '[14] The usage of ACEi/ARBs was debateable; there exists little evidence to recommend continuation or discontinuation of either drug.', '[15] In times of widespread travel bans and jeopardised medical services, there is a felt need for shift to virtual consulting.', 'India recently legalised teleconsultations to the same effect.', '[16] A pandemic of such magnitude is not without psychologic impact on the treating physicians either.', 'The dominant fears in this situation were mostly related to transmission to family and the patients.', 'The management of the disease was most likely to be affected in the CTD spectrum of RDs, suggesting the need to develop evidence for a triage-in-rheumatology protocol bracing for the times ahead.', 'A strength of our survey was that 60% of the respondents had been in rheumatology practice for more than 5 years.', 'Mhaskar et al. have reported 73% concordance between decision analysis driven by expert consensus with evidence gathered from RCTs.', '[17] Considering the potential limitations of generating evidence in the face of a global crises, it might be .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.03.20048389 doi: medRxiv preprint imperative to embark on a Delphi exercise to generate expert-opinion, while data from COVID-19 rheum registries in progress is awaited.', '[18] The present survey provides perspectives on rheumatology care during the COVID-19 pandemic from a single country and the response rate was modest, albeit represents the viewpoint of a large number of rheumatologists.', 'The findings of the survey may help shape future evidence-based opinions on managing patients with IS during COVID-19 pandemic.', 'Most practicing rheumatologists in India are of the opinion that the current management of .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.03.20048389 doi: medRxiv preprint', 'Most rheumatologists perceived the need to change treatment of RDs during the COVID-19 pandemic; reduce immunosuppression and defer the usage of rituximab and bDMARDs.']}\n", - "{'sentences': ['Hydroxychloroquine and ivermectin: a synergistic combination for COVID-19 chemoprophylaxis and/or treatment?']}\n", - "{'sentences': ['We searched PubMed on April 7, 2020, for studies using the terms (\"SARS-CoV-2\" OR \"COVID-19\" OR \"coronavirus\") AND (\"artificial intelligence\" or \"machine learning\" or \"data science\") without any restrictions regarding language or article type.', 'We found no articles describing predictive methods (type.', 'We found no articles describing predictive methods) for suspected patients based only on blood components.', 'Articles regarding artificial intelligence in this context were found for automatic 1 https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200405-sitrep-76-c ovid-19.pdf?sfvrsn=6ecf0977_2 2 https://www.saude.gov.br/noticias/agencia-saude/46623-brasil-inicia-a-distribuicao-de-500-mil-testes-r apidos assessment of chest CT.', 'Previous studies correlated the C reactive protein to viral infections, mildly elevated alanine aminotransferase (ALT) in acute respiratory distress syndrome (ARDS']}\n", - "{'sentences': ['An outbreak of a novel coronavirus (COVID-19 or 2019-CoV) infection has posed significant threats to international health and the economy.', 'In the absence of treatment for this virus, there is an urgent need to find alternative methods to control the spread of disease.', 'Here, we have conducted an online search for all treatment options related to coronavirus infections as well as some RNA virus infection and we have found that general treatments, coronavirus-specific treatments, and antiviral treatments should be useful in fighting COVID-19.', \"We suggest that the nutritional status of each infected patient should be evaluated before the administration of general treatments and the current children's RNA virus vaccines including influenza vaccine should be immunized for uninfected people and health care workers.\", 'In addition, convalescent plasma should be given to COVID-19 patients if it is available.', 'In conclusion, we suggest that all the potential interventions be implemented to control the emerging COVID-19 if the infection is uncontrollable.', 'This article is protected by copyright.', 'All rights reserved.']}\n", - "{'sentences': ['Coronavirus is an important pathogen causing respiratory and intestinal infection.', 'Of seven identified coronaviruses, the two very pathogenic viruses, SARS-COV and MERS-COV, cause severe ARDS and even acute respiratory failure.', 'With a mortality rate of more than 10% and more than 35% respectively [43] [44] .', 'The four other human coronaviruses In addition, we found that the number of males is more than that of females in either COVID-19 or MERS-COV population.', 'The possible reason of reduced susceptibility of females to viral infection is that females have a lot of X chromosome and estrogen that are vital components in development of innate and adaptive immunity [47] .', 'Meanwhile, numbers of patients with COVID-19 infection had chronic comorbidities, mainly hypertension, diabetes and cardiovascular disease, which is similar to MERS-COV population.', 'Those results indicate that older adult males with chronic underlying disease might be more susceptibility to COVID-19 or MERS-COV.', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.03.08.20032821 doi: medRxiv preprint 1 1 In terms of laboratory testing, reduced lymphocytes and increased CRP were found in both COVID-19 and MERS-COV patients.', 'This result indicates that COVID-19 might be associated with cellular immune response, mainly act on lymphocytes like MERS-COV does [48] .', 'The cells infected by viruses induce the release of numbers of pro-inflammatory cytokines and inflammation storm in the body.', 'Moreover, increased cytokines might make damage to related organs such as liver [49] .', 'Our results demonstrated that abnormal value of AST was found in MERS-COV population, but not in COVID-19 population.', 'The possible reason is that the follow-up time of COVID-19 population was too short, and the liver might remain to be in compensatory stage.', 'For this result, a long follow-up time study is urgently needed.', 'On the other hand, our results suggested that MERS-COV population had a higher rate of ICU admission and fatality than COVID-19 population, indicating that compared with MERS-COV, COVID-19 has less toxic and more easily cured.', 'However, lower discharge rate was found in COVID population than in MERS-COV population.', 'The possible explanation is that most of COVID-19 patients remained to be hospitalized at the time of manuscript submission, and data on those patients could not be obtained in time.', 'Thus, careful interpretation is urged for this result.', 'Up to now, no effective strategy has been found for treatment of COVID-19 infection [50] .', 'Currently, the measure to COVID-19 is to control the source of the infection; taking personal protective works to reduce the risk of transmission; and early diagnosing, isolating and supportive treating for confirmed patients.', 'In the present study, our systematic results of cure rate of drug for MERS-COV infection indicated that ribavirin and interferon, oseltamivir, antivirals and intravenous immunoglobulin all had been effective for MERS-COV infection, with the cure rate of those drugs was 74.2%, 69.2%, 67.1% and 62.5% respectively.', 'Thus, we .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.03.08.20032821 doi: medRxiv preprint 1 2 assume that those drugs might also be effective at COVID-19 infection.', 'However, further studies are needed to confirm this idea.', 'This study has several limitations.', 'First, many patients infected by COVID-19 remained to be hospitalized at the time of manuscript submission, leading to the unavailable of some data.', 'Second, the follow-up time of COVID-19 population is too short to get related data from long-term observations of this disease.', 'Third, finding of statistical tests and p values between COVID-19 and MERS-COV populations should be interpreted with caution.', 'Fourth, the number of MERS-COV patients treated by drugs is small, careful understanding is needed for the cure rate of drug for this disease.', 'Finally, as COVID-19 is still developing around the world and remains to have many unknowns, the results of this study are staged and need to be carefully understood.', 'More large-sample, multicentre, high-quality research should be performed to update this study.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Coronavirus disease 2019 (COVID-19) associated pneumonia caused by severe acute respiratory coronavirus 2 (SARS-COV-2) was first reported in Wuhan, China in December 2019.', 'Till date, no vaccine or completely effective drug is available to cure COVID-19.', 'Therefore, an effective vaccine against SARS-COV-2 is crucially needed.', 'This study was conducted to design an effective multiepitope based vaccine (MEV) against SARS-COV-2.', 'Seven antigenic proteins were taken as targets and different epitopes (B-cell, T-cell and IFN-γ inducing) were predicted.', 'Highly antigenic and overlapping epitopes were shortlisted.', 'Selected epitopes indicated significant interactions with the HLA-binding alleles and 99.29% coverage of the world population.', 'Finally, 505 amino acids long MEV was designed by connecting sixteen MHC class I and eleven MHC class II epitopes with suitable linkers and adjuvant.', 'Linkers and adjuvant were added to enhance the immunogenicity response of the MEV.', 'The antigenicity, allergenicity, physiochemical properties and structural details of MEV were analyzed in order to ensure safety and immunogenicity.', 'MEV construct was non-allergenic, antigenic, stable and flexible.', 'Molecular docking followed by molecular dynamics (MD) simulation analysis, demonstrated a stable and strong binding affinity of MEV with human pathogenic toll-like receptors (TLR), TLR3 and TLR8.', 'Codon optimization and in silico cloning of MEV ensured increased expression in the Escherichia coli K-12 system.', 'Designed MEV in present study could be a potential candidate for further vaccine production process against COVID-19.', 'However, to ensure its safety and immunogenic profile, the proposed MEV']}\n", - "{'sentences': ['Background: SARS-CoV-2-caused coronavirus disease (COVID-19) is posing a large casualty.', 'The features of COVID-19 patients with and without pneumonia, SARS-CoV-2 transmissibility in asymptomatic carriers, and factors predicting disease progression remain unknown.', 'Methods: We collected information on clinical characteristics, exposure history, and laboratory examinations of all laboratory-confirmed COVID-19 patients admitted to PLA General Hospital.', 'Cox regression analysis was applied to identify prognostic factors.', 'The last follow-up was February 18, 2020.', 'Results: We characterized 55 consecutive COVID-19 patients.', 'The mean incubation was 8.42 (95% confidence interval [CI], 6.55-10.29) days.', 'The mean SARS-CoV-2-positive duration from first positive test to conversion was 9.71 (95%CI, 8.21-11.22) days.', 'COVID-19 course was approximately 2 weeks.', 'Asymptomatic carriers might transmit SARS-CoV-2.', 'Compared to patients without pneumonia, those with pneumonia were 15 years older and had a higher rate of hypertension, higher frequencies of having a fever and cough, and higher levels of interleukin-6 (14.61 vs. 8.06pg/mL, P=0.040), B lymphocyte proportion (13.0% vs.10.0%, P=0.024), low account (<190/µL) of CD8 + T cells (33.3% vs. 0, P=0.019).', 'Multivariate Cox regression analysis indicated that circulating interleukin-6 and lactate independently predicted COVID-19 progression, with a hazard ratio (95%CI) of 1.052 (1.000-1.107) and 1.082 (1.013-1.155), respectively.', 'During disease course, T lymphocytes were .', 'CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', '(which was not peer-reviewed)', 'The copyright holder for this preprint .']}\n", - "{'sentences': ['As shown in Table 2 , patients with AGI grade III to IV had higher septic shock incidence than those without AGI (P =0.002) and with AGI grade I (P =0.001) and II (P =0.031).', 'Significant differences in 28-day mortality were found among the four groups (P <0.05) except for group AGI grade I and II (P =0.540).', 'No differences in MODS incidence were found among the four groups (P >0.05).', 'Non-survivors were accompanied by higher incidence of AGI grade III to IV than survivors (17.5% vs.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.25.20043570 doi: medRxiv preprint 0.0%, P =0.004) ( Table 3) .', 'Whereas survivors had higher incidence of no AGI than non-survivors (25.6% vs. 0.0%, P <0.001) ( Table 3) .', 'To determine the risk factors associated with AGI grade II and above, univariate logistic regression was performed using the above-mentioned variables (sex, age, days from onset to admission, BMI, APACHEII scores, SOFA scores, CRP, D-dimer, WBC counts, lymphocyte counts, PCT, blood lactate, MV days, CRRT days, and hospital stay).', 'Variables with P <0.1 in univariate analyses were tested in further multivariate logistic regression analyses.', 'As shown in Table 4 , three variables (SOFA scores, WBC counts, MV days) were established as independent risk factors for the development of AGI grade II and above.', 'The ROC curves were performed to evaluate the associations between AGI and clinical outcome variables.', 'The area under curves (AUCs) of MODS, septic shock, and 28-day mortality were 0.659 (P =0.022), 0.793 (P <0.001), and 0.716 (P =0.001']}\n", - "{'sentences': ['Comparative in vitro transcriptomic analyses of COVID-19 candidate therapy hydroxychloroquine suggest limited immunomodulatory evidence of SARS-CoV-2 host response genes.', 'Hydroxychloroquine (HCQ) has emerged as a potential and controversial antiviral candidate therapy for .', 'While many clinical trials are underway to test the efficacy of HCQ as a treatment for COVID-19, underlying mechanisms of HCQ in the setting of COVID-19 remain unclear.', 'Hence, we examined differential gene expression signatures of HCQ exposure, in vitro SARS-CoV-2 infection, and host signatures of COVID-19 in blood, bronchoalveolar lavage, and postmortem lung to evaluate whether HCQ transcriptome signatures associate with restoration of SARS-CoV-2-related host transcriptional responses.', 'Here, we show that 24 hours of in vitro treatment of peripheral blood mononuclear cells(PBMC) with HCQ significantly impacted transcription of 16 genes involved in immune regulation and lipid metabolism.', 'Using transcriptome data from in vitro SARS-CoV-2 infected NHBE and A549 cells and PBMC derived from confirmed COVID-19 infected patients, we determined that only 0.24% of the COVID-19 PBMC differentially expressed gene set and 0.39% of the in vitro SARS-CoV-2 cells differentially expressed gene set overlapped with HCQ-related differentially expressed genes.', 'Moreover, we observed that HCQ treatment significantly impacted transcription of 159 genes in human primary monocyte-derived macrophages involved in cholesterol biosynthetic process and chemokine activity.', 'Notably, when we compared the macrophage HCQ-related gene lists with genes transcriptionally altered during SARS-CoV-2 infection and in bronchoalveolar lavage of COVID-19+ patients, the CXCL6 gene was impacted in all three transcriptional signatures revealing evidence in favor of chemokine modulation.', 'HCQrelated transcriptional changes minimally overlapped with host genes altered in postmortem lung biopsies from COVID-19 participants.', 'These results may provide insight into the immunomodulation mechanisms of HCQ treatment in the setting of COVID-19 and suggest HCQ', 'All rights reserved.', 'No reuse allowed without permission.']}\n", - "{'sentences': ['<p><b></b> There is no specific drug that has been approved for 2019-nCoV. There are a number of factors that pose major challenges in their development.', 'Approaches to the development of anti-2019-nCoV include screening existing broad-spectrum antiviral drugs, repositioning of readily available clinical compounds, and <italic>de novo</italic> development of novel and specific agents for 2019-nCoV. Candidate compounds can be developed either to inhibit virus-based targets, such as RNA proteases, polymerase, spike glycoproteins, and viral envelop and membrane proteins, or to inhibit host-based targets, such as receptors and proteases that are utilized by virus for viral entry and endocytosis.', 'Recently, the RNA polymerase remdesivir had demonstrated clinical efficacy in one patient with severe novel coronavirus pneumonia (NCP).', 'The broad-spectrum viral protease inhibitor Kaletra<sup>®</sup> is also recommended in the current NCP clinical practice.', 'Both drugs had lately been proceeded into multiple controlled phase III clinical trials to test their safety and efficacy in NCP']}\n", - "{'sentences': ['An overweight 60-year-old man presented with fever that started ten days ago.', 'At admission, ear temperature was 38.5 • C and oxygen saturation was 99%.', 'Laboratory tests showed normal white blood cell count (5.000 per L), elevated serum lactate level (100 U/L) and elevated reactive C protein level (27 mg/dL).', 'Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2; formerly called 2019-nCoV) was detected in a throat swab sample by reverse transcription polymerase chain reaction on day 2.', 'On day 3, the patients developed dyspnea and oxygen saturation dropped to 90%.', 'D-dimer levels were increased (5411 ng/mL).']}\n", - "{'sentences': ['The new coronavirus (COVID-19) pneumonia outbreaking at the end of 2019 is highly contagious, with a crude mortality rate of about 2.3% [1] .', 'Currently, more than 74677 patients have been reported in the Mainland of China.', 'About 80.9% patients are with mild to moderate severity [1] , and with a better prognosis.', 'However, for patients developing into severe or critical levels, the mortality rate was significantly increased, and crude mortality rate reached 49% in critical patients [1] .', 'It plays key roles to identify severe and critical patients even earlier, aiming to improve the recovery rate and reduce mortality.', 'Clinically, many patients appeared short-term progressive aggravation, scholars speculated that \"inflammatory storms\" occurred, namely, overreaction of cytokine.', 'In a preprint article in medrxiv, the lymphocyte subsets and cytokines of 123 patients (102 mild and 21 severe patients) were analyzed and the researchers found the numbers of CD4+ T cells and CD8+ T cells decreased, and the levels of IL-6 and IL-10 increased in severe cases [7] .', 'In this study, a retrospective analysis was conducted about cytokines and other inflammatory indicators of 100 patients (including 66 severe or critical patients), and more indicators were expected to better identify critical patients and help clinical decision-making.', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', \"In accordance with Wan S's [7] and Liu J's [8] study, this study also found that the levels of IL-6 and IL-10 were associated with the severity of COVID-19 pneumonia; similar to Chaolin Huang's study [4] , TNFα concentration, NC count and LC count were also found correlated with disease severity.\", 'In addition, IL2R levels, ferroprotein levels, PCT levels, and EC counts were also related to the disease severity.', 'Besides, we also found the IL-6 levels in mild patients were lower than 100pg/mL. For eight patients who were deceased in critical group, IL-6 level was >100pg/mL in three persons.', 'IL-6 >100pg/mL might represent the emergence of \"inflammatory storm\".', 'IL-8 levels in mild and severe patients were normal, and for patients with IL-8 >62 pg/mL, more attention need to avoid the disease progression.', 'Based on clinical practice and ROC analysis between critical and non-critical patients, some cut-off values of the test items were obtained.', 'With age >67.5 years, IL2R >793.5U/mL, CRP >30.7ng/mL, ferroprotein >2252μg/L, WBC >9.5*10^9/L or NC>7.305*10^9/L, progress to critical illness should be closely observed and prevented.', 'Preventing recognition or blocking the occurrence of inflammatory action, new drugs development on immune regulation, might be new breakthroughs in the control of COVID-19 pneumonia.', 'Pathological examination found lymphocyte-dominated mononuclear cell infiltration in interstitial pulmonary tissue, CD4+ and CD8+ T cells were significantly reduced in peripheral blood cells, but a high ratio of CD38+ (CD4 3.47%) and HLA-DR+ (CD8 39.4%) T cells [9] , which suggested excessive activation of pro-inflammatory cells.', 'Presumably, lymphocyte deposition in lung tissue might contribute to lymphocyte reduction in peripheral blood.', 'In addition, researchers found that CCR4+ CCR6+ Th17 cells were increased, and the IL-17 inhibitor (Secukinumab) against activated Th17 cells is promising for disease control [9] .', 'In this study, IL-6, TNFα and IL-8 may be potential targets for immunotherapy of COVID-19.', \"With IL-6 >100pg/mL, the patient's condition was extremely critical.\", 'According to the news, a research team from First Affiliated Hospital of University of Science and Technology of China has used IL-6 receptor recombinant monoclonal antibody, Tozhu monoclonal antibody, in 14 critically or severely ill COVID-19 patients [10] .', 'The results were reported to be encouraging.', 'Respiratory oxygenation indices of 14 Table 3 Correlation coefficient and P value between items and disease severity. .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.02.25.20025643 doi: medRxiv preprint .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.02.25.20025643 doi: medRxiv preprint']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['We have used affinity purification-mass spectrometry to identify 332 high-confidence SARS-CoV-2human PPIs.', 'We find the viral proteins connected to a wide array of biological processes, including protein trafficking, translation, transcription and ubiquitination regulation.', 'Using a combination of a systematic chemoinformatic drug search with a pathway centric analysis, we uncovered close to 70 different drugs and compounds, including FDA approved drugs, compounds in clinical trials as well as preclinical compounds, targeting parts of the resulting network.', 'We are currently testing these compounds for antiviral activity and encourage others to do the same as well as extract insights from the map that could have therapeutic value.', 'More generally, this proteomic/chemoinformatic analysis is not only identifying drug and clinical molecules that might perturb the viral-human interactome, it gives these potentially therapeutic perturbations a mechanistic context.', 'Among those that may be infection relevant are the inhibition of lysosomal acidification and trafficking with Bafilomycin A1, via inhibition of V-ATPase 74 , and modulation of the ER stress and the protein unfolding response pathway by targeting the Sigma1 and Sigma2 receptor by drugs like haloperidol (Fig. 5a , Tables 1a,b).', 'Indeed, several of the human proteins in the interactome are targeted by drugs that have emerged phenotypically as candidate therapeutics for treating COVID-19, such as chloroquine 75, 76 .', \"While we do not pretend to have identified the molecular basis of chloroquine's putative activity, we do note that this drug targets the Sigma1 and Sigma2 receptors at mid-nM and low μM concentrations, respectively.\", 'Similarly, antibiotics like azithromycin have also been mooted as treatments for COVID-19.', 'While this too remains to be demonstrated, we note that Azithromycin has off-target activity against human mitochondrial ribosomes, components of which interact with the SARS-CoV-2 Nsp8 protein (MRPS5, MRPS27, MRPS2, and MRPS25).', 'Other antibiotics that also have an off-target effect on mitochondrial ribosomes, such as chloramphenicol, tigecycline, and Linezolid 77,78 may also merit study for efficacy.', 'Indeed, this logic may be extended.', 'Many COVID-19 patients will be on the drugs identified here, treating pre-existing conditions.', 'It may be useful to correlate clinical outcomes with the taking of these drugs, cross-referencing with the networks described here.', 'In some senses, this is already occurring phenomenologically, leading to concerns about ACE inhibitors such as captopril and enalapril, and for NSAIDs.', 'What this study provides is a systematic schema for clinical/drug associations going forward, giving them a mechanistic context that allows investigators to seek them directly.', 'Systematic validation using genetic-based approaches 79,80 will be key to determine the functional relevance of these interactions and if the human proteins are being used by the virus or are fighting off infection, information that would inform future pharmacological studies.', 'It is important to note that pharmacological intervention with the agents we identified in this study could be either detrimental or beneficial for infection.', 'For instance, the HDAC2 inhibitors may compound the potential action of the Nsp5 protease to hydrolyze this human protein.', 'Future work will involve generation of protein-protein interaction maps in different human cell types, as well as bat cells, and the study of related coronaviruses including SARS-CoV, MERS-CoV and the less virulent OC43 5 , data that will allow for valuable cross-species and viral evolution studies.', 'Targeted biochemical and structural studies will also be crucial for a deeper understanding of the viral-host complexes, which will inform more targeted drug design.', 'Along with SARS-CoV-2, we have previously utilized global affinity purification-mass spectrometry (AP-MS', 'Supplementary Information is available for this paper.', 'Correspondence and requests for materials should be addressed to nevan.krogan@ucsf.edu Reprints and permissions information is available at www.nature.com/reprints', 'The authors have not filed for patent protection on the SARS-CoV-2 host interactions or the use of predicted drugs for treating COVID-19 to ensure all the information is freely available to accelerate the discovery of a treatment.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.22.002386 doi: bioRxiv preprint similarity with the SARS-CoV homolog, and inferred function based on the SARS-CoV homolog.', '(c) Immunoblot detection of 2xStrep tag demonstrates expression of each bait in input samples, as indicated by red arrowhead.', '(d) Experimental workflow for expressing each 2xStrep tagged SARS-CoV-2 fusion protein in biological triplicate in HEK293T cells, followed by affinity purification-mass spectrometry, and PPI scoring to identify 332 high confidence protein-protein interactions.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.22.002386 doi: bioRxiv preprint transmembrane segment.', '(iii) Model of how E might mimic the BRD2 native interaction partner Histone 2A and how BRD2 can be targeted pharmacologically.', 'Chemoinformatic and expert analysis identified FDA approved drugs (green), clinical candidates (yellow), and preclinical candidates (purple) with experimental activities against the host proteins and processes, with representative chemicals shown.', '(b) Inosine Monophosphate Dehydrogenase 2 (IMPDH2) regulates de novo nucleic acid biosynthesis.', 'It is a target for proliferative diseases including cancer 81 and autoimmune disorders, for instance by the approved drug mycophenolic acid 82 , and as a broad spectrum antiviral by Ribavirin 83 .', 'While Ribavirin has activity against SARS in vitro 84 , it has low tolerability, something that might be addressed by the more selective Merimepodib, which is in phase II clinical trials 85 .', '(c) The mammalian target of Rapamycin (mTOR) pathway is a master regulator of cell proliferation and autophagy, which viruses including Influenza A are known to modulate 86, 87 .', 'Several proteins that interact with SARS-CoV-2 baits, including components of the Respiratory complex 1 by Nsp7, Nsp12, and Orf9c, the leucine importer B(0)AT2 (SLC6A15) 88,89 by Nsp6 and LARP1 by N (not shown).', 'In addition to Rapamycin, the mTOR', 'For each affinity purification, ten million HEK293T cells were plated per 15-cm dish and transfected with up to 15 μg of individual Strep-tagged expression constructs after 20-24 hours.', \"Total plasmid was normalized to 15 μg with empty vector and complexed with PolyJet Transfection Reagent (SignaGen Laboratories) at a 1:3 μg:μl ratio of plasmid to transfection reagent based on manufacturer's recommendations.\", \"After more than 38 hours, cells were dissociated at room temperature using 10 ml Dulbecco's Phosphate Buffered Saline without calcium and magnesium (Dulbecco's Phosphate Buffered Saline without calcium and magnesium) supplemented with 10 mM EDTA for at least 5 minutes and subsequently washed with 10 ml Dulbecco's Phosphate Buffered Saline without calcium and magnesium\", 'Frozen cell pellets were thawed on ice for 15-20 minutes and suspended in 1 ml Lysis Buffer [IP Buffer (50 mM Tris-HCl, pH 7.4 at 4°C, 150 mM NaCl, 1 mM EDTA) supplemented with 0.5% Nonidet P 40 Substitute (NP40; Fluka Analytical) and cOmplete mini EDTA-free protease and PhosSTOP phosphatase inhibitor cocktails (Roche)].', 'Samples were then frozen on dry ice for 10-20 minutes and partially thawed at 37°C before incubation on a tube rotator for 30 minutes at 4°C and centrifugation at 13,000 xg, 4°C for 15 minutes to pellet debris.', 'After reserving 50 μl lysate, up to 48 samples were arrayed into a 96-well Deepwell plate for affinity purification on the KingFisher Flex Purification System (Thermo Scientific) as follows: MagStrep \"type3\" beads (30 μl; IBA Lifesciences) were equilibrated twice with 1 ml Wash Buffer (IP Buffer supplemented with 0.05% NP40) and incubated with 0.95 ml lysate for 2 hours.', 'Beads were washed three times with 1 ml Wash Buffer and then once with 1 ml IP Buffer.', 'To directly digest bead-bound proteins as well as elute proteins with biotin, beads were manually suspended in IP Buffer and divided in half before transferring to 50 μl Denaturation-Reduction Buffer (2 M urea, 50 mM Tris-HCl pH 8.0, 1 mM DTT) and 50 μl 1x Buffer BXT (IBA Lifesciences) dispensed into a single 96-well KF microtiter plate, respectively.', 'Purified proteins were first eluted at room temperature for 30 minutes with constant shaking at 1,100 rpm on a ThermoMixer C incubator.', 'After removing eluates, on-bead digestion proceeded (below).', 'Strep-tagged protein expression in lysates and enrichment in eluates were assessed by western blot and silver stain, respectively.', 'The KingFisher Flex Purification System was placed in the cold room and allowed to equilibrate to 4°C overnight before use.', 'All automated protocol steps were performed using the slow mix speed and the following mix times: 30 seconds for equilibration/wash steps, 2 hours for binding, and 1 minute for final bead release.', 'Three 10 second bead collection times were used between all steps.', 'Bead-bound proteins were denatured and reduced at 37°C for 30 minutes and after bringing to room temperature, alkylated in the dark with 3 mM iodoacetamide for 45 minutes and quenched with 3 mM DTT for 10 minutes.', 'Proteins were then incubated at 37°C, initially for 4 hours with 1.5 μl trypsin (0.5 μg/μl; Promega) and then another 1-2 hours with 0.5 μl additional trypsin.', 'To offset evaporation, 15 μl 50 mM Tris-HCl, pH 8.0 were added before trypsin digestion.', 'All steps were performed with constant shaking at 1,100 rpm on a ThermoMixer C incubator.', 'Resulting peptides were combined with 50 μl 50 mM Tris-HCl, pH 8.0 used to rinse beads and acidified with trifluoroacetic acid (0.5% final, pH < 2.0).', 'Acidified peptides were desalted for MS analysis using a BioPureSPE Mini 96-Well Plate (20mg PROTO 300 C18; The Nest Group, Inc according to standard protocols.', 'Mass spectrometry data acquisition and analysis.', 'Samples were re-suspended in 4% formic acid, 2% acetonitrile solution, and separated by a reversed-phase gradient over a nanoflow C18 column (Dr. Maisch).', 'Each sample was analyzed on two different mass spectrometers.', 'First, a 75 min acquisition, in which peptides were directly injected via a Easy-nLC 1200 (Thermo) into a Q-Exactive Plus mass spectrometer) into a Q-Exactive Plus mass spectrometer (Thermo) into a Q-Exactive Plus mass spectrometer', 'For all proteins that fulfilled these criteria we extracted information about stable protein complexes they participate in from the CORUM 98 database of known protein complexes.', 'In the second step we then relaxed the stringency and recovered additional interactors that (1) form complexes with interactors determined in filtering step 1 and (2) fulfill the following criteria: MiST score ≥ 0.6, SAINTexpress BFDR ≤ 0.05 and average spectral counts ≥ 2.', 'Proteins that fulfilled filtering criteria in either step 1 or step 2 were considered to be HC-PPIs and visualized with cytoscape 99 .', 'Using this filtering criteria, nearly all of our baits recovered a number of HC-PPIs in close alignment with previous datasets reporting an average of ~6 PPIs per bait 100 .', 'However, for a subset of baits (Orf8, Nsp8, Nsp13, and orf9c) we observed a much higher number of PPIs passing these filtering criteria.', 'For these four baits, the MiST scoring was instead performed using an larger in-house database of 87 baits that were prepared and processed in an analogous manner to this SARS-CoV-2 dataset.', 'This was done to provide a more comprehensive collection of baits for comparison, to minimize the classification of non-specifically binding background proteins as HC-PPIs.', 'All mass spectrometry raw data and search results files have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD018117 101, 102 .', 'PPI networks have also been uploaded to NDEx.', 'Gene Ontology Over-representation Analysis.', 'The targets of each bait were tested for enrichment of Gene Ontology (GO Biological Process) terms.', 'The over-representation analysis (ORA', 'Virus Interactome Similarity Analysis.', 'Interactome similarity was assessed by comparing the number of shared human interacting proteins between pathogen pairs, using a hypergeometric test to calculate significance.', 'The background gene set for the test consisted of all unique proteins detected by mass spectrometry across all pathogens (N=10,181 genes).', 'Orf6 peptide modeling.', 'The proposed interaction between Orf6 and the NUP98-RAE1 complex was modeled in PyRosetta 4 103 (release v2020.02-dev61090) using the crystal structure of Vesicular stomatitis virus matrix (M) protein bound to NUP98-RAE1 as a template 66 (PDB 4OWR downloaded from the PDB-REDO server 104 ).', 'The M protein chain (C) was truncated after residue 54 to restrict the model to the putative interaction motif in Orf6 (M protein residues 49-54, sequence DEMDTH).', 'These residues were mutated to the Orf6 sequence, QPMEID, using the mutate_residue function in the module pyrosetta.toolbox, without repacking at this initial step.', 'After all six residues were mutated, the full model was relaxed to a low energy conformation using the FastRelax protocol in the module pyrosetta.rosetta.protocols.relax.', 'FastRelax was run with constraints to starting coordinates and scored with the ref2015 score function.', 'The resulting model was inspected for any large .', 'CC-BY 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.22.002386 doi: bioRxiv preprint energetic penalties associated with the modeled peptide residues or those NUP98 and RAE1 residues interacting with the peptide, and was found to have none.', 'The model was visualized in PyMOL (The PyMOL Molecular Graphics System,', 'Version 2.3.4 Schrödinger, LLC.', 'CUL2 ZYG11B homology model generation.', 'The CRL2 ZYG11B homology model was built with Swissmodel 105 and Modeller 106 by using the homology template of each domain from PDB database (PDB codes: 4b8o, 5jh5,1g03, and 6r7n).', 'The ZYG11B model has two structured domains: a leucine rich repeat (LRR) and Armadillo Repeat (ARM) at the N and C-terminus respectively.', 'The linker between each domain was not modelled due to high flexibility between residues 32 to 49 and residues 304 to 322.', 'Putative protein interaction surfaces on ZYG11B were modelled based on contiguous surface exposed residues that are conserved in ZYG11B orthologues from C. elegans to H. sapiens (ZY11B_HUMAN; ZY11B_MOUSE; F1M8P2_RAT; ZYG11_XENLA; ZYG11_DANRE; ZYG11_CAEEL) and located at typical substrate binding sites in the homologous structures of LRR and ARM']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Our society is currently experiencing an unprecedented challenge, managing and containing an outbreak of a new coronavirus disease known as COVID-19.', 'While China -where the outbreak started -seems to have been able to contain the growth of the epidemic, different outbreaks are nowadays being detected in multiple countries.', 'Much is currently unknown about the natural history of the disease, such as a possible asymptomatic spreading or the role of age in both the susceptibility and mortality of the disease.', 'Nonetheless, authorities have to take action and implement contention measures, even if not everything is known.', 'To facilitate this task, we have studied the effect of different containment strategies that can be put into effect.', 'Our work specifically refers to the situation in Spain as of February 28th, 2020, where a few dozens of cases have been detected.', 'We implemented an SEIR-metapopulation model that allows tracing explicitly the spatial spread of the disease through data-driven stochastic simulations.', 'Our results are in line with the most recent recommendations from the World Health Organization, namely, that the best strategy is the early detection and isolation of individuals with symptoms, followed by interventions and public recommendations aimed at reducing the transmissibility of the disease, which although not efficacious for disease eradication, would produce as a second order effect a delay of several days in the raise of the number of infected cases.', 'CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', '(which was not peer-reviewed)', 'The copyright holder for this preprint .']}\n", - "{'sentences': ['Currently, 90% to 95% of the medical imaging examinations for suspected patients with COVID-19 are chest CT, which has a high detection rate of viral pneumonia.', 'In contrast, the quality of available SARS-CoV-2 nucleic acid detection kits differs greatly, and the reliability of NAAT is still questionable.', 'Moreover, NAAT has a low detection rate for SARS-CoV-2 and thus needs to be repeated 2 to 3 times in many cases.', 'Some patients had negative NAAT results for the detection of SARS-CoV-2 from pharyngeal swabs but positive NAAT results for the detection of SARS-CoV-2 from bronchoalveolar lavage, leading to false-negative results.', 'Second, the number of people awaiting NAATs for the detection of SARS-CoV-2 greatly exceeds the capacity of medical institutions.', 'Many patients have not been diagnosed in a timely manner and thus have missed the chance of early isolation and early treatment.', 'Compared with various limitations of NAAT, chest CT examination is timely and rapid and has a high positive rate.1 The extent of lung lesions is closely related to clinical symptoms.', 'Therefore, chest CT examination is irreplaceable in the preliminary screening of COVID-19.', 'Coronavirus disease 2019 has different imaging manifestations at different stages, which are mainly related to pathogenesis.', 'The lesions at the early stage of COVID-19 are relatively localized and mainly manifest as inflammatory infiltration restricted to the subpleural or peribronchovascular regions of one lung or both lungs, exhibiting patchy or segmental pure GGOs with vascular dilation (Figure 1).', 'Very few cases have negative CT findings at the early stage.', 'In the progressive stage, CT shows mainly an increased range of pure GGOs (Figure 2), the involvement of multiple lobes (Figure 3), consolidations of some lesions, and GGOs surrounding consolidated lesions (the characteristic change of the progressive stage).', 'Interlobular septal thickening and an obvious crazy-paving pattern are often present, and air bronchograms are common (Figure 4).', 'At the advanced stage, the CT manifestations of patients are similar to those in other types of pneumonia and mainly include diffuse lesions in both lungs, which are mostly consolidated lesions, and GGOs surrounding consolidated lesions, which are mostly accompanied by parenchymal bands and occasionally by a small amount of pleural effusion.', 'This CT appearance is called lung whiteout.', 'Different imaging manifestations at different stages may be associated with the pathological mechanism of viral pneumonia, which at first is prone to affect the terminal bronchioles and their surrounding pulmonary parenchyma and then develop into infiltration of pulmonary lobules and, lastly, diffuse alveolar damage.6\\n', 'In imaging diagnosis, COVID-19 is difficult to distinguish from pneumonias caused by influenza A virus, influenza B virus, cytomegalovirus, adenovirus, respiratory syncytial virus, SARS-CoV, MERS coronavirus, and other viral pneumonias as well as bacterial pneumonia.2 Luckily, their treatment methods are similar.', 'There are no medicines specifically targeting COVID-19.', 'Viral pneumonias other than COVID-19 mainly manifest as peribronchial and perivascular interstitial inflammation that moves toward the inner part of the pulmonary interstitium, and their CT manifestations are multiple interlaced or parallel high-attenuation fibrous streaks or high-attenuation reticular patterns caused by infiltration of the interlobular septa.', 'The lesions mainly occur in the hilar and subpleural regions.7 If the pneumonia is secondary to bronchitis and does not involve the alveoli, inflammation often further develops into the bronchial wall.', 'When the bronchioles are partially or completely blocked, CT images show localized pulmonary edema and/or atelectasis.', 'The occurrence of viral pneumonia is correlated with the virulence of the virus, the transmission route, and the age and immunological status of the host.', 'In general, the incidence of viral pneumonias is higher in children than in adults.', 'In contrast, COVID-19 commonly occurs in 40- to 60-year-old patients with multiple comorbidities.', 'Compared to patients with SARS and MERS, patients with COVID-19 have no obvious complications or infections, and the disease progression is relatively slow.8\\n', 'Coronavirus disease 2019 also needs to be differentiated from bacterial pneumonia, mycoplasma pneumonia (MPP), and chlamydia pneumonia.9 Bacterial pneumonia occurs in the lung parenchyma and mainly manifests as bronchial pneumonia or lobar pneumonia with many inflammatory secretions in the bronchioles and alveoli.', 'Its CT manifestations are mainly extensive patchy consolidations of the lung parenchyma, and GGOs are less common.', 'Mycoplasma pneumonia commonly occurs in school-age children and adolescents but rarely occurs in adults.', 'The chest CT findings of MPP in adults are mostly bronchial wall thickening and centrilobular nodules; bronchial wall thickening is considered the manifestation of lobular pneumonia, and centrilobular nodules are small airway lesions.', 'The proportion of lung consolidation is as high as 61% in MMP.', 'In contrast, CT manifestations of COVID-19 are mainly pure GGOs at the early stage and visible consolidations in the center of the lesions at the progressive stage, but the proportion of consolidations in COVID-19 is less than that in MMP.', 'In addition, COVID-19 needs to be differentiated from lung disease caused by other diseases.10 For example, the 2 suspected patients reported above were given completely different treatments, which mainly aimed to control pneumonia and primary diseases.', 'Heart failure–induced pulmonary edema manifests differently at different stages of the disease.', 'It can be divided into 2 subtypes: pulmonary alveolar edema (type I) and interstitial pulmonary edema (type I) and interstitial pulmonary edema).', 'Computed tomography manifestations of type I pulmonary edema mainly include local or multiple GGOs, patchy high-attenuation patterns, and large patchy high-attenuation patterns in both lungs, which typically exhibit the high-attenuation butterfly sign with both hila as the center, accompanied by signs of interstitial pulmonary edema such as sporadic or local interlobular septal thickening.', 'Computed tomography manifestations of type I) and interstitial pulmonary edema', 'Although various types of pneumonias have certain imaging features, COVID-19 and other viral pneumonias, bacterial pneumonia, and some lesions share some common imaging features.12 In some cases, it is difficult to differentiate COVID-19 from them by imaging alone, and first clinical manifestations, contact history, and laboratory tests should also be considered to make the final diagnosis.', 'The conclusions are listed in Table 1.', 'In conclusion, in contrast to NAAT of SARS-CoV-2, which is restricted by false-negative results and detection limitations, chest CT, which is simple to perform and readily available, can quickly detect lung lesions and make imaging diagnoses at the early stage.', 'Therefore, it has great value in early screening, differential diagnosis, and disease severity assessment of COVID-19.', 'For patients with fever as the first symptom and with a history of exposure to COVID-19, chest CT examination should be performed as soon as possible.', 'If imaging shows the presence of typical manifestations of 2019-nCoV, even if the NAAT result for the detection of SARS-CoV-2 is unavailable or negative, it is still necessary to take isolation measures to avoid the spread of the epidemic.', 'To date, our institution has examined a total of 50 suspected patients with COVID-19, 15 of whom were diagnosed with COVID-19.', 'The main clinical manifestations of confirmed cases have been fever (100%; >38°C in most cases and >37.5°C in a few cases), cough and expectoration (46.7%), headache (20%), and diarrhea (13.3%).', 'No confirmed patients have had dyspnea.', 'Imaging findings have mainly included single or multiple lesions, patchy or segmental GGOs (93.3%), and reticular markings that mainly followed peribronchovascular and subpleural distributions.', 'Interlobular septal thickening might be present, and pleural effusion and enlarged mediastinal lymph nodes were rarely seen.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['[{\\'text\\': \"Single-cell RNA profiling of ACE2, the SARS-CoV-2 receptor, had proposed multiple tissue cells as the potential targets of SARS-CoV-2, the novel coronavirus causing the COVID-19 pandemic.', \"However, most were not echoed by the patients' clinical manifestations, largely due to the lack of protein expression information of ACE2 and co-factors.\", 'Here, we incorporated the protein information to analyse the expression of ACE2, together with TMPRSS2 and Furin, two proteases assisting SARS-CoV-2 infection, at single cell level in situ, which we called protein-proofed single-cell RNA (pscRNA) profiling.', 'Systemic analysis across 36 tissues revealed a rank list of candidate cells potentially vulnerable to SARS-CoV-2.', 'The top targets are lung AT2 cells and macrophages, then cardiomyocytes and adrenal gland stromal cells, followed by stromal cells in testis, ovary and thyroid.', 'Whereas, the polarized kidney proximal tubule cells, liver cholangiocytes and intestinal enterocytes are less likely to be the primary SARS-CoV-2 targets as ACE2 localizes at the apical region of cells, where the viruses may not readily reach.', 'These findings are in concert with the clinical characteristics of prominent lung symptoms, frequent heart injury, and uncommon intestinal symptoms and acute kidney injury.', 'Together, we provide a comprehensive view on the potential SARS-CoV-2 targets by pscRNA', 'The identification of lung macrophages and adrenal gland stromal cells as the SARS-CoV-2 targets might be much informative for clinical practises and translational researches, because the COVID-19 disease frequently proceeded to severe or very severe stage in a short period [1] , which suggests systemic conditions occurred probably due to the deregulated immune and endocrine systems.', 'Whereas, macrophages are critical inflammatory cells that were linked to the cytokine storm [43, 44] , a severe condition leading to patient death; meanwhile, adrenal gland, via producing multiple hormones such as glucocorticoid, plays a central role in the endocrine homeostasis [45] .', \"Therefore, it's conceivable that their infection by SARS-CoV-2 may be accountable for the rapid progression and severe conditions of COVID-19 disease.\", 'Additionally, stromal cells in reproductive system (ovary and testis) and thyroid gland were also identified as potential target cells under the condition of viremia, suggesting potential injuries in these tissues.', 'Actually, a recent study reported a significant change in certain male sex hormones in COVID-19 male patients [46] , which is consistent with the notion that testis is potentially targeted by SARS-CoV-2.', 'Previous analysis based solely on the mRNA expression of ACE2 suggested multiple tissue cells as potential targets of the novel coronavirus SARS-CoV-2, including cells from almost every important human system.', 'However, the COVID-19 patients primarily displayed symptoms from respiratory systems, where ACE2 is expressed in a small portion of cells.', 'Even for severely ill patients, the injuries or symptoms in the ACE2-high organs such as kidney and intestinal tract are relatively uncommon, with a rate of 1%-4.3% for acute kidney author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.06.028522 doi: bioRxiv preprint injury [1, 25] , and a rate of 3.5%-5.8% for intestinal symptoms [1, 47] .', 'Instead, the injuries in ACE2-median organs such as heart are more frequent (12%-19%) [1, 47] .', 'This obvious discrepancy suggests that mechanisms other than ACE2 expression level also play important roles in establishing efficient and successful infection.', 'Based on our above analysis by pscRNA expression profiling, we propose that three more factors, in addition to the mRNA level, should be taken into account in predicting the vulnerability of a specified target tissue/organ.', 'First, the protein information of expression level, subcellular localization may influence virus infection.', \"As shown above, the mRNA level is not often corresponding to protein level, such as in kidney and adipose tissue (Figure 1) , therefore, it's necessary to not only analyse mRNA expression, but also detect protein expression in situ.\", 'Moreover, membrane proteins such as ACE2 could be expressed either all around the surface of nonpolarized stromal cells such as Leydig cells in testis ( Figure 2F and 3F) , or specifically on the apical region of polarized epithelial cells such as the enterocytes in intestinal tracts ( Figure 2E ).', 'This means much for virus infection as it determines how the viruses may get access to their target cells and enter.', 'For the polarized cells, virus could only successfully infect cells from the luminal side, where ACE2 is expressed on apical surface but not the basal-lateral surfaces.', 'While for the non-polarized stromal cells, virus may readily come to see them from the blood stream.', 'Second, the co-expression of infection co-factors determines the efficiency of successful infection.', 'As for SARS-CoV-2, TMPRSS2 and Furin were demonstrated to be important proteases that cleave the S protein to promote host entry [13, 14, 16] .', 'Threrefore, their co-expression with ACE2, the cellular receptor for SARS-CoV-2, may dictate the vulnerability of the target tissues.', 'Actually, we found that some ACE2-high cells, such as stromal cells in testis and ovary, express TMPRSS2 at quite low levels ( Figure 2F-G) , suggesting that they may not be SARS-CoV-2 targets as susceptible as those co-expressing both ACE2 and TMPRSS2/Furin proteases, such as heart though cardiomyocytes express relatively lower level of ACE2.', \"It's conceivable that cells highly co-expressing ACE2, TMPRSS2 and Furin proteases, such as lung macrophages and stromal cells in adrenal gland, would be readily vulnerable to SARS-CoV-2 attack in the presence of viruses.\", 'Third, the feasible routes whereby viruses get access to their target cells are also accountable for clinical manifestations.', 'In theory, there are two major routes for virus transmission: 1) directly entering the luminal tracks via open entries of the body.', \"The potentially affected tissues/organs include those from the respiratory system, digestive system and urinary tract, among which the respiratory system is much easier than the rest two to be infected as it's almost a completely open system while the rest two are gated by multiple ways.\", 'This may explain the prominent symptoms in respiratory system but not in the digestive and urinary systems despite high level of co-expression of ACE2, TMPRSS2 and Furin in epithelial cells lining along the tracts of the later two systems; 2) transmitting via blood stream to the entire body.', 'This may theoretically affect all the internal organs with stromal cells expressing ACE2, with exception for those polarized cells in which the ACE2 protein is only expressed in the apical surface unreachable by the viruses from viremia.', 'The target tissue cells affected by this route may include cardiomyocytes, stromal cells in adrenal gland, Leydig cells in testis, and stromal cells in ovary and thyroid gland.', 'Among them, only the former two, but not the later three, are more likely the true or susceptible targets of SARS-CoV-2 when considering the co-expression of helping proteases with ACE2.', 'It should be noted that the precondition for this route is viremia, which, however to our best knowledge, was not clearly documented in COVID-19 patients up to date.', 'Nevertheless, frequent heart injuries in COVID-19 patients [1, 48] are consistent with the presence of occasional viremia.', 'Under such circumstances, adrenal gland may be another vulnerable target of SARS-CoV-2, which, to our best knowledge, is identified for the first time in this study.', 'In summary, we propose the pscRNA profiling a feasible way for gene expression analysis at both protein and mRNA levels.', 'And through systemic analysis of 36 human tissues/organs by pscRNA profiling of ACE2, TMPRSS2 and Furin proteases, we propose a rank list of tissue cells potentially vulnerable to SARS-CoV-2 attack.', 'For initial infection, ACE2-expression cells, with the co-expression of TMPRSS2 and Furin as a plus, in respiratory track are the primary targets.', 'These cells include the known lung AT2 cells, and macrophages in author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'this study, and also the nasal epithelial cells as reported recently [19] .', 'And the likelihood for epithelial cells in digestive and urinary system as the primary target are low.', \"During the period of viremia if there was, the top internal organ targets would be cardiomyocytes, and stromal cells in adrenal gland, both of them express all three ACE2, TMPRSS2 and Furin proteases; the descent targets may be Leydig cells in testis, and stromal cells in ovary and thyroid gland, these cells are un-polarized and ACE2-positve, but don't show ideal co-expression of TMPRSS2 or Furin proteases.\"]}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['The newly identified 2019 novel coronavirus (2019-nCoV) has caused more than 11,900 laboratory-confirmed human infections, including 259 deaths, posing a serious threat to human health.', 'Currently, however, there is no specific antiviral treatment or vaccine.', 'Considering the relatively high identity of receptor-binding domain (RBD) in 2019-nCoV and SARS-CoV, it is urgent to assess the cross-reactivity of anti-SARS CoV antibodies with 2019-nCoV spike protein, which could have important implications for rapid development of vaccines and therapeutic antibodies against 2019-nCoV. Here, we report for the first time that a SARS-CoV-specific human monoclonal antibody, CR3022, could bind potently with 2019-nCoV RBD (KD of 6.3 nM).', 'The epitope of CR3022 does not overlap with the ACE2 binding site within 2019-nCoV RBD.', 'These results suggest that CR3022 may have the potential to be developed as candidate therapeutics, alone or in combination with other neutralizing antibodies, for the prevention and treatment of 2019-nCoV infections.', 'Interestingly, some of the most potent SARS-CoV-specific neutralizing antibodies (e.g. m396, CR3014) that target the ACE2 binding site of SARS-CoV failed to bind 2019-nCoV spike protein, implying that the difference in the RBD of SARS-CoV and 2019-nCoV has a critical impact for the cross-reactivity of neutralizing antibodies, and that it is still necessary to develop novel monoclonal antibodies that could bind specifically to 2019-nCoV RBD']}\n", - "{'sentences': [\"[{'text': 'Background and aims: Multiple issues in management of COVID have emerged, but confusion persists regarding rational interpretation.\", 'Aim of this brief review is to review these issues based on current literature.', 'Methods: This is a narrative review with Pubmed and Google Scholar search till 23 March 2020.', 'Search terms were, COVID-19, treatment of coronavirus, COVID 19 and following terms; chloroquine, hydroxychloroquine, ibuprofen, ACE-inhibitors or angiotensin receptor blockers, cardiovascular disease, diarrhoea, liver, testis and gastrointestinal disease.', 'Results: We discuss evidence regarding role of chloroquine and hydroxychloroquine in treatment and prophylaxis, use of inhibitors of the renin angiotensin system, safety of ibuprofen, unusual clinical features like gastrointestinal symptoms and interpretation of tests for cardiac enzymes and biomarkers.', \"Conclusions: While our conclusions on management of COVID-19 patients with co-morbidities are based on current evidence, however, data is limited and there is immediate need for fast track research.', 'cite_spans': [], 'ref_spans': [], 'section': 'Abstract'}]\"]}\n", - "{'sentences': [\"[{'text': 'The 2019 Novel Coronavirus has caused an acute shortage of personal protective equipment (PPE) globally as well as shortage in the ability to test PPE such as respirator fit testing.\", 'This limits not only the ability to fit PPE to medical practitioners, but also the ability to rapidly prototype and produce alternative sources of PPE as it is difficult to validate fit.', 'At the George Washington University, we evaluated an easily sourced method of qualitative fit testing using a nebulizer or \"atomizer\" and a sodium saccharin solution in water.', 'If aerosolized saccharin entered candidate masks due to poor fit or inadequate filtration, then a sweet taste was detected in the mouth of the user.', 'This method was tested against previously fit tested Milwaukee N95 and 3D Printed Reusable N95 Respirator as a positive control.', 'A Chinese sourced KN95, cotton cloth material, and surgical mask were tested as other masks of interest.', 'Sensitivity testing was done with no mask prior to fit test.', 'A sweet taste was detected for both the surgical mask and cotton cloth, demonstrating a lack of seal.', 'However, there was no sweet taste detected for the Milwaukee N95, 3D Printed Reusable N95 Respirator, or Chinese KN95.', 'These results demonstrate this could be a valuable methodology for rapid prototyping, evaluation, and validation of fit in a non-clinical environment for use in creation of PPE.', 'This method should be not be used without confirmation in a formal qualitative or quantitative fit test but can be used to preserve those resources until developers are confident that potential new N95 comparable respirators will pass.', 'We strongly suggest validation of masks and respirators with Occupational Safety and Health Administration (OSHA']}\n", - "{'sentences': ['Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp', 'Journal Pre-proof J o u', 'r n a l P r e -p r o o f Abstract Aims: A new human coronavirus (HCoV', 'The spread of SARS-CoV-2 has been faster than any other coronaviruses that have succeeded in crossing the animal-human barrier.', 'There is concern that this new virus will spread around the world as did the previous two HCoVs-Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS)-each of which caused approximately 800 deaths in the years 2002 and 2012, respectively.', 'Thus far, 11,268 deaths have been reported from the 258,842 confirmed infections in 168 countries.', 'Main methods: In this study, the RNA-dependent RNA polymerase (RdRp) of the newly emerged coronavirus is modeled, validated, and then targeted using different anti-polymerase drugs currently on the market that have been approved for use against various viruses.', 'Key findings: The results suggest the effectiveness of Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir as potent drugs against SARS-CoV-2 since they tightly bind to its RdRp.', 'In addition, the results suggest guanosine derivative (IDX-184), Setrobuvir, and YAK as top seeds for antiviral treatments with high potential to fight the SARS-CoV-2 strain specifically.', 'Significance: The availability of FDA-approved anti-RdRp drugs can help treat patients and reduce the danger of the mysterious new viral infection COVID-19.', 'The drugs mentioned above can tightly bind to the RdRp of the SARS-CoV-2 strain and thus may be used to treat the disease.', 'No toxicity measurements are required for these drugs since they were previously tested prior to their approval by the FDA.', 'Keywords Journal Pre-proof J o u r n a l P r e -p r o o f COVID-19; SARS-CoV-2; RdRp; molecular docking; structural bioinformatics; drug repurposing 19 outbreak (Yang, 2020).', 'Ten days later, the WHO declared COVID-19 to be a Public Health Emergency of International Concern (Public Health Emergency of International Concern', 'Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir showed promising results for use against the newly emerged strain of coronavirus.', 'Besides, the IDX-184, Setrobuvir, and YAK compounds exhibited excellent results for binding SARS-CoV-2 RdRp.', 'We suggest utilizing GTP as a seed to obtain specific inhibitors against SARS-CoV-2 RdRp using its high-quality model.', 'J o u r n a l P r e -p r o o f Acknowledgment:', 'Mrs. Kauther M Shaltoot is appreciated for her kind help and support; without her, this work was not possible.', 'Dr. Wael Elshemey is appreciated for guidance and performing the docking calculations on his computational facility.']}\n", - "{'sentences': ['To our knowledge, this report is the largest multi-center case series data of hospitalized patients from one city with COVID-19.', 'By February 10th 2020, 149 patients were recruited from 3 tertiary hospitals in Wenzhou, which is the city with the most confirmed cases of COVID-19 outside Hubei province in China.', 'The main findings for this cohort is that patients had milder infection, especially relative to published data from Wuhan.', '2 , 4 , 6 , 9 In our study, the signs, symptoms and laboratory test characteristics of COVID-19 were generally consistent with these previous publications.', 'But none of our patients was sent to the ICU or had shock, while only two had used non-invasive mechanical ventilation.', 'In contrast, the rate of ICU, shock and mechanical ventilation of studies from Wuhan is much higher, being 23-31.7%, 4-16.7% and 17-46.3%, respectively.', '2 , 4 , 6 , 9 The announced mortality (2.6% vs 0%) and rate of severe cases (15.2% vs 5.2%) of Hubei vs. Wenzhou remains much higher showing a significant regional difference.', 'Our results appear to be similar to those 13 patients from Beijing 8 where all of them recovered.', 'The potential explanation of this difference is the lack of medical care resources in Hubei during the outbreak.', 'Hospitals in Wuhan tend to hospitalize severe patients, resulting in the high rate of severe cases and mortality in the publications.', \"According to the statistical paper by Zhou et al., the most conservative estimate of 54,0 0 0 infections in Wuhan, and the current 80 0 0 plus beds available in the local hospitals don't have enough space for patients with milder infections.\", 'Therefore, we presume in a region such as Wenzhou, where there are enough medical facilities and not so many patients that they can provide early medical care to all affected patients, therefore, making it appear that the prognosis of COVID-19 is improved.', 'Another concern from the point of view of etiology, for a pandemic disease, in general, pathogens tend to reduce their virulence in order to maximize their between-host transmission, 9 and hosts have been selected to reduce the harm caused by their pathogen, [10] [11] [12] otherwise the lack of adaptation in novel hostpathogen associations may suspend the transmission seen in some emerging diseases.', '18 Albeit, no significant difference of demographic, clinical characteristics, laboratory test or imaging manifestations has been found between patients with or without Hubei travel or resident history (all p > 0.05), although the severity of our cohort is less than that of Wuhan.', 'Further comparison studies could be carried out between patients with a long-term time gap of disease onset in the same geographic location.', 'Our study provided a meticulous evaluation of pulmonary infiltration of COVID-19 on CT.', 'The imaging pattern of multifocal peripheral GGO, mixed GGO or consolidation with predominance in the lower lung (S6,10), with more extensive mixed opacity than GGO and consolidation is highly suspicious of 2019-nCoV infection when considering an interval between symptom onset and CT examination of 7.61 (7) days.', 'The description of imaging features has been limited in the clinical literature.', 'Our findings are compatible with other small sample size (51 and 21 cases) radiological publications.', '19 , 20 Since the form of lesion could be oval sometimes instead of patchy, physicians and radiologists should keep in mind the diversity of imaging presentations of COVID-19.', 'Human coronaviruses are considered as important pathogens that cause respiratory infection.', 'There were two other previous coronavirus outbreaks, including (severe acute respiratory syndrome coronavirus) SARS-CoV and Middle East respiratory syndrome (MERS)-CoV. All these three coronavirus infections have similar common radiographic manifestations at presentation, including unilateral or bilateral GGO or consolidation, while COVID-19 shows more extensive GGO than consolidation, which is consistent with the clinical scenario.', '[21] [22] [23] [24] [25] [26] All reported patients in Wuhan showed pulmonary infiltration in chest computed tomography (CT).', '2 , 4 , 6 However, Guan et al. 9 reported 230 out of 1099 (20.1%) cases and Chuang et al. 20 reported 3 out of 21 (14.3%) having normal CT scans for patients diagnosed with symptoms plus RT-PCR positive findings.', 'In our study, 17 out of 149 (11.4%) of our patients had normal chest CT on admission and 12 remained negative 10 days later.', 'This finding suggests that a normal chest CT', 'As far as treating patients is concerned, antiviral treatment has been used for COVID-19.', '2 , 4 , 6 , 9 Nevertheless, until now, no specific treatment has been recommended except for supportive care.', 'He underwent a chest CT examination on January 24th, which showed subtle peripheral ground glass opacity in the middle lobe, and right inferior lobe.', 'He was hospitalized on the same day.', 'The RT-PCR test was done and was found to be positive.', 'The CT images of January 27th and February 2nd showed a significant increase of lesion number and density, especially in the both lower lobes.', 'Two RT-PCR tests were performed on February 4th and 7th and both results were negative.', 'The CT images of February 7th showed a decrease in density of the pulmonary lesions.', 'On the CT examination of February 15th, the lesions were absorbed and the patient was discharged.', 'During the hospitalization, the patient had arbidol as antiviral treatment and nasal spray of interferon, no oxygen therapy was performed since the oxygen saturation of the patient remained normal.', 'The patient had no fever during the entire disease course.', 'Randomized controlled trial are being rapidly initiated to assess the efficacy and safety of antiviral drugs.', 'This study has several limitations.', 'First, the incubation period, which is the time between the infection and symptom onset, was not analyzed in our study, since the time of infection cannot be determined for the patients with resident history in Hubei.', 'Second, it is reported that some patients with positive chest CT findings may have negative RT-PCR results.', 'In that case, it is suggested that the RT-PCR tests be repeated especially for the patients with high clinical suspicion of COVID-19.', 'Hence, only the positive cases confirmed by the CDC were included in our study.', 'The pre-transfer data was not available.', 'Third, a part of our patients still remain in the hospital, so technically the final clinic outcome is not complete.', 'In conclusion, most patients from Wenzhou city, Zhejiang province presented mild infection in our study.', 'The imaging pattern of multifocal peripheral GGO, mixed GGO or consolidation with predominance in the lower lung, more extensive mixed opacity than GGO and consolidation is highly suspicious of COVID-19 infection during the outbreak in the first week of disease onset.', 'Some patients with COVID-19 can present with normal chest findings, suggesting that a normal chest CT scan cannot exclude the diagnosis of COVID-19 ( Fig. 1 ) .']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes:', 'A systematic search and a narrative review with a special reference to India and other developing countries', 'The antiviral activity of chloroquine and HCQ have been identified in the in vitro studies and the growth of many different viruses have been inhibited in the cell culture line by both the agents, including the SARS coronavirus.', 'Mice studies have also demonstrated activity of these agents against human coronavirus OC43, enterovirus EV-A71, Zika virus and influenza A H5N1.', 'Moreover, these drugs are of low cost, reasonably safe (see below), and widely available in countries where malaria is endemic.', 'However, no benefit of chloroquine was seen in the prevention of influenza and dengue infection in a randomized, double-blind, placebocontrolled, clinical trial [29, 30] .', 'Similarly, chloroquine was active in ex vivo studies but not in the in vivo studies against ebolavirus, nipah and influenza viruses [31e33].', 'Data of chloroquine against chikungunya virus is even more intriguing.', 'While chloroquine had satisfactory antiviral activity against chikungunya in vitro, animal studies showed increase in virus replication, aggravation of fever and incomplete viral clearance [34] .', 'Human trials of chloroquine showed no improvement in chikungunya acute illness and rather an increase in chronic arthralgia was observed during post-illness period, compared to the controls [35] .', 'The role of chloroquine against Human Immunodeficiency Virus was inconclusive [36] .', 'The only viral disease where chloroquine was modestly effective so far before COVID-19 era was chronic hepatitis C suggesting an increased virological response to pegylated interferon plus ribavirin [37] .', 'Therefore, the results of chloroquine and HCQ so far done against COVID-19, more promising than previous trial in other viral diseases.', 'Although evidence of chloroquine and HCQ is limited (based on the experimental data and only two small human trials), considering the potentially favorable benefit-risk balance of chloroquine and HCQ in absence of any other valid treatment option, we believe that such treatment could be useful in the current context of pandemic COVID-19 outbreak.', 'We have summarized current consideration and proposed line of management in Table 3 .', 'The low cost of chloroquine and HCQ could also be an effective strategy to counter COVID-19 (especially in patients with diabetes and other co-morbidities in whom mortality is high) in resource constrained and COVID-19 overburdened heath care systems in middle-and low-income counties including India.']}\n", - "{'sentences': ['In this study, the full length genomes of two SARS-CoV-2 strains (EPI_ISL_412973 and EPI_ISL_412974) isolated in Italy, one from an Italian patient, the other from a Chinese tourist visiting Rome, are completely sequenced and analysed, after virus cultivation.', 'Compared to the viral genome sequence of the COVID-19 patient in Wuhan, the sequence from the Chinese tourist had two nt differences, while that of the Italian patient had four.', 'Phylogenetic analysis consistently placed the Italian patient’s strain in a distinct cluster from the tourist’s strain.', 'The strain of the Italian patient grouped with other viral strains identified in Germany and Mexico, while the strain from the Chinese tourist, related with the Wuhan virus strain, clustered with different European strains and a strain from Australia.', 'Other sequences from strains collected in Europe, which were included in the phylogenetic analysis, ended up in separate clusters from the ones respectively containing the sequences of the two patients reported here.', 'The results are consistent with several introductions of SARS-CoV-2 in Europe and/or further circulation of the single strain originating in Wuhan with concurrent evolution and accumulation of mutations.', 'The mutations found in the virus identified in Lombardy, compared with the reference Wuhan strain, and the identification of amino acids changes, should be further investigated to understand whether they may affect virus characteristics.', 'Some limitations need be mentioned: first, the lack of epidemiological information available with most sequences deposited in the database; second, the number of genomes available at the time of the analysis and consequently their selection.', 'Nevertheless, these data may be useful to understand the dynamics of the local transmission of SARS-CoV-2 in Europe.']}\n", - "{'sentences': ['Although the lethality of COVID-19 is lower than SARS-CoV (approximately 10%) and MERS-CoV (approximately 34%), COVID-19 rapidly spreads, resulting in a worldwide pandemic 14 .', 'The scope and development of the pandemic are much more severe than SARS and MERS.', 'Compared with the viral shedding at 6-12 days after symptom onset of SARS, the COVID-19 viral shedding is variable and even longer 15 .', 'Moreover, the nucleic-acids of SARS-CoV-2 have been continuously reported to still be detectable in patients who had been discharged after clinical recovery; however, this was not the case for the SARS and MERS nucleic-acids.', 'Therefore, a retrospective, single-center observational study was performed to provide the clinical evidence to determine the virologic characteristics of SARS-CoV-2.', 'It was found that clinical recovery of patients typically occurred with viral clearing in patients with good recovery.', 'However, it was also found that viral shedding could persist for an interval of few days, despite clinical improvements.', 'Although Zhou et al. reported out that the median duration of viral shedding was 20.0 days (IQR, 17-24 days) in survivors of COVID-19 16 , the duration of viral shedding was found to be greatly extended in this present study, with a median duration of 31 days after symptom onset (IQR, 27-34 days).', 'This difference might be due to specimen collection, disease severity, immunological response, corticosteroid usage, antiviral treatments, and the duration of the observational window in these various populations.', 'A 37-day observational study was conducted, and patient samples were consecutively collected from both the upper respiratory tract and the gastrointestinal tract to improve the detection of SARS-CoV-2 during the course of the disease.', 'This clinical data thus provides convincing evidence of the dynamic viral shedding picture for severely All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.04.03.20051763 doi: medRxiv preprint infected patients.', 'In addition, it was found that the interval of viral shedding in patients with poor recovery was markedly prolonged.', 'Importantly, both the IgM and IgG of SARS-CoV-2 in the patients with poor recovery remained positive during the late stage of the disease.', 'This indicated that these patients might have active viral replication in the upper airway, and that persistent viral shedding might be directly linked to the poor recovery of patients with COVID-19.', 'Supporting this notion, it was found that the SARS-CoV-2 RNA could persist until death in non-survivors 17 .', 'Based on the delayed interval of viral shedding pattern and the serologic features of SARS-CoV-2, it is proposed that severe-condition patients with COVID-19 may need at least three negative PCR results with an interval of a few days.', 'In addition, dynamic detection to improve the presence of IgM-negative should also be evaluated to guide discharge planning for COVID-19 patients.', 'Similar to SARS and MERS, the cytokine profile is closely associated with the severity of COVID-19.', 'Indeed, in this prognostic analysis, it was found that an active inflammatory response was more likely to be triggered in patients with poor recovery, marked by higher concentrations of CRP, ESR, ferritin, and hs-CRP, suggesting that these patients might have a pro-inflammatory factor storm.', 'Previously, Huang et al.', 'reported that the SARS-CoV-2 infection could initiate increased secretion of Thelper-2 (Th2', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.04.03.20051763 doi: medRxiv preprint regard, lung lesions could gradually resolve and viral clearance might be achieved.', 'Corticosteroids were used frequently for the treatment of severe patients to control the high amounts of cytokines.', 'However, it was found that corticosteroid therapy was closely associated with the poor recovery of severely infected patients.', 'Therefore, corticosteroids should be administrated with great caution if necessary.', 'In addition to the viral shedding, other risk factors for slower recovery in severe COVID-19 patients were also identified.', 'Consistent with previous studies 19, 20 , it was confirmed that older age, hypoproteinemia, and increased levels of LDH were associated with the poor clinical outcome of COVID-19 patients.', 'In particular, older age, hyperlipemia, hypoproteinemia, corticosteroid therapy, and increased levels of FIB and TG were associated with the poor recovery of COVID-19 patients.', 'Up-todate information regarding the risk factors associated with lung lesion resolution in severe-condition COVID-19 patients is scarce.', 'The clinical data in this study suggested that all of the patients had lung lesions on chest CT, and the consolidation pattern on chest CT was closely associated with poor recovery.', 'Intriguingly, prognostic factors, including hyperlipemia and hypoproteinemia, were also closely linked to the odds of impaired lung lesion resolution.', 'However, the association of hyperlipidemia and COVID-19 prognosis has not been reported.', 'A previous study All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.04.03.20051763 doi: medRxiv preprint reported an association of ACE2 polymorphisms with susceptibility to dyslipidemia 21 .', 'Intriguingly, more than half of the patients in the current study had dyslipidemia.', 'It is speculated that these patients might be particularly prone to SARS-CoV-2 infection, and ACE2 polymorphisms might be linked to patient recovery.', 'Thus, more studies are needed to explore this issue.', 'All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['To our best knowledge, this is the first prospective randomized trial to investigate the effect of NHC-NATCM-China guideline-based CHM in patients with severe COVID-19.', 'In this trial, the odds of a shift towards death or critically ill at 7 days after treatment was lower in the CHM plus group, at a non-significant level.', 'The result was collaborated with the universal normalization or near normalization of leukocytes and different inflammatory markers.', 'In a retrospective study with data of 1,099 patients with COVID-19, 5% of the patients were admitted to the ICU, 2% underwent invasive mechanical ventilation, and 1% died; whereas the composite of these endpoints occurred in 25% of the patients with severe disease (8) .', 'In our trial, 12% of the patients with severe COVID-19 required ICU care and 5% died within 7 days.', 'Disease severity is an important factor when considering treatment for COVID-19 and likely contributed to the differences between these two studies.', 'An All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', \"https://doi.org/10.1101/2020.03.27.20044974 doi: medRxiv preprint 8 ongoing trial of Gilead Sciences' Remdesivir utilized a category ordinal scale to define its primary outcome (NCT04257656).\", 'Although COVID-19 is caused by a virus and will heal without treatment in the majority of patients, most patients in the G-CHAMPS trial received antibiotics.', 'The percentages of antibiotic use are comparable to the previous study (80%) (8) .', 'Our study has several limitations, including an open-label design, a small sample size.', 'Additionally, this study lacks long term outcomes and the COVID-19 disease severity scale deserves further investigation.', 'Despite these substantial limitations, the G-CHAMPS trial provided an important opportunity to better understand CHM for severe COVID-19.', 'For the first time, the G-CHAMPS trial provided valuable information for the national guideline-based CHM treatment for hospitalized patients with severe COVID-19.', 'As effective antiviral treatment is still lacking for COVID-19 and SARS-CoV-2 continues to spread outside of China(9), all potentially effective treatments including CHM worth vigorous further investigation.', 'All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.27.20044974 doi: medRxiv preprint']}\n", - "{'sentences': ['The COVID-19 pandemic puts pressure on the healthcare system.', 'In a practice-changing situation such as this, there is a need for guidance at a time of threatening and ever-changing developments.', 'Every article that covers aspects of the management of patients in times of COVID-19 can only give a snapshot of the situation and might be outdated within a short time.', 'Definitely, there is a need for continuous adaptation of recommendations and guidelines.', 'Nevertheless, the present review is intended to collect and to discuss aspects of the current status of approaching the management of inpatients and outpatients in oral and maxillofacial surgery during the COVID-19 pandemic.', 'In oral and maxillofacial surgery elective procedures, urgent procedures and emergency procedures are performed.', 'In order to provide adequate healthcare resources for the treatment of critically ill COVID-19 patients, it makes sense not to perform elective procedures for a well-defined time interval that must be reevaluated on a regular basis.', 'Sometimes, there is overlap between different specialties as far as treatment of patients is concerned.', 'Obviously, this aspect is present between oral and maxillofacial surgery and ENT surgery and general dentistry.', 'In a situation in which saving healthcare resources is the priority, close collaboration between oral and maxillofacial surgery and otorhinolaryngology, for example, in tumor boards, should be standard.', 'There should be a clear agreement between oral and maxillofacial surgery and general dentistry regarding who is responsible for the variety of interventions that can be covered by both specialties in principle.', 'In times of limited resources, oral and maxillofacial surgery must focus on treatment of malignancies, traumatology, deep head and neck infection, severe hemorrhage, or severe temporomandibular joint pathologies that can be approached only by surgery.', 'General dentistry must take care of removal of teeth and related complications such as bleeding, treatment of localized abscesses in the oral cavity, treatment of pulpitis, repair of oro-antral fistulae, or craniomandibular disorders that cannot be approached by surgery.', 'The distribution of responsibilities for different diseases is independent of the SARS-CoV-2 infection status of the patient.', 'However, it is clear that the treatment of the infected patient needs an adequate infrastructure.', 'Providing this infrastructure is a political issue to a certain extent.', 'An approach to reduce the infection rate with SARS-CoV-2 is social distancing.', 'Even in healthcare, this principle should be adopted wherever it is adequate.', 'At a time in which there is a continuous increase and change in knowledge, guidelines, and standard operating procedures, etc., fast and ubiquitous dissemination of knowledge and new information on problems and solutions are important to keep every stakeholder up-to-date.', 'Healthcare workers have to spend a certain percentage of their working time on continuing education and transfer of their own knowledge within their institution and in between institutions.', 'In order not to neglect the aspect of social distancing at the same time, it is important to foster concepts of technology-enhanced learning, which also includes e-learning.', 'This approach has been developed to allow the reduction of face-to-face scenarios to a minimum while the intensity of the learning experience is kept at a high level (Nkenke et al., 2012a,b) .', 'In the field of e-learning, webinars are rising in relevance significantly.', 'They allow dissemination of new information in an interactive way, even at short notice, to a large audience.', 'Webinars also have been proved to be well accepted in medical education Wagner et al., 2019) .', 'This technology will be most important during the peak of the pandemic to keep everybody up-to-date without taking risks for infection as a consequence of unnecessary institutional meetings and conferences, for example, would pose (Merchant and Lurie, 2020) .', 'When treating patients during the SARS-CoV-2 pandemic, a major issue is disease transmission from the patient to the medical staff.', 'Patients with symptomatic COVID-19 should be treated in the field of oral and maxillofacial surgery only when the indication is urgent or an emergency.', 'Symptomatic patients are a main source of viral transmission and therefore must be treated in an adequate infrastructure with personal protective equipment.', 'Additionally, asymptomatic patients and patients undergoing the incubation period can be carriers of SARS-CoV-2 and can be responsible for infection transmission (Chan et al., 2020a) .', 'It is even debated whether patients in the recovery phase are potential sources of virus transmission (Rothe et al., 2020) .', 'As with every other infectious disease, the approach to the situation must be that the patient must be considered infective as long as the opposite is not proved.', 'Obviously, there is a need for sensitive, reliable, and rapid testing of patients who enter the private practice or the hospital for an urgent or emergency treatment.', 'The potential patients should be advised to first opt for a consultation on the telephone before they come for a face-to-face consultation.', 'A relevant number of issues can be clarified by telephone, helping to avoid face-to-face contact.', 'Based on current clinical evidence, it seems that transmission of SARS-CoV-2 takes place by respiratory droplets.', 'In addition, fecaleoral routes are discussed similarly to the former SARS epidemic (Drosten et al., 2003) .', 'Although COVID-19 does not include eye symptoms, it has been shown that the transmission of SARS-CoV-2 is not limited to respiratory and fecaleoral routes, but that eye exposure may provide an additional route for the virus to enter the body .', 'The transmission routes seem to include a direct one (cough, sneeze, and droplet inhalation) as well as a contact transmission (oral, nasal, and eye mucous membranes) (Lu et al., 2020) .', 'It also has been stated that SARS-CoV-2 may be airborne through aerosols produced during various procedures (Wax and Christian, 2020) .', 'In the context of transmission, it should be mentioned that an otorhinolaryngologist was the first doctor to die from COVID-19.', 'Therefore, it must be stressed that, especially, specialties such as otorhinolaryngology, general dentistry, and oral and maxillofacial surgery have to have adequate infrastructures and personal protection equipment in their inpatient and outpatient settings.', 'The aim is to protect patients as well as doctors from unnecessary infection while seeking or providing healthcare during the pandemic (Chan et al., 2020b ).', 'An early report on hospitalized patients revealed that hospital-acquired transmission accounted for 41.3% of these patients (Wang et al., 2020) .', 'Definitely, a hospital environment with inadequate viral transmission protection can be a relevant route for the spread of COVID-19.', 'Therefore, each and every measure should be taken to decrease the risk of disease transmission.', 'These measures can even include adapting the composition of mouth rinses.', 'SARS-CoV-2 seems to be sensitive to oxidation.', 'As a consequence, it has been recommended that 1% hydrogen peroxide or 0.2% povidone iodine should be used in addition to the more commonly used mouth rinses (Peng et al., 2020) .', 'Especially, aerosol-generating procedures are said to be responsible for a certain percentage of viral transmission.', 'In these situations, FFP3/N99 respirators, gown, cap, eye protection, and gloves should be considered mandatory.', 'So far there is only anecdotal evidence that power air-purifying respirators (PAPR) are needed to safely avoid infection transmission when aerosolgenerating surgery is performed in infected patients in the field of oral and maxillofacial surgery.', 'If the necessity of adoption of PAPR', 'The inpatient and outpatient infrastructure must be adjusted in such a way that separate gown-up and gown-down spaces are available to prevent cross-contamination in outpatient and inpatient units.', 'All patients visiting clinical departments must have their body temperatures checked.', 'Nevertheless, infected patients are not necessarily febrile despite being COVID-19 carriers.', 'Therefore, it is also important to assess recent travel histories and contacts with infected patients.', 'Before admission to wards or before surgery in the field of oral and maxillofacial surgery, testing of the patients for the virus should be performed.', 'Cancer patients are at special risk for SARS-CoV-2 infection compared with the community that does not have this kind of disease.', 'The problem is that patients with cancer are often recalled to inpatient and outpatient units for treatment and monitoring.', 'Therefore, they are at increased risk for contracting COVID-19.', 'Moreover, cancer treatments such as chemotherapy and radiotherapy are immunosuppressive (Kamboj and Sepkowitz, 2009; Yu et al., 2020) .', 'The latter corresponds with the fact that less than half of infected cancer patients are undergoing active treatments for cancer (Yu et al., 2020) .', 'Therefore, during the COVID-19 pandemic, the frequency of visits of cancer patients to inpatient and outpatient units must be reduced, weighing the risk of recurrence against the risk of infection.', 'For cancer patients who require treatment, proper isolation protocols must be in place to mitigate the risk of SARS-CoV-2 infection (Yu et al., 2020) .', 'Depending on the number of infected patients, there might come a time of risk of a scarcity of medical staff, ventilators, negative pressure rooms, and personal protective equipment.', 'Therefore, on one hand, it is most important to avoid infections; on the other hand, generally accepted recommendations must be developed that provide guidance in prioritizing treatments and triaging patients in oral and maxillofacial surgery (Lamontagne and Angus, 2020) .', 'The influence of the COVID-19 pandemic on the delivery of healthcare to the public is severe.', 'Redistribution of manpower and resources are required to meet current and future needs during the COVID-19 crisis.', 'A reduction of elective surgery is chosen to free manpower to allow room for specialties that treat COVID-19 itself and to maximize the number of available hospital beds in order to meet the prospective number of patients, including those who will become critically ill.', 'Nevertheless, urgent oncologic and emergency surgery still have to be performed.', 'The practice of triage helps to reduce unnecessary exposure to and contamination with the virus in inpatient and outpatient environments.', 'However, triage also leads to delayed patient treatment as far as elective procedures are concerned.', 'The affected patients must receive adequate treatment after the pandemic has settled.', 'Therefore, the change in orientation of oral and maxillofacial surgery from providing the full scope of the specialty with a high percentage of elective surgery to reducing the service to urgent and emergency surgery causes inconvenience for patients as well as medical staff during the COVID-19 crisis.', 'Additionally, administrative efforts such as rescheduling of patients occupy a relevant additional amount of time.', 'While the peak of the pandemic is still to come, already now strategies must be developed for a future situation in which the number of infections reduces but SARS-CoV-2 has become endemic and no effective medication of vaccination is available.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['In the present investigation, we used two independent well-characterized antibodies for immunohistochemical analysis of ACE2.', 'Based on stringent validation criteria and comparison of the protein expression profiles with multiple transcriptomics datasets, reliable expression could only be confirmed in microvilli of the intestinal tract and renal proximal tubules, in gallbladder epithelium, testicular Sertoli cells and Leydig cells, a subset of glandular cells in seminal vesicle and in cardiomyocytes, with no detectable expression in lung or respiratory epithelia.', 'No reliable data confirms protein level expression of ACE2 in AT2 cells, previously shown to harbor ACE2.', 'Limited expression of ACE2 in AT2 cells suggested in recent datasets based on scRNA-seq, however, this finding is only observed in some of the individuals, often at a low level and only in a small fraction of the cells.', 'All studied datasets confirm a consistent high expression in the intestinal tract, gallbladder and kidney.', 'Further studies are needed to explore the potential involvement of ACE2 in the manifestation of symptoms related to these organs as a result of COVID-19 disease.', 'In addition to respiratory symptoms, the closely related SARS-CoV that caused the SARS outbreak was shown to also cause diarrhea, impaired liver function and elevation of non-cardiac creatine kinase, suggesting tropism of the virus to other organs well in line with the tissues showing the highest expression levels of ACE2.', 'Interestingly, in a recent study on pediatric COVID-19 individuals, eight out of 10 cases showed rectal swabs positive for SARS-CoV-2, suggesting that the gastrointestinal tract may shed virus and that fecal-oral transmission may be a possible route for infection 27 .', \"It should also be noted that the prerequisites of the interplay between SARS-CoV-2 attachment pattern to human cell surface receptors and COVID-19 disease progression are multifactorial, including not only the binding of the virus to the target cells, but also other factors such as the host's immune system and the total virus load.\", 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.31.016048 doi: bioRxiv preprint', 'In summary, based on multiple datasets on the mRNA and protein level, using both single cell methods and larger tissue extracts, we here show that ACE2 expression in human tissues is mainly localized to microvilli of intestine and renal proximal tubules, gallbladder epithelium, testicular Sertoli cells and Leydig cells, glandular cells of seminal vesicle and cardiomyocytes.', 'Several additional locations suggested by previous studies, including expression in AT2 cells, could not be confirmed.', 'This raises questions regarding the role of ACE2 for infection of human lungs, and highlights the need to further explore the route of transmission during SARS-CoV-2 infection to understand the biology of the disease and to aid in the development of effective treatments to the viral infection.']}\n", - "{'sentences': ['COVID-19 (coronavirus disease-19) involves humans as well as animals and may cause serious damage to the respiratory tract including the lung.', 'This pathogenic virus has been identified in swabs performed on the throat and nose of patients who suffer from or are suspected of the disease.', 'When COVID-19 infect the upper and lower respiratory tract it can cause mild or highly acute respiratory syndrome with consequent release of pro-inflammatory cytokines, including interleukin (IL)-1b and IL-6.', 'The binding of COVID-19 to the Toll Like Receptor (TLR) causes the release of pro-IL-1b which is cleaved by caspase-1, followed by inflammasome activation and production of active mature IL-1b which is a mediator of lung inflammation, fever and fibrosis.', 'Suppression of pro-inflammatory IL-1 family members and IL-6 have been shown to have a therapeutic effect in many inflammatory diseases, including viral infections.', 'Cytokine IL-37 has the ability to suppress innate and acquired immune response and also has the capacity to inhibit inflammation by acting on IL-18Ra receptor.', 'IL-37 performs its immunosuppressive activity by acting on mTOR and increasing the adenosine monophosphate (AMP']}\n", - "{'sentences': ['The primary objective of this study was to decipher the role of the fibrinolytic niche in the re-alveolarization mediated by progenitor AT2 cells and underlying mechanisms in healthy and injured lungs.', 'We employed influenza-infected mice, Plau -/and Serpine1 Tg mouse strains, primary human AT2 cells from the human lungs of brain-dead patients with ARDS, and 3D organoids and polarized monolayers of AT2 cells to trace the cell fate in vivo and in vitro.', 'The results demonstrate that the impaired fibrinolytic niche in influenza-infected lungs and genetically engineered mice modeling impaired fibrinolytic niche results in a significant decline in the proliferative AT2 and differentiated AT1 cells.', 'These results thus demonstrate the novel finding that that the fibrinolytic niche may be critical for realveologenesis.', 'Previous studies suggest that Plau -/and PAI-1 Tg mice are more susceptible to lung fibrosis post bleomycin injury36 , 37.', 'Clinically, impaired fibrinolytic niche, including elevated PAI-1 contents and suppressed fibrinolytic activity, are prognostic markers for ARDS patients38 , 39.', 'Deficiency of plasminogen activators and plasminogen leads to dysfunctional repair of injured tissues (i.e., skin and muscle)40 , 41.', 'In contrast, regeneration author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.24.006270 doi: bioRxiv preprint of injured muscle is improved by knocking out the Serpine1 gene142.', 'The Plau gene regulates the proliferation of various cells, including renal epithelial cells43 , 44, umbilical vein endothelial cells45, vascular endothelial cells46, and keratinocytes47 , 48.', 'Contrary to this, Serpine1 is a negative regulator of cell proliferation through the phosphatidylinositol3-kinase/Akt pathway in endothelial cells49 , 50.', 'Our study uncovers a new signaling pathway of the fibrinolytic niche in the AT2 cell-mediated re-alveolarization.', 'The uPA/A6/CD44 /ENaC cascade is involved in the regulation of self-renewal and differentiation of mouse and human AT2 cells, particularly the CD44 + subpopulation.', 'This conclusion was further substantiated in Serpine1 Tg mice that have a disrupted fibrinolytic niche similar to the Plau -/mice, and both mouse lines are reasonable pre-clinical models of ARDS.', 'The proteolytic link between the fibrinolytic niche and ENaC proteins has been provided by other groups and us in vivo and in vitro27 , 51-53.', 'The differences between each component of the fibrinolytic niche are described previously.', 'For example, uPA but not tPA cleaves human gENaC subunits51.', 'PAI-1 or antiplasmin alone does not affect ENaC activity.', 'The slight diversity between the Plau -/and Serpine1 Tg models in this study could be due to their differential regulation of ENaC and other down-stream molecules.', 'CD44 is a crucial mediator for the regulation of re-alveologenesis by AT2 cells.', 'We previously demonstrated that CD44 receptors govern cell survival and the progression of lung fibrosis via the Toll-like receptors and hyaluronan54.', 'The connective domain of uPA has an eight L-amino acid sequence (Ac-KPSSPPEE-NH2), known as A6 peptide55.', 'Binding of the A6 peptide with the link domain of CD44 receptors initiates the downstream signaling56.', 'CD44 -/mice demonstrate an inflammatory phenotype characterized by increased inflammatory cell recruitment and are more susceptible to LPS induced injury.', 'CD44 deficiency leads to impaired expression of negative regulators of TLR signaling in macrophages, an essential event in the prevention of LPS induced inflammatory responses57.', 'Our study demonstrates a new mechanism that the CD44 receptors at the plasma membrane of AT2 cells are a key player for AT2 cell-mediated re-alveolarization.', 'In addition to the reduction in AT2 cells in injured mouse and human lungs associated with aberrant fibrinolytic niche, both Plau -/and Serpine1 Tg AT2 cells cannot develop organoids equal to those of wt mice in vitro, mostly likely due to the author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.24.006270 doi: bioRxiv preprint lesser expression of CD44 receptors in AT2 cells as A6 peptide compensates for the loss of organoids.', 'This is supported by our previously unreported observations that CD44 + AT2 cells have an enhanced capacity for selfrenewal and differentiation to AT1 cells.', 'Of note, both Plau -/and Serpine1 Tg mice have lesser CD44 + AT2 cells so that the total yield of primary AT2 cells is significantly reduced compared with wt controls.', 'The brain ENaC proteins encoded by the Scnn1a, 1b, 1d, and 1g are involved in adult neurogenesis by the transmembrane sodium signals for the deletion of Scnn1a or functional blockade by amiloride in neural stem cells strongly impairs their proliferation and differentiation58.', 'ENaC has been functionally detected in both club cells and AT2 cells59.', 'Whether ENaC is a member of the fibrinolytic niche for lung stem cell-mediated regeneration is unknown.', 'We recently reported that overexpression of the Scnn1d, a pseudogene in mice, significantly improves the development of organoids in 3D cultures of primary mouse AT2 cells60.', 'Together with abnormal ENaC activity in Plau -/and Serpine1 Tg AT2 cells, we conclude that the ENaC signal may be an essential regulator for the fate of AT2 cells in normal and injured lungs.', 'In summary, our study uncovers a novel role of the fibrinolytic niche in alveolarization via the uPA/A6/CD44 and the uPA/ENaC signaling pathways.', 'This study provides new evidence for the possible prognostic relevance of the fibrinolytic niche for ARDS patients.', 'Targeting the abnormality of the fibrinolytic niche could be a promising pharmaceutic strategy to accelerate reparative processes of injured alveolar epithelium in clinical disorders such as ARDS.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Our molecular phyloecological study demonstrates that spike protein shows significant Darwinian selection along two ancestral branches related to SARS-CoV and 2019-nCoV, suggesting their adaptive evolution to recognizing their own cell receptors.', 'Comparative sequence and phylogenetic analyses indicate a high similarity of RBD sequences of spike protein between SARS-related CoV and COVID-19related CoV. Subsequent ancestral sequence reconstruction and convergent evolution analyses reveal an unusually high incidence of parallel and convergent amino acid substitutions between them, suggesting an extremely strong adaptive evolutionary convergence in spike protein.', 'In addition to spike protein, we also found evolutionary convergence of its partner protein, ORF3a, suggesting their possible co-evolutionary convergence.', 'Finally, considering that SARS-CoV and 2019-nCoV have posed serious concerns to public health and safety, it should be noted that many other bat SARS-like CoV strains that were evolutionarily convergent with SARS-CoV and 2019-nCoV recognized in this study may be potential novel coronaviruses to infect humans in the future.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.04.975995 doi: bioRxiv preprint', 'We used likelihood ratio tests based on the branch and branch-site models implemented in the codeml program of PAML 17 to examine the possible Darwinian selection of all 11 genes annotated in the 2019-nCoV genome (NC_045512).', 'Positively selected genes (PSGs) were found by the branch-site model ( Table 1) , independent of the initial value variation of parameters (kappa and ω).', 'Specifically, for the branches leading to 2019-nCoV and SARS-CoV, no PSGs were found, nor were PSGs found along the branches leading to their sister coronaviruses.', 'However, we detected PSGs along the ancestral branch (branch C) of 2019-nCoV and its sister taxon, RaTG13, as well as along the ancestral branch (branch K) of SARS-CoV and its sister taxa, WIV16 and Rs4231 (Table 1 , Fig. 1 ).', 'For branch C, three PSGs', 'Given the positive selection of the S gene in both branches, C and K, we further examined its positive selection signals using branch-site model along all other main branches ( Fig. 1) to test whether the positive selection uniquely occurred along the branches related to 2019-nCoV and SARS-CoV. Our results showed positive selection signals along 10 out of 45 branches examined (Fig. 1, Table S3 ).', 'This may suggest that the S gene was widely subject to Darwinian selection in different coronavirus strains, indicating that it may be crucial for the successful survival of coronaviruses.', 'Further analyses of positive selection sites showed that most positive selection sites among all 12 branches under positive selection were located within subunit 1 of S gene ( Table 1, Table S3 ), which is used for receptor binding.', 'This may suggest that there are strong selection pressures of different coronavirus strains for their own receptor binding.', 'Given the selection intensification of S gene in 2019-nCoV since its evolutionary divergence from RaTG13, we conducted comparative sequence analyses between the two.', 'We found that there were more than 20 amino acid differences between them, and most of them were located within RBD, especially RBM (Fig. S2) , suggesting a high variability of RBM.', 'Given the importance of RBM for receptor binding, we further conducted a comparative sequence analysis among all the coronavirus strains studied to examine its variability.', 'The results showed high sequence variability, with insertion and/or deletion and amino acid substitutions among the coronavirus strains studied (Fig. 2) .', 'Despite the high variability of RBM, strikingly, we found that SARS-CoV and its phylogenetic relatives-including WIV16 (KT444582), Rs4231 (KY417146), Rs7327 (KY417151), Rs9401 (KY417152), and BtRs-BetaCoV/YN2018B (MK211376), called SARS-related CoV here, shared many identical or nearly identical amino acids with their phylogenetically distant coronavirus strains, including 2019-nCoV and RaTG13, which we called COVID-19-related CoV (Fig. 2) .', 'These shared amino acids were clearly distinct from bat SARS-like CoV that were phylogenetic intermediates between them (Fig. 2) .', 'Further analyses showed that such identical amino acids shared between SARS-related CoV and COVID-19-related CoV were not restricted to RBM, but rather, they were scattered throughout the spike protein, with a total of 32 such sites, which were centered on RBD (28 sites in total, Fig. S3 ).', 'To further examine whether such similarity occurred in other proteins, we analyzed all 11 genes studied among these coronaviruses, and we found that one additional gene, ORF3a, contained eight such sites (Fig. 1) .', 'The existence of these shared amino acids between SARS-related CoV and COVID-19-related CoV may suggest their high sequence similarity.', 'In support of this, we reconstructed maximum likelihood and neighbor-joining phylogenies using full-length RBD protein sequences, and both showed that SARS-related CoV and COVID-19-related CoV were grouped in the same clade, with relatively high support, which is consistent with two previous studies 6,7 , at the same time, their phylogenetic intermediates were clustered in distinct clades (Fig. 3, Fig. S4 ).', 'The phylogenetic uniting of SARS-related CoV and COVID-19-related CoV provide evidence of their high similarity of RBD protein sequences.', 'Given their genome-level phylogenetic disparity, the high similarity of RBD protein sequences between SARS-related CoV and COVID-19-related CoV may suggest their evolutionary convergence in the spike protein.', 'To test this possibility, we used an empirical Bayes approach in PAML 17 to reconstruct ancestral .', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.04.975995 doi: bioRxiv preprint amino acid sequences along internal nodes, and our results showed there were up to 35 evolutionary convergent sites, including 3 convergent and 32 parallel amino acid substitutions that were shared by two ancestral branches leading to SARS-related CoV and COVID-19-related CoV, respectively (Fig. 1) .', 'It should be noted that the 35 evolutionary convergent sites of spike protein were apparently underestimated, since those amino acid sites with alignment gaps were not considered by the approach used.', 'Still, these 35 sites represented an unusually high incidence of evolutionary convergence sites, which have rarely been found in previous studies related to molecular convergent evolution 20-26 .', 'This suggests a strong evolutionary convergence between SARS-related CoV and COVID-19-related CoV. On completion of our data analyses, one of the most recent studies showed that the RBD of the spike protein of Pangolin-CoV is nearly identical to that of 2019-nCoV, with only one amino acid difference 27 , suggesting that Pangolin-CoV also belongs to the clade of COVID-19-related CoV. It should be noted that the RBD sequences of two other coronavirus strains, BM48-31 (GU190215) and BtKY72 (KY352407), were grouped with SARS-related CoV and COVID-19-related CoV (Fig. 3, Fig. S4 ), suggesting an evolutionary convergence among them.', 'In addition to these evolutionarily convergent coronavirus strains, intriguingly, we found the evidence of evolutionary convergence of the spike protein between the ancestral branch leading to SARS-related CoV and the ancestral branch of COVID-19-related CoV and its sister strains (CoVZC45 and CoVZXC21), which harbored 9 evolutionary convergent amino acid sites (Fig. S5) .', 'These results suggest that the spike protein may have been subjected to a successive evolutionary convergence among ancestral coronavirus strains leading to SARS-related CoV, COVID-19related CoV and CoVZC45 and CoVZXC21.', 'Previous studies show that spike protein interacts tightly with a related protein ORF3a and they likely coevolved [28] [29] [30] .', 'If their coevolution does occur, we may expect that the evolutionary convergence of the spike protein found may have led to the occurrence of the evolutionary convergence of ORF3a as well.', 'To test this, we reconstructed ancestral amino acid sequences of ORF3a along internal nodes, and our results revealed 6 parallel amino acid substitutions shared between the ancestral branch leading to SARS-related CoV and the ancestral branch of COVID-19-related CoV and its sister strains (CoVZC45 and CoVZXC21) (Fig. S5 ).', 'And we also detected a parallel amino acid substitution of ORF3a between the two ancestral branches leading to SARS-related CoV and COVID-19-related CoV (Fig. S6 ).', 'Considering that these evolutionary convergent branches of ORF3a also showed evolutionary convergence in spike protein as mentioned above (Fig. 1, Fig. S5 ), it may suggest that spike protein and its partner protein ORF3a may have been subjected to a co-evolutionary convergence.', 'Evolutionary convergence may occur by chance or by Darwinian selection.', 'Our results showed that the evolutionary convergent sites found in this study were mainly restricted to two genes (S and ORF3a, Fig. 1 ), and in particular, they were centered within the RBD of the S gene.', 'This biased distribution of evolutionary convergent sites is difficult to explain according to chance; rather, Darwinian selection would be favored as a plausible explanation.', 'In support of this, we used CONVERG2 31 to evaluate the probability of the occurrence of our observed convergent sites of spike protein between the two ancestral branches leading to SARS-related CoV and COVID-19-related CoV, and the results showed high statistical significance (p = 0.000000), regardless of whether the JTT model or Poisson model was used.', 'This result apparently rejects chance or neutral evolution as a possible explanation; rather, it indicates a .', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.04.975995 doi: bioRxiv preprint predominately strong Darwinian selection.', 'Moreover, we observed an apparently accelerated evolution of RBD of SARS-related CoV and COVID-19-related CoV related to their phylogenetic intermediates (Fig. 3) , and we detected a significant Darwinian selection of the S gene along two branches (branches C and K) of SARS-related CoV and COVID-19-related CoV (Fig. 1 , Table 1 ).', 'These lines of evidence may strongly support the evolutionary convergence found in this study as a result of adaptive evolution.', 'Regarding the possible adaptive evolutionary convergence, previously proposed causes, such as gene duplication and horizontal gene transfer 21,32,33 , are less likely because only single-copy S genes were found in all 35 genomes examined and evolutionary convergent sites presented an apparently biased distribution pattern.', 'Parallel and/convergent evolution, which occur through point mutation, could contribute to our observed evolutionary convergence, but it could not account for the unusually high incidence of convergent sites observed in this study, representing a rare finding in previous studies 20- 26 .', 'Recent studies have shown a relatively high likelihood of occurrence of homologous recombination in spike protein 7,34,35 , and especially, it is considered that the RBD of 2019-nCov may be derived from a recombination event between that of human SARS-CoV and another (unsampled) SARS-like CoV 35 .', 'If this is the case, the homologous recombination, if any, may have occurred between the ancestors (branches C and K) of SARS-related CoV and COVID-19-related CoV, accounting for their unusually high incidence of convergent sites observed in this study.', 'Given the strong evolutionary convergence of RBD of spike protein between the two clades, COVID-19related CoV and SARS-related CoV, the coronaviruses of the two clades may have more likely adapted to similar or the same receptor.', 'To date, 2019-nCoV and SARS-CoV have been known to be capable of using the ACE2 receptor in human host 5,6,9,10 , but the receptors of their phylogenetic relatives from the two clades, COVID-19-related CoV and SARS-related CoV, are less clear 4,5,36,37 .', 'Regarding the bat SARSlike CoV, Rs4231 and Rs7327 are known to be able to use human ACE2 receptor 37 , while WIV16 is capable of using the ACE2 receptor from humans, civets and Chinese horseshoe bats (Rhinolophus sinicus) 4 .', 'The receptors of Rs9401, BtRs-BetaCoV/YN2018B, and BatCoV RaTG13 remain to be explored.', 'Further studies on the receptors of these bat SARS-like CoVs in their natural reservoirs are badly needed to determine whether ACE2 or other candidates, if any, represent their shared cell receptor, leading to their strong evolutionary convergence of spike protein.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Cardiovascular risks of hydroxychloroquine in treatment and prophylaxis of COVID-19 patients:', 'A scientific statement from the Indian Heart Rhythm Society', 'Hydroxychloroquine is being used globally for treatment and prophylaxis of COVID-19.', 'Various countries have issued recommendations on its use based on in-vitro, or small clinical studies.', 'In absence of randomized trial data, these recommendations reflect the extraordinary situation of a rapidly evolving pandemic of a highly contagious disease.', 'The guidelines are likely to change as more data from randomized clinical trials is available.', 'The decision to use HCQ for COVID-19 should take into account the occasional possibility of cardiac arrhythmia.', 'Indian Heart Rhythm Society recommends the use of HCQ as per the ICMR task force recommendations and strongly discourages its use for the general public without medical supervision and prescription.', 'Even though a 12-lead ECG is a widely available tool, obtaining ECG of every suspected or confirmed patient of COVID-19 may be impractical and strain healthcare resources in a pandemic situation.', 'Hence, using smartphone-based pocket ECG devices can potentially save healthcare resources in the current situation.', 'The measures of restrained advocacy for potentially beneficial effects of HCQ and advice against self-medication can help prevent adverse events related to this drug.']}\n", - "{'sentences': ['Objective To explore the value of chest CT features and clinical indexes in the differential diagnosis between suspected COVID-19 with two or more negative nucleic acid tests and confirmed COVID-19.', 'Methods The clinical data and chest CT images of 105 cases withconfirmedCOVID-19 (55 males and 50 females, aged from 2 month to 88 years) and 97 cases with suspected COVID-19(59 males and 38 females, aged from 1 month to 93 years) were analyzed retrospectively in Shiyan Taihe Hospital from January 21 to February 10, 2020.', '2 test and two independent sample t test were used to analyze the clinical data and CT signs of the two cases, with P<0.05 for the difference statistically significant.', 'Results Compared with the suspected patients, the average age of diagnosis of covid-19 was higher (t = 2.460, P = 0.01).', 'The main pathological changes were pure ground glass (68 cases) and mixed ground glass density (53 cases) ( χ 2 = 50.016, P < 0.01).', 'Interstitial thickening (83 cases) ( χ 2 = 55.395, P < 0.01), vascular thickening (73 cases) ( χ 2 = 57.527, P < 0.01), air bronchoscopic sign or bronchiectasis Zhang (67 cases) ( χ 2 = 17.899, P < 0.01), cord focus (54 cases) ( χ 2 = 5.500, P = 0.02), easily distributed under the pleura and the long axis of the lesion was parallel to the pleura (89 cases) ( χ 2 = 23.597, P < 0.01), most of them had no pleural effusion ( χ 2 = 7.017, P < 0.01); both lesions were mainly distributed in patches (89 cases were confirmed, 87 suspected) ( χ 2 = 19.573, P < 0.01).', 'In addition, the lesions of patients with confirmed covid-19 showed progress in short term (72 / 87, 82.76%), and those with suspected covid-19 showed remission in short term (63 / 89, 70.78%).', 'The difference was statistically significant ( χ 2 = 51.114, P < 0.01).', 'There was no significant difference in gender and distribution of pulmonary lobes ( χ 2 = 1.462, P = 0.23; χ 2 = 7.381, P = 0.19).', 'The number of white blood cells ( χ 2 = 17.891, P < 0.01) and the percentage of lymphocytes ( χ 2 = 11.151, P < 0.01) of covid-19 were mostly normal or decreased, creatine kinase ( χ 2 = 9.589, P < 0.01) were mostly normal, and erythrocyte sedimentation rate was mostly normal or increased ( χ 2 = 4.240, P = 0.04).', 'Conclusions The imaging features and biochemical indexes of diagnosed COVID-19 are different from those of suspected COVID-19.', 'The comparative analysis of imaging features, clinical indexes and reexamination are helpful for the differential diagnosis of COVID-19 and suspected COVID-19.']}\n", - "{'sentences': ['Free energies of interactions were calculated for several molecular complexes involving the RBD of SARS-CoV-1 and 2 spike proteins.', 'The present theoretical results confirmed that both RBD proteins have similar binding affinity to the ACE2 as previously reported in experimental studies.', 'This is observed at both acid and neutral pH regimes which probably indicates that the medium pH it is not so relevant for the beginning of the viral cell invasion.', 'pH seems to be more important for the next steps of the viral infection and not at the first entry level.', 'This has a direct implication for the drug development since the proposal of some like chloroquine is to raise cell pH.', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.05.026377 doi: bioRxiv preprint Analyzing the interactions between these RBD proteins and the SARS-CoV-1 S RBD specific neutralizing mAbs (80R, F26G19, m396, CR3022) allowed us to reproduce the experimental results.', 'The only mAb with measured affinities for the SARS-CoV-2 S RBD protein by BLI assay was CR3020 8 which was also the one with higher affinity quantified in the present theoretical study.', 'Moreover, we could map their electrostatic epitopes and identify that all mAbs tend to share the same titratable residues, and they are like the residues involved in the interaction with ACE2.', 'However, the RBD protein responsible for COVID-19 clearly has more titratable residues interacting with ACE2 than its precursor suggesting that its binding to ACE2 might be less specific.', 'This can explain the general difficulty that mAbs can experience to completely block the SARS-CoV-2 S RBD-ACE2 interaction.', 'Charge-charge interactions were found to be a good simple descriptor for a fast screening to the designing of improved mAb for diagnostics, therapeutics and vaccines.', 'Our theoretical approach, while still being further developed, has identified three amino acids substitution that can increase the binding affinity of CR3022 to the RBD protein responsible for the present pandemic.', 'These results can contribute to guide the design of new functional and high specific mAbs providing a cost-and-time-effective computational framework towards the development of better diagnostic strategies and an effective treatment and/or vaccine for COVID-19.']}\n", - "{'sentences': ['The efficacy of convalescent plasma for the treatment of severe influenza', 'Administration of convalescent plasma may be of clinical benefit for treatment of severe acute viral respiratory infections.', 'However, no clear evidence exists to support or oppose convalescent plasma use in clinical practice.', 'We conducted a systematic review and meta-analysis to assess the evidence of randomized controlled trials (RCTs', 'Healthcare databases were searched in February 2020.', 'All records were screened against the eligibility criteria.', 'Data extraction and risk of bias assessments were undertaken.', 'The primary outcome was case-fatality rates by influenza.', 'We identified 5 RCTs of severe influenza.', 'The pooled analyses showed no evidence for a reduction in mortality (Odds Ratio (OR) 1.06; 95% confidence interval (CI', 'Convalescent plasma appears safe but may not reduce mortality in severe influenza.', 'This therapy should be studied within the context of a well-designed clinical trial for treatment of SARS-Cov-2 infection.', 'CR, Convalescent Plasma Study G. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis.', 'J Infect Dis 2015; 211: 80-90.', 'Our analyses suggested that convalescent plasma may not have a clinically relevant impact in reducing the rate of mortality in patients with influenza.', 'We also found non-significant reductions in days in ICU and hospital, and days on mechanical We included 5 high quality RCTs of convalescent plasma and H-IVIG use in severe influenza.', 'The evidence for a reduction in mortality associated with convalescent plasma was strongest for influenza A (H1N1) (17) .', 'But we should interpret this with an appropriate level of caution because of the limited sample size (n=17) and early use (onset within 5 days).', 'In addition, the pooled data of 4 trails (n=567) that All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', '20.20025593 doi: medRxiv preprint reporting death showed no benefit for reducing the mortality of severe influenza with the treatment.', 'For secondary outcomes, including days in ICU and hospital, and days on mechanical ventilation, 3 RCTs reported relevant data showed non-significant reductions between H-IVIG/immune plasma group and control group (14, 17, 19) .', 'A and B (15, 18) , decreases influenza B viral loads (15) and cytokines levels in H1N1 (17), there was no clinical benefit observed in patients receiving H-IVIG/immune plasma infusion.', 'Available high quality evidence suggested that convalescent plasma/H-IVIG was safe but unlikely to reduce mortality in patients with severe influenza.', 'Despite the current outbreak and emergency of SARS-CoV-2 affecting public health, convalescent plasma should be carefully taken into consideration before a welldesigned clinical trial was carried out.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.02.20.20025593 doi: medRxiv preprint author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.02.20.20025593 doi: medRxiv preprint', 'The primary outcome of this review were case-fatality rates by influenza, reflecting the efficacy of convalescent plasma and hyperimmune immunoglobulin therapy.', 'Secondary outcomes included antibody levels, cytokine levels, viral loads, incidence of serious adverse events, days on mechanical ventilation, ICU and hospital.']}\n", - "{'sentences': ['Treatment with convalescent plasma for critically ill patients with SARS-CoV-2 infection', 'Treatment with convalescent plasma for critically ill patients with SARS-CoV-2 infection, CHEST (2020), doi: https://doi.', 'As of March 24, 2020, novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for 379,661 infection cases with 16,428 deaths globally and the number is still increasing rapidly.', 'Herein, we presented four critically ill patients with SARS-CoV-2 infection who received supportive care and convalescent plasma.', 'Although all the four patients (including a pregnant woman) recovered from SARS-CoV-2', 'Our results indicated convalescent plasma might be a potential therapy for critically ill patients infected with SARS-CoV-2.', 'We observed no serious adverse reactions associated with the transfusion of convalescent plasma.', \"However, the relative contributions of supportive care, investigational therapies, and patient's immune-response on survival could not be determined.\", 'Whether convalescent plasma and/or supportive care provide any clinical benefit is unknown.', 'The safety and efficacy of convalescent plasma transfusion in SARS-CoV-2-infected patients should be studied within the context of a well-designed clinical trial.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['A systematic review to assess seizure risk with chloroquine therapy in persons with epilepsy', 'Background: The goal of this systematic review is to assess the published literature for seizure risk with chloroquine therapy in persons with and without epilepsy.', 'With the COVID-19 pandemic, there is a desperate need for therapy against the SARS CoV-2 virus.', 'Chloroquine is one proposed medication that has received substantial public attention.', 'However, drug labeling in the package insertion states that persons with epilepsy have the risk of chloroquine provoking seizures, and this has increased questions and anxiety in the epilepsy community.', 'Methods: PubMed (1970 to March 27, 2020) and the Embase (1970 to March 27, 2020) were searched with the terms chloroquine and seizure or epilepsy.', 'Selected studies were reviewed, and the adverse drug reaction was classified.', 'Results: Only nine out of 27 studies were deemed eligible for systematic analysis.', 'Out of the nine studies, only one was a prospective study (N=109), two were case series (N=6), and the remaining 6 were case reports.', 'The dose of chloroquine ranged between 100-500 mg/day, except in one patient, the seizure was after taking 1000 mg.', 'The strength of causality for the drug causing seizures in healthy and persons with epilepsy was mostly possible or unlikely, and none were certain.', 'The only clinical trial that evaluated seizure risk with chloroquine failed to find any significant relation.', 'Conclusion: Although the drug insertion label states an increased risk of seizure, the systematic review highlights that such a statement is not supported by any class I studies but by anecdotal case reports.', 'The only randomized clinical study revealed that seizures were not associated with an increased blood level of chloroquine or its metabolite.', 'The present systematic review should provide reassurance to busy clinicians and persons with epilepsy that chloroquine, if prescribed to treat COVID-19, lacks any substantial evidence to suggest that the medication increases the risk of seizure.']}\n", - "{'sentences': ['In this study, we presented a network-based methodology for systematic identification of putative repurposable drugs and drug combinations for potential treatment of 2019-nCoV/SARS-CoV-2.', 'Integration of drug–target networks, HCoV–host interactions, HCoV-induced transcriptome in human cell lines, and human protein–protein interactome network are essential for such identification.', 'Based on comprehensive evaluation, we prioritized 16 candidate repurposable drugs (Fig. 5) and 3 potential drug combinations (Fig. 6) for targeting 2019-nCoV/SARS-CoV-2.', 'However, although the majority of predictions have been validated by various literature data (Table 1), all network-predicted repurposable drugs and drug combinations must be validated in various 2019-nCoV/SARS-CoV-2 experimental assays64 and randomized clinical trials before being used in patients.', 'We acknowledge several limitations in the current study.', 'Although 2019-nCoV/SARS-CoV-2 shared high nucleotide sequence identity with other HCoVs (Fig. 2), our predictions are not 2019-nCoV/SARS-CoV-2 specific by lack of the known host proteins on 2019-nCoV/SARS-CoV-2.', 'We used a low binding affinity value of 10 μM as a threshold to define a physical drug–target interaction.', 'However, a stronger binding affinity threshold (e.g., 1 μM) may be a more suitable cut-off in drug discovery, although it will generate a smaller drug–target network.', 'Although sizeable efforts were made for assembling large scale, experimentally reported drug–target networks from publicly available databases, the network data may be incomplete and some drug–target interactions may be functional associations, instead of physical bindings.', 'For example, Silvestrol, a natural product from the flavagline, was found to have antagonists vs. agonists).', 'The current systems pharmacology model cannot separate therapeutic activity against Ebola75 and Coronaviruses76.', 'After adding its target, an RNA helicase enzyme EIF4A76, silvestrol was predicted to be significantly associated with HCoVs (Z = –1.24, P = 0.041) by network proximity analysis.', 'To increase coverage of drug–target networks, we may use computational approaches to systematically predict the drug-target interactions further25,26.', 'In addition, the collected virus–host interactions are far from completeness and the quality can be influenced by multiple factors, including different experimental assays and human cell line models.', 'We may computationally predict a new virus–host interactome for 2019-nCoV/SARS-CoV-2 using sequence-based and structure-based approaches77.', 'Drug targets representing nodes within cellular networks are often intrinsically coupled with both therapeutic and adverse profiles78, as drugs can inhibit or activate protein functions (including antagonists vs. agonists).', 'The current systems pharmacology model cannot separate therapeutic (antagonists vs. agonists).', 'The current systems pharmacology model cannot separate therapeutic', 'Owing to a lack of the complete drug-target information (such as the molecular “promiscuity” of drugs), the dose–response and dose–toxicity effects for both repurposable drugs and drug combinations cannot be identified in the current network models.', 'For example, Mesalazine, an approved drug for inflammatory bowel disease, is a top network-predicted repurposable drug associated with HCoVs (Fig. 5a).', 'Yet, several clinical studies showed the potential pulmonary toxicities (including pneumonia) associated with mesalazine usage81,82.', 'Integration of lung-specific gene expression23 of 2019-nCoV/SARS-CoV-2 host proteins and physiologically based pharmacokinetic modeling83 may reduce side effects of repurposable drugs or drug combinations.', 'Preclinical studies are warranted to evaluate in vivo efficiency and side effects before clinical trials.', 'Furthermore, we only limited to predict pairwise drug combinations based on our previous network-based framework28.', 'However, we expect that our methodology remain to be a useful network-based tool for prediction of combining multiple drugs toward exploring network relationships of multiple drugs’ targets with the HCoV–host subnetwork in the human interactome.', 'Finally, we aimed to systematically identify repurposable drugs by specifically targeting nCoV host proteins only.', 'Thus, our current network models cannot predict repurposable drugs from the existing anti-virus drugs that target virus proteins only.', 'Thus, combination of the existing anti-virus drugs (such as remdesivir64) with the network-predicted repurposable drugs (Fig. 5) or drug combinations (Fig. 6) may improve coverage of current network-based methodologies by utilizing multi-layer network framework16.', 'In conclusion, this study offers a powerful, integrative network-based systems pharmacology methodology for rapid identification of repurposable drugs and drug combinations for the potential treatment of 2019-nCoV/SARS-CoV-2.', 'Our approach can minimize the translational gap between preclinical testing results and clinical outcomes, which is a significant problem in the rapid development of efficient treatment strategies for the emerging 2019-nCoV/SARS-CoV-2 outbreak.', 'From a translational perspective, if broadly applied, the network tools developed here could help develop effective treatment strategies for other emerging viral infections and other human complex diseases as well.']}\n", - "{'sentences': ['Second, it is probably a matter of patient.', 'Patients more prone to developing immune hyperactivation are probably those more likely to respond to ICI [23].', 'There is a possibility that such patients would be also more prone to fall in the cytokine storm in the case of SARS-CoV-2 infection.', 'Nevertheless, these patients do not correspond to the average advanced cancer patient, who is supposed to be immunosuppressed, with a blunted immune status [6].', 'The epidemiology of the COVID-19 observed up today suggests that SARS-CoV-2 tends to infect more frequently the frail patient populations, such as the elderly and cancer patients [4,5].', 'Cancer is usually associated with overexpression of immunosuppressive cytokines, suppression of proinflammatory danger signals, impaired dendritic cell maturation, and enhanced immunosuppressive leukocyte populations [6].', 'Since ICI can restore the immune-competence, if on one hand it can be paradoxically needed to develop the cytokine storm characterizing the acute respiratory distress syndrome (ARDS', 'Third, the efficacy of tocilizumab for COVID-19 is still under investigation, with still unexplored backstage and with uncomfortable upstream evidence coming from the setting of influenza infection.', 'Despite clinical studies associating IL-6 with high disease severity in influenza-infected patients and its levels correlated directly with symptom occurrence in human influenza virus infection, the role of this cytokine is still ambiguous [24].', 'It was demonstrated in mice models that IL-6 is essential for preventing virus-induced neutrophil cell death and H1N1-associated mortality, limiting influenza-induced cytokine storm and protecting against fatal lung pathology [25].', 'Furthermore, IL-6 is crucial in secondary infections to recall virus-specific memory CD4 T cells, favoring virus clearance and host survival, as supported by the inability of IL-6 deficient mice to control influenza viral titers in the lung [25].', 'Such preclinical evidence suggests that, despite probably being harmful in the ARDS phase, IL-6 role could be crucial, in the early phase of the viral infection, to defuse the pathogenesis of severe and lethal forms of influenza.', 'Thus, hoping for positive results from tocilizumab randomized clinical trial on COVID-19 patients, we could only argue about the evident diversity of this viral infection from previous SARS outbreaks and even more from influenza epidemics, probably both in terms of clinical features and of pathogenetic implications.', 'Since its first outbreak in China, COVID-19 was empirically treated with antiviral therapy, first employing agents already used in prior severe acute respiratory syndrome epidemics [18].', 'Then, several randomized clinical trials were initiated in China and more recently in Italy, investigating different treatment options, varying from classical antiviral drugs as lopinavir/ritonavir, to newer antiviral as remdesivir, to unconventional agents such as chloroquine and hydroxychloroquine [19].', 'The latest treatment frontier against COVID-19 seems to be represented by a recombinant humanized monoclonal antibody, named tocilizumab, which binds the human IL-6 receptor, inhibiting its signal transduction [20].', 'Tocilizumab is currently used for rheumatoid arthritis, but its efficacy has been demonstrated also against ICI-induced irAEs, starting from the rationale of an ICI-induced systemic inflammatory response syndrome similar to CRS [21].', 'Moreover, along with the improvement in symptoms related to systemic inflammatory response syndrome, some authors reported a clinical improvement in other irAEs with tocilizumab used in cancer patients with immune-related toxicity from anti-PD-1 agents [21,22].', 'With these premises, the risk of hasty conclusions is around the corner.', 'In fact, one can argue that the alleged tocilizumab efficacy both for treating COVID-19 and irAEs might suggest a potentially increased danger from SARS-CoV-2 infection for ICI-treated patients, maybe hypothesizing a synergy in the promotion of the viral morbidity.', 'Nevertheless, this is probably a thoughtless deduction.', 'First, it can be a matter of time.', 'The time at which the COVID-19 patient develops the pathologic hyperactivation of the immune response, eventually contributing to the final injury, is probably in the late phase of the disease manifestation, occurring together with the respiratory distress [17].', 'Furthermore, the time matters also in the case of ICI therapy, since the majority of patients develop irAEs within the first 6 months from the first administration [12].', 'Thus, a certain caution for ICI administration during the pandemics could be applied mostly for those patients needing therapy initiation or in their first months of treatment.']}\n", - "{'sentences': ['Early identification of patients approaching to severe COVID-19 patients will lead to better management and optimal use of medical resources.', 'In this research, we identified older age, higher LDH and CRP, DBIL, RDW, BUN, and lower ALB on admission correlated with higher odds of severe COVID-19.', 'Furthermore, we developed an effective prognostic nomogram composed of 7 features, had significantly high sensitivity and specificity to distinguish individuals with severe COVID-19 from non-severe COVID-19.', 'DCA and CICA further indicated that our All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.17.20037515 doi: medRxiv preprint nomogram conferred significantly high clinical net benefit, which is of great value for accurate individualized assessment of the incidence of severe COVID-19.', 'Furthermore, only seven easy-access features were included in our nomogram, including older age, higher LDH and CRP, DBIL, RDW, BUN, and lower ALB.', 'Among of them, age, NLR and LDH has been reported to be risk factors for severe patients with SARS-CoV-2 infection 3, 6, 7 .', 'NLR, a widely used marker for the assessment of system inflammation, was not identified by LASSO as an important feature instead of LDH and CRP, which are associated with the systemic inflammatory response 8 .', 'However, LDH could predict severity of tissue damage in early stage of diseases as an auxiliary marker 9 .', 'These might be reasons why the lasso model did not identified NLR as a more important feature.', 'Consistent with other reports, our results indicate that patients All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', '17.20037515 doi: medRxiv preprint with higher levels of inflammation at admission might be at higher risk for severe COVID-19 as well.', 'Interestingly, we found RDW was also an important prognostic predictor for severe COVID-19.', 'RDW, one of the numbers or blood cell indices, reflects the variation in the size of RBC (red blood cells), which has been tightly correlated with critical disease 10-12 but negligent in COVID-19.', 'It is a robust predictor of the risk of all cause patient mortality and bloodstream infection in the critically ill [11] [12] [13] [14] , including acute exacerbation of interstitial pneumonia, ARDS 10, 15 .', 'RDW also can predict prognosis of sepsis, which was tied to poor COVID-19', 'outcomes-death 16 .', 'The increased RDW in COVID-19 patients may be due to the increased turnover of erythrocytes: 1) Pro-inflammatory states may be responsible for insufficient erythropoiesis with structural and functional alteration of RBC, such as decreased deformability leading to more rapid clearing of RBC.', '2) Plasma cytokines such as interleukin 1 (IL-1) and tumor necrosis factor-α (TNF-α) could not only attenuate the renal erythropoietin (EPO) production, but also blunt the erythroid progenitor response to EPO.', 'In addition, INF-γ contributes to apoptosis of the erythroid progenitors and decrease the EPO', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.17.20037515 doi: medRxiv preprint severe COVID-19 patients.', 'Our study has several strengths: first, we provide a practical quantitive prediction tool based on only 7 features which were relatively inexpensive and easy to be obtained directly from the routine blood tests.', 'Second, to guarantee the robustness of the conclusion, we included the data from three centers with a large sample size and validation in independent cohorts.', 'The performance of our nomogram was efficient for clinical practice.', 'There were some limitations in the study.', 'First, this is a retrospective study, including 372 patients with non-severe COVID-19 on admission.', 'Second, some patients are still in hospital and their condition may change with follow-up.', 'More comprehensive investigations need to be conducted to explain the characteric of the 7 features.', 'In summary, our data suggest that our nomogram could early identify the severe COVID-19 patients, and RDW was vaulable for prediction of severe diseases.', 'Our nomogram is especially valuable for risk stratification management, which will be helpful for alleviating insufficient medical resources and reducing mortality.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019:', 'A retrospective cohort study', '[{\\'text\\': \"Background: Corona Virus Disease 2019 due to the 2019 novel coronavirus (SARS-CoV-2) emerged in Wuhan city and rapidly spread throughout China.', 'We aimed to compare arbidol and lopinavir/ritonavir(LPV/r) treatment for patients with COVID-19 with LPV/r only.', 'Methods: In this retrospective cohort study, we included adults (age ≥18years) with laboratory-confirmed COVID-19 without Invasive ventilation, diagnosed between Jan 17, 2020, and Feb 13, 2020.', 'Patients, diagnosed after Jan 17, 2020, were given oral arbidol and LPV/r in the combination group and oral LPV/r only in the monotherapy group for 5-21 days.', 'The primary endpoint was a negative conversion rate of coronavirus from the date of COVID-19 diagnosis(day7, day14), and assessed whether the pneumonia was progressing or improving by chest CT (day7).', 'Results: We analyzed 16 patients who received oral arbidol and LPV/r in the combination group and 17 who oral LPV/r only in the monotherapy group, and both initiated after diagnosis.', 'Baseline clinical, laboratory, and chest CT characteristics were similar between groups.', \"The SARS-CoV-2 could not be detected for 12(75%) of 16 patients' nasopharyngeal specimens in the combination group after seven days, compared with 6 (35%) of 17 in the monotherapy group ( p < 0 ·05).\", 'After 14 days, 15 (94%) of 16 and 9 (52 ·9%) of 17, respectively, SARS-CoV-2 could not be detected ( p < 0 ·05).', 'The chest CT scans were improving for 11(69%) of 16 patients in the combination group after seven days, compared with 5(29%) of 17 in the monotherapy group ( p < 0 ·05).', 'Conclusion: In patients with COVID-19, the apparent favorable clinical response with arbidol and LPV/r supports further LPV/r only.', 'Effective treatment interventions for patients with severe COVID-19 are still urgently needed.', 'Patients with SARS treated with LPV/r appeared to reduce the viral load, and LPV/r was recommended for patients with MERS-CoV. 7, 11 Arbidol and arbidol mesylate were shown to have a direct antiviral effect in early viral replication in vitro for SARS-CoV. 12, 13 It has been implied that there was a therapeutic window that could be exploited, provided an active antiviral agent was available.', '14 The fundamental strategy in the treatment of coronavirus is, therefore, to find an effective antiviral agent that would decrease the peak viral load and thus, the associated degree of immunopathological damage.', \"14 In typical patients without Invasive ventilation, our study shows that oral arbidol and LPV/r in the combination group is associated with a significant elevated negative conversion rate of coronavirus' test in 7-day and 14-day, compared with LPV/r only in the monotherapy group.\", 'Furthermore, combination therapy is associated with a significantly improved the chest CT scans in 7-day.', 'Fortunately, all the patients did not develop acute respiratory failure during the treatment period, but it was not clear whether it was an effect of antiviral drug.', 'According to that, we suppose that reducing the viral load as soon as possible could benefit the delay of the progression of lung lesions.', 'Stools of a portion of patients were positive for SARS-CoV-2 s test by RT-PCR.', 'And a few cases, patients in the monotherapy group tested remained positive for SARS-CoV-2 in stools after showing negative in respiratory samples.', 'Chest CT scans may be a better way to assess the effect of treatment compared to nasopharyngeal specimens test for coronavirus.', 'It has been proved that SARS-CoV-2 uses ACE2 as a viral receptor for entry process.', '15, 16 ACE2 mRNA is highly expressed in the gastrointestinal system, providing a prerequisite for SARS-CoV-2 infection.', '17 About 40% of a total intake dose of arbidol is excreted unchanged within 48 h, mainly with feces (38 ·9%) and much less with urine (0 ·12%), 18 and 20% of the LPV/r is found unchanged in the stool.', '19 Oral arbidol combine with LPV/r may achieve a high fecal concentration to stop viral replication at this site.', 'Combination therapy may likely be preferred in patients with stool tested positive.', 'The physical and biochemical examination of main organs and systems did not reveal any significant differences between arbidol-treated and control groups, indicating good tolerability and safety of arbidol in humans.', '20 Gastrointestinal symptoms, such as diarrhea and nausea, and elevated levels of bilirubin, are wellrecognized complication of LPV/r therapy and was noted previously.', '21 Treatment with arbidol and LPV/r was well tolerated in our study.', '43% of patients received corticosteroid therapy in the monotherapy group, nevertheless (31%) had improved the chest CT scans in day 7.', \"It is likely that corticosteroids didn't conducive to the recovery of lung injury.\", 'The use of corticosteroids is controversial.', 'It had been reviewed that although the glucocorticoid group was younger and had fewer underlying diseases, it had more adverse outcomes, increasing the risk of ICU admission and mortality for patients with SARS receiving hormone therapy.', '22 Glucocorticoids could delay the clearance of coronavirus nucleic acids without lower mortality for patients with MERS-CoV infection.', '23 One of the limitations of our study is its small size.', 'Our review, albeit little, is the most significant clinical investigation so far to assess the use of this combination in the treatment of patients with COVID-19.', 'Although baseline characteristics of our treatment and comparator groups seem to be reasonably balanced, substantial differences might not be apparent because of the small number of patients in the study.', 'Our review is also limited by its retrospective, nonrandomized nature, Inevitably, selection and unmeasured confounding bias cannot be excluded entirely.', 'There could be a few alternative interpretations of the results.', 'Undoubtedly, new interventions should ideally be assessed in randomized, controlled clinical trials.', 'However, such an approach is generally accepted to not always be practically feasible in the context of an emerging and relatively uncommon disease such as MERS-CoV infection at the very beginning.', '24 We selected our control group carefully, ensuring that the two cohorts were matched as closely as possible in their clinical characteristics, treatment interventions, and chest CT images other than the receipt of arbidol and LPV/r.', 'We removed four individuals be admitted and transferred to the ICU who had organ dysfunction outlying baseline serum creatinine from the comparator group to minimize the risk of any spurious conclusions driven by clinical characteristics that might be potentially detrimental to clinical outcome.', 'Clinical outcomes for each individual were masked from investigators who selected patients and did matching assessments.', 'Such measurements should be included in any future clinical studies exploring the therapeutic benefit of any antiviral intervention for patients with SARS-CoV-2 infection.', 'Recent research has suggested that COVID-19 was frequently associated with the presumed hospital-related transmission, 26% of patients required intensive care unit treatment, and mortality was 4 ·3% in Wuhan, China.', '3 The therapeutical emphasis of COVID-19 was, therefore, to antiviral early that would decrease the peak viral load and thus the associated degree of immunopathological damage.', '25 This would reduce the need for immunosuppressants, which were often associated with an increased risk of nosocomial infections.', '26 One possible implication of this is that, arbidol combine with LPV/r might benefit to delay of the progression of lung lesions and lower the possibility of respiratory and gastrointestinal transmission for decreasing the viral load of COVID-19 and containing a high fecal concentration.', 'Further randomized, prospective studies are still needed, and the mechanism of its antiviral effect to coronavirus remains unclear.']}\n", - "{'sentences': ['Lactate dehydrogenase, a Risk Factor of Severe COVID-19 Patients', 'Significantly higher scores were found in severe cases.', 'Among the risk factors we investigated in this study, we surprisingly discovered that LDH had the most positive relationship between both PSI and CT score.', 'In addition, it was also most positively relevant to APACHE II and SOFA scores, which reflected a strong correlation between LDH with lung damage as well as disease severity.', 'LDH is a major player in glucose metabolism which is present in tissues throughout the body and catalyzes pyruvate to lactate.', 'It is released from cells upon damage of their cytoplasmic membrane (10) .', 'Previous studies also had noted the importance of LDH as an indicator of lung diseases.', 'In a study on Epstein-Barr virus (EBV), researchers found that EBV', 'Furthermore, there was a case reported in 2017 that a patient with human Zika virus infection had markedly elevated LDH, which was associated with 70% mortality in All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.24.20040162 doi: medRxiv preprint further Zika infected animal study.', 'They considered LDH as an indicator of multiorgan injury, not only affecting liver or cardiac function(15).', 'LDH is found in all human cells, especially in myocardial and liver cells.', 'In our study, LDH elevation was positively associated with AST, cTnI and BNP, which verified it as an isozyme of heart and liver.', 'However, it was somewhat surprising that cTnI was neither associated with PSI nor CT semiquantitative score, while was relevant with disease severity.', 'Similarly, BNP that had a strong correlation with APACHE II and SOFA, was not associated with CT semiquantitative score, either.', 'Furthermore, AST which was associated with the APACHE II and SOFA score, was not related to PSI score.', 'This rather intriguing finding might be explained by the fact that the myocardial and liver injury caused by SARS-CoV-2 might be due to the direct damage of the virus to targeted organs, while not because of hypoxia induced by lung injury.', 'Since the outbreak of COVID-19, structural analysis of the virus has suggested that SARS-CoV-2 might be able to bind to the angiotensin-converting enzyme 2 (ACE2) receptor in humans(16, 17).', 'This epithelial expression, together with its presence in vascular endothelium(18), also provides a step in understanding the pathogenesis of ARDS, cardiac injury, liver injury and even MODS.', 'Furthermore, LDH was found to be positively associated with CRP and negatively with', 'An increase in CRP and decrease in lymphocytes were observed in severe cases during the 14-day observation period, which was consistent with findings of recent reports (1, 5, 6) .', 'In our study, the development of lymphopenia in severe patients was mainly related to the significantly decreased absolute counts of T cells, especially CD3 + , CD4 + , and CD8 + T cells, but not to B cells or NK cells.', 'The decrease of T cells in severe cases reached its trough within three days, and then slightly increased from the first week while still maintaining low levels and not recovering to the level of nonsevere patients over two weeks (data not shown).', 'All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.24.20040162 doi: medRxiv preprint LDH is not only a metabolic but also an immune surveillance prognostic biomarker, its elevation is harbinger of negative outcome in immunosuppressive patients (19) .', 'LDH increases production of lactate, leads to enhancement of immune-suppressive cells, including macrophages and dendritic cells (DCs', 'Also, significant correlations were found between LDH and cytokines/chemokines, therefore, LDH may be a useful biomarker to assist the clinician in the decision to hospitalize a child with bronchiolitis(24).', 'In our study, lymphocytes, especially CD3 + , CD4 + , and CD8 + T cells were significantly decreased and relevant with LDH elevation.', 'The decrease in T cell counts was strongly correlated with the severity of disease, which was in keeping with previous studies on SARS(25, 26).', 'On the other hand, elevation of LDH, the immune-related factor, could be considered as a predictive factor, that reflected a poor prognosis in severe COVID-19 patients.', 'Our study had some limitations.', 'This study was conducted at a single-center with limited sample size.', 'Furthermore, because many patients remained in hospital and outcomes were unknown at the time of writing, we only collected clinical data within two weeks for our analysis.', 'COVID-19 has spread rapidly and has a wide spectrum of severity.', 'A larger cohort study of patients with COVID-19 pneumonia globally would help to further define the clinical characteristics and risk factors of the disease.', 'All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.24.20040162 doi: medRxiv preprint', 'In this study, we analyzed the clinical features in 47 patients with COVID-19 who were admitted to Renmin Hospital of Wuhan University between February 1 and February 1, 2020.', 'Although the clinical characteristics of patients enrolled were somewhat akin to those reported in previous studies (1, 5, 7) , there were no differences in age, BMI, and proportion with underlying diseases between severe and non-severe patients, as well as smoking history.', 'In concert with recent studies (1, 5, 9) , we found that the clinical characteristics of COVID-19 mimic those of SARS-CoV. Fever and cough were the dominant symptoms, and both groups had similar days from symptom onset, similar maximum temperature, and number of patients who had dyspnea.', 'APACHE II and SOFA scores were calculated based on admission data.', 'PSI, CURB-65, and the semiquantitative score were used to assess the severity of lung damage.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Coronavirus is a highly contagious pathogen found in several domestic animals, pets, and humans, causing a variety of acute and chronic diseases.', '[6] Currently, six coronaviruses are known to infect humans, including 229E and NLR6 in the α-genus.', 'The β-genus comprises OC43, HKU1, Middle East respiratory syndrome-related coronavirus (MERSr-CoV), [7] and severe acute respiratory syndrome-related coronavirus (SARSr-CoV).', '[8] Coronavirus has gradually become a popular topic of research in the field of virology because of the outbreak of SARSr-CoV in 2003 and MERSr-CoV', 'The present study included 78 patients diagnosed with the COVID-19.', 'All patients were evaluated for therapeutic efficacy after at least two weeks of hospitalization.', 'These results indicated progression in 11 patients (14.1%) and improvement/stabilization in 67 patients (85.9%).', '80.8% of the patients were younger than 60 years, and the median age of the patients was 38 (33, 57) years, which suggest that middle-aged people are susceptible to COVID-19.', 'Also, the age of patients in the progression group was significantly higher than that in the improvement/stabilization group, and multivariate logistic analysis indicated that higher age was a risk factor for disease progression.', 'Elderly individuals are physically frail and are likely to have several comorbidities, which not only increases the risk of pneumonia [12] but also affects their prognosis [13] .', 'the assessment of comorbidities is an essential component in determining the prognosis of several diseases, especially pneumonia.', '[14] Probably because of the small sample size, there was no significant difference in any comorbidity including hypertension, diabetes, COPD, cancer, and others between the two groups.', 'The potential impact of comorbidities on the disease outcomes of patients with COVID-19 pneumonia requires further observation and research.', 'The proportion of patients with a history of smoking was significantly higher in the progression group compared to the improvement/stabilization group, suggesting that smoking is associated with disease progression.', 'A significant symptom of SARS is a body temperature above 38°C for over two weeks.', 'Additionally, 60% of patients diagnosed with MERS presented with fever.', '[15] In the present study, 73.1% of patients with COVID-19 sought treatment for the fever.', 'The results showed that the maximum body temperature at admission in the progression group was significantly higher than in the improvement/stabilization group, and multivariate logistic models indicated that higher temperature was a risk factor for disease progression.', 'Therefore, patients presenting with a high fever, long fever duration, and rapid fever progression should be monitored more closely during clinical diagnosis and treatment in order to avoid complications associated with high fevers, which lead to poor prognosis.', 'Vital signs are essential indicators for assessing the current symptoms of patients.', 'Respiratory system indices, such as respiratory rate and whether respiratory failure occurred, are particularly crucial for assessing the condition severity in patients with COVID-19.', 'The present study found that the median respiratory rate of 78 patients with COVID-19 pneumonia was 24 breaths/min, which was higher than the normal respiratory rate (12) (13) (14) (15) (16) (17) (18) (19) (20) breaths/min).', 'The respiratory rate and proportion of patients with respiratory failure in the progression group were significantly higher than in the improvement/stabilization group.', 'Abnormal respiratory indices can directly reflect the extent of lung invasion and multivariate logistic models revealed that respiratory failure was a risk factor for disease progression.', 'Therefore, respiratory indices should be one of the top priorities in the efficacy evaluation.', 'The present study suggests that elevated C-reactive protein, and decreased albumin are factors associated with poor prognosis of COVID-19 infection.', 'Albumin is the most intuitive index of the nutritional status of the body.', 'When albumin decreases, the body loses resistance to the virus, leading to disease progression .', '[16] Elevated C-reactive protein is an important inflammatory index in addition to abnormal blood coagulation function.', \"Close monitoring of dynamic changes in these indices has a significant proactive effect on understanding changes in the patient's condition.\", 'In addition, studies have shown that lymphocytes are the main target cells of viral infections.', '[17] Viral infections in the human body primarily involve damage to the immune system, which presents as decrease in the absolute number of lymphocytes .', '[18] The present study did not find these indices significant for assessing the outcome of COVID-19 patients, and their correlation requires further investigation.', 'This study included CT scan characteristics of patients with COVID-19 pneumonia for analysis and suggested that the extent and characteristics of the lesion had no statistical significance on disease outcomes.', 'However, the use of CT scans at earlier stages for disease assessment is still of great significance for early detection, early diagnosis, and improved prognosis.', 'Appropriate antibiotic treatment can be administered to prevent secondary infection in critical type viral pneumonia.', '[19] We analyzed the diagnosis and treatment protocols of patients with COVID-19 pneumonia, and results suggested that some patients undergoing antiviral treatment were also proactively undergoing antibacterial treatment.', 'Whether viral pneumonia should be treated with glucocorticoids has been controversial.', 'Some researchers believe that the use of glucocorticoids in viral pneumonia can easily aggravate the disease and increase the risk of secondary infections, leading to an increase in mortality, thus advocating against the use of glucocorticoids.', '[20] Other studies have suggested that the use of an appropriate dose of glucocorticoids at early stages could inhibit the elevated secretion of inflammatory cytokines due to excessive activation of immune cells because of the viral infection, thereby preventing continued exacerbation of lung injury .', '[21] We found that the combination of antivirals, antibacterials, and glucocorticoids had the highest use rate in the treatment of COVID-19 pneumonia.', 'Moreover, other researchers have suggested using thymosin and gamma globulin during the early stages of infection to improve patient immunity.', 'In addition, current ongoing related studies suggest that COVID-19 and HIV have structural similarities.', 'Thus, certain researchers have proposed that the anti-HIV drug, lopinavir, may play a role in inhibiting COVID-19.', 'In this study, a comparison of efficacy of antivirals/antibacterials, antivirals/antibacterials + glucocorticoids, antivirals/antibacterials + gamma globulin, antivirals/antibacterial + thymosins, and antivirals/antibacterials + lopinavir was performed.', 'The results did not suggest that drug protocols affected disease outcomes.', 'Therefore, further studies should include more drugs for the treatment of COVID-19.', 'COVID-19 pneumonia is characterized by an acute onset and rapid progression.', 'Therefore, the early use of glucocorticoids with proactive antiviral and antibacterial treatment after comprehensive evaluation may block the inflammatory cascade caused by severe viral infections and prevent acute inflammation.', 'The lung damage caused by such infections can further progress to acute respiratory distress syndrome.', 'Respiratory support is an essential treatment for patients with severe viral infections.', 'The present study revealed that all patients with COVID-19 were treated with respiratory support, and the majority of patients were administered nasal cannula oxygen and continuous positive air pressure.', 'The progression group was significantly more likely to receive higher levels of respiratory support.', \"No patients in this study were treated with invasive ventilation and ECMO due to the refusal of the patients' family.\", 'Treating patients with severe viral pneumonia, timely application of glucocorticoids and respiratory support therapy is essential, in combination with personalized treatment specific to each patient.', 'There were a few limitations for this observational study.', 'CT scan imaging has delayed scanning time, which may introduce bias in our results.', 'In addition, a relatively small sample size was included in this study, which may lead to biased results.', 'Thus, a multi-center largescale study with additional researchers is required.', 'Currently, the best diagnostic and treatment protocols for COVID-19 are still being investigated.', 'Early diagnosis and dynamic monitoring of prognostic factors are essential for improving the ability to treat the COVID-']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['SUMMARYThere is an urgent requirement for improved treatments of COVID-19 disease.', 'A strategy for chemotherapy is to increase levels of endogenous reactive metabolites - such as reactive oxygen species and arginine-directed glycating agent, methylglyoxal - for selective toxicity to SARS-CoV-2.', 'Sequence analysis of functional domains in the SARS-CoV-2 proteome showed 0.8-fold depletion of cysteine residues and 4.9-fold enrichment of arginine residues, suggesting methylglyoxal modification may inactivate the virus.', 'We discovered the peptide motif for MG modification: 3 – 5-fold enrichment of cationic residues preceding the target arginine.', 'There was 5-fold enrichment of methylglyoxal modification sites in the SARS-CoV-2 proteome, compared to the human host - indicating selective toxicity of methylglyoxal to the virus.', 'We found antitumor drugs, doxorubicin and paclitaxel, increase cellular methylglyoxal to virucidal levels.', 'Taken together, these findings reveal a proteomic vulnerability of SARS-CoV-2 to methylglyoxal modification and provide a rationale for repurposing doxorubicin and paclitaxel for COVID-19 treatment.']}\n", - "{'sentences': ['Lei, MD have contributed equally to this work.', 'Word count: 3166 All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'Background: The clinical outcomes of COVID-19 patients in Hubei and other areas are different.', 'We aim to investigate the epidemiological and clinical characteristics of patient with COVID-19 in Hunan which is adjacent to Hubei.', 'In this double-center, observational study, we recruited all consecutive patients with laboratory confirmed COVID-19 from January 23 to February 14, 2020 in two designated hospitals in Hunan province, China.', \"Epidemiological and clinical data from patients' electronic medical records were collected and compared between mild, moderate and severe/critical group in detail.\", 'Clinical outcomes were followed up to February 20, 2020.', 'Findings: 291 patients with COVID-19 were categorized into mild group (10.0%), moderate group (72.8%) and severe/critical group (17.2%).', 'The median age of all patients was 46 years (49.8% were male).', '86.6% patients had an indirect exposure history.', 'The proportion of patients that had been to Wuhan in severe/critical group (48.0% vs 17.2%, p=0.006) and moderate group (43.4% vs 17.2%, p=0.007) were higher than mild group.', 'Fever (68.7%), cough (60.5%), and fatigue (31.6%) were common symptoms especially for severe and critical patients.', 'Typical lung imaging finding were bilateral and unilateral ground glass opacity or consolidation.', 'Leukopenia, lymphopenia and eosinopenia occurred in 36.1%, 22.7% and 50.2% patients respectively.', 'Increased fibrinogen was detected in 45 of 58 (77.6%) patients with available results.', '29 of 44 (65.9%) or 22 of 40 (55.0%) patients were positive in Mycoplasma pneumonia or Chlamydia pneumonia antibody test respectively.', 'Compared with mild or moderate group, severe/critical group had a relative higher level of neutrophil, All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'In this double-center observational study, epidemiology and clinical characteristics of 291 COVID-19 All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.03.20030353 doi: medRxiv preprint patients in Hunan province were collected and analyzed.', 'Hunan is adjacent to Hubei province, and its provincial capital Changsha is 294 kilometers away from Wuhan, while another city Loudi is about 392 kilometers away from Wuhan.', 'Given the migrant data in previous years and the lockdown of Wuhan on Janurary 23, 2020, Changsha is a city with a high estimated number of imported cases.', '8 Our study attempted to provide some experience of diagnosis and treatment for the health workers in other areas.', 'To further show the characteristics in patients with different disease severity, we categorized the 291 by several epidemic prediction models seems to be higher than SARS.', '[10] [11] [12] After the fast increase in the number of patients in Wuhan during the middle of January, COVID-19 spread to the other provinces rapidly such as neighbor province Hunan because of the nearby location, developed traffic and large migrant population.', '11 In our study, none of 291 patients had a history of direct exposure to Huanan seafood market, but most patients (86.6%) had an indirect exposure history within 14 days before symptoms onset, including being to Wuhan (41.6%), having contact with people came from Wuhan (14.1%) and having contact with local diagnosed patients (38.5%).', 'Our study also showed the proportion of patients who had been to Wuhan in severe/critical group (48.0%) and moderate group (43.4%) were higher than mild group (17.2%).', 'Besides, both the two death cases in our study had a travel history in Wuhan while they both used to be in good health.', 'These showed the infectivity and All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.03.20030353 doi: medRxiv preprint transmission intensity of the virus, especially in the first or second generation of transmission, and may indicate that the virulence of the virus will decrease after limited generations of transmission.', '10, 12 Therefore doctors in areas outside Wuhan should be more cautious in clinical decision making when the patient have a recent history of exposure in Wuhan, including Wuhan residents and those who recently traveled to Wuhan before disease onset.', 'The proportion of family clusters infection in our study was 39.2% which was lower than other studies.', '3 Besides, none of our patient was medical staff while 1080 medical staff were infected in Wuhan until February 11, 2020.', '2 For demographic and clinical characteristics, 53.6% patients aged between 15-49 years, followed by the 50-64 years age group (27.5%).', 'In severe/critical group, 32.0% and 40.0% patients aged from 50 to 64 and over 64 respectively, consistent with report of Guan et al. 13 Female and male patients both accounted for half in all three groups.', 'The median time from disease onset to first admission in our study was 5.0 days.', 'Similar to the recent publications, [13] [14] [15] [16] our data also showed that fever, cough and fatigue were the most common symptoms.', 'The severe/critical group patients were more likely to have two or more symptoms at admission.', 'While most symptoms were more frequently seen in severe/critical group, nausea or vomiting were more common in mild group, which may indicate different body responses to SARS-CoV-2 infection in patients with different health state and immune system defensive characteristics.', '58.0% patients in severe/critical group had at least one underlying disease.', 'In concert with the study of Guan et al, 13 Bases on these findings, we suggest clinicians pay more attention to and closely observe patients with multiple symptoms and underlying diseases to prevent disease deterioration.', 'For laboratory inspection, blood routine test showed 36.1% and 22.7% of patients had leukopenia and lymphopenia respectively.', 'Interestingly, eosinopenia was detected in more than 50% patients, All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.03.20030353 doi: medRxiv preprint especially in the severe/critical group (74%), which was not emphasized in previous studies.', '17 This indicate that eosinophils could assist in the diagnosis and severity assessment of COVID-19.', 'Inconsistent with the other research 10 , elevated D-dimer was observed in majority of patients (83.5%) in our study, and its level was significantly higher in severe/critical group.', 'Consistent with the research of Guan, 13 Myocardial damage and elevated liver enzyme were not common and mainly happened in severe/critical group.', 'Besides, Obvious disorder of renal function and electrolyte were relatively rare in our patients.', '77.6% patients with available coagulation function test result had elevated fibrinogen on admission, and the proportion in severe/critical group was even higher, which have not been observed in other studies.', 'In the early stages of SARS patients, researchers also found an increase in fibrinogen.', '18 Previous studies had shown that SARS-CoV 3a protein can up regulate the expression of fibrinogen in lung epithelial cells.', '19 We speculate in the lung inflammation caused by SARS-CoV-2 or the secondary systemic inflammation, the activated body stress system may lead to the increase of fibrinogen.', 'Another interesting phenomenon was that considerable proportion of patients had positive results in Mycoplasma pneumonia or Chlamydia pneumonia antibody tests, which indicate Mycoplasma pneumonia or Chlamydia pneumonia co-infection, which was higher than other research.', 'Previous report indicated that Mycoplasma fermentans enhanced the cytotoxicity against Vero E6 cells infected with SARS-CoV. 20 This indicate COVID-19 patients co-infected with the two types of pathogens may lead to more severe state, thus clinicians need pay attention to the screening of these two pathogens in these patients.', 'Compared with the patient confirmed as COVID-19 in Wuhan 14-16 , our study showed that patients in Hunan had relatively higher discharge rate and lower mortality.', 'In our study, 82.8% patients were prone to a mild or moderate type and 54.6% patients were discharged at the end of follow-up.', 'The All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.03.20030353 doi: medRxiv preprint length of stay in hospital ranged from 5 to 25 days in discharged patients.', '2 of 291 (0.7%) patients died during hospitalization.', 'One death case was a 64 years old man in moderate group without any underlying disease.', 'He had a fever for 3 days before admission and was treated by antiviral therapy including lopinavir and ritonavir tablets.', 'The other death case was a 58 years old man in severe/critical group also without any underlying disease, but had symptoms of fever, cough, dyspnea and fatigue for 7 days before admission.', 'Laboratory tests detected a decreased level of WBC (2.26*10 9 /L), lymphocyte Although there has been a lack of evidence-based specific antiviral drugs, almost all patients in this study received antiviral therapy (96.6%), lopinavir and ritonavir tablets (75.9%), recombinant human interferon α2b (45.4%) were the most commonly used treatment.', 'Besides, chloroquine phosphate was reported to have apparent efficacy and acceptable safety against COVID-19 in a multicenter clinical trials 21 and had just been included in the latest edition of the guidelines for China.', 'According to this guideline, two patients in the study were given chloroquine for antiviral therapy.', 'However, the safety and efficacy of antiviral therapies used in COVID-19 patients need further studied.', 'Our study provided more information about epidemiology and clinical profiles of COVID-19 in adjacent area around Hubei Province.', 'It is hoped that our study may provide the basis for the epidemiology related measures of patients in covid-19 import area as well as for clinicians to make medical decisions.', 'There are several limitations in our study.', \"Firstly, due to the limitations of the retrospective study, laboratory examinations were performed according tothe clinical care needs of the patient, thus some patients' laboratory exam results were incomlpeted.\", 'Secondly, given the short observation period, All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.03.20030353 doi: medRxiv preprint nearly half of our patients were still receiving treatment in hospital at the end of our follow-up and we could not decide the mortality and prognosis of the whole case series.', 'Moreover, it is difficult to distinguish the specific efficacy of one single drug as various treatment were applied simultaneously, and the guideline about diagnosis and treatment of COVID-19 were updated frequently.', 'Therefore, the treatment experience in our study should be carefully thought when treating patients in different places and circumstances, and further researches are needed to verify the the safety and efficacy.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['COVID-19 is an emerging infectious disease and was recently declared as a pandemic by WHO.', 'Currently, there is no vaccine or therapeutic available for this disease.', 'Drug repositioning represents the only feasible option to address this global challenge and a panel of 48 FDAapproved drugs that have been pre-selected by an assay of SARS-CoV was screened to identify potential antiviral drug candidates against SARS-CoV-2 infection.', 'We found a total of 24 drugs which exhibited antiviral efficacy (0.1 µM < IC 50 < 10 µM) against SARS-CoV-2.', 'In particular, two FDA-approved drugs -niclosamide and ciclesonide -were notable in some respects.', 'These drugs will be tested in an appropriate animal model for their antiviral activities.', 'In near future, these already FDA-approved drugs could be further developed following clinical trials in order to provide additional therapeutic options for patients with COVID-19.', 'All rights reserved.', 'No reuse allowed without permission.', 'corroborated our finding of ciclesonide as a potential antiviral drug against SARS-CoV-2 12 .', 'A treatment report of three patients who were infected by SARS-CoV-2 in Japan (https://www3.nhk.or.jp/nhkworld/en/news/20200303_20/) warrants further clinical investigation of this drug in patients with COVID-19.', 'Intriguingly, an underlying mechanism for the suppression of viral infection by ciclesonide has been revealed by the isolation of a drug-resistant mutant 12 .', 'The isolation of the drug-resistant mutant indicated that NSP15, a viral riboendonuclease, is the molecular target of ciclesonide.', 'Together, it is not unreasonable to consider that ciclesonide exhibits a direct-acting antiviral activity in addition to its intrinsic antiinflammatory function.', 'In the future, siRNA targeting the hormone receptor will allow to assess the extent of direct-acting antiviral activity.', 'With its proven anti-inflammatory activity, author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'ciclesonide may represent as a potent drug which can manifest dual roles (antiviral and antiinflammatory) for the control of SARS-CoV-2 infection.', 'Prior to our evaluation of 48 drugs against SARS-CoV-2 infection, we also tested antiviral activity of several other drugs based on the cytopathic effect of the virus in the presence of each drug ( Figure 2 ).', 'In particular, the effect of favipiravir and atazanavir was compared to those of the reference drugs (chloroquine, lopinavir, remdesivir) because favipiravir is considered as a drug candidate for clinical trials and atazanavir was recently predicted as the most potent antiviral drug by AI-inference modeling 13 .', 'However, in the current work, we did not observe any antiviral activity of either favipiravir or atazanavir.', 'In summary, we selected and screened 48 FDA-approved drugs based on our SARS-CoV screening and our screening campaign revealed 24 potential antiviral drug candidates against SARS-CoV-2.', 'Our findings could be further validated in an appropriate animal model, and hopefully developed through subsequent clinical trials in order to provide additional therapeutic options for patients with COVID-19.', 'We screened approximately 3,000 FDA-and IND-approved drug library against SARS-CoV to identify antiviral drug candidates (manuscript in preparation).', 'Since the SARS-CoV and SARS-CoV-2 are very similar (79.5% sequence identity) 1 , the drugs which show antiviral activity against SARS-CoV are expected to show similar extent of antiviral activity against SARS-CoV-2.', 'A total of 35 drugs were selected from the earlier SARS-CoV screening results.', 'In addition, 13 drugs were included based on recommendations from infectious diseases specialists (Table 1) .', 'For screening experiments, Vero cells were used and each drug was added to the cells prior to the virus infection.', 'At 24 h after the infection, the infected cells were scored by immunofluorescence analysis with an antibody specific for the viral N protein of SARS-CoV-2.', 'The confocal microscope images of both viral N protein and cell nuclei were analyzed using our in-house Image Mining (IM) software and the dose-response curve (DRC', 'Among these 24 drugs, two FDA-approved drugs drew our attention.', 'First, niclosamide, an antihelminthic drug, exhibited very potent antiviral activity against SARS-CoV-2 (IC 50 = 0.28 µM).', 'Not surprisingly, its broad-spectrum antiviral effect has been well documented in the Second, ciclesonide is another interesting drug candidate for further development although its antiviral potency was much lower (IC 50 = 4.33 µM) than niclosamide.', 'It is an inhaled corticosteroid used to treat asthma and allergic rhinitis 11 .', 'A recent report by Matsuyama et al.']}\n", - "{'sentences': ['COVID-19 and the RAAS—a potential role for angiotensin II?']}\n", - "{'sentences': ['In this study, we revealed the clinical characteristics of 3 critical patients with COVID-2019, and found that (1) hypoxemia severity was strongly correlated to the expression levels of immune cells, which indicated that immuno-depletion may well be a key risk factor in the development of COVID-2019, and (2) the imbalance of gut microbiota was also found in these critical patients, which may lead to microbial translocation and a second infection.', 'The balance between virus and host immunity is closely associated with the outcome of an infection.', 'Clinical studies have shown that coronavirus infection severity was linked to patient health status and an immunocompromised state carried an increased risk of death 6, 7 .', 'It was also demonstrated that the immunosuppressed rhesus macaques had markedly increased MERS-Coronavirus replication in the lung, suggesting the inability in virus clearance 8 Multiple studies have demonstrated the interaction between immune system and gut All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.03.20030650 doi: medRxiv preprint microbiota, and gut microbiota homeostasis is modulated by the immune system 12 .', 'It was shown that a variety of immune factors was capable of altering gut microbiota homeostasis balance, such as IL-10, IL-23, NLRP6, NOD-like receptor protein 3, and IgA 13 .', 'And the imbalance or dysbiosis in gut microbiota would contribute to an enhanced mucosal permeability and thus leading to microbial translocation and a second infection.', 'Moreover, gut microbiota was able to modulate the immune response and played an important role in immune-mediated diseases, suggesting a vicious circle between immune disorder and gut microbiota imbalance 14 .', 'All these findings indicated that the balance of gut microbiota can be disrupted in case of coronavirus infection due to the immune disorder.', 'In this study, we further identified the changes in gut microbiota during the novel coronavirus infection and found that (1) the proportion of probiotics was significantly reduced, such as Bifidobacterium, Lactobacillus, and Eubacterium, and (2) the proportion of conditioned pathogenic bacteria was significantly increased, such as Corynebacterium of Actinobacteria and Ruthenibacterium of Firmicutes.', 'In addition, we also found that the fungi in the gut microbiota of the two patients are not common fungi in healthy cohort (eg.', 'Candida and Saccharomyces cerevisiae), some rare fungi dominate the fungal of gut microbiota, such as Aspergillus, Kluyveromyces.', 'Insight into which species of the microbiota are altered by immune-depletion associated with novel coronavirus infection can help us have a better understanding of the characteristics of COVID-2019.', 'Based on our findings, we suggested that the early interventions of host immune system and gut microbiota are necessary for COVID-2019 patients with refractory hypoxia.', 'For these critical patients, extracorporeal membrane oxygenation (ECMO', 'In conclusion, we discussed the dynamic characteristics of host immune system and the imbalance of gut microbiota in 3 critical patients with COVID-2019.', 'Hypoxemia severity was closely related with host immune cell levels, and the vicious circle between immune disorder and gut microbiota imbalance may be a high risk of fatal pneumonia.']}\n", - "{'sentences': ['Importance Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that was first reported in Wuhan, China, and has subsequently spread worldwide.', 'Risk factors for the clinical outcomes of COVID-19 pneumonia have not yet been well delineated.', 'Objective To describe the clinical characteristics and outcomes in patients with COVID-19 pneumonia who developed acute respiratory distress syndrome (ARDS) or died.', 'Design, Setting, and Participants Retrospective cohort study of 201 patients with confirmed COVID-19 pneumonia admitted to Wuhan Jinyintan Hospital in China between December 25, 2019, and January 26, 2020.', 'The final date of follow-up was February 13, 2020.', 'Exposures Confirmed COVID-19 pneumonia.', 'Main Outcomes and Measures The development of ARDS and death.', 'Epidemiological, demographic, clinical, laboratory, management, treatment, and outcome data were also collected and analyzed.', 'Results Of 201 patients, the median age was 51 years (interquartile range, 43-60 years), and 128 (63.7%) patients were men.', 'Eighty-four patients (41.8%) developed ARDS, and of those 84 patients, 44 (52.4%) died.', 'In those who developed ARDS, compared with those who did not, more patients presented with dyspnea (50 of 84 [59.5%] patients and 30 of 117 [25.6%] patients, respectively [difference, 33.9%; 95% CI, 19.7%-48.1%]) and had comorbidities such as hypertension (23 of 84 [27.4%] patients and 16 of 117 [13.7%] patients, respectively [difference, 13.7%; 95% CI, 1.3%-26.1%]) and diabetes (16 of 84 [19.0%] patients and 6 of 117 [5.1%] patients, respectively [difference, 13.9%; 95% CI, 3.6%-24.2%]).', 'In bivariate Cox regression analysis, risk factors associated with the development of ARDS and progression from ARDS to death included older age (hazard ratio [HR], 3.26; 95% CI 2.08-5.11; and HR, 6.17; 95% CI, 3.26-11.67, respectively), neutrophilia (HR, 1.14; 95% CI, 1.09-1.19; and HR, 1.08; 95% CI, 1.01-1.17, respectively), and organ and coagulation dysfunction (eg, higher lactate dehydrogenase [HR, 1.61; 95% CI, 1.44-1.79; and HR, 1.30; 95% CI, 1.11-1.52, respectively] and D-dimer [HR, 1.03; 95% CI, 1.01-1.04; and HR, 1.02; 95% CI, 1.01-1.04, respectively]).', 'High fever (≥39 °C) was associated with higher likelihood of ARDS development (HR, 1.77; 95% CI, 1.11-2.84) and lower likelihood of death (HR, 0.41; 95% CI, 0.21-0.82).', 'Among patients with ARDS, treatment with methylprednisolone decreased the risk of death (HR, 0.38; 95% CI, 0.20-0.72).', 'Conclusions and Relevance Older age was associated with greater risk of development of ARDS and death likely owing to less rigorous immune response.', 'Although high fever was associated with the development of ARDS, it was also associated with better outcomes among patients with ARDS.', 'Moreover, treatment with methylprednisolone may be beneficial for patients who develop ARDS']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial', 'Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and reported to be efficient in Chinese COV-19 patients.', 'We evaluate the role of hydroxychloroquine on respiratory viral loads.', 'French Confirmed COVID-19 patients were included in a single arm protocol from early March to March 16 th , to receive 600mg of hydroxychloroquine daily and their viral load in nasopharyngeal swabs was tested daily in a hospital setting.', 'Depending on their clinical presentation, azithromycin was added to the treatment.', 'Untreated patients from another center and cases refusing the protocol were included as negative controls.', 'Presence and absence of virus at Day6-post inclusion was considered the end point.', 'Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms.', 'Twenty cases were treated in this study and showed a significant reduction of the viral carriage at D6-post inclusion compared to controls, and much lower average carrying duration than reported of untreated patients in the literature.', 'Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination.', 'Despite its small sample size our survey shows that hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin.', 'For ethical reasons and because our first results are so significant and evident we decide to share our findings with the medical community, given the urgent need for an effective drug against SARS-CoV-2 in the current pandemic context.', 'We show here that hydroxychloroquine is efficient in clearing viral nasopharyngeal carriage of SARS-CoV-2 in COVID-19 patients in only three to six days, in most patients.', 'A significant difference was observed between hydroxychloroquine-treated patients and controls starting even on day3 post-inclusion.', 'These results are of great importance because a recent paper has shown that the mean duration of viral shedding in patients suffering from COVID-19 in China was 20 days (even 37 days for the longest duration) [19] Very recently, a Chinese team published results of a study demonstrating that chloroquine and hydroxychloroquine inhibit SARS-CoV-2 in vitro with hydroxychloroquine (EC50=0.72%µM) found to be more potent than chloroquine (EC50=5.47%µM) [14] .', 'These in vitro results corroborate our clinical results.', 'The target values indicated in this paper [14] were reached in our experiments.', 'The safer dose-dependent toxicity profile of hydroxychloroquine in humans, compared to that of chloroquine [13] allows using clinical doses of hydroxychloroquine that will be over its EC50 observed in vitro [14] .', 'Our preliminary results also suggest a synergistic effect of the combination of hydroxychloroquine and azithromycin.', 'Azithromycin has been shown to be active in vitro against Zika and Ebola viruses [20] [21] [22] and to prevent severe respiratory tract infections when administrated to patients suffering viral infection [23] .', 'This finding should be further explored to know whether a combination is more effective especially in severe cases.', 'Speculated potential risk of severe QT prolongation induced by the association of the two drugs has not been established yet but should be considered.', 'As for each treatment, the cost benefits of the risk should be evaluated individually.', 'Further studies on this combination are needed, since such combination may both act as an antiviral therapy against SARS-CoV-2 and prevent bacterial super-infections.', 'The cause of failure for hydroxychloroquine treatment should be investigated by testing the isolated SARS-CoV-2 strains of the non-respondents and analyzing their genome, and by analyzing the host factors that may be associated with the metabolism of hydroxychloroquine.', 'The existence of hydroxychloroquine failure in two patients (mother and son) is more suggestive of the last mechanism of resistance.', 'including vaccine development could be also effective, but only in the future.', 'We therefore recommend that COVID-19 patients be treated with hydroxychloroquine and azithromycin to cure their infection and to limit the transmission of the virus to other people in order to curb the spread of COVID-19 in the world.', 'Further works are also warranted to determine if these compounds could be useful as chemoprophylaxis to prevent the transmission of the virus, especially for healthcare workers.', 'Our study has some limitations including a small sample size, limited long-term outcome follow-up, and dropout of six patients from the study, however in the current context, we believe that our results should be shared with the scientific community.', 'a control patients from centers other than Marseille did not underwent daily sampling, but were sampled every other day in most cases, they were considered positive for PCR when actually positive the day(s) before and the day(s) after the day(s) with missing data.']}\n", - "{'sentences': ['Resemble to the other two coronaviruses, SARS-CoV and MERS-CoV, SARS-CoV-2 can cause patients severe respiratory symptoms and even leads to death with average mortality rate of 3.4% (according to the data reported from WHO) though most cases of COVID-19 are acute and resolve fast.', 'Liver damage has been identified in around 60% of patients suffering from SARS and viral RNA was detected by RT-PCR in liver tissue(10), which providing the evidence that SARS-CoV involved in liver injure.', 'Liver impairment has been also reported in MERS patients(11).', 'According to the clinical reports from different centers with large scale of COVID-19 cases, SARS-.', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', '1101 /2020 CoV-2 has been found to be associated with damage or dysfunction of liver tissue(9, 12-18) and about 14% -53% COVID-19 cases showed liver function damage with abnormal level of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).', 'Our study is in line with previous observations.', 'We found in COVID-19 cases without HBV infection that about 50.9% (55/108) patients have the dysfunction of liver symptoms by measuring the level of ALT, AST, TBIL, GGT, and ALP during the disease progress.', 'In our enrolled cases, we also discovered that there is higher incidence of abnormal liver function (81.8%, 27/33) in severe COVID-19 patients than did in mild cases (43.3%, 39/90, data not shown), which agrees with the study that lower incidence of AST', 'According to other study from 1099 cases, around 23.7% of confirmed patients have at least one comorbidity(13).', 'Among these pre-existing chronic diseases, abnormal liver function is one of most common features in COVID-19 patients and severe patients are more likely to have HBV infection.', 'In our research, about one out of five (7/33, 21.8%) COVID-19 severe patients were found to coinfect with HBV infection.', 'It has been suggested that liver impairment in COVID-19 patients could be due to the virus direct attack or resulted by other causes such as drug toxicity and systemic inflammation(18).', 'To detect the viral RNA and viral particles from liver biopsies of COVID-19 patients will be helpful to elucidate if virus infect liver tissue.', 'Our results pointed out that as high as around 50% (7/15) of HBV patients were identified as severe COVID-19 cases.', 'It is more likely that HBV patients will suffer .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.03.23.20040733 doi: medRxiv preprint from more severe situation during the disease progress when were encountered with SARS-CoV-2 infection.', 'In our enrolled cases, two patients with SARS-CoV and HBV coinfection died on admission.', 'One patient died from severe liver disease, haptic sclerosis.', 'And the other died from intestinal hemorrhage, which seems to be associated the impairment of gastrointestinal tract.', 'More coinfection cases analysis are required to further understand whether SARS-CoV-2 infection aggerates the progress of pre-existing disease and thereby cause death.', 'There are different phases for HBV chronic infection including immunotolerant, viral suppression under longterm treatment with nucleotide analogues.', 'In our current study, we collected the data of HBV on 15 coinfection patients at one time point, which were mainly used to identify HBV infection.', 'More coinfection cases analysis is required to provide further evidences for evaluating the effects of SARS-CoV-2 infection on active HBV replication and live impairment at different time points for the HBV patients in different phases.', 'In conclusion, by respectively analyzing the patients with coinfection of SARS-CoV-2 and HBV, we found that the patients with pre-existing HBV infection will be much more vulnerable to SARS-CoV-2 infection.', 'During the pandemic of SARS-CoV-2 infection, HBV patients should be given the specific protection.']}\n", - "{'sentences': ['We present here the design of the Mechanical Ventilator Milano (MVM), a novel mechanical ventilator designed for mass scale production in response to the COVID-19 pandemics, to compensate for the dramatic shortage of such ventilators in many countries.', 'This ventilator is an electro-mechanical equivalent of the old, reliable Manley Ventilator.', 'Our design is optimized to permit large sale production in short time and at a limited cost, relying on off-the-shelf components, readily available worldwide from hardware suppliers.', 'Operation of the MVM requires only a source of compressed oxygen (or compressed medical air) and electrical power.', 'At this stage the MVM is not a certified medical device.', 'Construction of the first prototypes is starting with a team of engineers, scientists and computing experts.', 'The purpose of this paper is to disseminate the conceptual design of the MVM broadly and to solicit feedback from the scientific and medical community to speed the process of review, improvement and possible implementation.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['A Systematic Review of Lopinavir Therapy for SARS Coronavirus and MERS Coronavirus–A Possible Reference for Coronavirus Disease-19 Treatment Option', 'Abstract In the past few decades, coronaviruses have risen as a global threat to public health.', 'Currently, the outbreak of coronavirus disease-19 (COVID-19) from Wuhan caused a worldwide panic.', 'There are no specific antiviral therapies for COVID-19.', 'However, there are agents that were used during the SARS and MERS epidemics.', 'We could learn from SARS and MERS.', 'Lopinavir (LPV) is an effective agent that inhibits the protease activity of coronavirus.', 'In this review, we discuss the literature on the efficacy of LPV in vitro and in vivo, especially in patients with SARS and MERS, so that we might clarify the potential for the use of LPV in patients with COVID-19']}\n", - "{'sentences': ['As of 8 February 2020, more than 30 000 laboratory confirmed cases of infection with the novel coronavirus (SARS-Cov-19) were reported in China.', 'The number of infections is increasing rapidly.', 'It is possible that an even greater number of infected patients exist without a diagnosis because their symptoms were less severe and because of the incubation period.', 'Thousands of patients with suspected SARS-Cov-2 infection could eventually receive a diagnosis.', 'The clinical features of early cases of covid-19 in Wuhan were not the same as those in other areas of China.', 'According to our data, none of the infected patients in Zhejiang province had been exposed to the Huanan seafood market, and as the number of familial clusters in infected patients in our study is large, this might suggest human to human transmission.', 'This finding is also consistent with a published article.', '10 Further detailed investigations should aim to ascertain the exact mode of transmission.', 'Most of the infected individuals in Zhejiang province were male patients, but the age range of patients is large as SARS-Cov-2 also infected children and those older than 65 years.', '9 13 No major differences were found between the initial clinical symptoms of patients in Zhejiang province and those in Wuhan.', 'Most of http://www.bmj.com/ the patients in Zhejiang province, however, had mild to moderate symptoms, and only a small portion of them had dyspnoea.', 'Only one patient developed acute respiratory distress syndrome and was admitted to an intensive care unit.', 'The laboratory test results showed that the patients also experienced mild illness.', 'There were fewer patients with abnormal renal function and lactate dehydrogenase and procalcitonin levels.', 'Through media and national advocacy, patients with fever, cough, expectoration, and other upper respiratory tract symptoms were asked to go to hospital at an early stage.', 'Even those who had contact with other patients, or patients with suspected infection were asked to go to hospital.', 'We also analysed patients with symptoms for more than 10 days after illness onset.', 'We found that the clinical features of patients with symptoms for longer than 10 days in Zhejiang province were less severe than those of the primary infected patients from Wuhan.', '9 13 This phenomenon was also apparent during the transmission of MERS-CoV. The global case mortality of MERS-CoV was about 40%, whereas the mortality from second generation MERS-CoV was about 20%.', '14 15 Patients in the two cohorts received antiviral treatment, but the types of drugs used varied between patients.', 'Treatment with lopinavir and ritonavir were reported to have the potential to treat SARS infections, 16 and we suppose this treatment might be a beneficial part of the treatment for covid-19.', 'The rate of antibiotic and corticosteroid use was different.', 'Less than half the patients in Zhejiang province received antibiotics.', 'Whether the use of antivirals, antibiotics, or steroids affects the prognosis of patients remains unknown.', 'Given that most infections in Zhejiang province were in patients who had no direct contact with the original site of outbreak, our findings provide valuable information in the understanding of the clinical features of covid-19, as the number of people with confirmed disease continues to increase rapidly.', 'Our study population might represent most of the clinical characteristics of infected patients since January 2020.', 'Further containment proposals should be implemented by the Chinese government, such as preventing people from Wuhan having contact with those elsewhere, banning gatherings of more than 100 people, conducting daily public-wide educational campaigns on precautionary measures against exposure to SARS-Cov-2, encouraging people to cancel traditional family gatherings such as during the Chinese lunar new year, and extending the Chinese lunar new year holiday to prevent large scale spread.']}\n", - "{'sentences': [\"[{'text': '2019-nCoV is a newly identified coronavirus with high similarity to SARS-CoV. We performed a structural analysis of the receptor binding domain (RBD) of spike glycoprotein responsible for entry of coronaviruses into host cells.\", 'The RBDs from the two viruses share 72% identity in amino acid sequences, and molecular simulation reveals highly similar ternary structures.', 'However, 2019-nCoV has a distinct loop with flexible glycyl residues replacing rigid prolyl residues in SARS-CoV. Molecular modeling revealed that 2019-nCoV RBD has a stronger interaction with angiotensin converting enzyme 2 (ACE2).', 'A unique phenylalanine F486 in the flexible loop likely plays a major role because its penetration into a deep hydrophobic pocket in ACE2.', 'ACE2 is widely expressed with conserved primary structures throughout the animal kingdom from fish, amphibians, reptiles, birds, to mammals.', 'Structural analysis suggests that ACE2 from these animals can potentially bind RBD of 2019-nCoV, making them all possible natural hosts for the virus.', '2019-nCoV is thought to be transmitted through respiratory droplets.', 'However, since ACE2 is predominantly expressed in intestines, testis, and kidney, fecal-oral and other routes of transmission are also possible.', 'Finally, antibodies and small molecular inhibitors that can block the interaction of ACE2 with RBD', 'Since its initial outbreak, the 2019-nCoV infection is much more contagious than it was originally thought.', 'We know that the virus is capable of spreading quickly from human to human and that people can spread the virus even before they become symptomatic [1] .', 'This makes it harder to contain the virus, and many are concerned about the possibility of a new pandemic.', 'Our study suggests unique structural features of the spike glycoprotein RBD of 2019-nCoV that confers potentially higher affinity binding for its receptor than found with SARS-CoV. With a higher affinity binding capability, the number of viruses required to infect a cell is much reduced.', 'This partly explains why 2019-nCoV appears to be more aggressive than SARS-CoV. This also reminds us of a lesser-known coronavirus HCoV-NL63 that also uses ACE2 also as a receptor.', 'HCoV-NL63 was initially isolated from a child with bronchiolitis in the Netherlands [21] .', 'It belongs to the alphacoronavirus subfamily.', 'The RBD of SARS-CoV shares no structural homology with that of SARS-CoV but recognizes the same region in ACE2.', 'However, cocrystal structure reveals that RBD of NL63-CoV has a narrower contact with ACE2, involving fewer amino acids [22] .', 'This presumably results in a weaker interaction.', 'Evidently, NL63-CoV does not spread aggressively and only causes mild to moderate respiratory infections [23] .', 'The exact mode of transmission for 2019-nCoV has not been firmly established.', 'SARS-CoV is thought to be transmitted by respiratory droplets produced when an infected person coughs or sneezes [19] .', 'The respiratory droplets spread can occur only through direct person-to-person contact or at a close distance.', 'Presumably, 2019-nCoV can be transmitted through respiratory droplets.', 'It may also be transmitted more effectively through the air over a long distance (airborne spread) or by other ways.', 'Considering the predominant expression of ACE2 in intestines and kidney, 2019-nCoV may infect cells in these tissues and find its way into feces and urine.', 'This makes transmission through the fecal-oral route and bodyfluids (urine) possible.', 'The presence of 2019-nCoV in feces supports such a notion [20] .', 'Specific RBD-receptor binding determines if a cell or animal can be infected and also serves as a target for therapeutic inventions to treat diseases caused by coronaviruses.', 'By binding directly to ACE2 on the surface of host cells, spike glycoprotein plays an essential role in virus infection.', 'An obvious way to stop the virus infection is to block the RBD and ACE2 interaction.', 'This can be achieved by using antibodies or small molecular inhibitors.', 'Naturally, antibodies and inhibitors that can disrupt the interaction of RBD with ACE2 is of therapeutic importance.', 'By using a molecular docking approach, an earlier study identified N-(2-aminoethyl)-1 aziridineethanamine as a novel ACE2 inhibitor that effectively blocks the SARS-CoV RBD-mediated cell fusion [24] .', 'This has provided a potential candidate and lead compound for further therapeutic drug development.', 'Meanwhile, biochemical and cell-based assays can be established to screen chemical compound libraries to identify novel inhibitors.', 'On the other hand, many ACE inhibitors are currently used to treat hypertension and other cardiovascular diseases [25] .', 'Among them are captopril, perindopril, ramipril, lisinopril, benazepril, and moexipril.', 'Although these drugs primarily target ACE, a homolog of ACE2 with 42% sequence identity and 61% sequence similarity in the catalytic domain, they may be effective toward ACE2 as well [26] .', 'It should be noted that ACE inhibitors bind to the catalytic center rather than RBD binding site.', 'Nonetheless, these enzymatic inhibitors may indirectly alter conformation of the RBD binding site and thereby affect the interaction of ACE2 with RBD.', 'It is certainly worthwhile to test these drugs for their ability to block the RBD/ACE2 interaction.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Nelfinavir inhibits replication of severe acute respiratory syndrome coronavirus 2 in vitro.', 'In December 2019, severe acute respiratory syndrome coronavirus 2 (severe acute respiratory syndrome coronavirus 2) emerged in Wuhan, Hubei Province, China.', 'No specific treatment has been established against coronavirus disease-2019 (COVID-19) so far.', 'Therefore, it is urgently needed to identify effective antiviral agents for the treatment of this disease, and several approved drugs such as lopinavir have been evaluated.', 'Here, we report that nelfinavir, an HIV-1 protease inhibitor, potently inhibits replication of severe acute respiratory syndrome coronavirus 2.', 'The effective concentrations for 50% and 90% inhibition (EC50 and EC90) of nelfinavir were 1.13 µM and 1.76 µM respectively, the lowest of the nine HIV-1 protease inhibitors including lopinavir.', 'The trough and peak serum concentrations of nelfinavir were three to six times higher than EC50 of this drug.', 'These results suggest that nelfinavir is a potential candidate drug for the treatment of COVID-19 and should be assessed in patients with COVID-19', 'All rights reserved.', 'No reuse allowed without permission.', 'Nelfinavir showed the lowest EC 50 (1.13 µM), the highest SI (23.32), the second highest C max -EC 50 ratio (6.23), and the highest C trough -EC 50 ratio (3.43) among the tested HIV-1 protease inhibitors.', 'These data indicate that nelfinavir is the best of nine drugs as a potential drug candidate for the treatment of COVID-19.', 'Lopinavir showed the inferior results to nelfinavir, namely, higher EC 50 (5.73 µM), lower SI (12.99), lower C max -EC 50 ratio (2.72), and lower C trough -EC 50 ratio (1.97) than nelfinavir.', 'In a recent randomized, controlled, open-label trial, lopinavir-ritonavir did not significantly accelerate clinical improvement, reduce 28-day mortality, or decrease throat viral RNA amount in patients with severe COVID-19 6 .', 'One of the reasons why the efficacy of author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.06.026476 doi: bioRxiv preprint lopinavir-ritonavir was not confirmed in the clinical trial might be associated with insufficient C max -EC 50 and C trough -EC 50 ratio to treat severe COVID-19.', 'It remains to be determined whether earlier lopinavir-ritonavir treatment in mild COVID-19 could have clinical benefit.', 'Tipranavir showed the highest C max -EC 50 ratio (6.46) and the second highest C trough -EC 50 ratio (2.89) of all tested drugs.', 'This is because C max and C trough are much higher than the other tested drugs (Fig. 1j) .', 'Since SI of tipranavir was less than that of nelfinavir (5.76 vs. 21.52), nelfinavir seems better than tipranavir.', 'The low SI of tipranavir may raise concern about adverse effects to COVID-19 patients.', 'Our findings reveal that nelfinavir is highly effective in inhibiting SARS-CoV-2 replication in vitro and has the high C max -EC 50 and C tough -EC 50 ratio.', 'We suggest that nelfinavir is a potential candidate drug for the treatment of COVID-19 and should be assessed in the patients with COVID-19.', 'All rights reserved.', 'No reuse allowed without permission.', 'For the evaluation of the nine HIV-1 protease inhibitors, the 50% effective concentration (EC 50 ), the 50% cytotoxic concentration (CC 50 ), and the selectivity index (SI, CC 50 /EC 50 ) were analyzed.', 'Moreover, based on the mean peak and trough serum concentration (C max and C trough ) of the compounds in human, C max -EC 50 ratio (C max /EC 50 ) and C trough -EC 50 ratio (C trough /EC 50 ) were calculated to assess the safety and efficacy of these compounds.', 'Among these inhibitors tested, the high concentrations of drugs were required to inhibit SARS-CoV-2 replication in amprenavir (EC 50 = 31.32 µM, CC 50 > 81 µM, SI > 2.59), darunavir (EC 50 = 46.41 µM, CC 50 > 81 µM, SI > 1.75), and indinavir (EC 50 = 59.14 µM CC 50 > 81 µM, SI > 1.37) (Fig. 1g , h, i, j).', 'Tipranavir inhibited replication of SARS-CoV-2, but SI was relatively low (EC 50 = 13.34 µM, CC 50 = 76.80 µM, SI = 5.76) (Fig. 1f, j) .', 'Ritonavir (EC 50 = 8.63 µM, CC 50 = 74.11 µM, SI = 8.59), saquinavir author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.06.026476 doi: bioRxiv preprint (EC 50 = 8.83 µM, CC 50 = 44.43 µM, SI = 5.03), and atazanavir (EC 50 = 9.36 µM, CC 50 > 81 µM, SI > 8.65) suppressed SARS-CoV-2 at less than 10 µM (Fig. 1c , d, e, j).', 'Lopinavir, which has been clinically tested in patients with SARS and COVID-19, blocked SARS-CoV-2 replication at a low concentration range and its SI was relatively high among nine inhibitors (EC 50 = 5.73 µM, CC 50 = 74.44 µM, SI = 12.99) (Fig. 1b, j) .', 'Notably, nelfinavir (EC 50 = 1.13 µM, CC 50 = 24.32 µM, SI = 21.52) potently inhibited virus replication at the lowest concentration and exhibited the highest SI in the tested HIV-1 protease inhibitors (Fig. 1a, j) .', 'To examine the target step of HIV-1 protease inhibitors in the virus life cycle, time-of-addition assays were performed.', 'Intra-cellular viral RNA was quantified at 6 hpi with varying timing of drug addition.', 'Nelfinavir and lopinavir suppressed multiplication of viral RNA in the cells even when these drugs were added at 3.5 hpi (Fig. S1 ).', 'These results suggest that both drugs functioned at the post-entry step.', 'Next, C max -EC 50 ratio and C trough -EC 50 ratio of nine compounds were calculated to estimate the clinical efficacy against COVID-19.', 'Nelfinavir (C max /EC 50 = 6.23, C trough /EC 50 = 3.43), lopinavir (C max /EC 50 = 2.72, C trough /EC 50 = 1.97), and tipranavir (C max /EC 50 = 6.46, C trough /EC 50 = 2.89) exhibited C trough -EC 50 ratio higher than one (Fig. 1k ).', 'Ritonavir exceeded one in C max -EC 50 ratio, but did not in C trough -EC 50 ratio (C max /EC 50 = 1.80, C trough /EC 50 = 0.56).', 'Saquinavir (C max /EC 50 = 0.73, C trough /EC 50 = 0.07), atazanavir (C max /EC 50 = 0.93, C trough /EC 50 = 0.19), amprenavir (C max /EC 50 = 0.46, C trough /EC 50 = 0.09), darunavir (C max /EC 50 = 0.27, C trough /EC 50 = 0.05), and indinavir (C max /EC 50 = 0.21, C trough /EC 50 = 0.004) could not reach one in the C max -EC 50 ratio.', 'These results suggest that nelfinavir, lopinavir, and tipranavir can achieve EC 50 of each drug in human and are effective in the treatment of COVID-19 patients.']}\n", - "{'sentences': ['Lack of Antiviral Activity of Darunavir against SARS-CoV-2', 'Given the high need and the absence of specific antivirals for treatment of COVID-19 (the disease caused by severe acute respiratory syndrome-associated coronavirus-2 [SARS-CoV-2]), human immunodeficiency virus (HIV) protease inhibitors are being considered as therapeutic alternatives.', 'Prezcobix/Rezolsta is a fixed-dose combination of 800 mg of the HIV protease inhibitor darunavir (DRV) and 150 mg cobicistat, a CYP3A4 inhibitor, which is indicated in combination with other antiretroviral agents for the treatment of HIV infection.', 'There are currently no definitive data on the safety and efficacy of DRV/cobicistat for treatment of COVID-19.', 'The in vitro antiviral activity of darunavir against a clinical isolate from a patient infected with SARS-CoV-2 was assessed.', 'DRV showed no activity against SARS-CoV-2 at clinically relevant concentrations (EC 50 >100 μ M).', 'Remdesivir, used as a positive control, showed potent antiviral activity (EC 50 = 0.38 μ M).', 'Overall, the data do not support the use of DRV', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'Current efforts to manage the COVID-19 pandemic have largely focused on improved hygiene, quarantine of infected individuals, social distancing to limit transmission and development of a vaccine (15) .', 'Despite the expedited efforts to develop a vaccine and collaborative efforts to screen compounds in discovery and development across the broader pharmaceutical industry for activity against COVID-19, patients are in immediate need of therapeutic interventions (12, 16) .', 'Current data on the therapeutic effect of HIV protease inhibitors in patients with COVID-19 are far from comprehensive.', 'This study demonstrated that DRV showed no in vitro antiviral activity against SARS-CoV-2 at clinically relevant concentrations.', 'Furthermore, structural analyses using protease structures are consistent with these data.', \"DRV binds to the active site of the HIV virus' dimeric aspartic protease (14) .\", 'The crystal structure of this protease is well-elucidated and has been shown to have an extensive hydrogen-bonding network with DRV, allowing for the potent in vitro activity (EC 50 values = 1.2 to 8.5 nM) of this protease inhibitor against HIV (6-7).', 'By contrast, the SARS-CoV-2 main protease is a cysteine protease (Protein Data Bank-code 6LU7) and while several docking poses have been found for DRV in in silico models, unlike in HIV, these poses showed little interaction with the SARS-CoV-2 main protease active site.', 'Several publications describe in silico docking experiments on the main coronavirus protease that specifically focus on or include DRV (17) (18) (19) (20) (21) .', 'Although these studies suggest DRV as a candidate for further investigation, such promising docking results could not be reproduced in our in silico docking studies.', 'Such discrepancies can often result from in silico docking, which is primarily a useful approach for identifying subsets of molecules for in vitro activity testing.', 'No in vitro antiviral activity of DRV against SARS-CoV-2 was found in the experiments reported here.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', '03.20052548 doi: medRxiv preprint In this study, remdesivir demonstrated activity against SARS-CoV-2 with an EC 50 of 0.38 μ M, which is in line with the earlier reported remdesivir EC 50 of 0.77 µM, indicating that the in vitro antiviral assay used is appropriate to assess antiviral activity against SARS-CoV-2 (12) .', 'In conclusion, the lack of in vitro antiviral activity of DRV against SARS-CoV-2 does not support the use of DRV for treatment of COVID-19.', 'Hence, the use of DRV (boosted with either ritonavir or cobicistat) should remain solely for treatment of patients with HIV infection.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.03.20052548 doi: medRxiv preprint']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['In this study, we found enhanced IgM levels at early stage, and high levels were more frequently found in patients with severe disease.', 'IgG levels increased at late stage, whereas high levels of IgG were frequently found in patients with severe disease.', 'These results indicated that beside the antiviral efficacy, the antibody response might be associated with secondary antibody-mediated organ damage.', 'Using NLR and IgG levels detected in sera at late stage, we develop a combined immune response phenotype, which could predict disease severity and the outcome of COVID-19 patient.', 'To our knowledge, this is the first in the literatures to combine indicators from innate and acquired immunity to predict disease severity and outcome.', 'Anti-SARS-CoV-2-IgG can be detected at day 4 after onset, and it has peak levels at the fourth week, which is similar to the Anti-SARS-CoV-IgG response profile.', '6 Previous data showed severe SARS was associated more robust serological responses including early seroconversion (70%) in the neutralization assay, and therefore, may explain the little difference among difference groups.', 'All the m336-based fusion proteins could be easily produced in E. coli in large amount and low production cost.', 'Their sizes are larger than m336 scFv or HR2P peptides, suggesting that they would possess longer in vivo half-life.', 'Still, their half-life would be shorter than full-size IgG due to the lack of Fc region.', 'Therefore, their prophylactic and therapeutic efficacy against MERS-CoV should be assessed carefully using different approaches and doses in vivo.', 'However, the RBD of MERS-CoV specifically targets on human DPP4 [29], and most small animal models are not susceptible to MERS-CoV infection [55], which pose a significant barrier to the development of anti-MERS-CoV inhibitors.', 'Fortunately, researchers have constructed several animal models recently that simulate the morbidity and mortality of human infections, of which nonhuman primates (NHP']}\n", - "{'sentences': ['Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro', \"[{'text': 'An escalating pandemic by the novel SARS-CoV-2 virus is impacting global health and effective therapeutic options are urgently needed.\", 'We evaluated the in vitro antiviral effect of compounds that were previously reported to inhibit coronavirus replication and compounds that are currently under evaluation in clinical trials for SARS-CoV-2 patients.', 'We report the antiviral effect of remdesivir, lopinavir, homorringtonine, and emetine against SARS-CoV-2 virus in Vero E6 cells with the estimated 50% effective concentration at 23.15 μM, 26.63 μM, 2.55 μM and 0.46 μM, respectively.', 'Ribavirin or favipiravir that are currently evaluated under clinical trials showed no inhibition at 100 μM. Synergy between remdesivir and emetine was observed, and remdesivir at 6.25 μM in combination with emetine at 0.195 μM may achieve 64.9% inhibition in viral yield.', \"Combinational therapy may help to reduce the effective concentration of compounds below the therapeutic plasma concentrations and provide better clinical benefits.', 'cite_spans': [], 'ref_spans': [], 'section': 'Abstract'}]\"]}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Indomethacin has a potent antiviral activity against SARS CoV-2 in vitro and canine coronavirus in vivo', 'The outbreak of SARS CoV-2 has caused ever increasing attention and public panic all over the world.', 'Currently, there is no specific treatment against the SARS CoV-2.', 'Therefore, identifying effective antiviral agents to combat the disease is urgently needed.', 'Previous studies found that indomethacin has the ability to inhibit the replication of several unrelated DNA and RNA viruses, including SARS-CoV. We found that indomethacin has a directly and potently antiviral activity against the SARS CoV-2 pseudovirus.', 'In canine coronavirus-infected dogs, recovery occurred significantly sooner with symptomatic treatment + oral indomethacin (1 mg/kg body weight) daily treatments than with symptomatic treatment + ribavirin (10-15 mg/kg body weight) daily treatments (P =0.0031), but was not significantly different from that with symptomatic treatment + anti-canine coronavirus serum + canine hemoglobin + canine blood immunoglobulin + interferon treatments (P =0.7784).']}\n", - "{'sentences': ['Abstract Background From December 2019 to February 2020, 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a serious outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China.', 'Related clinical features are needed.', 'Methods We reviewed 69 patients who were hospitalized in Union hospital in Wuhan between January 16 to January 29, 2020.', 'All patients were confirmed to be infected with SARS-CoV-2 and the final date of follow-up was February 4, 2020.', 'Results The median age of 69 enrolled patients was 42.0 years (IQR 35.0-62.0), and 32 patients (46%) were men.', 'The most common symptoms were fever (60[87%]), cough (38[55%]), and fatigue (29[42%]).', 'Most patients received antiviral therapy (66 [98.5%] of 67 patients) and antibiotic therapy (66 [98.5%] of 67 patients).', 'As of February 4, 2020, 18 (26.9%) of 67 patients had been discharged, and five patients had died, with a mortality rate of 7.5%.', 'According to the lowest SpO2 during admission, cases were divided into the SpO2≥90% group (n=55) and the SpO2<90% group (n=14).', 'All 5 deaths occurred in the SpO2<90% group.', 'Compared with SpO2≥90% group, patients of the SpO2<90% group were older, and showed more comorbidities and higher plasma levels of IL6, IL10, lactate dehydrogenase, and c reactive protein.', 'Arbidol treatment showed tendency to improve the discharging rate and decrease the mortality rate.']}\n", - "{'sentences': [\"[{'text': 'Background: The safety of performing spinal anaesthesia for both patients and anaesthetists alike in the presence of active infection with the novel coronavirus disease 2019 (COVID-19) is unclear.\", 'Here, we report the clinical characteristics and outcomes for both patients with COVID-19 and the anaesthetists who provided their spinal anaesthesia.', 'Methods: Forty-nine patients with radiologically confirmed COVID-19 for Caesarean section or lower-limb surgery undergoing spinal anaesthesia in Zhongnan Hospital, Wuhan, China participated in this retrospective study.', 'Clinical characteristics and perioperative outcomes were recorded.', 'For anaesthesiologists exposed to patients with COVID-19 by providing spinal anaesthesia, the level of personal protective equipment (PPE) used, clinical outcomes (pulmonary CT scans), and confirmed COVID-19 transmission rates (polymerase chain reaction [PCR]) were reviewed.', 'Results: Forty-nine patients with COVID-19 requiring supplementary oxygen before surgery had spinal anaesthesia (ropivacaine 0.75%), chiefly for Caesarean section (45/49 [91%]).', 'Spinal anaesthesia was not associated with cardiorespiratory compromise intraoperatively.', 'No patients subsequently developed severe pneumonia.', 'Of 44 anaesthetists, 37 (84.1%) provided spinal anaesthesia using Level 3 PPE.', 'Coronavirus disease 2019 infection was subsequently confirmed by PCR in 5/44 (11.4%) anaesthetists.', 'One (2.7%) of 37 anaesthetists who wore Level 3 PPE developed PCR-confirmed COVID-19 compared with 4/7 (57.1%) anaesthetists who had Level 1 protection in the operating theatre (relative risk reduction: 95.3% [95% confidence intervals: 63.7e99.4]; P<0.01).', 'Conclusions: Spinal anaesthesia was delivered safely in patients with active COVID-19 infection, the majority of whom had Caesarean sections.', 'Level 3 PPE', 'This is the largest case series exploring the risk for anaesthetists of developing COVID-19 through exposure to infected surgical patients undergoing spinal anaesthesia.', 'The clinical characteristics of the 49 infected surgical patients were typical of the majority of adults with COVID-19 infection.', '8 We found that spinal anaesthesia had no adverse effects, either during the intraoperative period or subsequently.', 'However, based on our follow-up of 44 anaesthetists who delivered spinal anaesthesia, our data suggest that Level 3 PPE is likely to reduce the risk of acquiring COVID-19.', 'Spinal anaesthesia is the anaesthetic of choice for many surgical procedures, in particular Caesarean sections.', 'However, whether the risk of spinal anaesthesia to anaesthetists being undertaken in patients with COVID-19 is uncertain.', 'Using ropivacaine, we found that spinal anaesthesia had no adverse impact during the intraoperative period.', '10 Typical changes in leucocyte count were observed after surgery.', '11 Most importantly, spinal anaesthesia did not appear to worsen the outcome of patients with SARS-CoV-2 pneumonia.', 'Level 3 PPE 12 was used by most anaesthetists, but seven anaesthetists used Level 1 protection because of delayed confirmation of COVID-19 in patients undergoing surgery.', 'Our study provides further evidence of human-to-human transmission in hospitals, although this is lower than previous reports.', '13 Most infected anaesthetists had mild symptoms.', 'The low transmission rate may, however, be attributable to additional factors.', 'First, most operating theatres are under positive pressure with up to 20 room air exchanges per hour, thereby reducing viral exposure rapidly.', 'Second, all surgical patients in this study had mild symptoms.', 'Third, several anaesthetists were fully protected and took prophylactic drugs.', 'We confirmed previous studies demonstrating that asymptomatic infected anaesthetists, as confirmed by PCR, frequently do not have concomitant radiological abnormalities.', '15 False-negative PCR testing for throat swabs has been documented during this outbreak, highlighting the importance of clinical symptoms (fever, fatigue, dry cough, myalgia, and dyspnoea) in recognising COVID-19 at an early stage.', 'This study clearly has multiple limitations.', 'First, throat swabs were used to diagnose COVID-19 through RTePCR, rather than blood samples.', 'False-negative tests may occur using throat swab samples.', 'Second, as most patients with COVID-19 undergoing surgery had mild symptoms, we cannot address whether tracheal intubation/extubation is similarly, or more, hazardous compared with regional anaesthesia.', 'We also cannot exclude that anaesthetists became infected through other sources (e.g. colleagues in the hospital).', 'In summary, spinal anaesthesia appears to be safe in mildly symptomatic COVID-19 patients.', 'Our study suggests that using Level 3 PPE is likely to reduce the risk to anaesthetic staff of acquiring COVID-19 even from patients with mild symptoms.', 'Considering the significance of this ongoing global public health emergency, our report contributes valuable data to inform the perioperative community.']}\n", - "{'sentences': ['Favorable changes of CT findings in a patient with COVID-19 pneumonia after treatment with tocilizumab']}\n", - "{'sentences': ['23 BACKGROUND 24 The ongoing worldwide outbreak of the 2019-nCoV is markedly similar to the severe acute 25 respiratory syndrome (SARS) outbreak 17 years ago.', 'During the 2002-2003 SARS', 'A long-term prospective cohort study followed 34 SARS-CoV-infected healthcare workers from a 31 hospital with clustered infected cases during the 2002-2003 SARS outbreak in Guangzhou, China, 32 with a 13-year follow-up.', 'Serum samples were collected annually from 2003-2015.', 'Twenty 33 SARS-CoV-infected and 40 non-infected healthcare workers were enrolled in 2015, and their serum 34 samples were collected.', 'All sera were tested for IgG antibodies with ELISA using whole virus and a 35 recombinant nucleocapsid protein of SARS-CoV, as a diagnostic antigen.', 'Anti SARS-CoV IgG was found to persist for up to 12 years.', 'IgG titers typically peaked in 2004,', 'declining rapidly from 2004-2006, and then continued to decline at a slower rate.', 'IgG titers in 39 .', 'CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', '(which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.02.12.20021386 doi: medRxiv preprint SARS-CoV-infected healthcare workers remained at a significantly high level until 2015.', 'Patients 40 treated with corticosteroids at the time of infection were found to have lower IgG titers than those 41 without.', '42 CONCLUSIONS 43 IgG antibodies against SARS-CoV can persist for at least 12 years.', 'The presence of SARS-CoV IgG 44 might provide protection against SARS-CoV and other betacoronavirus.', 'This study provides valuable 45 information regarding humoral immune responses against SARS-CoV and the 2019-nCoV.']}\n", - "{'sentences': ['Structural Basis for the Inhibition of the RNA-Dependent RNA Polymerase from SARS-CoV-2 by Remdesivir', 'become a global crisis.', 'The replication of SARS-CoV-2 requires the viral RNA-dependent RNA polymerase (RdRp), a direct target of the antiviral drug, Remdesivir.', 'Here we report the structure of the SARS-CoV-2 RdRp either in the apo form or in complex with a 50base template-primer RNA and Remdesivir at a resolution range of 2.5-2.8 Å. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp', 'The pandemic of COVID-19 caused by infection of SARS-CoV-2 has become a humanitarian crisis, with over 1.5 million infections and 87,000 death as reported on April 8 th of 2020(1, 2).', 'SARS-CoV-2 is closely related to severe acute respiratory syndrome coronavirus (SARS-CoV) and several members from the beta coronavirus family, including bat and pangolin coronaviruses(3-5).', 'Possibly due to the stronger binding affinity of the virus spike protein with the host receptor(6-10), SARS-CoV-2 appears to have much higher incidence of human to human transmission, resulting in much faster pace of infection worldwide.', 'Tremendous challenges remain with ongoing battles against this notorious viral infection in many countries and finding an effective cure is an urgent need.', 'SARS-CoV-2 is a positive strand RNA virus, whose replication is mediated by a multi-subunit replication/transcription complex of viral non-structural proteins (nsp)(11).', 'The core component of this complex is the catalytic subunit (nsp12) of an RNA-dependent RNA polymerase (RdRp) (12, 13) .', 'The nsp12 by itself has little activity and its functions require accessary factors including nsp7 and nsp8 (14, 15) , which increase the RdRp activity in template binding and processivity.', 'The RdRp is also proposed to be the target of nucleotide class of antiviral drugs, including Remdesivir(16-18), which is a prodrug that is converted to the active drug in the triphosphate form (RTP) within cells (19) .', 'As such, RdRp has been a subject of intensive efforts of structural biology.', 'The structures of nsp7, nsp8, and the complex of nsp12-nsp7-nsp8 have been determined (15, (20) (21) (22) (23) , providing an overall architecture of the RdRp']}\n", - "{'sentences': ['The current study was designed to construct possible vaccines against the Wuhan Novel Coronavirus 2019 (study was designed to construct possible vaccines against the Wuhan Novel Coronavirus 2019', 'The physicochemical property analysis was conducted for the two predicted antigenic proteins.', 'The extinction coefficient can be defined as the amount of light that is absorbed by a particular compound at a certain wavelength [186] [187] .', 'Surface glycoprotein had the highest predicted extinction co-efficient of 148960 M -1 cm -1 .', 'The aliphatic index of a protein corresponds to the relative volume occupied by the aliphatic amino acids in the side chains of the protein, for example: alanine, valine etc.', 'Surface glycoprotein also had the highest predicted aliphatic index among the two proteins (84.67).', 'For this reason, surface glycoprotein had greater amount of aliphatic amino acids in its side chain than the nucleocapsid phosphoprotein.', 'The grand average of hydropathicity value (GRAVY', 'The epitopes with high antigenicity, non-allergenicity and non-toxicity were selected to vaccine construction.', 'The B-cell epitopes (predicted by the server) that were more than ten amino acids long were taken into consideration and the antigenic and non-allergenic epitopes were selected for vaccine construction.', 'However, most of the epitopes were found to be residing within the cell membrane.', 'The cluster analysis of the MHC alleles which may interact with the selected epitopes during the immune response, showed quite good interaction with each other.', 'Next the 3D structures of the selected epitopes were generated for peptide-protein docking study.', 'The docking was carried out .', 'CC-BY 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.02.05.935072 doi: bioRxiv preprint to find out whether all the epitopes had the capability to bind with their respective MHC class-I and MHC class-II alleles.', 'Since all the epitopes generated quite good docking scores, it can be concluded that, all of them had the capability to bind with their respective targets and induce potential immune response.', 'However, among the selected epitopes, QLESKMSGK, LIRQGTDYKHWP, GVLTESNKK and TSNFRVQPTESI generated the best docking scores.', 'After the successful docking study, the vaccine construction was performed.', 'The linkers were used to connect the T-cell and B-cell epitopes among themselves and also with the adjuvant sequences as well as the PADRE sequence.', 'The vaccines, with three different adjuvants, were constructed and designated as: CV-1, CV-2 and CV-3.', 'Since all the three vaccines were found to be antigenic, they should be able to induce good immune response.', 'Moreover, all of them were possibly nonallergenic, they should not be able to cause any allergenic reaction within the body as per in silico The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.02.05.935072 doi: bioRxiv preprint antigen.', 'Moreover, the conventional approach of vaccine development have raised many safety concerns in many pre-clinical and clinical trials.', 'The subunit vaccines like the vaccines predicted in the study could overcome such difficulties [196] - [200] .', 'Finally, this study recommends CV-1 as the best vaccine to be an effective worldwide treatment based on the strategies employed in the study to be triggered against SARS-CoV-2 infection.', 'However, further in vivo and in vitro experiments are suggested to strengthen the findings of this study.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Our report of the first confirmed case of 2019-nCoV in the United States illustrates several aspects of this emerging outbreak that are not yet fully understood, including transmission dynamics and the full spectrum of clinical illness.', 'Our case patient had traveled to Wuhan, China, but reported that he had not visited the wholesale seafood market or health care facilities or had any sick contacts during his stay in Wuhan.', 'Although the source of his 2019-nCoV infection is unknown, evidence of person-to-person transmission has been published.', 'Through January 30, 2020, no secondary cases of 2019-nCoV related to this case have been identified, but monitoring of close contacts continues.19', 'Detection of 2019-nCoV RNA in specimens from the upper respiratory tract with low Ct values on day 4 and day 7 of illness is suggestive of high viral loads and potential for transmissibility.', 'It is notable that we also detected 2019-nCoV RNA in a stool specimen collected on day 7 of the patient’s illness.', 'Although serum specimens from our case patient were repeatedly negative for 2019-nCoV, viral RNA has been detected in blood in severely ill patients in China.4 However, extrapulmonary detection of viral RNA does not necessarily mean that infectious virus is present, and the clinical significance of the detection of viral RNA outside the respiratory tract is unknown at this time.', 'Currently, our understanding of the clinical spectrum of 2019-nCoV infection is very limited.', 'Complications such as severe pneumonia, respiratory failure, acute respiratory distress syndrome (ARDS', 'Our case patient initially presented with mild cough and low-grade intermittent fevers, without evidence of pneumonia on chest radiography on day 4 of his illness, before having progression to pneumonia by illness day 9.', 'These nonspecific signs and symptoms of mild illness early in the clinical course of 2019-nCoV infection may be indistinguishable clinically from many other common infectious diseases, particularly during the winter respiratory virus season.', 'In addition, the timing of our case patient’s progression to pneumonia on day 9 of illness is consistent with later onset of dyspnea (at a median of 8 days from onset) reported in a recent publication.4 Although a decision to administer remdesivir for compassionate use was based on the case patient’s worsening clinical status, randomized controlled trials are needed to determine the safety and efficacy of remdesivir and any other investigational agents for treatment of patients with 2019-nCoV infection.', 'We report the clinical features of the first reported patient with 2019-nCoV infection in the United States.', 'Key aspects of this case included the decision made by the patient to seek medical attention after reading public health warnings about the outbreak; recognition of the patient’s recent travel history to Wuhan by local providers, with subsequent coordination among local, state, and federal public health officials; and identification of possible 2019-nCoV infection, which allowed for prompt isolation of the patient and subsequent laboratory confirmation of 2019-nCoV, as well as for admission of the patient for further evaluation and management.', 'This case report highlights the importance of clinicians eliciting a recent history of travel or exposure to sick contacts in any patient presenting for medical care with acute illness symptoms, in order to ensure appropriate identification and prompt isolation of patients who may be at risk for 2019-nCoV infection and to help reduce further transmission.', 'Finally, this report highlights the need to determine the full spectrum and natural history of clinical disease, pathogenesis, and duration of viral shedding associated with 2019-nCoV infection to inform clinical management and public health decision making.']}\n", - "{'sentences': ['Contamination of frequent touch surfaces in healthcare settings are a potential source of viral transmission.', 'Data on the transmissibility of coronaviruses from contaminated surfaces to hands were not found.', 'However, it could be shown with influenza A virus that a 5 s contact is sufficient to transfer 31.6% of the viral load to the hands [9] .', 'The transfer efficiency was lower with parainfluenza-virus 3 (1.5%) [10] .', 'Although the viral load of coronaviruses on inanimate surfaces is not known during an outbreak situation it seems plausible to reduce the viral load on surfaces by disinfection, especially on frequent touch surfaces in the immediate patient surrounding where the highest viral load can be expected.', 'The WHO recommends \"to ensure that environmental cleaning and disinfection procedures are followed consistently and correctly.', 'Thoroughly cleaning environmental surfaces with water and detergent and applying commonly used hospital-level disinfectants (such as sodium hypochlorite) are effective and sufficient procedures.', '[11] The typical use of bleach is at a dilution of 1:100 of 5% sodium hypochlorite resulting in a final concentration of 0.05% [12] .', 'The recently published data with coronaviruses suggest that a concentration of 0.1% is effective in 1 min [7] .', 'That is why it seems appropriate to recommend a dilution 1:50 of standard bleach in the coronavirus setting.', 'For the disinfection of small surfaces ethanol (62%e71%; carrier tests) revealed a similar efficacy against coronavirus [7] .', 'Ethanol at 70% ethanol is also recommended by the WHO for disinfecting small surfaces [12] .', 'On inanimate surface human coronaviruses can remain infectious for up to 9 d. A surface disinfection with 0.1% sodium hypochlorite, 0.5% hydrogen peroxide or 62%e71% ethanol can be regarded as effective against coronaviruses within 1 min.', 'A similar effect can be expected against the SARS-CoV-2.']}\n", - "{'sentences': ['The etiologic agent of an outbreak of pneumonia in Wuhan, China, was identified as severe acute respiratory syndrome coronavirus 2 in January 2020.', 'A patient in the United States was given a diagnosis of infection with this virus by the state of Washington and the US Centers for Disease Control and Prevention on January 20, 2020.', 'We isolated virus from nasopharyngeal and oropharyngeal specimens from this patient and characterized the viral sequence, replication properties, and cell culture tropism.', 'We found that the virus replicates to high titer in Vero-CCL81 cells and Vero E6 cells in the absence of trypsin.', 'We also deposited the virus into 2 virus repositories, making it broadly available to the public health and research communities.', 'We hope that open access to this reagent will expedite development of medical countermeasures.']}\n", - "{'sentences': ['Im Zusammenhang mit der Corona-Pandemie tauchten alarmierende Meldungen auf, die vor dem Einsatz von Ibuprofen und anderen NSAR bei einer vermuteten SARS-CoV-2-Infektion warnen. Diese Medikamente, so wird spekuliert, könnten den Verlauf der Infektion verschlimmern. Was hinter solchen Spekulationen steckt und wie der aktuelle Stand der Empfehlungen ist, erläutert der Schmerzexperte Prof. Hartmut Göbel, Kiel.']}\n", - "{'sentences': ['Telehealth: Helping Your Patients and Practice Survive and Thrive During the COVID-19 Crisis with Rapid Quality Implementation']}\n", - "{'sentences': ['We showed that ACE2 expression profile in human tissues was in agreement with clinical observations of SARS-CoV-2 infected individuals.', 'For example, ACE2 was by far most strongly expressed in testis.', 'SARS is known to cause orchitis and destruction to male germ cells 38 .', 'Similar effect from COVID-19 was speculated, but a most recent study had just provided the first direct evidence that SARS-CoV-2 infection impacts male sex hormones 39 .', 'Similarly, small intestine is the tissue with the second highest level of ACE2 expression, while SARS-CoV-2 was found in stool samples of COVID-19 patients both in China and the United States 7,42 , even after the viral RNA decreased to undetectable level in respiratory tract 43 .', 'Additionally, we found in our normalized dataset that heart tissues also had the third highest level of ACE2 expression.', 'This observation is also in line with reports showing that COVID-19 patients complicated with cardiac diseases are subject to the highest mortality risk 40, 41 .', 'Together, the consistence between our results and clinical observations demonstrated that ACE2 expression is a reasonable indicator for susceptibility to SARS-CoV-2 infection.', 'Our analyses showed that mammalian ACE2 genes are highly conserved across lineages and exhibit broad expression patterns.', 'However, tissue-specific expression profiles varied from species to species, suggesting certain mammals may be the hosts of SARS-CoV-2, i.e., carriers without significant symptoms.', \"Compared to humans, other mammals examined in this study either don't express ACE2 in their testes, or at a low level.\", 'On the contrary, among non-human species kidney was almost always the tissue with highest ACE2 expression.', 'Meanwhile, it is worth noting that mouse is a .', 'CC-BY 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.30.015644 doi: bioRxiv preprint common model species for many human medical studies, including COVID-19.', 'However, we showed that in ACE2 proteins, mice and rats are the only mammals that have different amino acids in the two virus-binding hotspots from humans, which is consistent with previous in vitro virus infection experiments 2 .', 'Moreover, ACE2 was barely expressed in any of the cell types in murine lungs.', 'Thus, both observations argue against using mice as the optimal animal model for studying coronavirus related diseases.', 'Most notably, our analyses revealed that ACE2 expression levels are particularly high in cats and dogs.', 'Especially in cats, expression levels in top four ACE2 expression hotspot tissues are all magnitudes higher than any other mammals examined.', 'Intriguingly, in the ACE2 phylogenic tree, both cats and dogs are also cluster closer to humans than other mammals ( Figure 1B) , suggesting potentially higher affinity to coronaviruses in these pets.', 'SARS-CoV is known to infect cats 44 , while SARS-CoV-2 positive cats and dogs had also been reported 45, 46 , therefore our analyses suggest high possibility that cats and dogs can host SARS-CoV-2.', 'Furthermore, in both cats and dogs, skin had high abundant ACE2 expression, so did ear tip in cats and retina in dogs.', 'High ACE2 expression levels in these exterior body parts makes them particularly likely to host SARS-CoV-2 and pass on to humans via skin to skin contact.', 'Stray animals can even be more serious transmitters of coronaviruses.', 'It is estimated that there are approximately 500 million stray dogs and similar number of stray cats worldwide 47 .', 'Cats and dogs are sometimes slaughtered for meat, including a large proportion of stray ones 48 .', 'Therefore, it is likely that cats and dogs may have contributed to the COVID-.', 'CC-BY 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.30.015644 doi: bioRxiv preprint 19 19 pandemic.', 'For the least, people should also be vigilant with handling of pets in the effort of containing the spread of SARS-CoV-2.', 'In conclusion, in this study, we had reported the high conservation and built the first expression atlas of ACE2 gene in common mammals.', 'Our analyses revealed species and tissues susceptible to SARS-CoV-2 infection, thus yielding novel insights in tracing the origin and transmission of the virus.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study', \"[{'text': 'An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its caused coronavirus disease 2019 has been reported in China since December 2019.\", 'More than 16% of patients developed acute respiratory distress syndrome, and the fatality ratio was about 1%-2%.', 'No specific treatment has been reported.', 'Herein, we examine the effects of Favipiravir (FPV) versus Lopinavir (LPV)/ritonavir (RTV) for the treatment of COVID-19.', 'Patients with laboratory-confirmed COVID-19 who received oral FPV (Day 1: 1600 mg twice daily; Days 2-14: 600 mg twice daily) plus interferon (IFN)-a by aerosol inhalation (5 million U twice daily) were included in the FPV arm of this study, whereas patients who were treated with LPV/RTV (Days 1-14: 400 mg/100 mg twice daily) plus IFN-a by aerosol inhalation (5 million U twice daily) were included in the control arm.', 'Changes in chest computed tomography (CT), viral clearance, and drug safety were compared between the two groups.', 'For the 35 patients enrolled in the FPV arm and the 45 patients in the control arm, all baseline characteristics were comparable between the two arms.', 'A shorter viral clearance time was found for the FPV arm versus the control arm (median (interquartile range, IQR), 4 (2.5-9) d versus 11 (8-13) d, P < 0.001).', 'The FPV arm also showed significant improvement in chest imaging compared with the control arm, with an improvement rate of 91.43% versus 62.22% (P = 0.004).', 'After adjustment for potential confounders, the FPV arm also showed a significantly higher improvement rate in chest imaging.', 'Multivariable Cox regression showed that FPV was independently associated with faster viral clearance.', 'In addition, fewer adverse reactions were found in the FPV arm than in the control arm.', 'In this open-label nonrandomized control study, FPV showed significantly better treatment effects on COVID-19 in terms of disease progression and viral clearance; if causal, these results should be important information for establishing standard treatment guidelines to combat the SARS-CoV-2']}\n", - "{'sentences': ['In the present study, three SARS-CoV-2-specific commercial ELISA assays and six POC rapid tests were evaluated using sera from hospitalized adult patients with PCR-confirmed diagnoses for SARS-CoV-2 and a collection of control serum samples taken before the emergence of the virus in China in December 2019.', 'Overall, the Wantai Total Ab ELISA had superior sensitivity and specificity compared to both Euroimmun IgA and IgG ELISAs.', 'The POC tests varied notably, with the best performance observed for the test produced by AutoBio Diagnostics, followed by the tests produced by Dynamiker Biotechnology and CTK Biotech.', 'The differences observed for the sensitivity and specificity of the SARS-CoV-2-specific total antibody testing and antibody type ELISAs correspond to previous reports. .', 'This notably lower sensitivity for SARS-CoV-2-specific IgG detection is in agreement to that observed here for the Euroimmun IgG ELISA (65%).', 'In the present study the Wantai IgG and Euroimmun IgG ELISAs could not be compared due to unavailability of the former.', 'The possibility that overall lower sensitivity of SARS-CoV-2 IgG ELISAs may be a more universal occurrence rather than manufacturer dependent warrants further investigation.', 'In addition to lower sensitivities, the Euroimmun IgA and IgG ELISAs are also more prone to cross-react with negative sera as described in the present study and in a separate analysis of the beta-versions of these assays [10].', 'The differences between the assays may, in part, be explained by the SARS-CoV-2 antigen targeted and the ELISA format used.', 'Both kits detect antibodies to the S1 subunit of the SARS-CoV-2 spike protein; however, the Wantai Total Ab ELISA only targets the RBD within the S1.', 'The RBD represents approximately 33% of the S1 subunit, thus epitopes that may be recognized by cross-reacting epitopes outside of this domain are absent.', 'Furthermore, the RBD is highly diverse between SARS-CoV-2 and other beta-coronaviruses (hCoV-OC43 and hCoV-HKU1), which may further reduce the likelihood of cross-reaction with these circulating coronaviruses.', 'Moreover, the Wantai Total Ab ELISA uses an antigen-antibody-antigen(peroxidase) format whereas the Euroimmun ELISAs employ an antigen-antibody-antibody(peroxidase) format.', 'The specificity of the former is determined by a single antibody, whereas the latter has a second antibody that may introduce additional specificities.', 'The antigen-antibody-antibody format is required to distinguish between specific antibody types, but may not necessarily have lead to decreased specificity as shown for in-house ELISAs [10].', 'The clinical sensitivity of IgM for early diagnosis of COVID-19 is currently unclear.', 'SARS-CoV-2-specific IgM does not consistently appear before its IgG counterpart, with some studies reporting detection of SARS-CoV-.', 'CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'In conclusion, our findings show that in an ELISA format the sensitivity of detecting total SARS-CoV-2 RBDspecific antibodies is higher than that of assays detecting spike-specific IgA or IgG only.', 'It is important to note that the presence of SARS-CoV-2-specific antibodies does not necessarily correspond to protection against SARS-CoV-2 infection and disease.', 'In order to define antibody-mediated protection, further investigation of virus-specific antibody functions that include neutralization and Fc-mediated effector functionality are needed.', 'Sero-epidemiological investigations together with longitudinal studies on sequential samples taken from SARS-CoV-2 patients are necessary to characterize the spread of the virus and the long term protection of the antibodies measured.', 'Due to comparatively poorer assay performance in an initial round of testing, further testing were suspended.', 'CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. .', 'CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. .', 'CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', '(which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.09.20056325 doi: medRxiv preprint .', 'CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', '(which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.09.20056325 doi: medRxiv preprint .', 'CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', '(which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.09.20056325 doi: medRxiv preprint']}\n", - "{'sentences': ['TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 inhibitor Fedratinib', \"[{'text': 'COVID-19 emerges as a pandemic disease with high mortality.\", 'Development of effective prevention and treatment is an urgent need.', 'We reviewed TH17 responses in patients with SARS-CoV-2 and proposed an FDA approved JAK2 inhibitor Fedratinib for reducing mortality of patients with TH17 type immune profiles.']}\n", - "{'sentences': ['We report the clinical course and outcomes of the first 28 patients with COVID-19 in Republic of Korea.', 'The clinical severity was mild symptomatic or asymptomatic in 78.6% (22/28) of the patients.', 'The most common prodromal symptoms were sore throat, cough, fever, and myalgia, which was suggestive of common cold.', 'Although radiological pneumonia was detected in the majority (22/28, 78.6%) of the patients, only 27.3% (6/22) of them required supplemental oxygen therapy.', 'Radiological pneumonia was detected as early as from the 1st day of illness onset, and was even identified in patients who did not have any symptoms of the LRT infection, such as cough, sputum, chest pain, or dyspnea.', 'Although they had radiological pneumonia, they did not feel unwell and were able to carry on their daily activities as usual (“walking pneumonia”).', 'The titers of SARS-CoV-2 shedding from the URT were very high from the prodromal phase of illness until day 5 of illness.', 'In our patient cohort, the clinical features of COVID-19 during the prodromal phase were insidious and mild.', 'Fever was absent in 75.0% of the patients at the time of admission.', 'Throat symptoms, such as pain, discomfort and globus sensation and cough were ranked as relatively common, but only 1/3 had these symptoms.', 'As the prodromal symptoms were mild and did not begin abruptly, most of the patients were not able to tell exactly when they had become ill.', 'And because of this benign nature of the prodromal symptoms, they did not realize that they had been infected with SARS-CoV-2, and went out to carry on usual activities, while spreading the virus inadvertently.', 'The defining clinical characteristic of COVID-19 was an early development of radiological pneumonia.', 'During the prodromal phase, only 1/3 of our patients developed any clinical features suggesting pneumonia, such as cough, sputum, or chest discomfort.', 'Chest radiographs on hospitalization did not reveal any infiltrates in more than 50% of patients.', 'However, chest CT scans, which were performed on hospitalization or within 1–2 days, showed infiltrates in the lungs suggesting viral pneumonia in 16/18 (88.9%) patients (Table 1).', 'If we had not taken CT scans of the lungs, we would have easily missed the pneumonia diagnosis.4', 'The radiological pneumonia from CT scan was detected as early as day 1 of illness onset.', 'The most common findings of CT scans were bilateral, ground-glass opacity in the periphery of the lungs as described in previous studies.91112 Despite radiological pneumonia, the patients were clinically stable and mobile during the first week of illness (“walking pneumonia”).', 'We assessed the progression of COVID-19 pneumonia using the chest radiograph scoring, and it remained stable during the first week of illness, but increased around the day 7 of illness.', 'This pattern of pneumonia progression was also noted in patients with MERS-CoV infection.18 The early onset of the lung infiltrates and few clinical manifestations of LRT infection may suggest that the virus can invade into the LRT, evading innate immune mechanisms and replicate before adaptive immune response begins to play a role.', 'A tissue biopsy and immunohistopathological studies of the lungs may elucidate this unique and interesting clinical feature of SARS-CoV-2 infection.', 'Gastrointestinal manifestations were relatively uncommon in our patient cohort.', 'While 10% of the patients had diarrhea, 3% had vomiting, and 3% had abdominal pain at presentation, all of them revealed other common symptoms of acute respiratory illness.', 'Overall, diarrhea was present in 39% (11/28) of patients during hospitalization from the admission in this study.', 'As diarrhea is an adverse effect of lopinavir/ritonavir, we reassessed the frequency of diarrhea according to the patients being treated with lopinavir/ritonavir or not, and 53% (10/19) and 11% (1/9', 'It is important to note that the virus titers in the respiratory specimens peaked on early days after illness onset (Fig. 2A and B).', 'Of the seven infectors of our cohort, two transmitted the virus on the first day of illness, one on the 8th day of illness, and 4 via household transmission.', 'The Ct values of the URT specimens ranged from 18–25 in the 4 infectors within the 5 days of illness: 18.74, 18.33, 25.12, and 21.5 for each patient.', 'Our data suggest that the viral shedding from the URT may reach its peak during the first 3-5 days after illness onset.', 'A recent study on virus shedding kinetics is also in line with our finding.24 This “shift to the left” pattern of virus shedding kinetics is strikingly different from that of SARS-CoV, which shows an inverted V pattern, with its peak at day 10 of illness.25 Also of note is that 57.1% (4/7) of infectors had cough or sputum, in contrast to only 23.8% (5/21) of non-infectors having cough.', 'These findings suggest that the transmissions of SARS-CoV-2 may occur easily and begin from the prodromal phase of illness, just like common cold or influenza viruses.', 'Considering that the median time from symptom onset to isolation of the patients was 3 days, and that high titers of virus shedding began from day 1 of illness with the peak around day 3–5 of illness, early detection and isolation strategy may be relatively less effective in containing the virus in COVID-19.', 'The clinical outcomes of most patients in this study were not complicated.', 'As of 17 February 2020, no patient required supplemental oxygen therapy with mechanical ventilation nor any organ-supporting treatments in intensive care unit.', 'A total of 10 cases have fully recovered from the infection and have been discharged from hospital.', 'Of the 18 confirmed cases who are still in hospital, most are stable or improving.', 'There are some limitations in our study.', 'Only 28 patients from our cohort were included in this study.', 'However, we gathered and analyzed the detailed clinical information about all of the first 28 cases nationwide in Republic of Korea.', 'Moreover, some cases were confirmed during the surveillance test for COVID-19 after exposure to SARS-CoV-2.', 'The proportion of elderly patients and frequency of underlying conditions were small, and therefore the first 28 patients from the early phase of the COVID-19 outbreak in Korea had relatively favorable outcomes.26 Most of the enrolled patients would be healthier than the population of recent larger outbreaks showing worse outcomes, mostly in the elderly group.', 'The results regarding outcomes in this study should be interpreted cautiously.', 'In most cases, we did not perform virologic tests for coinfection of other respiratory viruses such as influenza.', 'Our study suggests that (1) the prodromal symptoms of SARS-CoV-2 infection were mild, (2) radiological pneumonia was very common, and developed from the early days of illness, (3) pneumonia may progress at day 7 of illness, (4) high titers of the virus shed from the URT during the prodromal phase (5), and the median time from symptom onset to defervescence was 10 days and to off-isolation 18.5 days.', 'During the hospitalization, six patients (21.4%) required oxygen supplement therapy: four with nasal cannula and two with face mask.', 'No one required mechanical ventilator or ECMO therapy.', 'Nineteen patients (67.9%) received lopinavir/ritonavir for antiviral therapy.', 'Ultimately, pneumonia was present in 22 patients (78.5%) and the proportion of pneumonia was 91.3% (21/23) among the patients who received a CT scan (Table 2).', 'Seventeen patients (60.7%) developed fever and became afebrile during the hospitalization and the median day of defervescence was 9 days (range, 3–18) after symptom onset (Supplementary Fig. 1).', 'By February 17, 10 patients were off isolation or discharged, and the median day of off-isolation/discharge was 18.5 days after symptom onset (range, 11–27).']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Apart from the timely diagnosis of cases, the achievement of favorable clinical outcomes depends on the timely treatment administered.', 'ACE2 has been reported to be the same cell entry receptor used by 2019-nCoV to infect humans as SARS-CoV [113].', 'Hence, clinical similarity between the two viruses is expected, particularly in severe cases.', 'In addition, most of those who have died from MERS-CoV, SARS-CoV and 2019-nCoV were advance in age and had underlying health conditions such as hypertension, diabetes or cardiovascular disease that compromised their immune systems [114].', 'Coronaviruses have error-prone RNA-dependent RNA polymerases (RdRP', 'However, in the years following two major coronavirus outbreaks SARS-CoV in 2003 and MERS-CoV in 2012, there remains no consensus on the optimal therapy for either disease [116,117].', 'Well-designed clinical trials that provide the gold standard for assessing the therapeutic measures are scarce.', 'No coronavirus protease inhibitors have successfully completed a preclinical development program despite large efforts exploring SARS-CoV inhibitors.', 'The bulk of potential therapeutic strategies remain in the experimental phase, with only a handful crossing the in vitro hurdle.', 'Stronger efforts are required in the research for treatment options for major coronaviruses given their pandemic potential.', 'Effective treatment options are essential to maximize the restoration of affected populations to good health following infections.', 'Clinical trials have commenced in China to identify effective treatments for 2019-nCoV based on the treatment evidence from SARS and MERS.', 'There is currently no effective specific antiviral with high-level evidence; any specific antiviral therapy should be provided in the context of a clinical study/trial.', 'Few treatments have shown real curative action against SARS and MERS and the literature generally describes isolated cases or small case series.', 'Many interferons from the three classes have been tested for their antiviral activities against SARS-CoV both in vitro and in animal models.', 'Interferon β has consistently been shown to be the most active, followed by interferon α.', 'The use of corticosteroids with interferon alfacon-1 (synthetic interferon α) appeared to have improved oxygenation and faster resolution of chest radiograph abnormalities in observational studies with untreated controls.', 'Interferon has been used in multiple observational studies to treat SARS-CoV and MERS-CoV patients [116,117].', 'Interferons, with or without ribavirin, and lopinavir/ritonavir are most likely to be beneficial and are being trialed in China for 2019-nCoV. This drug treatment appears to be the most advanced.', 'Timing of treatment is likely an important factor in effectiveness.', 'A combination of ribavirin and lopinavir/ritonavir was used as a post-exposure prophylaxis in health care workers and may have reduced the risk of infection.', 'Ribavirin alone is unlikely to have substantial antiviral activities at clinically used dosages.', 'Hence, ribavirin with or without corticosteroids and with lopinavir and ritonavir are among the combinations employed.', 'This was the most common agent reported in the available literature.', 'Its efficacy has been assessed in observational studies, retrospective case series, retrospective cohort study, a prospective observational study, a prospective cohort study and randomized controlled trial ranging from seven to 229 participants [117].', 'Lopinavir/ritonavir (Kaletra) was the earliest protease inhibitor combination introduced for the treatment of SARS-CoV. Its efficacy was documented in several studies, causing notably lower incidence of adverse outcomes than with ribavirin alone.', 'Combined usage with ribavirin was also associated with lower incidence of acute respiratory distress syndrome, nosocomial infection and death, amongst other favorable outcomes.', 'Recent in vitro studies have shown another HIV protease inhibitor, nelfinavir, to have antiviral capacity against SARS-CoV, although it has yet to show favorable outcomes in animal studies [118].', 'Remdesivir (Gilead Sciences, GS-5734) nucleoside analogue in vitro and in vivo data support GS-5734 development as a potential pan-coronavirus antiviral based on results against several coronaviruses (CoVs), including highly pathogenic CoVs', 'Improved mortality following receipt of convalescent plasma in various doses was consistently reported in several observational studies involving cases with severe acute respiratory infections (SARIs) of viral etiology.', 'A significant reduction in the pooled odds of mortality following treatment of 0.25 compared to placebo or no therapy was observed [119].', 'Studies were however at moderate to high risk of bias given their small sample sizes, allocation of treatment based on the physician’s discretion, and the availability of plasma.', 'Factors like concomitant treatment may have also confounded the results.', 'Associations between convalescent plasma and hospital length of stay, viral antibody levels, and viral load respectively were similarly inconsistent across available literature.', 'Convalescent plasma, while promising, is likely not yet feasible, given the limited pool of potential donors and issues of scalability.', 'Monoclonal antibody treatment is progressing.', 'SARS-CoV enters host cells through the binding of their spike (S) protein to angiotensin converting enzyme 2 (ACE2) and CD209L [118].', 'Human monoclonal antibodies to the S', 'Other therapeutic agents have also been reported.', 'A known antimalarial agent, chloroquine, elicits antiviral effects against multiple viruses including HIV type 1, hepatitis B and HCoV-229E.', 'Chloroquine is also immunomodulatory, capable of suppressing the production and release of factors which mediate the inflammatory complications of viral diseases (tumor necrosis factor and interleukin 6) [121].', 'It is postulated that chloroquine works by altering ACE2 glycosylation and endosomal pH. Its anti-inflammatory properties may be beneficial for the treatment of SARS.', 'Niclosamide as a known drug used in antihelminthic treatment.', 'The efficacy of niclosamide as an inhibitor of virus replication was proven in several assays.', 'In both immunoblot analysis and immunofluorescence assays, niclosamide treatment was observed to completely inhibit viral antigen synthesis.', 'Reduction of virus yield in infected cells was dose dependent.', 'Niclosamide likely does not interfere in the early stages of virus attachment and entry into cells, nor does it function as a protease inhibitor.', 'Mechanisms of niclosamide activity warrant further investigation [122].', 'Glycyrrhizin also reportedly inhibits virus adsorption and penetration in the early steps of virus replication.', 'Glycyrrhizin was a significantly potent inhibitor with a low selectivity index when tested against several pathogenic flaviviruses.', 'While preliminary results suggest production of nitrous oxide (which inhibits virus replication) through induction of nitrous oxide synthase, the mechanism of Glycyrrhizin against SARS-CoV remains unclear.', 'The compound also has relatively lower toxicity compared to protease inhibitors like ribavirin [123].', 'Inhibitory activity was also detected in baicalin [124], extracted from another herb used in the treatment of SARS in China and Hong Kong.', 'Findings on these compounds are limited to in vitro studies [121,122,123,124].', 'Due to the rapidly evolving situation of the 2019-nCoV, there will be potential limitations to the systematic review.', 'The systematic review is likely to have publication bias as some developments have yet to be reported while for other developments there is no intention to report publicly (or in scientific platforms) due to confidentiality concerns.', 'However, this may be limited to only a few developments for review as publicity does help in branding to some extent for the company and/or the funder.', 'Furthermore, due to the rapid need to share the status of these developments, there may be reporting bias in some details provided by authors of the scientific articles or commentary articles in traditional media.', 'Lastly, while it is not viable for any form of quality assessment and meta-analysis of the selected articles due to the limited data provided and the heterogeneous style of reporting by different articles, this paper has provided a comprehensive overview of the potential developments of these pharmaceutical interventions during the early phase of the outbreak.', 'This systematic review would be useful for cross-check when the quality assessment and meta-analysis of these developments are performed as a follow-up study.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Calcium channel blocker amlodipine besylate is associated with reduced case fatality rate of COVID-19 patients with hypertension', 'The coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now spread to more than 100 countries posing as a serious threat to the public health on a global scale.', 'Patients with comorbidity such as hypertension suffer more severe infection with elevated case fatality rate.', 'Development of effective anti-viral drug is in urgent need to treat COVID-19 patients.', 'Here we report that calcium channel blockers (CCBs), a type of anti-hypertension drugs that are widely used in the clinics, can significantly inhibit the post-entry replication events of SARS-CoV-2 in vitro.', 'Comparison with two other major types of anti-hypertension drugs, the angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), showed that only CCBs display significant anti-SARS-CoV-2 efficacy.', 'Combined treatment with chloroquine and CCBs']}\n", - "{'sentences': ['We delineated the characteristics of a retrospective cohort of 338 adult patients collected at a single center from Shenzhen city of China, and developed a non-invasive method to evaluate the risk of progression to severe conditions.', 'The independent predisposition factors of progression include old age, high BMI, fever, and co-existing hypertension or diabetes diseases.', 'However, using age as a single prognostic factor could lead to erroneous results since young patients were not necessarily progression-free.', 'Different from previous studies 4-6 , the severe group in this cohort has a significantly higher proportion of patients with fever symptom at admission (82.9% vs. 54.2%).', 'Moreover, we identified, for the first time, that overweight is associated with disease severity.', 'These findings benefit the risk assessment analysis as we showed that a model combining these indicators can substantially improve the prediction performance as compared to a model that only contains univariate predictor (mean time-dependent AUC= 0.824 versus 0.751).', 'SARS-CoV-2 entry host cell through angiotensin-converting enzyme 2 (ACE2) 7 , whose expression can be enhanced by the usage of hypertension medicine such as ACE inhibitors or angiotensin II type-I receptor blockers (ARBs', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.25.20043166 doi: medRxiv preprint COVID-19 pneumonia is a multistate disease with clinically relevant intermediate endpoint like severity onset.', 'Most survival data analyses set the onset as the primary end point, and censor recovery or hospital discharge.', 'However, when competing risks of severity onset are present, this analytical method induces bias.', 'In this study, the risk of severe progression assessed without considering the competition would be overestimated because the patients who would never progress (those who discharged from hospital without progression) were treated as if they could progress.', 'The extent of such bias and its adjustment by competing risks modeling have been evaluated in clinical virology and oncology research [10] [11] [12] [13] .', 'We incorporated high-dimensional variable selection techniques into the competing risks modeling so that quantitative image features can be extensively evaluated according to their contribution to risk prediction.', 'Our evaluation results showed that incorporating CT image can significantly improve the prediction performance as compared to those only based on demographical and clinical information (mean time-dependent AUC = 0.880 versus 0.824).', 'In particular, such improvement was achieved with only one additional image feature, suggesting the importance of using multi-modality data in risk analysis.', 'The laboratory testing results in this study showed that, at the time of admission, the severe group patients already presented a sign of function impairment in organs such as liver (eg: lactate dehydrogenase and prealbumin), heart (eg: multiple types of myocardial enzymes including troponin I, N-terminal brain natriuretic peptide, creatine kinase myocardial band, mitochondrial-Aspartate transaminase and Aspartate transaminase) and kidney (eg: glomerular filtration rate, cystatin C and β 2-Microglobulin).', 'The signal of abnormality in blood oxygen also emerges, as PaO2/FiO2, a ratio used to determine severity onset in this study, showed a significant, All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.25.20043166 doi: medRxiv preprint although not ideal, difference between the two groups upon admission.', 'Consistent with previous studies 2, 5, 6, 14, 15 , the severe group of this cohort demonstrated, at an early stage, a substantial increase in inflammatory factors such as C-reactive protein and interleukin-6, and dysfunction of coagulation.', 'Incorporating laboratory biomarkers tested at an early stage can also significantly improve risk prediction performance as compared to the best model without considering them (mean AUC = 0.884 versus 0.813).', 'We are still left with a few possible extensions.', 'First, the laboratory testing data had not been integrated into the CT image-based model because blood sample was not collected along with imaging in the center.', 'A more complicated statistical model is required to account for the error caused by time difference inherent in input data.', 'Second, the occurrence of severity may depend on other factors such as treatment, viral load or genetic factors.', 'Our model can include such additional covariates.', 'However, the availability of well-processed data on these factors is scarce, and we have shown that the current model can have reasonable prediction performance even without considering them.', 'Third, because of limited sample size of patients progressed to severity, we only evaluated model prediction performance by cross-validation.', 'Further validation needs to be conducted on external datasets.', 'Fourth, we restricted our analysis of the severe group up to the severity onset.', 'Factors related to the recovery from severe conditions have not been evaluated.', 'Finally, this study does not include young patients (age<18).', 'To our knowledge, this is the first attempt to estimate the real-time occurrence risk of severity from a cohort featured with a significant amount of imported cases.', 'We believe that the results All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.25.20043166 doi: medRxiv preprint from this study will be helpful to medical practitioners as they consider how to better manage the care of COVID-19 pneumonia patients upon admission.', 'Figure 1 : Analysis of representative features significantly associated with the severe group.', 'A, the age distribution of the study cohort, which is overlaid with kernel density estimates (solid curve); B, boxplot summary of the age and BMI as stratified by the severe and non-severe group; C, levels of individual laboratory biomarker plotted along with the time after symptom onset.', 'Data at the same day from multiple patients were collapsed together and only the median value (solid dots) was shown.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.25.20043166 doi: medRxiv preprint Figure 2 : Cumulative probability of developing severe conditions or being discharged from hospital after hospital admission for the study cohort.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.25.20043166 doi: medRxiv preprint All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.25.20043166 doi: medRxiv preprint']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['According to the recommendations from WHO, the United States Centers for Disease Control and Prevention and the European Center for Disease Prevention and Control, at least two sequential respiratory tract specimens, collected at least 24 h apart, are required for discharge criteria in clinically recovered patients [12-14].', 'Nevertheless, our findings suggest that, even in paucisymptomatic patients, consecutive multiple-site biological samples may be required in settings with limited community transmission for discontinuation of infection control and transmission-based isolation precautions.', 'We present a detailed report of a paucisymptomatic COVID-19 patient with biological samples consecutively collected from different sites.', 'To our knowledge, a previous asymptomatic case in a 10-year old boy, part of a COVID-19 family cluster, with ground-glass lung opacities at chest CT scan has been reported [8].', 'Our patient was tested for SARS-CoV-2 within the WHO contact protocol applied to the 56 Italians medically evacuated from Wuhan.', 'Otherwise, with no clear exposure or direct contact with possible sources of SARS-CoV-2 infection, he would not have been included in the COVID-19 case definition and not considered for viral screening [5].', 'Moreover, considering the limited data available at the time on treatment and clinical outcome in COVID-19 patients, an early and off-label treatment with oral lopinavir/ritonavir was started and it could have affected the natural course of the disease.', 'A Chinese familial cluster of five patients with COVID-19 pneumonia infected by an asymptomatic carrier has also been described [9].', 'Two further cases have been reported who transmitted virus during the pre-symptomatic phase and eventually developed fever and respiratory symptoms [10].', 'It is important to highlight that in our case, the patient, still undiagnosed, did probably not transmit the SARS-CoV-2 infection to his asymptomatic Chinese close contacts and to the other 55 Italian citizens.', 'Finally, the patient presented persistent viral shedding in stools despite the lack of any gastrointestinal signs and symptoms.', 'In a previous study, the presence of SARS-CoV-2 RNA in faeces was associated with gastrointestinal symptoms [11].', 'The evidence of extrapulmonary detection of viral RNA in both symptomatic and asymptomatic subjects is of clinical interest in terms of pathogenesis and routes of transmission.', 'However, our results are limited to the molecular detection that does not necessarily mean that infectious virus was present.', 'Additional studies, such as virus culture, should be done to investigate potential infectiousness.']}\n", - "{'sentences': ['Objective: To analyze the clinical characteristics of cases of novel coronavirus pneumonia and a preliminary study to explore the relationship between different clinical classification and liver damage.', 'Methods: Consecutively confirmed novel coronavirus infection cases admitted to seven designated hospitals during January 23, 2020 to February 8, 2020 were included.', 'Clinical classification (mild, moderate, severe, and critical) was carried out according to the diagnosis and treatment program of novel coronavirus pneumonia (Trial Fifth Edition) issued by the National Health Commission.', 'The research data were analyzed using SPSS19.0 statistical software.', 'Quantitative data were expressed as median (interquartile range), and qualitative data were expressed as frequency and rate.', 'Results: 32 confirmed cases that met the inclusion criteria were included.', '28 cases were of mild or moderate type (87.50%), and four cases (12.50%) of severe or critical type.', 'Four cases (12.5%) were combined with one underlying disease (bronchial asthma, coronary heart disease, malignant tumor, chronic kidney disease), and one case (3.13%) was simultaneously combined with high blood pressure and malignant tumor.', 'The results of laboratory examination showed that the alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), and total bilirubin (TBil) for entire cohort were 26.98 (16.88 ~ 46.09) U/L and 24.75 (18.71 ~ 31.79) U/L, 39.00 (36.20 ~ 44.20) g/L and 16.40 (11.34- ~ 21.15) mmol/L, respectively.', 'ALT, AST, ALB and TBil of the mild or moderate subgroups were 22.75 (16.31- ~ 37.25) U/L, 23.63 (18.71 ~ 26.50) U/L, 39.70 (36.50 ~ 46.10) g/L, and 15.95 (11.34 ~ 20.83) mmol/L, respectively.', 'ALT, AST, ALB and TBil']}\n", - "{'sentences': ['Recent studies suggest that hydroxychloroquine (HCQ) could be effective against COVID-19.', 'It is reasonable to expect that if HCQ can prevent or reduce the adverse effects of influenza, it may also reduce the effects of COVID-19 in humans.', 'The objective of this study was to test whether HCQ can prevent or reduce the risk and severity of influenza.', 'This is an observational cohort study using medico-administrative data from Quebec.', 'Patients included had at least one emergency department (ED) visit in 2012 or 2013, with a prior diagnosis of chronic conditions, and were admissible to the public drug insurance plan.', 'Two sub-cohorts were considered depending on reasons for ED visit: other than influenza or pneumonia (primary prevention) and influenza or pneumonia (sub-cohorts were considered depending on reasons for ED visit: other than influenza or pneumonia (primary prevention) and influenza or pneumonia).', 'In the primary prevention analysis (n=417,353), patients taking HCQ (n=3,659) had an increased risk of hospitalization for pneumonia in the following year compared to those who did not (5.2% vs. 2.9%; adjusted OR=1.25, p=0.0079).', 'In the sub-cohorts were considered depending on reasons for ED visit: other than influenza or pneumonia (primary prevention) and influenza or pneumonia analysis (n=27,152), patients taking HCQ (n=392), compared to those who did not had a modest and non-significant increased risk of hospitalization for pneumonia after 30 days (25.8% vs. 22.6%; adjusted OR=1.14, p=0.3177).', 'Interpretation: Based on the assumption that HCQ has similar effects on the COVID-19 as those observed on influenza, we can infer that it will not have positive effects on COVID-19.', 'We should therefore act cautiously before initiating prospective interventional studies on the use of HCQ']}\n", - "{'sentences': ['[{\\'text\\': \"SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 pandemic.', 'Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously demonstrated that three nucleotide analogues inhibit the SARS-CoV RNA-dependent RNA polymerase (RdRp).', 'Here, using polymerase extension experiments, we have demonstrated that the active triphosphate form of Sofosbuvir (a key component of the FDA approved hepatitis C drug EPCLUSA), is incorporated by SARS-CoV-2 RdRp, and blocks further incorporation.', 'Using the same molecular insight, we selected the active triphosphate forms of three other anti-viral agents, Alovudine, AZT (an FDA approved HIV/AIDS drug) and Tenofovir alafenamide (TAF, an FDA approved drug for HIV and hepatitis B) for evaluation as inhibitors of SARS-CoV-2 RdRp.', \"We demonstrated the ability of these three viral polymerase inhibitors, 3'-fluoro-3'-deoxythymidine triphosphate, 3'-azido-3'deoxythymidine triphosphate and Tenofovir diphosphate (the active triphosphate forms of Alovudine, AZT and TAF, respectively) to be incorporated by SARS-CoV-2 RdRp\", 'Given the 98% amino acid similarity of the SARS-CoV and SARS-CoV-2 RdRps, 10 we reasoned that the four nucleotide analogues listed in Fig. 1 would also inhibit the SARS-CoV-2 polymerase.', \"We thus assessed the ability of 2'-F,Me-UTP, 3'-F-dTTP, TFV-DP, and 3'-N 3 -dTTP (the active triphosphate forms of Sofosbuvir, Alovudine, TAF and AZT, respectively), to be incorporated by SARS-CoV-2 RdRp into an RNA primer and terminate the polymerase reaction.\", 'The RdRp of SARS-CoV-2, referred to as nsp12, and its two protein cofactors, nsp7 and nsp8, whose homologs were shown to be required for the processive polymerase activity of nsp12 in SARS-CoV, 11, 12 were cloned and purified as described in the Methods.', 'These three viral gene products in SARS-CoV-2 have high homology (e.g., 96% identity and 98% similarity for nsp12, with similar homology levels at the amino acid level for nsp7 and nsp8) to the equivalent gene products from SARS-CoV, the causative agent of SARS.', \"We performed polymerase extension assays with 2'-F,Me-UTP, 3'-F-dTTP, 3'-N 3 -dTTP or TFV-DP + UTP, following the addition of a pre-annealed RNA template and primer to a pre-assembled mixture of the SARS-CoV-2 RdRp (nsp12) and two cofactor proteins (nsp7 and nsp8).\", 'The extended primer products from the reaction were subjected to MALDI-TOF-MS analysis.', \"The RNA template and primer, corresponding to the 3' end of the SARS-CoV-2 genome, were used for the polymerase assay, and their sequences are indicated at the top of Fig. 2 .\", \"Because there are two A's in a row in the next available positions of the template for RNA polymerase extension downstream of the priming site, if the 2'-F,Me-UTP, 3'-F-dTTP or 3'-N 3 -dTTP are incorporated by the viral RdRp, a single nucleotide analogue will be added to the 3'-end of the primer strand.\", \"If they are indeed inhibitors of the polymerase, the extension should stop after this incorporation; further 3'extension should be prevented.\", \"Because the two A's in the template are followed by 4 U's, in the case of the TFV-DP/UTP mixture, two UTP's should be incorporated prior to the incorporation and termination by TFV-DP, which has an adenosine base.\", 'As shown in Fig. 2 , this is exactly what we observed.', \"In the MALDI-TOF MS trace in Fig. 2a , a peak indicative of the molecular weight of a single base primer extension product with one 2'-F,Me-UTP was obtained (6644 Da observed, 6634 Da expected).\", \"Similarly, in the trace in Fig. 2b , a single extension peak indicative of a single base extension by 3'-F-dTTP is revealed (6623 Da observed, 6618 Da expected), with no further incorporation.\", 'In both of the above cases, the primer was nearly completely extended.', \"In the trace in Fig. 2d , a single extension peak indicative of a single-base extension by 3'-N 3 -dTTP is seen (6633 Da observed, 6641 Da expected), with no evidence of further incorporation, though the incorporation efficiency was lower than for 2'-F,Me-UTP and 3'-F-dTTP, which may require further optimization.\", \"Finally, in the trace in Fig. 2c , a peak indicative of the molecular weight of a primer extension product formed by incorporating 2 U's and 1 TFV is found (7198 Da observed, 7193 Da expected), in addition to other peaks representing partial incorporation (1 U, 6623 Da observed, 6618 Da expected) or misincorporation (3 U's, 7235 Da observed, 7230 Da expected).\", 'Importantly, once the TFV-DP was incorporated, there was no further extension, indicating it was a permanent terminator.', \"In summary, these results demonstrate that the nucleotide analogues 2'-F,Me-UTP, 3'-F-dTTP, 3'-N 3 -dTTP, and TFV-DP are permanent terminators for the SARS-CoV-2 RdRp.\", \"Their prodrug versions (Sofosbuvir, 3'-F-5'-O-phosphoramidate dT nucleoside, 3'-N 3 -5'-O-phosphoramidate dT nucleoside, and TAF) are available or can be readily synthesized using the ProTide prodrug approach, 18 as shown in Fig. 1 a-d, and can be developed as therapeutics for COVID-19.\", 'Importantly, since Sofosbuvir, Tenofovir and AZT are widely .', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.18.997585 doi: bioRxiv preprint available FDA approved drugs, they can be evaluated quickly in laboratory and clinical settings for COVID-19 treatment.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Background and objective: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced coronavirus disease 2019 has been pandemic worldwide.', 'Several reports observed a reduction of lymphocytes among COVID-19 patients.', 'However, clinical significance of lymphocyte reduction in COVID-19 patients remains unclear.', 'The objective of this study was to analyze the association between lymphocyte reduction at early stage and the prognosis of COVID-19 patients.', 'All 192 hospitalized patients with COVID-19 were enrolled.', 'Electronic medical records, including demographic data, clinical characteristics, comorbidities and exposure history, were collected.', 'Biochemical indexes on admission and chest computed tomography (CT', 'Results: On admission, 84 (43.8%) patients suffered from lymphocyte reduction among COVID-19 patients.', 'The count and percentage of lymphocytes on admission were lower among more than seventy-year-old patients than those of younger patients.', 'Multivariate logistic regression revealed that older age was a risk factor of lymphocyte reduction.', 'Of interest, chest CT score, a key marker of lung injury, was increased among COVID-19 patients with lymphocyte reduction.', 'By contrast, PaCO2, SpO2 and oxygenation index, several respiratory function markers, were decreased in COVID-19 patients with lymphocyte reduction.', 'Moreover, TBIL and DBIL, two markers of hepatic injury, creatinine and urea nitrogen, two indices of renal function, and creatine kinase, AST and LDH, three myocardial enzymes, were elevated in COVID-19 patients with lymphocyte reduction.', 'Among 84 COVID-19 patients with lymphocyte reduction, 32.1% died.', 'Fatality rate was obviously higher in COVID-19', 'The present research analyzed the association between lymphocyte reduction at early stage and prognosis of COVID-19 patients in a hospital-based case-cohort study.', 'The main findings of the present research include: older COVID-19 patients are more susceptible to lymphocyte reduction; lymphocyte reduction on admission aggravates the severity of multiple organ injuries among COVID-19 patients; lymphocyte reduction on admission elevates death risk of COVID-19 patients.', 'Several studies found that lymphocyte count was decreased in COVID-19', 'patients (1, 7, 10, 11) .', 'In addition, several reports showed that lymphocyte count was lower in severe COVID-19 patients than in common ones (12) .', 'What factors lead to lymphocyte reduction on admission among COVID-19 patients remains obscure.', 'In the present research, we analyzed the relationship between age and lymphocyte reduction among COVID-19 patients.', \"Our results showed that almost half of patients' lymphocyte count and percentage were reduced to below normal range.\", 'Moreover, the number and percentage of lymphocytes were lower in COVID-19 patients over 70 years old than those of younger patients.', 'The effects of gender and comorbidities on lymphocyte reduction were analyzed among COVID-19 patients.', 'Our results showed that lymphocyte percentage were obviously decreased in males than those of females.', 'Of interest, lymphocyte percentage was reduced only in COVID-19 patients with either cardiac diseases or pulmonary chronic diseases.', 'To control possible confounding factors, multivariable logistic regression was used to further analyze the influence of gender, age and comorbidities on lymphocyte reduction in COVID-19 .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'We found that older age was the major risk factor of lymphocyte reduction on admission among COVID-19 patients.', 'Our results suggest that lymphocytes may be a direct target of SARS-CoV-2.', 'Elderly patients are more susceptible to suffer from lymphocyte reduction at the early stage of SARS-CoV-2 infection.', 'Previous studies found that multiple organ injures were prevalent in almost all COVID-19 patients, especially in critical ill cases (13) (14) (15) ).', 'In the present research, we evaluated the severity of lung injury in COVID-19 patients using CT scores.', 'We observed an obvious lung damage in almost all COVID-19 patients.', 'Moreover, the CT scores were higher in COVID-19 patients with lymphocyte reduction than those in COVID-19 patients with normal lymphocyte.', 'Correlation analysis revealed that lymphocyte counts were negatively associated with CT scores.', 'The association between lymphocyte reduction and respiratory function indices was then analyzed among COVID-19 patients.', 'As expected, PaCO2, SpO2 and oxygenation index, several respiratory function markers, were decreased in COVID-19 patients with lymphocyte reduction.', 'Next, the association between lymphocyte reduction and extrapulmonary organ injuries was analyzed among COVID-19 patients.', 'We found that TBIL and DBIL, two markers of hepatic injury, creatinine and urea nitrogen, two indices of renal function, and creatine kinase, AST and LDH, three myocardial enzymes, were obviously elevated in COVID-19 patients with lymphocyte reduction.', 'These results suggest that lymphocyte reduction at the early stage may be a potential indicator of multiple organ injures among COVID-19 patients.', 'Several reports demonstrated that lymphocyte reduction was more obvious in critical ill patients (16) (17) (18) (19) .', 'However, the relationship between lymphocyte reduction at the early stage and the severity and death risk of COVID-19 patients has not yet to be determined.', 'Our results showed that the severity of COVID-19 patients was positively associated with lymphocyte reduction on admission.', 'Moreover, fatality rate was higher in patients with lymphocyte reduction than those of patients with normal lymphocyte.', 'These results indicate that lymphocyte reduction elevates the severity .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'and death risk of COVID-19 patients, which explains why the fatality rate was higher in older COVID-19 patients than in younger ones.', 'The present study provides evidence that lymphocyte reduction on admission may be a potential negative prognostic indicator for COVID-19 patients.', 'In summary, the present study analyzed the association between lymphocyte reduction at the early stage and prognosis of COVID-19 patients.', 'We showed that older patients were more susceptible to lymphocyte reduction.', 'Moreover, lymphocyte reduction on admission was positively associated with multiple organ injuries.', 'In addition, lymphocyte reduction on admission elevated the severity and death risk of COVID-19 patients.', 'Our results suggest that lymphocytes may be a direct target of SARS-COV-2.', 'We provide evidence that lymphocyte reduction at early stage may be a potential negative prognostic indicator for COVID-19 patients.', 'Therefore, surveillance of lymphocyte count is helpful for the early screening, diagnosis and treatment of critical ill COVID-19 patients.']}\n", - "{'sentences': ['The SARS-CoV-2 virus emerged in December 2019 and then spread rapidly worldwide, particularly to China, Japan, and South Korea.', 'Scientists are endeavoring to find antivirals specific to the virus.', 'Several drugs such as chloroquine, arbidol, remdesivir, and favipiravir are currently undergoing clinical studies to test their efficacy and safety in the treatment of coronavirus disease 2019 (COVID-19']}\n", - "{'sentences': ['The global pandemic of severe acute pneumonia syndrome (COVID-19) caused by SARS-CoV-2 urgently calls for prevention and intervention strategies.', 'The densely glycosylated spike (S) protein highly exposed on the viral surface is a determinant for virus binding and invasion into host cells as well as elicitation of a protective host immune response.', 'Herein, we characterized the site-specific N-glycosylation of SARS-CoV-2 S protein using stepped collision energy (SCE) mass spectrometry (MS).', 'Following digestion with two complementary proteases to cover all potential N-glycosylation sequons and integrated N-glycoproteomics analysis, we revealed the N-glycosylation profile of SARS-CoV-2 S proteins at the levels of intact N-glycopeptides and glycosites, along with the glycan composition and site-specific number of glycans.', 'All 22 potential canonical N-glycosites were identified in S protein protomer.', 'Of those, 18 N-glycosites were conserved between SARS-CoV and SARS-CoV-2 S proteins.', 'Nearly all glycosites were preserved among the 753 SARS-CoV-2 genome sequences available in the public influenza database Global Initiative on Sharing All Influenza Data.', 'By comparison, insect cell-expressed SARS-CoV-2 S protein contained 38 N-glycans, which were primarily assigned to the high-mannose type N-glycans, whereas the human cell-produced protein possessed up to 140 N-glycans largely belonging to the complex type.', 'In particular, two N-glycosites located in the structurally exposed receptor-binding domain of S']}\n", - "{'sentences': ['In a very recent work by a research team led by Drs.', 'Gengfu Xiao, Wu Zhong and Zhihong Hu, the antiviral efficiency of the FDA-approved drugs including ribavirin, penciclovir, nitazoxanide, nafamostat, chloroquine (CQ) and two well-known broad-spectrum antiviral drugs remdesivir (RDV, GS-5734) and favipiravir (T-705) were evaluated against a clinical isolate of 2019-nCoV in a cell culture infection model (Wang et al.2020).', 'The authors found that two compounds CQ (EC50 value?=?1.13 µmol/L; CC50?>?100 µmol/L, SI?>?88.50) and RDV (EC50?=?0.77 µmol/L; CC50?>?100 µmol/L; SI?>?129.87) potently blocked virus infection at low-micromolar concentration and showed high selectivity index (SI']}\n", - "{'sentences': ['The feasibility of convalescent plasma therapy in severe COVID-19 patients: a pilot study', 'Currently, there are no approved specific antiviral agents for 2019 novel coronavirus disease .', 'In this study, ten severe patients confirmed by real-time viral RNA test were enrolled prospectively.', 'One dose of 200 mL convalescent plasma (CP) derived from recently recovered donors with the neutralizing antibody titers above 1:640 was transfused to the patients as an addition to maximal supportive care and antiviral agents.', 'The primary endpoint was the safety of CP transfusion.', 'The second endpoints were the improvement of clinical symptoms and laboratory parameters within 3 days after CP transfusion.', 'The median time from onset of illness to CP transfusion was 16.5 days.', 'After CP transfusion, the level of neutralizing antibody increased rapidly up to 1:640 in five cases, while that of the other four cases maintained at a high level (1:640).', 'The clinical symptoms were significantly improved along with increase of oxyhemoglobin saturation within 3 days.', 'Several parameters tended to improve as compared to pre-transfusion, including increased lymphocyte counts (0.65×10 9 /L vs. 0.76×10 9 /L) and decreased C-reactive protein (55.98 mg/L vs. 18.13 mg/L).', 'Radiological examinations showed varying degrees of absorption of lung lesionswithin 7 days.', 'The viral load was undetectable after transfusion in seven patients who had previous viremia.', 'No severe adverse effects were observed.', 'This study showed CP therapy was welltolerated and could potentially improve the clinical outcomes through neutralizing viremia in severe COVID-19 cases.', 'The optimal dose and time point, as well as the clinical benefit of CP', 'COVID-19is currently a big threat to global health.', 'However, no specific antiviral agents are available for its treatment.', 'In this work, we explored the feasibility of convalescent plasma (CP) transfusion to rescue severe patients.', 'The results from 10 severe adult cases showed that one dose (200 mL) of CP', 'To our knowledge, this is the first study to explore the feasibility of CP therapy in COVID-19.', 'All enrolled severe COVID-19 patients achieved primary and secondary outcomes.', 'One dose of 200 mL CP transfusion was welltolerated, while the clinical symptoms significantly improved with the increase of oxyhemoglobin saturation within 3 days, accompanied by rapid neutralization of viremia.', 'Severe pneumonia caused by human coronavirus was characterized by rapid viral replication, massive inflammatory cell infiltration, and elevated proinflammatory cytokines or even cytokine storm in alveoli of lungs, resulting in acute pulmonary injury and acute respiratory distress All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', '16.20036145 doi: medRxiv preprint syndrome (ARDS) (17).', 'Recent studies on COVID-19 demonstrated that the lymphocyte counts in the peripheral blood were remarkably decreased and the levels of cytokines in the plasma from patients requiring ICU support, including IL-6, IL-10, TNF-ɑ, GM-CSF, were significantly higher than those who did not require ICU conditions (2, 18) .', 'CP, obtained from recovered COVID-19 patients who had established humoral immunity against the virus, contains a large quantity of neutralizing antibodies capable of neutralizing SARS-CoV-2 and eradicating the pathogen from blood circulation and pulmonary tissues (19) .', 'In the present study, all investigated patients achieved serum SARS-CoV-2 RNA negativity after CP transfusion, accompanied by the increase of oxygen saturation and lymphocyte counts, and the improvement of liver function and C-reactive protein.', 'The results suggested that the inflammation and overreaction of the immune system were alleviated by antibodies contained in CP.', 'The case-fatality rates (CFRs) in the present study were 0% (0/10), which was comparable to the CFRs', 'The first key factor associated with CP therapy is the neutralizing antibody titer.', 'A small sample study in MERS-CoV infection showed that the neutralizing antibody titer should exceed 1:80 to achieve effective CP therapy (12) .', 'To find eligible donors who have high levels of neutralizing antibody is a prerequisite.', 'Cao (23) et al showed that the level of specific neutralizing antibody to SARS-CoV decreased gradually 4 months after the disease process, reaching undetectable levels in 25.6% (IgG) and 16.1% (neutralizing antibody to SARS-CoV decreased gradually 4 months after the disease process, reaching undetectable levels in 25.6% (IgG) and 16.1%) of patients at 36 months after disease status.', 'A study from the MERS-CoV infected patients and the exposed healthcare workers showed that the prevalence of MERS-CoVIgGseroreactivity was very low (2.7%), and the antibodies titer decreased rapidly within 3 months (24) .', 'These studies suggested that the neutralizing antibody to SARS-CoV decreased gradually 4 months after the disease process, reaching undetectable levels in 25.6% (IgG) and 16.1%', 'The second key factor associated with efficacy is the treatment time point.', 'A better treatment outcome was observed among SARS patients who were given CP before 14 dpoi (58.3% vs 15.6%; P < 0.01), highlighting the importance of timely rescue therapy (9) .', 'The mean time from onset of illness to CP transfusion was 16.5 days.', 'Consistent with previous research, all three patients All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', '16.20036145 doi: medRxiv preprint receiving plasma transfusion given before 14 dpoi (patients 1, 2 and 9) in our study showed a rapid increase of lymphocyte counts and a decrease of CRP, with remarkable absorption of lung lesions in CT.', 'Notably, patients who received CP transfusion after 14 dpoi showed much less significant improvement, such as patient 10.', 'However, the dynamics of the viremia of SARS-CoV-2 was unclear, so the optimal transfusion time point needs to be determined in the future.', 'In the present study, no severe adverse effects were observed.', 'One of the risks of plasma transfusion is the transmission of the potential pathogen.', 'Methylene blue photochemistry was applied in this study to inactivate the potential residual virus and to maintain the activity of neutralizing antibodies as much as possible, a method known to be much better than ultraviolet C light (25) .', 'No specific virus was detected before transfusion.', 'Transfusion-related acute lung injury (TRALI', 'Another rare risk worth mentioning during CP therapy is antibody-dependent infection enhancement, occurring at sub-neutralizing concentrations, which could suppress innate antiviral systems and thus could allow logarithmic intracellular growth of the virus (28).', 'The special immune enhancement was reportedly more common in Dengue fever, but also could be found in SARS-']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Current knowledge about the antivirals remdesivir (GS-5734) and GS-441524 as therapeutic options for coronaviruses', 'Recent international epidemics of coronavirus-associated illnesses underscore the urgent medical and public health need for vaccine development and regulatory body approved therapies.', 'In particular, the current coronavirus disease 2019 (COVID-19) pandemic has quickly intensified interest in developing treatment options to mitigate impact on human life.', 'Remdesivir (GS-5734™) is a broad-spectrum antiviral drug that is now being tested as a potential treatment for COVID-19', 'While previous studies on remdesivir are promising, formal clinical evaluation is strongly warranted.', 'In general, there are many reasons why favorable preclinical data can fail to translate directly into human clinical trial results [46], such as inadvertent use of irrelevant models, inability to achieve effective serum drug concentrations in patients, or the occurrence of unanticipated severe adverse events among patients.', 'Therefore, postulating on expected results of the trials is extremely challenging.', 'Nonetheless, there are hundreds of clinical trials ongoing internationally on different drugs that utilize various mechanisms of action [41,51], including trials on other nucleosides inhibitors (e.g., ribavirin), protease inhibitors (e.g., lopinavir/ritonavir), and interleukin-6 receptor inhibitors (e.g., sarilumab) [41,47].', 'Another well-known candidate that is being evaluated in multiple trials against COVID-19 is chloroquine (or hydroxychloroquine), which is already approved as an antimalarial (and for extraintestinal amebiasis) [41,48].', 'Results of the clinical trials currently underway in the U.S. and China will provide crucial information about whether remdesivir represents a viable treatment option for COVID-19 [20,49].', 'If the trial findings are ultimately positive, it will be imperative to ensure that the drug is produced on a commercial scale capable of meeting the demand generated by both the current pandemic and future outbreaks.', 'Such a change in production may also allow for the added benefit of the drug becoming more available for agricultural and veterinary use for relevant indications.']}\n", - "{'sentences': ['The host tropism of zoonotic coronavirus is hybrid, and it is important to determine the natural host and host range of coronavirus.', 'In the past two decades, SARS-CoV, MERS-CoV and SARS-CoV-2 have caused serious outbreaks of human infectious diseases.', 'All the three human coronaviruses originated from bats, but the intermediate hosts were different.', 'SARS-CoV is believed to come from the Paguma larvata [18] , and the intermediate host of MERS-CoV is Camelus dromedaries [19] .', 'The new coronavirus SARS-CoV-2 has recently caused a serious epidemic in China, but its intermediate hosts are not clear.', 'S protein of SARS-CoV-2 interacts with human ACE2, which promotes the entry of SARS-CoV-2, indicating that human ACE2 is the receptor of SARS-CoV-2 [3] .', 'ACE2 contains at least five key amino acids critical for binding S protein of SARSr-CoV [15] .', 'Based on these five amino acids, we analyzed the corresponding amino Table 1 Prediction of the RBD binding capacity of mammalian ACE2.']}\n", - "{'sentences': ['COVID-19 is a new and highly contagious respiratory disease that has caused global spread, high case fatality rate in severe patients, and a huge medical burden due to invasive mechanical ventilation.', 'The current diagnosis and treatment guidelines are still need to be improved, and more excellent clinical experience is needed to provide reference.', 'We analyzed and summarized clinical data of 97 confirmed COVID-19 adult patients (including 26 severe cases) ,included laboratory examination results, imaging findings, treatment effect, prognosis , etc, in order to put forward prediction index of severe COVID-19 patients, principles of early intervention and methylprednisolone usages in COVID-19 patients.', 'Hypoxemia, hyperlactic acid, hypoproteinemia, and hypokalemia were prevalent in COVID-19 patients.', 'The significant low lymphocyte count, hypoproteinemia, hypokalemia, the persistent or worsen high CRP, high D-dimer, and high BNP, and the occurrence of hemoptysis and novel coronavirus (SARS-CoV-2) viremia were important indicators for early diagnosis and prediction of severe disease progression.', 'CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', '(which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.06.20054890 doi: medRxiv preprint 2.', 'Characteristic images of lung CT had a clear change in COVID -19, Ground-glass opacity (GGO) and high-density linear combinations may indicate different pathological changes.', 'Rapid lobular progression of GGO', 'According to severity, oxygenation index, body weight, age, underlying diseases, appropriate amount methylprednisolone application on severe/critical COVID-19 patients on demand, improved blood oxygen and reduced the utilization rate of invasive mechanical ventilation, case fatality rate and medical burden significantly.', 'The most common indications for invasive mechanical ventilation should be strictly control in critical COVID-19 patients.', '1.Accurate and timely identification of clinical features in severe risks, and early and appropriate intervention can block disease progression.', '2.Appropriate dose of methylprednisolone can effectively avoid invasive mechanical ventilation and reduce case fatality rate in critical COVID-19 patients.', 'After summarizing the successful treatment of 97 COVID-19 patients (26 severe cases) by our team, we found accurate and timely identification of clinical features in severe risks, and early and appropriate intervention could block disease progression.', 'Appropriate dose of methylprednisolone can effectively avoid invasive mechanical ventilation and reduce case fatality rate in severe and critical COVID-19 patients.', 'CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.']}\n", - "{'sentences': ['Background In December 2019, human infection with a novel coronavirus, known as SARS-CoV-2, was identified in Wuhan, China.', 'The mortality of critical illness was high in Wuhan.', 'Information about critically ill patients with SARS-CoV-2 infection outside of Wuhan is scarce.', 'We aimed to provide the clinical features, treatment, and prognosis of the critically ill patients with SARS-CoV-2 infection in Guangdong Province.', 'In this multi-centered, retrospective, observational study, we enrolled critically ill patients with SARS-CoV-2 pneumonia who were admitted to the intensive care unit (ICU', 'Results Forty-five critically ill patients with SARS-CoV-2 pneumonia were identified in 7 ICUs in Guangdong Province.', 'The mean age was 56.7 years, and 29 patients (64.4%) were men.', 'The most common symptoms at the onset of illness were high fever and cough.', 'Majority of patients presented with lymphopenia and elevated lactate dehydrogenase.', 'Treatment with antiviral drugs was initiated in all the patients.', 'Thirty-seven patients (82.2%) had developed acute respiratory distress syndrome, and 13 (28.9%) septic shock.', 'A total of 20 (44.4%) patients required intubation and 9 (20%) required extracorporeal membrane oxygenation.', 'As of February 28 th 2020, only one patient (2.2%', 'Conclusions Infection with SARS-CoV-2 in critical illness is characterized by fever, lymphopenia, acute respiratory failure and multiple organ dysfunction.', 'Compared with critically ill patients infected with SARS-CoV-2 in Wuhan, the mortality of critically ill patients in Guangdong Province was relatively low.', 'These data provide some general understandings and experience for the critical patients with SARS-CoV-2 outside of Wuhan.', 'The study presented a multi-center cohort of 45 patients admitted to ICUs for SARS-CoV-2 infection out of Wuhan.', 'The findings showed that the majority of the patients were seriously ill at ICU admission.', 'Of all included patients, 37 (82.2%) had developed ARDS, 20 (44.4%) required invasive mechanical ventilation and 9 (20.0%) required ECMO, suggesting that the SARS-CoV-2 can cause severe illness.', 'Our study population might represent most of the clinical characteristics of patients with SARS-CoV-2 infection.', 'Lymphocytopenia occurred in more than 90% of critically ill patients, which was similar in Wuhan cohort (6) .', 'Moreover, we found that intubated patients had significantly lower lymphocyte counts than without intubation.', 'Chi-square test had shown lower lymphocyte counts was more likely to be at high risk for intubation.', 'Spearman correlation analyses showed that lymphocyte count was significantly negatively correlated with SOFA score at ICU admission.', 'In fact, lymphocytopenia was common in viral pneumonia, particular in severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS', 'Although antiviral drugs, including osehamivir and ribavirin had been applied to our patients, to date no effective antiviral to treat COVID-19 has been identified.', 'The current approach to clinical management is general supportive care supplemented with critical care and organ support when necessary.', 'It has been suggested that the administration of high-titer anti-influenza immune plasma derived from convalescent or immunized individuals may be clinically beneficial for the treatment of SARS, MERS and seasonal influenza (21) (22) (23) .', 'Convalescent plasma was a potential treatment in coronavirus infection and suggested using in COVID-19 (24).', 'Therefore, convalescent plasma of COVID-19 was applied in 6 patients (13.3%) and no transfusion reactions occurred in our cohort.', 'However, according to our data, at this point, our findings could not All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the ECMO were also applied for management of ARDS.', 'In addition, many of our patients developed extrapulmonary organ dysfunction including sepsis shock, acute liver dysfunction, and acute renal injury.', 'As of February 28, 2020, the mortality of our critically ill cases of COVID-19 were 2.2%', '(1 of 45) in our cohort, which was lower than those (61.5%, 32 of 52) in Wuhan.', 'The outbreak of SARS-CoV-2 led to more than 65,000 infected patients in Wuhan (CCDC report on February 28, 2020).', 'The massive infux of patients, inadequately protective clothing and medical personnel, particularly in critical care resources, may account for the unacceptable high mortality in Wuhan.', 'In contrast, protective clothing and medical personnel could cover the relative less patients in Guangdong Province.', 'In addition, a well design Web-based video consultation system for critically ill patients with COVID-19 was established and applied across different cities in Guangdong Province.', 'Then specialists in critical care medicine could share their experience and help the management of the critical illness in a remote way across hospitals and cities.', 'Moreover, aggressive treatments and intensive care were applied for the severe patients, including convalescent plasma, invasive mechanical ventilation, CRRT, ECMO.', 'Therefore, the mortality was relatively lower in critically ill patients with SARS-CoV-2 infection in Guangdong Province.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['We reported on 36 patients who died from SARS-CoV-2 infection in a single hospital of Wuhan.', 'All these patients had ARDS and 28 (77.78%) patients needed mechanical ventilation.', 'Bilateral pneumonia was detected in most patients on admission.', 'Previous studies have shown that elder patients and males who were confirmed with coronavirus infection are at higher risk of ARDS, 10 All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.02.27.20029009 doi: medRxiv preprint which was consistent with our study.', 'Antibiotic treatment was used to prevent secondary infections since these patients were critically ill.', 'Antiviral regimes were also used in most patients which we hoped may have roles but still need more data.', 'However, there were no specific remedies for SARS-CoV-2 yet 11, 12 .', 'Therefore, most patients were treated with supportive treatment and intensive care.', \"Unfortunately, due to restrictions of hospital's conditions and the heavy burden of COVID-19 in Wuhan City, neither were we able to provide patients in need with advanced life support systems like Extracorporeal Membrane Oxygenation (ECMO\", 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.02.27.20029009 doi: medRxiv preprint', 'As reported in previous studies, patients who are male, elder or have a history of cerebrovascular disease are at higher risk of SARS-CoV-2 infection 2,14,15 .', 'In our study, we found that the majority of coronavirus non-survivors were male patients, elder patients and patients with chronic diseases, which indicated that these patients might be also at increased risk of becoming critically ill or death.', 'Cerebrovascular diseases were the most common comorbidities.', 'Twentytwo (61.11%) non-survivors had cerebrovascular diseases in our report, and the percentage of cerebrovascular diseases among non-survivors was higher than that reported by Yang et al 13 .', 'Besides, there were 4 (11.11%) non-survivors who had smoking history and 4) non-survivors who had smoking history and 4 (11.11%) non-survivors who had smoking history and 4) had preexisting COPD.', 'According to previous studies on middle east respiratory syndrome coronavirus (MERS-CoV', 'In our cohort, lymphocytopenia occurred in more than 70% of patients at admission, which is a main laboratory feature in COVID-19 patients 15, 17 .', 'Lymphocytopenia have been identified in the critically ill patients with SARS-CoV and MERS infection 18, 19 .', 'As mentioned in previous studies, the severity of lymphocytopenia might indicate the severity of COVID-19, under the assumption of SARS-CoV-2 viral could attack and destroy the lymphocyte targetedly 2 .', 'Further studies are warranted to confirm these findings.', 'Increased levels of serum CRP, PCT, IL-6 were also found.', 'It indicated the obvious inflammatory response among these patients.', 'In addition, we noticed that All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.02.27.20029009 doi: medRxiv preprint the increased CRP, PCT concentration and decreased lymphocyte count from admission to death (Supplementary Figure 2) , which may represent more prominent inflammation in severe patients.', 'Therefore, intravenous glucocorticoids therapy, intravenous immunoglobulin therapy and interferon-alpha (α-IFN) aerosol inhalation were also used to restore homeostasis, without solid evidence.', 'To our knowledge, there is still no specific medicine for COVID-19 till now.', 'Clinical trials on promising regimens for COVID-19, such as remdesivir, lopinavir, and chloroquine phosphate are ongoing, which shed light on conquering the COVID-19 epidemic 12 .', 'This study has several limitations.', 'First, only 36 dead cases were included.', 'However, this is the largest cohort about the non-survivors of COVID-19 up to now.', 'Second, some specific clinical information was insufficient, such as mechanical ventilation settings, oxygen concentration, and detailed medication history.', 'Third, this is a retrospective, single-centered study.', 'It may be limited to the hospital critical care resources.', 'Further studies are still needed.', 'In conclusion, most non-survivors are older men with comorbidities (especially cardiovascular diseases).', 'They finally progressed to ARDS.', 'The median time from onset to ARDS was 11 days.', 'The mean survival time in our cohort of COVID-19 non-survivors was about 2 weeks.', 'Gradually decreased lymphocytes and increased inflammation biomarkers were found in these patients, and need to be monitored in the routine treatment.', 'Early detection and intervention of patients are especially important which can delay the development from mild to severe cases.']}\n", - "{'sentences': ['An exploratory randomized, controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol treating adult patients hospitalized with mild/moderate COVID-19 (ELACOI)', 'The novel coronavirus pneumonia outbreak has caused a global pandemic, however, effective antiviral therapeutics are still unavailable.', 'Our study (NCT04252885), designated as ELACOI, was an exploratory randomized (2:2:1) and controlled one, exploring the efficacy and safety of lopinavir/ritonavir (LPV/r', 'Results: This study successful enrolled 44 patients with mild/moderate COVID-19, with 21 randomly assigned to receive LPV/r, 16 to arbidol and 7 to no antiviral medication as control.', 'Baseline characteristics of three groups were comparable.', 'The median time of positive-to-negative conversion of SARS-CoV-2 nucleic acid was 8.5 (IQR 3, 13) days in the LPV/r group, 7 (IQR 3, 10.5) days in the arbidol group and 4 (IQR 3, 10.5) days in the control group (P=0.751).', 'The positive-to-negative conversion rates of SARS-CoV-2 nucleic acid at day 7 and 14 did not show significant differences in the LPV/r group (42.9%, 76.2%), the arbidol group (62.5%, 87.5%) and the control group (71.4%, 71.4%) (all P>0.53).', 'No statistical differences were found among three groups in the rates of antipyresis, cough alleviation, improvement of chest CT or the deterioration rate of clinical status (all P > 0.05).', 'Overall, 5 (23.8%) patients in the LPV/r All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The mean time to positive-to-negative conversion of SARS-CoV-2 nucleic acid during the 21-day follow-up period was 8.5 (IQR, [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] With respect to other secondary outcomes, the rate of antipyresis, rate of cough resolution, and rate of improvement on chest CT imaging at day 7 and 14 did not show any statistical difference between the three groups (P >0.05).', 'All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is During the study period, two (9.5%) patients in the LPV/r group, 2 (12.5%) in the arbidol group and 1 (14.3%) in the control group used gamma globulin (10 g, once a day, for 2-3 days).', 'Moreover, 6 (28.6%) patients in the LPV/r group, 2 (12.5%) patients in the arbidol group, and 2 (28.6%) patients in the control group used glucocorticoids (methylprednisolone 40 mg, once a day, for 3-5 days) without statistical difference among 3 groups (P=0.547).', 'Eighteen (85.7%) patients (13 patients using low flow supply, 5 using high flow oxygen supply) in the LPV/r group, 11 (68.8%) patients (9 patients using low flow, 2 high flow oxygen supply) in the arbidol group and 6 (85.7%) patients (all using low flow oxygen supply) in the control group received oxygen therapy, which did not show statistical difference (P =0.466) (table 1).', 'During the follow-up period, 5 (23.8%) patients in the LPV/r group experienced adverse events including diarrhea (3/21,14.3%), loss of appetite (2/21, 9.5%) and elevation of ALT over 2.5-fold upper normal limit (1/21, 4.8%).', 'No apparent adverse events occurred in the arbidol group or in the control group.', 'Notably, one serious adverse event occurred in a 79-year-old man with All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.19.20038984 doi: medRxiv preprint underling diseases including diabetes and hypertension in the LPV/r group, characterized by severe diarrhea on day 3.', 'This patient progressed to critical condition and received extracorporeal membrane oxygenation (ECMO']}\n", - "{'sentences': ['Arguments in favour of remdesivir for treating SARS-CoV-2 infections', 'With an effective reduction of pulmonary viral load in a murine model of SARS-CoV infection, potent antiviral activity against SARS-CoV-2, acceptable safety profile of parenteral remdesivir therapy in two case reports, and a randomised trial of Ebola virus disease, the clinical use of remdesivir in the cases of COVID-19 is are highly anticipated.', 'Two randomised clinical trials of parenteral remdesivir therapy in the treatment of COVID- 19 in China may open the window for effective antiviral therapy for such an epidemic infectious disease.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': [\"It is an ugly fact that a significant amount of the world's population will contract SARS-CoV infection with the current spreading.\", 'While specific treatment is not yet coming soon, individual risk assessment and management strategies are crucial.', 'The individual preventive and protective measures drive the personal risk of getting the disease.', 'Among the virus-contracted hosts, their different metabolic status, as determined by their diet, nutrition, age, sex, medical conditions, lifestyle, and environmental factors, govern the personal fate toward different clinical severity of COVID-19, from asymptomatic, mild, moderate, to death.', 'The careful individual assessment for the possible dietary, nutritional, medical, lifestyle, and environmental risks, together with the proper relevant risk management strategies, is the sensible way to deal with the pandemic of SARS-CoV-II.', 'J o u', 'r n a l P r e -p r o o f Journal Pre-proof [5] .', 'COVID-19 is the third-known zoonotic disease from coronavirus after severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) [6] .', 'SARS-CoV-II belongs to the family of coronaviridae and the genus of betacoronavirus, which includes SARS-CoV and MERS-CoV [7-9].', 'The current data suggest the mortality rate from COVID-19 at 2-5 %, which is substantially lower than the mortality rate of 10% and 40% in SARS and MERS', 'However, the concerning high transmissibility of SARS-CoV-II, with the basic reproduction number (R 0 ) at 1.4-5.5, make it a rapidly spreading disease, as compared to the R 0 of SARS-CoV and MERS-CoV at 2-5 and less than 1, respectively [11, 12] .', 'The viral genome analysis suggested that the SARS-CoV-II was a recombinant virus between the bat coronavirus and an unidentified-origin coronavirus [13, 14] .', 'While the human transmission is presumably from the animals, there is still inconclusive whether the animal origins in the human transmission chain are from bats, snakes, or others [11, 15, 16] .', 'However, there were positive virus findings in the environmental samples from the seafood industry and the seafood markets.', 'The respiratory droplets from coughing or sneezing are the primary mediums for human-to-human transmission [17] .', 'The frequent symptoms of respiratory illnesses, i.e., a fever higher than 38.1°C (98% of patients), coughing fits (76% of patients), and finally severe fatigue or myalgia (44% of patients) have been reported in several patients [18] .', 'Dyspnea (55% of patients) appears after eight J o u r n a l P r e -p r o o f Journal Pre-proof 4 days and is the first severe complication of the disease.', 'However, headache, diarrhea, hemoptysis, and dyspnea have been reported as clinical manifestations of 19] .', 'A study from China also reported that the majority of patients (80.9%) were considered to have mild pneumonia or being asymptomatic, which posed big challenges for the spreading of .', 'The close contact to infected individuals, either asymptomatic or clinical COVID-19 cases, increase the risk of infection.', 'The monitor of a cluster of COVID-19 cases in China suggested the possibility of indirect viral transmission without a history of close physical connection to the infected individuals.', 'The viral transfer is possible through the common contaminated objects, viral aerosolization in confined space, or from the asymptomatic viral carriers [21].', 'The general preventive guidelines include frequent hand washing, mouth and nose covering during coughing, sneezing, and cooking.', 'Social distancing helps to avoid close contact with symptomatic and asymptomatic individuals [17] .', 'The rapid identification, case detection, isolation, and treatment will contain the public spreading of SARS-CoV-II.', 'The host metabolic conditions also determine the clinical course and outcomes of COVID-19.', 'As there is no specific treatment for COVID-19, most of the case management is supportive and symptomatic measures.', 'With global pandemic spreading, most of us may get the SARS-CoV-II infection at a certain period.', 'Therefore, individual actions that minimize the infection risk and modulate the severity of the clinical courses are crucial amidst all public healthcare measures.', 'Figure 1 represents this conceptual framework.', 'In this article, we reviewed the personal preventive measures, the predisposing host factors, some potential therapeutically options, and suggested a comprehensive approach for COVID-19 management.', 'While the SARS-CoV-II remains viable in the aerosols for only three hours, it can live on the different surface materials up to three days on polypropylene plastic, couple days on stainless steel, twenty-four hours on cardboard, and four hours on copper [22] .', 'The increased temperature and J o u r n a l P r e -p r o o f Journal Pre-proof humidity can reduce the transmission of COVID-19 for a certain degree [23] .', 'The surface disinfectants, including 62-71% ethanol, 0.5% hydrogen peroxide, or 0.1% sodium hypochlorite, can efficiently inactivate SARS-CoV-II within one minute.', 'In contrast, other biocidal agents, such as 0.05-0.2% benzalkonium chloride, or 0.02% chlorhexidine digluconate, are less effective [24] .', 'The avoidance of these contaminated mediums is, therefore, the critical preventive measure, together with the social distancing from the possible infected individual.', 'Personal hygiene could reduce individual exposure to SARS-CoV-II contaminated surfaces.', 'These measures include regular hand washing, particularly after sneezing, coughing, exposure to the public washroom, or before the meal preparation.', 'The regular cleaning of the public-touch surfaces and the common tools and utensils with disinfectants is also necessary.', 'The avoidance of face, eyes, nose, and mouth touching reduces the introduction of contaminated hands to the respiratory mucosal surfaces [25].', 'Social distancing prevents contact with the aerosol droplets from infected individuals or asymptomatic carriers.', 'The face mask may not be necessary for a healthy person.', 'While the facecovering provides a sense of protection in people, the inappropriate use and disposal of the mask may increase their infection risks.', 'Hence, there is a recommendation to use a face mask only in individuals with symptoms or under quarantines [26].', 'With the spreading of SARS-CoV-II, one can reduce their viral contracting risk through these preventive measures.', 'Reports from China and Italy suggested a high mortality rate of COVID-19 in older male patients who had multiple metabolic comorbidities [19, 27] .', 'The host metabolic status, as influenced by age, sex, medical conditions, and lifestyle factors such as cigarette smoking, determine the clinical severity of 29] .', \"A new study is refining our knowledge of the symptoms caused by the COVID-19 epidemic, which affects the world's population.\", 'It also highlights the presence of aggravating factors in the most severe J o u r n a l P r e -p r o o f Journal Pre-proof cases.', 'When looking at critically ill patients, two prevalent illnesses appear to worsen infection.', 'The first is hypertension, since 23.7% of patients in critical condition suffering from it.', 'In the second position comes diabetes, without a distinction of the type being made, which affects 16.2% of the most severe cases [30, 31] .', 'Moreover, the comorbidities of coronary heart disease (5·8%), and cerebrovascular disease (2·3%) have been reported in severe cases [32].', 'Bad lifestyle habits, such as smoking, can also play a role.', 'While 85.6% of the infected patients are non-smokers, 16.9% of severe cases declared that they used tobacco (compared to 11.8% of less severe cases) [33].', 'Co-existing metabolic diseases include type 2 diabetes, hypertension, heart disease, a history of stroke, and cancers.', 'Therefore, the host predisposing factors significantly determine the illness course, the progression, and the outcome of 17] .', 'The elders are more prone to infection, including respiratory diseases than young people, while accompanied by the increased mortality rate.', 'These age-related immunologic changes are probably the results of primary or secondary structural and functional changes of bone marrow, thymus, lymphoid organs, and immune cells [34] .', 'Despite the multifaceted process of aging, the elders commonly have a decreased ability to fight infection, diminished response to the vaccine, increased prevalence of autoimmunity, and constitutive low-grade inflammation [34] .', 'Conforming to this fact, the mortality rate from COVID-19 is increasing in older adults in the clinical settings [19, 27, 28] .', 'The study of blood mononuclear cells suggested that the epigenomic signature of declining naïve T cells and increasing monocyte and cytotoxic cell functions were higher in male than female elders [35] .', 'The age-related immunologic changes and sex differences first occurred around the age of latethirties, with the second-biggest spike after the age of sixty-five.', 'The older man is more prone to infectious diseases with high pro-inflammatory immune responses and low adaptive immune responses than an older woman [35, 36] .', 'The COVID-19 cases in both China and Italy reported higher fatality in males than women [19, 27] .', 'J o u r n a l P r e -p r o o f Journal Pre-proof through their metabolites, such as the Clostridium orbiscindens-derived desaminotyrosine [49].', 'Certain strains of Lactobacillus also influence the IFN responses following the influenza infection [50].', 'Host dietary pattern is the pivotal determinant of gut microbiota community, structure, and function [51, 52] .', 'In general, the balanced diet with a variation of the prebiotic fibers, probiotics, and J o u r n a l P r e -p r o o f Journal Pre-proof polyphenols, promote the healthy, diverse microbiota [53] .', 'Improving the diet quality in susceptible individuals for COVID-19 might alleviate their risk of severe infection [54] .', 'Despite the inconclusive pieces of evidence, oral probiotics are expecting to be the rational adjunctive option in various viral disease management [55] [56] [57] .', 'Diet and nutrition invariably influence the immune system competence and determine the risk and severity of infections.', 'There are bi-directional relationships among diet, nutrition, infection, and immunity.', 'The changes in one component have an impact on the others [58] .', 'The macro-, micronutrients, and phytonutrients in diet, mainly the fruits and colorful vegetables, generally promote healthy immune responses.', 'These micro-and phytonutrients provide the antioxidants and the anti-inflammatory nutrients, including beta-carotene, vitamin C, vitamin E, and polyphenolic compounds, which modulate the immune functions [30, 59] .', 'The anti-inflammatory strategy, either by foods, nutrients, or medicines, is a viable option for COVID-19 management [60, 61] .', 'Apart from the age-related micronutrient insufficiency, as previously mentioned, the nutritional status of an individual affects the risk of SARS-CoV-II infection, the clinical course, and the outcomes of COVID-19.', 'Therefore, the maintenance of host macro-and micronutrient status is an important preventive measure for COVID-19.', 'Numerous micronutrients are essential for immunocompetence, particularly vitamin A, C, D, E, Bs, iron, selenium, and zinc.', 'Dietary pattern is vital for maintaining the individual nutritional status.', 'However, diet alone may not be sufficient in certain metabolic and lifestyle conditions, including advancing age, co-existing medical condition, cigarette smoking, or occupational exposure to environmental toxins [58] .', 'We herein reviewed some micronutrients that require attention for risk reduction and clinical course modulation of COVID-19.', 'Vitamin D Several meta-analysis and systematic reviews supported the protective role of vitamin D supplementation for the prevention of acute respiratory tract infection [62-65].', 'The effective J o u r n a l P r e -p r o o f Journal Pre-proof 10,000 IU/d of vitamin D 3 for a few weeks to rapidly raise 25(OH)D concentrations, followed by 5000 IU/d.', 'Vitamin A Despite the established roles of vitamin A in supporting the immune functions, there is inadequate evidence to support the supplementation benefit in healthy individuals for the prevention of acute viral respiratory infection [76].', 'However, vitamin A deficiency people are prone to the increased risk, the high severity, and the impaired immune responses to viral infections, including the respiratory syncytial virus, measle virus, and the influenza virus [77, 78].', 'The immune-supporting roles of vitamin A include the promotion of mucins and keratins, lymphopoiesis, apoptosis, cytokine J o u r n a l P r e -p r o o f Journal Pre-proof']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Objective To investigate and analyze the epidemiological and clinical characteristics of some cases of coronavirus disease 2019 (COVID-19) in Beijing.', 'Methods A retrospective study was conducted to analyze the data of 46 patients with COVID-19 in Beijing from 20th January 2020 to 8th February 2020 at the Fifth Medical Center of the PLA General Hospital.', 'Features of clinical symptoms, laboratory inspections and imaging inspections were analyzed.', 'Statistical analysis used Fisher exact test.', 'If P <0.05, post-hoc test was used for pairwise comparison, and the statistics were corrected by Bonferroni test.', 'Results Among the 46 patients included in this study, 27 were male and 19 were female.', 'The age range was between 3 - 79 years old, and the mean age was (41.8 ± 16.3) years old.', 'The average incubation period was (4.85 ± 3.00) days.', 'A total of 26 cases (56.5%) were clustered patients, and 12 (26.1%), 23 (50.0%) and 11 patients (23.9%)were assigned to the mild group, common group, and sever group, respectively.', 'Fever (39.8%), cough (27.6%), and fatigue (25.3%) was the main clinical symptom for these patients.', 'The decrease in white blood cell counts occurred in 12 patients, four had the decrease in T lymphocyte counts, 17 had the decrease in CD4 + T lymphocyte counts, seven had the decrease in CD8 + T lymphocyte counts, 21 had the increase level of C-reactive protein (45.7%), and IL-6 level increased in 32 cases (69.6%), erythrocyte sedimentation rate increased in 20 cases(50.0%), serum ferritin level increased in 26 cases (56.5%), and blood lactate level increased in nine cases.', 'There was a statistically significant difference in the number of cases in which the absolute value of T lymphocytes and of CD8 + T lymphocytes decreased among the mild, common and severe groups (all P <0.05).', 'Comparing the number of cases in the three groups with elevated C-reactive protein, interleukin-6, erythrocyte sedimentation rate, serum ferritin and blood lactate levels, the differences were statistically significant (all P <0.05).', 'The number of cases with elevated C-reactive protein levels was higher in severe group than that in mild and common group.', 'The number of cases with elevated interleukin-6, erythrocyte sedimentation rate, and serum ferritin levels were higher in severe group than in mild group.', 'The number of cases with elevated blood lactic acid levels was higher in severe group than in mild group.', 'The differences between the above groups were statistically significant (both adjusted P <0.017).', 'Analysis of chest X-rays showed that 34 patients (73.9%) had inflammation in the lungs.', 'Conclusions The epidemiological characteristics of cases with COVID-19']}\n", - "{'sentences': ['Previous studies showed that CoVs genomes display a high degree of plasticity in terms of gene content and recombination.', 'Furthermore, the relatively large CoV genome increases the probabilities for adaptive mutations, with it being relative easy for the spike protein to exploit multiple cellular receptors for virus attachment and entry [52, [77] [78] [79] .', 'These features are likely the cause of this alarming propensity of CoVs for host-species expansion.', 'Unfortunately, China has seen a number of interspecies transmissions by CoV in recent years [80] [81] [82] .', \"Whether this current COVID-19 epidemic 'frizzles out' or expands into a full-blown pandemic remains to be seen.\", 'It might also be desirable to monitor farm animals and pet cats for infection with 2019-nCoV, since their ACE2 receptor responsible for 2019-nCoV binding differs in only a few amino acids from human ACE2.', 'Surveillance might prevent the virus establishing itself in another animal species that is in close contact to humans.', 'In addition, in light of the fact that there are multiple species of CoVs circulating in wildlife species and that these animals are constantly interacting with each other, host-species expansion or interspecies transmission of new CoV to humans seems to be inevitable.', 'Major knowledge gaps regarding the emergence of 2019-nCoV remain exists but worldwide scientists are working with unprecedented speed to investigate the virus, rushing to develop targeted therapeutics (see Outstanding Questions).', \"Notwithstanding, a global surveillance network involving veterinarians and animal biologists is urgently needed to monitor, and possibly to predict, potential sources for the emergence of another highly pathogenic CoV. We propose the concept of 'One Health' to facilitate scientific exchange across disciplines, sharing of data, and coordinated efforts in order to prevent future outbreaks.\", 'From surveillance and evolutionary studies on animal viruses, can their zoonotic potential be identified before interspecies transmission occurs?', 'What are the key interactions between the spike protein (S) of 2019-nCoV and its receptor angiotensin-converting enzyme 2 (ACE 2)?', 'Which amino acids in ACE2 determine whether S', 'Is expression of the trans-membrane protease/serine another decisive factor for infection of a cell?', 'Is the newly acquired polybasic cleavage site in S associated with cross-species transmission of 2019-nCoV?', 'What are the similarities and differences of COVID-19 epidemiology in comparison with SARS and MERS?', 'What is the basic reproductive number (R 0 ) , the real incubation period, and the morbidity and mortality rate?', 'Can COVID-19 develop into an endemic or seasonal infectious disease, like the flu?', 'With the experience of mitigating the outbreaks of SARS and avian influenza, what strategies can be applied in mitigating COVID-19 and future CoV outbreaks?', 'Should veterinarians play more important roles in the prevention and control of emerging zoonoses in the future?']}\n", - "{'sentences': ['Viral RNA was cleared in 89% of the COVID-19 patients within 21 days after illness onset.', 'The use of antiviral drugs (chloroquine, oseltamivir, arbidol, and lopinavir/ritonavir) did not shorten viral RNA clearance, especially in non-serious cases.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'Background: The novel coronavirus disease 2019 (COVID-19', 'In this retrospective study, we included patients with confirmed COVID-19', 'The associations of clinical characteristics and treatment regimens on time to viral RNA clearance were analyzed.', ': We examined 284 consecutive COVID-19 cases, accounting for 82% of confirmed cases in Guangzhou during this period.', 'At the time of reporting (20 th March 2020), 276 (97.2%) had recovered and were discharged from hospital with a median hospital stay of 18 days (interquartile range [IQR]:13-24).', 'Overall, 280 patients achieved viral RNA clearance with a median length of 12 days (IQR: 8-16) after onset of illness.', 'Amongst them, 66.1% had viral RNA cleared within 14 days, and 89.3% within 21 days.', 'Older age, severity of disease, time lag from illness onset to hospital admission, high body temperature, and corticosteroid use were associated with delayed clearance of viral RNA.', 'None of the antiviral regimens (chloroquine, oseltamivir, arbidol, and lopinavir/ritonavir) improved viral RNA clearance.', 'The use of lopinavir/ritonavir was associated with delayed clearance of viral RNA after adjusting for confounders.', 'In patients with COVID-19, isolation for a minimum of 21 days after onset of illness may be warranted, while the use of antiviral drugs does not enhance viral RNA clearance.', 'In this retrospective study, 89% of patients with COVID 19 achieved viral RNA clearance within 21 days.', 'Time lag from illness onset to hospital admission, old age, disease severity, high body temperature, and corticosteroid use were associated with delayed clearance of viral RNA.', 'The use of antiviral drugs (chloroquine, oseltamivir, arbidol, and lopinavir/ritonavir) had no benefit on such clearance.', 'After adjusting for confounders, the use of lopinavir/ritonavir or the combination of two antiviral drugs tended to delay the clearance of viral RNA.', 'In this study, the median time from illness onset to viral RNA clearance was 12 days.', 'This was compared to 15 days reported in patients from Wuhan [18] , which might reflect the more severe nature of the latter patients.', 'Currently, there is no consensus on the de-isolation management for patients with COVID-19, especially in asymptomatic subjects with high risk of infectivity.', 'In this cohort, 89% of patients achieved viral RNA clearance within 21 days, and only 66% within 14 days.', 'Specifically, all asymptomatic patients achieved viral RNA clearance within 21 days.', 'These data suggested that isolation for at least 21 days after the onset of symptom or first positive PCR test is warranted in both patients without or with improving symptoms. .', 'This drug is being recommended for the treatment of hospitalized COVID-19 patients in China and some countries [11, 17] .', 'In this study, 28 patients were treated with chloroquine which did not appear to improve viral RNA clearance compared to supportive treatment.', 'Large scale randomized controlled studies are needed to confirm its benefit, if any.', 'Lopinavir/ritonavir is a fixed dose combination of anti-HIV protease inhibitors acting against the viral 3CL protease [21] .', 'Although it has been used to treat COVID-19 [22], its benefits has not been confirmed in a clinical trial involving COVID-19 patients with pneumonia in Wuhan [16] .', 'In our study, apart from lack of benefit, the use of lopinavir/ ritonavir tended to delay viral RNA clearance, even after adjusting for factors including disease severity.', 'Arbidol is an antiviral drug approved in Russia and China for treating influenza.', 'It acts against influenza A and B by inhibiting viral fusion with cellular membrane and blocking the virus entry into host cells [23] .', 'In a retrospective cohort study, arbidol accelerated the clearance of viral RNA in patients with COVID-19 compared to empirical treatment [14] .', 'In China, it has been recommended as one of the antiviral drugs for COVID-19 [11] .', 'Oseltamivir is another drug approved for the treatment of influenza A and B [24], and has been used in some patients with COVID-19 [3, 7] .', 'In this study, neither arbidol nor oseltamivir exhibited positive effects on the viral RNA clearance of COVID-19.', 'Further, the combination of arbidol with another antiviral drug, oseltamivir or lopinavir/ritonavir, tended to delay clearance of viral RNA.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.09.20058941 doi: medRxiv preprint', 'In this study, only 10% of patients received corticosteroid treatment compared to 50%-79% as reported in patients from Wuhan [7, 9] .', 'Our analysis indicated that corticosteroid use was associated with delayed viral RNA clearance, in line with a recent report from Wuhan [18].', 'This may be due to selection bias since patients with serious/critical illness were more likely to be treated with corticosteroid.', 'Moreover, corticosteroid can suppress the immune systemand delay clearance of viral RNA [25], calling for its cautious use in patients with COVID-19.', 'Older age and disease severity are major determinants of persistence of viral RNA.', 'While the immune system weakens with aging [26], disease severity is a reflection of the host immunity.', 'Indeed, over 35% of patients aged 65 years old or above had serious or critical illness.', 'Here, public health measures such as social distancing, widespread testing, quarantine and contact tracing will not only reduce the spread of COVID-19 but also allows early detection of patients with mild disease for timely supportive treatment.', 'This will help reduce the burden on the healthcare system for treating patients with serious illness and reduce morbidity mortality rates.', 'In Guangzhou, with increased vigilance after the initial outbreak, these measures together with adequate medical facilities and support, the mortality rate was less than 1% compared to 3-4% during the early phase of the outbreak in Wuhan.', 'There were some limitations in this study.', 'First, due to small sample size, our data regarding treatment efficacy of antiviral drugs should be interpreted with caution.', 'Second, our patients had predominately mild to moderate illness and the results may not apply to those with serious or critical illness.', 'Third, the RT-PCR test used to detect viral nuclear acid in this study may not be sensitive enough to detect samples with low viral load with possible false-negative results.', 'Fourth, the viral RNA test was repeated every 2-3 days after hospitalization, therefore the time to viral RNA clearance may have a little bias.', 'Lastly, it is a retrospective single-center study, and large-scale prospective studies are needed to confirm these findings.', \"In conclusion, in patients with COVID-19, a minimum of 21 days' isolation since illness onset may be warranted even for asymptomatic patients.\", 'Old people are more likely to have serious illness with delayed clearance of viral RNA, and may require prolonged period of support and isolation.', 'The use of antiviral drugs (chloroquine, oseltamivir, arbidol, and lopinavir/ritonavir) did not improve viral RNA clearance, while corticosteroid use was associated with delayed clearance of viral RNA and should be used with caution.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.09.20058941 doi: medRxiv preprint All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.09.20058941 doi: medRxiv preprint']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['The ongoing outbreak of COVID-19, starting in December 2019, has quickly become a sweeping and unprecedented global challenge.', 'Because COVID-19 can spread from person to person [10, 11] , a major challenge in controlling the disease is recognizing and quarantining potential infectious sources as soon as possible [12] .', 'As Li reported, the median incubation period is 4-5.2 days and the 95th percentile of the distribution is 12.5 days [13] .', 'Unfortunately, COVID-19 patients can be infective before the disease onset and maintain infective ability during the convalescent phase [3, 4, 14] .', \"According to Cao's report [15] , the shortest observed duration of viral shedding was 8 days, whereas the longest was 37 days.\", 'However, to date, no article has reported what kind of patients have a longer viral shedding time.', 'In the family we report here, the index patient, Case 1, was from Wuhan and had contact with COVID-19 patients before she returned to Yiyang city.', 'The other 4 family members were from Yiyang and had never left Yiyang, nor did they have contact with any other COVID-19 patients.', 'It is most likely that Case 1 was the infective source in this family.', 'By further examining their epidemiological data, we find that the incubation period of COVID-19 and the shedding duration of SARS-CoV2 might be extremely long in this case.', 'The index patient did not develop atypical symptoms (including a mild cough and a runny nose) until 28 days after she had returned from Wuhan.', 'Remarkably, Case 1 was immunocompromised due to her long-term use of oral prednisone, which might explain why she did not develop typical symptoms at first and why she had a longer duration of viral shedding.', 'In summary, it is important to recognize potential patients who might have no or only mild symptoms.', 'Therefore, we highly recommend that all people with an exposure history be strictly quarantined, and for immunocompromised people with long-term use of glucocorticoids, this time should not be limited to 14 days.']}\n", - "{'sentences': ['[{\\'text\\': \\'As the coronavirus disease 19 global pandemic rages across the globe, the race to prevent and treat this deadly disease has led to the \"off-label\" repurposing of drugs such as hydroxychloroquine and lopinavir/ritonavir, which has the potential for unwanted QT-interval prolongation and a risk of drug-induced sudden cardiac death.', \"With the possibility that a considerable Q6', 'cite_spans': [], 'ref_spans': [], 'section': 'Abstract'}]\", 'As this coronavirus pandemic continues to spread and wreak havoc, economic loss, and more importantly, the tragic deaths of thousands throughout the world, we must all do our part in this war on COVID-19.', 'Washing hands and physical distancing are core components of containment efforts to \"flatten the curve.', '\" Development of a coronavirus vaccine is progressing at unprecedented speed but is still at least 12 to 18 months away.', 'In the meantime, there is hope that a long-ago discovered antimalarial drug, hydroxychloroquine, may have lifesaving therapeutic efficacy against COVID-19.', \"And if it does, we hope that this simple QTc surveillance strategy, enabled by innovation and the FDA's emergency approval, will help prevent altogether or at least substantially reduce the number of druginduced ventricular arrhythmias and sudden cardiac deaths, particularly if there is widespread adoption and utilization of these medications for COVID-19.\"]}\n", - "{'sentences': ['There were 40 cases (97.6%) received at least one kind of antiviral drugs empirically including oseltamivir, ribavirin, arbidol or lopinavir/ritonavir (Kaletra), which were accessible clinically in China.', 'Antibiotics or anti-fungus drugs were applied in 95.1% cases regarding to confirmed secondary infection or preventing secondary infection in relatively severe cases.', 'Corticosteroid was used in 78.0% cases to control immune overreaction.', 'Human albumin was applied when serum albumin decreased below 30g/L. Immunoglobulin was also applied empirically, as well as .', 'CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The analyzed population is characterized as younger age, less comorbidities than common community patients [11, 12] , and mostly featured non-severe course of There is no specific antiviral drug for SARS-CoV-2 infection up to now.', 'Expectation mainly comes from evidences that remdesivir and chloroquine are highly effective in the control of 2019-nCoV infection in vitro, while their cytotoxicity remains in control [22] .', 'It was reported that remdesivir, a nucleotide analogue prodrug, in previously clinical development for treatment of Ebola virus disease, exhibited broad-spectrum .', 'CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. .', 'CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.']}\n", - "{'sentences': ['Chloroquine and hydroxychloroquine as available weapons to fight COVID-19']}\n", - "{'sentences': ['Although there are currently no available therapies that are directly active against SARS-CoV-2, several medications have emerged as potential treatments.', 'Due to the low cost, easy accessibility, and lack of alternative treatment options, treatment with a combination of hydroxychloroquine and azithromycin is often considered for hospitalized patients with moderate to severe COVID-19.', 'It should be noted that the use of antimalarials for COVID-19 is based on a single study with a small sample size, nonrandomized control group, and significant drop out in the treatment group (25) .', 'As such, the efficacy of this treatment is still questionable, and the risk of significant adverse effects should be considered prior to initiating treatment with these drugs.', 'Among antivirals, remdesivir could be a promising candidate and may be more widely available in the upcoming weeks.', 'Passive immunization has been successfully used in the past; however, the efficacy of convalescent plasma in the treatment of critically ill patients with COVID-19 is still largely unknown.', 'Many institutions are beginning to use this treatment as more individuals recover from the disease and convalescent plasma becomes available.', 'Although there were many concerns regarding the use of medications such as ibuprofen and RAAS antagonists in patients with COVID-19, current guidelines state that ibuprofen may be used and recommend against the discontinuation of ACE inhibitors and ARBs.', 'We must continue to reevaluate current treatment recommendations as new data emerges and discourage inappropriate prescribing and hoarding of medications.', 'At the same time, parallel efforts are also J o u', 'r n a l P r e -p r o o f focusing on vaccine development, infection control measures, as well as optimal respiratory and supportive care.', '(Table 1 )']}\n", - "{'sentences': ['The COVID-19 epidemic represents a health emergency that is inevitably affecting the management of a complex disease such as RA [115, 116] .', 'As a chronic autoimmune inflammatory disorder, RA carries a higher infectious risk than the general population.', 'The use of synthetic and biologic disease-modifying drugs is associated with a potential further increase in the incidence of serious infections, but the poor control of RA disease activity is an even greater infectious risk factor.', 'Thus, RA patients should be encouraged to continue their treatment even during COVID-19 outbreak.', 'In our opinion, this strategy is reasonable as it aims to prevent disease flares that can contributes to increase patient burden, disability, poor quality of life, and healthcare use [117] .', 'In addition, the discontinuation of ongoing treatments could lead to the need to introduce CS as bridging therapy, which may further increase the risk of viral infection, as well as being inappropriate for the management of SARS-CoV2 interstitial pneumonia.', 'Chloroquine and hydroxychloroquine are currently included in the treatment protocol for the management of COVID-19 infections and might be useful to prevent or mitigate the course of infection in patients with RA taking them as csDMARDs.', 'The use of IL-6 inhibitors as tocilizumab or sarilumab seems to be promising for the management of most critical cases of interstitial pneumonia complicated by CRS, but the identification of definite criteria to discriminate patients to be treated with these compounds is still under debate.', 'Finally, although baricitinib has the potential to affect SARS-CoV2 penetration into pulmonary epithelial cells, major concerns remain about the inhibition of IFNs activity which could be detrimental in the course of viral infection.']}\n", - "{'sentences': ['Currently, the new coronavirus (COVID-19) pneumonia has widespread many countries in the world, caused more than 400,000 infections and 18,000 deaths.', 'According to more than 7,000 cases that have been reported in China, a crude mortality of COVID-19 was about 2.3%.', 'Among the diagnosed patients, about 80.9% were just showed mild to moderate symptoms and had a good prognosis [7] .', 'However, for patients who had progressed to severe or critical status, the mortality rates significantly increased to as high as 49% [5] .', 'And so far there was no effective treatment for COVID-19 patients, especially for severe and critical patients [8] .', 'So it is urgent to distinguish and interfere in advance to prevent those patients who were likely to progress to severe and critical status.', 'Previous study reported a high severe rate and death rate in male patients relative to female patients [2] .', 'However, the possible reason underlying was not referred.', 'Here we reported that the production and dynamic of IgG antibody were different between male and female patients.', 'In the early phase of the disease, the IgG antibody presented a stronger production in female patients.', 'In the severe status, contrast with the male, SARS-CoV-2 IgG antibody in female tended to enrich in the high levels.', 'The above two phenomena may be good reasons to explain the different outcomes between male and female COVID-19 patients.', 'However, the exact mechanism contributing to this difference remains elusive and needs further investigation.', 'At present, convalescent plasma was considered as a potential therapy for COVID-19 and now has been used in sever and critical patients in clinical [9] .', 'Our study proposed that convalescent plasma should be used in advance especially for female patient with low IgG antibody for a long time to prevent the disease from progressing to severe and critical status, if the convalescent plasma is available.', 'In addition, our study also supported that monitoring the SARS-CoV-2 antibody for routine examination maybe an efficient way to predict the progression of COVID-19 patients.', 'It should be noted that there were some limitations of this study.', 'Firstly, as all the cases are collected in a signal hospital (Wuhan union hospital), the sample size was relatively small.', 'Secondly, there were no critical cases enrolled in this study.', 'Thirdly, All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.26.20040709 doi: medRxiv preprint probably due to limited sample size, the rate of severe cases for male and female patients did not showed a consistent tendency as previously reported.', 'Nevertheless, the data showed in our study revealed a different pattern of IgG antibody after infection.', 'In conclusion, in this study we detected and analyzed the SARS-CoV-2 IgG antibody of 331 patients and found that, compared with male patients, more female patients maintained a high level of IgG antibody after SARS-CoV-2 infection.', 'And the production of IgG in female patients tended to be stronger than male patients in early phase of COVID-19.', 'We propose here that our doctors and nurses should pay more attention to the patients whose IgG antibody were at low levels.', 'And monitoring IgG antibody maybe a potential method to assess COVID-19 progression.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Introduction: More than 93,000 cases of coronavirus disease have been reported worldwide.', 'We describe the epidemiology, clinical course, and virologic characteristics of the first 12 U.S. patients with COVID-19.', 'We collected demographic, exposure, and clinical information from 12 patients confirmed by CDC during January 20-February 5, 2020 to have COVID-19.', 'Respiratory, stool, serum, and urine specimens were submitted for SARS-CoV-2 rRT-PCR testing, virus culture, and whole genome sequencing.', 'Results: Among the 12 patients, median age was 53 years (range: 21-68); 8 were male, 10 had traveled to China, and two were contacts of patients in this series.', 'Commonly reported signs and symptoms at illness onset were fever (n=7) and cough (n=8).', 'Seven patients were hospitalized with radiographic evidence of pneumonia and demonstrated clinical or laboratory signs of worsening during the second week of illness.', 'Three were treated with the investigational antiviral remdesivir.', 'All patients had SARS-CoV-2 RNA detected in respiratory specimens, typically for 2-3 weeks after illness onset, with lowest rRT-PCR Ct values often detected in the first week.', 'SARS-CoV-2 RNA was detected after reported symptom resolution in seven patients.', 'SARS-CoV-2 was cultured from respiratory specimens, and SARS-CoV-2 RNA was detected in stool from 7/10 patients.', 'In 12 patients with mild to moderately severe illness, SARS-CoV-2 RNA and viable virus were detected early, and prolonged RNA detection suggests the window for diagnosis is long.', 'Hospitalized patients showed signs of worsening in the second week after illness onset.', 'for use under a CC0 license.', 'We describe the first 12 patients with confirmed COVID-19 in the United States, including clinical course of the first 7 hospitalized patients.', 'Nine patients had traveled to Wuhan City, the epicenter of the outbreak, one had traveled to China', 'but not to Hubei Province, and two had close contact with a patient with confirmed COVID-19 in the United States, representing domestic human-to-human transmission.', 'Illness ranged from mild to moderately severe, and hospitalized patients showed signs of clinical worsening in the second week.', 'All patients recovered or are improving, and three patients tolerated treatment with the investigational antiviral remdesivir.', 'SARS-CoV-2 RNA was detected in upper and lower respiratory specimens, stool, and serum.', 'The highest viral RNA levels were detected in upper respiratory tract specimens, typically during the first week of illness.', 'SARS-CoV-2 was cultured from the initial respiratory specimens of mild and moderately ill patients.', 'Viral RNA was still detected after reported symptom resolution for seven patients.', 'SARS-CoV-2 genome sequencing and phylogenetic for use under a CC0 license.', 'This article is a US Government work.', 'It is not subject to copyright under 17 USC 105 and is also made available author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', \"https://doi.org/10.1101/2020.03.09.20032896 doi: medRxiv preprint analysis from these 12 patients' respiratory tract specimens support a single recent zoonotic transmission event in Wuhan City and subsequent human-to-human transmission.\", 'Overall, these patients had milder disease than those in initial reports from China describing higher rates of complications and death.', '[15] [16] [17] [18] Initial case identification in China focused on hospitalized patients with pneumonia, but recent reports have described a milder clinical course, consistent with our findings.', '[19] [20] [21] [22] [23] Among hospitalized patients in this report, the second week of illness was characterized by clinical or laboratory signs of worsening such as hypoxemia, increase in fever, or elevation of aminotransferases.', 'Although some patients received empiric antibiotic treatment for possible secondary bacterial pneumonia, no definitive evidence of bacterial co-infection was found.', 'Worsening in the second week of illness is consistent with previous reports 15, 17 and highlights the importance of close monitoring beyond the first week of illness, even in patients with mild illness or no initial radiographic abnormalities.', 'Patient 9, the most severely ill among this series, experienced sudden clinical deterioration late in the second week of illness.', 'This was the only patient with SARS-CoV-2 RNA detected in serum, and detection in serum was temporally related to clinical deterioration.', 'Similar observations have been described previously.', '24, 25 Increased proinflammatory cytokines have been observed in patients with COVID-19, 17 and it is possible that cytokine dysregulation and endothelial dysfunction contribute to both clinical worsening and SARS-CoV-2 RNA detection in serum.', 'Characterizing SARS-CoV-2 shedding is important to understand transmission and guide prevention strategies.', 'We detected viral RNA and cultured virus from upper respiratory specimens, even from patients with lower respiratory tract illness.', 'In general, Ct values in upper respiratory tract specimens were lowest during the first week of illness (suggesting high RNA counts), consistent with previous reports.', '25-27 SARS-CoV-2 RNA was detected in respiratory tract specimens for 2-3 weeks in most patients and for up to 29 days as of February 22.', 'In two patients with a productive cough, viral RNA was detected in sputum after RNA was no longer detectable in NP or OP specimens.', 'SARS-CoV-2 RNA levels and duration of RNA detection did not appear to vary by illness severity, and several patients had viral RNA detected in respiratory specimens after reported symptom resolution.', 'We detected SARS-CoV-2 RNA in stool of multiple patients; testing continues to assess if this represents viable virus.', \"SARS-CoV-2 was cultured from one patient's stool in China 28 but the implications for transmission are unclear.\", 'We detected SARS-CoV-2 RNA in the serum of one hospitalized patient but did not detect RNA in urine.', 'More data are needed to better understand how duration of RNA detection, RNA levels, and viable virus are related to symptom progression, illness severity, and transmission.', \"Three hospitalized patients received the investigational antiviral remdesivir under expanded access (compassionate use) at the time of clinical worsening based upon a decision by each patient's clinician.\", 'Remdesivir inhibits viral replication through premature termination of RNA transcription.', '29, 30 In vitro studies have demonstrated that remdesivir inhibits SARS-CoV-2 replication in non-human cells.', '31 Because remdesivir use was not given as part of a randomized controlled trial, we are unable to assess its effectiveness or safety.', 'Randomized controlled trials of remdesivir are underway.', '[32] [33] [34] Two hospitalized patients received corticosteroids.', 'WHO interim guidance for clinical management of severe acute respiratory infection with suspected COVID-19 advises against use of corticosteroids unless indicated for another reason.', '35 Several limitations should be considered when interpreting our findings.', 'Our sample of patients is small.', 'Information collected from patient interviews may have been subject to response bias.', 'The threshold for admitting patients and for monitoring in the hospital was likely lower than for other respiratory infections because of uncertainty about the clinical course of COVID-19.', 'Dates of illness resolution may be for use under a CC0 license.', 'This article is a US Government work.', 'It is not subject to copyright under 17 USC 105 and is also made available author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.09.20032896 doi: medRxiv preprint imprecise due to non-specific lingering symptoms or symptoms from chronic or unrelated conditions.', 'Clinical laboratory tests and radiographic studies were ordered as a part of routine patient care and were not collected systematically.', 'SARS-CoV-2 RNA detection does not necessarily reflect the presence of infectious virus, and rRT-PCR Ct values may have varied due to specimen collection or handling.', 'Specimen collection is ongoing to inform both clinical management and infection prevention and control practices, and findings will be updated as more information becomes available.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['We reported the first confirmed case of novel coronavirus pneumonia (NCP) in Taiwan.', 'In accordance with the first report from China, the major symptoms of COVID-19 infection were mainly cough, fever and dyspnea.', '2 Our case presented with mild fever, dyspnea and mild hypoxemia on day 10 of initial illness.', 'At the same time, the chest X-ray showed bilateral infiltrating pneumonia, which progressed diffusely later.', 'The progression of symptoms in this case also coincided with the first confirmed COVID-19 case in the U.S., with fever on day 5 of illness, dyspnea with mild hypoxemia and radiographical pneumonia on day 9 of illness.', '3 Furthermore, reports from China showed all patients had bilateral pneumonia on high resolution CT with different severity even in mild cases.', '2, 4 These findings suggested that lower respiratory tract seems to be an important location for the replication of SARS-CoV-2.', 'Our case turned afebrile since admission (illness day 10), even without antiviral treatment.', 'Despite pneumonia on chest Xrays worsen in the following seven days, respiratory failure did not occur eventually.', 'Even though ceftriaxone was used, the evidence of negative culture and the worsening chest X-ray findings under antibiotic treatment were not compatible with the clinical picture of bacterial pneumonia.', 'The effective medical treatment against COVID-19 remains unknown.', 'In spite of the first-reported case in the U.S. showing promptly-subsided fever after Remdesivir used on day 12 of illness, with well-improved clinical symptoms later, the effectiveness of Remdesivir was still questioned.', 'The randomized-controlled trial of treating Middle East respiratory syndrome coronavirus by the combination of lopinavir/ritonavir/interferon-beta-1b is ongoing, more evidence-based data are needed.', '5 Some laboratory abnormalities in our case, such as elevated CRP, LDH, ALT and AST, were also observed in influenza virus pandemic.', '6 Lymphopenia has been considered as a poor prognostic factor for severe hospitalized influenza (H1N1) pandemic 2009, 7 as well as severe acute respiratory syndrome (SARS', 'Similar to viral pneumonia due to other etiologies, ground-glass opacities (GGOs) are the main CT findings of the patients with COVID-19.', '9e12 Reticular and/or interlobular septal thickening, and consolidation are common associated findings.', '9 Crazy-paving pattern was also detected in some cases.', '10, 13 Pure consolidation without GGO is less common.', '10 These lesions usually involve bilateral lungs.', '9,10 Peripheral distribution of disease was noted in 33% and 85% of patients, respectively.', 'However, normal scan at the early stage of COVID-19 can be found in a few patients when the disease is diagnosed.', '10 As the NCP progresses, increasing size and density of these GGOs or crazy paving pattern were reported.', '9, 10, 13, 15 On the contrary, the GGOs']}\n", - "{'sentences': ['In the present study, a multivariate statistical analysis of a large dataset revealed new evolutionary features of viral overlapping genes.', 'They show a common, and peculiar, pattern of nucleotide and amino acid composition.', 'Thanks to discriminant analysis, overlapping genes can be separated from non-overlapping genes with high accuracy.', 'Thus, the model I developed is a valuable tool for identifying new potential dual-coding regions in the viral genome sequences deposited in databases and, possibly, also in the eukaryotic genome sequences.', \"A preliminary application of the model to SARS-CoV-2 led to prediction of 2 putative overlaps in the 3' genome region.\", 'The finding that the proteins encoded by the de novo frames differ significantly from those encoded by the ancestral frames supports the view that overprinting is a valuable source of genetic novelties.', 'This view is corroborated by the notion that 2 de novo proteins (apoptin from CAV and X protein from BDV) can exert functions that are not virus-specific, such as a selective anticancer toxicity in human tumour cell lines and a protection against neurodegeneration in tissue culture, respectively.', 'The search for variants of these proteins with an enhanced therapeutic effectiveness is an intriguing field of research.', 'The contribution provided by this study could be helpful for future experimental studies.', 'Finally, the wide collection of processed genome sequences given in Supplementary Files can be used by others as reference datasets for subsequent evolutionary studies (e.g. the relative age of overlapping genes or the occurrence of symmetric and asymmetric evolution in different regions of the same overlap).', 'were correctly classified as overlap (their score ranged from -53.91 to -35.36).', 'With the same score, a high percentage (97.1%) of non-overlapping genes were correctly classified as non-overlap (their score ranged from -35.31 to 0.84).', 'Overlap 3a protein/hypothetical protein: the nucleotide sequence (from nt 25522 to 25698) encodes the region of 3a protein spanning residues 44-102.', 'The +2 overlapping frame (from nt 25524 to 25697) encodes a hypothetical protein (underlined characters) with a length of 57 amino acids.', 'and in the respective +1 de novo frames (grey columns).', 'With a discriminant score of 18.02, a high percentage (97.6%) of ancestral frames were correctly classified as ancestral (their score ranged from 18.29 to 36.29).', 'With the same score, a high percentage (98.4%) of the +1 de novo frames were correctly classified as de novo (their score ranged from -3.96 to 17.95).', '(B) Histogram of the distribution of the LDA score in 68 ancestral frames (black columns) and in the respective +2 de novo frames (grey columns).', 'With a discriminant score of -15.92, all the ancestral frames and all the +2 de novo frames were correctly classified as ancestral and de novo, respectively.', 'Fig. 7 .', 'Alignment of the 7 most divergent apoptins yielded by simulation (from #1 to #7) with the apoptin of Chicken anemia virus (sequence NC_001427).', 'Italic characters indicate the N-terminal apoptosis-inducing domain (Pro-rich region from residue 9 to 28 and Ile/Leu rich region from residue 33 to 46), the C-terminal apoptosis-inducing domain (NLS1 from residue 82 to 88, NES from residue 97 to 105, and NLS2 from residue 111 to 121), and a critical threonine site (residue 108).', 'Due their critical role, these protein regions were excluded from random permutation.']}\n", - "{'sentences': ['Caution and clarity required in the use of chloroquine for COVID-19']}\n", - "{'sentences': ['Background: Information on kidney impairment in patients with coronavirus disease 2019 (COVID-19) is limited.', 'This study aims to assess the prevalence and impact of abnormal urine analysis and kidney dysfunction in hospitalized COVID-19', 'We conducted a consecutive cohort study of COVID-19 patients admitted in a tertiary teaching hospital with 3 branches following a major outbreak in Wuhan in 2020.', 'Hematuria, proteinuria, serum creatinine concentration and other clinical parameters were extracted from the electronic hospitalization databases and laboratory databases.', 'Incidence rate for acute kidney injury (AKI', 'We included 710 consecutive COVID-19 patients, 89 (12.3%) of whom died in hospital.', 'The median age of the patients was 63 years (inter quartile range, 51-71), including 374 men and 336 women.', 'On admission, 44% of patients have proteinuria hematuria and 26.9% have hematuria, and the prevalence of elevated serum creatinine and blood urea nitrogen were 15.5% and 14.1% respectively.', 'During the study period, AKI occurred in 3.2% patients.', 'Kaplan-Meier analysis demonstrated that patients with kidney impairment have higher risk for in-hospital death.', 'Cox proportional hazard regression confirmed that elevated serum creatinine, elevated urea nitrogen, AKI, proteinuria and hematuria was an independent risk factor for in-hospital death after adjusting for age, sex, disease severity, leukocyte count and lymphocyte count.', 'All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', '/2020 Conclusions: The prevalence of kidney impairment (hematuria, proteinuria and kidney dysfunction) in hospitalized COVID-19 patients was high.', 'After adjustment for confounders, kidney impairment indicators were associated with higher risk of inhospital death.', 'Clinicians should increase their awareness of kidney impairment in hospitalized COVID-19 patients.', 'In this large consecutive cohort study conducted in a tertiary teaching hospital with 3 branches in Wuhan, we have determined the prevalence of kidney impairment in hospitalized COVID-19 patients was high.', \"By analyzing clinic data and patients' outcome, we also demonstrated that kidney impairment was associated with in-hospital All rights reserved.\", 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', '18.20023242 doi: medRxiv preprint death.', 'In our study, a lot of patients have kidney impairment, including abnormal urinary analysis (proteinuria, hematuria) and kidney dysfunction (elevated BUN and Scr) on admission.', 'Indeed, multiple organ involvements including the liver, gastrointestinal tract and kidney have been reported during the course of SARS in 2003 8 and COVID-19 9 .', \"Of note, the high prevalence of kidney impairment at baseline may be explained by the fact that many COVID-19 patients couldn't be admitted to hospital in the early stage of disease outbreak because of large number of patients and limited beds in hospital in Wuhan.\", 'In addition, another explanation is that some COVID-19 patients may have a past history of chronic kidney disease (CKD) and CKD patients have a proinflammatory milieu and functional defects in innate and adaptive immune cell populations 10 .', 'In a community-based cohort of nearly 10,000 adult individuals, reduced eGFR and elevated albumin creatinine ratio were associated with higher risk for hospitalization with infection and subsequent mortality 11 .', 'AKI is a syndrome of abrupt loss of kidney function that is strongly associated with higher mortality and morbidity 14 .', 'In our cohort the detect rate of AKI in COVID-19 patients was 3.2%, which was similar to that reported in previous studies with small patients numbers 1, 4, 9, 15 and higher than 0.5% in a large observational study 16 .', 'This may be explained by that the proportion of severe patients was extremely high in previous case series and only 15.7% in the large observational study.', 'In our large cohort study, 35.5% patients were severe and this may illustrate the real detection rate of AKI in All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', '18.20023242 doi: medRxiv preprint clinic practice in Wuhan.', 'Importantly, the present method of detecting AKI is mainly based on changes in Scr and the frequency of Scr tests has a substantial impact on the detection rate of AKI 17 .', 'In a nationwide cross-sectional survey of hospitalized adult patients in China, the detection rate of AKI was only 0.99% by KDIGO criteria 18 .', 'After adjusting for frequency of Scr, the incidence of AKI in Chinese hospitalized adults gave rise to 11.6% 19 .', 'Thus, in order to improve early detection kidney injury, more frequent Human tissues RNA-seq data demonstrate that the ACE2 expression in urinary organs (kidney) was much higher (nearly 100-fold) than that in respiratory organs (lung) 22 .', 'Therefore, the kidney impairment may be caused by coronavirus entering the cells through ACE2 that are highly expressed in the kidney.', 'Second, deposition of immune complexes of viral antigen or virus-induced specific immunological effector mechanisms (specific T lymphocyte or antibody) may damage the kidney.', 'However, the data of kidney specimens from SARS patients showed normal glomerular histology with absence of electron-dense deposits, indicating the possibility of an active immunemediated glomerulonephritis was low.', 'Thus, kidney histology of COVID-19 patients is All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is This is the first study indicated the association of kidney impairment and inhospital death in patients with COVID-19.', 'It is reported that AKI is associated with an increased risk of death in patients with SARS 5 , which is in consistence with our study.', 'We also confirmed the value of Scr on admission in predicting the in-hospital death of patients with COVID-19 and AKI was more likely to occur in patients with elevated baseline Scr.', 'It is noteworthy that most COVID-19 patients developed acute kidney injury in the early period of hospitalization, especially in only 2 days after admission in patients with elevated baseline Scr.', \"Therefore, in the treatment of COVID-19, early prevention of kidney impairment, including adequate hemodynamic support and avoiding nephrotoxic drugs, is particularly important and early renal replacement treatment may improve the patients' prognosis.\", 'Beyond insufficiency in kidney function， the abnormal urine analysis, including proteinuria and hematuria, was also associated with in-hospital death.', 'This indicated that more attention should be paid to urine test in clinic.', 'Even though this study included a large number of patients from a tertiary teaching hospital in Wuhan, there are several limitations.', 'First, this was an observational study, All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', '18.20023242 doi: medRxiv preprint which may lead to underestimate of AKI or erroneous associations.', 'However, the large number of COVID-19 case in this study may minimize the potential for bias.', 'Second, although we attempted to adjust for many confounders, there may exist confounders either unmeasured or unknown that could explain our observed results.', 'Third, the clinic data of patient after discharge is lacking, so we could not assess the effect of COVID-19 on long-term outcome.', \"The further impact of COVID-19 on patients' kidney function, especially the incidence of chronic kidney disease in these patients should be the focus of future research.\"]}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['This case report describes the first two confirmed cases of COVID-10 in the Philippines and highlights several important clinical and public health issues.', 'Despite both patients being young adults with no significant past medical history, they had very different clinical courses, illustrating how COVID-19 can present with a wide spectrum of disease [8].', 'Whilst patient 1 had a mild uncomplicated illness consistent with an upper respiratory tract infection and recovery, patient 2 developed a severe pneumonia and died.', 'One possible explanation for the differing clinical courses is the presence of co-infection.', 'In both patients, the real-time PCR detection panel was reported to be positive for multiple pathogens.', 'The Staphylococcus aureus and Klebsiella pneumoniae detected in patient 1 most likely represent bacterial colonisation, and it is unclear to what extent her presentation was due to influenza or COVID-19 or both.', 'Patient 2 tested positive for COVID-19, Influenza B, and Streptococcus pneumoniae, all of which can cause respiratory infection and severe pneumonia.', 'Unfortunately, sputum culture was not possible due to biosafety concerns.', 'It is unclear which pathogen was the leading cause of death, but previous research has shown that outcomes of acute viral respiratory infection are worse if multiple pathogens are present [9].', 'This highlights the importance of testing for other respiratory pathogens in addition to COVID-19 in order to optimise antimicrobial therapy.', 'Patient 2 developed increasing dyspnoea on day 11 of illness, similar to the first COVID-19 case in the USA, where mild symptoms were initially reported with progression to pneumonia on day 9 of illness [10].', 'The median time from illness onset to dyspnoea in a case series in Wuhan was 8 days (range 5–13) [11].', 'The explanation for patient 2’s worsening condition and development of haemoptysis was progression of pneumonia rather than acute respiratory distress syndrome or pulmonary embolism, but it was not possible to perform a CT scan, additional laboratory tests or an autopsy to further assess this.', 'Although he was treated with broad-spectrum antimicrobials, it is not clear if the outcome would have been better in a high-resource setting.', 'Both patients were treated with oseltamivir in view of positive results for Influenza B. Further studies are required to establish the optimal treatment and role of antiviral medication for patients with suspected or confirmed COVID-19 infection.', 'Our cases contrast with the US case in terms of the relative paucity of lab data and time to receive results.', 'Limited in-house testing was undertaken due to biosafety concerns.', 'In the case of patient 2, the diagnosis of COVID-19 was not made until a day before the patient died.', 'This was because SARS-2-CoV testing was being established in the Philippines at the time that the patients were admitted, and initial samples had to be sent to Australia.', 'Although the delay of diagnosis is unlikely to have altered management, expansion of COVID-19 diagnostics including multiplex panels for other respiratory pathogens is urgently needed for prompt diagnosis of patients for screening of hospital personnel or other contacts.', 'Three SLH hospital staff who were caring for the patients developed symptoms and themselves became PUIs, but were later discharged following negative SARS-CoV-2 testing and symptom resolution.', 'This highlights the risk of an outbreak in the hospital, or a ‘super-spreader’ scenario, as was observed in other settings during the early stages of the SARS coronavirus infections in 2003 [12].', 'In the case of SARS, as with COVID-19, SLH managed two cases and was able to contain the infection without further spread [13].', 'The third confirmed COVID-19 case was announced on February 3 from a sample taken on January 23, also a Chinese national who had travelled from Wuhan.', 'She recovered and returned to China on January 31.', 'Contact tracing has been undertaken of all three patients [14].', 'Despite travel to several locations in the Philippines whilst experiencing symptoms, as of March 1, there has not been any confirmed local transmission arising from these cases and the number of PUIs has decreased [3].', 'However, as infection can be mild or subclinical, local transmission cannot be excluded.', 'Increasing the number of laboratories able to perform SARS-CoV-2 testing would allow better surveillance and improve detection of COVID-19 cases.', 'In conclusion, as of March 1, there have been three confirmed COVID-19 cases in the Philippines including the first death outside of China.', 'No local transmission has been confirmed.', 'Continued vigilance is required to identify new cases.']}\n", - "{'sentences': ['Use of siltuximab in patients with COVID-19 pneumonia requiring ventilatory support', 'COVID-19 is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SAR-CoV-2), resulting in symptoms, such as fever, cough, and shortness of breath.', 'The SARS-CoV-2 virus has also been suggested to initiate a cytokine storm in patients with COVID-19 evidenced by elevated cytokines, such as interleukin-6 (IL-6) and Creactive protein (CRP', 'We report preliminary data from 21 patients with COVID-19 who developed pneumonia/acute respiratory distress syndrome (ARDS', 'All 21 patients received intravenous siltuximab -a chimeric mAb that binds to and blocks the effect of IL-6 -at a dose ranging between 700 to 1,200 mg (median 900 mg).', 'The median age of patients treated was 64 years, and all patients were followed for a median of eight days.', 'Serum CRP levels reduced in all 16 patients with available .', 'CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', '(which was not peer-reviewed)', 'The copyright holder for this preprint .', 'This compassionate-use program was initiated to understand the feasibility of suppressing CRP production with siltuximab and improving the outcomes in patients with COVID-19 requiring CPAP or NIV for pneumonia/ARDS treatment.', 'Initial evidence from China where the first cases of COVID-19 emerged, indicate that excessive production inflammatory markers, such as IL-6 and CRP, correlate with severity of disease (Chen X et al. 2020; Conti P et al. 2020; Diao B et al. 2020; Gong J et al. 2020; Liu et al. 2020; Yang et al. 2020) , and many more studies report a significant increase in IL-6 or CRP levels in patients with severe or critical COVID-19 compared with those patients with mild disease (Cai et al. 2020; Chen J et al. 2020; Feng C et al. 2020; Huang Y et al. 2020; Liu J et al. 2020; Qin C et al. 2020; Ruan Q et al. 2020; Shi Y et al. 2020; Wang Y et al 2020; Wang Z et al. 2020; Wu C et al.2020; Xu W et al. 2020; Xu X et al. 2020; Zeng Q et al. 2020; Zhao Z et al. 2020; Zhang B et al. 2020; Zhou F et al. 2020; Zhou Y et al. 2020) .', 'Similarly, data from our retrospective analysis also show that baseline IL-6 levels and serum CRP levels were elevated beyond the normal range in all of the patients with available data, indicating the presence of inflammation, and suggesting that these .', 'CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.']}\n", - "{'sentences': ['A Rush to Judgment?', 'Rapid Reporting and Dissemination of Results and Its Consequences Regarding the Use of Hydroxychloroquine for COVID-19', 'Hydroxychloroquine, an essential treatment for many patients with rheumatologic conditions, has recently garnered widespread attention as a potential treatment for COVID-19 infection.', 'The authors appraise the study generating this interest and highlight the potential consequences of rapid dissemination of overinterpreted data, particularly for people with conditions for which hydroxychloroquine has demonstrated benefits in preventing organ damage and life-threatening disease flares.']}\n", - "{'sentences': ['Efficacy of remdesivir versus placebo for the treatment of COVID-19: A protocol for systematic review and meta-analysis of randomized controlled trials', 'Background: In spite of the global containment on prevention efforts, the spread of coronavirus disease 2019 is continuing to rise, with 1.1 million confirmed cases and 60,124 deaths recorded worldwide since 04 April 2020.', 'The outbreak has a significant threat to international health and economy.', 'At present, there is no approved vaccine or treatment for the disease, while efforts are underway.', 'Remdesivir, a nucleotide-analogue antiviral drug developed for Ebola, is determined to prevent and stop infections with COVID-19, while results are yet controversial.', 'Here, we aim to conduct a systematic review and meta-analysis of randomized controlled trials to compare the effectiveness of remdesivir and placebo in patients with COVID-', 'Method and analysis: We will search MEDLINE-PubMed, Embase, Cochrane Library, ClinicalTrials.gov, and Google scholar databases without restriction in year of publication.', 'We will include randomized controlled trials that assessed the effectiveness of remdesivir versus placebo for patients confirmed with COVID-19.', 'We will follow the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA 2015) guidelines for the design and reporting of the results.', 'The primary endpoint will be time to clinical recovery.', 'The secondary endpoints will be all cause mortality, discharged date, frequency of respiratory progression, and treatment-emergent adverse events.', 'Two independent authors will perform study selection, data extraction, and methodology quality assessment.', 'RevMan 5.3 software will be used for statistical analysis.', 'Random/fixed effect model will be carried out to calculate mean differences for continuous outcomes and risk ratio for dichotomous outcomes between remdesivir and placebo.', \"This study does not require ethical approval, because no participant's data will be involved in this systematic review and meta-analysis.\", 'The findings of this study will be published in reputable and peer-reviewed journal.', 'Registration: This review protocol is submitted in PROSPERO database for registration and we will include the registration number in the revised version of the manuscript.']}\n", - "{'sentences': ['Coronavirus disease 2019 is an illness caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).', 'The disease was first identified as a cluster of respiratory illness in Wuhan City, Hubei Province, China in December 2019, and has rapidly spread across the globe to greater than 200 countries.', 'Healthcare providers are at an increased risk for contracting the disease due to occupational exposure and require appropriate personal protective equipment (PPE), including N95 respirators.', 'The rapid worldwide spread of high numbers of COVID-19 cases has facilitated the need for a substantial supply of PPE', 'Creative solutions for the decontamination and safe reuse of PPE to protect our frontline healthcare personnel are essential.', 'Here, we describe the development of a process that began in late February 2020 for selecting and implementing the use of hydrogen peroxide vapor (HPV) as viable method to reprocess N95 respirators.', 'Since pre-existing HPV', 'Details are provided about the prioritization and implementation of processes for collection and storage, pre-processing, HPV decontamination, and post-processing of filtering facepiece respirators (FFRs']}\n", - "{'sentences': ['Background: The coronavirus disease 2019 (COVID-19) is spreading worldwide with 16,558 deaths till date.', 'Serum albumin, high-density lipoprotein (HDL-C), and C-reactive protein have been known to be associated with the severity and mortality of community-acquired pneumonia.', 'However, the characteristics and role of metabolic and inflammatory indicators in COVID-19 is unclear.', 'Methods: We included 97 hospitalized patients with laboratory-confirmed COVID-19.', 'Epidemiological, clinical, and laboratory indices; radiological features; and treatment were analysed.', 'The differences in the clinical and laboratory parameters between mild and severe COVID-19 patients and the role of these indicators in severity prediction of COVID-19 were investigated.', 'Results: All were Wuhan residents with contact with confirmed COVID-19 cases.', 'The median age was 39 years (IQR: 30-59).', 'The most common presenting symptoms were fever (58.8%), cough (55.7%), and fatigue (33%).', 'Other features were lymphopenia, impaired fasting glucose, hypoproteinaemia, hypoalbuminemia, low high-density lipoproteinemia.', 'Decrease in lymphocyte count, serum total protein, serum albumin, high-density lipoprotein cholesterol (HDL-C), ApoA1, CD3+T%, and CD8+T% were found to be valuable in predicting the transition of COVID-19 from mild to severe illness.', 'Chest computed tomography (CT) images showed that the absorption of bilateral lung lesions synchronized with the recovery of metabolic and inflammatory indicators.', 'Conclusions: Hypoproteinaemia, hypoalbuminemia, low high-density lipoproteinemia, and decreased ApoA1, CD3+T%, and CD8+T% could predict severity of COVID-19.', 'Lymphocyte count, total serum protein, and HDL-C may be potentially useful for the evaluation of COVID-19']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Triphosphates of the Two Components in DESCOVY and TRUVADA are Inhibitors of the SARS-CoV-2 Polymerase', \"[{'text': 'SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 pandemic.\", 'We previously demonstrated that four nucleotide analogues (specifically, the active triphosphate forms of Sofosbuvir, Alovudine, AZT and Tenofovir alafenamide) inhibit the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp).', 'Tenofovir and emtricitabine are the two components in DESCOVY and TRUVADA, the two FDA-approved medications for use as pre-exposure prophylaxis (PrEP) to prevent HIV infection.', 'This is a preventative method in which individuals who are HIV negative (but at high-risk of contracting the virus) take the combination drug daily to reduce the chance of becoming infected with HIV.', 'PrEP can stop HIV from replicating and spreading throughout the body.', 'We report here that the triphosphates of tenofovir and emtricitabine, the two components in DESCOVY and TRUVADA, act as terminators for the SARS-CoV-2 RdRp catalyzed reaction.', 'These results provide a molecular basis to evaluate the potential of DESCOVY and TRUVADA as PrEP', 'We tested the ability of the active triphosphate forms of both tenofovir and emtricitabine to be incorporated by the SARS-CoV-2 RdRp.', 'The RdRp of SARS-CoV-2 (referred to as nsp12) and its two protein cofactors (nsp7 and nsp8), whose homologs were shown to be required for the processive polymerase activity of nsp12 in SARS-CoV, 24,25 were cloned and purified as previously described.', '11 We then performed polymerase extension assays with UTP + TFV-DP, and UTP + ATP + Ec-TP, following the addition of a pre-annealed RNA template and primer to a pre-assembled mixture of the SARS-CoV-2 RdRp (nsp12) and the two cofactor proteins (nsp7 and nsp8).', 'The primer extension products from the reaction were analyzed by MALDI-TOF-MS.', \"The RNA template and primer, corresponding to the 3' end of the SARS-CoV-2 .\", 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.03.022939 doi: bioRxiv preprint genome, were used for the polymerase assay; their sequences are indicated at the top of Fig. 2 .', \"In the case of tenofovir diphosphate (TFV-DP) that contains an adenine base, because there are two A's in a row followed by a U in the next available positions of the template for RNA polymerase extension downstream of the priming site, we added both UTP and TFV-DP in the extension reaction.\", 'Based on results we previously obtained for TFV-DP, 11 we reduced the ratio of UTP and TFV-DP from 1:10 to 1:100 in this current experiment.', 'If TFV-DP acts as a permanent terminator of the RdRp reaction, we would ideally observe a peak in the spectrum at the third primer extension position caused by incorporation of two Us and one TFV-DP.', 'In the case of emtricitabine triphosphate (Ec-TP), which is a C analogue, we need to extend the primer to the first available G in the template sequence.', 'Since the next available positions in the template consist of two As, four Us, another A and a G, we included UTP, ATP and Ec-TP in the extension reaction.', 'Thus, if Ec-TP serves as a permanent inhibitor of the RdRp reaction, we would ideally observe a peak in the spectrum at the eighth primer extension position caused by incorporation of two Us, four As, another U and one Ec-TP', 'The results of the MALDI-TOF MS analysis of the primer extension products are shown in Fig. 2 .', 'The observed peaks generally fit the predictions above; however, additional peaks from products assigned to intermediate stages of the extension reaction were also observed.', 'In the case of TFV-DP (Fig. 2a) , a peak with the expected molecular weight representing incorporation of two Us and one TFV-DP was obtained (7196 Da observed, 7193 Da expected).', 'As anticipated, partial extension products were also observed for a single U (6621 Da observed, 6618 Da expected) and for two Us (6927 Da observed, 6924 Da expected).', 'Most importantly, once the TFV-DP was incorporated, there was no further extension, which confirms that it is a permanent terminator.', 'These results are similar to our previous primer extension reactions with UTP and TFV-DP.', 'However, we previously observed significant amounts of misincorporation products (3 Us) due to the higher concentration of UTP.', 'Under the current conditions, misincorporations were insignificant (Fig. 2a) .', \"In the case of Ec-TP (Fig. 2b) , an expected peak indicating extension by three Us, four As and one Ec-TP was observed (8863 Da observed, 8855 Da expected), but shorter extension products also occurred, such as the extension by one U (6626 Da observed, 6618 Da expected), or a longer primer extension product containing the sequence Primer-UUAAAAU-3' but excluding the incorporation of an Ec-TP (8556 Da observed, 8546 Da expected).\", \"The extra peak at the right (9191 Da) could be explained by misincorporation events, such as a longer primer extension product containing the sequence Primer-UUAAAAUUA-3' (9181 Da expected) in which a U (italicized) was incorporated instead of a C, followed by the incorporation of an A. The occurrence of misincorporation indicates that SARS-CoV-2 RdRp has low fidelity, a property similar to other RNA viruses.\", '5, 26 In summary, these results demonstrate that the nucleotide analogues TFV-DP and Ec-TP are permanent terminators for the SARS-CoV-2 RdRp catalyzed reaction.', \"Their prodrug versions (TAF or TDF and Emtricitabine or Emtricitabine-5'-O-phosphoramidate that can be readily synthesized using the ProTide prodrug approach 27 ) can be used as lead compounds for COVID-19 therapeutics development.\", 'More importantly, since these molecules are contained in the FDA-approved combination drugs TRUVADA and DISCOVY, our results provide a molecular basis to further evaluate them in SARS-CoV-2 virus inhibition and animal models to test their efficacy for the development of potential COVID-19 medications.', 'These current and future studies may also provide potential options for preventing COVID-19 infection in a manner similar to PrEP for HIV prevention.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.03.022939 doi: bioRxiv preprint Fig. 2 Incorporation of TFV-DP and Ec-TP by SARS-CoV-2 RdRp to terminate the polymerase reaction.', \"The sequences of the primer and template used for these extension reactions, which are at the 3' end of the SARS-CoV-2 genome, are shown at the top of the figure.\", 'Polymerase extension reactions were performed by incubating (a) UTP + TFV-DP, and (b) UTP + ATP + Ec-TP with pre-assembled SARS-CoV-2 polymerase (nsp12, nsp7 and nsp8), the indicated RNA template and primer, and the appropriate reaction buffer, followed by the detection of reaction products by MALDI-TOF MS.', 'The detailed procedure is described in the Methods section.', 'The accuracy for m/z determination is ± 10 Da.']}\n", - "{'sentences': ['Over the past 20 years, highly infectious pathogens have been emerging increasingly, such as SARS-CoV in 2003 and MERS-CoV in 2012.20–22 In 2018, WHO proposed “Disease X” in the blueprint priority diseases for any new unknown pathogen that may cause an epidemic or pandemic in the future, calling for the development of effective and safe vaccines and antivirals to prevent and treat such Disease X. Indeed, at the end of 2019, the outbreak of Wuhan pneumonia with an unknown etiological agent, the first Disease X following WHO’s announcement was reported to WHO.', 'Shortly thereafter, a novel coronavirus, SARS-CoV-2 (also known as 2019-nCoV or HCoV-19), was identified to be the etiology of the Wuhan pneumonia, i.e., COVID-19 as designated by WHO.', 'Unlike SARS-CoV, live SARS-CoV-2-infected cells were found to form typical syncytium, suggesting that SARS-CoV-2 may mainly utilize the plasma membrane fusion pathway to enter and replicate inside host cells.', 'Consistently, in the cell–cell fusion system, SARS-CoV-2 S protein could effectively mediate the formation of syncytium between the effector cell and the target cell in the absence of an exogenous proteolytic enzyme, e.g., trypsin, while SARS-CoV S protein could not.', 'Actually, the plasma membrane fusion pathway is more efficient than the endosomal membrane fusion pathway for most viruses because the latter is more prone to activating the host cell antiviral immunity.23,24 Generally, β-B coronaviruses lack the S1/S2 furin-recognition site, and their S proteins are uncleaved in the native state.', 'For example, SARS-CoV enters into the cell mainly via the endosomal membrane fusion pathway where its S protein is cleaved by endosomal cathepsin L and activated.25 Inducing the S1/S2 furin-recognition site could significantly increase the capacity of SARS-CoV S protein to mediate cellular membrane surface infection.26 Interestingly, SARS-CoV-2 harbors the S1/S2 cleavage site in its S protein, but its specific role in S protein-mediated membrane fusion and viral life-cycle remains to be further explored (Supplementary information, Fig. S7).', 'A recent report suggested that SARS-CoV-2 mainly used TMPRSS2 for plasma membrane fusion; this means that the TMPRSS2 inhibitor might constitute an option for blocking SARS-CoV-2 fusion with and entry into the host cell.27', 'The 6-HB structure formed by HR1 and HR2 regions in the S2 subunit of HCoVs plays a key role during the viral membrane fusion process, which makes it one of the most important targets for drug design.', 'In previous studies, we have found that HR1 and HR2 of SARS-CoV-2 could form a stable coiled-coil complex, but the detailed conformations remain unknown.', 'According to the X-ray crystallographic analysis of the complex formed by HR1 and HR2 of SARS-CoV-2 (Fig. 2b), it is a typical 6-HB fusion core structure similar to those of SARS-CoV and MERS-CoV. Although the amino acid sequences of HR2 domain from SARS-CoV and SARS-CoV-2 are fully identical, multiple residue differences occur in the HR1 domain of SARS-CoV-2.', 'However, instead of weakening the interaction between HR1 and HR2, such unilateral difference seems to form new interactions in some regions and enhance the existing ones in other regions (Fig. 3).', 'When K991 in SARS-CoV HR1 was replaced with S929 in SARS-CoV2 HR1, a new, strong hydrogen bond was formed with a distance of 2.4 Å. K933 forms a new interaction with N1192 in SARS-CoV-2 with a distance of 2.7 Å, whereas the corresponding position in SARS-CoV has no such interaction.', 'In the other two regions, E918 binds to R1166 and K929 binds to E1163 in SARS-CoV, both of which were enhanced in SARS-CoV-2.', 'These results suggest that this new HCoV has evolved with improved binding affinity between HR1 and HR2 domains, which may accelerate the viral membrane fusion process and enhance viral infectivity or transmissibility.', 'A recent study also found that the binding affinity between ACE2 receptor on the host cell and RBD in S protein of SARS-CoV-2 is more than 10-fold higher than that of SARS-CoV, which may also be associated with the increased infectivity and transmissibility of SARS-CoV-2.12', 'The conjugation of cholesterol to viral entry inhibitor has been proved to be an effective strategy to enhance the antiviral activity, such as C34 peptide for HIV-1.28 However, the mechanism of this enhancement, especially the role of cholesterol group in the C-terminal tail of entry inhibitor, is still unclear.', 'There is a possibility that the cholesterol group could anchor to the target membrane to facilitate the binding of inhibitor to the HR1 targets.', 'However, we noticed that binding affinity between EK1C4 and SARS-CoV-2-HR1P is significantly enhanced than EK1 peptide alone, which suggested that cholesterol group may be involved in binding to HR1P directly (Supplementary information, Fig. S4).', 'Therefore, using structural simulation and docking method, we predicted a possible model of EK1C4 in binding with SARS-CoV-2 HR1P (Supplementary information, Fig. S8).', 'In this model, the EK1C4 peptide anchors to one of the three hydrophobic grooves of HR1 trimer via its EK1 moiety, and also anchors to another adjacent hydrophobic groove of HR1 trimer via its cholesterol moiety.', 'The cholesterol group of EK1C4 may bind to HR1P through hydrophobic interactions, while several hydrogen bonds may form between HR1 and helical region of EK1C4.', 'The intermediated GSGSG-PEG4 linker of EK1C4 peptide is just enough to connect these two moieties on the two binding targets.', 'Admittedly, the exact mechanism and structure of EK1C4 need more studies in the future.', 'In the past few decades, the viral HR1 domain has been proved to be an important target for the development of viral fusion and entry inhibitors.', 'In the early outbreak of MERS, we quickly solved the 6-HB fusion core structure formed by MERS-CoV S protein HR1 and HR2 domains and designed the fusion inhibitory peptide HR2P-M2 which proved to be highly effective in blocking its spike protein-mediated membrane fusion and inhibit in vitro MERS-CoV infection.16', 'The results from animal experiments showed that intranasal application of HR2P-M2 peptide could effectively protect mice from MERS-CoV infection with reduction of virus titers in the lung more than 1000-fold.29 However, the MERS-CoV HR2P-M2 peptide could not inhibit SARS-CoV infection, suggesting that this peptide lacks cross-inhibitory activity against other β-CoVs, such as SARS-CoV and bat SARSr-CoVs.', 'To be well prepared for combating the emerging coronaviruses with epidemic or pandemic potential, we designed and synthesized the first pan-coronavirus fusion inhibitor, EK1, and found that EK1 exhibited potent inhibitory activity against all HCoVs that we tested, including SARS-CoV and MARS-CoV, as well as bat SARSr-CoVs.', 'As expected, we recently have shown that EK1 is also effective in inhibiting infection of the novel β-CoV, SARS-CoV-2.15 We then optimized EK1 peptide in hopes of improving its fusion inhibitory activity.', 'Indeed, we found that one of the modified EK1 peptides, EK1C4, was 226-fold and 149-fold more potent against SARS-CoV-2 S protein-mediated membrane fusion and PsV infection, respectively, than EK1.', 'EK1C4 also showed broad-spectrum inhibitory activity against infection by SARS-CoV, MERS-CoV and other HCoVs.', 'EK1C4 showed prolonged and significant prophylactic effect against HCoV-OC43 infection in mouse model, suggesting that EK1C4 may also be used as an inhibitor against SARS-CoV-2 infection in vivo.', 'Consistent with other studies,30 HCoV-OC43 was shown as a typical neurotropic virus in the mouse model, and quickly entered and established infection in mouse brain tissue, leading to the relatively weak therapeutic effect of EK1C4 via intranasal administration.', 'However, SARS-CoV-2 mainly infected and caused severe pathological changes in human lung tissue.4 Therefore, EK1C4 administered intranasally is expected to have good therapeutic potential against SARS-CoV-2 infection.', 'Currently, no specific anti-CoV therapeutics or prophylactics have been used in clinics for treatment or prevention of SARS-CoV-2 infection.', 'A number of nonspecific antiviral drugs, including IFN, lopinavir-ritonavir (HIV protease inhibitors), chloroquine, favipiravir (T-705) and remdesivir (GS-5734), have been used in clinics in China to treat SARS-CoV-2 infection.31 Their in vivo efficacies still require further confirmation.', 'Their potential use for treatment of infection by other coronaviruses and emerging coronaviruses in the future is unclear.', 'Compared with these clinically used nonspecific antiviral drugs, EK1C4 has more advantages for treatment and prevention of SARS-CoV-2 infection.', 'First, the sequence of its target, the HR1 domain in S2 subunit of S protein, is highly conserved.', 'Therefore, EK1C4 possesses a high genetic barrier to resistance and cannot easily induce drug-resistant mutations.', 'Second, EK1C4 can be used in an intranasal formulation to prevent coronavirus infection.', 'The small bottles can be carried easily by persons who will have close contact with infected patients or high-risk populations.', 'Third, EK1C4 can be used in inhalation formulation for treatment of patients to reduce the viral loads in their lungs, thus attenuating the acute lung injury caused by viral infection and reducing the chance to spread the virions to the closely contacted persons.', 'The inhalation equipment can be used in home or hotel room, reducing the expense of staying in hospitals.', 'Fourth, EK1C4 is expected to be safe to humans because it will be used locally, not systemically, and peptide drugs are generally safer than chemical drugs.', 'Fifth, because of its broad-spectrum anti-coronavirus activity, EK1C4 can be used for treatment and prevention of infection by not only SARS-CoV-2, but also other HCoVs.', 'Sixth, recently 103 SARS-CoV-2 genomes have been identified,32 but we found that both HR1 and HR2 domains among those reported genomes show 100% identity (Supplementary information, Fig. S9), indicating the high conservation of EK1C4 target.', 'In the meantime, the HR2 derived peptides have much larger interface on HR1 domain, making it more resistant to the viral mutations.', 'Therefore, EK1C4 shows exceptional promise to be developed as the first pan-CoV fusion inhibitor-based antiviral therapeutic or prophylactic for treatment or prevention of infection by the currently circulating SARS-CoV-2 and MERS-CoV and the future reemerging SARS-CoV and emerging SARSr-CoVs.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Quantifying treatment effects of hydroxychloroquine and azithromycin for COVID-19: a secondary analysis of an open label non-randomized clinical trial (Gautret et al, 2020)', 'Human infections with a novel coronavirus (SARS-CoV-2) were first identified via syndromic surveillance in December of 2019 in Wuhan China.', 'Since identification, infections (coronavirus disease-2019; COVID-19) caused by this novel pathogen have spread globally, with more than 250,000 confirmed cases as of March 21, 2020.', 'An open-label clinical trial has just concluded, suggesting improved resolution of viremia with use of two existing therapies: hydroxychloroquine (HCQ) as monotherapy, and in combination with azithromycin (HCQ) as monotherapy, and in combination with azithromycin', 'The results of this important trial have major implications for global policy in the rapid scale-up and response to this pandemic.', 'The authors present results with p-values for differences in proportions between the study arms, but their analysis is not able to provide effect size estimates.', 'To address this gap, more modern analytical methods including survival models, have been applied to these data, and show modest to no impact of HCQ treatment, with more significant effects from the HCQ-AZ combination, potentially suggesting a role for co-infections in COVID-19 pathogenesis.', 'The trial of Gautret and colleagues, with consideration of the effect sizes, and p-values from multiple models, does not provide sufficient evidence to support wide-scale rollout of HCQ monotherapy for the treatment of COVID-19; larger randomized studies should be considered.', 'These data also suggest further randomized-controlled studies of HCQ-AZ combination therapy should be undertaken.']}\n", - "{'sentences': ['Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods, Acta Pharmaceutica Sinica B, https://doi.', 'Twenty structures including 19 SARS-CoV-2 targets and 1 human target were built by homology modeling.', 'Library of ZINC drug database, natural products, 78 anti-viral drugs were screened against these targets plus human ACE2.', 'This study provides drug repositioning candidates and targets for further in vitro and in vivo studies of SARS-CoV-2.', '(Mengzhu Zheng), xingzhouli@aliyun.com (Xingzhou Li', 'Abstract SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths.', 'There are currently no registered therapies for treating coronavirus infections.', 'Because of time consuming process of new drug development, drug repositioning may be the only solution to the epidemic of sudden infectious diseases.', 'We systematically analyzed all the proteins encoded by SARS-CoV-2 genes, compared them with proteins from other coronaviruses, predicted their structures, and built 19 structures that could be done by homology modeling.', 'By performing target-based virtual ligand screening, a total of 21 targets (including two human targets) were screened against compound libraries including ZINC drug database and our own database of natural products.', 'Structure and screening results of important targets such as 3-chymotrypsin-like protease (3CLpro), Spike, RNA-dependent RNA polymerase (RdRp), and papain like protease (PLpro', 'The ongoing SARS-CoV-2 epidemic makes us painfully realize that our current For those targets which are difficult to find direct inhibitors, or non-druggable targets, just like Nsp1, Nsp3b, Nsp3c, and E-channel, etc., currently popular PROTAC technology may be a good strategy to degrade these proteins and then inhibit the virus.', 'The potential binding compounds found in this study for these targets might be a good start point.', 'For Spike protein, we found only one compound, natural hesperidin was targeting the binding between Spike RBD and human ACE2.', 'However, not like the ACE2 binding compounds, non-interface binding compound may still meaningful applications, considering that the fusion of CoVs membrane with host cell membrane need the big conformational change of remained Spike part after RBD removal 55 .', 'Any small molecule bound to Spike at this time may interfere the re-folding of Spike therefore inhibits the viral infection process.', 'Furthermore, small molecule that can target any part of Spike protein may be a good start point to design PROTAC based therapy.', 'Also, we dock existing anti-viral drugs with our targets, analyze the possible targets of each anti-viral drug horizontally, and analyze the drugs that may interact with 21 targets vertically.', 'We analyzed 21 targets based on the docking results and found that Nsp3b, Nsp3c, Nsp7_Nsp8 complex, Nsp14, Nsp15, PLpro, 3CLpro, RdRp, helicase, E-channel, Spike and ACE2 are more likely to be therapeutic targets of anti-viral drugs.', 'The three targets Nsp3b, Nsp3c, and E-channel are screened more anti-viral drugs.', 'This may be due to the model problem because of flexible small protein (Nsp3b and Nsp3c) or partial model (E-channel).', 'Whether the screened anti-viral drugs really work on these targets needs further verification.', 'We also do not recommend the application of new coronavirus pneumonia to compounds for which no target has been predicted.', 'The triphosphate nucleotide product of remdesivir, remdesivir-TP, competes with RdRp for substrate ATP, so it can interfere with viral RNA synthesis.', 'Our docking results show that remdesivir-TP binds to SARS-CoV-2 RdRp, with a score of -112.8, and the docking results are consistent with its original anti-viral mechanism, so we think remdesivir may be good in treating SARS-CoV-2 pneumonia.', 'In addition, remdesivir also predicted to bind with the human TMPRSS2, a protein facilitating the virus infection, this is a new discovery and provides ideas for subsequent research.', 'Chloroquine phosphate has shown better anti-SARS-CoV-2 effects in recent studies, but this drug has no clear target of action.', 'In our docking results, chloroquine phosphate is predicted to possibly combine with', 'Nsp3b and E-channel.', 'But we need to do further experiments to verify this conclusion.']}\n", - "{'sentences': ['COVID-19: Melatonin as a potential adjuvant treatment', 'The possible beneficial effects of melatonin as adjuvant use in COVID-19 in anti-inflammation, anti-oxidation, immune response regulation has been repeatedly demonstrated in respiratory disorder models induced by infections and associated complications.', 'Melatonin has a high safety profile.', 'Although the direct evidence of melatonin application in COVID-19 is unclear, both its use in experimental animal models and in studies on humans has continuously documented its efficacy and safety and its use by COVID-19 patients predictably would be highly beneficial.']}\n", - "{'sentences': ['First Clinical Study Using HCV Protease Inhibitor Danoprevir to Treat Naive and Experienced COVID-19 Patients']}\n", - "{'sentences': ['Human Coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle east respiratory syndrome coronavirus (MERS-CoV), and 2019 novel coronavirus (2019-nCoV), lead global epidemics with high morbidity and mortality.', 'However, there are currently no effective drugs targeting 2019-nCoV. Drug repurposing, represented as an effective drug discovery strategy from existing drugs, could shorten the time and reduce the cost compared to de novo drug discovery.', 'In this study, we present an integrative, antiviral drug repurposing methodology implementing a systems pharmacology-based network medicine platform, quantifying the interplay between the HCoV-host interactome and drug targets in the human protein-protein interaction network.', 'Phylogenetic analyses of 15 HCoV whole genomes reveal that 2019-nCoV has the highest nucleotide sequence identity with SARS-CoV (79.7%) among the six other known pathogenic HCoVs.', 'Specifically, the envelope and nucleocapsid proteins of 2019-nCoV', 'Using network proximity analyses of drug targets and known HCoV-host interactions in the human protein-protein interactome, we computationally identified 135 putative repurposable drugs for the potential prevention and treatment of HCoVs.', 'In addition, we prioritized 16 potential anti-HCoV repurposable drugs (including melatonin, mercaptopurine, and sirolimus) that were further validated by enrichment analyses of drug-gene signatures and HCoV-induced transcriptomics data in human cell lines.', 'Finally, we showcased three potential drug combinations (including sirolimus plus dactinomycin, mercaptopurine plus melatonin, and toremifene plus emodin) captured by .', 'CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'In this study, we presented a network-based methodology for systematic identification of putative repurposable drugs and drug combinations for potential treatment of HCoV.', 'Integration of drug-target networks, HCoV-host interactions, HCoV-induced transcriptome in human cell lines, and human protein-protein interactome network are essential for such identification.', 'Based on comprehensive evaluation, we prioritized 16 putative repurposable drugs ( Figure 5 ) and 3 putative drug combinations (Figure 6 ) for the potential treatment of HCoVs, including 2019-nCoV. However, all network-predicted repurposable drugs and drug combinations must be validated in preclinical models and randomized clinical trials before being used in patients.', 'We acknowledge several limitations in our current study.', 'In this study, we used a low binding affinity value of 10 µM as a threshold to define a physical drug-target .', 'CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.02.03.20020263 doi: medRxiv preprint interaction.', 'However, a stronger binding affinity threshold (e.g., 1µM) may be a more suitable cut-off in drug discovery, although it will generate a smaller drug-target network.', 'Although sizeable efforts were made for assembling large-scale, experimentally reported drug-target networks from publicly available databases, the network data may be incomplete and some drug-protein interactions may be functional associations, instead of physical bindings.', 'We may use computational approaches to systematically predict the drug-target interactions further [24, 69] .', 'In addition, the collected virus-host interactions are far from complete and the quality can be influenced by multiple factors, including different experimental assays and human cell line models.', 'We may computationally predict a new virus-host interactome for HCoVs using sequence-based and structure-based approaches [70] .', 'The current systems pharmacology model cannot separate therapeutic antiviral effects from those predictions due to lack of detailed pharmacological effects of drug targets and unknown functional consequences of virushost interactions.', 'Drug targets representing nodes within cellular networks are often intrinsically coupled with both therapeutic and adverse profiles [71] , as drugs can inhibit or activate protein functions (including antagonists versus agonists).', 'Comprehensive identification of the virus-host interactome for 2019-nCoV, with specific biological effects using functional genomics assays [72, 73] , will significantly improve the accuracy of current network-based methodologies.', \"Owing to lack of the complete drug target information (such as the molecular 'promiscuity' of drugs), the dose-response and dose-toxicity effects for both repurposable drugs and drug combinations cannot be identified in current network models.\", 'For example, Mesalazine, an approved drug for inflammatory bowel disease, is .', 'CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.02.03.20020263 doi: medRxiv preprint a top network-predicted candidate drug ( Figure 5A ) associated with HCoVs.', 'Yet, several clinical studies showed the potential pulmonary toxicities (including pneumonia) associated with mesalazine usage [74, 75] .', 'Preclinical studies are warranted to evaluate in vivo efficiency and side effects before clinical trials.', 'Furthermore, we only limited to predict pairwise drug combinations based on our previous network-based framework [25] .', \"However, we expect that our methodology reminds to be a useful network-based tools for prediction of combining multiple drugs toward exploring network relationships of multiple drugs' targets with the HCoV-host subnetwork in the human interactome.\", 'Finally, we aimed to systematically identify repurposable drugs by specifically targeting nCoV host proteins only.', 'Thus, our current network models cannot predict repurposable drugs from the existing anti-virus drugs that target virus proteins only.', 'Thus, combination of the existing anti-virus drugs (such as remdesivir [76] ) with the networkpredicted repurposable drugs (Figure 5 ) or drug combinations (Figure 6 ) may improve coverage of current network-based methodologies by utilizing multi-layer network framework.', 'In conclusion, this study offers a powerful, integrated network-based systems pharmacology methodology for rapid identification of repurposable drugs and drug combinations for the potential treatment of HCoV. Our approach can minimize the translational gap between preclinical testing results and clinical outcomes, which is a significant problem in the rapid development of efficient treatment strategies for the emerging 2019-nCoV outbreak.', 'From a translational perspective, if broadly applied, the network tools developed here could help develop effective treatment strategies for other types of virus and human diseases as well.', 'CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.02.03.20020263 doi: medRxiv preprint']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Remdesivir for severe acute respiratory syndrome coronavirus 2 causing COVID-19: An evaluation of the evidence', \"[{'text': 'The novel coronavirus infection that initially found at the end of 2019 has attracted great attention.\", 'So far, the number of infectious cases has increased globally to more than 100 thousand and the outbreak has been defined as a pandemic situation, but there are still no \"specific drug\" available.', 'Relevant reports have pointed out the novel coronavirus has 80% homology with SARS.', 'In the difficulty where new synthesized drug cannot be applied immediately to patients, \"conventional drug in new use\" becomes a feasible solution.', 'The first medication experience of the recovered patients in the US has led remdesivir to be the \"specific drug\".', 'China has also taken immediate action to put remdesivir into clinical trials with the purpose of applying it into clinical therapeutics for Corona Virus Disease 2019 (COVID-19).', 'We started from the structure, immunogenicity, and pathogenesis of coronavirus infections of the novel coronavirus.', 'Further, we analyzed the pharmacological actions and previous trials of remdesivir to identify the feasibility of conducting experiments on COVID-19', 'Strategic reservation for antiviral drugs will avoid the difficulty of medicine unavailable when an outbreak comes again.', \"Remdesivir's situational and political superiority, as well as its previous research results and application effects make it imperative to carry out the clinical trials focusing on the SARS-CoV-2.\", 'Given that SARS-CoV-2 is an RNA virus that is easy to mutate, the rapid starting of clinical trials is undoubtedly a right choice to prevent the resistance mutation due to blind medication.', \"It has been covered in the World Health Organization (WHO) Director-General's opening remarks at the media briefing on COVID-19 on February 20, 2020 that the two clinical trials on remdesivir of therapeutics prioritized by the WHO R&D Blueprint are Y.-c.\", 'Cao, et al. Travel Medicine and Infectious Disease xxx (xxxx) xxxx expected preliminary results in three weeks.', 'On February 24, the WHO']}\n", - "{'sentences': ['The clinical features and laboratory test results of the five patients are summarized in Table 2 .', 'Fever, cough, and dyspnea were the most common symptoms.', 'The white blood cell counts varied among these patients, but the lymphocyte counts were generally low.', 'The alanine aminotransferase and serum creatine levels were normal or only slightly increased.', 'Bilateral ground-glass opacities and consolidation were observed on chest radiography from two representative patients, Patient 2 based on aortic arch scan [ Figure 4A ] and pulmonary vein scan [ Figure 4B ] on day 10 after symptoms onset and Patient 5 taken on day 12 [ Figure 4C ] and 13 [ Figure 4D ] after symptoms onset.', 'Several complications were observed in these patients.', 'Four of the five patients (except for Patient 3) developed acute respiratory distress syndrome requiring oxygen therapy, and two patients were given extracorporeal membrane oxygenation.', 'Two patients (Patients 1 and 5) experienced secondary infections, and Patient 5 later developed septic shock as well as acute kidney injury, and ultimately died of multi-organ failure.', 'Patient 3 was discharged on January 8, 2020 (day 17 after symptoms onset).', 'The other three patients were still hospitalized at the time of manuscript preparation.', 'The treatments for these patients were shown in Table 1 .']}\n", - "{'sentences': ['Here we describe the structure of the recombinantly expressed Nsp9COV19 as part of a global effort to characterise the virus causing a current global pandemic.', 'Nsp9 is important for virulence in SARS-CoV (Miknis et al., 2009) .', 'It remains to be understood whether Nsp9COV19 plays a similar role in SARS-CoV-2, however the 97 % sequence identity suggests a high degree of functional conservation.', 'The CoV Nsp9 proteins are seemingly obligate dimers comprising a unique fold that associates via an unusual a-helical GxxxG interaction motif.', 'The integrity of this motif is considered important for viral replication (Miknis et al., 2009 ), leading to a proposal that disruption of the unusual dimer interface impacts on RNA binding and function (Hu et al., 2017) .', 'Mutation of the same interaction motif in the porcine delta coronavirus Nsp9PDCoV also disrupted nucleotide binding capacity (Zeng et al., 2018) .', 'We describe the ability to produce homogenous Nsp9COV19 which purifies as an obligate dimer, consistent with other Nsp9 proteins.', 'Our preliminary nucleotide binding assays brought into question the RNA binding capacity of Nsp9COV19.', 'The structure of the Nsp9COV19 showed conservation of the unique Nsp9 fold when compared with homologues from SARS (Egloff et al., 2004) (Sutton et al., 2004) .', 'Indeed, the topological fold was conserved as was the Nsp9 specific ahelical GxxxG dimerisation interface.', 'This a-helical interface is encircled by hydrophobic residues but the interface includes considerable cavities as observed previously (Egloff et al., 2004) .', 'We made a serendipitous discovery in our 3C-Nsp9COV19 structure, whereby the hydrophobic cavity captured the 3C cleavage sequence LEVL.', 'The extraneous residues were tightly bound on all sides within the site situating themselves proximal to the conserved GxxxG motif.', 'Coordination of the 3C sequence induced changes within interfacing residues, serving to both restructure key structural elements and cause a modest shift in subunit orientation.', 'At this stage it is unclear whether the bound residues within our structure have any bearing on the physiological function of Nsp9COV19.', 'In the first instance this would seem unlikely, however our sequence is that of a rhinoviral 3C protease site and the SARS-CoV main protease cleaves consensus sequences following an LQ sequence (Zhu et al., 2011) .', 'The bound 3C-LE residues have hallmarks of the LQ motif and are proximal to the highly conserved GxxxG motif.', 'There are no obvious structural features to preclude, or select for, a Glu to Gln substitution within our .', 'CC-BY-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.28.013920 doi: bioRxiv preprint bound sequence.', 'Notably the M pro cleavage sequence occurs at multiple points throughout the CoV genome as the majority of viral proteins are released by its activity, thus it remains possible that Nsp9 may associate with unprocessed viral polyproteins retaining them near the viral RNA.', 'Within our structure Met-101 provides contacts with the bound valine sidechain but the presence of Asn-33 nearby may also accommodate residues such as lysine at this position.', 'Peptide-binding assays will need to be developed to rigorously assess such possibilities.', 'In summary we have established a protocol for the production and purification of SARS-CoV-2 Nsp9 protein.', 'We determined the structure of the Nsp9COV19 and described the conservation of the unique fold and dimerisation interface identified previously for members of this protein family.', 'We also determined structure of Nsp9COV19 in complex with a 3C sequence, although the significance of this is yet to be established.', 'The structures we describe here could potentially be utilised in drug screening and targeting experiments to disrupt a dimer interface known to be important for coronavirus replication.']}\n", - "{'sentences': ['Like the outbreaks caused by SARS and MERS, the recent outbreak of COVID-19 in China is creating a substantial public health challenge.', 'In 2002, traditional Chinese herbal medicine played an important role in the treatment of SARS, and 58.3% of confirmed cases received traditional Chinese herbal medicine [32].', 'A Cochrane Review [33] found that Chinese herbs combined with western medicine significantly improved symptoms of SARS, including decreasing body temperature, cough and breathing difficulties, dosages of corticosteroids, improving absorption of pulmonary infiltration, and quality of life.', 'A review [34] of 90 studies of traditional Chinese herbal medicine for SARS revealed positive but inconclusive results about the efficacy of combined treatment, using traditional Chinese herbal medicine as an adjuvant.', 'Based on previous experience of treating SARS with traditional Chinese herbal medicine, the General Office of the National Health and Health Commission of China and the Office of the State Administration of Traditional Chinese Medicine encouraged the integration of traditional Chinese herbal medicine and western medicine.', 'Different prescriptions are recommended in different stages of disease.', 'This is the first systematic review to examine empirical evidence of the application of traditional Chinese herbal medicine for COVID-19 pneumonia.', 'It will provide an overview of the application of traditional Chinese herbal medicine for treating COVID-19 patients and assess the strengths and limitations of available evidence.', 'Furthermore, it will be guided by the PRISMA statement [25] and A MeaSurement Tool to Assess systematic Reviews', '(MeaSurement Tool to Assess systematic Reviews']}\n", - "{'sentences': ['Factors associated with prolonged viral shedding and impact of Lopinavir/Ritonavir treatment in patients with SARS-CoV-2 infection', 'Background: The duration of viral shedding is central to guide decisions around isolation precautions and antiviral treatment.', 'However, studies about risk factors associated with prolonged SARS-CoV-2 shedding and the potential impact of Lopinavir/Ritonavir (LPV/r) treatment remain scarce.', \"Methods: In this retrospective study, data were collected from all SARS-CoV-2 infected patients who were admitted to isolation wards and had RT-PCR conversion at the NO.3 People's hospital of Hubei province between 31 January and 09 March 2020.\", 'We compared clinical features and SARS-CoV-2 RNA shedding between patients with LPV/r treatment and those without.', 'Logistic regression analysis was employed to evaluate risk factors associated with prolonged viral shedding.', 'Results: Of 120 patients, the median age was 52 years, 54 (45%) were male and 78 (65%) received LPV/r treatment.', 'The median duration of SARS-CoV-2 RNA detection from symptom onset was 23 days (IQR, 18-32 days).', 'Older age (odd ratio [OR] 1.03, 95% confidence interval [CI] 1.00-1.05, p=0.03) and lack of LPV/r treatment (OR 2.42, 95% CI 1.10-5.36, p=0.029) were independent risk factors for prolonged SARS-CoV-2 RNA shedding in multivariate logistic regression analysis.', 'The median duration of viral shedding was shorter in the LPV/r treatment group (n=78) than that in no LPV/r treatment group (n=42) (median, 22 days vs. 28.5 days, p=0.02).', 'Only earlier administration of LPV/r treatment (≤10 days from symptom onset) could shorten the duration of viral shedding.', 'Conclusions: Older age and lack of LPV/r treatment were independently associated with prolonged SARS-CoV-2 RNA shedding in patients with COVID-19.', 'Earlier administration of LPV/r']}\n", - "{'sentences': ['Background As the number of patients increases, there is a growing understanding of the form of pneumonia sustained by the 2019 novel coronavirus (SARS-CoV-2), which has caused an outbreak in China.', 'Up to now, clinical features and treatment of patients infected with SARS-CoV-2 have been reported in detail.', 'However, the relationship between SARS-CoV-2 and coagulation has been scarcely addressed.', 'Our aim is to investigate the blood coagulation function of patients with SARS-CoV-2 infection.', 'Methods In our study, 94 patients with confirmed SARS-CoV-2 infection were admitted in Renmin Hospital of Wuhan University.', 'We prospectively collect blood coagulation data in these patients and in 40 healthy controls during the same period.', 'Results Antithrombin values in patients were lower than that in the control group (p < 0.001).', 'The values of D-dimer, fibrin/fibrinogen degradation products (FDP), and fibrinogen (FIB) in all SARS-CoV-2 cases were substantially higher than those in healthy controls.', 'Moreover, D-dimer and FDP values in patients with severe SARS-CoV-2 infection were higher than those in patients with milder forms.', 'Compared with healthy controls, prothrombin time activity (PT-act) was lower in SARS-CoV-2 patients.', 'Thrombin time in critical SARS-CoV-2 patients was also shorter than that in controls.', 'Conclusions The coagulation function in patients with SARS-CoV-2 is significantly deranged compared with healthy people, but monitoring D-dimer and FDP']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Co-infection with SARS-CoV-2 and Influenza A Virus in Patient with Pneumonia, China', 'We report co-infection with severe acute respiratory syndrome coronavirus 2 (severe acute respiratory syndrome coronavirus 2) and influenza A virus in a patient with pneumonia in China.', 'The case highlights possible co-detection of known respiratory viruses.', 'We noted low sensitivity of upper respiratory specimens for severe acute respiratory syndrome coronavirus 2']}\n", - "{'sentences': ['Out study unraveled the clinic features and risk factors for the fatal outcome in subjects with laboratory confirmed COVID-19 based on a national cohort.', 'By January 31st 2020, the National Health Commission had issued 11,791 patients with laboratory-confirmed COVID-19 in China.', 'Our cohort represent 13.5% of infected patients and is able to provide a more panoramic picture regarding on the fatal cases with COVID-19.', 'In our study, some independent risk factors for the fatal outcome were found using a multivariate Cox regression analysis.', 'Further, our study firstly developed a nomogram In our cohort, an overall confirmed case fatality ratio is 3.14%, which resemble that in WHO report in March 8 (3.39%).', '1 This is lower than the earlier reports from single site in Wuhan.', '3, 8 It might due to difficulty of insufficient laboratory diagnosis ability and admission of infected patients with mild symptom at early stage of disease outbreak.', 'Though the CFR is obviously lower than SARS(10%) 9 and Middle Eastern respiratory syndrome MERS(36%), 10 the transmissibility of COVID seem to be much higher.', 'Recent study has found the 2019-nCoV (SARS-CoV-2) spike (S', 'Our study showed that risk of death was increased 7.86-fold in patients older than 75 years and 3.43-fold in patients of age between 65 to 75, compared with patients younger than 65 years old.', 'In the nomogram model, age was the most important predictor for the fatal outcome.', 'Base the report from China CDC including 44 672 confirmed cases(updated through February 11), Case-fatality rate reach 14.8% in patients aged≥80 years (208 of 1408), 8.0% in patients aged 70-79 years (312 of 3918) 12 .', 'More intensive surveillance is needed in elderly patients.', 'Earlier reports showed that male seems more common in infected patients, which may be due to a higher probability of occupational exposure.', '3, 8 However, the subsequent reports showed equivalence of gender in infected cases.', '14 Our study indicates that gender is not the core factor accounting for death based on the multivariate Cox regression analysis.', 'Non-survivors present higher proportion of various co-existing chronic illness in univariate analysis.', 'Previous studies reported similar findings.', '2,4,15 CHD and CVD are confirmed to be independent risk factors for death through the multivariate Cox regression analysis and enter the nomogram model.', 'As the functional receptor of SARS-CoV-2, ACE2 is mainly expressed not only in lung alveolar type II (AT2) epithelial cells but also in blood vessels.', '16, 17 ACE2 also serves as a negative regulatory factor for the renin-angiotensin system (RAS) via ACE2/Ang 1-7 axis.', '18 Exhaustion of ACE2 could activate RAS and enhance susceptibility to heart failure or pulmonary edema.', '19 SARS-CoV-2 may act similarly as SARS-CoV and result in an over activation of RAS in patients with pre-existing chronic cardiovascular diseases, which lead to a poor outcome of fatality.', '20 Though hypertension is common in non-survivors, whether taking RAS', 'Dyspnea was found in 74% of fatal cases at disease onset and it was proved to be an independent risk factor for developing death.', 'With the progress of disease in some cases , hypoxemia would get worse and acute respiratory distress syndrome(ARDS) may develop.', 'It is needed to identify these patients with hypoxemia and provide appropriate intervention.', 'ARDS, is the most common complication associated with death , following by secondary infection and septic shock.', 'A pathological evidence of ARDS in case with COVID-19 showed obvious desquamation of pneumocytes, hyaline membrane formation and pulmonary edema, 21 which is similar to those seen in SARS and MERS coronavirus infection.', 'In our cohort, NIV(noninvasive ventilation) and IMV were performed in 68.8% and 62.5% of fatal cases, respectively.', '11% of cases were given ECMO.', 'There is still controversy the usage of the high flow nasal cannula(HFNC) or NIV in patients with ARDS.', 'However, two recent study indicated that early application of HFNC or HFNC with prone positioning could be considered as first-line therapy in acute respiratory failure, and may help avoid intubation in patients with ARDS.', '22, 23 A series of laboratory abnormalities on admission were more common in fatal cases, compared with the survivors.', 'Some independent laboratory predictors of the fatal outcome were found via multivariate Cox regression analysis.', 'Procalcitonin (PCT) is a calcitonin pro-peptide synthesized by C cells of the thyroid gland and released from leukocytes, which is significantly increased in bacterial infections and the SEPSIS.', 'It has been proved a high specificity for bacterial infection and an good correlation with severity of illness.', '24 Procalcitonin (PCT)-guided antibiotic stewardship (ABS) has been shown to reduce antibiotics, with lower side-effects and an improvement in clinical outcomes.', '25 In the nomogram model of our study , an elevated level of PCT', 'Elevated AST (>40U/liter) was also associated with a greater risk for death in the nomogram model.', 'Increased creatinine (≥133 μmol/liter) and total bilirubin(>17.1 μmol/liter) might associated with the death outcome.', 'Since ACE2 is widely expressed in multiple organs besides lung , it is possible that SARS-CoV-2 could invade the local tissues and lead to a direct damage and indirect damage.', 'The following activation of immune response and cytokines storm will also play an important role in the organ dysfunction.', 'Over activation of peripheral T cells, present as increase of CC4+CCR6+Th17 and high cytotoxicity of CD8 T cells，may contribute to the immune injury in severe case with COVID-19.', \"21 What's more, the usage of the nonsteroidal anti-inflammatory drugs, antivirus, antibiotics, and traditional Chinese medicine which might associated with liver and renal injury.\", 'These findings call for multidisciplinary cooperation and monitoring of the organ dysfunction.', 'There are some limitations of this study.', 'First, in some cases, there were incomplete documentation of the history, symptoms or laboratory findings in the electronic database, even after trying effort to feedback and recollect.', \"Some diagnosis of co-existing illness were from patients' self-reports at admission, which might lead to the recalling bias.\", 'Although the cohort had a broad coverage of all patients and regions, the non-responsive bias cannot be fully excluded.', 'Second, as a retrospective and observational study, we currently could not set up a validation cohort to assess the predictive accuracy due to the urgent timeline under this special situation.', 'However, we use the bootstrap resampling cohort and show that the C-index is ideal, suggesting the nomogram is a good model for predicting outcomes.', 'Likewise, the calibration curves for survival probability also demonstrated a good consistence between the prediction and the observation.', 'Collectively, our study provided the evidence that advanced age, dyspnea, coronary heart disease, cerebrovascular disease, elevated PCT and AST are independent risk factors associated with fatal outcome.', 'The nomogram proposed in our study objectively predicted the prognosis of patients with COVID-19.', 'Earlier identification, more intensive surveillance and appropriate therapy should be considered in these patients with high risk.', 'Calibration curves of the nomogram predict (A)14-day, (B) 21-day and (C) 28-day overall survival in COVID-19 patients.', 'Nomogram-predicted probability of overall survival is plotted on the x-axis; actual overall survival is plotted on the y-axis.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Objective: To analyse the clinical features of COVID-19 parturients, and to compare anaesthetic regimen and clinical outcomes in parturients with or without COVID-19 undergoing cesarean delivery.', 'Methods: Data were extracted from the electronic medical record of 3 medical institutions in Hubei Province, China, from June 1, 2019 to March 20, 2020 according to inclusion and exclusion criteria.', 'After propensity score matching with demographics, the clinical and laboratory characteristics of parturients with or without COVID-19 were analysed.', 'The anaesthetic regimen and clinical outcomes of themselves and their infants were compared in these two groups of parturients.', 'Results: A total of 1,588 patients without SARS-CoV-2 infection undergoing cesarean delivery were retrospectively included.', 'After achieving a balanced cohort through propensity score matching, 89 patients (COVID-19 group), who were diagnosed with COVID-19 by SARS-CoV-2 nucleic acid test and CT scan matched with 173 patients without COVID-19 (Control group).', 'The SARS-CoV-2 infected parturients in the early stages of COVID-19 outbreak was much more than during the later stage.', 'The main clinical characteristics of parturients with COVID-19 were fever (34.8%), cough (33.7%), an increased plasma CRP (52.8%) and a decreased lymphocyte counting (33.7%).', 'A high rate of emergency and a high incidence of anaesthesia-related complications, such as pharyngalgia, multiple puncture, intraoperative hypotension, nausea, vomiting, vertigo and chills in the COVID-19 parturients.', 'In addition, the parturients with COVID-19 had a long duration of operation and hospital stay, and an increased intraoperative oxytocin utilization and postoperative oxygen therapy.', 'The newborns from the SARS-CoV-2 infected mothers, who received general anaesthesia, had a high risk of Apgar score ≤ 8 at 1 and 5 minutes after delivery and a higher rate of neonatal intensive care unit (NICU', 'Conclusions: Anaesthesia-related complications occur more frequently in the COVID-19 parturients and their newborns have a high risk of distress.', 'The length of surgical operation and duration of hospital stay were significantly prolonged in the COVID-19 group compared with the Control group (both p<0.05).', 'The intraoperative blood loss in the COVID-19 group was higher than that in the Control group, but there was no difference (p>0.05).', 'Besides, the frequency use of intraoperative oxytocin and the time of postoperative oxygen therapy were significant higher in the COVID-19 group than that in the Control group (both p<0.05).', 'There were no patients required peripartum admission to the intensive care unit (ICU', 'In this study, we comparatively analyzed the epidemiological data, anaesthetic techniques and management, complications and outcomes of maternal patients with and without COVID-19 in the 3 hospitals in Hubei Province.', 'The results indicated that the high rates of emergency and general anaesthesia use were likely due to the high risk for parturients and newborn.', 'Consisting with previous reports 9 , the clinical manifestation of parturients with COVID-19 had mild symptoms and none severe phenotype if the disease was in our study.', \"Thus, the intrathecal anaesthesia was the first choice for parturients with COVID-19 in order to reduce medical staff exposing to virus via patient's airway.\", 'Spinal anaesthesia is a safe and quick technique for cesarean delivery due to its quality of sensory blockade and reliability.', 'However, the risk of high level of sensory blockade and the high incidence and degree of hypotension may be the disadvantages when compared with epidural anaesthesia.', 'Although none of the mothers who received intrathecal anaesthesia for delivery had any complications in this study, considering that SARS-CoV-2 virus may also invade the central nervous system 10 , epidural anaesthesia seems to be superior for patients with COVID-19.', 'Due to the limited tactile sensation of PPE, it is necessary to use ultrasound guide epidural procedure for avoiding unintentional dural puncture and subarachnoid catheterization.', \"In the period of COVID-19 outbreak, routine prenatal examination was limited by traffic control and isolation policy in place, and hence pathological pregnancy can't be found timely, which may be the reasons for the high emergency caesarean delivery and general anaesthesia use in the COVID-19 patients in this study.\", 'Although general anaesthesia would induce or exacerbate pulmonary complications in parturients 11 with COVID-19, the cesarean delivery under general anaesthesia is necessarily to be used for fetal distress, potential contraindication of intrathecal anaesthesia, as well as intrathecal anaesthesia failure.', 'The rapid-sequence induction by using propofol, rocuronium and remifentanil was used in our COVID-19 patients and the excellent maternal hemodynamic stability was noted.', 'However, the possible risk of short-time neonatal depression and required short periods of mask ventilation or tactile stimulation of the neonate were found.', 'However, in this study, either intravenous or inhalational induction was not difference in term of the safety of maternal and neonatal and the risk infection of medical staff.', 'To avoid hemorrhage resulted from uterine atony, inhalational sevoflurane was switched into intravenous anaesthetics after umbilical cordligation.', 'Notably, PPE increased the difficult in airway management and it was necessary for the use of visual laryngoscopes, and the supraglottic airway was considered as a remedy for failed tracheal intubation in emergency general anaesthesia 12 .', 'There was a high incidence of intraoperative hypotension in the COVID-19 patients.', 'The risk of hypotension was likely due to anaesthesia induced sympathetic inhibition, preoperative fasting.', 'A recent study showed that the S protein of SARS-CoV-2 binds to the ACE2 receptor 13 , suggesting that the high susceptible of the circulatory system to SARS-CoV-2 infection might be one of the reasons of hypotension in this study.', 'Together with liquid loading and left lateral position, prophylactic phenylephrine was effective and safe in maintaining blood pressure.', 'Prophylactic uterotonic agents (oxytocin) treatment and controlled umbilical cord traction during placenta delivery were also the effective ways to prevent hemorrhage-induced hypotension.', 'As such, it is necessary for COVID-19 parturients to have a contingency plan in place for the high risk of obstetric hemorrhage.', 'Although a little evidence supported that supplemental oxygen improves maternal and neonatal outcomes 14 , parturients with COVID-19 were routinely treated with oxygen during operation to prevent maternal and infant hypoxia.', 'However, considering the oxygen free radical production and atelectasis, continuous inspiration of high oxygen concentration was not used 15 .', 'It is critical to apply the lung expansion and positive end-expiratory pressure technique for COVID-19 patients receiving general anaesthesia to eliminate atelectasis formation 16 .', 'As for parturients with COVID-19 undergoing intrathecal anaesthesia, the deep-breathing exercises were also encouraged.', 'Our data showed a down-trend in the number of parturients with COVID-19, which implied the importance of proper home quarantine and personal protection to reduce exposure, and ultimately reduced the chance of COVID-19 infection in pregnant women.', \"Besides, the delivery of infected parturients to designated hospitals was to ensure the safety of the pregnant women and their newborns, while preventing and controlling newborns' infection with SARS-Cov-2.\", 'Potential multi-target organ damage caused by SARS-CoV-2 infection in pregnant women may increase the chance of COVID-19 parturients received caesarean section.', 'Taken more precaution care for those patients are necessary.', 'Cesarean delivery increased the risk of microenvironmental aerosols.', 'Consequently, the fetus should be cleaned of amniotic fluid and blood from the mouth and nose and then transferred to incubator rapidly after delivery to reduce neonatal infection.', 'Additionally, SARS-CoV-2 virus may also invade the central nervous system, indicating that the risk of maternal nervous system injury cannot be ignored.', 'While, none was diagnosed with postpartum depression in the present study, which might be attributed to the implementation of multimode analgesia management in our patient population 17 .', 'In summary, the current data suggested that the proper home quarantine and personal protection can help to reduce the risk of parturients infected with SARS-Cov-2.', 'Anaesthesia-related complications occurred more frequently in the COVID-19 parturients, while their newborn born also have a high risk of distress and high admission to NICU.', 'From our experience, spinal or epidural anaesthesia can be safely used for such patients.', 'General anaesthesia in general results in more hypotension and open airway for a high risk of virus exposure to medical staff and thus it should be avoided unless it is inevitably used for emergency case.', 'Data sharing: No additional data available.', \"The manuscript ' s guarantor affirms that the manuscript is an honest, accurate, and All rights reserved.\", 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.24.20042176 doi: medRxiv preprint transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned and registered have been explained.', 'Fatigue, n(%) 2(18.2) 6(7.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.24.20042176 doi: medRxiv preprint the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.24.20042176 doi: medRxiv preprint the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.24.20042176 doi: medRxiv preprint the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.24.20042176 doi: medRxiv preprint All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.24.20042176 doi: medRxiv preprint']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Comparative effectiveness and safety of ribavirin plus interferon-alpha, lopinavir/ritonavir plus interferon-alpha and ribavirin plus lopinavir/ritonavir plus interferon-alphain in patients with mild to moderate novel coronavirus pneumonia']}\n", - "{'sentences': ['Many trials are now underway to inform decision-makers on potential effects of treatments for COVID-19.', 'To provide sufficient information for all involved decision-makers (clinicians, public health authorities, drug regulatory agencies) a multiplicity of endpoints must be considered.', 'It is a challenge to generate detailed high quality evidence from data while ensuring fast availability and evaluation of the results.', 'We reviewed all interventional COVID-19 trials on Remdesivir, Lopinavir/ritonavir and Hydroxychloroquine registered in the National Library of Medicine (NLM) at the National Institutes of Health (NIH', 'There are currently, March 27, 2020, 23 registered interventional trials investigating the potential benefits of Remdesivir, Lopinavir/ritonavir and Hydroxychloroquine.', 'The endpoints are highly heterogeneous.', 'Follow-up for the primary endpoints ranges from four to 168 days.', 'A detailed precisely defined endpoint has been proposed by the global network REMAP-CAP, which is specialized on community-acquired pneumonia.', 'Their seven-category endpoint accounts for major clinical events informative for all decision-makers.', 'Moreover, the Core Outcome Measures in Effectiveness Trials (Core Outcome Measures in Effectiveness Trials', 'Multistate model analysis is a powerful tool to study clinically heterogeneous endpoints (mortality, discharge) as well as endpoints influencing hospital capacities (duration of hospitalization and ventilation) simultaneously over time.', 'Our proposed model extracts all information available in the data and is -by harmonizing endpoints within and between trials -a step towards faster decision making.', 'All ongoing clinical trials, especially those with severe cases, should accommodate primary analysis with a stacked probability plot of the major events mechanical ventilation, discharge alive and death.', 'All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'Our review of registered interventional COVID-19 trials revealed high heterogeneity in the definition of primary endpoints.', 'Most of the studies used a recovery endpoint for the primary analysis.', 'We propose to accompany the primary analysis with multistate methodology.', 'We highlight, that literature provides an extensive statistical tool box of suitable models to analyze clinical trials.', 'All ongoing clinical trials, especially those with severe cases, should accommodate primary analysis with a stacked probability plot of the major events mechanical ventilation, discharge alive and death.', 'The resulting informative plot is a powerful tool to harmonize the diversity of clinical endpoints and lengths of follow-up and thereby fastening accessibility of evidence and thus decision making.', 'Additionally, treatment effects on a number of (potentially clinically opposite) endpoints can be studied simultaneously over time using cause-specific Cox regression and by estimating sojourn time spent in the various states.', 'Moreover, while mechanical ventilation, hospitalization and mortality are objective outcomes, recovery and other states of severity are influenced by clinical judgement and may be additionally subject to measurement errors.', 'Besides these potentials, both of the proposed multistate models have the limitation that they do not account for patient triage possibly necessitated by ICU congestion (19).', 'Additional research is needed to avoid selection bias arising from this special clinical situation.', 'Finally, our proposal should be understood as a complement for the primary analysis.', 'Rather than suggesting COS for COVID-19 trials, we provide a way for simultaneous evaluation of multiple endpoints within COS using information all of the available data.', 'To conclude, we recommend to complement the primary analysis with a stacked probability plot for the clinical events mechanical ventilation, discharge alive and death.', 'Figure 1 .', 'The plot is based on a simulated data setting and illustrates for the treatment and respectively control group the probability to be mechanically ventilated, hospitalized without ventilation, discharged alive and dead over the course of time.', 'All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.31.20049007 doi: medRxiv preprint Figure 3 : Detailed multistate model to allow for more sensitive endpoints in moderate and mild cases.', 'The colors indicate how the model relates to the multistate in Figure 1 .', 'The discharge state in Figure 1 can be considered as a combination of \"Discharged\" and \"Cured\".', '\"Hospitalized Normal ward\" and \"Hospitalized ICU\" describe in more detail the state \"Non ventilated\" in Figure 1 .', 'The labels \"mild type\" to \"critical type\" for the various states shall only give an idea on how the model accounts for the different types of severity of COVID-19.', 'We do not claim to give a precise clinical definition.', 'All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.31.20049007 doi: medRxiv preprint Table 1 : Selected columns of Table S1 summarizing the results of the primary outcomes review.', 'The category \"unclear\" for the columns mortality, mechanical ventilation and hospitalization indicates that we do not have sufficient information to judge whether this information is collected.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.']}\n", - "{'sentences': ['Neuropsychiatric adverse events of chloroquine: A real-world pharmacovigilance study using the FAERS database', 'Objectives: As of the early April 2020, the antimalarial drug, chloroquine, has been approved as an emergency treatment for the coronavirus disease 2019 in the United States and in Europe.', 'Although infrequent, neuropsychiatric symptoms have been reported in patients who received chloroquine for the treatment of malaria or autoimmune diseases.', 'In this study, we investigated these adverse events (AEs', 'We conducted a disproportionality analysis for the detection of neuropsychiatric AE signals associated with the use of chloroquine (or hydroxychloroquine), reported to FAERS database between the fourth quarter of 2012 and the fourth quarter of 2019.', 'Adjusted reporting odds ratio (ROR', 'We included 2,389,474 AE cases, among which 520 cases developed neuropsychiatric AE following the use of chloroquine.', 'Exposure to chloroquine was associated with a statistically significant high reporting of amnesia, delirium, hallucinations, depression, and loss of consciousness, (lower 95% confidence interval of the adjusted ROR > 1), although the degree of increase in their ROR was limited.', 'There was no statistically significant high reporting of any other neuropsychiatric AE, including suicide, psychosis, confusion, and agitation.', 'Conclusion: Current pharmacovigilance study results did not suggest any potential link between the use of chloroquine and an increased risk of suicide, psychosis, confusion, and agitation, which would be informative during the emergency use of chloroquine for the treatment of COVID-19.', 'In this study, we investigated reports of neuropsychiatric AEs that were developed following exposure to chloroquine as a treatment for malaria or autoimmune diseases.', 'The major strength of our study is that it was based on a database that includes global real-world data from a very large number of patients.', 'Our results showed a statistically significant association (albeit marginal) between the use of chloroquine and the reporting of LOC, amnesia, delirium, hallucination, and depression, however, there was no statistically significant association between the use of chloroquine and the reporting of suicide, psychosis, confusion, or agitation, suggesting that there is no link between the use of chloroquine and the increased risk of these AEs.', 'Conversely, mefloquine showed to be associated with statistically significant high reporting of most of the neuropsychiatric AEs, which is consistent with some of the earlier literature reports [12, 19] .', 'Our study has some limitations, resulting from the use of self-reported data [11] , and it therefore includes some bias that cannot be eliminated.', 'First, this setting may be associated with a reporting bias, that is, over-or under-reporting of neuropsychiatric AEs following the use of chloroquine.', 'Second, due to the absence of denominators, we were not able to discuss the incidence rate of each neuropsychiatric AE.', 'Third, in our multivariate adjustment, we did not consider the use of concomitant medications or the medical history of the patients, both of which could have potentially contributed to the development or to the worsening of some neuropsychiatric symptoms.', 'Fourth, while suicide was .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.10.20061358 doi: medRxiv preprint 1 3 included as one of the AEs in our analysis, it is possible that some of the suicide cases represent suicide by chloroquine overdose, which is known to be cardiotoxic, and not an AE of chloroquine [6] .', 'have not included the timing or the total dose of chloroquine and mefloquine in the analysis.', 'Lastly, it is possible that our final dataset included duplicated cases that should have been excluded.', 'To conclude, the current pharmacovigilance study, using the FAERS database, did not suggest a potential link between the use of chloroquine and an increased risk of suicide or psychosis.', 'These results provide information that can be essential when the use of chloroquine is considered for the treatment of patients with COVID-19.', 'Since this study was based on a self-reporting database that inevitably contains several biases, cohort studies are needed, to validate these results and to confirm the neuropsychiatric safety of chloroquine.', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .']}\n", - "{'sentences': [\"[{'text': 'In the current COVID-19 pandemic context, proposing and validating effective treatments represents a major challenge.\", 'However, the lack of biologically relevant pre-clinical experimental models of SARS-CoV-2 infection as a complement of classic cell lines represents a 35 major barrier for scientific and medical progress.', 'Here, we advantageously used human reconstituted airway epithelial models of nasal or bronchial origin to characterize viral infection kinetics, tissue-level remodeling of the cellular ultrastructure and transcriptional immune signatures induced by SARS-CoV-2.', 'Our results underline the relevance of this model for the preclinical evaluation of antiviral candidates.', 'Foremost, we provide evidence on the antiviral 40 efficacy of remdesivir and the therapeutic potential of the remdesivir-diltiazem combination as a rapidly available option to respond to the current unmet medical need imposed by COVID-19.', ': bioRxiv preprint 65 reported the advantage of using more physiological models such as in-house or commercially available reconstituted human airway epithelia (HAE']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Actually, except for the common topological localization, the predicted Ab-binding epitopes differ between the two proteins, both in their sequence and 3D structural organization (Table 1 , 2 and Figure 1 ).', 'In some cases, linear sequences spanning distant segments of the primary structure come together in the three-dimensional structure to form extended substructures potentially (pre)organized for binding.', 'This is particularly true for the conformational epitope at the N-and Cterminal region of SARS-CoV-2 RBD: the interacting region spans a large part of a well-defined betasheet subdomain (Table 1 , 2 and Figure 2 ).', 'It is tempting to suggest that the expression of such subdomain in isolation could give rise to a highly immunoreactive molecule [19] [20] [21] .', 'In SARS-CoV-2 RBD, the knowledge of substructures representing potential conformational epitopes may be helpful in guiding the development of peptide-based immunogens able to elicit antibodies that specifically target the cognate protein to which the predicted epitopes belong (Figure 2 ).', 'Simply speaking, the termini of the linear segments making up the conformational epitopes could be aptly bridged with a number of Gly residues sufficient to approximate the distance in the experimental structure (Table 3 ).', 'Antibodies raised against these molecules, which recapitulate the main determinants of immunoreactivity of the full protein, could have useful applications in a therapeutic setting [19] [20] [21] .', 'Furthermore, information on potentially specific SARS-CoV-2 spike RBD-specific epitopes The copyright holder for this preprint (which was not peer-reviewed) is the .', \"https://doi.org/10.1101/2020.03.13.990267 doi: bioRxiv preprint function both as antigen-mimicking baits to target virus-specific antibodies in patients' fluids, and as immunogens to generate new Abs able to detect relevant antigens [22] [23] .\", 'Importantly, after we ran our predictions on the SARS-CoV-2 RBD, crystal structures of this domain in complex with the cellular receptor protein ACE2 was reported by 24 and by Yan et al. 25 .', 'Of note, one predicted interaction region almost completely overlaps with the substructure of spike protein RDB engaged in binding with ACE2 (478 TPCNGVEGF 486).', 'Synthetic mimicry of this sequence could aptly generate high priority candidates aimed at disrupting PPIs between SARS-CoV-2 RBD and its cell receptor ACE2.', 'Such molecules could be used to block viral entry into cells.', 'Similarly, our approach also predicts a patch on SARS-CoV spike RBD, which is partly involved in binding ACE2 (see 26 ).', 'Overall, while the two RBD proteins likely evolved from a common ancestor and share a common fold, they are characterized by different sequences.', 'The physico-chemical properties determined by such sequence differences, efficaciously unveiled by MLCE, reverberate in the modulation of the networks of intraprotein interactions that underlie the (pre)organization of regions for potential recognition of binding partners (cell receptors or antibodies).', 'These results represent, to the best of our knowledge, one of the first molecular physical-chemistry based rationalization of the reasons why some of the tested SARS-CoV RBD monoclonal Abs do not have appreciable cross-reactivity to SARS-CoV-2 RBD 15 , despite the fact that the two domains were recently reported to display the same affinity for the ACE2, with KD values of 15.2 nM and 15 nM for SARS-CoV-2 and SARS-CoV, respectively 27 .', 'In this complex scenario, our predictions can help disentangle some of the issues related to betacoronavirues infectivity and immunological response.', 'Acknowledgement We acknowledge funding by Regione Lombardia, project READY (Regional Network for developing diagnostic methods in rapid response to emerging epidemics and bio-emergencies) Missing residues belonging to highly flexible loops not solved in the structure of the Spike protein were modeled by homology using the SwissModel web server (https://swissmodel.expasy.org/), that retrieved the structure of the SARS-CoV 5x58 as the best template.', 'The structures were used as input for epitope prediction using the Matrix of Local Coupling Energies method (Matrix of Local Coupling Energies method', 'If the structure of the protein is known, one can estimate a contact matrix %& by assuming two amino acids in contact if the distance between two of their heavy atoms is smaller than a threshold.', 'Hadamard product of the two matrices gives us the matrix of the local coupling energies %& = / %& • %& We will select as possible interacting zones sets of close by residues that show weak or frustrated interactions.', 'The analysis of the energetic properties of the surface residues is based on the MLCE method.', 'Basically, we perform a MM/GBSA analysis of the structure in a force field, obtaining a symmetric per-residue interaction matrix %& keeping only non-bonded interaction (i.e. electrostatic, van der Waals and solvation contributions).', 'We diagonalize the matrix, obtaining a set of eigenvectors (%) sorted following the increasing value of their eigenvectors % where is the number of amino acids in the sequence.', 'We thus can write the original matrix %', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.13.990267 doi: bioRxiv preprint', 'Here, we took advantage of the recent publication of the structures of SARS-CoV-2 spike protein in its pre-fusion state (doi.org/10.1126/science.abb2507) and of known structure of the SARS-CoV spike protein to comparatively apply our interaction epitope prediction method MLCE.', 'The application of MLCE to the Receptor Binding Domain (RBD, aa 319-591) of the SARS-CoV-2 spike protein (pdb code 6vsb; doi: 10.2210/pdb6vsb/pdb) 15 and of the SARS-CoV spike protein (pdb code 5x58; doi: 10.2210/pdb5X58/pdb) ( Figure 1 ) shows that the two protein regions that contain potential interaction regions/Ab-binding epitopes share the same topological localization at the two opposite ends of the 3D structures ( Figure 1 ).', 'However, this trait appears to be the only common one.', 'The linear sequences that correspond to the predicted interacting epitope regions are reported in Table 1 .', 'Importantly, the predicted epitopes for SARS-CoV spike RBD show a good degree of overlap with the epitopes mapped for neutralizing Ab 80R 16 , S230 17 and m396 18 , providing a relevant validation of our approach.', 'However, in spite of the high degree of structural similarity between the two spike proteins, these mAbs failed to bind SARS-CoV-2 RBD, probably due to the low degree of sequence conservation in the regions contacted by these antibodies.', 'The fact that most of the SARS-CoVdirected mAbs are not reactive against the novel betacoronavirus once more highlights the need to discover specific epitopes in SARS-CoV-2.']}\n", - "{'sentences': ['We here presented a SIR model with a potential change points for spreading rate combined with Bayesian parameter estimation.', 'This model allowed us to estimate the unperturbed central basic epidemiological parameters in the earliest days of the COVID19 outbreak in Germany, but also the detection of two change points in the spreading rate.', 'We could show that change points in the spreading rate will be reflected in confirmed case numbers with a median delay of D = 9.5 days and could, this way, link the observed changes to two measures taken by the German government: (1) travel warnings, and the ban on all large events with more than 1000 participants (effected around 2020/03/08), and (2) the closing of schools, childcare centers and many shops (announced 2020/03/15).', 'The introduction of explicit modeling of change points has a considerable advantage in terms of data efficiency in that all available data could be used for estimating change-point independent model parameters.', 'As long as it is plausible that additional measures will not change model parameters other than λ our approach can be extend by adding further change points and then be reused for further short-term forecasts.', 'Under novel developments, such as the introduction of novel, effective therapies influencing the recovery rate µ our approach provides the algorithmic blueprint for modeling and detecting such change points as well.', 'Our model comparison also ruled out models without a change point or with only one change point.', 'While this may seem trivial, it has important consequences for making the short term forecasts that decision makers rely on.', 'Demonstrating and quantifying the effect of change points in the past enables us to project the effects of change points in the recent past on the future development of case numbers, even if they are not apparent yet in the observed case numbers.', 'Hence, it is important to look out for and identify potential change points as early as possible, and incorporate them appropriately into the forecast model.', 'Our results rely on a straight-forward implementation of time-varying spreading rates, that assumed spreading rates to be constant in time, except for rate changes occurring only at the time of interventions -the change points -where we formulated broad prior distributions for the new spreading rate and the time-point of the change.', 'Our results seem to indicate that this modeling approach is sufficient at present for Germany: While we introduced fairly broad priors on the spreading rates we obtained a fairly narrow posterior distribution for the changed spreading rates (Fig. 4 B) , indicating that the assumption of discrete steps in the spreading rates is viable.', 'With respect to the posterior distributions for the dates of the change points, we also found the data to provide valuable information in narrowing the posterior distribution for the first change point, compared to the prior, and in slightly moving the posterior mode for the second change point.', 'Change point detection and interpretation hinges on proper estimation on the delay D between a new infection and recording a newly confirmed case.', 'Thus, it seems important to assess whether the posterior median value of D = 9.5 days is at least compatible with what is known.', 'In our model D sums up at least three separate factors, i.e. the biological incubation period, and an additional delay from first very mild symptoms to symptoms warranting testing under the constraint of limiting testing capacities, and a possible delay before a testing slot is available.', \"At present, the incubation is reported by the WHO as being in a broad range from 1-14 days with a mean of 5 days [29] , and the WHO states that 'symptoms are usually mild and begin gradually'.\", 'A gradual onset of symptoms may delay testing because people tend to wait before asking to be tested, or may be asked to wait as testing in more urgent cases is prioritized.', 'Adding a mean of 5 days of incubation period to the patient waiting for three days after gradual symptom onset before asking for a test, and waiting 1 days for a test would be a plausible scenario in Germany.', 'The resulting 9 days are compatible with the median and spread of the posterior median of D = 9.5 we found, given the wide range of durations for the incubation period.', 'It should be noted in addition, that once mass-testing for asymptomatic members of the general population is available, or even mandatory, a change point for D will certainly have to be added to the model.', 'Since most of the forecast uncertainty comes from scenario assumptions and uncertainties in model parameters, we purposely kept the dynamic model as simple as possible for it to remain tractable.', 'Focusing on a simple model, we have excluded many details that are relevant for precise modelling of epidemics, especially at very late stages or in small populations.', 'Such details include explicit (modeling of) incubation times [20, 30] , spatial heterogeneity [15, 20] , isolation [14, 30] , or subsampling effects hiding undetected cases even beyond the reporting delay [31] .', 'However, we argue that most of these effects are small compared to the scale of uncertainty between different forecast scenarios that may help decision makers take action, and for short term forecasts.', 'In conclusion, with our model we could detect and quantify the effect of the two recent governmental interventions from the German COVID-19 data.', 'Furthermore, we forecasted the effects of the most recent intervention.', 'Together, our work showed how important the precise timing and magnitude interventions are for the forecasted case numbers, and how to incorporate the substantial delay D between the date of an infection and the date of the confirmed case.', 'Hence, All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.02.20050922 doi: medRxiv preprint the development of case numbers in the coming week mainly depends on our behavior in the past week.', 'Likewise, our behavior now determines whether or not we will continue to see exponential growth of case numbers, or whether we achieve a transition to exponential decay by reducing our contact and consequently the spreading rate sufficiently.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Aminoquinolines against coronavirus disease 2019 (COVID-19): chloroquine or hydroxychloroquine']}\n", - "{'sentences': ['With the expanding use of molecular assays, viral pathogens are increasingly recognized among critically ill adult patients with community-acquired severe respiratory illness; studies have detected respiratory viral infections (RVIs) in 17–53% of such patients.', 'In addition, novel pathogens including zoonotic coronaviruses like the agents causing Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS) and the 2019 novel coronavirus (2019 nCoV) are still being identified.', 'Patients with severe RVIs requiring ICU care present typically with hypoxemic respiratory failure.', 'Oseltamivir is the most widely used neuraminidase inhibitor for treatment of influenza; data suggest that early use is associated with reduced mortality in critically ill patients with influenza.', 'At present, there are no antiviral therapies of proven efficacy for other severe RVIs.', 'Several adjunctive pharmacologic interventions have been studied for their immunomodulatory effects, including macrolides, corticosteroids, cyclooxygenase-2 inhibitors, sirolimus, statins, anti-influenza immune plasma, and vitamin C, but none is recommended at present in severe RVIs']}\n", - "{'sentences': ['Objective To analyze the clinical characteristics of one living-related kidney transplant recipient infected with 2019 coronavirus disease (characteristics of one living-related kidney transplant recipient infected with 2019 coronavirus disease) .', 'Method The clinical diagnosis and treatment of one relative renal transplant recipient after the occurrence of characteristics of one living-related kidney transplant recipient infected with 2019 coronavirus disease were analyzed retrospectively, including the course of onset, clinical manifestations, blood routine test, renal function, lung CT scan, nucleic acid detection, outpatient and inpatient therapies and outcomes.', 'Result The case was diagnosed as characteristics of one living-related kidney transplant recipient infected with 2019 coronavirus disease (severe type) with influenza A virus infection.', 'The clinical symptoms were gradually relieved and the lung lesions were absorbed through the treatment of reduce and stop taking immunosuppressant, antiviral therapy of abidol/oseltamivir, prevention of bacterial infection, hormone anti-inflammatory, oxygen inhalation, nutritional support and adequate rest.', 'Conclusion This case present typical characteristics of characteristics of one living-related kidney transplant recipient infected with 2019 coronavirus disease in epidemiological investigation, clinical manifestation, examination, pulmonary imaging and etiology.', 'After comprehensive treatment including reduce and stop immunosuppressive therapy, clinical cure was achieved.', 'The long-term effect of characteristics of one living-related kidney transplant recipient infected with 2019 coronavirus disease']}\n", - "{'sentences': ['The infection of a novel coronavirus found in Wuhan of China (2019-nCoV) is rapidly spreading, and the incidence rate is increasing worldwide.', 'Due to the lack of effective treatment options for 2019-nCoV, various strategies are being tested in China, including drug repurposing.', 'In this study, we used our pretrained deep learning-based drug-target interaction model called Molecule Transformer-Drug Target Interaction (MT-DTI) to identify commercially available drugs that could act on viral proteins of 2019-nCoV. The result showed that atazanavir, an antiretroviral medication used to treat and prevent the human immunodeficiency virus (HIV', 'designed to target viral proteinases.', 'However, in our prediction, they may also bind to the replication complex components of 2019-nCoV with an inhibitory potency with Kd < 1000 nM. In addition, we also found that several antiviral agents, such as Kaletra, could be used for the treatment of 2019-nCoV, although there is no real-world evidence supporting the prediction.', 'Overall, we suggest that the list of antiviral drugs identified by the MT-DTI model should be considered, when establishing effective treatment strategies for 2019-nCoV.', 'In many cases, DTI prediction models serve as a tool to repurpose drugs to develop novel usages of existing drugs.', 'However, the application of DTI prediction in the present study may be useful to control The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.01.31.929547 doi: bioRxiv preprint Table 1 .', 'Drug-target interaction (DTI) prediction results of FDA approved antviral drugs available on markets against a novel coronavirus (2019-nCoV, NCBI reference sequence NC_045512.2) 3C-like proteinase (accession YP_009725301.1).', 'Ritonavir is expressed in canonical and isomeric forms SMILES, and * indicates isomeric form SMILES of ritonavir.', 'Table 3 .', 'Drug-target interaction (DTI) prediction results of antiviral drugs available on markets against a novel coronavirus (2019-nCoV, NCBI reference sequence NC_045512.2) helicase (accession YP_009725308.1).', 'Ritonavir is expressed in canonical and isomeric form SMILES, and * indicates isomeric form SMILES of ritonavir.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org /10.1101 /10.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.01.31.929547 doi: bioRxiv preprint Table 6 .', 'Drug-target interaction (DTI', 'The 2019-nCoV 3C-like proteinase was predicted to bind with atazanavir (Kd 94.94 nM), followed by efavirenz, ritonavir, and other antiviral drugs that have a predicted affinity of Kd > 100 nM potency (Table 1 ).', 'No other protease inhibitor antiviral drug was found in the Kd < 1,000 nM range.', 'Although there is .', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org /10.1101 /10.', '/2020 no real-world evidence about whether these drugs will act as predicted against 2019-nCoV yet, some case studies have been identified.', 'For example, a docking study of lopinavir along with other HIV proteinase inhibitors of the CoV proteinase (PDBID 1UK3) suggests atazanavir and ritonavir, which are listed in the present prediction results, may inhibit the CoV proteinase in line with the inhibitory potency of lopinavir (14) .', 'According to the prediction, viral proteinase-targeting drugs were predicted to act more favorably on the viral replication process than viral proteinase through the DTI model (Table 2 -6) .', 'The results include antiviral drugs other than proteinase inhibitors, such as guanosine analogues (e.g., acyclovir, ganciclovir, and penciclovir), reverse transcriptase inhibitors, and integrase inhibitors.', 'Among the prediction results, atazanavir was predicted to have a potential binding affinity to bind to Table 2 -6) .', \"Also, ganciclovir was predicted to bind to three subunits of the replication complex of the 2019-nCoV: RNA-dependent RNA polymerase (Kd 11.91 nM), 3'-to-5' exonuclease (Kd 56.29 nM), and RNA helicase (Kd 108.21 nM).\", \"Lopinavir and ritonavir, active materials of AbbVie's Kaletra, both were predicted to have a potential affinity to 2019-nCoV helicase (Table 3 ) and are suggested as potential MERS therapeutics (15) .\", 'Recently, approximately $2 million worth of Kaletra doses were donated to China (16) , and a previous clinical study of SARS by Chu et al. (17) may support this decision (17).', \"Another anti-HIV drug, Prezcobix of Johnson & Johnson, which consists of darunavir and cobicistat, was to be sent to China (16) , and darunavir is also predicted to have a Kd of 90.38 nM against 2019-nCoV's helicase (Table 3) .\", 'However, there was no current supporting literature found for darunavir to be used as a CoV therapeutic.']}\n", - "{'sentences': ['Metronidazole; a Potential Novel Addition to the COVID-19 Treatment Regimen', 'Coronavirus disease 2019 or COVID-19 has rapidly emerged as a global pandemic.', 'This viral infection involves the upper respiratory tract and could lead to severe pneumonia with respiratory distress or even death.', 'Certain studies have found higher initial plasma levels of most pro-inflammatory cytokines during the course of the infection.', 'In this context, both in vitro and in vivo studies have revealed that metronidazole could decrease the levels of several cytokines, which are known to increase during the COVID-19 infection, including interleukin (IL)8, IL6, IL1B, tumor necrosis factor (TNF)α, IL12, IL1α, and interferon (IFN)γ, as well as the levels of C-reactive protein (CRP']}\n", - "{'sentences': ['COVID-19 was firstly reported as ‘pneumonia of unknown aetiology’ or ‘pneumonia of unknown cause’ in late December 2019.', 'On 8 January 2020, a novel coronavirus was identified as the cause of this disease.', 'The disease was first named Novel coronavirus pneumonia by the NHC of China on 8 February and later ‘coronavirus disease 2019’ (abbreviated ‘COVID-19’) on 11 February by the WHO.', 'Our search period was defined from January 16 to February 11.', 'Therefore, we think that the two keywords ‘pneumonia’ and ‘coronavirus’ were sufficient to include most Internet content related to COVID-19 in this period.', 'We also used other terms such as ‘新冠‘ (novel coronavirus), ‘新型冠状病毒肺炎’ (novel coronavirus pneumonia) as keywords but they returned much smaller numbers of queries and posts and we did therefore not include them in the analysis.', 'It is also notable that the strength of correlation was different for different keywords.', 'On Google, the keyword ‘coronavirus’ had the highest correlation coefficient (r = 0.958) with daily new laboratory-confirmed cases, and ‘pneumonia’ had the highest correlation coefficient with daily new suspected cases (r = 0.960).', 'We found the same pattern in the Baidu Index and Sina Weibo Index.', 'An explanation could be that ‘coronavirus’ is linked to the viral pathogen which should be investigated by a laboratory test, while ‘pneumonia’ is a clinical term and should link stronger to the suspected cases that are based on clinical and imaging evidence.', 'A limitation of our study is its retrospective nature.', 'If the Internet search engines and social media data were used in a real-time surveillance system, finding the best lag time would be a challenge because we would not have any training data to calibrate the analysis for a new disease.', 'Our study demonstrated that the data obtained from Google Trends, Baidu Index and Sina Weibo Index on searches for the keywords ‘coronavirus’ and ‘pneumonia’ correlated with the published NHC data on daily incidence of laboratory-confirmed and suspected cases of COVID-19, with the maximum r > 0.89.', 'We also found that the peak interest for these keywords in Internet search engines and social media data was 10–14 days earlier than the incidence peak of COVID-19 published by the NHC.', 'The lag correlation showed a maximum correlation at 8–12 days for laboratory-confirmed cases and 6–8 days for suspected cases.', 'COVID-19 is a rapidly spreading infectious disease with, at the time of submission, more than 80,000 cases and a mortality so far known to be 3.4% [10].', 'It is important to predict the development of this outbreak as early and as reliably as possible, in order to take action to prevent its spread.', 'Our data showed that the two popularly used Internet search engines, Google and Baidu, and the social media platform, Sina Weibo, were able to predict the disease outbreak 1–2 weeks earlier than the traditional surveillance systems.', 'The role of Internet surveillance tools in early prediction of other epidemics has been reported previously, including for influenza [4], dengue fever [5], H1N1 [6], Zika [7], measles [8] and Middle East respiratory syndrome [9].', 'The availability of early information about infectious diseases through Internet search engines and social media will be helpful for making decisions related to disease control and prevention.', 'Internet search data have been shown to enable the monitoring of Middle East respiratory syndrome 3 days before laboratory confirmations [9].', 'However, our results showed a much longer lag time for reported new laboratory-confirmed and suspected COVID-19 cases compared with digital surveillance data.', 'There are several explanations.', 'Firstly, COVID-19 is a novel disease just recently recognised.', 'The first version of a guideline for diagnosis and management of COVID-19 was announced on 16 January 2020.', 'It took time for the medical professionals to learn about the virus and the disease in order to make correct diagnosis.', 'Secondly, the diagnosis of COVID-19 requires two independent confirmatory laboratory tests, which should be taken at least 1 day apart.', 'Our results showed that the lag correlation is shorter for the suspected than for laboratory-confirmed cases.', 'Thirdly, the supply of laboratory testing kits may have been insufficient in the early stages of the coronavirus outbreak, which would have limited the number of patients that can be confirmed.', 'Finally, the Internet searches and social media mentions are not only initiated by the patients and their family members, but also globally by the general public who are concerned about this rapidly spreading disease.', 'In addition, we found that the data from the Baidu Index and Sina Weibo Index could monitor the number of daily new confirmed and suspected cases from the NHC earlier than the data from Google Trends.', 'A possible explanation is that the Google is not a major search engine used in China, where Baidu and Sina Weibo are widely used.', 'The peak in the Sina Weibo Index was reached earlier than in Google Trends and Baidu Index.', 'This suggests that Sina Weibo, which also serves as a social medium, disseminated the information faster than traditional websites.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Local DNA structures have been shown to play important roles in basic biological processes, including replication and transcription Travers and Muskhelishvili, 2015; Surovtsev and Jacobs-Wagner, 2018) .', 'PQS analyses of human viruses have clearly demonstrated that these sequences are conserved also in the viral genomes (Lavezzo et al., 2018) and could be targets for antiviral therapies (Wang et al., 2015; Krafčíková et al., 2017; Ruggiero and Richter, 2018) .', 'For example, the conserved PQS sequence present in the L gene of Zaire ebolavirus and related to its replication is inhibited by interaction with G-quadruplex ligand TMPyP4, and this finding has led to suggestions that G-quadruplex RNA stabilization could constitute a new strategy against Ebola virus disease (Wang et al., 2016) .', 'Our results found only one PQS in the genomic sequence of SARS-CoV-2, that having an absolute (Fehr and Perlman, 2015) .', 'It would be of great value to know whether TMPyP4 or other G-quadruplex stabilizing compounds can inhibit replication processes of SARS-CoV-2.', 'RNA hairpins, which are formed by IRs, are basic structural elements of RNA and play crucial roles in gene expression and intermolecular recognition.', 'Conserved palindromic RNA structures have been found in many viral genomes, including HIV-1, and play a crucial role in their replication (Liu et al., 2018) .', 'We have found an abundance of IRs inside 5′UTR in Nidovirales genomes.', 'In general, 5′UTR is an important locus for regulation of viral replication and gene expression.', 'It has been demonstrated that stem integrity of phylogenetically conserved stem-loop structure located in 5′UTR of the PRRSV virus from the Arteriviridae family is crucial for viral replication and subgenomic mRNA synthesis.', 'Similar secondary structures have been proposed for several viruses from the Arteriviridae and Coronaviridae families (Lu et al., 2011) .', 'Our analyses of annotated features in Figure 5 therefore support this report.', 'The discrete locations of specific IRs in viral genomes could therefore be additional targets for their regulation.', 'Targeting viral proteins is usually effective only against specific viral strains and fails even for closely related viral species.', 'It appears that targeting host proteins should be able to provide a response toward a wider spectrum of viruses inasmuch as different viruses exploit common cellular pathways.', 'CC-BY-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https: //doi.org/10.1101 //doi.org/10.', '/2020 This is a provisional file, not the final typeset article cellular RNA-binding proteins (RBPs) containing well-established RNA-binding domains (RBDs) are known to be critical for infection by different viruses.', 'Recently, 472 RBPs', 'Virus reproduction is dependent on the cellular transcription machinery, and therefore the interaction of the cellular proteins with viral RNA could be another target for antiviral therapy (Roberts et al., 2009 ).', 'Our analysis predicted several QBPs to be capable to bind SARS-CoV-2 RNA.', 'One of these, HNRNPA1 protein, is responsible for nuclear-cytoplasm shuttling (Garcia-Moreno et al., 2018) .', 'Like some other RNA-binding proteins, HNRNPA1 forms so-called membraneless organelles.', 'These organelles are assemblies of proteins along with RNA or DNA that condense in specific cellular loci.', 'The organelles can undergo transition from liquid-like droplets to amyloid fibrils, and mutations in socalled low complexity domains of these proteins lead to formation of amyloid aggregations that are found in many neurodegenerative diseases (Gui et al., 2019) .', 'HNRNPA1 is involved in many different cellular processes and has been targeted in various diseases.', 'One such example is the varicella zoster virus that causes chicken pox.', 'Moreover, this response to varicella zoster virus has been connected with autoimmune disease that complicates multiple sclerosis (Kattimani and Veerappa, 2018) .', 'HNRNPA1 is known to bind and resolve G-quadruplex formed in TRA2B promoter and to promote its transcription.', 'Dysregulation of this binding leads to progression of colon cancer.', 'This interaction has been targeted by the well-known G-quadruplex stabilizer pyridostatin, which led to decreased transcription from the TRA2B promoter (Nishikawa et al., 2019) .', 'Furthermore, HNRNPA1 is coexpressed with bromodomain and extraterminal domain protein BRD4 in human tumor samples.', 'It has been shown experimentally that the well-described, naturally occurring polyphenolic flavonoid quercetin inhibited this protein and thereby led to better susceptibility to treatment in cancer patients (Pham et al., 2019) .', 'Both SRSF7 and TRA2A proteins, which are predicted to interact with SARS-CoV-2 RNA, play roles in alternative splicing (Ghosh et al., 2016) .', 'SRSF7 is a serine and argininerich splicing factor and is part of the spliceosome.', 'Its expression has been connected to several types of cancer and it has been shown that its knockdown induced p21 expression and thus reduced cancer development (Saijo et al., 2016) .', 'Little is known about TRA2A protein.', 'It was first identified in insects together with its paralog TRA2B, which has been studied to a greater extent .', 'It has .', 'CC-BY-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.09.031252 doi: bioRxiv preprint been found that TRA2A can promote paclitaxel therapy and promote cancer progression in triplenegative breast cancers (Liu et al., 2017) .', 'A role of TRA2A protein in regulation of HIV1 virus replication has been described.', 'Both TRA2A and TRA2B bind to a specific HIV1 sequence and regulate its replication within the cell through alternative splicing of viral RNA (Erkelenz et al., 2013) .', 'Scientists around the world are united in their efforts to find an effective therapy against coronavirus disease .', 'Among the most promising candidates are remdesivir and chloroquine.', 'Remdesivir is an adenosine analogue that incorporates into nascent viral RNA chains and results in premature termination.', 'Preliminary data have shown that remdesivir effectively inhibited virus infection in a human liver cancer cell line .', 'Chloroquine is a potential broadspectrum antiviral drug and it already has been widely used as a low-cost and safe anti-malarial and autoimmune disease drug for more than 70 years.', 'Application of chloroquine causes elevation of endosomal pH and also interferes with terminal glycosylation of the cellular receptor ACE2.', 'This probably has a negative influence on virus-receptor binding and abrogates the infection (Vincent et al., 2005) .', 'Drug repurposing seems like a very good strategy for quickly and at low cost finding a new therapy for new human diseases (Oprea and Mestres, 2012) .', 'To date, there are few substances with Gquadruplex stabilizing features.', 'One example is topotecan (also known by its brand name Hycamtin ® ), which frequently is used for treating ovary cancer.', 'If everything else fails, it seems to be an option.', 'On the other hand, topotecan cause unpleasant side effects, such as nausea, vomiting, and diarrhea (Topotecan -Chemotherapy Drugs -Chemocare).', 'Many studies have described strong G-quadruplex stabilization effects (Li et al., 2018; Satpathi et al., 2018) , which might be one possible mode of action.', 'Moreover, it has been proven that higher structures of nucleic acids, and G-quadruplex especially, might be stabilized by use of various natural substances.', 'Berbamine is one such substance and is a component of traditional Chinese medicine.', 'It frequently is used for treating chronic myeloid leukemia or melanoma and has strong binding affinity to G-quadruplex structures (Tan et al., 2014) .', 'Viral nucleic acids and their loci with G-quadruplex-forming potential are in all cases very specific and are promising molecular targets for treating serious diseases.', 'Evidence of G-quadruplex formation as a potential target for therapy was proven for Hepatitis A, flu virus, and HIV-1 (Métifiot et al., 2014) .', 'Because all the aforementioned cases concern RNA viruses, the viral G-quadruplexes are localized in the cytoplasm of the host cell.', 'One of the main conclusions to be drawn from this study is that sequences able to form G-quadruplex structures in the Nidovirales (infecting human) family are very rare, and this suggests intentional suppression during evolution to simplify viral RNA replication.', 'Finding the proper stabilizers of viral higher RNA structures might be crucial for inhibiting or stopping .', 'CC-BY-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.09.031252 doi: bioRxiv preprint']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['The newly emerged coronavirus in Wuhan city in China has a health concern since the last outbreak of these types of viruses (SARS) in the year 2002-2003 in the same country leaving > 700 deaths and 8000 cases in hospitals.', 'Besides, another outbreak in the Middle East region has an entirely different infection pattern (MERS) leaving > 800 deaths and 2500 hospitalizations.', 'The present study aimed to test and suggest possible inhibitors, DAA drugs, currently in the market stop the infection immediately.', 'Sofosbuvir, Ribavirin, and Remdisivir can be used against the new strain of coronavirus that emerged with promising results.', 'GTP derivatives may be used as specific inhibitors against COVID-19.']}\n", - "{'sentences': [\"[{'text': 'Treatments are desperately needed to lower the hospitalization and case fatality rates of SARS CoV-2 infection.\", 'In order to meaningfully impact the COVID-19 pandemic, promising antiviral therapies must be identified within the next several months.', 'However, the number of clinical trials that can be performed in this timeframe is limited.', 'We therefore developed a mathematical model which allows projection of all possible therapeutic approaches.', 'Our model recapitulates off-treatment viral dynamics and predicts a three-phase immune response.', 'Addition of treatment with remdesivir, hydroxychloroquine, neutralizing antibodies or cellular immunotherapy demonstrates that if in vivo drug potency is high, then rapid elimination of virus is possible.', 'Potent therapies dosed soon after peak viral load when infected people typically develop symptoms, are predicted to decrease shedding duration and intensity of the effector immune response, but to have little effect on viral area under the curve, which is driven by high levels of early SARS CoV-2 replication.', 'Potent therapy dosed prior to peak viral load, when infection is usually pre-symptomatic, is predicted to be the only option to lower viral area under the curve.', 'We also identify that clinically meaningful drug resistance is less likely to emerge with a highly potent agent that is dosed after peak viral load.', 'Our results support an early test and treat approach for COVID-19, but also demonstrate the need to identify early viral shedding kinetic features that are the most predictive surrogates of clinical severity and transmission risk.', 'We next simulated therapy at day 10 of infection (Fig. 4a) , when severely infected people often seek hospital care, and at day 5 of infection immediately after viral peak (Fig. 4b) , when infected people often become symptomatic.', 'In both cases, when remdesivir in vivo potency was assumed to be high (EC50=0.8 uM), viral elimination occurred rapidly after initiation of therapy.', 'This effect occurred because of unopposed removal of approximately 100-1000 infected cells per day by an ongoing innate immune response (Fig. 2b) .', 'Simulations with the assumption of a less potent version of remdesivir (EC50= 8 or 80 uM) resulted in a lower viral clearance slope.', 'This result implies that viral clearance slope in clinical trials can be used in concert with our model to directly estimate the in vivo intracellular EC50 value of remdesivir in each treated patient.', 'The model can then be used to project the effect of increasing or decreasing doses in subsequent trials.', 'SARS CoV-2 infection is characterized by a stereotypical viral kinetic pattern with a high peak viral load during the first several days of infection, a subsequent short rapid decay period followed by a slower clearance phase of variable duration, and a final, rapid elimination phase.', 'Our mathematical model reproduces this data and explains that the transition from first to second phase viral decay is governed by a density dependent term in which a massive die off of infected cell occurs during peak viremia.', 'Viral clearance rate slows considerably once the viral load decreases below a threshold of ~10 5 RNA copies.', 'A late slowly expanding cytolytic T cell response is predicted to induce eradication of infected cells in the upper airway 2-20 days later.', 'The timing of this final response appears to be variable among infected people.', 'Moreover, it is unknown if cessation of viral replication in the nasopharynx guarantees the same result in the lung or other anatomic compartments (8) .', 'We built therapy simulations on top of these natural kinetics to glean knowledge about the possible impact of antiviral therapies.', 'While accurate prediction is impossible in the absence of clinical trial data, we are able to make several observations which highlight the importance of off treatment viral dynamics in understanding treatment effects.', 'Our results can guide future study design and assist in interpretation of forthcoming trial data in multiple ways.', 'First, it is critical to know whether in vitro potency assessments of remdesivir, hydroxycholorquine and bNAbs can be projected onto human infection.', 'We previously demonstrated that in vivo IC50 values for antiviral agents can exceed estimates derived from cell cultures experiments by a multiple of 5-10 for small molecule antiviral drugs (19) .', 'A similar observation has been hypothesized for HIV targeting monoclonal neutralizing antibodies (23) .', 'It is unclear if this discrepancy occurs due to low blood levels in tissue, different cell metabolism of drug in tissue or higher protein binding in vivo.', 'Whatever the case, if in vitro potency measurements of hydroxycholoroquine and remdesivir overestimate in vivo activity, or if higher intracellular levels are required than in plasma, then these drugs may be less effective in clinical trials.', 'Higher dosing may be a possible solution to circumvent this issue.', 'Second, effective dosing after symptom development predicts rapid subsequent elimination of infected.', 'Most current clinical trials are focused primarily on hospitalized patients whereas our results and those from other COVID models suggest that treatment in the days immediately following symptom onset will decrease the duration of detectable viral shedding (24, 25) .', 'Our model also predicts that early treatment will limit the extent of the cytolytic immune response required to clear infection.', 'If either of these outcomes are correlates of progression to severe disease and transmission risk, then as with HIV (26), influenza (27) , and Ebola (28), early test and treat is a vital, currently overlooked strategy.', 'Third, effective dosing soon after onset of symptoms is predicted to have an insignificant effect on viral load AUC.', 'This phenomenon occurs because the amount of virus produced per hour at the early peak is far higher than the amount produced per day during the lower viral load second decay phase.', 'This finding provides a cautionary message: if subsequent disease severity and development is imprinted during the high viral load, pre-symptomatic phase of infection, then early antiviral therapy could theoretically eliminate further shedding without altering clinical outcomes.', 'Moreover, if extremely high viral load periods are responsible for most transmissions as suggested by the 5-day generation time of infection (29) , then early elimination of shedding may not lower transmissibility either.', 'Overall this result highlights the urgent need for studies which identify early viral and immune correlates of severe disease and .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'Indeed, preliminary studies suggest that presenting viral load may impact disease severity (30) .', 'Fourth, if therapy is initiated during the pre-symptomatic stage of infection as may occur during post exposure prophylaxis (31) , then its effectiveness is predicated on high potency.', 'Subtherapeutic small molecular agents may in fact prolong infection.', 'Based on this result, we suggest sampling at late timepoints during post exposure prophylaxis trials.', 'Fifth, our approach suggests that while development of drug resistance will occur commonly during COVID-19 treatment with remdesivir, it is unlikely to predispose to treatment failure provided the drug is potent against the predominant susceptible strain.', 'Resistant variants will likely be present at low levels relative to susceptible strains making transmission of resistance far less likely.', 'Important exceptions may occur in immunocompromised hosts who might shed respiratory viruses for longer and at higher levels, thereby increasing the chance of de novo resistance (32) , or in the context of only moderately potent antiviral therapy.', 'Finally, our model projects a high likelihood of success for neutralizing antibodies and cellular immunotherapies provided that they achieve adequate potency and are dosed early.', 'In summary, our model provides a broad platform for assessment of all major types of therapies.', 'Our results demonstrate the need to differentiate whether duration of viral shedding or viral area under the curve is the more relevant surrogate of severity.', 'If viral area under the curve is most predictive of poor outcomes, then all forms of antiviral therapy outside of potent post exposure prophylaxis are unlikely to provide clinical benefit.', 'However, if shedding duration is the best surrogate, then an early test and treat approach is highly promising for limiting the likelihood of severe disease.', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'Heatmaps comparing variance in drug potency measured by in vivo EC50 (x-axis) and timing of treatment initiation (y-axis) for A. Shedding duration, B. viral load area under the curve (AUC) and C. extent of T cell response required for viral elimination.', 'Potent therapy within the first 5 days of infection limits shedding duration and the extent of the T cell response.', 'However, only extremely early therapy during the pre-symptomatic phase of infection lowers viral AUC', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', '10.20061325 doi: medRxiv preprint Figure 6 .', 'Projections of remdesivir drug resistance during therapy.', 'Simulations are with high potency (EC50=0.8 uM) and the assumption that mutants confer partial drug resistance.', 'Treatment initiation is at timepoints generally consistent with hospitalization (day 10 after first positive sample), first symptoms (day 5 after first positive sample), pre-symptomatic post-peak phase (day 2 after first positive sample) or pre-symptomatic pre-peak phase (day 0).', 'A. Projections of no treatment, treatment with no assumed drug resistance, and treatment with assumed drug resistance.', 'B. Projections of assumed drug resistance with trajectories of sensitive strains, single mutants and double mutants.', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', '10.20061325 doi: medRxiv preprint Figure 7 .', 'Projections of remdesivir drug resistance during therapy.', 'Simulations are with moderate potency (EC50=8.0 uM) and the assumption that mutants confer partial drug resistance.', 'Treatment initiation is at timepoints generally consistent with hospitalization (day 10 after first positive sample), first symptoms (day 5 after first positive sample), pre-symptomatic post-peak phase (day 2 after first positive sample) or pre-symptomatic pre-peak phase (day 0).', 'A. Projections of no treatment, treatment with no assumed drug resistance, and treatment with assumed drug resistance.', 'B. Projections of assumed drug resistance with trajectories of sensitive strains, single mutants and double mutants.', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint . .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'Projections of remdesivir drug resistance during therapy.', 'Simulations are with high potency (EC50=0.8 uM) and the assumption that mutants confer complete drug resistance.', 'Treatment initiation is at timepoints generally consistent with hospitalization (day 10 after first positive sample), first symptoms (day 5 after first positive sample), pre-symptomatic post-peak phase (day 2 after first positive sample) or pre-symptomatic pre-peak phase (day 0).', 'A. Projections of no treatment, treatment with no assumed drug resistance, and treatment with assumed drug resistance.', 'B. Projections of assumed drug resistance with trajectories of sensitive strains and single mutants. .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'Treatment projections of hydroxychloroquine assuming different potency and timing of treatment.', 'Each set of simulations is performed under assumptions of high, medium and low potency.', 'Treatment initiation is at timepoints generally consistent with a. hospitalization (day 10 after first positive sample), b. first symptoms (day 5 after first positive sample), c. presymptomatic post-peak phase (day 2 after first positive sample) and d. pre-symptomatic pre-peak phase (day 0).', 'Overall, early potent treatment limits duration of infection.', 'Heatmaps comparing variance in drug potency measured by in vivo EC50 (x-axis) and timing of treatment initiation (y-axis) for e. Shedding duration, f. viral load area under the curve (AUC', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?', 'Chloroquine has been shown to be capable of inhibiting the in vitro replication of several coronaviruses.', 'Recent publications support the hypothesis that chloroquine can improve the clinical outcome of patients infected by SARS-CoV-2.', 'The multiple molecular mechanisms by which chloroquine can achieve such results remain to be further explored.', 'Since SARS-CoV-2 was found a few days ago to utilise the same cell surface receptor ACE2 (expressed in lung, heart, kidney and intestine) as SARS-CoV-1 [85 , 86] ( Table 1 ) , it may be hypothesised that chloroquine also interferes with ACE2 receptor glycosylation thus preventing SARS-CoV-2 binding to target cells.', 'Wang and Cheng reported that SARS-CoV and MERS-CoV upregulate the expression of ACE2 in lung tissue, a process that could accelerate their replication and spread [85] .', 'Although the binding of SARS-CoV to sialic acids has not been reported so far (it is expected that Betacoronavirus adaptation to humans involves progressive loss of hemagglutinin-esterase lectin activity), if SARS-CoV-2 like other coronaviruses targets sialic acids on some cell subtypes, this interaction will be affected by chloroquine treatment [87 , 88] .', 'Today, preliminary data indicate that chloroquine interferes with SARS-CoV-2 attempts to acidify the lysosomes and presumably inhibits cathepsins, which require a low pH for optimal cleavage of SARS-CoV-2 spike protein [89] , a prerequisite to the formation of the autophagosome [49] .', 'Obviously, it can be hypothesised that SARS-CoV-2 molecular crosstalk with its target cell can be altered by chloroquine through inhibition of kinases such as MAPK.', 'Chloroquine could also interfere with proteolytic processing of the M protein and alter virion assembly and budding ( Fig. 1 ) The S glycoprotein determines the host tropism.', 'There is indication that SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) expressed on pneumocytes [85 , 99] .', 'Binding to ACE2 is expected to trigger conformational changes in the S glycoprotein allowing cleavage by the transmembrane protease TMPRSS2 of the S protein and the release of S fragments into the cellular supernatant that inhibit virus neutralisation by antibodies [100] .', 'The virus is then transported into the cell through the early and late endosomes where the host protease cathepsin L further cleaves the S protein at low pH, leading to fusion of the viral envelope and phospholipidic membrane of the endosomes resulting in release of the viral genome into the cell cytoplasm.', 'Replication then starts and the positive-strand viral genomic RNA is transcribed into a negative RNA strand that is used as a template for the synthesis of viral mRNA.', 'Synthesis of the negative RNA strand peaks earlier and falls faster than synthesis of the positive strand.', 'Infected cells contain between 10 and 100 times more positive strands than negative strands.', 'The ribosome machinery of the infected cells is diverted in favour of the virus, which then synthesises its non-structural proteins (NSPs) that assemble into the replicase-transcriptase complex to favour viral subgenomic mRNA synthesis (see the review by Fehr and Perlman for details [101] ).', 'Following replication, the envelope proteins are translated and inserted into the endoplasmic reticulum and then move to the Golgi compartment.', 'Viral genomic RNA is packaged into the nucleocapsid and then envelope proteins are incorporated during the budding step to form mature virions.', 'The M protein, which localises to the trans-Golgi network, plays an essential role during viral assembly by interacting with the other proteins of the virus.', 'Following assembly, the newly formed viral particles are transported to the cell surface in vesicles and are released by exocytosis.', 'It is possible that chloroquine interferes with ACE2 receptor glycosylation, thus preventing SARS-CoV-2 binding to target cells.', 'Chloroquine could also possibly limit the biosynthesis of sialic acids that may be required for cell surface binding of SARS-CoV-2.', 'If binding of some viral particles is achieved, chloroquine may modulate the acidification of endosomes thereby inhibiting formation of the autophagosome.', 'Through reduction of cellular mitogen-activated protein (MAP']}\n", - "{'sentences': ['The Role of Vitamin D in Suppressing Cytokine Storm in COVID-19 Patients and Associated Mortality', 'Background: Statistical analysis of data obtained from hospitals and clinics across the world has been analyzed to illuminate new insights into characteristics of COVID-19 and to discern whether a link exists between severe cases of COVID-19 that feature cytokine storm and vitamin D (Vit D) deficiency.', 'Method: Daily admission, recovery and deceased rate data for patients with COVID-19 from countries with over 5,000 confirmed cases through March 21, 2020, were selected.', 'A potential association between severe Vit D deficiency and age-specific case fatality (CFR) was investigated.', 'Reported medical characteristics of 793 COVID-19 patients were used to evaluate the intensity of cytokine storm in severe COVID-19 using C-reactive protein (CRP) levels.', 'Medical data reported from a national study of 3,848 participants in 2007-2008 was used to investigate the association between Vit D status and CRP.', 'Odds ratio and risk factors from these conditions were used to predict the potential impact of Vit D on the reduction of cytokine storm and severe COVID-19.', 'Findings: Age-specific CFR in Italy, Spain, and France (70 yo ≤ age < 80 yo) was substantially higher (>1.9 times) than other countries (Germany, South Korea, China); for the elderly (age ≥70 yo), Italy and Spain present the highest CFR (>1.7 times that of other countries).', 'The age-specific ratio of confirmed cases in Italy, Spain, and France has also been substantially higher than in other countries.', 'A more severe deficiency of Vit D (mean 25-hydroxyvitamin D (25OHD) concentration <0.25 ng/L) is reported in Italy and Spain compared to other countries.', 'Our analysis of the reported clinical data (25OHD, CRP) from multiple studies suggests that elimination of severe Vit D deficiency reduces the risk of high CRPlevels (in the US) and laboratory data (odds ratio of 2) which may be used as a surrogate marker of cytokine storm which was estimated to a potential reduction in severe COVID-19 cases of up to 15%.', 'Interpretation: The substantially higher age-specific CFR and the age-specific ratio of confirmed cases in Italy and Spain (countries with low mean 25OHD level) suggest a potential link between severe Vit D deficiency and severe COVID-19, which can lead to a higher CFR.', 'No direct link between the performance of health care systems, the age distribution of the nation, or Vitamin A deficiency and the CFR of COVID-19 were observed.', 'Our analysis of the published data on the status of Vit D and CRPlevels (in the US) and laboratory data (in the US) and laboratory data (CRPlevels (in the US) and laboratory data) reported from 792 patients in China suggests that a proper supplementation of Vit D']}\n", - "{'sentences': ['Introduction pressure of oxygen < 300 mmHg, requiring hospitalization.', 'Critical illness was defined as having 114 respiratory failure, circulatory shock, end-organ failure or any combination of the above 115 requiring intensive care.', 'In addition, the following variables were extracted as potential 116 covariates of the above outcomes.', 'Central tendency (i.e. mean or median) and dispersion (i.e. 117 SD, SE, 95%CI, IQR or range) of age were extracted.', 'When not reported, study level means and 118 standard deviations for age were imputed from the available statistics (i.e. median, IQR or 119 range).', '12 Proportions of the following variables within a study sample were extracted: age < 18 120 years, age > 60 years, female sex, diabetes mellitus, hypertension, heart disease, chronic liver 121 disease, chronic kidney disease, chronic obstructive pulmonary disease, malignancy, 122 immunosuppression (e.g. HIV), smoking and pregnancy.', 'Proportions of patients with specific 123 presenting symptoms (i.e. fever, cough, sore throat, shortness of breath, headache, diarrhea), 124 asymptomatic cases, specific laboratory parameters (i.e. positive nucleic acid test for COVID-19, 125 leukopenia, leukocytosis, thrombocytopenia, lymphopenia, elevated lactate dehydrogenase 126 (LDH), elevated C-reactive protein (CRP), elevated erythrocyte sedimentation rate (ESR']}\n", - "{'sentences': ['CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.09.20059659 doi: medRxiv preprint (a) (b) (c) Fig. 1.', 'Top row (a, b) : Prevalence of obesity among adults, BMI ≥ 30, age-standardized in 2016 labelled as \"Obesity (%),\" cancer data age-standardized incidence rates per 10,000 labelled as \"Cancer per 10,000,\" prevalence of insufficient physical activity among adults aged 18+ years in 2016 labelled as \"Ins.', 'PA (%),\" population aged 15-64 labelled as \"Ages 15-64 (%),\" high total cholesterol (>= 5.0 mmol/L) (age-standardized estimate) in 2008 labelled as \"Raised TC 25+,\" gross national income in 2018 labelled as \"GNI (in $thousands),\" diabetes % of total population in 2016 labelled as \"Diabetes (%),\" prevalence of smoking in 2016 labelled as \"Smoking (%),\" raised blood pressure (SBP ≥ 140 or DBP ≥ 90), age-standardized (%) labelled as \"Raised BP (%),\" CO 2 per capita emissions in 2018 labelled as \"CO 2 emission,\" gross domestic product in 2018 labelled as \"GDP (in $trillions)\", and population aged 65 and older labelled as \"Ages 65+\" in each country.', 'The data for obesity, diabetes, raised blood pressure, raised total cholesterol, insufficient physical activity are from the World Health Organization, those for age population, prevalence of smoking, GDP and GNI from the World Bank, while the data for CO 2 per capita emissions are from Emission Database for Global Atmospheric Research (Emission Database for Global Atmospheric Research) of the European Commission.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.09.20059659 doi: medRxiv preprint', 'The data presented in Fig. 1 enables us to investigate the simultaneous relation between the 12 variables considered in the present study, on the one hand, and the total ND, on the other hand, whereas the relationship between the variables compared to other countries are summarized.', 'Similarly, we also have analysed the trends of each variable and the ND separately in order to provide how each variable affects the ND.', 'The results are presented in To identify quantitatively the variables that are correlated with the total ND recorded in each country, the statistical procedure explained in the previous section was employed.', 'Our results show that among the variables considered in the present study, the diabetes percentage of the total population and the population age 65 and higher had significant correlation with the total ND recorded in each country as of 06 April 2020.', 'While the effect of the latter factor has been known, the fact that our statistical model correctly highlights its correlation indicates its internal consistency.', 'The estimated coefficients for these two variables are summarized in Table 1 . .', 'CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint To further demonstrate the correlation of our findings with the total ND, the spatial relationship between the total ND, diabetes percentage of the total population and the population ages 65 and higher is shown in Figure 3 , where the colour map presents the total ND in each country.', 'Figure 3 suggests that the countries with a higher percentage of diabetes and population ages 65 and older experience more fatality due to COVID-19, at least as of 06', 'Fig. 3 .', 'The spatial relation between the diabetes percentage of the total population, the population ages 65 and higher, and the total number of deaths ND, recorded in each country due to COVID-19, as of 06 April 2020.', 'The colour map indicates the total number of death (ND', 'The data provided by World Health Organization (WHO) 10 , the World Bank 11 , and the Emission Database for Global Atmospheric Research (Emission Database for Global Atmospheric Research) of the European Commission 12 were used to obtain the 12 environmental, economic and heath variables investigated in this study, with the data presented in Figure 1 (a,b) .', 'Moreover, we used the daily death data in each country released by the WHO']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['We report on 52 critically ill patients with con firmed SARS-CoV-2 infection, characterised by severe hypoxaemia.', '32 (61·5%) of critically ill patients had died at 28 days.', 'Of all included patients, 37 (71%) required mechanical ventilation and 35 (67%) had ARDS.', 'Since no specialised medication to treat SARS-CoV-2 infection has been identified at this time, the mainstay of treatment has been supportive care.', 'Patients are being treated in isolation, and their close contacts are being quarantined.', 'For non-critically ill patients, close followup is likely to be sufficient to manage the disease.', '1-3 For critically ill patients, however, aggressive treatments and intensive care are needed.', 'To our knowledge, this is the first study to characterise critically ill patients infected by SARS-CoV-2.', 'In three previously published studies of crtically ill patients, the patient numbers were too small to summarise the characteristics and mortality of these patients with SARS-CoV-2 pneumonia.', '1, 2, 5 Like SARS-CoV and Middle Eastern respiratory syndrome (MERS)-CoV, SARS-CoV-2 is a coronavirus that can be transmitted to humans, and these viruses are all related to high mortality in critically ill patients.', '12 However, the mortality rate in patients with SARS-CoV-2 infection in our cohort is higher than that previously seen in critically ill patients with SARS.', 'In a cohort of 38 critically ill patients with SARS from 13 hospitals in Canada, 29 (76%) patients required mechanical ventilation, 13 (43%) patients had died at 28 days, and six (16%) patients remained on mechanical ventilation.', '8 17 (38%) of 45 patients and 14 (26%) of 54 patients who were critically ill with SARS infection were also reported to have died at 28 days in a Singapore cohort 13 and a Hong Kong cohort, 14 respectively.', 'The mortality rate in our cohort is likely to be higher than that seen in critically ill patients with MERS infection.', 'In a cohort of 12 patients with MERS from two hospitals in Saudi Arabia, seven (58%) patients had died at 90 days.', '15 Since the follow-up time is shorter in our cohort, we postulate that the mortality rate would be higher after 28 days than that seen in patients with MERS-CoV.', 'The fundamental pathophysiology of severe viral pneumonia is severe ARDS.', 'Men and people of an older age (>65 years) are more likely to develop ARDS than women or those of a younger age.', 'Therefore, it is reasonable that the mortality at 28 days of severe SARS-CoV-2 pneumonia is similar to the mortality of severe ARDS, which is near 50%.', '17 With a substantial increase in the number of critically ill patients infected by SARS-CoV-2, more provisional ICUs are being established in Wuhan, China.', 'Qualified specialists are coming to Wuhan from other provinces of China and are currently working in these provisional ICUs, fever clinics, and newly constructed hospitals.', '18 As the clinical capacity to treat patients improves, the mortality of critically ill patients with SARS-CoV-2 pneumonia is expected to decrease.', 'As mentioned in previous studies, nearly 70% of patients infected by SARS-CoV-2 were men.', '1, 2 The patients are older in our study than in previous studies.', '1, 2 We observed that non-survivors were older than survivors.', 'Based on previous studies, evidence suggests that older, male patients are the most susceptible to SARS-CoV-2 infection, 2 which is supported by our data.', 'As previously reported, patients with a history of cerebrovascular disease are at increased risk of becoming critically ill or dying if they have SARS-CoV-2 infection.', '2, 5 In our cohort, fever is the most common symptom in patients with SARS-CoV-2 pneumonia, which is in accordance with previous studies, but not all patients had fever.', '1, 2, 5 We also found that fever was not detected at the onset of illness in six (11·5%), and that it was in fact detected 2-8 days later.', 'The delay of fever manifestation hinders early identification of patients infected with SARS-CoV-2-if patients are asymptomatic identification of suspected cases is more difficult.', '19, 20 The median duration from onset of symptoms to radiological confirmation of pneumonia was 5 (3-7) days, meaning that early or repeated radiological examinations are useful in screening patients with SARS-CoV-2 pneumonia.', '4 As for laboratory tests, lymphocytopenia occurred in more than 80% of critically ill patients in our cohort.', 'Lymphocytopenia is a prominent feature of critically ill patients with SARS-CoV infection because targeted invasion by SARS-CoV viral particles damages the cytoplasmic component of the lymphocyte and causes its destruction.', '21 Additionally, lymphocytopenia is also common in the critically ill patients with MERS infection, which is the result of apoptosis of lymphocytes.', '22, 23 Therefore, we postulate that necrosis or apoptosis of lymphocytes also induces lymphocytopenia in critically ill patients with SARS-CoV-2 infection.', 'In a previous study, mainly in non-critical patients infected with SARS-CoV-2, 35% of patients had only mild lymphocytopenia, 2 suggesting that the severity of lymphocytopenia reflects the severity of SARS-CoV-2 infection.', 'Mechanical ventilation is the main supportive treatment for critically ill patients.', 'The PaO 2 /FiO 2 ratio was lower in our patients than in patients admitted to Zhongnan Hospital.', '5 The substantial difference in PaO 2 /FiO 2 ratio between survivors and non-survivors in our study, indicates this ratio is associated with the severity of illness and thus prognosis.', 'Barotrauma seems less severe in patients with SARS-CoV-2 infection who are being mechanically ventilated than that seen in mechanically ventilated patients with SARS-CoV. In our study, barotrauma occurred in only one (2%) patient, who had been hospitalised for nearly 1 month, and he is currently on a ventilator and receiving ECMO.', 'In patients with SARS, barotrauma occurred in about 25% of patients on mechanical ventilation.', '14 The lower occurrence of barotrauma in our cohort is probably related to the widely accepted strategy of protective ventilation in mainland China.', '24 At the same time, prone position and ECMO have been used to treat patients with SARS-CoV-2 pneumonia.', 'Without solid evidence, nearly half of the patients were given antiviral agents, and more than half were given intravenous glucocorticoids.', 'Patients treated with lopinavir were from an ongoing clinical trial registered on Chinese Clinical Trial Registry (ChiCTR2000029308).', 'Remdesivir was given to the first patients with SARS-CoV-2 pneumonia in the USA.', '4 Trials on remdesivir are about to recruit both mild to moderate patients (NCT04252664) and severe patients (NCT04257656) infected with SARS-CoV-2.', 'Although, intravenous glucocorticoids were commonly used in patients with severe SARS or MERS pneumonia, their efficacy remains controversial and their use to treat SARS-CoV-2 infection is also controversial.', '5, 25 An ongoing clinical trial (NCT04244591) might shed some light on the safety and efficacy of these drugs as treatment.', 'This study has several limitations.', 'First, only 52 critically ill patients were included.', 'However, the population from which they were sampled was much larger than that of the three studies previously published.', '1, 2, 5 We included all the critically ill patients being cared for in the ICU of Jin Yin-tan hospital who met the inclusion criteria.', 'Due to the exploratory nature of the study, which was not driven by formal hypotheses, the sample size calculation was waived.', 'Instead, we hope that the findings presented here will encourage a larger cohort study or potentially some randomly controlled trials.', 'Second, some specific information from the ICU was missing, such as mechanical ventilation settings.', 'The data on radiographical examination, supportive treatment, living status, and the duration from ICU admission to death, however, are indisputable.', 'Third, this is a retrospective study.', 'The data in this study permit a preliminary assessment of the clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia.', 'Further studies are still needed.', 'In conclusion, the mortality of critically ill patients with SARS-CoV-2 pneumonia is high.', 'The survival term of the non-survivors is likely to be within 1-2 weeks after ICU admission.', 'Older patients (>65 years) with comorbidities and ARDS are at increased risk of death.', 'The severity of SARS-CoV-2 pneumonia poses great strain to hospital critical care resources, especially if they are not adequately staffed or resourced.', 'The primary outcome was 28-day mortality after ICU admission.', 'Secondary outcomes included incidence of SARS-CoV-2-related acute respiratory distress syndrome (ARDS) and the proportion of patients requiring mechanical ventilation.', 'ARDS and shock were defined according to the guidance of WHO for novel coronavirus disease 2019 (COVID-19).', '6 Acute kidney injury was identified on the basis of serum creatinine.', '11 Cardiac injury was diagnosed if the serum concentration of hypersensitive cardiac troponin I (hsTNI']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': [\"[{'text': 'Repurposing existing drugs is a timely option to cope with COVID-19.\", 'We predicted therapeutic candidates that could reverse the gene expression of coronavirus-infected host cells.', 'Thirteen expression signatures computed from various experimental conditions and preclinical models could be reversed by those compounds known to be effective against SARS-or MERS-CoV, as well as the drug candidates recently shown to be effective against SARS-CoV-2.', 'We selected ten novel candidates to further evaluate their in vitro efficacy against SARS-CoV-2 infection.', 'Four compounds bortezomib, dactolisib, alvocidib and methotrexate inhibited the formation of virus infection-induced cytopathic effect in Vero E6 cells at 1 µM, yet such a concentration seems toxic to the cells as well.', \"While the evaluation in other permissive cells and', 'cite_spans': [], 'ref_spans':\"]}\n", - "{'sentences': ['Abstract Background In the recent outbreak of novel coronavirus infection in Wuhan, China, significantly abnormal coagulation parameters in severe novel coronavirus pneumonia (NCP) cases were a concern.', 'Objectives To describe the coagulation feature of patients with NCP.', 'Methods Conventional coagulation results and outcomes of consecutive 183 patients with confirmed NCP in Tongji hospital were retrospectively analysed.', 'Results The overall mortality was 11.5%, the non-survivors revealed significantly higher D-dimer and fibrin degradation product (FDP) levels, longer prothrombin time and activated partial thromboplastin time compared to survivors on admission (P<0.05).', '71.4% of non-survivors and 0.6% survivors met the criteria of disseminated intravascular coagulation during their hospital stay.', 'Conclusions The present study shows that abnormal coagulation results, especially markedly elevated D-dimer and FDP are common in deaths with NCP']}\n", - "{'sentences': ['No Evidence of Rapid Antiviral Clearance or Clinical Benefit with the Combination of Hydroxychloroquine and Azithromycin in Patients with Severe COVID-19 Infection']}\n", - "{'sentences': ['Background Since December, 2019, an outbreak of coronavirus disease 2019 (COVID-19) has spread globally.', 'Little is known about the epidemiological and clinical features of paediatric patients with COVID-19', 'Methods We retrospectively retrieved data for paediatric patients (aged 0-16 years) with confirmed COVID-19 from electronic medical records in three hospitals in Zhejiang, China.', \"We recorded patients' epidemiological and clinical features.\", 'were decreased lymphocytes, elevated body temperature, and high levels of procalcitonin, D-dimer, and creatine kinase MB.', 'All children received interferon alfa by aerosolisation twice a day, 14 (39%) received lopinavir-ritonavir syrup twice a day, and six (17%) needed oxygen inhalation.', 'Mean time in hospital was 14 (SD 3) days.', 'By Feb 28, 2020, all patients were cured.', 'Interpretation Although all paediatric patients in our cohort had mild or moderate type of COVID-19, the large proportion of asymptomatic children indicates the difficulty in identifying paediatric patients who do not have clear epidemiological information, leading to a dangerous situation in community-acquired infections.']}\n", - "{'sentences': ['Endotracheal intubation is an independent risk factor for respiratory infectious diseases.', 'We conducted a retrospective study in 12 cases with COVID-19 who underwent endotracheal intubation at ICU of the Guangzhou eighth hospital from January 20 to February 10, 2020.', 'The intubation procedure, anesthetic regimen, and complication were collected and analyzed.', 'The 9 healthcare workers who involved in intubation received virus nucleic acid test and 14 days temperature monitoring.', 'All 12 patients were successfully intubated under the guidance of bronchoscope, without any complications.', 'Midazolam, Propofol and Morphine or fentanyl were used for sedation and analgesia, avoiding patients cough and agitated during the procedure.', 'The 9 healthcare workers were protected under the Personal Protective Equipment(PPE) with positive pressure protective hood.', 'The detection of oropharyngeal swab virus nucleic acid were negative in all 9 healthcare workers, none of them had fever or any respiratory symptoms.', 'The PPE with positive pressure protective hood should be needed to perform bronchoscope-guided endotracheal intubation in patients with COVID-19, it could strengthen to protect healthcare workers from virus exposure.']}\n", - "{'sentences': ['Background: Since mid-December 2019, a cluster of pneumonia-like diseases caused by a novel coronavirus, now designated COVID-19 by the WHO, emerged in Wuhan city and rapidly spread throughout China.', 'Here we identify the clinical characteristics of COVID-19 in a cohort of patients in Shanghai.', 'Methods: Cases were confirmed by real-time RT-PCR and were analysed for demographic, clinical, laboratory and radiological features.', 'Of 198 patients, the median duration from disease onset to hospital admission was 4 days.', 'The mean age of the patients was 50.1 years, and 51.0% patients were male.', 'The most common symptom was fever.', 'Less than half of the patients presented with respiratory systems including cough, sputum production, itchy or sore throat, shortness of breath, and chest congestion.', '5.6% patients had diarrhoea.', 'On admission, T lymphocytes were decreased in 45.8% patients.', 'Ground glass opacity was the most common radiological finding on chest computed tomography.', '9.6% were admitted to the ICU because of the development of organ dysfunction.', 'Compared with patients not treated in ICU, patients treated in the ICU were older, had longer waiting time to admission, fever over 38.5 o C, dyspnoea, reduced T lymphocytes, elevated neutrophils and organ failure.', 'In this single centre cohort of COVID-19 patients, the most common symptom was fever, and the most common laboratory abnormality was decreased blood T cell counts.', 'Older age, male, fever over 38.5 o C, symptoms of dyspnoea, and underlying comorbidity, were the risk factors most associated with severity of disease.', 'We obtained epidemiological, demographic, clinical, laboratory and management data from the medical records of patients infected with SARS-Cov-2.', 'On Jan 20, 2020, the first human case of in Shanghai was confirmed.', 'Since then all hospitals in Shanghai have opened special fever clinics to screen suspected patients, and laboratory confirmed patients were then admitted to a single designated hospital in Shanghai (Shanghai Public Health Clinical Centre).', 'Laboratory confirmation of COVID-19 was done by the Chinese Centre for Disease Control and Prevention.', 'Throat-swab specimens from the upper respiratory tract were obtained from all patients at admission and maintained in viral transport medium.', 'COVID-19 was confirmed by real-time RT-PCR using the same protocol as described previously 3 .', 'Confirmed patients were hospitalized into negative pressure wards for further medical observation and treatment.', 'We collected data from patients who were admitted from Jan. 20 up to Feb. 15.', 'All the data collected from the included cases have been shared with the WHO.', 'Epidemiological exposure data, patient characteristics, clinical symptoms, laboratory and imaging findings and medical history were extracted from electronic medical records and analysed by licensed physicians.', 'Laboratory data were recorded in standardized form.', 'Initial investigations included a complete blood count, routine urinalysis, blood gases, coagulation function, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum biochemical testing (including renal and liver function, serum lactate, lactate dehydrogenase, and electrolytes).', 'To characterize the effect of coronavirus on the immune system, immunologic factors including serum immunoglobulin, complements, cytokines, rheumatoid factor (RF', 'Non-laboratory information, including patient characteristics, epidemiological and medical history, were obtained and recorded by licensed physicians from direct interviews of patients and their relatives.', 'Two researchers independently reviewed the data collection forms to review the data extracted.', 'Written informed All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'In this single centre cohort of confirmed COVID-19 cases in Shanghai, the median duration of symptoms from disease onset to hospital admission was 4 days.', 'Compared to the previously reported duration of 7-10 days between symptom onset and hospitalization in Wuhan 3 5 6 , patients in Shanghai received earlier in-ward observation and medical service, most likely due to improved monitoring and increased awareness of the outbreak.', 'As a result, our data likely were recorded closer to the onset date of the disease, which may explain some of the differences between the results reported from Wuhan and Shanghai.', \"In terms of patient's characteristics, we observed a comparatively equal male to female ratio in this study, which differs from the data reported in Wuhan 3 5 6 .\", 'This may be because most of these initial cases in Shanghai had a history of exposure in Wuhan (63.6%), and the disease thereafter appeared in a family cluster pattern.', 'Almost half of the patients in Shanghai were under 50 years old, in contrast with the predominantly older patient population reported in Wuhan.', 'In addition, 69 (34.8%) patients in our cohort had pre-existing comorbidities.', 'Whether the disease is more likely to manifest in patients with comorbidities and/or older patients remains unclear and requires further study.', 'Regarding laboratory evaluation, low or normal levels of white blood cell (WBC', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org /10.1101 /10.', 'In addition, we observed a marked reduction in T and T H subtype cells in infected patients, suggesting that SARS-Cov-2 infection may impair cellular immunity.', 'It is known that MERS-CoV is able to infect both CD4 + and CD8 + primary human T cells and, upon infection induces T cell apoptosis in vitro 7 .', 'While the cell surface receptor for SARS-Cov-2 has now been identified as ACE2 8 , other receptors may also exist on immune cells to bind to coronavirus [9] [10] [11] .', 'As there is no proven antiviral treatment yet available, strategies to enhance the immune system may be considered.', 'Since the most common haematological changes in COVID-19 patients were lymphopenia and immunodeficiency, we postulate that hematopoietic growth factors such as G-CSF, by mobilizing endogenous blood stem cells and endogenous cytokines, may represent a potential haematological treatment for COVID-19 patients 12 .', 'Interestingly, a noticeable increase of glutathione reductase (GR) level occurred in 40.2% of the COVID-19 patients in our cohort, while ALT and AST are normal in most patients.', 'GR is an essential enzyme that recycles oxidized glutathione back to the reduced form 13 .', 'GR is known to participate in an oxidative defence system required for effective immune responses against bacteria 14 15 .', 'We observed that 65.4% of COVID-19 patients had decreased serum calcium levels.', 'Calcium influx regulates both clathrin-mediated and clathrin-independent endocytosis during viral infection, thus constituting a key mechanism for regulation of influenza A virus internalization and infection 16 .', 'Based on this theory, calcium channel blockers, including amlodipine, verapamil, and diltiazem, as well as BAPTA-AM, have been proven effective in inhibiting IAV replication in a dose-dependent manner in a canine kidney cell model 17 .', 'Moreover, diltiazem may have both prophylactic and therapeutic effects in IAV treatment according to both ex vivo and in vivo testing 17 .', 'We therefore propose the hypothesis that Ca 2+ levels and/or Ca 2+ channels may play a role in endocytosis and infection of SARS-Cov-2.', 'Further studies are needed to characterize the functional importance of this potential pathway.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.04.20030395 doi: medRxiv preprint', 'The patients admitted to the ICU were more likely to be older, male, with temperature over 38.5 o C, symptom of dyspnoea, underlying cardiovascular disease, and longer waiting period from onset of symptom to hospital admission, compared to those not admitted to the ICU.', 'This suggests that age, sex, high fever, admission time and co-morbidity are risk factors for disease severity.', 'Compared with non-ICU patients, patients who received ICU care had numerous laboratory abnormalities.', 'These abnormalities suggest that SARS-Cov-2 infection can be associated with cellular immune deficiency, coagulation activation, myocardial injury, hepatic injury and kidney injury.', 'These laboratory abnormalities are similar to those previously observed in patients with MERS-Cov and SARS-Cov infection 18 19 .', 'The longitudinal profile of laboratory findings was dynamically tracked for those patients requiring ICU care.', 'When these patients were subdivided into severe and critical ill subgroups, we observed that white blood cell count, neutrophil count, D-dimer, BUN, creatinine, myoglobulin and troponin I levels were higher in critical cases than in severe cases.', 'Neutrophilia may be associated with secondary infection, while coagulation activation could be related to sustained inflammatory responses.', 'Acute heart and kidney injury could be related to direct effects of the virus or possibly hypoxia 9 20 .', 'Our study has several limitations.', 'First, although we obtained data from the initial 198 patients with laboratory-confirmed COVID-19 in Shanghai, the cohort is still relatively small.', 'More patients need to be analysed to provide a comprehensive and precise description of the spectrum of disease associated with this infection.', 'Secondly, our study reports primarily baseline results from patients upon hospital admission, and more longitudinal data regarding disease progression and clinical outcomes will require further collection and study.', 'Despite these limitations, our study provides data from the first large cohort outside Wuhan and adds important laboratory information to the rapidly accumulating body of information about COVID-19.', 'These results will assist in multi-centre monitoring of the disease.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.04.20030395 doi: medRxiv preprint', 'In conclusion, COVID-19 affects a wide-range of patients, from youth to the elderly.', 'Fever is consistently the most common symptom of onset, but multiple other clinical manifestations occur, including a spectrum form T cell deficiency to symptoms of digestive system involvement.', 'Older age, male, fever over 38.5 o C, symptom of dyspnoea, the presence of underlying cardiovascular disease, and longer waiting period from onset of symptom to hospital admission are risk factors associated with the severity of disease.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.04.20030395 doi: medRxiv preprint author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.04.20030395 doi: medRxiv preprint Fig. 1 All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.04.20030395 doi: medRxiv preprint Fig. 2 All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.04.20030395 doi: medRxiv preprint author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.04.20030395 doi: medRxiv preprint']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['[{\\'text\\': \"Coronaviruses such as the newly discovered virus from Wuhan, China, 2019-nCoV, and the viruses that cause SARS and MERS, have resulted in regional and global public health emergencies.', \"Based on our molecular insight that the hepatitis C virus and the coronavirus use a similar viral genome replication mechanism, we reasoned that the FDA-approved drug EPCLUSA (Sofosbuvir/Velpatasvir) for the treatment of hepatitis C will also inhibit the above coronaviruses, including 2019-nCoV. To develop broad spectrum anti-viral agents, we further describe a novel strategy to design and synthesize viral polymerase inhibitors, by combining the ProTide Prodrug approach used in the development of Sofosbuvir with the use of 3'-blocking groups that we have previously built into nucleotide analogues that function as polymerase terminators.\"]}\n", - "{'sentences': ['About 70% of the emerging pathogens infecting humans originate from animals, and CoVs are among the forefronts of these pathogens45.', 'The newly emerged SARS-CoV-2 infects human and causes severe pneumonia, and as of 10 February, 2020, the current outbreak has spread to 25 countries with over 40,000 confirmed cases and 900 deaths46.', 'However, little is known about its biology.', 'Since the virus is categorized as a biosafety level 3 (BSL3', 'Utilizing this pseudotype system, we screened a panel of human and monkey cell lines for their susceptibility of SARS-CoV-2 S-mediated transduction.', 'In line with SASR-CoV-2 causing respiratory infections in humans, we found that human lung cancer cell line Calu3 is highly susceptible to SARS-CoV-2 S-mediated entry.', 'LLCMK2 cells, a rhesus monkey kidney epithelium cell line, exhibited different susceptibility to SARS-CoV S and SARS-CoV-2 S transduction, but the reasons for this are currently not known and require further investigation.', 'Both S proteins use hACE2 as the receptor for binding and entry13,21, which we further confirmed by flow cytometry analysis and competitive inhibition experiment using soluble hACE2 in this study (Fig. 3b, c).', 'While full-length S proteins of SARS-CoV-2 and SARS-CoV S share almost 76% identities in amino acid sequences, the NTDs show only 53.5% of homology.', 'Of note, NTDs of different CoVs S proteins have been shown to bind different sugar.', 'While NTD of MERS-CoV prefers α2,3-linked sialic acid over α2,6-linked sialic acid47, NTDs of human CoVs OC43 and HKU1 bind to 9-O-acetylated sialic acids48,49.', 'No sugar binding has been reported for NTD of SARS-CoV. Whether or not NTD of SARS-CoV-2 binds to sugar and whether sugar binding of NTD affects virus entry remains to be determined.', 'Successful conformational changes of S proteins, leading to membrane fusion, not only require receptor binding, but also need appropriate protease activation.', 'There is a furin site between S1 and S2 (amino acids 682-685, RRAR) subunits in SARS-CoV-2 S protein, similar to what happens in high-pathogenic influenza viruses.', 'Whether the presence of this furin site has any effect on viral pathogenesis and virus spreading among humans remains to be determined.', 'Although majority of SARS-CoV-2 S proteins in pseuodvirions were cleaved, endocytosis is the main entry pathway on 293/hACE2 cell.', 'In our experiments, lysosomal cathepsin L, not B, appeared critical for SARS-CoV-2 S protein activation, similar to what was reported for SARS-CoV and MERS-CoV28,29,50.', 'Trypsin could also activate SARS-CoV-2 S protein efficiently and induce large syncytium formation.', 'To our surprise, we found that, even without trypsin, SARS-CoV-2 S protein could trigger syncytium formation on 293/hACE2 cells, a phenomena similar to what was observed in MHV S protein in certain aspect51.', 'This led us to speculate that SARS-CoV-2 S protein is capable of triggering protease-independent and receptor-dependent syncytium formation.', 'Such a mechanism might enhance virus spreading through cell–cell fusion and this might partially explain rapid progress of the diseases10,11.', 'However, we have not excluded a potential role for other endogenous proteases in HEK293T cells for syncytium formation and we have also not evaluated entry into other cell types.', 'This requires further research.', 'Recent studies showed that early to late endosome maturation is regulated by PI(3,5)P2, and inhibition of PIKfyve, the key enzyme synthesizing PI(3,5)P2, and TPC2, a downstream effector in lysosome, significantly reduced virus entry of MERS-CoV52.', 'We confirmed this in this study, and further showed that blocking PIKfyve and TPC2 also strongly inhibited entry mediated by SARS-CoV-2 S protein, indicating that PI(3,5)P2 pathway might be considered as potential general drug target for CoV infection.', 'CoV S protein is one of the key components determining virus virulence, tissue tropism and host range, and it is also a main target for neutralizing antibodies and vaccine design.', 'Although the S proteins of SARS-CoV-2 and SARS-CoV are highly homologous, polyclonal rabbit anti-SARS S1 antibodies T62 did not bind to SARS-CoV-2 S protein well, and poorly neutralized SARS-CoV-2 S protein-mediated virus entry.', 'Further analysis reveals that major immune-epitopes for T62 antibodies likely lie in the region of RBD (Fig. 4a).', 'We further evaluated cross-neutralization of SARS-CoV and SARS-CoV-2 using convalescent sera from SARS and COVID-19 patients.', 'We only saw moderate cross-neutralization activities between SARS-CoV-2 and SARS-CoV convalescent sera, suggesting that those previously recovered from SARS-CoV infection may not be fully protected against SARS-CoV-2 infection, and vice versa.', 'While this manuscript was under review, Hoffmann et al.53 reported that human ACE2 is the entry receptor of SARS-CoV-2, and that serine protease TMPRSS2 is important for SARS-CoV-2 S activation, consistent with our findings.', 'In agreement with our work, sera from convalescent SARS patients neutralized SARS-CoV-2 S pseudovirion entry with lower efficiency than SARS-CoV S pseudovirion entry, showing moderate cross-neutralization.', 'In conclusion, we demonstrated that SARS-CoV-2 S protein entry on 293/hACE2 cells is mainly mediated through endocytosis, and that PIKfyve, TPC2, and cathepsin L are critical for virus entry.', 'We further found that SARS-CoV-2 S protein could trigger syncytia in 293/hACE2 cells independent of exogenous protease.', 'Finally, there was limited cross-neutralization activity between convalescent sera from SARS and COVID-19 patients.', 'Our findings provide potential targets for development of drugs and vaccines against this newly emerging lineage B beta-CoV.']}\n", - "{'sentences': [\"[{'text': 'Coronavirus disease 2019 (COVID-19) is a new emerging human infectious disease caused by Severe Acute 24 Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, also previously known as 2019-nCoV), originated in 25 Wuhan seafood and animal market, China.\", 'Since December 2019, more than 69,000 cases of COVID-19 have 26 been confirmed in China and quickly spreads to other counties.', 'Currently, researchers put their best efforts to 27 identify effective drugs for COVID-19.', 'The neutralizing antibody, which binds to viral capsid in a manner that 28 inhibits cellular entry of virus and uncoating of the genome, is the specific defense against viral invaders.', 'In this 29 study, we investigate to identify neutralizing antibodies that can bind to SARS-CoV-2 Sipke (S) protein and 30 interfere with the interaction between viral S protein and a host receptor by bioinformatic methods.', 'The 31 sequence analysis of S protein showed two major differences in the RBD region of the SARS-CoV-2 S protein 32 compared to SARS-CoV and SARS-CoV related bat viruses (btSARS-CoV).', 'The insertion regions were close to 33 interacting residues with the human ACE2 receptor.', 'Epitope analysis of neutralizing antibodies revealed that 34 SARS-CoV neutralizing antibodies used conformational epitopes, whereas MERS-CoV neutralizing antibodies 35 used a common linear epitope region, which contributes to form the β-sheet structure in MERS-CoV S protein 36 and deleted in SARS-CoV-2 S protein.', 'To identify effective neutralizing antibodies for SARS-CoV-2, the 37 binding affinities of neutralizing antibodies with SARS-CoV-2 S protein were predicted and compared by 38 antibody-antigen docking simulation.', 'The result showed that CR3022 neutralizing antibody from human may 39 have higher binding affinity with SARS-CoV-2 S protein than SARS-CoV S protein.', 'We also found that 40 F26G19 and D12 mouse antibodies could bind to SARS-CoV S']}\n", - "{'sentences': ['COVID-19 in a MS patient treated with ocrelizumab: does immunosuppression have a protective role?']}\n", - "{'sentences': ['The COVID-19 is an acute infectious disease that caused by SARS-CoV-2 infection.', 'It has been a worldwide epidemic outbreak because SARS-CoV-2 is highly infectious and does not respond to .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint We here showed that the expression of SARS-CoV-2 receptor ACE2 is found in macrophages in human spleen and hilar LNs from autopsy as well as normal healthy (Figure 1) .', 'Similarly, all of the spleens exhibited atrophy of white pulps, with complete loss in some cases.', 'The red pulp is markedly congested and hemorrhagic (Figure 3) .', 'This phenomenon is consistent with older reports of patients infected with SARS-CoV. 27, 28 Taken together, these results demonstrate that SARS-CoV-2 directly infects LNs and spleens to cause severe tissue damage.', 'We then sought to investigate the route and identities of the cells that could potentially contribute to SARS-CoV-2 transports into spleens and LNs.', 'From our in situ immunohistochemistry, we showed that viral NP antigen was restricted to the macrophages of the infected tissues, while, human T cells and B cells were negative for viral NP antigen, suggesting SARS-CoV-2 cannot directly infect T and B cells ( Figure 2B ).', 'Most importantly, viral NP + CD68 + macrophages were observed in capillaries of spleens and LNs, indicating that SARS-CoV-2 migrates into spleens and LNs through macrophages.', 'An interesting finding is that overwhelming numbers of NP + cells are observed in red pulp of spleens and within marginal sinus of lymph nodes (Figure 2A) .', 'Previous work have showed that tissue-resident CD169 + macrophages are positioned in the splenic MZ and reside in the subcapsular sinus of LNs.', '7, 16 The strategic anatomical positioning of CD169 + macrophages in the spleen and LNs suggest these cells are the first to interact with invading pathogen.', 'Here, we also found that most CD169 + macrophages are positive for viral NP antigens ( Figure 2B) .', 'We therefore reasoned that the CD169 + macrophages play a central role in mediating SARS-CoV-2 translocation in spleens and LNs, and thus contribute to viral growth and spread.', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.03.27.20045427 doi: medRxiv preprint', 'The presence of viral antigens would activate T cells and B cells in spleen and LNs, and thus lead to Fas and FasL mediated AICD.', '17, 19 Although the level of FasL in spleens and LNs is similar in tissues from postmortem and age-match normal healthy controls, the expression of Fas is dramatically higher in virus infected tissue than healthy controls (Figure 4) .', 'In addition to antigen persistence stimulation, some proinflammatory cytokines like IL-6, TNF-α and IFN-γ can also can mediate cellular apoptosis and necrosis.', '20, 21 We focused here on IL-6 because it contributes to host defense against to several kinds of pathogen infections.', '21, 29 We also reported that the serum concentration of IL-6 is negative to blood CD4 + and CD8 + T cells in COVID-19 patients.', '14 Interestingly, exposure to viral Spike protein can trigger Il6 gene transcription in macrophages in vitro, and SARS-CoV-2 infected macrophage also manifested high levels of IL-6 in vivo ( Figure 5 ).', '22, 23 We thereby conjecture that macrophages-derived IL-6 would trigger lymphocyte apoptosis and necrosis, while also enhancing Fas expression.', 'Tocilizumab, a humanized anti-IL-6 receptor antibody, has been developed and approved for the treatment of rheumatoid arthritis (RA', 'In conclusion, we have demonstrated that the SARS-CoV-2 virus can directly infect human LNs and spleens and consequently lead to tissue damage and lymphocyte reduction.', 'We also showed that CD169 + macrophages play a central role in mediating SARS-CoV-2 translocation.', 'Mechanistically, we observed that viral infected macrophages can promote lymphocyte apoptosis though enhancing IL-6 mediated Fas upregulation.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['When interpreting the landscapes, it is important to note that the PIPE-Sites algorithm used here is simplistic in its implementation.', 'Briefly, a maximum of three potential peaks in the landscape are identified and a walk algorithm expands the predicted site of interaction until the score falls below a given threshold [8] .', 'The highlighted sites may appear \"shifted\" relative to the highlighted cells (typically in the bottom-left); this is due to the algorithm\\'s use of a window of 20 amino acids in length that extends both to the left (along the x-axis) and upwards (along the y-axis).', 'Consequently, the minimum PIPE-Site size is 20×20 with the peak in the bottom-left corner.', 'Additionally, this implementation may result in the predicted site extending past the coloured matrix, either to the right or above.', 'This defined window size additionally prevents predictions within the terminal 20 amino acids of both sequences given that the widow sizes in these regions would necessarily be less than 20 amino acids in length.', 'Finally, the PIPE-Sites may overlap when numerous hits appear within close proximity, as is the case when a \"band\" of hits appears in the matrix.', 'Finally, when the peak of the landscape comprises only a few hits (generally <3) the entire landscape is predicted as a site of interaction; evidently, these should be disregarded.', 'Therefore, when interpreting the landscapes, it is important not to solely rely on these proposed regions; they function as an initial guide, yet other high-scoring, or \"hot-spot\", regions of interest may exist in the landscape.', 'By providing a matrix of raw scores (in the form of a space-separated .mat file), visual interpretation of the results promise to reveal notable subsequences as well as enable the application of related interaction site predictors to identify putative sites of interaction.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.29.014381 doi: bioRxiv preprint Figure 6 : The PIPE-Sites Landscape between the SARS-CoV-2 Spike protein and human ACE2 protein.', 'The three red rectangles represent the predicted PIPE-Sites regions.']}\n", - "{'sentences': ['Qing Mao (Phone +86 135 9418 0020;', 'Abstract: An excessive immune response contributes to SARS-CoV, MERS-CoV and SARS-CoV-2 pathogenesis and lethality, but the mechanism remains unclear.', 'In this study, the N proteins of SARS-CoV, MERS-CoV and SARS-CoV-2 were found to bind to MASP-2, the key serine protease in the lectin pathway of complement activation, resulting in aberrant complement activation and aggravated inflammatory lung injury.', 'Either blocking the N protein:MASP-2 5 interaction or suppressing complement activation can significantly alleviate N protein-induced complement hyper-activation and lung injury in vitro and in vivo.', 'Complement hyper-activation was also observed in COVID-19 patients, and a promising suppressive effect was observed when the deteriorating patients were treated with anti-C5a monoclonal antibody.', 'Complement suppression may represent a common therapeutic approach for pneumonia induced by these 10 highly pathogenic coronaviruses.', 'Short Title: SARS-CoV N over-activates complement by MASP-2 One Sentence Summary: The lectin pathway of complement activation is a promising target for 15 the treatment of highly pathogenic coronavirus induced pneumonia.', 'All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'medRxiv preprint Previously, we demonstrated that the SARS-CoV N protein interacts with a number of host proteins, including MAP19 (21), an alternative splicing product of MASP-2.', 'Thus, in this 40 study, the interactions of the SARS-CoV, MERS-CoV and SARS-CoV-2 N proteins with MASP-2 were intensively investigated, and the pathological effects of these interactions on host immunity and inflammation were also elucidated, which provides a mechanism support for immunomodulation-based therapy against current COVID-19 epidemic.', '45 All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.']}\n", - "{'sentences': ['C3A is a sub-clone of human hepatoblastoma HepG2 cell line with the strong contact inhibition 26 of growth.', 'We fortuitously found that C3A was more susceptible to human coronavirus HCoV-27 OC43 infection than HepG2, which was attributed to the increased efficiency of virus entry into 28 C3A cells.', 'In an effort to search for the host cellular protein(s) mediating the differential 29 susceptibility of the two cell lines to HCoV-OC43 infection, we found that ADAP2, GILT and 30 LY6E, three cellular proteins with known activity of interfering virus entry, expressed at 31 significantly higher levels in HepG2 cells.', 'Functional analyses revealed that ectopic expression 32 of LY6E, but not GILT or ADAP2, in HEK 293 cells inhibited the entry of HCoV-OC43.', 'While 33 overexpression of LY6E in C3A and A549 cells efficiently inhibited the infection of HCoV-34 OC43, knockdown of LY6E expression in HepG2 significantly increased its susceptibility to 35', 'Moreover, we found that LY6E also efficiently restricted the entry 36 mediated by the envelope spike proteins of other human coronaviruses, including the currently 37 pandemic SARS-CoV-2.', 'Interestingly, overexpression of serine protease TMPRSS2 or 38 amphotericin treatment significantly neutralized the IFITM3 restriction of human coronavirus 39 entry, but did not compromise the effect of LY6E on the entry of human coronaviruses.', 'The 40 work reported herein thus demonstrates that LY6E is a critical antiviral immune effector that 41 controls CoV infection and pathogenesis via a distinct mechanism.']}\n", - "{'sentences': [\"[{'text': 'In December 2019, the first cases of a novel coronavirus infection were diagnosed in Wuhan, China.\", 'Due to international travel and human-to-human transmission, the virus spread rapidly inside and outside of China.', 'Currently, there is no effective antiviral treatment for COVID-19, therefore research efforts are focused on the rapid development of vaccines and antiviral drugs.', 'The SARS-CoV-2 M pro protease constitutes one of the most attractive antiviral drug targets.', 'To address this emerging problem, we have synthesized a combinatorial library of fluorogenic substrates with glutamine in the P1 position.', 'We used it to determine the substrate preferences of the SARS-CoV and SARS-CoV-2 proteases, using natural and a large panel of unnatural amino acids.', 'The results of our work provide a structural framework for the design of inhibitors as antiviral agents or diagnostic tests.', 'To determine the SARS-CoV M pro and SARS-CoV-2 M pro substrate preferences, we natural and over 100 unnatural amino acids, Figure 1 ).', 'We incorporated glutamine at the P1 position, because the available crystal structures of SARS-CoV M pro revealed that only glutamine (and, at a very small number of cleavage sites, histidine) residue can occupy the S1 pocket of this enzyme.', '[9, 12] The imidazole of His163, located at the very bottom of the S1 proteases, which explains less stringent specificity.', '[11] The S2 pocket can form hydrophobic interactions with P2 residues that are not only limited to leucine.', 'The S3 pocket of SARS M pro .', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'bioRxiv preprint is not very well defined which is also reflected in our P3 substrate specificity profile.', 'The S4 pocket can be occupied by small residues due to crowded cavity formed by Pro168, L167 at the bottom and T190, A191 at the top wall.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.07.981928 doi: bioRxiv preprint .', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.07.981928 doi: bioRxiv preprint To validate the results from library screening, we designed and synthesized ACClabeled substrates containing the most preferred amino acids in each position.', 'Then, we measured the rate of substrate hydrolysis relevant to each protease (Figure 3) .', 'The data clearly demonstrate that SARS-CoV M pro and SARS-CoV-2 M pro exhibit the same activity toward tested substrates.', 'The results are consistent with the HyCoSuL screening data.', 'The most preferred substrate, Ac-Abu-Tle-Leu-Gln-ACC, is composed of the best amino acids in each position.', 'Kinetic parameters were determined for the two best substrates (Ac-Abu-Tle-Leu-Gln-ACC, Ac-Thz-Tle-Leu-Gln-ACC) and one containing the best recognized natural amino acids (Ac-Val-Lys-Leu-Gln-ACC) ( Table 1 ) toward SARS-CoV-2 M pro .', 'Due to substrates precipitation due to high concentration needed in the assay, kinetic parameters toward SARS-CoV M pro could not be determined.', 'Analysis of kinetic parameters revealed that these three substrates differ in the k cat value, while K M values are comparable.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'In summary, we established substrate specificity profiles at the P4-P2 positions of the SARS-CoV M pro and SARS-CoV-2 M pro proteases using a combinatorial approach.', 'Our data clearly demonstrate that these two enzymes display very similar substrate preferences.', 'Information provided here can be used for the design of inhibitors and activity-based probes against the SARS-CoV-2.']}\n", - "{'sentences': ['Protocol of a randomized controlled trial testing inhaled Nitric Oxide in mechanically ventilated patients with severe acute respiratory syndrome in COVID-19 (SARS-CoV-2).']}\n", - "{'sentences': ['SARS-CoV-2 is a zoonotic virus that has caused a pandemic of severe respiratory disease-COVID-19within several months of its initial identification.', \"Comparable to the first SARS-CoV, this novel coronavirus's surface Spike (S) glycoprotein mediates cell entry via the human ACE-2 receptor, and, thus, is the principal target for the development of vaccines and immunotherapeutics.\", 'Molecular information on the SARS-CoV-2 S glycoprotein remains limited.', 'Here we report the crystal structure of the SARS-CoV-2 S receptor-binding-domain (RBD) at a the highest resolution to date, of 1.95 Å. We identified a set of SARS-reactive monoclonal antibodies with cross-reactivity to SARS-CoV-2 RBD and other betacoronavirus S glycoproteins.', 'One of these antibodies, CR3022, was previously shown to synergize with antibodies that target the ACE-2 binding site on the SARS-CoV RBD and reduce viral escape capacity.', 'We determined the structure of CR3022, in complex with the SARS-CoV-2 RBD, and defined a broadly reactive epitope that is highly conserved across betacoronaviruses.', 'This epitope is inaccessible in the \"closed\" prefusion S', 'High resolution structure of the SARS-CoV-2 Receptor-Binding-Domain (RBD', 'Structure of the SARS-COV-2 RBD in complex with antibody CR3022.', 'Identification of a cryptic site of vulnerability on the SARS-CoV-2 Spike.', 'Recently, the molecular structure of recombinant full-length SARS-CoV-2 Spike protein was solved in a stabilized pre-fusion state, by single particle cryo-Electron Microscopy (cryo-EM), at a resolution of 3.8 Å (Wrapp et al., 2020) .', 'Despite the comprehensive structural characterization of the spike protein as a whole, movement of the RBD between \"up\" and \"down\" conformational states prevented complete modeling of the RBD domains.', 'The SARS-CoV-2 RBD (residues 313-532), with a C-terminal His-tag, was expressed in 293F cells, and purified by NiNTA affinity, and size-exclusion chromatography.', 'Crystallization condition screening identified 20% Jeffamine D2000, 10% Jeffamine M2005, 0.2 M NaCl, 0.1M MES pH 5.5 for diffraction quality crystal growth.', 'Crystals diffracted to <1.8 Å in group P 41 21 2 and to a complete dataset to 1.95 Å that could be scaled and processed ( Table 1) .', 'The structure was refined to an Rfree of 20% and Rwork of 22% with no Ramachandran outliers.', 'S residues 313-532 were clearly interpretable from the electron density map, with a dual conformation of a loop containing residues 484 to 487 clearly visible in the electron density map (Figure 1) .', 'Structure comparison of the unliganded RBD structure presented here, with the stabilized prefusion SARS-CoV-2 Spike (S-2P) molecule structure determined by Cryo-EM (PDB ID: 6VSB) (Wrapp et al., 2020) shows high structural similarity, with an RMSD of 0.68, 0.68, and 0.71 for each of the spike protomers.', 'In the structure of the S-2P molecule (S-2P']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['This study describes 48 critically ill patients with COVID 19 and severe acute respiratory failure in Vitoria, Spain, from March 04, 2020 to March 24, 2020.', 'Patients received HFNT or intubation, but non-invasive mechanical ventilation was not applied.', 'Two weeks after ICU admission, three out of ten intubated patients have died, and half of the patient cohort required prolonged ventilatory support.', 'Two out of ten intubated patients were extubated (and discharged), most at the second week of ventilation.', 'Plasma procalcitonin (threshold 0.5µg/L) failed to predict mortality.', 'Our findings suggest that an oxygenation strategy emphasising optimisation of oxygenation, intubation based on clinical criteria of hyperventilation and avoiding ventilator-induced lung injury associated with non-invasive mechanical ventilation would be life-saving in a significant proportion of patients.', 'Table 1 compares current findings with first series of SARS-CoV2 in the ICU in China, USA, and 2009 pandemic influenza in Spain.', 'Clinical presentation is consistent with a recent systematic review [9] , lymphocytopenia and coagulation alterations being common at hospital admission, with some important differences documented when compared with pandemic influenza in 2009 (Table 1) , as reported elsewhere [2] , and also with the first ICU series reported from Wuhan [10] .', 'Obesity was the most common comorbidity in our report, suggesting differences in western countries regarding Wuhan reports (11), followed by hypertension and chronic respiratory J o u r n a l P r e -p r o o f diseases.', 'The low prevalence of immunocompromised (solid organ transplants or HIV) and pregnant patients compared with severe influenza-infected patients may be associated with the interaction of coronavirus with innate immunity.', 'Fei Zhou et al. [5] reported a risk of death above 90% in patients with high procalcitonin, which is not consistent with our findings.', 'This can be due to different laboratory techniques, co-infection rates or degree of acute lung injury (no NIV was applied in our cohort).', 'Although more information on procalcitonin is required [12] , our findings suggest that no prognostic information can be inferred.', 'This early report of characteristics of SARS-CoV-2 influenza in Spain is of interest, as most information currently available is coming from large cohorts in China, or short case series from Italy or USA (5, 6, 11, 13) .', 'An important characteristic is that in the current cohort, no patients were exposed to prior non-invasive ventilation, which was commonly performed using a facial mask in Wuhan or a helmet in Italy, with a protocol of earlier intubation based on hyperventilation unable to maintain Satv02 above 90%.', 'Patients in this cohort were intubated a median of 7 days after onset, which is later than in pandemic influenza but earlier than in 15 to 19) days.', 'Although 28-day mortality was not available due to the early report, 7day mortality was estimated to be lower than 15% in our cohort and 10 patients were extubated within the second week, which means that the prognosis is better with different strategies of oxygenation.', 'In contrast with reports from China or Seattle suggesting a severe ARDS, a strategy of early intubation disclosed that SARS-CoV-2 does not lead to a typical ARDS.', 'In our experience, two thirds of our patients have initial lung compliance > 40 ml/cm H20 postintubation being consistent with a preliminary report with 16 patients by Gattinoni et al. (6) , suggesting that ARDS is a consequence of acute lung injury associated with delayed intubation or super-infection.', 'Thus, non-invasive ventilation seems not recommended and early high PEEP (above 10 cm H20 is probably not the right ventilatory strategy) may be harmful.', 'Our experience suggests avoiding spontaneous ventilation early in the ED or ward may be harmful.', 'Thus, SARS-CoV-2 patients can be maintained with high-flow oxygen nasal therapy (HFNT', 'Lastly, although we did not document pulmonary embolisms in our cohort (autopsies were not allowed), laboratory tests are consistent with endothelial injury and micro-thrombosis.', 'Zhou et al. (5) reported serum ferritin with a median above 1400 ng/L among 54 non-survivors in a context of hyperinflammatory states.', 'These patients should receive sCD25 measurements and a bone marrow aspirate to rule out systemic haemophagocytic lymphocytosis, which should be treated with 500 mg/kg gamma globulins/day and dexamethasone 10 mg/12 h for 4 days.', 'The same authors also reported D-dimer above 1 ug/ml among 81% of non-survivors and our J o u r n a l P r e -p r o o f findings are consistent with these observations.', 'Although no difference on overall 28-day mortality was found between heparin users and non-users (30.3% vs. 29.7%, p = 0.91) in a report among 449 patients with severe SARS-CoV-2 infection in China (14) , the 28-day mortality was significantly reduced in those receiving low molecular weight heparin with a D-dimer > 6 fold the upper limit of normal (32% vs. 52%, p = 0.01) or a SIC score (15) > 4 (40% vs. 64%, p = 0.02).', 'Our study has several limitations.', 'More than half of the cohort remained in the ICU at the time of censoring on April 6 th , 2020 and further outcomes assessment have to be performed.', 'Our sample size is small, because we focused on critically ill, and data cannot be extrapolated to patients hospitalised in medical wards.', 'However, it is an early report illustrative of the epidemiology in South Europe, which can be compared with Wuhan and initial reports of pandemic influenza A H1N1pdm 2009 in Spain (table 1).', 'We already expanded the ICU capacity above two-fold in March 18 th and data cannot be generalisable to patients with another acceleration phase or with different available resources, but may serve to develop contingency plans in other geographical regions.', 'Procalcitonin technique of determination may influence values and data may not be comparable when using other methods, such as KRIPTOR® to determine plasma values.', 'Similarly, the strategy of early intubation, without prior non-invasive ventilation trial would means that data cannot be extrapolated to sites with other management strategies.', 'Lastly, pulmonary compliance and driving pressure was not recorded in the study protocol, limiting identification of phenotypes and extrapolation to other sites.']}\n", - "{'sentences': ['Objective To study the effect of low-to-moderate dose glucocorticoid therapy on viral clearance time in patients with COVID-19.', 'Methods A total of 72 patients diagnosed with COVID-19 from January 19 to February 17, 2020 at the First Affiliated Hospital, School of Medicine, Zhejiang University were recruited.', 'All patients received oral abidol and/or combined lopinavir/ritonavir, darunavir antiviral, and symptomatic supportive care.', 'Among them, 51 patients received methylprednisolone (0.75-1.50 mg·kg -1 ·d -1 ) (glucocorticoid treatment group), and 21 patients who did not use glucocorticoid were the control group.', 'The time of stable virologic conversion insputumand the time of radiologic recovery in lungsince onset were compared between the two groups and among the normal patients.', 'The Kruskal-Wallis test or Fisher exact test was used to compare the difference between groups.', 'Results The median ages of the glucocorticoid group and the control group were 52 [interquartile range (IQR):45, 62] years and 46 (IQR: 32, 56)years, and the differences were significant ( P <0.05).', 'The clinical conditions at hospital admission were different between the two groups ( P <0.01).', 'There were 52.0% critical ill patients in the glucocorticoid treatment group, compared to that of 71.4% normal patients in the control group.', 'The median times from the onset tostable virologic conversion to negative in the two groups were 15 (IQR:13,20) days and 14 (IQR:12,20) days ( P >0.05), and the difference was no statistically significant.', 'The median times from onset to radiologic recovery were 13 (IQR: 11,15) days and 13 (IQR:12,17) days in the two groups, and there was no difference ( P >0.05).', 'In ordinary patients, the median timesfrom the onset tostable virologic conversion insputum were no difference ( P >0.05), with 13 (IQR:11,18) days in the glucocorticoid group and 13 (IQR:12,15) days in the control group; The median times from onset to radiologic recovery in lungwere also no difference ( P >0.05), with 12 (IQR: 10,15)days in the glucocorticoid group and 13 (IQR: 12,17) days inthe control group.', 'Conclusions Low-to-moderate glucocorticoid treatment has no effect on the time of virus clearance in patients with different clinical types of COVID-19.', 'The glucocorticoid is not recommended since no effectiveness on accelerating the improvement of radiologic recovery in lung has been observed.']}\n", - "{'sentences': ['Use of Hydroxychloroquine and Chloroquine During the COVID-19 Pandemic:', 'What Every Clinician Should Know', 'Two medications often used for treatment of immune-mediated conditions, hydroxychloroquine and chloroquine, have recently attracted widespread interest as potential therapies for coronavirus disease 2019.', 'The authors of this commentary provide guidance for clinical decision making for patients with coronavirus disease 2019 as well as for patients with rheumatologic conditions, such as systemic lupus erythematosus and rheumatoid arthritis']}\n", - "{'sentences': [\"In this study, we comprehensively described the clinical characteristics of all the patients with either confirmed or suspected COVID-19 who were hospitalized in a COVID-19 designated hospital during a period from January 21 to February 5, 2020, and then developed a simple prognostic tool called ACP index, only composed of patient's age and CRP tested at admission, that could accurately predict the COVID-19-related mortality risk within 12 days after admission.\", 'To our knowledge, this is the first-ever study to compare the clinical characteristics of pneumonia patients who were either positive or negative for SARS-CoV-2 by RT-PCR assay, and to develop a first-ever COVID-19 mortality risk index derived from patients in highly endemic areas during early stage of outbreak.', 'In this large-sample size cohort, the percentage of pneumonia patients with positive results for SARS-CoV-2 result was around 40%, which was consistent with the report of Wuhan government.', 'We found that almost all the characteristics including clinical presentations, laboratory testing results, as .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'With the increasing number of confirmed cases and deaths from SARS-CoV-2 infection, the city of Wuhan is facing a big challenge with the overwhelmed medical capacity to provide essential medical .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', \"The ACP index was consisted of two components -patient's age and CRP tested at admission.\", 'Presumably, age should be more likely to correlate with underlying medical conditions and comorbidities.', 'In our cohort, an age of more than 60 years old indicates higher mortality in COVID-19 patients, which is consistent with previous studies on severe acute respiratory syndrome and Middle', 'East respiratory syndrome (MERS) related pneumonia.', '11, 12 Moreover, CRP, an indicator of inflammatory response, has been described as a predictor of disease progression in MERS, 13 influenza-infected 14 and community acquire pneumonia patients.', '15 In the current study, a CRP levels higher than 34 mg/L in the early course of COVID-19 is associated with increased mortality from SARS-CoV-2 infection, which may reflect an intense inflammatory response or/and an underlying secondary infection.', 'Management decision for high risk patients with COVID-19 must be made quickly, which often based upon scanty evidence.', 'Under this pressing circumstance, the quality of evidence becomes especially crucial.', 'The ACP index, with a high level of differentiating power, can be regarded as such quality evidence in providing an efficient, feasible and accessible approach to establish a hierarchical management system of COVID-19 in the SARS-CoV-2 highly endemic areas where medical resources are extremely limited.', 'To be specific, it is suggested, by applying the ACP index, that patients classified in the grade one (low-risk) group, accounting for about 44.7% of the studied population, should be .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', '1 4 isolated and treated in \"Mobile Cabin Hospitals\", an isolation place converted from sports stadium, convention centers, etc.', 'with easily installed structures by the government.', 'For patients in the grade two (medium-risk) group, which has the 12-day mortality of approximately 6%, they should be treated in the general wards, whereas the patients in the grade three group should be transferred to intensive care unit for more comprehensive treatment due to as high as 33% mortality within 12 days from admission ( Figure 3 ).', 'It is projected that this approach would benefit a considerable number of patients with COVID-19 by directing the medical resources appropriate for the severity of the disease, and thus reduce the mortality and save the socioeconomic resources.', 'We also comprehensively describe the characteristics of severe (vs. mild) and death patients in our cohort.', 'We noticed that severe patients had high frequencies of decreased lymphocytes, higher D-dimer, and lower albumin, suggesting that severe patients may had higher probability of immune deficiency, coagulation activation, and disease exhaustion condition.', 'In addition, we also noticed abnormal ALT and creatinine levels in most patients who died, but most of the abnormalities were mild, suggesting that COVID-19 patients may die primarily from respiratory failure caused by SARS-CoV-2 infection, rather than multiple organ failure.', 'The high mortality rates in our study may be due to differences in the population composition.', 'Patients in three first designated hospitals are reasonable to have much progressed disease and higher mortality than the national-wide population, as reported by Huang et al and Chen et al. 1, 8 Notably, Hankou', 'Hospital is the nearest medical center from the Huanan wholesale seafood market, which is reported as the first place of cluster onset.', 'Most patients in Hankou Hospital are residents nearby and are believed to be the earliest infected population who may have close contact with live animals or the first generation of confirmed cases.', 'In addition, Wuhan, as the endemic area, includes a considerable .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Severe acute respiratory syndrome coronavirus 2 (Severe acute respiratory syndrome coronavirus 2) is the causative agent of the Coronavirus disease 2019 (COVID-19) which is currently negatively affecting the population and disrupting the global economy.', 'Severe acute respiratory syndrome coronavirus 2 belongs to the +RNA virus family that utilize single-stranded positive-sense RNA molecules as genomes.', 'Severe acute respiratory syndrome coronavirus 2, like other coronaviruses, has an unusually large genome for a +RNA virus that encodes four structural proteinsthe matrix (M), small envelope (E), spike (S) and nucleocapsid phosphoprotein (N) -and sixteen nonstructural proteins (nsp1-16) that together ensure replication of the virus in the host cell.', 'The nucleocapsid phosphoprotein N is essential for linking the viral genome to the viral membrane.', 'Its N-terminal RNA binding domain (N-NTD) captures the RNA genome while the Cterminal domain anchors the ribonucleoprotein complex to the viral membrane via its interaction with the M', 'Here, we characterized the structure of the N-NTD and its interaction with RNA using NMR spectroscopy.', 'We observed a positively charged canyon on the surface of the N-NTD lined with arginine residues suggesting a putative RNA binding site.', 'Next, we performed an NMR titration experiment using an RNA duplex.', 'The observed changes in positions of signals in the N-NTD NMR spectra allowed us to construct a model of the N-NTD in complex with RNA.', 'Effective drugs are urgently needed to combat the COVID-19 disease.', 'Most patients are not given any drug and the treatment relies on curing the symptoms.', 'The most promising drug is remdesivir, a nucleotide analog that targets the viral RNA-dependent RNA-polymerase (RdRp']}\n", - "{'sentences': ['The outbreak of COVID-19, which is caused by SARS-CoV-2 virus, continues to spread 23 globally, but there is currently very little understanding of the epitopes on the virus.', 'In 24 this study, we have determined the crystal structure of the receptor-binding domain 25 (RBD) of the SARS-CoV-2 spike (S) protein in complex with CR3022, a neutralizing 26 antibody previously isolated from a convalescent SARS patient.', 'CR3022 targets a highly 27 conserved epitope that enables cross-reactive binding between SARS-CoV-2 and 28 SARS-CoV. Structural modeling further demonstrates that the binding site can only be 29 accessed when at least two RBDs on the trimeric S', 'Overall, this study provides structural and molecular insight into the antigenicity of 31 SARS-CoV-2.', 'ONE SENTENCE SUMMARY', 'Structural study of a cross-reactive SARS antibody reveals a conserved epitope on the 35 SARS-CoV-2 receptor-binding domain.']}\n", - "{'sentences': ['Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study', 'Raoult D, Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study, Travel Medicine and Infectious Disease (2020), doi: https://doi.', 'We need an effective treatment to cure COVID-19 patients and to decrease virus carriage duration.', 'We conducted an uncontrolled non-comparative observational study in a cohort of 80 relatively mildly infected inpatients treated with a combination of hydroxychloroquine and azithromycin over a period of at least three days, with three main measurements: clinical outcome, contagiousness as assessed by PCR and culture, and length of stay in infectious disease unit (IDU', 'All patients improved clinically except one 86 year-old patient who died, and one 74 year-old patient still in intensive care.', 'A rapid fall of nasopharyngeal viral load was noted, with 83% negative at Day7, and 93% at Day8.', 'Virus cultures from patient respiratory samples were negative in 97.5% of patients at Day5.', 'Consequently patients were able to be rapidly discharged from IDU with a mean length of stay of five days.', 'We believe there is urgency to evaluate the effectiveness of this potentially-life saving therapeutic strategy at a larger scale, both to treat and cure patients at an early stage before irreversible severe respiratory complications take hold and to decrease duration of carriage and avoid the spread of the disease.', 'Furthermore, the cost of treatment is negligible.', 'COVID-19 poses two major challenges to physicians.', 'The first is the therapeutic management of patients.', 'In this context, it is necessary to avoid a worsening evolution, which usually occurs around the tenth day and may result in acute respiratory distress syndrome, the prognosis of which, in particular in the elderly, is poor, whatever the cause.', 'Therefore, the primary therapeutic objective is to treat people who have moderate or severe infections at an early enough stage to avoid progression to a serious and irreversible condition.', 'By administering hydroxychloroquine combined with azithromycin, we were able to observe an improvement in all cases, except in one patient who arrived with an advanced form, who was over the age of 86, and in whom the evolution was irreversible.', 'For all other patients in this cohort of 80 people, the combination of hydroxychloroquine and azithromycin resulted in a clinical improvement that appeared superior when compared to outcomes of other hospitalized patients, as described in the literature.', 'In a cohort of 191', 'Chinese inpatients, of whom 95% received antibiotics and 21% received a combination of lopinavir and ritonavir, the median duration of fever was 12 days and that of cough 19 days in survivors, with a 28% case-fatality rate [19] .', 'The favourable evolution of our patients under hydroxychloroquine and azithromycin paralleled a relatively rapid decrease in viral RNA load as assessed by PCR, which was even more rapid when assessed by culture.', 'These data are important to compare with that of the literature which shows that the viral RNA load can remain high for about three weeks in most patients in the absence of specific treatment [19, 23] with extreme cases lasting for more than a month.', 'A study conducted in 76 Chinese COVID-19 in patients showed that high viral RNA load is associated with the severity of the disease [24] .', 'Furthermore, in a study conducted on a small group of 16 Chinese COVID-19', 'inpatients, viral RNA was positively detected in 50% of them, after resolution of symptoms for a median duration of 2.5 days and a maximum of eight days [25] .', 'Therefore, the rapid 14 14 decrease in viral RNA load is one element suggesting the effectiveness of this treatment.', 'Furthermore, to our knowledge, the measurement of viral culture during treatment was also evaluated for the first time.', 'The fall in culture positivity from the second day is remarkable, although, in a relatively small number of cases, some people maintain a positive culture.', 'The second challenge is the rapid spread of the disease in the population through contagious individuals.', 'The elimination of viral carriage in the human reservoir of the virus has recently been recognised as a priority [26] .', \"To this end, the rapid decease in positivity in cultures from patients' respiratory samples under treatment with hydroxychloroquine plus azithromycin supports an effectiveness of this combination.\", 'Thus, in addition to its direct therapeutic role, this combination can play a role in controlling the disease epidemic by limiting the duration of virus shedding, which can last for several weeks in the absence of specific treatment.', 'In our Institute, which contains 75 individual rooms for treating highly contagious patients, we currently have a turnover rate of 1/3 per day which allows us to receive a large number of these contagious patients with early discharge.', 'Chloroquine and hydroxychloroquine are extremely well-known drugs which have already been prescribed to billions of people.', 'Because of anecdotical reports of heart complications with such drugs in patients with underlying conditions, it would be useful to perform an ECG before or at the very beginning of the treatment [27] .', 'This problem is solved by hospitalising patients at risk in continuing care units with ECG monitoring allowing for the early detection and treatment of possible cardiac side-effects.', 'Azithromycin is the drug that has been the most widely prescribed against respiratory infections and a recent (2010) study showed that one in eight American patients, has been prescribed azithromycin [28] .', 'Indeed, there have probably been more than a billion azithromycin prescriptions around the world since it was first discovered.', 'The toxicity of each of these two drugs does not, therefore, pose a major problem.', 'Their possible toxicity in combination has been suggested in a few anecdotal reports but, to our knowledge, has never been demonstrated.', 'Our work has some limitations.', 'This is a descriptive pilot study conducted in only 80 patients with relatively mild clinical presentation and we did not attempt an analytic approach to account for possible confounds including notably the severity of illness.', 'Such an approach is currently planned in a larger set of patients under treatment in our institute.', 'In conclusion, we have provided evidence of a beneficial effect of co-administration of hydroxychloroquine with azithromycin in the treatment of COVID-19 and its potential effectiveness in the early reduction of contagiousness.', 'Given the urgent therapeutic need to manage this disease with effective and safe drugs, and the negligible cost of both hydroxychloroquine and azithromycin, we believe that there is an urgent need to evaluate this strategy further, both to treat and cure patients at an early stage before irreversible severe respiratory complications take hold, and to decrease duration of carriage and avoid the spread of the disease.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Patients of COVID-19 may benefit from sustained lopinavir-combined regimen and the increase of eosinophil may predict the outcome of COVID-19 progression', 'Abstract Objectives To explore the epidemiological information, clinical characteristics, therapeutic outcomes and temporal progression of laboratory findings in 2019-coronavirus disease (COVID-19) patients exposed to lopinavir.', 'Methods We collected data from ten COVID-19 patients admitted between January 22, 2020 and February 11, 2020 at Xixi hospital in Hangzhou, China.', 'Results Of ten patients, secondary, tertiary and quartus patients emerged, the incubation period was 3–7 days.', 'Mainly initial symptoms were cough and low fever (37.3–38.0 ℃).', 'An asymptomatic case presented normal radiography, the others existed ground glass opacities.', 'All cases (three transferred, seven discharged) exposed to lopinavir on initial hospitalization.', 'Three patients stopped lopinavir using because of adverse effect, two of them deteriorated, one hospitalized longer than others who with sustained lopinavir using.', 'Levels of potassium, albumin, lymphocyte were low, but increased persistently after treatment.', 'Eosinophil values were low on initial hospitalization, then all returned to normal before discharge.', 'Viral load of SARS-CoV-2, radiography and eosinophil improved continuously in 3–14, 6–8 and 7–9 days, respectively.', 'Conclusions Increasing eosinophils may be an indicator of COVID-19 improvement.', 'The COVID-19 patients may benefit from sustained lopinavir using.', 'More researches on a larger scale are needed to verify these points.']}\n", - "{'sentences': ['The aim of the study was to analyze the incidence of COVID-19 with early renal injury, and to explore the value of multi-index combined detection in diagnosis of early renal injury in COVID-19.', 'The study was an observational, descriptive study.', 'This study was carried out in a tertiary hospital in Guangdong, China.', 'patients diagnosed with COVID-', 'The primary outcome was to evaluate the incidence of early renal injury in COVID-19.', 'In this study, the estimated glomerular filtration rate (eGFR), endogenous creatinine clearance (Ccr) and urine microalbumin / urinary creatinine ratio (UACR) were calculated to assess the incidence of early renal injury.', 'Secondary outcomes were the diagnostic value of urine microalbumin (UMA), α 1-microglobulin (A1M), urine immunoglobulin-G (IGU', 'While all patients had no significant abnormalities in serum creatinine (Scr) and blood urea nitrogen (BUN), the abnormal rates of eGFR, Ccr, and UACR were 66.7%, 41.7%, and 41.7%, respectively.', 'Urinary microprotein detection indicated that the area under curve (AUC) of multi-index combined to diagnose early renal injury in COVID-19 was 0.875, which was higher than UMA (0,813), A1M (0.813), IGU (0.750) and TRU (0.750) alone.', 'Spearman analysis showed that the degree of early renal injury was significantly related to C-reactive protein (CRP) and neutrophil ratio (NER', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'Coronaviruses are single-stranded positive-strand RNA viruses.', 'In 2014, the Peng Zhou et al [11] reported the identification and characterization of 2019-nCoV. Through full-length genome sequences analysis, they found that the whole genome of 2019-nCoV shared 79.5% sequence identify to SARS-CoV. The pairwise protein sequence analysis of seven conserved non-structural proteins showed that this virus belongs to the species of severe acute respirator syndrome-related All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.07.20032599 doi: medRxiv preprint coronaviruses (SARSr-CoV).', 'In addition, they also confirmed that 2019-nCov used the same cell entry receptor, Angiotensin converting enzyme II (ACE2), as SARS-CoV. The high degree of similarity in gene sequence and cellular mechanism of 2019-nCoV and SARS-CoV suggests that the risk factors of mortality could also be similar.', 'SARS is an acute respiratory infectious disease with pulmonary parenchyma and/or interstitium as the main site of invasion and multiple organ injury.', 'Previous clinical studies have found that, similar to SARS, the causes of death caused by 2019-nCov are not only lung tissue damage, but also heart, liver, kidney and other organ dysfunction or even failure, which is one of the important causes of aggravation and death.', '[8, 9] In the previous SARS case study [12] , acute renal injury was found to be the top risk factor of mortality, even higher than acute respiratory distress.', 'In that case study, all patients who eventually died had a progressive rise of Scr, and the rise of Scr was rapid in those who succumbed early in their illness.', 'Previously, an ongoing case study reported 59 patients infected by 2019-nCoV, including 28 severe cases and 3 death.', 'In that study, 63% of the patients exhibited proteinuria, and 19% and 27% of the patients had an elevated level of Scr and BUN respectively.', 'Computed tomography (CT) scans revealed abnormal renal imaging in all patients.', 'The results suggested that renal injury was common in COVID-19, which may contribute to multiorgan failure and death eventually.', '[13] In this study, 12 COVID-19 cases were analyzed.', 'Although all the patients still had normal level of Scr and BUN, the high incidence of early renal injury in COVID-19 was found by calculating eGFR, CCR and UACR.', 'The abnormal rates of eGFR, Ccr, and UACR were 66.7%, 41.7%, and 41.7%, respectively.', 'Combined detection of UMA, A1M, IGU, and TRU could be helpful for the diagnosis of early renal injury in COVID-19.', 'Furthermore, the study also found that the degree of early renal injury was significantly related to C-reactive protein (CRP) and neutrophil ratio (NER', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.07.20032599 doi: medRxiv preprint the single-cell RNA sequencing datasets to explore the expression of ACE2 in the main physiological systems of the human body, including the respiratory, cardiovascular, digestive and urinary system.', 'The study showed that heart, esophagus, kidney, bladder, and ileum have similar or higher ACE2 expression than in alveoli.', 'In the analysis of specific cell types, the expression of ACE2 in renal proximal tubule cells was about four times higher than that of type II alveolar cells (AT2).', 'The results suggest that the kidney may be one of the primary targets of attack for the 2019-nCov.', 'α 1-microglobulin can pass through the glomerular filtration membrane, and 95% to 99% is reabsorbed in the proximal tubule, and it is not affected by pH. In the early stage of renal injury, the renal tubule reabsorption function reduced, resulting in urine α 1-microglobulin excretion increased, and the elevation is consistent with the degree of renal tubular injury.', '[16] Due to the large molecular weight, immunoglobulin G is All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.07.20032599 doi: medRxiv preprint difficult to pass through the glomerular filtration membrane.', 'When renal function is impaired, it can lead to increased permeability of the glomerular filtration membrane.', 'The excretion of albumin in urine increases, and as the lesions worsen, the excretion of immunoglobulin G in urine also increases.', 'Therefore, the detection of urine immunoglobulin G can help to judge the degree of damage on the glomerular filtration membrane.', '[17] The main physiological function of transferrin is to transport iron ions.', 'It is a negatively charged protein, and its isoelectric point is one unit higher than that of albumin.', 'Normally, it cannot pass through the positively charged glomerular filtration membrane.', 'Urine transferrin is one of the indicators of early glomerular injury, which mainly reflects the damage of glomerular filtration membrane charge selection barrier.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL (pro structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates', 'We prepared the three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like protease (3CL (pro using the crystal structure of the highly similar (96% identity) ortholog from the SARS-CoV. All residues involved in the catalysis, substrate binding and dimerisation are 100% conserved.', 'Comparison of the polyprotein PP1AB sequences showed 86% identity.', 'The 3C-like cleavage sites on the coronaviral polyproteins are highly conserved.', 'Based on the near-identical substrate specificities and high sequence identities, we are of the opinion that some of the previous progress of specific inhibitors development for the SARS-CoV enzyme can be conferred on its SARS-CoV-2 counterpart.', 'With the 3CL (pro) molecular model, we performed virtual screening for purchasable drugs and proposed 16 candidates for consideration.', 'Among these, the antivirals ledipasvir or velpatasvir are particularly attractive as therapeutics to combat the new coronavirus with minimal side effects, commonly fatigue and headache.', 'The drugs Epclusa (velpatasvir/sofosbuvir) and Harvoni (ledipasvir/sofosbuvir) could be very effective owing to their dual inhibitory actions on two viral enzymes.', 'We identified five trials on\\nClinicalTrials.gov involving antiviral and immunomodulatory drug treatments for SARS (\\nTable 5), all without reported results; i.e., at present, there are no safe and effective drug candidates against SARS-CoV. This is because once the epidemic is over, there are no patients to recruit for clinical trials.', 'Only the study with streptokinase succeeded in completion of phase 3.', 'It is disappointing that little progress in SARS drug development has been made in the past 17 years.', 'After the 2003 outbreak, numerous inhibitors for the 3CL\\npro enzyme have been proposed\\n16,\\n17, yet no new drug candidates have succeeded to enter the clinical phase 1.', 'One record which receives a lot of attention amid the current outbreak is the lopinavir/ritonavir combination\\n18.', 'They are protease inhibitors originally developed against HIV.', 'During the 2003 SARS outbreak, despite lacking a clinical trial, they were tried as an emergency measure and found to offer improved clinical outcome\\n18.', 'However, some scientists did express scepticism\\n19.', 'By analogy, these compounds were speculated to act on SARS-CoV 3CL\\npro specifically, but there is as yet no crystal structure to support that, although docking studies were carried out to propose various binding modes\\n20–\\n23.', 'The IC\\n50 value of lopinavir is 50 μM (\\nK\\ni = 14 μM) and that for ritonavir cannot be established\\n24.', 'Although this is far from a cure, based on our results that the two CoV 3CL\\npro enzymes are identical as far as protein sequences and substrate specificities are concerned, we are of the opinion that this is still one of the recommended routes for immediate treatment at the time of writing (early February 2020).', 'If we look beyond the 3CL\\npro, an earlier screen produced 27 candidates that could be repurposed against both SARS-CoV and MERS-CoV\\n25.', 'In addition, the other coronaviral proteins could be targeted for screening.', 'Treatment of the COVID-19 with remdesivir (a repurposed drug in development targeting the RdRp) showing improved clinical outcome has just been reported and clinical trial is now underway\\n26.', 'We consider this work part of the global efforts responding in a timely fashion to fight this deadly communicable disease.', 'We are aware that there are similar modelling, screening and repurposing exercises targeting 3CL\\npro reported or announced\\n20,\\n27–\\n33.', 'Our methods did not overlap, and we share no common results with these studies.']}\n", - "{'sentences': ['Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection']}\n", - "{'sentences': [\"'Background: As the novel coronavirus triggering COVID-19 has broken out in Wuhan, China and spread rapidly worldwide, it threatens the lives of thousands of people and poses a global threat on the economies of the entire world.\", 'However, infection with COVID-19 is currently rare in children.', 'Objective: To discuss the latest findings and research focus on the basis of characteristics of children confirmed with COVID-19, and provide an insight into the future treatment and research direction.', 'Methods: We searched the terms \"COVID-19 OR coronavirus OR SARS-CoV-2\" AND \"Pediatric OR children\" on PubMed, Embase, Cochrane library, NIH, CDC, and CNKI.', 'The authors also reviewed the guidelines published on Chinese CDC and Chinese NHC.', 'Results: We included 25 published literature references related to the epidemiology, clinical manifestation, accessary examination, treatment, and prognosis of pediatric patients with COVID-19.', 'Conclusion: The numbers of children with COVID-19 pneumonia infection are small, and most of them come from family aggregation.', 'Symptoms are mainly mild or even asymptomatic, which allow children to be a risk factor for transmission.', 'Thus, strict epidemiological history screening is needed for early diagnosis and segregation.', 'This holds especially for infants, who are more susceptible to infection than other age groups in pediatric age, but have most likely subtle and unspecific symptoms.', 'They need to be paid more attention to.', 'CT examination is a necessity for screening the suspected cases, because most of the pediatric patients are mild cases, and plain chest X-ray do not All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', ': medRxiv preprint usually show the lesions or the detailed features.', 'Therefore, early chest CT examination combined with pathogenic detection is a recommended clinical diagnosis scheme in children.', 'The risk factors which may suggest severe or critical progress for children are: Fast respiratory rate and/or; lethargy and drowsiness mental state and/or; lactate progressively increasing and/or; imaging showed bilateral or multi lobed infiltration, pleural effusion or rapidly expending of lesions in a short period of time and/or; less than 3 months old or those who underly diseases.', 'For those critical pediatric patients with positive SARS-CoV-2 diagnosis, polypnea may be the most common symptom.', 'For treatment, the elevated PCT seen in children in contrast to adults suggests that the underlying coinfection/secondary infection may be more common in pediatric patients and appropriate antibacterial treatment should be considered.', 'Once cytokine storm is found in these patients, anti-autoimmune or blood-purifying therapy should be given in time.', \"Furthermore, effective isolation measures and appropriate psychological comfort need to be provided timely.', 'cite_spans': [], 'ref_spans': [], 'section': 'Abstract'}]\", 'To our best knowledge on COVID-19, among the patients confirmed with COVID-19, the population of pediatric patients is rather small [4] .', 'The children confirmed with COVID-19 mostly have good prognosis.', 'A single child patient passed away; for other child patients, progression of the disease was observed as mild [9, 10] .', 'Yet, in more general, infectious diseases often tend to behave less aggressively in child patients.', 'For severe respiratory distress syndrome (SARS', 'Nevertheless, the children, especially infants, who are confirmed with COVID-19 could be an insidious infectious source because of their asymptomatic or mild symptomatic infection due to a weak immune system or their own physical characteristics.', 'A largely asymptomatic infant with COVID-19 with high viral load was reported in Singapore, and this case highlights the difficulties in establishing the true incidence of COVID-19, as asymptomatic individuals may play important roles in human-to-human transmission in the community [13] .', 'A study focused on 24 asymptomatic infections identified that the infection period of asymptomatic patients may be as long as three weeks, and the infected patients may develop into serious diseases [14] .', 'Furthermore, the bad habits of young children such as sucking hands, putting their hands all around and unwilling to wash hands could be important risk factors in contact transmission for children.', 'Thus, it is necessary to guarantee family daily prevention to keep children from COVID-19 infection and assure awareness of the importance of its early diagnosis.', \"Also, during the epidemic period, children's health clinics and vaccination clinics should be reduced reasonably, and parent-child activities, kindergartens, primary schools, and other group activities related to children should be suspended.\", 'In clinical case, screening was mostly based on the epidemiological track record.', 'Additional basis were raised body temperature and symptoms of the respiratory tract.', 'For children, it is more important to trace close contact history, and pathogen examination needs to be timely executed along with longitudinal monitoring through viral nucleic acid detection.', 'Further isolation recommendations and ongoing nucleic acid testing are also recommended for discharged patients [14] .', \"Additionally, it appears crucial to follow up with infants'respiratory as well as gastrointestinal symptoms and vital indications steadily, which is the most susceptible population in children, at mild onset that could progress into severe at a later stage [11] .\", 'Moreover, for screening the suspected cases, since \"most of the pediatric patients are mild cases, plain chest X-ray often fails to show the lesions or the detailed features, leading to misdiagnosis or missed diagnosis\" [4, 8, 16] .', 'As a consequence, chest CT early on is seen mandatory.', 'Also, a number of suspected pediatric patients with a negative nucleic acid of SARS-CoV-2 virus were rightfuly considered potential infection cases in accordance with usual chest CT visible lesions.', 'This further encourages early diagnosis and treatment, but also isolating of infected children in effective ways [8] .', 'In a recent report, the authors studied the CT features of 20 children, and came to the conclusion that consolidation with surrounding halo signs are frequent in children with COVID-19.', 'Interestingly, these are dissimilar from those of grown-ups.', 'One may assume such consolidation with surrounding halo signs as a distinctive feature of young individuals affected [8] .', 'Another study reported the CT results of 3 children with positive COVID-19 diagnosis which showed patchy ground-glass opacities that were similar, but more modest compared to reports in adults [18] .However, the samples of both studies are indeed small, in the future, large-scale studies focusing on the imaging features of children with COVID-19 are needed.', 'Furthermore, the data from the first group also showed that the PCT has significantly increased in 80% of the cases in this study with or without coinfection evidence existing, which is not common in adult patients [8] .', 'This suggests that the underlying coinfection or secondary infection may be more common in pediatric patients.', 'If a secondary infection/coinfection is suspected, a collection of the specimen should be executed to detect potential secondary bacterial and/or fungal infections, and routine antibacterial treatment also should be considered in this situation [2, 8] .', 'In 2017, a large-scale retrospective research focusing on epidemiology as well as on clinical attributes of HCoVs (HKU1, 229E, OC43, and NL63) in the pediatric population (261 cases) showed the risks linked to aggravation of infection.', 'The risk factors were: younger than two years of age and in addition cardiovascular, genetic or congenital and respiratory chronic complex conditions which in the context of requiring respiratory support.', 'Genetic or congenital underlying disorders were associated with PICU admission [17] .', 'For those critical pediatric patients with positive COVID-19 diagnosis, the most frequently observed symptoms were polypnea, then fever, and finally coughing [19] .', 'Some severe or critical children were found to have an excessive active immune response, which may result in long-term lung injury as well as fatal health problems.', 'Coronaviruses including SARS-CoV-2, SARS, and MERS were proved to have the potential ability to lead to significant and peculiar destructive host immune response that is related to severe lung damage.', 'Researches exhibited the lung impairment is mostly observed in patients in a critical state, linked to a cytokine storm, marked by raised levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-12, TNF, IFN-γ), as well as of anti-inflammatory cytokines (IL-4, IL-10, IL-13, TGF-β) [12, [19] [20] [21] [22] [23] [24] [25] .', 'These findings suggest that it is necessary to detect the indicator of the inflammatory and immune status, which could help doctors to assess the clinical progress, be on alert for severe and critical cases, and provide anti-autoimmune or blood-purifying therapy in time, once cytokine storm occurs [2, 19] .', 'Early identification and diagnosis of the severe/critical pediatric patients are always the priority to result in appropriate treatment and good prognosis.', 'In the latest version of \"Scheme for Diagnosis and Treatment of the 2019 Novel Coronavirus Pneumonia\", pediatric patients with \" fast respiratory rate and/or; lethargy and drowsiness mental state and/or; lactate progressively increasing and/or; imaging showed bilateral or multi lobed infiltration, pleural effusion or rapidly expending of lesions in a short period of time and/or; less than 3 months old or those which underly diseases (congenital heart disease, bronchopulmonary dysplasia, respiratory tract deformity, abnormal hemoglobin, severe malnutrition, etc and/or, immune deficiency/hypofunction (long-term use of immunosuppressant drugs)\", are in high risk progressing into severe to critical illness, and intravenous immunoglobulin may be considered in those children [2] .', 'For those children isolated alone from their parents, maternal separation may cause anxiety and depression to infants or children.', 'For this reason, their psychological caretaking for their wellbeing needs to be assured.', 'All of the treatment plan and segregation situation have to be discussed with the responsible care-takers of the young individuals.', 'Psychologists or suited related experts are required to help cease their anxiety and panic.', 'In conclusion, the numbers of children with COVID-19 pneumonia infection are small, and most of them come from family aggregation.', 'Symptoms are mainly mild or even asymptomatic which allow children to be a risk factor for transmission.', 'Thus, strict epidemiological history screening is needed for early diagnosis and segregation.', 'This holds especially for infants, who are more susceptible to infection than other age groups in pediatric age, but have most likely subtle and unspecific symptoms.', 'They need to be paid more attention to.', 'CT examination is a necessity for screening the suspected cases, because the majority of the young COVID-19 infected are classified as mild infection, and plain chest X-ray mostly gives not sufficient insight into the lesions or lung details.', 'Therefore, early chest CT examination combined with pathogenic recognition is a recommended clinical diagnosis scheme in children.', 'The risk factors which may suggest severe or critical progress for children are: Fast respiratory rate and/or; lethargy and drowsiness mental state and/or; lactate progressively increasing and/or; imaging showed bi-or multi-lobed infiltration, pleural effusion, or rapidly expending of lesions in a short period of time and/or; less than 3 months old or those who underly diseases.', 'For those critical pediatric patients with positive SARS-CoV-2 diagnosis, polypnea may be the most common symptom.', 'For treatment, the elevated PCT seen in children in contrast to adults suggests that the underlying coinfection/secondary infection may be more common in pediatric patients and appropriate antibacterial treatment should be considered.', 'Once cytokine storm is found in these patients, anti-autoimmune or bloodpurifying therapy should be given in time.', 'Finally, it is of crucial importance to assure early isolation combined with best possible psychological support for the young patients.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Chloroquine and hydroxychloroquine for the treatment of COVID-19: A living systematic review protocol', 'To determine the relative impact of the use of chloroquine and hydroxychloroquine on outcomes important to patients with COVID 19.', 'This is the protocol of a living systematic review.', 'We will follow a common protocol for multiple parallel systematic reviews, already published and submitted to PROSPERO (awaiting ID allocation).', 'We will include randomised controlled trials evaluating the effect of chloroquine and hydroxychloroquine -as monotherapy or in combination with other drugs -versus placebo or no treatment in patients with COVID-19.', 'Randomised trials evaluating chloroquine and hydroxychloroquine in infections caused by other coronaviruses, such as MERS-CoV and SARS-CoV, and non-randomised studies in COVID-19 will be searched in case no direct evidence from randomised trials is found, or if the direct evidence provides low-or very low-certainty for critical outcomes.', 'Two reviewers will independently screen each study for eligibility, extract data, and assess the risk of bias.', 'We will perform random-effects meta-analyses and use GRADE to assess the certainty of the evidence for each outcome.']}\n", - "{'sentences': ['A recently developing pneumonia caused by SARS-CoV-2 was originated in Wuhan, China, and has quickly spread across the world.', 'We reported the clinical characteristics of 82 death cases with COVID-19 in a single center.', \"Clinical data on 82 death cases laboratory-confirmed as SARS-CoV-2 infection were obtained from a Wuhan local hospital's electronic medical records according to previously designed standardized data collection forms.\", 'Results: All patients were local residents of Wuhan, and the great proportion of them were diagnosed as severe illness when admitted.', 'Most of the death cases were male (65.9%).', 'More than half of dead patients were older than 60 years (80.5%) and the median age was 72.5 years.', 'The bulk of death cases had comorbidity (76.8%), including hypertension (56.1%), heart disease (20.7%), diabetes (18.3%), cerebrovascular disease (12.2%), and cancer (7.3%).', 'Respiratory failure remained the leading cause of death (69.5%), following by sepsis syndrome/MOF (28.0%), cardiac failure (14.6%), hemorrhage (6.1%), and renal failure (3.7%).', 'Furthermore, respiratory, cardiac, hemorrhage, hepatic, and renal damage were found in 100%, 89%, 80.5%, 78.0%, and 31.7% of patients, respectively.', 'On the admission, lymphopenia (89.2%), neutrophilia (74.3%), and thrombocytopenia (24.3%) were usually observed.', 'Most patients had a high neutrophil-to-lymphocyte ratio of >5 (94.5%), high systemic immune-inflammation index of >500 (89.2%), increased C-reactive protein level (100%), lactate dehydrogenase (93.2%), and D-dimer (97.1%).', 'A high level of IL-6 (>10 pg/ml) was observed in all detected patients.', 'Median time from initial symptom to death was 15 days , and a significant association between aspartate aminotransferase (p=0.002), alanine All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', ': medRxiv preprint aminotransferase (p=0.037) and time from initial symptom to death were interestingly observed.', 'Older males with comorbidities are more likely to develop severe disease, even die from SARS-CoV-2 infection.', 'Respiratory failure is the main cause of COVID-19, but either virus itself or cytokine release storm mediated damage to other organ including cardiac, renal, hepatic, and hemorrhage should be taken seriously as well.', 'To our knowledge, this is the first study to describe the clinical characteristics of dead patients with COVID-19.', 'The mortality of 6.2% from current study was lower than that of SARS infection in 2003.', 'However, the mortality rate from this center is a little All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.02.26.20028191 doi: medRxiv preprint bit higher than previously reported.', 'We speculated the reason might be that fewer patients in our study were transferred to the ICU in time when their condition rapidly worsened.', 'On the other hand, limited death cases, less than 15 patients were included in their cohort, 8, 9 while much more death cases were included in the present study.', 'Our study firstly focused on the epidemiological characteristics of dead patients with COVID-19.', 'Several factors were responsible for the death of these patients included in this study.', 'A majority of patients were older than 60 years in our study, and a borderline significant association between age and time from initial symptom to death were interestingly observed.', 'These results are consistent with that older age was more likely occurred in critically ill patients.', '16 Moreover, we found underlying diseases such as hypertension, heart disease and diabetes were very common in our death cases, and 30.5% of patients had 2 or more comorbidities.', 'These features are consistent with previous report that patients with underlying diseases more likely developed to severe illness.', '9 Cancer patients is comprised of 7.3% in our cohort, much higher than cancer morbidity, suggest that cancer patients more likely develop to severe disease, even death.', 'These results are consistent with the findings from a national wide analysis in China.', '17 Immune deficiency to virus infection seems to be the common features in older males with comorbidities.', 'We further analyzed the cause of death case with COVID-19 and found that respiratory failure remained the leading cause of death.', 'It has been reported that the binding receptor for SARS-CoV-2, ACE2 is mainly expressed in blood vessels and lung alveolar type II (AT2) epithelial cells, 13 Similar to the SARS-CoV and MERS-CoV, SARS-CoV-2 can directly attack ACE2-expressing cells.', 'Indeed, All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.02.26.20028191 doi: medRxiv preprint pathological findings indicated that infected lungs with SARS-CoV-2 present as ARDS, pulmonary edema with hyaline membrane formation, evident desquamation of pneumocytes.', 'Therefore, our finding that respiratory failure is the leading cause of death, is consistent with the underlying pathological mechanism of COVID-19.', 'Besides respiratory failure, cardiac failure, hemorrhage, renal failure and even MOF were also recognized as the cause of death by COVID-19 in our study.', 'Laboratory findings also revealed cardiac, hepatic, and renal damage in some of patients.', 'We also observed a significant association between aspartate aminotransferase, alanine aminotransferase and time from initial symptom to death.', 'These clinical phenomena could be explained by virus itself attack and cytokine release storm (CRS) mediated tissue damage.', 'First, ACE2 expression is also found in the kidney, heart, and liver etc, therefore SARS-CoV-2 could invade the cells of above tissues, reproduce and damage these organ.', '14, 15 Second, virus infection and subsequent tissue damage either in the lung or other target organ could elicit immune cells to produce pro-inflammatory cytokines, namely CRS', 'Obviously, increased amounts of cytokines, including IL-1β, IL-6, and monocyte chemotactic protein-1 (MCP-1), are associated with severe lung injury in patients infected with SARS-CoV and MERS-CoV. 19, 20 A recent study showed high levels of IL-1β, interferon γ -induced protein 10 , and MCP-1', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org /10.1101 /10.', 'We also depicted the immune status of COVID-19 patients with severe illness.', 'Most of patients in our study presented as neutrophilia and lymphopenia on admission, specifically reduced CD3+, CD4+, and CD8+ T-cell counts were observed in some patients.', 'A high NLR was also observed on the admission and 24 hours before the death.', 'These results, consistent with the previous findings found in the patients with severe illness, suggest perturbation of immune system contribute the pathogenesis of SARS-CoV-2.', 'These observations could be also explained why older males with comorbidities likely succumb to COVID-19.', 'Our study has some limitations.', 'Firstly, some patients did not receive timely supportive interventions such as admission to ICU, because increasing number of severe patients occurred in a short period.', 'However, present data could partially be scenario where COVID-19 patients progress in a natural pathophysiology rather than outcome from intervention by treatment.', 'Secondly, consecutive detection of cytokines was lacking, which fail to truly monitor the severity of CRS.', 'Thirdly, organ damage could originate from a history of medication including nonsteroidal anti-inflammatory drugs, antibiotics, and traditional Chinese medicine which are associated with renal or liver injury.', '21, 22 In our study, all patients received intravenous of antibiotics and anti-virus drugs.', 'Overall, from the point of view of the causes of death, we presented the clinical characteristics of patients with COVID-19.', 'Lung injury begins with an insult to the lung epithelium mainly attacked by SARS-CoV-2 itself because of ACE2 expressed in the lungs, which leads to most common respiratory failure.', 'Other organs or tissues, more or less, are potentially damaged through direct attack from SARS-CoV-2.', 'In All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.02.26.20028191 doi: medRxiv preprint addition, damages of multiple systems including the lungs, might originate with systemic damage due to CRS following SARS-CoV-2 infection.', 'Considering the pandemic potential and moderate threaten of COVID-19 for population with multiple underlying diseases, further studies are required to focus on pathology and pathophysiology of tissue injury caused by SARS-CoV-2 infection, especially on the activation process of immune response and cytokines storm.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['We report a cohort of 34 ICU patients with laboratory-confirmed SARS-CoV-2 infection, characterised by severe or critical coronavirus pneumonia.', '67.6% patients were men, with a median age of 66 years (IQR 58-76) and the oldest patient, a 94 years old man has been discharged.', 'Of the 34 patients, 19 patients (55.9%) only received noninvasive respiratory support (including nasal oxygen therapy in one case and HFNC in 18 patients) and 15 (44.1%) required IMV.', 'By the end of Mar 5 2020, the complications rate (including, acute liver injury, acute cardiac injury and AKI) and discharge rate were significantly different between the two groups.', 'More than 100 COVID-19 patients were admitted to our designated hospital.', 'Patients in general isolation ward were mild to moderate, and most ICU patients without IMV required have got better and discharged.', 'However, the majority of ICU cases with IMV required are still under respiratory support, including 11 ECMO operating.', 'So, the main battlefield of the epidemic war is in ICU, and the key to the success of the epidemic fighting is striving to improve and perfect the management and treatment of severe and critical patients.', 'Most common complication was ARDS (33 [97.1%] of 34 patients) in the research, so, respiratory support is essential.', 'By now, no antiviral treatment has been proven to be effective for coronavirus infection.', '97.1% infected patients received single or combined antiviral, including baloxavir, favipiravir, darunavir, arbidol, or interferon alpha inhalation.', 'Corticosteroid and gamma globulin were administrated to a part of patient, but the efficacy needs to be further confirmed.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.12.20062604 doi: medRxiv preprint lymphocyte destruction.', 'Lymphocytopenia occurred in more than 60% patients in our cohort on the first day of admission.', 'As the disease progresses, more patients developed lymphocytopenia.', 'In the IMV group with more severe illness, lymphocyte levels dropped progressively and more severe lymphopenia occurred compared to no-IMV group, which suggested that the severity of lymphocytopenia reflects the severity of SARS-CoV-2 infection.', 'As the research of SARS-CoV infected cases shows that patients with more severe clinical illness, or patients who died, had significantly more profound lymphopenia [17] .', 'The lymphocyte counts can gradually rise to normal level until discharge in a part of patients without IMV in our cohort.', 'Lymphopenia was prolonged, and the lymphocyte returned towards normal after five weeks of illness in patients with SARS-CoV [17] infection or within 2-3 weeks after the disease onset in cases with severe pandemic H1N1 influenza A [18] .', 'Further analysis in our cohort showed that T lymphocytopenia was more pronounced than B lymphocytopenia which was similar to previous study in Patients with SARS [19] .', 'The mechanism behind the dynamics is not clear, which need to be confirmed in cell and animal experiments.', 'We noted that SARS-CoV-2 infection caused increase in plasma IL-6 levels, which were consistently at a high levels in IMV cases in our cohort.', 'Early studies also have shown that increased concentrations of proinflammatory cytokines (eg, IL-6, TNFα and IFNγ) in SARS patients [20] and MERS-CoV cases [21] .', 'Increased amounts of anti-inflammatory cytokine, IL-10, in plasma was found in SARS-CoV-2 infected patients with IMV, which differs from SARS-CoV infection [12] , but supported by Huang et al. [8] in patients with the same disease.', 'BUN is a key element reflecting the intricate interrelation between nutritional status, protein metabolism and renal situation of the patient [22] .', 'BUN were significantly elevated in IMV patients compared with NIV cases which may cause by high catabolism.', 'The characteristics of inflammation and metabolism, combined with lymphocytopenia, suggested that we have to be on the alert of the existence of persistent inflammation-immunosuppression and catabolism syndrome (PICS) in IMV cases.', 'This study has several limitations.', 'Firstly, limited samples in our cohort are analyzed.', 'A previous report enrolled 52 critically ill patients with SARS-CoV-2 infection from Wuhan Jin Yin-tan hospital.', 'However, in places outside Hubei province, the total number of cases and the All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', '/2020 number of critical patients are relatively small.', \"Secondly, most IMV patients had not been discharged at the time of manuscript submission, so we can't use survival or death as a clinical end point.\", 'The case mortality rate and other outcome indicators need to be reported later.']}\n", - "{'sentences': ['Combined prophylactic and therapeutic use maximizes hydroxychloroquine anti-SARS-CoV-2 effects in vitro', \"[{'text': 'While the SARS-CoV-2 pandemic is hardly hitting the world, it is of extreme importance that significant in vitro observations guide the quick set up of clinical trials.\", 'In this study, we evidence that the anti-SARS-CoV2 activity of a clinically achievable hydroxychloroquine concentration is maximized only when administered before and after the infection of Vero E6 cells.', 'This strongly suggests that only a combined prophylactic and therapeutic use of hydroxychloroquine may be effective in limiting viral replication in patients.']}\n", - "{'sentences': [\"The Author's Response: Case of the Index Patient Who Caused Tertiary Transmission of Coronavirus Disease 2019 in Korea: the Application of Lopinavir/Ritonavir for the Treatment of COVID-19 Pneumonia Monitored by Quantitative RT-PCR\"]}\n", - "{'sentences': ['Achieving information sharing in clinical trials is the key to accelerating the transformation of clinical resources and promoting scientific breakthroughs [7] .', 'In the face of a public safety crisis such as an outbreak, the timely sharing of information is even more important, and it All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', '1101 /2020 can provide real-time guidance for preventing and controlling the epidemic, assessing development trends and the effects of intervention measures [8] .COVID-19\\'s \"war epidemic\" and \"epidemic prevention\" strategies are closely related to the important measure of improving the transparency of clinical trials, including sharing of the subject\\'s original data and standardizing trial design, registration, and implementation [9].', \"At present, China's clinical trial registration policy is to implement registration[10], which requires registration in accordance with the ChiCTR registration guidelines.\", 'The ChiCTR registration guidelines divide research types into 7 categories, such as interventional studies, preventive studies, diagnostic tests, and observational studies, etc.', 'However, it is ambiguous that the registration guidelines classify studies by their nature and purpose.', 'According to international standards, it may be more clear to classify intervention and observation [12] .', 'In order to regulate registration, more details should be provided on the randomization procedure and blind method.', 'We found that most interventional studies use randomized allocation, but there are low blinding rates and lack of information.', 'The possible reason is that it is difficult to implement blind method in epidemic situation, but it may also be incomplete information.', 'More than half of the studies did not indicate blind method information.', 'Missing information means that no information about the size of the study is available, which adversely affects the transparency of registration [13] .The', 'results showed that more than half of the studies were not confirmed by the data management committee.', \"Low blinding rate and lack of information may be related to it's.\", 'The detection or guidance of the data management committee should be further strengthened to improve the quality of research design [14] .', 'It is worth noting that 22.84% of the studies failed ethical verification.', 'All human-oriented clinical trials must in any case follow the \"Helsinki Declaration\", which has become a consensus of the medical community, and follow the basic ethical principle of \"doctors should provide medical care in the best interests of patients\" to ensure the subjects [15, 16] .The', 'ChiCTR Center has issued a warning and requested the supplementary information of the failed units to be reviewed.', 'Medical ethics review should strictly abide by the review work content of the \"Ethical Review Methods for Biomedical Research Involving', 'Humans\" [17] , and here are two suggestions: (1) undertake experimental projects that match actual capabilities; (2) design of experimental schemes An appropriate research method must be selected based on the nature of the problem to be solved.', 'As of February 24, 2020, the overall number of COVID-19 registered clinical studies is on the rise.', 'The possible reason is that China has already initiated a first-level response to All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', '1101 /2020 major public health emergencies, and conducting relevant clinical trials is critical to epidemic prevention and control.', 'In addition, in order to cooperate with the epidemic prevention and control work, many national drug clinical trial institutions(GCP) in China have established detailed work guidelines and guidelines to effectively speed up clinical trial review.', \"From the statistical analysis of China's geographical distribution, it is found that the number of registered provinces in Hubei Province ranks first, and the number of registered provinces close to it is higher than that of other provinces.\", 'The possible reason is that the COVID-19 epidemic was mainly concentrated in Wuhan, Hubei Province, China.', 'There was no large-scale epidemic outbreak in remote provinces, and there were relatively few NCP patients.', 'We found significant differences in the dimension of study design characteristics for different study types.', 'The results showed that compared to observational studies, most interventional studies had fewer than 100 participants.', 'However, 8.62% of observational study designs were completed within 1 month.', 'Such designs were not reflected in interventional studies, and most of the interventional studies were completed in 4-12 months.', 'Similarly, compared to observational studies, most interventional studies use randomized allocation.', 'These results imply that different interventions have an impact on the design of clinical trials.', 'The design of COVID-19 clinical trials should give priority to \"timeliness\".', 'The trial sample size needs to consider the balance between clinical and statistical significance, and its estimated volume reflects the reliability and repeatability of the research results [18] .As public health emergencies do not allow more time for exploratory clinical research and there is no historical data, the sample size estimation of such trials may encounter unprecedented problems.', 'Some scholars have proposed [19] , whether it is possible to reduce the required sample size by \"reducing the power\" or \"increasing the type I error rate\" to complete the clinical trial as soon as possible?But such an approach requires a variety of trade-offs between regulators, sponsors, and researchers.', 'In addition, the study period is also \"time-effective\".', 'If a clinical study is long, it may not make much sense in terms of public health emergencies to respond to the outbreak.', 'From the statistical data, it can be seen that the time limit for completing most of the clinical studies of COVID-19 is concentrated within 4-12 months, and very few studies are completed within 1 month.', 'The clinical research to deal with the epidemic is to race against the virus and the epidemic.', 'This time limit seems too long.', 'Is it possible to conduct mid-term analysis or other adaptive, new design methods?', 'Clinical trial statistics need to be continuously developed All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', '1101 /2020 based on actual needs.', 'In addition to the prevention and control of the epidemic, vaccines and drugs are the two major weapons to overcome the epidemic.', 'The previous SARS-CoV epidemic, the 2009 influenza epidemic, and the Ebola epidemic in West Africa were basically approved for marketing at the end of the epidemic, with a lag [20, 21] .Similarly, the development of specific drugs is also very difficult.', 'The \"old medicine\" is a new way to increase the indications, and conducting clinical research on anti-COVID-19 may be an important means to respond to the current epidemic.', 'The \"New Coronary Virus Pneumonia Diagnosis and Treatment Scheme (Trial Version 6)\" (hereinafter referred to as the \"Scheme\") states that there are currently no effective drugs to treat NCP patients.', 'Drugs such as lopinavir / ritonavir, interferon, abidol, and chloroquine phosphate can be tried, but their effectiveness needs to be confirmed in clinical studies.', 'In the registration trial, the main treatment was drug therapy, accounting for 68.97%.', 'Among them, there are more CMT and TCM studies, and relatively few BI studies.', 'The most frequently studied CMT is chloroquine phosphate.', 'Chloroquine phosphate is an antimalarial drug marketed for many The \"Scheme\" emphasizes the important role of TCM.', 'The treatment of the \"pathogenic factor\" the mechanism by which TCM treats the cause of COVID-19 [28] .', 'In addition, its All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.16.20034934 doi: medRxiv preprint multi-target regulation of the body\\'s immune system has a therapeutic effect on \"cytokine This study has some limitations.', 'The data for this study were derived only from ChiCTR.', 'There may be other databases containing COVID-19 clinical studies.', 'The time limit for research registration is short, and relevant registration information has not been filled in, and it cannot truly reflect its true quantity and level.', 'However, the innovation of this article is to summarize and analyze the registration of ChiCTR\\'s COVID-19 clinical research in a timely manner, reflecting the research status and development trend of clinical trials in this field, which is \"time-effective\".']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['We have developed a machine learning model for high throughput screening of synthetic antibodies to discover antibodies that potentially inhibit the COVID-19.', 'Our approach can be widely applied to other viruses where only the sequences of viral coat protein-antibody pairs can be obtained.', 'The ML models were trained on 14 different virus types and achieved over 90% fivefold test accuracy.', 'The out of class prediction is 100% for SARS and 84.61% for Influenza, demonstrating the power of our model for neutralization prediction of antibodies for novel viruses like COVID-19.', 'Using this model, the neutralization of thousands of hypothetical antibodies was predicted, and 18 antibodies were found to be highly efficient in neutralizing COVID-19.', 'Using MD simulations, the stability of predicted antibodies were checked and 8 stable antibodies were found that can neutralize COVID-19.', 'In addition, the interpretation of ML model revealed that mutating to Methionine and Tyrosine is highly efficient in enhancing the affinity of antibodies to COVID-19.', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.14.992156 doi: bioRxiv preprint Jayan for her support and Junhan Li for his help in collecting the data.']}\n", - "{'sentences': ['A vaccine against SARS-CoV-2 should, for several reasons, be easier to generate than those against many other viruses (Gralinski and Baric, 2015; Li, 2016) .', 'First, coronaviruses have exceptionally large genomes compared to other RNA viruses, and, to avoid error catastrophe, their viral polymerase has acquired a proof-reading function.', 'Thus any individual gene, for example that of the S protein, is likely to retain its original sequence over multiple replication cycles.', 'Second, coronaviruses in general, and clearly SARS-CoV-2 in particular, transmits to a new host more rapidly than an adaptive immune response can emerge.', 'A likely consequence of this strategy is that one of its most critical epitopes, namely its RBD, is exposed on the virion (Li, 2016; Walls et al., 2020; Wong et al., 2004; Wrapp et al., 2020) , favoring transmission efficiency over antibody resistance.', 'Finally, the stability and compactness of the SARS-CoV-1 and SARS-CoV-2 RBD means that it can be easily manufactured and presented to the immune system using many production technologies, presentation scaffolds, and delivery systems (Wong et al., 2004) .', 'Many efforts are now underway to develop vaccines based on stabilized soluble trimeric forms of the S protein ectodomain (Wrapp et al., 2020) .', 'It is at this moment unclear whether these S-protein trimers, RBDs, or some parallel or serial combination thereof, will make better antigens.', 'Recent studies suggest that neutralization activity of patient sera correlates with its RBD recognition, and that most neutralizing antibodies bind the RBD (To et al., 2020).', 'It is possible that the remainder of the S protein presents non-neutralizing epitopes that are more immunogenic than the RBD, and thus the RBD by itself may elicit antisera that are more neutralizing.', 'However, other antibody effector functions, including antibody-dependent cell-mediated cytotoxicity (ADCC', 'As observed with flaviviruses, there is a qualitative difference between ADE mediated by neutralizing and by non-neutralizing antibodies (Dejnirattisai et al., 2010; Shim et al., 2019; Takada et al., 2003) .', 'In the case of neutralizing antibodies, ADE is a consequence of insufficient coating of the virion surface, due to lower affinity or concentration of the antibody.', 'If concentrations or affinity is raised, neutralization dominates.', 'In contrast, ADE mediated by nonneutralizing antibodies increases with increasing concentration.', 'We therefore speculated that it would be difficult of observe ADE with rat antisera targeting the SARS-CoV-2 RBD, a key neutralizing epitope.', 'Indeed, although rat anti-Zika virus antisera mediated robust ADE of ZIKV in two different Fc receptor-expressing cell lines, no ADE of S-protein pseudoviruses was observed with anti-RBD anti-sera, whether or not the SARS-CoV-2 receptor ACE2 was present.', 'These data suggest that, at least for RBD-based vaccines, ADE is likely to be less of a concern than with vaccines against flaviviruses such as ZIKV or dengue viruses.', 'However they do not .', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.10.036418 doi: bioRxiv preprint exclude ADE mediated by other S-protein epitopes or other mechanisms by which a vaccine can be deleterious.', 'A key remaining question is whether these studies, conducted in rodents, imply that an RBD-based vaccine could be effective in humans.', 'Here experimental details become important.', 'We immunized rats with an adjuvant system (AS01) already in human use, notably for vaccines for shingles (Shingrix TM ) and malaria (Mosquirix TM ).', 'The RBD used here was conjugated to a carrier protein, Keyhole limpet hemocyanin, proven safe over decades in humans (Swaminathan et al., 2014) .', 'However KLH can be problematic for those with shellfish allergies, and alternate scaffolds for presenting the RBD may be necessary.', 'Rats were immunized with two sets of escalating inoculations, each administered over seven days.', 'This strategy has been shown to maximize immune responses against HIV-1 antigens (Tam et al., 2016), but it may not be a practical means of addressing the current pandemic with a subunit vaccine.', 'That said, the escalating dosage strategy used here may more accurately reflect the kinetics of an mRNA-delivered vaccine, and indeed we would argue that an RBD antigen would be a preferable alternative, or at least a useful complement, to mRNA expression of the S-protein trimer.', 'However, it remains to be determined whether a more limited number of injections of an RBD subunit vaccine would raise a protective response.', 'A key point relevant to this question is that the neutralizing activity elicited in these studies is likely much greater than would be necessary to prevent a new SARS-CoV-2 infection.', 'Rat antisera on average neutralized more efficiently than naive sera bearing 100 µg/ml of ACE2-Ig, which itself neutralizes with an IC50 of less than 1 µg/ml, consistent with its activity against infectious SARS-CoV-1 (Moore et al., 2004) .', 'To provide some context for these numbers, eCD4-Ig, an immunoadhesin that emulates HIV-1 viral receptors and neutralizes with neutralization potency similar to that of ACE2-Ig, affords robust protection against high-dose intravenous challenges with an HIV-1-like virus when it is present in serum in the range of 5-10 µg/ml (Gardner et al., 2019; Gardner et al., 2015) .', 'Thus it is possible that a less robust response could still be protective.', 'Perhaps as important as these quantitative considerations, our data show that the RBD alone is sufficient to elicit a potent neutralizing antibody response.', 'It remains to be determined whether trimer-based vaccines, or trimer/RBD combinations, can be more effective, and whether they carry additional safety concerns.', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.10.036418 doi: bioRxiv preprint', 'In short, our data suggest that an RBD vaccine could protect many individuals from SARS-CoV-2 and that it is unlikely to promote infection through conventional ADE mechanisms.', 'Given the exposure of this key neutralizing epitope, the ease with which this compact domain can be produced and presented, and its clear immunogenicity, we propose that the RBD be considered as a key component of any SARS-CoV-2 vaccine strategy.', 'Tian, X., Li, C., Huang, A., Xia, S., Lu, S., Shi, Z., Lu, L., Jiang, S., Yang, Z., Wu, Y., et al. (2020) .', 'provided critical reagents and advice.', 'M.F. wrote the manuscript with critical assistance from H.C.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Companies producing vaccines and other therapeutics for infectious diseases have gradually been retreating from these spaces in recent years.', 'The number of companies producing vaccines has dwindled over the past few decades, and the top four vaccine companies now make up more than 90% of the global market (Evaluate, 2018) .', 'CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint It should be no surprise that investors are unwilling to invest in companies producing vaccines and treatments for infectious diseases given the economics of this market (Vu et al., 2020) .', 'These have been generally regarded as low-margin products, and they have low growth potential compared to treatments in other therapeutic areas, such as oncology or cardiovascular diseases.', 'As a comparison, Revlimid, the blockbuster cancer drug for multiple myeloma, earned $9.69 billion for Celgene in 2019 (, the blockbuster cancer drug for multiple myeloma, earned $9.69 billion for Celgene in 2019', 'This lack of investment has resulted in a relatively low number of development programs for vaccines and treatments of infectious diseases.', 'Only 5,689 industry-sponsored programs were initiated in the past two decades, a mere 12.5% of all industry-sponsored drug development programs launched in the same period.', 'Our study indicates that the technical success rate is unlikely to be a barrier to investments in new vaccines and treatments for infectious diseases, unlike cancer drugs, where the financial risk of new R&D projects comes from the reduced chance of bringing a drug-indication pair from phase 1 to market.', 'The overall PoS of industry-sponsored vaccines and treatments for infectious diseases are above the average for all therapeutic groups (see Table 2 in the Supplementary Materials).', 'It is often suggested that the fundamental issue behind this lack of investment is that the market for vaccines and treatments for infectious diseases is simply not lucrative enough.', 'Despite the expense of research and development and the need for large-scale production (Weir & Gruber, 2016) , anti-infective disease treatments are used only occasionally, while vaccine companies face an avalanche of liability lawsuits (Hensley & Wysocki Jr., 2005) .', 'Furthermore, the companies are at the mercy of government pricing decisions (Hu, 2018) .', 'It remains to be seen if more non-industry-sponsored research can alleviate the issue.', 'Our study shows that only 6.8% (SE: 1.0%) and 8.2% (SE: 0.6%) of non-industry-sponsored vaccines and non-vaccine infectious disease development programs transition from phase 1 to approval, respectively.', 'However, this may be a result of selection bias: promising vaccine and therapeutics initiated in non-industry settings are often pursued in conjunction with industry-sponsored sponsors, whereas commercially less promising projects are more likely to be pursued by non-profit organizations.', 'CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint']}\n", - "{'sentences': ['The response to the COVID19 epidemic is generating severe shortages of personal protective equipment around the world.', 'In particular, the supply of N95 respirator masks has become severely depleted with supplies having to be rationed and health care workers having to use masks for prolonged periods in many countries.', 'We sought to test the ability of 4 different decontamination methods including autoclave treatment, ethylene oxide gassing, ionized hydrogen peroxide fogging and vaporized hydrogen peroxide exposure to decontaminate 4 different N95 masks of experimental contamination with SARS-CoV-2 or vesicular stomatitis virus as a surrogate.', 'In addition, we sought to determine whether masks would tolerate repeated cycles of decontamination while maintaining structural and functional integrity.', 'We found that one cycle of treatment with all modalities was effective in decontamination and was associated with no structural or functional deterioration.', 'Vaporized hydrogen peroxide treatment was tolerated to at least 5 cycles by masks.', 'Most notably, standard autoclave treatment was associated with no loss of structural or functional integrity to a minimum of 10 cycles for the 3 pleated mask models.', 'The molded N95 mask however tolerated only 1 cycle.', 'This last finding may be of particular use to institutions globally due to the virtually universal accessibility of autoclaves in health care settings.', 'The COVID19 pandemic is proving to be an exceptional stress on hospital and health systems resources around the world.', 'Many countries are experiencing or imminently expecting shortages for a variety of equipment and disposable supplies.', 'A tightening supply of N95 masks that allow for protection from airborne pathogens and aerosolized viruses including SARS-CoV-2 is of particular and immediate concern.', 'Without an adequate supply of N95 masks, health care providers are at extreme risk of acquisition of COVID19 disease.', 'The occurrence of patient to health care workers spread of SARS-CoV-2 at sufficiently high rates would lead to demoralization of the workforce, depletion of health care workers for quarantine and turn hospitals into extreme hotspots for infection transmission.', 'The unprecedented nature of the COVID19 epidemic has revealed previously unrecognized deficiencies in pandemic preparations globally.', 'In particular, the depletion of single-use disposable personal protective gear has resulted in considerable health care worker anxiety and prolonged use of gear far beyond standard recommendations.', 'The international shortage of N95 masks that protect from aerosolized virus (which may occur during intubation and other invasive tracheobronchial procedures) is of particular concern given the respiratory nature of the SARS-CoV-2 infections.', 'The shortage of these masks and their use for periods beyond recommended may be part of the reason for the reported high incidence of acquisition of infection by health care workers.', 'We sought to determine which standard decontamination techniques used in hospitals might be suitable for the task of sterilizing a variety of N95 masks without compromising their structural or functional integrity.', 'We also sought to ensure that each technique was effective in eliminating any viable virus by potential penetration through the surface as might be seen with large contaminated droplet deposition.', 'Efforts at ultraviolet light decontamination, for example, might only sterilize the mask surface without having an impact on virus particles that have been deposited deeper [3] .', 'Our tests of effectiveness of decontamination demonstrate that all decontamination methods assessed are highly effective in sterilizing all four N95 models (contaminated group).', 'No viable virus (including, as a surrogate, VSV but also SARS-CoV-2) was found on any experimentally contaminated mask following any decontamination procedure (autoclave, EtO gas, iHP or VHP).', 'This is an expected result but is useful in that previous studies have made the assumption that such techniques would necessarily be effective on N95 masks [3] [4] [5] [6] .', 'Vesicular stomatitis virus, a bullet shaped enveloped, negative-sense RNA virus of the Rhabdoviridae family that commonly infects animals [7] , was used as a surrogate for SARS-CoV-2 for decontamination procedures (iHP and EtO) only available at our hospital.', \"We could not validate SARS-CoV-2 against these two technologies because it is a Risk Group 3 virus, which can't be manipulated outside of CL3.\", 'More importantly, our results clearly show that the use of individual N95 masks can potentially be extended several-fold without degradation of functional integrity.', 'VHP [8] appears to be most effective across all masks.', 'There is recent preprint data that supports this possibility [4] .', 'We demonstrated that the VHP method allows at least 10 cycles of decontamination without impairment of mask function.', 'The disadvantage of VHP is its limited availability.', 'iHP is commonly used in most hospitals for decontamination of high value reusable equipment such as endoscopes [9] .', 'However, we were able to demonstrate only that the N95 masks tolerated one cycle of treatment.', 'With 5 or more cycles, quantitative fit testing was consistently impaired.', 'We have not yet assessed whether a number of cycles between 1 and 5 might be viable.', 'EtO gas treatment is an older method of decontaminating materials [10] .', 'The process is somewhat more complex than others and there can be safety concerns in that the gas is flammable, explosive and potentially carcinogenic [11] .', 'A prolonged period of aeration following item exposure to the gas is required to eliminate chemical residua.', 'This result in an extremely long cycle time of more than 20 hours compared to less than one hour for other decontamination methods.', 'Despite these drawbacks, some institutions in poorly resourced setting may not have iHP or VHP.', 'For that reason, our finding that all four mask models tolerate at least 3 cycles of EtO decontamination without significant structural or functional deterioration may be useful.', 'However, we would recommend against the use of this approach unless and until there is advanced testing to ensure that all traces of ethylene oxide and its related breakdown products are entirely eliminated with sufficient aeration [12] .', 'Finally, as expected, standard autoclaving is effective in eliminating any viable virus.', 'Surprisingly, however, 3 of the 4 respirator mask models tolerated up to 10 cycles while maintaining structural and functional integrity according to our testing.', 'Although all masks maintained integrity after one autoclave cycle, only the more rigid, non-pleated 3M 1860 model demonstrated loss of function with more than a single autoclave cycle.', 'The other layered fabric, pleated models all retained integrity with up to 10 autoclave cycles.', 'This finding will be highly relevant to institutions in poorly resourced areas of the world in that one might reasonably hope that autoclaves would be available in any recognized hospital around the world.', 'Unfortunately, we were unable to examine the differences in mask materials and construction that might contribute to the failure of the 3M 1860 model compared to the others due to the proprietary nature of the technology.', 'Single use of N95 masks for each patient encounter is ideal and recommended; unfortunately, the resource stress due to the current COVID-19 crisis has breached this ideal.', 'According to public reporting, extended use and re-use of N95 masks has become common in hospitals in areas where SARS-CoV-2 is high.', 'This risks functional failure of N95 masks, spread of infection to wearers and increased risk of virus transmission from health care workers to others.', 'Our data suggests that all decontamination methods are effective for at least one decontamination cycle without loss of structural integrity.', 'However, neither iHP nor EtO gas are recommended at this time due to limited tolerance of N95 masked tested to repeat cycles, prolonged cycle times and/or potential toxicity.', 'Both VHP and autoclaving can be used to decontaminate N95 masks through multiple cycles without loss of filtering function.', 'Although VHP has more limited availability, autoclaves, which can be used on a subset of N95 mask types, may be easily accessed by any health care institution when N95 mask shortages occur.', \"Although we tested the functional integrity of decontaminated masks via quantitative fit testing, our testing cannot take into account the respirator's ability to withstand the rough handling that extended wear by health care workers, with stress and perspiration can inflict.\", 'Another limitation of this study is that our findings may or may not apply to other types of N95 masks.', 'Nonetheless, it is reassuring that the practice of use of appropriate decontamination and subsequent reuse of N95 mask should not pose a health risk to already taxed health care workers. .', 'CC-BY 4.0 International license', 'It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.05.20049346 doi: medRxiv preprint']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['On the use of corticosteroids for 2019-nCoV pneumonia']}\n", - "{'sentences': ['Baricitinib as potential treatment for 2019-nCoV acute respiratory disease']}\n", - "{'sentences': ['Objective To investigate the clinical experience of patients with novel coronavirus (2019-ncov) infection after kidney transplantation.', 'Method Clinical data of two patients with 2019-nCoV infection after renal transplantationin Jan 2020 Renmin Hospital of Wuhan Universiyt were retrospectively analyzed.', 'Case 1 was a 48-year-old male with CMV pneumonia secondary to 2019-nCoV infection at 4 months after transplantation.', 'CT imaging showed multiple patchy ground-glass images of both lungs.', 'Case 2 was a 59-year-old male, who was screened positive for 2019-nCoV nucleic acid due to fever at 9 days after renal transplantation and showed no clinical manifestations of pneumonia.', 'After diagnosis, case 1 was transferred to a designated hospital for isolation.', 'Treatment regimens: cefoperazone sulbactam sodium + linezolid to resist infection, gamma globulin to enhance immunity function, methylprednisolone to control inflammatory response, antiviral regimens including arbidol tablets + lopina-velitonavir tablets.', 'Case 2 was treated with isolated treatment in a single room.', 'The treatment plan included anti-infection (cefoperazone sulbactam sodium), enhancing immunity function (gamma globulin), antivirus therapy with arbidol and other symptomatic treatment.', 'Result Follow up with 3 weeks, case 1 recovered with renal dysfunction, nucleic acid test with nasopharyngeal swabs turned negative, and pulmonary imaging improved.', 'Case 2 showed no obvious clinical symptoms, and the nucleic acid test of nasopharyngeal swabs turned negative for 3 times.', 'Conclusion Renal transplant recipients should receive fine protection to avoid exposure to high-risk environments.', 'Diagnosis should be defined with combination of clinical manifestations, nucleic acid test and pulmonary imaging.', 'At present, there are no antiviral drugs and symptomatic treatment is the main choice.']}\n", - "{'sentences': ['BACKGROUND: Since December 2019, 2019 novel coronavirus pneumonia emerged in Wuhan city and rapidly spread throughout China and even the world.', 'We sought to analyse the clinical characteristics and laboratory findings of some cases with 2019 novel coronavirus pneumonia .', 'METHODS: In this retrospective study, we extracted the data on 95 patients with laboratory-confirmed 2019 novel coronavirus pneumonia in Wuhan Xinzhou District People’s Hospital from January 16th to February 25th, 2020.', 'Cases were confirmed by real-time RT-PCR and abnormal radiologic findings.', 'Outcomes were followed up until March 2th, 2020.', 'RESULTS: Higher temperature, blood leukocyte count, neutrophil count, neutrophil percentage, C-reactive protein level, D-dimer level, alanine aminotransferase activity, aspartate aminotransferase activity, α - hydroxybutyrate dehydrogenase activity, lactate dehydrogenase activity and creatine kinase activity were related to severe 2019 novel coronavirus pneumonia and composite endpoint, and so were lower lymphocyte count, lymphocyte percentage and total protein level.', 'Age below 40 or above 60 years old, male, higher Creatinine level, and lower platelet count also seemed related to severe 2019 novel coronavirus pneumonia and composite endpoint, however the P values were greater than 0.05, which mean under the same condition studies of larger samples are needed in the future.', 'CONCLUSION: Multiple factors were related to severe 2019 novel coronavirus pneumonia and composite endpoint, and more related studies are needed in the future.', 'According to the results of our study, higher temperature, blood leukocyte count, neutrophil count, neutrophil percentage, C-reactive protein level, D-dimer level, alanine aminotransferase activity, aspartate aminotransferase activity, α - hydroxybutyrate dehydrogenase activity, lactate dehydrogenase activity and creatine kinase activity were related to severe 2019 novel coronavirus pneumonia and composite endpoint, and so were lower lymphocyte count, lymphocyte percentage and total protein level.', 'Age below 40 or above 60 years old, male, higher Creatinine level, and lower platelet count also seemed related to severe 2019 novel coronavirus pneumonia and composite endpoint, however the P values were greater than 0.05, which mean under the same condition studies of larger samples are needed in the future.', 'Different from the results of previous studies [2, 9, 10], our study indicated that severe 2019 novel coronavirus pneumonia and composite endpoint had more to do with leukocytosis rather than leukopenia.', 'This difference is mainly because of the different inclusion criteria and evaluation index we used.', 'The leukocytosis was unlikely to be caused by bacterial infection because we excluded common bacteria or viruses associated with community-acquired pneumonia and procalcitonin level of all patients in our study was no greater than 0.5 ng/ml.', 'We think that the leukocytosis was a reflection of excessive inflammation.', 'The excessive inflammation was also reflected by the much higher C-reactive protein level of patients with severe 2019 novel coronavirus pneumonia as shown by Table 2.', 'In our study, the leukocytosis was always accompanied by an increase in neutrophil count and neutrophil percentage.', 'That makes sense because the overwhelming majority of blood leukocyte was neutrophils, and the highest percentage of neutrophils was 97.5% in our study.', 'As described above, neutrophilia was related to severe 2019 novel coronavirus pneumonia and composite endpoint.', 'However, Up to now most of the research have focused on the role of lymphocyte in 2019 novel coronavirus pneumonia.', 'We think that the role of neutrophils in 2019 novel novel coronavirus pneumonia shouldn’t be ignored and further related researches are needed in the future.', 'The leukocytosis was also accompanied by a decrease in lymphocyte count and lymphocyte percentage.', 'It should be noted that leukocytosis was not incompatible with lymphopenia, and lymphopenia could occur both when blood leukocyte count incarease and decrease.', 'Consistent with previous studies [11], lymphopenia was more severe and common in patients with severe 2019 novel coronavirus pneumonia.', 'As suggested, the lymphopenia was probably caused by the translocation of lymphocyte from peripheral blood to lungs [11].', 'We also evaluated the Coagulation, liver and renal function of patients with 2019 novel coronavirus pneumonia.', 'In light of our observation, D-dimer was the most common abnormal coagulation index.', 'As described above, higher D-dimer level was strongly related to severe 2019 novel coronavirus pneumonia and composite endpoint (R1 = 0.717, P1<0.001, R2 = 0.737, P<0.001).', 'The increased D-dimer level reflected a hypercoagulable state, which might promote pulmonary microthrombosis.', 'This hypothesis need to be further confirmed.', 'Alanine aminotransferase activity and aspartate aminotransferase activity were used to evaluate liver function in our study.', 'As shown by Table 2, about half of the patients were found liver fuction injury, and liver fuction injury was related to severe 2019 novel coronavirus pneumonia and composite endpoint.', 'However we didn’t see an obvious difference between 40 and 80 U/L group and >80 U/L group, and most of the liver fucntion were temporary and reversible.', 'That means the liver function injury might be caused by multiple factors: immunity, inflammation and drugs.', 'Creatinine level was used to evaluate renal function in our study.', 'A recent research indicated that the 2019 novel coronavirus was found in patients’ urine [12].', 'However, we didn’t see an obvious difference in creatinine level between severe group and non-severe group.', 'Therefore, the influence of 2019 novel coronavirus on renal function need to be further studied though the 2019 novel coronavirus was found in patients’ urine.', 'Besides, higherα- hydroxybutyrate dehydrogenase activity, lactate dehydrogenase activity and creatine kinase activity were related to severe cases and reach of composite endpoint.', 'In our study, 92.6% of the patients had an increase in α- hydroxybutyrate dehydrogenase activity, 77.9% of the patients had an increase in lactate dehydrogenase activity, and 29.5% of the patients had an increase in creatine kinase activity.', 'α- hydroxybutyrate dehydrogenase activity, lactate dehydrogenase activity and creatine kinase activity were usually used to evalue the degree of myocardial injury.', 'However, we had no direct radiological or histopathological evidence to prove that myocardial injury really happened.', 'Thus the influence of 2019 novel coronavirus on heart also need to be further studied.', 'In addition we used the total protein level to evaluate the nutritional condition of patients with 2019 novel coronavirus pneumonia.', 'According to our study, about 68.4% of the patients had a decrease in total protein level.', 'Lower total protein level correlated with severe 2019 novel coronavirus pneumonia and composite endpoint.', 'The decrease in total protein level reflected a high consumption state of nutrition, which suggested that patients with 2019 novel coronavirus pneumonia needed more nutrition during hospitalization.', 'Moreover, we compared the clinical characteristics and laboratory findings between death group and survival group as shown by Supplementary Table 1 and Supplementary Table 2.', 'Age above 60 years old, male, blood leukocyte count > 10*10^9/L, neutrophil count > 7*10^9/L, neutrophil percentage > 85%, lymphocyte count <0.4* 10^9/L, lymphocyte percentage<10%, C-reactive protein level >150 mg/L, D-dimer level >1 mg/L, α - hydroxybutyrate dehydrogenase activity>540 U/L and lactate dehydrogenase activity>720 U/L were obviously related to a consequence of death.', 'In some degree, our research was different from pevious similiar studies [2, 9, 10].', 'Firstly we adopted a different inclusion criteria:patients with chronic or severe underlying diseases were excluded as described above.', 'Secondly we applied different evaluation index:when assessing the relationship between candidates with the severity of 2019 novel coronavirus pneumonia, we used the highest or lowest level of candidates during hospitalization while the previous studies mainly used the fixed value of candidates on admission.', 'We adopted different inclusion criteria and evaluation index for the following reasons: Firstly, chronic or severe underlying diseases could make it difficult to fully assess the role of 2019 novel coronavirus in 2019 novel coronavirus pneumonia without too much interference.', 'Secondly, the laboratory findings of patients on admission could be unrepresentative because laboratory findings may vary depending on patient’s condition, and many cases that reached composite endpoint during hospitalization could be non-severe cases on admission.', 'However, there were also some limitaions of our study.', 'The main limitations included the reseach type (Single center retrospective study) and a lack of cases.', 'And it was not credible to conduct a multivariate analysis because of the lack of cases in our study.', 'Above are the main points of our study.', 'Our study was different from pevious similiar studies because of the different inclusion criteria and evaluation index we applied, which offered another perspective on the relationship between various factors and 2019 novel coronavirus pneumonia.', 'Different from previous study we found that severe 2019 novel coronavirus pneumonia and composite endpoint had more to do with leukocytosis rather than leukopenia.', 'Leukocytosis was always accompanied by an increase in neutrophil count and neutrophil percentage.', 'The role of neutrophils in 2019 novel coronavirus pneumonia shouldn’t be ignored and further related researches are needed in the future.', 'Consistent with previous studies, lymphopenia was found more severe and common in patients with severe 2019 novel coronavirus pneumonia.', 'The lymphopenia was probably caused by the translocation of lymphocyte from peripheral blood to lungs [11].', 'Besides higher D-dimer level and impaired liver function were related to severe 2019 novel coronavirus pneumonia and composite endpoint.', 'The increased D-dimer level reflected a hypercoagulable state, which might promote pulmonary microthrombosis.', 'This hypothesis need to be further confirmed.', 'Most of the liver fucntion were temporary and reversible, and the liver function injury might be caused by multiple factors: immunity, inflammation and drugs.', 'However, we didn’t see an obvious difference in creatinine level between severe group and non-severe group.', 'In addition, higherα- hydroxybutyrate dehydrogenase activity, lactate dehydrogenase activity and creatine kinase activity were related to severe cases and reach of composite endpoint.', 'The influence of 2019 novel coronavirus on heart also need to be further studied.', 'Furthermore the decrease in total protein level reflected a high consumption state of nutrition, which suggested that patients with 2019 novel coronavirus pneumonia need more nutrition during hospitalization.', 'In summary, multiple factors were found related to the severity of 2019 novel coronavirus pneumonia and composite endpoint.', 'More related studies are needed in the future.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['J o u r n a l P r e -p r o o f 2 (Lanjuan Li); yidayang65@zju.edu.cn (Yida Yang', 'Purpose: To investigate the epidemiological, clinical characteristics of COVID-19 patients with abnormal imaging findings.', 'Jan 17 to Feb 8 underwent CT or x-ray were enrolled.', 'Epidemiological, clinical data were analyzed between those with abnormal or normal imaging findings.', 'Results: Excluding 72 patients with normal images, 230 of 573 patients affected more than two lobes.', \"The median radiograph score was 2.0 and there's negative correlation between the score and oxygenation index (ρ=-0.657, P<0.001).\", 'Patients with abnormal images were older (46.65±13.82), with higher rate of coexisting condition(28.8%), lower rate of exposure history and longer time between onset and confirmation(5d) than non-pneumonia patients(all P<0.05).', 'Higher rate of fever, cough, expectoration, and headache, lower lymphocytes, albumin, serum sodium levels and higher total bilirubin, creatine kinase, lactate dehydrogenase and C-reactive J o u r n a l P r e -p r o o f 3 protein levels and lower oxygenation index were observed in pneumonia patients (all P<0.05).', 'Muscle ache, shortness of breath, nausea and vomiting, lower lymphocytes levels and higher serum creatinine and radiograph score at admission were predictive factors for severe/critical subtype.', 'Patients with abnormal images have more obvious clinical manifestations and laboratory changes.', 'Combing clinical features and radiograph score can effectively predict severe/critical type.', 'The recent emergence of SARS-CoV-2 has caused an outbreak of unusual viral pneumonia in patients in Wuhan.', 'In a short period, national spreading and global dispersal of the causative agent have become a big threat to global health (Biscayart et al., 2020 , WorldHealthOrganization, 2020a .', 'The symptoms of COVID-19 are similar to other respiratory viruses, including fever, cough and fatigue, diarrhea and vomiting, with radiographs showing invasive lesions in the lung.', 'And some of patients may be presented with serious complications such as acute respiratory distress syndrome or shock (Chen et al., 2020 , Huang et al., 2020 , Zhu et al., 2020 .', 'With the continuous improvement of modern imaging technology, imaging examination is more conducive to the objective assessment and early detection of lung abnormality.', 'In view of the current situation that images conform to features of SARS-CoV-2 pneumonia while the etiology test is negative at initial until the subsequent repeated tests are positive (Xie et al., 2020) , combing images with clinical features is necessary to diagnosis.', 'Therefore, in our retrospective J o u r n a l P r e -p r o o f study, we evaluated the epidemiological, clinical features, laboratory data of those with abnormal imaging findings.', 'The imaging findings of SARS-CoV-2 pneumonia are similar to acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS', 'Therefore, we evaluated the basic and clinical characteristics of SARS-CoV-2 pneumonia.', 'Among those with abnormal images, fever and cough are the most common symptoms, followed by sputum production, which was consistent with former report (Chen et al., 2020) .', 'Different from former report, which tended to infect older (median 55.5y), man (68%) with underlying medical condition (50%), the average age of novel coronavirus pneumonia was 46.65±13.82y, the gender ratio was close to 1:1 and the rate of patients with coexisting condition was 28.8% in our study (Chen et al., 2020) .', 'One possibility was that the number of cases of our study was larger than that of 99 cases.', 'Another was that our results were based on Zhejiang province, far away from J o u', 'r n a l P r e -p r o o f Wuhan and SARS-CoV-2 itself may has virulence changes during human-to-human dissemination, including epidemiological features.', 'Our results may suggest general susceptibility.', 'Compared with patients with normal imaging findings, the average age of patient with pneumonia appearance was older and the rate of at least one coexisting medical condition was higher.', 'This may suggest that relatively older patients and accompanying with chronic diseases are prone to have lung injury.', 'Interestingly, the rate of exposure history from Wuhan and/or contact with confirmed patients was higher and the time from onset to SARS-CoV-2 infection confirmation was shorter in non-pneumonia patients.', 'A possible explanation for these results were that those patients were in the state of medical observation.', 'Once they were presented with any discomfort, they were requested to test whether the SARS-CoV-2 was positive and even some patients were initiative to ask for testing.', 'Besides, we identified significantly higher rate of symptoms of fever, cough, sputum production and headache.', 'The rate of sore throat of patients with abnormal images was significantly lower than that of the counterpart.', 'Since former report indicated that the initial and early-progress radiograph can be normal (Holshue et al., 2020) , the clinical symptoms were not typical and obvious.', 'The imaging of non-pneumonia patients at the initial of admission may gradually progress.', 'As there was no obvious abnormality in CT examination of patients with positive nucleic acid test, which suggested that there might be some lag between X-ray and CT examination, those patients should be monitored closely in case of timely treatment.', 'However, different J o u r n a l P r e -p r o o f from patients infected with H1N1 that diarrhea is associated with chest X-ray abnormalities (Cao et al., 2009) , the difference of gastrointestinal symptoms of two groups in our study were not significant.', 'One possible explanation is that SARS-CoV-2 can bind to ACE2 of intestinal tract (Hao Zhang ZK, Wan et al., 2020) while H1N1 binds to Saα2, 3Gal receptor (Riquelme et al., 2009) , but the specific mechanism is not clear at present.', 'Laboratory results were also monitored, as we found that the patients with imaging abnormalities had lower lymphocytes, albumin, serum sodium levels and higher lactate dehydrogenase and C-reactive protein levels.', 'This finding may suggest that that having pneumonia may be associated with severe disease, and patients tended to have more severe clinical features, which was in accordance with lower oxygenation index, an index to evaluate respiratory function and the severity of the disease.', 'For further study, radiograph score which may be helpful for rough estimation lung lesions was proposed.', 'Then we found a significant negative correlation (ρ=-0.657, P<0.001) between radiograph score and oxygenation index.', 'Therefore, we guess the more involvement of lobes, the worse pulmonary functions.', 'Currently, no effective antiviral therapy for COVID-19 was confirmed (Zhang and Liu, 2020) .', \"Interferon-α, Lopinavir/Ritonavir and Arbidol were used according to previous experience, however, there's a lack of evidence of unified treatment plan.\", 'A significant higher rate of glucocorticoid application in patients with abnormal imaging than that the counterpart.', 'A former study showed proper use of corticosteroid in critical SARS reduced the mortality (Chen et al., 2006) .', 'Thus, patients with multiple lobes involvement may be considered for corticosteroid to control the progression.', 'Oxygen J o u r n a l P r e -p r o o f therapy plays a key role in supportive care of patients.', 'Generally, patients with hypoxemia (PaO2 <60mmHg or SaO2<90% under the condition of air) or with symptom of dyspnea may be considered for it by nasal cannula or mask.', 'When the symptom or hypoxemia is improved (SaO2>90% or the level of PaO2 reach to 60-70mmHg), the flow of oxygen can be gradually reduced and even stopped.', 'Otherwise, high flow oxygen inhalation or noninvasive ventilation is considered and invasive ventilation can be adopted if the disease still progress (Medicine, 2020) .', 'However, some patients may be administrated with low flow oxygen therapy on admission in order to reduce the burden of lung.', 'In our study, we also found the rate of oxygen therapy in patients with abnormal imaging was significantly higher, which may be related to lower oxygenation index.', 'In view of the current stage to explore a standard treatment regimen, we are not sure early use of oxygen therapy is helpful for prognosis, which can be further discussed.', 'We also in depth analyzed the predictive factors of severe/critical novel coronavirus pneumonia.', 'Patients with the symptoms of shortness of breath and nausea and vomiting tended to be severe, and the similar results related to H1N1 pneumonia had been revealed in previous report, showing that the symptoms mentioned above were risk factors (Kanchana et al., 2013 , Na et al., 2011 .', 'Lower lymphocytes level at initial of admission was also the significantly predictive factors, which were also described as prognostic indicators for ARDS and death in H5N1 and H1N1 infections (Chotpitayasunondh et al., 2005 , Reyes et al., 2011 .', 'Besides, we found higher serum creatinine was one of predictors, as former study revealed acute kidney injury was the common J o u r n a l P r e -p r o o f complication of severe H1N1 infection and related to higher mortality (Trimarchi et al., 2010) .', 'Higher radiograph score was related to severity of disease, in accordance with former report which used another CT score (Xu et al., 2020) .', 'These clinical features may be a useful tool for predicting of severe/critical type as it is convenient to tested in hospitals.', 'There are several limitations of our study.', \"Firstly, at the time of this writing, only preliminary data have been collected and many patients still remained in the hospital, and it's better to obtain the progress of imaging and the outcomes of patients.\", 'Second, the description of imaging should be more detailed, which may be helpful for the judgment of the disease and the treatment in the later stage.', 'Thirdly, our study was limited by the observational nature of the investigation.', 'Finally, according to the data in admission, risk factors for severe/critical type of COVID-19 were identified, however, it is still lack prediction model for disease progression.', 'In conclusion, there are some certain characteristics in chest imaging of COVID-19.', 'And we reported the difference of specific epidemiological and clinical features of between patients with abnormal or normal imaging, including fever, cough and sputum production and relatively poor laboratory results.', 'Symptoms of muscle ache, shortness of breath and nausea and vomiting, lower lymphocytes and higher serum creatinine and radiograph score were predictive factors for severe/critical subtype.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['All of these patients were admitted to negative pressure isolation wards.', 'Patients were given supportive treatment after admission.', 'Antiviral drugs (e.g., lopinavir/ritonavir, arbidol) were tried in a small proportion of patients.', 'Corticosteroid was not used unless a panel discussion by experts considered necessary (e.g., ARDS).', 'A total of 22(8.8%) patients were admitted in ICU 8.5 ± 4.0 days after onset of symptoms.', 'A total of 8(3.2%) patients developed ARDS 4.8 ± 2.4 days after onset of symptoms.', 'To the time of submission, a total of 215 (86.3%) patients were discharged after 16 (12) (13) (14) (15) (16) (17) (18) (19) (20) days hospitalization, 13 patients were still in ICU and 19 patients in stable condition.', 'A total of 2 patients died (0.8%).', 'Studies on COVID-19 have generally been limited to the description of the epidemiology characteristics, initial clinical, hematological and radiological findings.', '[11] [12] [13] [14] [15] [16] To our knowledge, this is the first report to date that describes the temporal clinical progression of COVID-19.', 'In the current study, most of the cases were mild as evidenced by relatively low rates of ICU admission and high rate of cure rate.', 'This is inconsistent with a recent report which showed more than 80% of COVID-19 cases were mild in China.', 'However, nearly 10% were severe and critical, indicating that exploring the clinical progression and possible mechanisms is essential to the disease control.', 'The clinical progression of COVID-19 in our patients showed a biphasic pattern.', 'The first phase was characterised by fever, cough, fatigue and other systemic symptoms.', 'In consistent with previous studies, we found that fever was the most common symptom in patients with COVID-19.', 'As high as 94.3% of the patients in this study, including those who were afebrile on admission had fever.', 'Guan et al. recently showed that only 43.8% of the patients with COVID-19 on presentation but developed fever in 87.9% following hospitalization, indicating the afebrile patients may be at the early stage of the disease.', '15 During this first phase, consistent with fever, the disease progressed as evidenced by radiological worsening within 7 days after onset of symptoms.', 'The disease progression during this time could be explained by uncontrolled viral replication as most majority of the patients showed positive results for SARS-CoV-2 PCR from their upper respiratory specimen.', 'As the disease progressed into week 2, symptoms began to relieve in most of the patients.', '10 days after onset of symptoms, half of the patients were estimated to restore normal body temperature.', 'The duration of fever was comparable to that in patients with SARS (11.4 days), but longer than those with MERS (8 days [range, 0-54 days]) and other coronavirus diseases.', '[18] [19] [20] However, different from SARS, whose patients frequently had recurrence of fever in week 2, most of the patients with COVID-19 had normal temperature thereafter.', '21 In line with defervescence, half of the patients also became PCR negative with their upper respiratory tract samples.', 'In addition, radiological improvement was observed in 94.5% of the patients whose radiological images showed worsening in the first week.', 'The median time to viral clearance in this study was 11 days after onset of symptoms, which was significantly shorter than that in MERS (17 days), indicating it is virulence maybe lower than MERS.', '19 Actually, most of the patients are able to clear the virus and their clinical course fit the biphasic model well.', 'However, viral clearance was observed in only a small proportion of patients in ICU.', 'Therefore, the clinical progression in these severe cases may not fit this biphasic model.', 'Indeed, patients admitted to ICU were unable to defervesce without corticosteroid therapy or had significantly longer duration of fever compared with those in the non-ICU group.', 'Persistent fever, lung damage and diseases progression could be partially explained by uncontrolled viral replication.', 'To reduce the risk of disease progression and poor outcome, an effective antiviral to early reduce the viral load may be important.', 'Several drugs are potential candidates to inhibit SARS-CoV-2 replication, including remdesivir which is under clinical trial.', '5 The host immune responses against the SARS-CoV-2 may also contribute substantially to COVID-19 pathogenesis.', 'In the current study, both older age and lower CD4 T cells count, indicators of immunosuppression, were significantly associated with ICU admission.', 'For our patients who stayed in ICU, elevated interleukin 6 levels had been observed (data not shown), which is in consistent with the previous reports.', '12 , 22 Therefore, the persistence of COVID-19 induced excessive but aberrant non-effective response which is associated with cytokine storm.', '11 , 23 A small proportion of patients developed ARDS early in the clinical course and five of the patients in ICU did not improve significantly after viral control.', 'Consistently, inflammation persists after viral clearance in SARS.', '21 Taken together, these evidences indicate that disease progression may be a result of an over exuberant host response.', 'Along this line, apart from effective antiviral agents which could decrease viral load at the early stage and in turn result in decreased immunopathological damage, the role of host-directed therapy could be an important tool to reduce the mortality.', '24 Theoretically, corticosteroid treatment could have a role in the treatment of COVID-19 as it suppress lung inflammation.', 'Despite of fever persistence and radiological worsening in the first week, most of the patients had normal temperature and improvement in images with or without supportive therapy from the second week after onset of symptoms.', 'Most importantly, corticosteroid had been shown to delay clearance of MERS-CoV from respiratory tract and SARS-CoV from blood, respectively.', '25 , 26 In the current study, delayed COVID-19 clearance was associated with ICU admission.', 'Therefore, in agreement with the WHO guideline, we are against the usage of corticosteroid for the treatment of COVID-19.', '4 , 27 There are some limitations of our study.', 'First, a small proportion the patients were still hospitalized at the time of manuscript submission.', 'Therefore, clinical outcomes in these patients were not available and continued observations are still needed.', 'Second, we did not test SARS-CoV-2 daily for everybody.', 'Hence, the actual duration to viral clearance should be shorter than the estimated one.', 'Meanwhile, we did not quantify the viral load of the SARS-CoV-2 and false negative of the PCR result for upper respiratory sample has also been reported.', '15 For that reason, studies on the dynamic changes of the viral load are still warranted.', 'In summary, the majority of COVID-19 cases are mild.', 'The two phase pattern of the disease progression suggests that early control of viral replication and application of host-directed therapy at later stage is essential to improve the prognosis of CVOID-19.']}\n", - "{'sentences': ['The IMPDH inhibitor merimepodib suppresses SARS-CoV-2 replication in vitro', 'The ongoing COVID-19 pandemic continues to pose a major public health burden around the world.', 'The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected over one million people worldwide as of April, 2020, and has led to the deaths of nearly 300,000 people.', 'No approved vaccines or treatments in the USA currently exist for COVID-19, so there is an urgent need to develop effective countermeasures.', 'The IMPDH inhibitor merimepodib (MMPD) is an investigational antiviral drug that acts as a noncompetitive inhibitor of IMPDH.', 'It has been demonstrated to suppress replication of a variety of emerging RNA viruses.', 'We report here that MMPD suppresses SARS-CoV-2 replication in vitro.', 'After overnight pretreatment of Vero cells with 10 μM of MMPD', 'The effect is dose-dependent, and concentrations as low as 3.3 μM significantly reduced viral titers when the cells were pretreated prior to infection.', 'The results of this study provide evidence that MMPD may be a viable treatment option for COVID-19.']}\n", - "{'sentences': [\"[{'text': 'Introduction: COVID-19 may predispose to both venous and arterial thromboembolism due to excessive inflammation, hypoxia, immobilisation and diffuse intravascular coagulation.\", 'Reports on the incidence of thrombotic complications are however not available.', 'Methods: We evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism in all COVID-19 patients admitted to the ICU of 2 Dutch university hospitals and 1 Dutch teaching hospital.', 'Results: We studied 184 ICU patients with proven COVID-19 pneumonia of whom 23 died (COVID-19 pneumonia of whom 23 died), 22 were discharged alive (12%) and 139 (76%) were still on the ICU on April 5th 2020.', 'All patients received at least standard doses thromboprophylaxis.', 'The cumulative incidence of the composite outcome was 31% (95%CI 20-41), of which CTPA and/or ultrasonography confirmed VTE in 27% (95%CI 17-37%) and arterial thrombotic events in 3.7% (95%CI 0-8.2%).', 'PE was the most frequent thrombotic complication (n = 25, 81%).', 'Age (adjusted hazard ratio (aHR) 1.05/per year, 95%CI 1.004-1.01) and coagulopathy, defined as spontaneous prolongation of the prothrombin time > 3 s or activated partial thromboplastin time > 5 s (aHR']}\n", - "{'sentences': ['The secondary outcomes were also improved (Table 4).', 'Considering, for example, the critically severe patient 1, the lymphopenia was significantly improved after the cell transplantation.', 'The patient was isolated in the hospital isolation ward with a history of hypertension and blood pressure reaching grade 3 hypertension.', 'On Feb 1, biochemical indicators in the blood test showed that aspartic aminotransferase, creatine kinase activity and myoglobin increased sharply to 57 U/L, 513 U/L, and 138 ng/ml, respectively, indicating severe damage to the liver and myocardium.', 'However, the levels of these functional biochemical indicators were decreased to normal reference values in 2~4 days after treatment (Table 4).', 'On February 13, all the indexes reached normal levels, namely 19 U/L, 40 U/L, and 43 ng/ml, respectively.', 'The respiratory rate was decreased to the normal range on the 4th day after MSC transplantation.', 'Both fever and shortness of breath disappeared on the 4th day after MSCs transplantation.', 'Chest CT imaging showed that the ground-glass opacity and pneumonia infiltration were largely reduced on the 9th day after MSC transplantation (Fig. 2).', 'The immunomodulating function of MSCs contributed to the main efficacy outcome and the transplantation of MSCs showed impressive positive results (Table 3).', 'For the primary outcome in the critically severe patient 1, the plasma C-reaction protein level decreased from 105.5 g/L (Jan 30) to 10.1 g/L (Feb 13), which reached the highest level of 191.0 g/L on Feb 1, indicating that the inflammation status was alleviating quickly.', 'The oxygen saturation, without supplementary oxygen, rose from 89% (Jan 31) to 98% (Feb 13), which indicated the pulmonary alveoli regained the air-change function.']}\n", - "{'sentences': ['COVID-19 and Chloroquine/Hydroxychloroquine: is there Ophthalmological Concern?']}\n", - "{'sentences': ['Addition of adjuvant corticosteroid therapy to standard antiviral treatment of patients with coronavirus disease (COVID-19) is common in clinical practice.', 'However, evidence is scarce regarding the efficacy of adjuvant corticosteroids in patients who are critically ill.', 'We retrospectively evaluated the effects of adjuvant corticosteroid treatment on the outcome of 244 critically ill patients with COVID-19, using a risk stratification model that adjusts for potential differences between the steroid group']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['As of 22 February 2020, more than 77662 cases of confirmed COVID-19 have been documented globally with over 2360 deaths.', 'Common presentations of confirmed cases include fever, fatigue, dry cough, upper airway congestion, sputum production, shortness of breath, myalgia/arthralgia with lymphopenia, prolonged prothrombin time, elevated C-reactive protein, and elevated lactate dehydrogenase.', 'The reported severe/critical case ratio is approximately 7-10% and median time to intensive care admission is 9.5-10.5 days with mortality of around 1-2% varied geographically.', 'Similar to outbreaks of other newly identified virus, there is no proven regimen from conventional medicine and most reports managed the patients with lopinavir/ritonavir, ribavirin, beta-interferon, glucocorticoid and supportive treatment with remdesivir undergoing clinical trial.', 'In China, Chinese medicine is proposed as a treatment option by national and provincial guidelines with substantial utilization.', 'We reviewed the latest national and provincial clinical guidelines, retrospective cohort studies, and case series regarding the treatment of COVID-19 by add-on Chinese medicine.', 'We have also reviewed the clinical evidence generated from SARS and H1N1 management with hypothesized mechanisms and latest in silico findings to identify candidate Chinese medicines for the consideration of possible trials and management.', 'Given the paucity of strongly evidence-based regimens, the available data suggest that Chinese medicine could be considered as an adjunctive therapeutic option in the management of COVID-19.']}\n", - "{'sentences': ['The literature reports several symptoms of SARS-CoV-2 in humans such as fever, cough, fatigue, pneumonia, and headache.', 'Furthermore, patients infected with similar strains (SARS-CoV and MERS-CoV) suffered testis, liver, or thyroid damage.', 'Angiotensin-converting enzyme 2 (ACE2) serves as an entry point into cells for some strains of coronavirus (SARS-CoV, MERS-CoV, SARS-CoV-2).', 'Our hypothesis was that as ACE2 is essential to the SARS-CoV-2 virus invasion, then brain regions where ACE2', 'Thus, the expression of other genes which are also over-expressed in those damaged areas could be affected.', 'We used mRNA expression levels data of genes provided by the Allen Human Brain Atlas (ABA', 'In this study we explored the topographical network of genes that are overexpressed in the same regions as ACE2.', 'Our first objective was to topographically localize the mRNA expressions of ACE2.', 'Consequently, we explored the topographical network of genes with the highest mRNA expressions in the same brain regions.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.06.027318 doi: bioRxiv preprint significant increase in concentration of their mRNAs in the same regions where ACE2 mRNA levels are the highest.', 'NCBI and GenesCards platforms were used to explore the other organs where these 100 genes are most expressed.', 'All these results can be observed interactively on LinkRbrain platform via the link http://authorized2019.linkrbrain.org/query/#5937, or in the generated file referenced as supplementary material (SM', 'Analyzing the biological functions of these 75 genes allowed us to categorize them into 16 groups (see Table 1 ).', 'The first group concerns olfactory receptors (which can be the entry point for the virus into the brain), but also genes that are most expressed in the organs related to the symptoms reported in the literature, such as the lymph nodes (for immunity), testis, spleen, liver, and intestines.', 'Ding et al. [9] reported that the coronavirus was detected in some organs like lungs or intestine, However, no trace of this virus was detected in damaged organs such asSARS-CoVdamaged organs like oesophagus, thyroid, spleen, lymph node, bone marrow, testis, ovary, uterus, or heart.', 'In summary, the list of organs where genes sharing local over-expression with the ACE2 gene are the most expressed is astonishingly similar to that of the organs affected by Covid-19.']}\n", - "{'sentences': ['A novel coronavirus (2019-nCoV) outbreak has caused a global pandemic resulting in tens of thousands of infections and thousands of deaths worldwide.', 'The RNA-dependent RNA polymerase (RdRp, also named nsp12), which catalyzes the synthesis of viral RNA, is a key 5 component of coronaviral replication/transcription machinery and appears to be a primary target for the antiviral drug, remdesivir.', 'Here we report the cryo-EM structure of 2019-nCoV full-length nsp12 in complex with cofactors nsp7 and nsp8 at a resolution of 2.9-Å. Additional to the conserved architecture of the polymerase core of the viral polymerase family and a nidovirus RdRp-associated nucleotidyltransferase (NiRAN', 'One Sentence Summary: Structure of 2019-nCov RNA polymerase.', 'infections and 4291 fatalities have been confirmed globally.', '2019-nCoV is reported to be a new member of the betacoronavirus genus and is closely related to severe acute respiratory syndrome coronavirus (SARS-CoV) and to several bat coronaviruses (4).', 'Compared to SARS-CoV', 'CoVs employ a multi-subunit replication/transcription machinery, being assembled by a set of non-structural proteins (nsp) produced as cleavage products of the ORF1a and ORF1ab viral polyproteins (5) to facilitate virus replication and transcription.', 'A key component, the RNA-10 dependent RNA polymerase (nsp12), catalyzes the synthesis of viral RNA and thus plays a central role in the replication and transcription cycle of 2019-nCoV, possibly with the assistance of nsp7 and nsp8 as co-factors (5, 6).', 'Therefore, nsp12 is a primary target for the nucleotide analog antiviral inhibitors, e.g. remdesivir which shows potential to treat 2019-nCoV infections (7, 8).', 'To inform drug design we have determined the structure of nsp12, in complex with its cofactors nsp7 15 and nsp8 by cryo-Electron Microscopy (Cryo-EM', 'The bacterially expressed full-length 2019-nCoV nsp12 (residues S1-Q932) was incubated with nsp7 (residues S1-Q83) and nsp8 (residues A1-Q198), and the complex was then purified (fig. S1).', 'Cryo-EM grids were prepared using this complex and preliminary screening revealed 20 excellent particle density with good dispersity.', 'After collecting and processing 7,994 micrograph movies, we obtained a 2.9-Å resolution 3D reconstruction of one nsp12 monomer in complex with one nsp7-nsp8 pair and one nsp8.', 'Like that observed in SARS-CoV nsp12-nsp7-nsp8 (6), we observed classes corresponding to an nsp12 monomer in complex one nsp8, as well as individual nsp12s, but these do not give atomic resolution reconstructions ( fig. S2 ).', 'However, the nsp12-25 nsp7-nsp8 complex provides all the structural information for complete and comprehensive analysis.', 'The structure of the 2019-nCoV nsp12 contains a \"right hand\" polymerase domain (residues S367-F920), and a nidovirus-unique N-terminal extension domain (residues D60-R249) adopting a nidovirus RdRp-associated nucleotidyltransferase (NiRAN)(9) architecture, being connected by 30 an interface domain (residues A250-F369) (Figs. 1, A and B).', 'An additional N-terminal β-hairpin (V31-K50) was built with the guidance of an unambiguous cryo-EM map (fig. S3A), inserting into the groove clamped by the NiRAN domain and the palm subdomain in the RdRp domain (Fig. 2) .', 'The nsp7-nsp8 pair shows a conserved structure similar to the SARS-CoV nsp7-nsp8 pair (6, 10).', 'The orientation of the N-terminal helix of another individual nsp8 bound to nsp12 is shifted 35 compared with that in the nsp7-nsp8 pair ( fig. S4 ).', 'The polypeptides of nsp12 can be traced in the map, except for S1-V30, T51-S68, H75, K103-V111, D336, T896-S904, F921-Q932, which cannot be observed.', 'Although the overall architecture of 2019-nCoV nsp12-nsp7-nsp8 complex is generally similar to that of SARS-CoV with an r.m.s.d value of 0.82 for 1,078 Cɑ atoms there are key features that 40 distinguish them.', 'First, the cryo-EM map allows us to build the structure of 2019-nCoV nsp12 covering almost all residues, presenting the first insight into the complete architecture of coronaviral RdRp.', 'In SARS-CoV nsp12, there are seven helices with a three-stranded β-sheet at the end that make up the NiRAN domain (6) ( Fig. 2A) .', 'Residues Y69-R118 constitute an additional structural block with three anti-parallel β-strands and one helix.', 'Residues N215-D218 45 author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', ': bioRxiv preprint 4 form a β-strand in 2019-nCoV nsp12.', 'We reasoned that the contact of this region with the strand (residues V96-A100) helps to stabilize it.', 'As a result, these four strands form a compact semi βbarrel architecture.', 'Therefore, we identify residues Y69-R249 as the complete coronaviral NiRAN domain.', 'Second, the cryo-EM map helps us to identify a unique N-terminal β-hairpin (Figs. 1A and 2A).', 'This β-hairpin inserts in the groove clamped by the NiRAN domain and the palm 5 subdomain in the RdRp domain and forms a set of close contacts to stabilize the overall structure ( Fig. 2B and fig. S5 ).', 'Another point to note is that, we have observed C301-C306 and C487-C645 form disulfide bonds in the absence of DTT (Dataset-1).', 'However, in the presence of DTT (Dataset-2), chelated zinc ions are present and in the same location as that observe in SARS-CoV ( fig. S3B) .', 'We reasoned the different purification buffer has led to this variation.', 'The polymerase domain adopts the conserved architecture of the viral polymerase family (11) and is composed of three subdomains, including a fingers subdomain (residues S397-A581 and K621-G679), a palm subdomain (residues T582-P620 and T680-Q815), and a thumb subdomain (residues H816-E920) (Fig. 1) .', 'The catalytic cations, which are usually observed in viral polymerase structure for RNA synthesis (12, 13) are not observed, possibly because manganese 15 was not included in the buffer for purification or in the cryo-EM sampling buffer.', 'The active site chamber of 2019-nCoV RdRp domain is formed by the conserved polymerase motifs A-G in the palm domain and configured like other RNA polymerases (Figs. 1A and 3A; fig. S6).', 'Motif A covers residues 611-TPHLMGWDYPKCDRAM-626 with a potential divalentcation-binding residue D618, which is conserved in HCV ns5b (residue D220) and poliovirus (PV) 20 3D pol (residue D233) (12, 13) (Figs. 3, B and C).', 'Motif B is in the region 680-TSSGDATTAYANSVFNICQAVTANVNALLST-710.', 'Motif C (residues 753-FSMMILSDDAVVCFN-767) contains the catalytic residues (759-SDD-761) in the turn between the two β-strands.', 'These catalytic residues are also conserved in viral RdRp, e.g. 317-GDD-319 in HCV ns5b and 327-GDD-329 PV', 'In this structure, the four positively charged solvent-accessible paths converge into a central cavity 30 where the RdRp motifs mediate template-directed RNA synthesis (Fig. 3D ).', 'The configurations of the template/primer entry paths, the nucleoside triphosphate (NTP) entry channel, and the nascent strand exit path are similar to those described for HCV and PV polymerase (14) (Figs. 3, B and C).', 'Remdesivir, the single Sp isomer of the 2-ethylbutyl L-alaninate phosphoramidate prodrug (15) ( fig. S7 ), has been reported to inhibit 2019-nCoV proliferation and have potential to treat patients 40 in the clinic (7, 8).', 'The efficacy of chain-terminating nucleotide analogs requires viral RdRps to recognize and successfully incorporate the active form of the inhibitors into the growing RNA strand.', \"Because of the structural conservation on the polymerase catalytic chamber between 2019-nCoV and HCV ns5b polymerase, as well as the likely similar mechanisms of action of remdesivir and sofosbuvir (12, 16) (2'-F-2'-C-methyluridine monophosphate prodrug which targets HCV 45 author/funder.\", 'All rights reserved.', 'No reuse allowed without permission.', ': bioRxiv preprint 5 ns5b and has been approved for the treatment of chronic HCV infection) ( fig. S7) , a model of 2019-nCoV nsp12 with remdesivir diphosphate is proposed (Fig. 4) .', \"In 2019-nCoV nsp12, the 2' hydroxyl of the incoming NTP is likely to form hydrogen bonds with T680 and N691 in motif B (Figs. 4, A and B ).\", \"In addition, D623 in motif A is positioned to interrogate the 3' hydroxyl through hydrogen bonding.\", 'Moreover, the hydrophobic side chain of V557 in motif F is likely to stack with 5 and stabilize the +1 template RNA uridine base to base pair with the incoming triphosphate remdesivir (ppp-remdesivir).', 'In the structures of HCV ns5b elongation complex or its complex with pp-sofosbuvir, a key feature is that the incorporated pp-sofosbuvir disrupts the hydrogen bonding network between S282 and D225 (Figs. 4, C and D), which is necessary to stabilize the incoming natural nucleotide (12).', 'However, key contacts formed by S282 with the incoming 10 nucleotide and the surrounding environment can result in an S→T resistance mutation that is already observed in the clinic (17).', 'In the structure of apo 2019-nCoV nsp12, the orientation of S682 and D623, which are strictly conserved with S282 and D225 in HCV ns5b, is similar to that observed in the HCV ns5b-pp-sofosbuvir complex, indicating a different recognition mechanism with that inhibitor.', 'Nevertheless, the close distance of S682 with the incoming ppp-remdesivir', 'The rapid global spread of 2019-nCoV has emphasized the need for the development of new coronavirus vaccines and therapeutics.', 'The viral polymerase nsp12 looks an excellent target for new therapeutics, especially given that lead inhibitors already exist in the form of compounds such 20 as remdesivir.', 'This target, in addition to other promising drug targets such as the main protease, whose structure was recently determined by our group (18) in complex with an inhibitor (19, 20) will support the development of a cocktail of anti-coronavirus treatments that potentially can be used for the discovery of broad-spectrum antivirals.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Background In December 2019, novel coronavirus (SARS-CoV-2) infected pneumonia occurred in Wuhan, China.', 'The number of cases has increased rapidly but information on the clinical characteristics of SARS-CoV-2 pneumonia without comorbidities compared to normal controls in Chinese Han population is limited.', 'Our objective is to describe the epidemiological and clinical characteristics of SARS-CoV-2 pneumonia without comorbidities compared to normal controls in the Chinese Han population.', 'Methods Retrospective, multi-center case series of the 69 consecutive hospitalized patients with confirmed SARS-CoV-2 pneumonia,', 'The study population included 69 hospitalized patients with confirmed SARS-CoV-2 pneumonia without comorbidities and 14,117 normal controls.', '50.7% patients were male and 49.3% were female; 1.5% patients were asymptomatic cases, 63.8% patients were mild cases, and 36.2% patients were severe or critical cases.', 'Compared with mild patients (n=44), severe or critical patients (n=25) were significantly older (median age, 67 years [IQR, vs. 49 years [IQR, 36-60]; p<0.01).', 'Fever was present in 98.6% of the patients.', 'The second most common symptom was cough (62.3%), fatigue (58.0%), sputum (39.1%), and headache (33.3%).', 'The median incubation period was 4 days (IQR, 2 to 7).', 'Leukocyte count was 74.1% of normal controls and lymphocyte count was 45.9% of normal controls.', 'The phenomenon of lymphocyte depletion (PLD', 'Levels of lactate dehydrogenase, D-dimer, procalcitonin, and interleukin-6 were showed significant differences between mild and severe or critical cases.', 'Chest computed tomographic scans showed bilateral patchy patterns (49.3%), local patchy shadowing (29.0%), and ground glass opacity (21.7%).', '7.3% patients were diagnosed ARDS, 7.3% patients were diagnosed acute cardiac injury (troponin I >28 pg/mL) and 4.4% patients were diagnosed fungal infections or shock.', '4.3% patients have been discharged; 1.5% patient had died; 1.5% patient had recovery.', 'Conclusions In this multicenter case series of 69 patients without comorbidities, the full All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', ': medRxiv preprint 3 spectrum of asymptomatic, mild, severe, and critical cases is described.', '50.7% patients were male and 49.3% were female; 1.5% patients were asymptomatic cases, 63.8% patients were mild cases, and 36.2% patients were severe or critical cases.', '4.3% patients have been discharged; 1.5% patient had died; 1.5% patient had recovery.', 'Among the 25 patients with severe or critical disease, 12.0% patients were underwent non-invasive mechanical ventilation, 8.0% patients underwent invasive mechanical ventilation, and 4.0% patients died.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'All patients were treated in isolation.', '38 (55.1%) patients received antiviral treatment, including oseltamivir (75 mg every 12 h, orally).', '31 (44.9%) patients were treated with All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.08.20031658 doi: medRxiv preprint 11 antibiotics.', 'The antibiotics used generally covered mild pathogens and some atypical pathogens; when secondary bacterial infection occurred, medication was administered according to the results of bacterial culture and drug sensitivity.', 'The antibiotics used were moxifloxacin, ceftriaxone, azithromycin, and tigecycline or linezolid against methicillin-resistant Staphylococcus aureus, as well as antifungal drugs.', 'Six patients significantly increased in IL6 were also treated with methylprednisolone.', 'Three patients used non-invasive ventilator mechanical ventilation.', 'Two patients used an invasive ventilator to assist ventilation.', 'The ventilator adopted P-SIMV mode, the inhaled oxygen concentration was 35-100%, and the positive end-expiratory pressure was 6-12 cm H 2 O. No patients were treated with extracorporeal membrane oxygenation (ECMO', 'By the end of February 29, three (4.3%) patients have been discharged; one (1.5%) patient had died; one) patient had died; one (1.5%) patient had died; one', 'This report, to our knowledge, is the first retrospective multicenter study of COVID-19 with normal controls.', 'The study population included 69 hospitalized COVID-19 patients without comorbidities and 14,117 normal controls.', '50.7% patients were male and 49.3% were female; 1.5% patients were asymptomatic cases, 63.8% patients were mild cases, and 36.2% patients were severe or critical cases.', 'The median incubation period was 4 days (IQR, 2 to 7).', 'The median age of the patients was 57 years (IRQ, 43 to 69); 39.1% of the patients were older than 60 years of age.', 'Fever was present in 98.6% of the patients.', 'The second most common symptom was cough (62.3%), fatigue (58.0%), sputum (39.1%), and headache (33.3%).', 'Less common symptoms were chill, sore throat, shortness of breath, anorexia, diarrhea, nausea, All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'There is no acute kidney injury since serum creatinine level is within a normal range ( Table 1, Table 2 ), indicating that patients with comorbidities might prone to acute kidney injury.', '14 For the asymptomatic case, we speculate that the patient is currently taking HIV medications and the medication is interfering with the results of RT-PCR.', 'Further research and observation are needed.', 'Our findings included the PLD at presentation were associated with the severity of disease.', 'The severe PLD or the acquired immunodeficiency (CD4 lymphocytes are below 200 cells/mm 3 ) is common in HIV patients.', 'When CD4 lymphocytes are below 200 cells/mm 3 , clinicians might pay attention to fungal infections.', 'There were three cases of fungal infections seen in our study indicating the lymphocyte depletion associated with fungal infections (Table 1, Table 3 ) as patients with T cell depletion have increased susceptibility to fungal infections.', '15, 16 Our findings also show significant differences (p < 0.01) in IL6 and D-dimer between mild and severe or critical groups, suggesting that IL6 and D-dimer are important parameters for the severity of disease (Table 1) .', 'It has been reported that SARS-CoV directly infects monocytes, macrophages and T lymphocytes in human.', 'The PLD may also be secondary to activation of T lymphocytes.', '18 COVID-19 has spread rapidly since it was first identified in Wuhan and has been shown to have a wide spectrum of severity as SARS-CoV-2 binds to ACE2 receptors in 10-20 fold higher affinity than SARS-CoV binds to the same receptors.', '7, 19 The report shows SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2.', 'Therefore, it is necessary to further study whether lymphocytes have ACE2 receptor and TMPRSS2 expression during the developmental stage since the PLD exists.', 'A SARS-CoV-2 RT-PCR assay for lymphocyte subsets in severe or critical cases should be followed up.', 'Our findings also suggest that All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'In this multicenter case series of 69 patients without comorbidities, the full spectrum of asymptomatic, mild, severe, and critical cases is described.', '50.7% patients were male and 49.3% were female; 1.5% patients were asymptomatic cases, 63.8% patients were mild cases, and 36.2% patients were severe or critical cases.', '4.3% patients have been discharged; 1.5% patient had died; 1.5% patient had recovery.', 'Among the 25 patients with severe or critical disease, 12.0% patients were underwent non-invasive mechanical ventilation, 8.0% patients underwent invasive mechanical ventilation, and 4.0% patients died.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.08.20031658 doi: medRxiv preprint Chest computed tomography imaging from mild cases (top two imaging) and from severe cases (bottom two imaging).', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.08.20031658 doi: medRxiv preprint author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the *ALT: alanine aminotransferase, AST: aspartate aminotransferase, CRP: C-reactive protein, ARDS: acute respiratory distress syndrome, ECMO: extracorporeal membrane oxygenation.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.08.20031658 doi: medRxiv preprint White blood cell 10 9 /L 6.50 Table 3 .', 'Lymphocyte subsets in COVID-19 pneumonia mild vs. severe or critical All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.08.20031658 doi: medRxiv preprint']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['18 SARS-CoV-2 is a novel coronavirus currently causing a pandemic.', 'We show 19', 'that the majority of amino acid positions, which differ between SARS-CoV-2 and the 20 closely related SARS-CoV, are differentially conserved suggesting differences in 21 biological behaviour.', 'In agreement, novel cell culture models revealed differences 22', 'between the tropism of SARS-CoV-2 and SARS-CoV. Moreover, cellular ACE2 23', '(SARS-CoV-2 receptor) and TMPRSS2 (enables virus entry via S protein cleavage) 24 levels did not reliably indicate cell susceptibility to SARS-CoV-2.', 'SARS-CoV-2 and 25 SARS-CoV further differed in their drug sensitivity profiles.', 'Thus, only drug testing 26 using SARS-CoV-2 reliably identifies therapy candidates.', 'Therapeutic concentrations 27 of the approved protease inhibitor aprotinin displayed anti-SARS-CoV-2 activity.', 'The 28 efficacy of aprotinin and of remdesivir (currently under clinical investigation against 29 SARS-CoV-2) were further enhanced by therapeutic concentrations of the proton 30 pump inhibitor omeprazole (aprotinin 2.7-fold, remdesivir 10-fold).', 'Hence, our study 31 has also identified anti-SARS-CoV-2 therapy candidates that can be readily tested in 32 patients.']}\n", - "{'sentences': [\"[{'text': 'Objective: To optimize clinical laboratory diagnosis of COVID-19 from suspect cases by Likelihood Ratio of SARS-CoV-2 IgM and IgG antibody.\", 'Methods: By reinterpreting the data in the article \"Diagnostic Value of Combined Detection of Serum 2019 novel coronavirus IgM and IgG Antibodies in novel coronavirusin Infection\", the positive likelihood ratio of IgM and IgG antibody in diagnosis of COVID-19 (nucleic acid positive patients) was calculated, and the posterior probability of IgM and IgG antibodies and their tandem detection to diagnose was finally calculated.', 'Results: The positive likelihood ratios of single IgM and IgG antibody were 18.50 and 12.65 respectively, and the posterior probabilities were 90.18% and 86.26% respectively.', 'However, the posterior probability of the two antibodies tandem detection is 99.15%, which can give clinicians quantitative confidence in the diagnosis of COVID-19 from suspected cases.', 'According to the results of this study, combining the advantages and disadvantages of nucleic acid detection and antibody detection, the clinical pathway for clinicians to diagnose COVID-19 is found.', 'Conclusion: For suspected cases, IgM and IgG antibody tests should be firstly done at the same time.', 'If the antibody tests are all positive, COVID-19 can be confirmed.', \"If not, nucleic acid detection (one or more times) is performed, and in extreme cases, high-throughput viral genome sequencing is performed.', 'cite_spans': [], 'ref_spans': [], 'section': 'Abstract'}]\"]}\n", - "{'sentences': ['The length of the paper: 1846 J o u r n a l P r e -p r o o f Highlights 1.', 'There are no clear expert consensus or guidelines on how to treat COVID-19.', 'We developed a risk-adapted treatment approach according to the illness severity.', 'This strategy was effective in symptoms alleviation and chest CT recovery.', 'This strategy is a useful and efficient approach for COVID-19 patients.', 'Background: There are no clear expert consensus or guidelines on how to treat 2019 coronavirus disease .', 'The objective of this study is to investigate the shortterm effect of risk-adapted treatment strategy on patients with COVID-19.', 'We collected the medical records of 55 COVID-19 patients for analysis.', 'We divided these patients into mild, moderate and severe groups, and risk-adapted treatment approaches were given according to the illness severity.', 'Results: Twelve patients were in mild group and 22 were in moderate group (non-severe group, n=34), and 21 patients were in severe group.', 'At the end of the first two weeks after admission, clinical manifestations had completely despeared in 31(91.2%)patients in non-severe group, and 18(85.7%) patients in severe group (p=0.85).', 'Both groups had a satisfied chest CT imaging recovery, which includes 22(64.7%) patients in non-severe group and 12(57.1%) patients in severe group recovered at least 50% of the whole leisions in the first week, and 28(82.4%) and 16(76.2%) recovered at least 75% in the second week, respectively.', 'There were no significant differences in SARS-CoV-2 RNA clearance between two group (p=0.92).', 'There were also no significant differences in the levels of SARS-CoV-2-IgM and IgG antibody production between the two groups (p=0.13, 0.62).', 'There were 45 cases were discharged from the hospital, and no patients died at the time of this clinical analysis.', 'Conclusions: Risk-adapted treatment strategy was associated with significant clinical manifestations alleviation and clinical imaging recovery.', 'In severe COVID-19 patients, early and short-term use of low-dose methylprednisolone was beneficial and did not delay SARS-CoV-2 RNA clearance and influence IgG antibody production.', 'J o u r n a l P r e -p r o o f 3', 'However, critical influenza may also cause complications with high morbidity and mortality, such as pneumonia, myocarditis, central nervous system disease and death [9] .', 'In this situation, we recommend to use a broad-spectrum molecular diagnostic panel for rapid detection of the most common respiratory pathogens to make a differential diagnosis [10] .', 'In clinical emergency or intensive care unit, pneumonia with unknown cause is accompanied by lymphocytopenia, elevated interleukin-6 level and other obvious abnormal laboratory parametres, clinicians should ask if the patients or their families have any contact history with COVID-19 patient, and SARS-CoV-2 nucleic acid should be detected timely [10] .', \"For the diagnosis and treatment of COVID-19, clinicians need to conduct clinical classification based on patient's clinical symptoms and laboratory test results (including chest CT).\", 'Different clinical types indicate that patients have different pathophysiological processes or are at different stages of disease development, and therefore require tailored treatment aproaches.', 'Although the efficacy of antiviral therapy is still uncertain, combination treatment based on the inhibition of viral replication might reduce the inflammatory injury, and can allow the body to gradually produce enough virus-specific antibodies to clear the virus through the immune response, and ultimately cure the disease.', 'There is a great debate on the use of corticosteroids for coronavirus infection such as severe acute respiratory syndrome (SARS) [11, 12] and Middle East respiratory ryndrome (MERS', 'In conclusion, we established a risk-adapted treatment strategy for COVID-19, and this strategy could be considered a useful and efficient approach for these patients based on our short-term observation.', 'However, this study has certain limitations.', 'It is a retrospective study in a single center, and the sample is relatively small, and the observation time is short; continued evaluations of this risk-adapted treatment strategy are needed.', 'In this study, we developed a risk-adapted treatment approach for COVID-19 according to the illness severity (mild, moderate and severe).', 'Our study indicates that use of riskadapted treatment approach in patients with COVID-19 was associated with significant clinical manifestations alleviation and clinical imaging recovery; and in patients with severe COVID-19, early and short-term use of low-dose methylprednisolone did not delay SARS-CoV-2 RNA clearance and influence the IgG type antibody production when compared with non-severe patients.', 'COVID-19 is characterized by fever, dry cough and fatigue, and a few patients have symptoms of nausea or vomiting and diarrhea, etc [1] [2] [3] [4] [5] .', 'However, in clinical practice, COVID-19 and other viral infections like influenza need to be further differentiated.', 'Influenza is also a contagious respiratory illness caused by influenza viruses that infect upper respiratory tract, and sometimes the lungs; the main symptoms of influenza are sudden high fever, headache, myalgia, general malaise; It can cause mild to severe illness, and at times can lead to death [7] [8] [9] .', 'In this study, severe patients had abnormal hematological manifestations including significant lower lymphocytes and CD3+T cells, increased fibribogen, D-dimer and fibrin/fibrinogen degradation products (FDP']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19', 'a b s t r a c t a r t i c l e i n f o', 'Purpose: COVID-19 (coronavirus disease 2019) is a public health emergency of international concern.', 'As of this time, there is no known effective pharmaceutical treatment, although it is much needed for patient contracting the severe form of the disease.', 'The aim of this systematic review was to summarize the evidence regarding chloroquine for the treatment of COVID-19.', 'Methods: PubMed, EMBASE, and three trial Registries were searched for studies on the use of chloroquine in patients with COVID-19.', 'Results: We included six articles (one narrative letter, one in-vitro study, one editorial, expert consensus paper, two national guideline documents) and 23 ongoing clinical trials in China.', 'Chloroquine seems to be effective in limiting the replication of SARS-CoV-2 (virus causing COVID-19) in vitro.', 'Conclusions: There is rationale, pre-clinical evidence of effectiveness and evidence of safety from long-time clinical use for other indications to justify clinical research on chloroquine in patients with COVID-19.', 'However, clinical use should either adhere to the Monitored Emergency Use of Unregistered Interventions (Monitored Emergency Use of Unregistered Interventions', 'Our search also identified ongoing 23 trials, all in China ( Table 1 ).', 'The trials varied in study design, severity of the disease in the target population and in dosing and duration of the treatment.', 'Indeed, the trial registrations varied also in quality of the reported information.', 'That so many such studies are being conducted in parallel suggests that that the scientific community is making a huge effort to clarify this question, but this effort is probably insufficiently coordinated.', 'In support of this observation, the Chinese authorities have recently issued a directive to regulate and coordinate clinical trials studying potential pharmacological treatments for COVID-19 [11] .', 'The results of these trials will be the first available on humans, since studies published to date on the characteristics and management of patients with COVID-19 did not report data about chloroquine use [1, [12] [13] [14] [15] .', 'Of note, the WHO published a generic protocol for randomized clinical trials to investigate the clinical efficacy and safety of drugs in hospitalized patients with COVID-19 (i.e. a \"master template\" for researching drugs in this setting)', 'The vital ethical issue is whether administration of chloroquine in the setting of COVID-19 is experimental, and therefore requires ethical trial approval, or off-label (i.e. ethically justifiable as the best available treatment).', 'Additional information on chloroquine will soon be released in the context of the evolving outbreak.', 'Timely release of this information can be of importance due to the growing number of infected patients, and the absence of licensed specific drugs.', 'Meanwhile, the recommendations for \"Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected\", published by the WHO, confirm that there is currently no evidence from RCTs to inform on specific drug treatment of COVID-19 and that unlicensed treatments should be administered only in the context of ethically-approved clinical trials or the Monitored Emergency Use of Unregistered Interventions Framework (Monitored Emergency Use of Unregistered Interventions Framework', 'There is sufficient pre-clinical rationale and evidence regarding the effectiveness of chloroquine for treatment of COVID-19 as well as evidence of safety from long-time use in clinical practice for other indications [3] to justify clinical research on the topic.', 'The current circumstances justify prioritization of ethical review of study proposals above other, less pressing, research topics (i.e. fast track institutional ethical review).', 'Although the use of chloroquine may be supported by expert opinion, clinical use of this drug in patients with COVID-19 should adhere to the MEURI framework or after ethical approval as a trial as stated by the WHO.', 'Data from high-quality, coordinated, clinical trials coming from different locations worldwide are urgently needed.', 'The research letter, written by a group of Chinese researchers, studied the effect of chloroquine in vitro, using Vero E6 cells infected by SARS-CoV-2 at a multiplicity of infection (MOI) of 0.05.', 'The study demonstrated that chloroquine was highly effective in reducing viral replication, with an Effective Concentration (EC', 'A narrative letter by Chinese authors reported that a news briefing from the State Council of China had indicated that \"Chloroquine phos-phate… had demonstrated marked efficacy and acceptable safety in treating COVID-19 associated pneumonia in multicentre clinical trials conducted in China\" [5] .', 'The authors also stated that these findings came from \"more than 100 patients\" included in the trials [5] .', 'We sought for evidence of such data in the trial registries we reviewed and found none.', 'The Editorial written by French researchers, underlined the in-vitro efficacy of chloroquine in other viral infections, especially SARS (whose disappearance resulted in limited further research).', 'They also discussed the potentially favourable risk-benefit balance, the high safety, and the low expenditure of such treatment in the context of the current COVID-19 outbreak [3] .', 'Since cases were reported in 85 countries so far (5th March 2020), the low cost of chloroquine is a major benefit for both the highly stressed healthcare systems of involved high-income countries and the underfunded heathcare systems of middle-and low-income counties [10].', 'The expert consensus was published on 20th February by a multicentre collaboration group of the Department of Science and For data entry, we used the definitions and the information provided by the investigators in the trial registries, if available.', 'The number of patients in the Population columns refers to the reported sample size.', \"In the 'Primary outcomes column' we reported only the primary outcomes, as described by the investigators; BID: twice per day; RCT: Randomized controlled trial.\", 'Technology of Guangdong Province and Health Commission of Guangdong Province paper and related specifically to the use of chloroquine phosphate [7] .', 'No information was provided on the method used to achieve consensus [7] .', 'Based on in vitro evidence and still unpublished clinical experience, the panel recommended chloroquine phosphate tablet, at a dose of 500 mg twice per day for 10 days, for patients diagnosed as mild, moderate and severe cases of SARS-CoV-2 pneumonia, provided that there were no contraindications to the drug.', 'The panel recommended using several precautions, including blood testing to rule out the development of anemia, thrombocytopenia or leukopenia as well as serum electrolyte disturbances and/or hepatic and renal function dysfunction.', 'Also recommended were routine electrocardiography to rule out the development of QT interval prolongation or bradycardia and patient interviews to seek the appearance of visual and/or mental disturbance/deterioration.', 'The panel recommended avoiding concurrent administration of other drugs known to prolong the QT interval (i.e. chinolones, macrolides, ondansetron) as well as various antiarrhythmic, antidepressant and antipsychotic drugs [7] .', 'The Dutch Center of Disease control (CDC', 'Another guideline document by the Italian Society of Infectious and Tropical disease (Lombardy section) recommend the use of chlorochine 500 mg × 2/die or hydroxychloroquine 200 mg die for 10 days, although the treatment may vary from 5 to 20 days according to clinical severity.', 'The suggested target population ranged from patients with mild respiratory symptoms and comorbidities to patients with severe respiratory failure [9] .']}\n", - "{'sentences': ['A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19', 'BACKGROUND: No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2.', 'METHODS: We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao(2 of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao(2 to the fraction of inspired oxygen (Fio(2 of less than 300 mm Hg.', 'Patients were randomly assigned in a 1:1 ratio to receive either lopinavir–ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone.', 'The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first.', 'RESULTS: A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir–ritonavir group, and 100 to the standard-care group.', 'Treatment with lopinavir–ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.24; 95% confidence interval [CI], 0.90 to 1.72).', 'Mortality at 28 days was similar in the lopinavir–ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI, −17.3 to 5.7).', 'The percentages of patients with detectable viral RNA at various time points were similar.', 'In a modified intention-to-treat analysis, lopinavir–ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91).', 'Gastrointestinal adverse events were more common in the lopinavir–ritonavir group, but serious adverse events were more common in the standard-care group.', 'Lopinavir–ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events.', 'CONCLUSIONS: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard care.', 'Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit.', '(Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308', 'Patients assigned to lopinavir–ritonavir did not have a time to clinical improvement different from that of patients assigned to standard care alone in the intention-to-treat population (median, 16 day vs. 16 days; hazard ratio for clinical improvement, 1.31; 95% confidence interval [CI], 0.95 to 1.85; P=0.09) (Figure 2).', 'In the modified intention-to-treat population, the median time to clinical improvement was 15 days in the lopinavir–ritonavir group, as compared with 16 days in the standard-care group (hazard ratio, 1.39; 95% CI, 1.00 to 1.91) (Table S1 and Fig. S1 in the Supplementary Appendix).', 'In the intention-to-treat population, lopinavir–ritonavir treatment within 12 days after the onset of symptoms was not found to be associated with a shorter time to clinical improvement (hazard ratio, 1.25; 95% CI, 0.77 to 2.05); similar results were found regarding later treatment with lopinavir–ritonavir (hazard ratio, 1.30; 95% CI, 0.84 to 1.99) (Fig. S2A and S2B).', 'No significant differences were observed when the time to clinical improvement was assessed by NEWS2 score at entry in the intention-to-treat population (Fig. S3A and S3B).', 'In addition, when the time to clinical deterioration (defined as a one-category increase on the seven-category scale) was compared between the two groups, no difference was observed (hazard ratio for clinical deterioration, 1.01; 95% CI, 0.76 to 1.34) (Fig. S4).', 'The 28-day mortality was numerically lower in the lopinavir–ritonavir group than in the standard-care group for either the intention-to-treat population (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI, −17.3 to 5.7) or the modified intention-to treat population (16.7% vs. 25.0%; difference, −8.3 percentage points; 95% CI, −19.6 to 3.0) (Table 3).', 'Patients in the lopinavir–ritonavir group had a shorter stay in the intensive care unit (ICU', 'This randomized trial found that lopinavir–ritonavir treatment added to standard supportive care was not associated with clinical improvement or mortality in seriously ill patients with Covid-19 different from that associated with standard care alone.', 'However, in the modified intention-to-treat analysis, which excluded three patients with early death, the between-group difference in the median time to clinical improvement (median, 15 days vs. 16 days) was significant, albeit modest.', 'Of note, the overall mortality in this trial (22.1%) was substantially higher than the 11% to 14.5% mortality reported in initial descriptive studies of hospitalized patients with Covid-19,1,2 which indicates that we enrolled a severely ill population.', 'Our patient population was heterogeneous with regard to duration and severity of illness at enrollment.', 'In a post hoc subgroup analysis, the difference in mortality between the lopinavir–ritonavir group and the standard-care group was observed to be numerically greater among patients treated within 12 days after the onset of symptoms than among those treated later.', 'The question of whether earlier lopinavir–ritonavir treatment in Covid-19 could have clinical benefit is an important one that requires further study.', 'The finding is consistent with studies showing that patients with SARS-CoV-2 viral pneumonia have progression in the second week of illness1 and with the time-to-treatment effects observed in previous antiviral studies in SARS20 and severe influenza.21-23 In addition, we found that the numbers of lopinavir–ritonavir recipients who had serious complications (acute kidney injury and secondary infections) or requiring noninvasive or invasive mechanical ventilation for respiratory failure were fewer than in those not receiving treatment.', 'These observations are hypothesis-generating and require additional studies to determine whether lopinavir–ritonavir treatment given at a certain stage of illness can reduce some complications in Covid-19.', 'We did not find that adding lopinavir–ritonavir treatment reduced viral RNA loads or duration of viral RNA detectability as compared with standard supportive care alone.', 'SARS-CoV-2 RNA was still detected in 40.7% of the patients in the lopinavir–ritonavir group at end of the trial (day 28).', 'A recent report showed that the median duration of viral shedding in Covid-19 was 20 days in patients with severe illness and could be as long as 37 days.24 Neither that study nor the current one found evidence that lopinavir–ritonavir exerted a significant antiviral effect.', 'The reasons for the apparent lack of antiviral effect are uncertain, but the sampling methods used in the current trial were most likely suboptimal.', 'Samples were taken only intermittently (on days 1, 5, 10, 14, 21, and 28), and more frequent sampling in the first 5 days could have provided more detailed characterization of viral load kinetics in the two groups over this critical period.', 'In addition, previous studies have shown that throat-swab specimens have lower viral loads than nasopharyngeal samples,25 and importantly, we were unable to do sampling of lower respiratory tract secretions.', 'Of note, depending on cell type used, the 50% effective concentrations (EC50) of lopinavir in vitro for SARS-CoV has ranged from 4.0 to 10.7 μg per milliliter,5,6,8 although other studies reported that lopinavir was inactive26 or that higher concentrations (25 μg per milliliter) were required for inhibition.7 For MERS-CoV, the EC50 values have ranged from 5 to approximately 7 μg per milliliter).1,8,13 Both the mean peak (9.6 μg per milliliter) and trough (5.5 μg per milliliter) serum concentrations of lopinavir in adults just approach these concentrations.', 'Whether the EC50 value is an adequate threshold and whether unbound lopinavir concentrations in human plasma are sufficient for inhibition of SARS-CoV-2 are questionable.1', 'Nearly 14% of lopinavir–ritonavir recipients were unable to complete the full 14-day course of administration.', 'This was due primarily to gastrointestinal adverse events, including anorexia, nausea, abdominal discomfort, or diarrhea, as well as two serious adverse events, both acute gastritis.', 'Two recipients had self-limited skin eruptions.', 'Such side effects, including the risks of hepatic injury, pancreatitis, more severe cutaneous eruptions, and QT prolongation, and the potential for multiple drug interactions due to CYP3A inhibition, are well documented with this drug combination.', 'The side-effect profile observed in the current trial arouses concern about the use of higher or more prolonged lopinavir–ritonavir dose regimens in efforts to improve outcomes.', 'Our trial has several limitations.', 'In particular, the trial was not blinded, so it is possible that knowledge of the treatment assignment might have influenced clinical decision-making that could have affected the ordinal scale measurements we used.', 'We will continue to follow these patients to evaluate their long-term prognosis.', 'The characteristics of the patients at baseline were generally balanced across the two groups, but the somewhat higher throat viral loads in the lopinavir–ritonavir group raise the possibility that this group had more viral replication.', 'Although we did not observe differences between groups in the frequency of use of concurrent pharmacologic interventions, such as glucocorticoids, this might have been another confounder.', 'In addition, approximately 45% and 40% of the patients in lopinavir–ritonavir group had positive RNA detection by throat swabs on day 14 and day 28, respectively, but we do not know if infectious virus was still present, since we did not attempt virus isolation or assess the possible emergence of SARS-CoV-2 variants with reduced susceptibility to lopinavir.', 'Finally, we do not have data on the lopinavir exposure levels in these seriously and often critically ill patients.', 'In conclusion, we found that lopinavir–ritonavir treatment did not significantly accelerate clinical improvement, reduce mortality, or diminish throat viral RNA detectability in patients with serious Covid-19.', 'These early data should inform future studies to assess this and other medication in the treatment of infection with SARS-CoV-2.', 'Whether combining lopinavir–ritonavir with other antiviral agents, as has been done in SARS5,20 and is being studied in MERS-CoV,15 might enhance antiviral effects and improve clinical outcomes remains to be determined.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['BACKGROUND: Since December 2019, novel coronavirus (SARS-CoV-2)-infected pneumonia (COVID-19) occurred in Wuhan, and rapidly spread throughout China.', 'This study aimed to clarify the characteristics of patients with refractory COVID-19.', 'METHODS: In this retrospective single-center study, we included 155 consecutive patients with confirmed COVID-19 in Zhongnan Hospital of Wuhan University from January 1st to February 5th.', 'The cases were divided into general and refractory COVID-19 groups according to the clinical efficacy after hospitalization, and the difference between groups were compared.', 'RESULTS: Compared with general COVID-19 patients (45.2%), refractory patients had an older age, male sex, more underlying comorbidities, lower incidence of fever, higher levels of maximum temperature among fever cases, higher incidence of breath shortness and anorexia, severer disease assessment on admission, high levels of neutrophil, aspartate aminotransferase (AST), lactate dehydrogenase (LDH']}\n", - "{'sentences': ['SARS-CoV-2 is a novel virus that infects the respiratory system.', 'The pulmonary infection manifests as COVID-19.', 'Through this study, we first found that COVID-19 patients may exhibit no pneumonia on thin-section CT.', 'Second, lesions in patients with COVID-19 commonly involved the lower lobes of both lungs and mostly showed subpleural distribution.', 'Third, all patients showed GGO on thin-section CT, more than half of which were round GGO; 89.36% of the patients showed the crazy-paving pattern, and air bronchogram could develop in GGO.', 'Fourth, the consolidations can appear in the center of the GGO, and can be patchy.', 'Fifth, enlarged mediastinal lymph nodes and pleural effusion were rare.', 'Sixth, during the short-term follow-up period, lesions were gradually resorbed in a few patients, and most patients experienced gradual disease progression.', 'Before SARS-CoV-2, there are six coronavirus, four of which are less pathogenic and generally cause mild respiratory symptoms, the other two coronavirus has caused two epidemics since the beginning of the 21st century.', 'The first epidemic was severe acute respiratory syndrome (SARS) caused by SARS-associated coronavirus (SARS-CoV) in 2003, which is also known as atypical pneumonia, with a mortality rate of 9.6% (5).', 'The second was Middle East respiratory syndrome (MERS) cause by MERS-associated coronavirus (MERS-CoV) in 2012 and 2015, with a mortality rate of 35.7% (6) .', 'The third is COVID-19 caused by SARS-CoV-2 (7).', 'The CT imaging features are closely related to the pathology.', 'At present, one study showed the similar pathological characteristics to the same SARS-CoV infection (8) .', 'It is reported in the literature that acute diffuse alveolar injury can be observed in the acute stage (<11 days) of SARS, and in the late stage, diffuse alveolar injury and acute fibrous and organic pneumonia can be observed (9) .', 'The pathological changes include thickening of the basement membrane of the alveoli capillary, edema of the alveoli septum, hyperplasia of the interstitium, apoptosis and desquamation of the alveolar epithelium cells, formation of the pulmonary hyaline membrane by exudate and other cellular components in the alveoli, hyperemia and edema of the bronchioles, infiltration of inflammatory cells and inflammatory edema, red blood cells in the alveoli, and microthrombosis formation in the blood vessels (10, 11) .', 'Due to the small number of autopsies on patients with MERS, detection of pathological basis was limited.', 'Diffuse alveolar damage was also found in the lungs in two autopsies, including damage to alveolar epithelial cells, multinuclear epithelial cells, and submucosal glands (12, 13) .', 'In the animal model of MERS, consolidation, edema, and inflammation can be found in the infected lungs, and diffuse alveolar injury with hyaline membrane formation can also be observed (14À16).', 'Based on the pulmonary infection of SARS-CoV-2 and SARS-CoV (8À11), GGOs may be due to mild edema of the alveolar septi, hyperplasia of the interstitium, partial filling of airspaces, or a combination of these features.', 'The crazy-paving pattern may correlate with hyperplasia of interlobular and intralobular interstitia.', 'Consolidation may be related to acute diffuse alveolar injury, including edema, red blood cells and cellulose deposition.', 'Stripe may reflect the thickening pulmonary interstitium or fibrosis.', 'Whether stripes are resorbed should be observed in the future.', 'SARS, MERS, and COVID-19 are all infectious diseases caused by coronaviruses, so the CT images of patients with these three diseases are similar.', 'The earliest stage of SARS manifests as GGO, which mainly follows a subpleural distribution.', 'SARS with diffuse GGOs progresses into acute respiratory distress syndrome (17, 18) , and the reticulation superimposed on GGO can present as a crazy-paving pattern.', 'Consolidation is common, and the margins are obscure.', 'Air bronchograms and cavity can be observed.', 'The presence of spontaneous pneumomediastinum can distinguish SARS from other diseases (17) .', 'SARS rapidly progresses, and multiple segments and multiple lobes are involved.', 'MERS mainly manifests as subpleural GGO, and the range of GGO is larger than that of consolidations; some lesions can be distributed along the bronchovascular bundles.', 'Pleural effusion can occur in some cases (19, 20) .', 'The CT imaging findings of COVID-19 partially overlap those of SARS and MERS', 'In this study, among the 53 cases with COVID-19, pneumonia was absent in the initial CT examination of six patients with positive NAAT results for the detection of SARS-CoV-2.', 'But two of the six patients showed pneumonia during follow-up.', 'Therefore, CT manifestations of COVID-19 lag behind the NAAT detection.', 'Although CT imaging has certain lag time, nucleic acid, and gene sequencing detection require a relatively longer time compared to CT.', 'Thus, for the timely and accurate diagnosis of COVID-19, CT can quickly identify suspected patients and significantly help in isolating the source of infection, cutting off the route of transmission, and avoiding further spread of infection.', 'In this study, a few patients had a clear epidemiological history and typical CT findings indicative of COVID-19, while the nucleic acid test was negative, and the final diagnosis of COVID-19 was determined after several rounds of negative results.', 'Therefore, CT scanning is necessary for patients suspected of having COVID-19.', 'This study has two limitations.', 'First, all cases were examined by CT, and plain chest radiographs were not obtained.', 'Although plain chest radiography and CT are both necessary to examine lung lesions and can demonstrate disease progression, plain chest radiographs are superimposed imaging that cannot clearly display GGO lesions.', 'In contrast, CT imaging, especially thin-section CT imaging, which is comparable to directly viewing the anatomy, can clearly reveal the structures of both lungs with high resolution, can aid in the diagnosis of lung diseases, and can be used for the timely and accurate observation of disease progression (21) .', 'Therefore, thin-section CT is recommended for patients at the early stage of COVID-19 to avoid missing lesions, and plain chest radiography is recommended for re-examination in patients with severe conditions and in patients who cannot undergo CT to observe changes in their conditions.', 'Second, due to the rapid onset of COVID-19, the interval between examinations was short.', 'We will continue to conduct follow-up studies to observe the dynamic changes in COVID- 19.', 'In summary, COVID-19 pneumonia manifests primarily as GGO and consolidation distributed predominantly along the subpleural area of the lung.', 'Round GGO and crazy-paving pattern are commonly seen.', 'Air bronchograms are often found in both GGO and consolidation.', 'Cavities, enlarged mediastinal lymph nodes, or pleural effusions are absent on the initial CT examinations.', 'In the short-term follow-up, more patients had disease progression than absorption.', 'Identification of CT features of COVID-19 pneumonia provide timely diagnostic evidence of the disease enabling early diagnosis and treatment.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Background: COVID-19 is an emerging disease caused by the SARS-CoV-2 virus; no specific medication has been identified to date.', 'We aimed to investigate the administered medications and intervention times for patients who completely recovered from COVID-19.', \"Methods: This single-center, retrospective, and observational study included 55 patients with COVID-19 who were transferred to Shenyang Sixth People's Hospital between January 20 and March 15, 2020.\", 'Demographic information, symptoms, laboratory indicators, treatment processes, and clinical outcomes were collected.', 'Administered drugs and intervention times were compared in 47 and eight patients with mild and severe symptoms, respectively.', 'Findings: All 55 patients recovered.', 'Fifty-three patients (96·36%) received antiviral therapy, including 45 in the mild group (median treatment: 14 days; 17 received umifenovir) and all eight severe-group patients (median treatment: 17·5 days; four received lopinavir/ritonavir).', 'Twenty-nine patients (52·72%) were administered antibiotics, including 21 in the mild group (median treatment: 13·5 days; 15 received moxifloxacin) and all eight in the severe group (median treatment: 9 days; two received linezolid).', 'Moreover, seven patients (12·72%) were treated with glucocorticoids and nine (16·36%) with immunomodulators.', 'Patients with COVID-19 in the present study achieved a 100% recovery rate.', 'No effective antiviral drugs that treat COVID-19 have been identified to date, and opinions on whether antiviral drugs should even be used to treat COVID-19 differ.', \"1 The National Health Commission of the People's Republic of China has repeatedly issued and revised the COVID-19 Diagnosis and Treatment Plan, which recommends antiviral drugs such as lopinavir/ritonavir, ribavirin, umifenovir, .\", 'CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.03.28.20045955 doi: medRxiv preprint and alpha-interferon.', '2 In the present study, 53 patients (96·36%) received antiviral therapy early in the course of their disease for a median time of 14 days (IQR 12-18 days).', 'In the mild group, 17 ( 37·78%) of the patients were treated with umifenovir and another 17 (37·78%) received a combination of umifenovir + lopinavir/ritonavir for a median time of 14 days (IQR 12-17 days).', 'Liu et al. 4 Ribavirin and interferon are also mentioned in the COVID-19 Diagnosis and Treatment Plan; 2 in the present study, four patients in the mild group (7·27%) were administered ribavirin combined with antiviral therapy.', 'Nucleoside analogs theoretically ought to possess anti-coronavirus activity to a certain extent; 8 however, ribavirin was found to have a minimal antiviral effect against coronavirus in vitro.', '9 In the present study, 20 patients received aerosol inhalation of alpha-interferon soon after diagnosis (50 µg, twice per day).', 'A retrospective study of patients with Middle East Respiratory Syndrome (MERS', 'In terms of antimicrobial use, the WHO recommends empirical antimicrobial therapy based on the clinical diagnosis.', \"3 China's COVID-19 Diagnosis and Treatment Plan 2 also emphasizes the avoidance of blind or inappropriate use of antibiotics.\", 'Kim et al. 12 found that 38% of their patients .', 'CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The WHO does not recommend the systematic use of glucocorticoids for viral pneumonia or concurrent ARDS.', \"3 China's COVID-19 Diagnosis and Treatment Plan recommends hormones as adjuvant therapy.\", '2 In the present study, 48 (87·28% ) of the patients did not receive glucocorticoids, while 7 (12·72%) did receive such agents during the rapid progression of their disease to inhibit inflammation and improve oxygenation at a dose of 1-2 mg/kg/day.', 'Treatment was gradually reduced over 5-7 days until discontinuation, and showed no adverse reactions.', 'As such, glucocorticoids appear to be unnecessary for patients with mild manifestations of COVID-19, while their use in treating patients with severe disease is controversial.', \"China's COVID-19 Diagnosis and Treatment Plan 2 suggests that immunotherapy can be attempted for patients with severe COVID-19.\", 'In the present study, 9 (16·36%) of the patients were administered thymalfasin.', 'There has been no additional evidence gathered regarding the effectiveness of immunomodulatory drugs for viral pneumonia; 15 hence, this notion requires further clinical observation and study.', 'While high-flow oxygen therapy, invasive mechanical ventilation, .', 'CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.03.28.20045955 doi: medRxiv preprint and extracorporeal membrane oxygenation were provided to patients in the present study, their use was not investigated.', 'Our findings suggest that, while specific antiviral drugs are yet to be developed, currently available antiviral agents should be considered when treating patients with COVID-19.', 'The prophylactic administration of single antiviral drugs to patients with severe symptoms, as well as to a proportion of those with mild manifestations, may help reduce the risk of co-infection.', 'However, the use of glucocorticoids and immunomodulators needs further study.', 'Our study had some limitations given its single-center, retrospective, and observational nature.', 'Owing to its small sample size, only descriptive data were available, and no statistical analyses were performed.', 'Hence, randomized, double-blind, and controlled trials remain necessary for more accurate conclusions.', 'Nevertheless, our data ought to provide helpful preliminary information at this stage of the COVID-19 pandemic.']}\n", - "{'sentences': ['On January 30 th 2020, the World Health Organization declared the current SARS-CoV-2 outbreak a public health emergency of international concern (WHO, 2020).', 'To gain insight into the biology and evolution of emerging SARS-CoV-2, a comprehensive analysis of genome composition, codon and amino acid usage of βCoV strains isolated in China from humans, bats, civets and ferret hosts was performed, including SARS-CoV-2 strains recently isolated from current outbreak.', 'The results of these studies revealed that SARS-CoV-2 strains enrolled in these analyses have a distinct genome composition in relation to other βCoV strains isolated from human (SARS-CoV), bats, civets and ferrets (see Fig. 1 ).', 'This is in agreement with very recent studies revealing that SARS-CoV-2 is sufficiently divergent from SARS-CoV to be considered a new human-infecting βCoV (Lu et al., 2020; Zhu et al., 2020) .', 'This distinct genomic composition is also reflected in its codon and amino acid usage patterns (see Fig. 2 ).', 'Moreover, correlation distances and average linkage suggests a closer relation among SARS-CoV-2 and bats βCoV isolated in China and a more distant relation to SARS-CoV or SARS-like βCoV isolated from civets or ferrets (see Fig. 2 ).', 'This is in agreement with recent results suggesting that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan (Lu et al., 2020; Chan et al., 2020b) .', 'This speaks of the importance of bats as a reservoir of potential emerging CoV. Moreover, significant numbers of new βCoV have been discovered in Chinese bats species, particularly Rhinolophus affinis (Li et al., 2017) .', 'Interestingly, a clear degree of variation in codon and amino acid usage was observed among βCoV isolated J o u r n a l P r e -p r o o f from bats included in these studies (see Fig. 2 ).', 'Nevertheless, bats might represent an intermediate host facilitating the emergence of the SARS-CoV-2 in humans (Wong et al., 2019) .', 'More studies will be needed to address this important issue.', 'In these studies, a biased nucleotide composition was found for SARS-CoV-2 genome (Fig. 3) .', 'This bias can also have a major influence on derived parameters, as previously demonstrated for other CoVs (Berkhout and Van Hemert, 2015) .', 'This is in agreement with the results of this work, since the nucleotide composition of SARS-CoV-2 has a strong influence in the codons that are used by this virus for the translation of its RNA genome.', 'Previous studies on codon usage in RNA viruses have shown that mutational pressure is the major factor in shaping codon usage patterns in comparison with natural selection (Jenkins and Holmes, 2003; Wang et al., 2011) .', 'Although mutational pressure is still a major driving force, it is certainly not the only evolutionary force that might be considered in RNA viruses.', 'In these studies, a significant A genomic content was found in SARS-CoV-2 in comparison with other human CoVs (Fig. 3) .', 'Previous studies done in Human Immunodeficiency virus (HIV) found that this virus has an A-rich genome and this property has been proposed to help the virus to avoid recognition by the innate immune system (Vabret et al.,2012) .', 'This could provide a strong selective pressure on retroviruses as well as many others RNA viruses, including CoVs (Kindler and Thiel, 2014; van Hemert et al., 2014) .', 'Moreover, previous studies done in HIV suggest that an RNA genome with A-rich domains may provide a molecular signature that is recognized during virus replication (van Hemert et al., 2013) .', 'In the context of CoV, A-rich regions, like the Transcription Regulation Sequence (TRS', 'A mean ENC value of 48.54 ± 2.34 was obtained for SARS-CoV-2 strains enrolled in these studies, suggesting that the overall codon usage among SARS-CoV-2 is similar among themselves and slightly biased.', 'This is in agreement with mean ENC values obtained for other CoV, like SARS-CoV (ENC = 48.99) (Gu et al., 2004) ; Bovine Coronavirus (BCoV', 'In these studies, significant differences in RSCU frequencies among SARS-CoV-2 and human cells were found (Table 1) .', 'A strong bias toward A and U ending codons was found.', 'This in agreement with very recent studies revealing a significant predominance of A and U at third codon positions in CoV genomes (Sheikh et al., 2020; Wang et al., 2018; Kandeel et al., 2020) .', 'These results also suggest that these differences are related to codon usage preferences.', 'Previous studies have shown that both cytosine deamination and selection of CpG-suppressed clones are the major factors that shape codon bias in CoV genomes (Woo et al., 2007) .', 'MERS-CoV codon usage revealed a bias among hydrophobic amino acids, being CCG (Pro) and GUU (Val) the least and most frequently used codons (Chen et al., 2017) .', 'The same results were found in this work for SARS-CoV-2 ORFs, since CCG y GUU resulted to be the least and most frequently hydrophobic codons (11 and 352 times, respectively).', 'Regarding hydrophilic amino acids, the least and most frequently used codons in MERS-CoV were CGG (Arg) and GAU (Asp), respectively (Chen et al., J o u r n a l P r e -p r o o f 2017).', \"These codons were also the least and most frequently hydrophilic codons used in SARS-CoV-2 ORF's (11 and 310 times, respectively).\", 'Similarly, CpG and UpU dinucleotide frequencies resulted to be the lowest and highest frequencies found in MERS-CoV (Chen et al., 2017) .', 'The same results were obtained in these studies on SARS-CoV-2, since CpG and UpU were the lowest and highest dinucleotide frequencies found (0.22 and 1.96, respectively) (see Supplementary Material Table 2 ).', 'Again, these analyses revealed that genomic composition affects the codon usage pattern in both, MERS-CoV and SARS-CoV-2 viruses.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['SARS-CoV-2, a member of the coronavirus family, has caused a global public health emergency.', 'Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously reasoned that the FDA-approved heptatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) should inhibit coronaviruses, including SARS-CoV-2.', '2 Here, using model polymerase extension experiments, we demonstrate that the activated triphosphate form of Sofosbuvir is incorporated by low-fidelity polymerases and SARS-CoV RNA-dependent RNA polymerase (RdRp), and blocks further incorporation by these polymerases; the activated triphosphate form of Sofosbuvir is not incorporated by a host-like high-fidelity DNA polymerase.', 'Using the same molecular insight, we selected two other anti-viral agents, Alovudine and AZT (an FDA approved HIV/AIDS drug) for evaluation as inhibitors of SARS-CoV RdRp.', \"We demonstrate the ability of two HIV reverse transcriptase inhibitors, 3'fluoro-3'-deoxythymidine triphosphate and 3'-azido-3'-deoxythymidine triphosphate (the active triphosphate forms of Alovudine and AZT), to be incorporated by SARS-CoV RdRp\", 'The recent appearance of a new coronaviral infection, COVID-19, in Wuhan, China, and its worldwide spread, has made international headlines.', 'Already more than 3,000 deaths have been ascribed to this virus, and COVID-19 has reached near pandemic status.', 'The virus has been isolated from the lower respiratory tracts of patients with pneumonia, sequenced and visualized by electron microscopy.', '1 The virus, designated SARS-CoV-2, is a new member of the subgenus Sarbecovirus, in the Orthocoronavirinae subfamily, but is distinct from MERS-CoV and SARS-CoV. 1 The coronaviruses are single strand RNA viruses, sharing properties with other single-stranded RNA viruses such as hepatitis C virus (HCV), West Nile virus, Marburg virus, HIV virus, Ebola virus, dengue virus, and rhinoviruses.', 'In particular, coronaviruses and HCV are both positive-sense single-strand RNA viruses, 3,4 and thus have a similar replication mechanism requiring a RNA-dependent RNA polymerase (RdRp', 'The coronavirus life cycle has been described.', '3 Briefly, the virus enters the cell by endocytosis, is uncoated, and ORF1a and ORF1b of the positive strand RNA is translated to produce nonstructural protein precursors, including a cysteine protease and a serine protease; these further cleave the precursors to form mature, functional helicase and RNA-dependent RNA polymerase.', 'A replication-transcription complex is then .', 'CC-BY-NC-ND 4.0 : bioRxiv preprint sequence of the primer and template used for this extension reaction is shown at the top of the figure.', 'Polymerase extension reactions were performed by incubating UTP with pre-assembled SARS-CoV polymerase (nsp12, nsp7 and nsp8), the indicated RNA template and primer, and the appropriate reaction buffer, followed by detection of reaction products by MALDI-TOF MS.', 'The detailed procedure is shown in the methods.', 'The accuracy for m/z determination is ± 10 Da.']}\n", - "{'sentences': ['The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has attracted increasing worldwide attention.', 'Cases of liver damage or dysfunction (mainly characterized by moderately elevated serum aspartate aminotransferase levels) have been reported among patients with COVID-19.', 'However, it is currently uncertain whether the COVID-19-related liver damage/dysfunction is due mainly to the viral infection per se or other coexisting conditions, such as the use of potentially hepatotoxic drugs and the coexistence of systemic inflammatory response, respiratory distress syndrome-induced hypoxia, and multiple organ dysfunction.', 'Based on the current evidence from case reports and case series, this review article focuses on the demographic and clinical characteristics, potential mechanisms, and treatment options for COVID-19-related liver dysfunction.', 'This review also describes the geographical and demographic distribution of COVID-19-related liver dysfunction, as well as possible underlying mechanisms linking COVID-19 to liver dysfunction, in order to facilitate future drug development, prevention, and control measures for COVID-19']}\n", - "{'sentences': ['Data on the stability of darunavir/cobicistat suspension after tablet manipulation', \"[{'text': 'Data on the stability of darunavir/cobicistat suspension after tablet manipulation, Data in Brief (2020), doi: https://doi.', 'cite_spans': [], 'ref_spans': [], 'section': 'Abstract'}]\", 'The COVID-19 outbreak is now one of the most critical crises to manage for most of the national healthcare systems in the world.', 'In the absence of authorised pharmacological treatments, many antiretrovirals, including darunavir/cobicistat fixed combination, were used off-label in the hospital wards as life-treating medicines for COVID-19 patients.', 'Unfortunately, for most of them, the drug products available on the market are not designed to be administered by a nasogastric tube to inpatients of intensive care units.', \"Therefore, their manipulation, even if it can strongly affect the product quality, is necessary for the preparation of suspension to meet patients' need.\", 'In this situation, it is urgent to provide data and guidance to support hospital pharmacist and clinicians in their activity.', 'The data in this article indicate that darunavir/cobicistat suspensions compounded by pharmacists using as active ingredient a commercially available tablet can be stable at least for one week.']}\n", - "{'sentences': ['Convalescent plasma as a potential therapy for COVID-19', \"[{'text': '1 Holshue ML, DeBolt C, Lindquist S, et al. First case of 2019 novel coronavirus in the United States.\", 'N Engl J Med 2020; published online Jan 31.', '2 Lai ST.', 'Treatment of severe acute respiratory syndrome.', 'Eur J Clin Microbiol Infect Dis 2005; 24: 583-91.', \"3 Soo YO, Cheng Y, Wong R, et al. Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients.', 'cite_spans': [], 'ref_spans':\"]}\n", - "{'sentences': ['Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of coronavirus SARS-CoV-2.', 'Existing direct-acting antiviral (DAA) drugs cannot be applied immediately to new viruses because of virus-specificity, and the development of new DAA drugs from the beginning is not timely for outbreaks.', 'Thus, host-targeting antiviral (HTA', 'Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knocking-out cells.', 'We also proposed the drug combination of DAA and HTA was a promising strategy for anti-virus treatment and proved that S312 showed more advantageous than Oseltamivir to treat advanced influenza diseases in severely infected animals.', 'Notably, S416 is reported to be the most potent inhibitor with an EC50 of 17nM and SI value >5882 in SARS-CoV-2-infected cells so far.', 'This work demonstrates that both our self-designed candidates and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-repression may have clinical potentials not only to influenza but also to']}\n", - "{'sentences': ['The coronavirus disease 2019 (COVID-19) world health emergency is calling scientists for unprecedented, huge investigation efforts to urgently answer key questions: what is the natural origin of the SARS-CoV-2 virus?', 'What molecular changes account for its aggressiveness and mortality in humans?', 'What immunological responses are specifically activated and how long will acquired immunity last in recovered people?', 'Is there a most susceptible, exposed population based on the genetic background?', 'Are patients treated with angiotensin-converting enzyme (ACE) inhibitors at increased risk for COVID-19 infection?', 'On top of these, what are the best therapeutic options we have ready to help cure COVID-19', 'New interventional clinical trials for COVID-19 treatment involve the use of an antiviral drug previously used to treat the Ebola virus known as remdesivir or the combination of two antivirals: ritonavir + lopinavir, previously approved to treat the HIV infection.', 'Additional active clinical trials involve the use of drugs approved for different therapeutic indications.', 'This is the case, for example, for: (i) the FDA-approved antimalarial drugs chloroquine and hydroxychloroquine, owing to their ability to interfere with basic cellular pathogenetic mechanisms; and (ii) monoclonal antibodies against interleukin-6 receptor (anti-IL-6R', 'J o u r n a l P r e -p r o o f']}\n", - "{'sentences': ['In the present study, we described the clinical characteristics of elderly COVID-19 patients who were faced with the highest risk of death after SARS-CoV-2 infection.', 'And we investigated the prognostic factors of COVID-19 based on at least 4 weeks of follow-up.', 'SARS-CoV-2 caused a much more severe pneumonia in the aged people than younger patients.', 'Of the 339 elderly COVID-19 patients included, over 70% were severe or critical, and the case fatality rate was 19%.', 'Fast progress of disease was found in the dead with a median survival time of 5 days after admission.', 'Several factors were found to be predictors for poor outcomes, such as symptom of dyspnea, comorbidities like cardiovascular disease and COPD, and complications like ARDS.', 'It should be noted that once ARDS occurred, the probability of death would increase dramatically.', 'On the other side, increased lymphocyte count was predictive of better outcomes.', 'The distinct features of COVID-19 in these included elderly patients were evidently increased severity and fatality.', 'The reported proportion of severe-to-critical patients in the whole population was 18.5% and the case-fatality rate was 2.3%, 9 significantly lower than the present study.', 'As Renmin Hospital of Wuhan University was a designated hospital for severe COVID-19 patients, the proportion of severe and critical patients and fatality rate might be different from other centers.', 'In the 65 dead cases 92.3% were critically ill.', 'The only one death in moderate cases was caused by sudden cardiac death.', 'As indicated by the short length of stay (median, 5 days) for the dead, the disease progressed considerably fast for those patients.', 'The most common symptoms at admission were fever, cough, dyspnea and fatigue, which was consistent with the general symptoms of viral infection and pneumonia.', 'Dyspnea was more prevalent in the dead patients.', 'In consistence, the respiration rate at admission was significantly higher in the dead group compared with survival group.', 'The incidence of comorbidities was relatively higher in the elderly COVID-19 patients compared with the whole population.', '9 The most common comorbidities were hypertension, diabetes, cardiovascular disease and cerebrovascular disease.', 'The median heart rate, blood pressure and respiration rate were in the normal range at admission both in survival and dead group, indicating that the vital signs of most patients were stable at admission.', 'Common complications during hospitalization were bacterial infection, liver enzyme abnormalities, ARDS and acute cardiac injury.', 'Significant differences were found in laboratory findings between the dead and survivors.', 'Generally, evident decrease of lymphocytes was observed in the dead group.', 'Specifically, the count of CD4 + and CD8 + lymphocytes were both significantly reduced in the dead group, indicating the suppressed cellular immunity in these patients.', 'At the same time, more severe inflammatory reactions might exist in the dead cases as represented by significant increase of inflammatory markers.', 'In addition, more frequent coagulation disorders, myocardial injuries and bacterial infections were found in the dead group compared to the survival group, as revealed by the related markers.', 'Compared with the survivors, serum concentrations of urea and creatinine were higher in the dead, indicating worse renal functions, although the median values were still within the normal range.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Baricitinib for COVID-19: a suitable treatment?']}\n", - "{'sentences': ['Convalescent Plasma to Treat COVID-19: Chinese Strategy and Experiences', 'The COVID-19 is currently spreading around the world, which has posed significant threats to global health and economy.', 'Convalescent plasma is confirmed effective against the novel corona virus in preliminary studies.', 'In this paper, we first described the therapeutic schedule, antibody detection method, indications, contraindications of the convalescent plasmas, and reported the operability of the treatment by case study.']}\n", - "{'sentences': ['The aim of this study was to investigate the effects of social capital on sleep quality and the mechanisms involved in people who self-isolated at home for 14 days in January 2020 during the coronavirus disease 2019 (COVID-19) epidemic in central China.', 'Social capital was assessed using the Personal Social Capital Scale 16 (PSCI-16) questionnaire, which measured social trust, belonging, and participation.', 'Anxiety was assessed using the Self-Rating Anxiety Scale (SAS) questionnaire, stress was assessed using the Stanford Acute Stress Reaction (SASR) questionnaire, and sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) questionnaire.', 'Path analysis was performed to evaluate the relationships between a dependent variable (social capital) and two or more independent variables, using Pearson’s correlation analysis and structural equation modeling (SEM', 'The findings from this study showed that anxiety and stress of isolated individuals were at high levels, while the sleep quality was low, which indicates that psychological health should be considered for individuals who isolate during epidemics and that levels of social capital may affect mental health and sleep.', 'These findings are supported by previous studies, including the findings reported in 2012 by Valencia-Garcia et al., which confirmed that increased social capital reduced the levels of depression and anxiety [21].', 'Li et al. showed that for children living in poverty, more family members, peer support, and school friends in their social capital were associated with better mental health [22].', 'Yamada et al. showed that social capital contributed to reducing distress and preventing complications in patients with diabetes [23].', 'The findings from the present study, and the findings from previous studies, provide support for improving physical and mental health from the perspective of social capital and may be applied to individuals who self-isolate during epidemics, such as the recent COVID-19 epidemic in central China.', 'Individuals who self-isolate at home will suffer from physical stress due to lack of space for physical activity, stress due to limited social interactions, and anxiety associated with fear of the consequences of infection.', 'Most individuals who self-isolate live alone or live with their families and may be more likely to feel lonely.', 'Also, because they are isolated at home rather than in the hospital, they may feel more insecure than the patients who have been hospitalized, with increased uncertainty about their own risk of developing severe disease, or of not being diagnosed or treated in time.', 'Therefore, the mental health of these individuals requires more attention.', 'Social capital may require attention to reduce negative emotions and to cope with the risks from an infection epidemic with a more positive attitude.', 'This study found that the influence of social capital on sleep was mediated by anxiety and stress.', 'In the first path identified, social capital affected anxiety, and anxiety directly influenced sleep quality.', 'Social capital affects anxiety because when an individual has a wide social network, they may be more likely to interact with other people [24].', 'Social support and social resources reduce negative emotions, such as anxiety [25].', 'Therefore, when individuals are isolated, including during epidemics, online social groups that expand social networks and provide mutual support may reduce the anxiety of isolation [26].', 'The effects of anxiety on sleep have been previously identified [27].', 'Subjectively, people with anxiety may find it difficult to fall asleep, or they may wake up easily [28].', 'Anxiety may lead to increased cortisol levels, changes in cortisol secretion rhythms, and reduced melatonin synthesis, all of which reduces sleep quality [29,30].', 'In the second path identified in this study, social capital affected stress, and then stress affected sleep.', 'The stress response refers to the individual nonspecific response caused by various stressors [31].', 'Stress is closely associated with mood, behavior, a sense of wellbeing, and health [32].', 'People who have more social capital usually have less stress because they have spiritual or material support from others.', 'Social support helps to reduce the perception and evaluation of the threat of stress events, the physiological response and inappropriate behavior caused by stress, and the level of fear and anxiety induced by stress [33,34].', 'Stress is associated with sleep quality [35].', 'When individuals experience stress, they often feel physical tension and mental pressure, they are more sensitive to the sleeping environment, or they focus on sleep too much, which will reduce their sleep quality [36].', 'Also, some variables may interact with each other.', 'For example, anxiety may increase stress, and stress may increase anxiety [37].', 'Also, increased anxiety may lead to poor sleep, and poor sleep may increase anxiety [38].', 'Therefore, all the variables included in the present study, social capital, stress, anxiety, and sleep require attention to prevent a negative cycle of psychological and physical harm.', 'Therefore, more measures are needed to improve the social capital and mental health status of isolated people during epidemics of infectious disease.', 'For example, professional medical staff should provide online health education to reduce uncertainty and panic caused by a lack of knowledge of new infections and diseases.', 'Social workers and psychotherapists may provide online help or support or support by phone to provide encouragement to communicate with relatives and friends using the internet or phone.', 'These approaches to improving mental health and sleep may also improve immune function, which may improve the ability to resist infectious disease [39,40].', 'This study investigated social capital, anxiety, stress, and sleep quality in a population who self-isolated for 14 days during the COVID-19 outbreak in January 2020 and analyzed the relationships between the variables.', 'Social capital affected sleep quality through the mediation effects on anxiety and stress, as people who had high levels of social capital had better sleep quality.', 'However, this study had several limitations.', 'The study sample size was small, and a cross-sectional study design was used, which may have prevented the identification of other associations between social capital and sleep.', 'Also, social capital was measured using the PSCI-16 questionnaire, and the data relied on the ability of the individual to interpret the questions and provide accurate responses, but these responses were not verified objectively.', 'Therefore, some causal relationships may have been missed.', 'Further cohort studies with more samples should be performed, and non-subjective methods should be used.', 'For example, sleep can be measured objectively by polysomnography, and stress levels can be detected using objective measurements of serum cortisol levels.']}\n", - "{'sentences': ['[{\\'text\\': \"Objective: To discuss hospital pharmacists\\' role in providing pharmaceutical care for hospitalized patients with COVID-19 to promote patient care and management during the pandemic.', 'Method: Based on the method of evidence-based pharmacy, clinical evidence of therapeutical drugs for COVID-19 were retrieved and summarized.', \"Based on clinical experience Chinese hospital pharmacists gained from providing pharmaceutical care services during COVID-19 pandemic, taking COVID-19 hospitalized patients' needs into consideration, the methods and strategies hospital pharmacists shall use to provide pharmaceutical care were analyzed and summarized.\", 'Results: Hospital pharmacists shall support pharmaceutical care services by participating in making evidence-based decisions for medication, monitoring and evaluation of medication safety and efficacy, providing strengthened care for special population and patients with combined underlying diseases, monitoring and management of convalescent plasma therapy, providing emotional counselling and psychological support, and providing scientific information about COVID-19 vaccines.', 'Conclusion: The need of pharmaceutical care services in COVID-19 hospitalized patients during this pandemic was quite distinguished from the past.', \"Hospital pharmacists shall join the collaborative multidisciplinary team to improve COVID-19 patients' outcome and reduce mortality, and to facilitate the pandemic control.\", 'For hospitalized patients with COVID-19, pharmaceutical care services are indispensable supplements for clinical treatment and management.', 'Hospital pharmacists providing targeted pharmaceutical care is of great significance for improving the level of drug therapy.', 'Based on the Chinese perspective of \"centralizing COVID-19 patients and centralized inpatient treatment\", the paper established a pharmaceutical care framework of COVID-19 hospitalized patients, including participating in making evidence-based decisions for medication, monitoring and evaluation of medication safety and efficacy, strengthened care for special population and patients with combined underlying diseases, monitoring and management of convalescent plasma therapy (CPT']}\n", - "{'sentences': ['Azithromycin and ciprofloxacin have a chloroquine-like effect on respiratory epithelial cells', \"[{'text': 'There is interest in the use of chloroquine/hydroxychloroquine (CQ/HCQ) and azithromycin (AZT) in COVID-19 therapy.\", 'Employing cystic fibrosis respiratory epithelial cells, here we show that drugs AZT and ciprofloxacin (CPX) act as acidotropic lipophilic weak bases and confer in vitro effects on intracellular organelles similar to the effects of CQ.', 'These seemingly disparate FDA-approved antimicrobials display a common property of modulating pH of endosomes and trans-Golgi network.', 'We believe this may in part help understand the potentially beneficial effects of CQ/HCQ and AZT in COVID-19, and that the present considerations of HCQ and AZT for clinical trials should be extended to CPX', 'In conclusion, the relationships demonstrated in this study indicate that a set of FDA-approved drugs, CQ, AZT, CPX, with known safety profiles, act by controlling pH of intracellular organelles in respiratory epithelial cells, a highly relevant target for CoV2.', 'Furthermore, our previous studies of phosphodiesterase 5 inhibitiors show similar effects, and these may also be further tested.', '30 The alterations of pH in organelles of the secretory pathway, especially TGN 31 , may alter glycosylation of both the receptors for CoV2, such as ACE2, which binds the spike protein, and glycosylation of CoV2 proteins during their biogenesis and assembly.', 'Importantly, coronavirus M proteins govern viral budding at the ERto-Golgi intermediate compartment but penetrate deeper into the Golgi apparatus 54 , and among the pathogenic CoVs, at least the MERS CoV M protein possesses TGN localization signals 55 .', 'The effects of chloroquine have been observed with other viruses including HIV gp120 glycosylation defect and loss of infectivity 56, 57 as well as HSV arrest of noninfectious parties in the TGN 58 .', 'Our studies here show that CF respiratory epithelial cell normalization is based on a neutralization of the pre-existing pathologically hyperacidified compartments due to the underlying CF disease, resulting in normalization of glycosylation in CF respiratory epithelial cells.', 'We postulate here that the acidotropic and neutralization effects of AZT, CPX and CQ in normal cells would result in vectorially similar pH shifts away from optimal for the function of enzymes within the secretory pathway that would also alter glycosylation.', 'The alterations of pH in organelles of the endosomal pathway may have effects on host proteases acting upon the CoV2 Spike protein to execute its cleavage necessary for virus entry.', 'The inhibition of viral entry in recent cellular systems is best achieved with a combination of camostat mesylate (an inhibitor of TMPRSS2 protease) plus E-64d, an inhibitor of lysosomal cathepsins 59 .', 'It has been noted that CoV2, unlike SARS-CoV, possesses a novel furin cleavage site within its Spike protein 60 .', 'Our studies here show that AZT can reduce furin activity that is abundantly present in respiratory epithelial cells.', 'Multiple proteases are proposed to cleave CoV2 Spike, including TMPRSS2 59 (which also acts on SARS-CoV 61-63 ), furin 60 , and lysosomal hydrolases 59 .', 'This warrants consideration of a more general approach to their inhibition, such as altering pH, rather than focusing solely on a specific host protease.', 'We propose that the drugs studied here, CQ, AZT and CPX, may modulate these aspects of host-pathogen interactions and virus infectious cycle, with immediate compassionate use in the clinic or in controlled clinical trials.', 'A validation of the effects of CPX in COVID-19 patients would enable the utilization of this drug to alleviate likely shortages in HCQ and AZT.', 'CPX is a part of the US Health and Human Services Strategic National Stockpile 64 , which can be mobilized during regional or national emergencies.', 'CC-BY-NC 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.29.008631 doi: bioRxiv preprint Methods Cells, tissue culture and chemicals.', 'IB3-1 is a bronchial epithelial cell line derived from a CF patient with a ΔF508/W1282X CFTR mutant genotype 65 .', 'S9 is a derivative of IB3-1 corrected for chloride conductance by stable transfection with a functional CFTR.', 'The cells were maintained in LHC-8 Media (Biosource Int., MD).', 'The CF cell line CFBE41ō (ΔF508/ΔF508) and normal human bronchial epithelial cells16HBEō (from D. Gruenert) were maintained in complete MEMmedia (GibcoBRL, Life Technologies, MD).', 'The normal human tracheal cell line 9HTEō, transfected with pCEP-R or pCEP were from P. Davis, and were maintained in complete DMEM (GibcoBRL, Life Technologies, MD).', 'Primary bronchial epithelial cells were from Clonetics (NHBE) or from P. Karp (CF lung transplants) and were maintained in supplemented BEMB (Lonza, MD).', 'AZT was from Fluke (Switzerland) and CPX-HCL was from Sigma (St. Louis, MO).', 'Transfections and microscopy.', 'TGN38 and cellubrevin fusion with pH sensitive GFP was from J. Rothman 36 .', 'Cells were transected with 1 µg/ml DNA using Effectene (Siegen, CA) for 48 h prior to measuring pH. Co focal fluorescence microscopy of fixed samples was carried out on Zeus 510 META microscope.', 'Ratiometric pH determination.', 'The ratio of emission at 508 nm upon excitation at 410 nm vs. 470 nm was obtained described previously 28, [34] [35] [36] .', 'A pH standard curve was generated by collapsing the pH-gradient by incubating cells in 10 µM monensin and 10 µM nigericin for 30 min at 37 o C in buffer at pH 7.4, 6.5 or pH 5.5 and ratios were recorded for internal standards.', 'Fluorescence images were taken upon excitation at 410 and 470 nm (6 consecutive exposures).', 'Three regions of interest were selected and the standard curve was plotted as averaged 410/470 ratio values for a given buffer pH. Cells were incubated with 1-100 µM AZT for 1 h or 48 hrs, prior to determining pH. The ratio 410/470 of the samples was read against the standard curve and converted into pH units.', 'Azithromycin corrects organellar pH in CF lung epithelial cells.', 'We tested the effects of AZT on CF respiratory epithelial cells in the absence of bacteria or microbial innate immunity agonists.', 'Among the tests employed, we examine the pH of intracellular organelles since prior studies [27] [28] [29] [32] [33] [34] [35] have indicated that these organelles display subtly increased acidification in CF respiratory epithelial cells.', 'Of further relevance, unlike most other macrolides that show little benefit in CF 14 , AZT possesses two weak base functional groups with pKa of 8.2 and 8.6 (Fig. 1A) .', 'The pH of the lumen of the trans-Golgi network (TGN) and recycling endosomes (RE) in CF lung cells were measured by ratiometrically applying an intracellular pH-sensitive probe, pHlourin GFP 36 .', 'The pH sensitive GFP was fused to TGN38 or cellubrevin thus localizing the pHluorin GFP to the lumen of the TGN or RE 36 in CF respiratory epithelial cells 35 34 .', 'Primary CF bronchial epithelial cells treated with AZT displayed correction of the previously reported TGN and RE hyperacidifcation [27] [28] [29] [32] [33] [34] [35] (Fig. B-G) .', 'Treatment of IB3-1 (CF cells) with either 100 µM (for 1 h) or 1 µM AZT (for 48 h), led to a correction of TGN pH from 6.2 ± 0.1 (control) to 7.1 ± 0.1 or to 6.7 ± 0.2 ( Fig. 1C) , comparable to the pH of 6.7 ± 0.1 within the TGN of S9 cells (CFTR-corrected IB3-1 cells).', 'In primary CF bronchial epithelial cells (Fig 1D) , AZT treatment corrected their TGN', 'The pH of the recycling endosome in CF was similarly corrected with AZT ( Fig. 1E -G).', 'Treatment of IB3-1 (CF cells) with 100 µM AZT for 1 h or 1 µM for 48 h led to a correction of RE pH from 6.1 ± 0.3 to 6.8 ± 0.2 (Fig. 1F ).', 'In primary CF bronchial cells, 100 µM AZT corrected the pH of RE from 6.1 ± 0.1 to pH 6.7 ± 0.2 ( Fig. 1E ,G).', 'Acidotropic correction of acidified intracellular compartments in CF respiratory epithelial cells is not restricted to azithromycin.', 'CPX, another antibiotic (fluoroquinolone) (Fig. 2 ) effective in CF is also a weak base with pKa 8.76 37 .', 'We tested CPX effects on CF cells.', 'We used pCEP-R cells, the human normal bronchial epithelial cells (16HBE) transfected with R-region of CFTR, which renders them phenotypically express CF characteristics, and found that CPX (100 µM, 1 h) corrected pH in the TGN (Fig. 2 ).', 'This shows that pH correction in CF is not limited to AZT but that other antibiotics with weak base chemical properties may display this property.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['While there is some preliminary descriptive data on clinical management, randomized controlled trials are needed to determine the best treatment options for COVID-19.', 'For now, the World Health Organization has issued interim guidelines for clinical management, adapted from their guidance for MERS-CoV. It includes recommendations for early recognition, early supportive therapy (oxygen, fluids, empirical antimicrobials) and against routine use of systemic corticosteroids unless indicated for another reason.', 'They also provide guidelines for cases of septic shock [30].', 'Clinical trials to test therapeutic efficacy are ongoing, such as a trial of lopinavir/ritonavir (https://www.pharmaceutical-technology.com/analysis/coronavirus-mers-cov-drugs/).', 'More studies are expected soon [19].', 'Most of studies identified in the SARS and MERS review were descriptive treatment studies.', 'These observational studies are practical in the fast-paced outbreak setting, as they are easier than randomised controlled trials (RCTs) to design and require less administrative effort.', 'However, when it comes to treatment, RCTs', 'The RCT on Ebola therapeutics in the Democratic Republic of the Congo is evidence that conducting clinical therapeutics research is possible in the context of an outbreak [41].', 'The WHO has released a Master Protocol for a multi-centre, adaptive, randomized, double-blind placebo-controlled clinical trial to evaluate safety and efficacy of therapeutic agents for the treatment of hospitalized patients with COVID-19.', 'Using a Master Protocol across international sites can speed the implementation of clinical trials and quickly inform treatment options (https://www.who.int/blueprint/priority-diseases/key-action/multicenter-adaptive-RCT-of-investigational-therapeutics-for-COVID-19.pdf?ua=1).']}\n", - "{'sentences': ['These findings warrant further investigation, to confirm our preliminary findings and allow implementing guidelines on the management of these patients during the SARS-CoV-2 global pandemic.', 'After more than one month from the SARS-CoV-2 outbreak in Bergamo and its surrounding area, no cases of have been reported in our IBD cohort.', 'The recent onset of this pandemic outbreak, which is still ongoing, and the lack of epidemiologically robust data, preclude us from drawing certain conclusions regarding its incidence and its effects in specific populations of patients.', 'However, if we base our calculation on a mathematical model applied to the Wuhan region, which estimated a 86% undocumented cases, we could speculate that in Bergamo province a total of 46.220 patients were infected by SARS-CoV-2, accounting for 4% of the total population 4 .', 'From this model we could estimate that 21 cases among our IBD cohort should have been infected.', 'Furthermore, biologic treatments, administered either in hospital setting (Infliximab, Vedolizumab) or at home (Adalimumab, Golimumab and Ustekinumab), were regularly continued without complications.', 'There is lack of evidence regarding Coronaviridiae infection in IBD patients, especially those under immunosuppressive treatment.', 'An extensive nationwide population based study performed in France, and including nearly 191.000 adult patients with IBD, showed a total of 262 opportunistic infections, with an apparent decreased risk in patients on anti-TNF monotherapy compared with those on thiopurines monotherapy (HR, 0.57; 95% CI, 0.38-0.87) 5 .', 'If we look back to recent history, we can find two outbreaks of Coronaviruses with high lethality, sharing with SARS-CoV-2 the same family of viruses and the characteristics of zoonoses: the severe acute respiratory syndrome (SARS) and the MERS-CoV infection.', 'Immunosuppression was not found to be a risk factor neither for SARS nor MERS, and no patient with IBD as the only risk factor was reported to develop severe SARS', \"Systemic inflammation is a crucial target for the treatment of COVID-19 pneumonia 6 , even though salicylates haven't been tested as a modifying agent.\", 'However, a recent report seems to suggest an important role of a cytokine cascade in the development of COVID-19 acute respiratory distress 7 .', 'This speculation supports the theory that patients on immunosuppressive treatment could be at lower risk of developing complicated SARS-CoV-2 complications.', 'Our data cannot definitely ascertain what can be the rate of SARS-CoV-2 infected patients in our cohort of IBD patients.', 'In fact, only patients with severe symptoms and/or with established contact with infected patients received a nasopharyngeal swab, leaving the asymptomatic subjects out of the count.', 'However we believe our estimated rate of infection should be reliable, since it has been calculated according to well-established criteria (https://www.cdc.gov/coronavirus/2019ncov/symptoms-testing/index.html ).', 'Based on our evaluation, as of March 23 nd , we conclude that none of our patients with IBD was affected by a complicated SARS-CoV-2 related pneumonia.', 'All our patients were advised to continue their current immunosuppressive regimen,.']}\n", - "{'sentences': ['AbstractReverse genetics has been an indispensable tool revolutionising our insights into viral pathogenesis and vaccine development.', 'Large RNA virus genomes, such as from Coronaviruses, are cumbersome to clone and to manipulate in E. coli hosts due to size and occasional instability1-3.', 'Therefore, an alternative rapid and robust reverse genetics platform for RNA viruses would benefit the research community.', 'Here we show the full functionality of a yeast-based synthetic genomics platform for the genetic reconstruction of diverse RNA viruses, including members of the Coronaviridae, Flaviviridae and Paramyxoviridae families.', 'Viral subgenomic fragments were generated using viral isolates, cloned viral DNA, clinical samples, or synthetic DNA, and reassembled in one step in Saccharomyces cerevisiae using transformation associated recombination (TAR) cloning to maintain the genome as a yeast artificial chromosome (YAC']}\n", - "{'sentences': ['Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: Preliminary safety results of a randomized, double-blinded, phase IIb clinical trial (CloroCovid-19 Study)', 'Before the CloroCovid-19 trial began, to our knowledge, there were no published reports of robust clinical studies on the safety and/or efficacy of chloroquine (CQ) and/or hydroxychloroquine (HCQ', \"We searched PubMed and also MedRxiv.org (pre-print server for health sciences, without peer review), without any language restrictions and including Chinese publications, for studies published between Dec 2019 and April 5, 2020, using the search terms 'COVID-19, coronavirus, SARS-Cov-2'.\", 'We found three non-randomized studies with limited sample sizes in which (1)', 'In a unique pandemic situation, health professionals have to choose between offering medical assistance and generating and reporting reliable data, a dichotomy that compromises the generation of good quality evidence for clinical management.', 'Global recommendations for COVID-19 are being made based on unpowered studies, however, and due to the chaotic urgency, such drugs are being prescribed in a compassionate manner given the severity of this disease.', 'However, CQ, despite being a safe drug used for more than 70 years for malaria, might be toxic in the dosages recommended by Chinese authorities (high dosage 10g, for 10 days).', 'Our study raises enough red flags to stop the use of such dosage (12g of CQ in total, .', 'CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'for 10 days, due to the presentation of CQ tablets, 150mg, from Farmanguinhos) worldwide in order to avoid more unnecessary deaths.', 'We were not able to independently assess the toxic role of azithromycin because all patients were already using this antibiotic as per hospital protocol.', 'Oseltamivir, which also increases QTc, could potentiate cardiac side effects, because most of the patients (89.6%) were also in use of this drug for suspected influenza infection.', 'With the ethical impossibility of using a placebo arm, we were compelled to use historical data, based on very similar patients not using CQ.', 'Fatality rates observed here were not lower, however one cannot reliably conclude that CQ is of no benefit.', 'Placebo-controlled studies could still be performed in countries not routinely using the drug.', 'Several ongoing trials have been addressing the early use of CQ, in which the anti-inflammatory properties could be more helpful.', 'That information is urgently needed.', 'In addition to helping patients improve, CQ could be used to decrease the viral load in respiratory secretions, allowing less nosocomial and post-discharge transmission.', 'However, our limited data provided no evidence of such an effect.', 'Patients using CQ (irrespective of dosage) failed to present evidence of viral clearance by the fifth day (Day 4) of positive RT-PCR, even with the concomitant use of azithromycin.', 'Therefore, we do not envision such use as an antiviral drug.', 'Viremia dynamics in response to the drug will be further studied in our samples.', 'CQ is recommended for the treatment of malaria in particular due to its low cost; few doses resulting in safe concentrations are needed to treat the disease 25 .', 'CQ can deposit in tissues, especially the eye, causing retinal toxicity, which is associated only with prolonged use 23,24 .', 'QTc prolongation >500ms was seen in 17.9% of patients, which is not too dissimilar from what has been reported in patients with COVID-19 using HCQ (11.0%) 36 .', 'Myopathy has also been associated with CQ use 25 .', 'In our study, one patient developed rhabdomyolysis, which was attributed to CQ, and the drug was withdrawn.', 'In two patients, myocarditis was suspected based on the CKMB elevation since the first day of hospitalization, suggesting myocarditis related to SARS-CoV-2 itself.', 'In such cases, drugs prolonging QTc could lead to severe arrhythmias.', \"Unfortunately, this study's randomization, probably due to the low sample size, assigned older patients with heart disease to the high dosage arm.\", 'Therefore, one limitation .', 'CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.07.20056424 doi: medRxiv preprint for the conclusions of the study on lethality per arm is that high CQ dosage arm presented more patients prone to cardiac complications, with or without CQ.', \"The occurrence of myocarditis in our sample together with the confirmed QTc prolongation, warrants caution in relation to this drug's safety, particularly considering the eventual increase in fatal arrythmias.\", 'This study had some strengths, as it was: (1) In conclusion, the high CQ dose scheme (12g), given for 10 days, was not sufficiently safe to warrant continuation of that particular study arm.', 'We therefore strongly recommend that this dosage is no longer used anywhere for the treatment of severe COVID-19, especially because in the real world older patients using cardiotoxic drugs should be the rule.', 'No apparent benefit of CQ was seen regarding lethality in our patients so far, but we will still enroll patients in the low CQ dose group to complete the originally planned sample size.', 'In order to better understand the role of CQ or HCQ in COVID-19 38 , we recommend the following next steps: (1) trials evaluating its role as a prophylactic drug; (2) trials evaluating its efficacy against progression to severity when administered to patients with mild/moderate disease.', 'Even if we fail to generate good evidence in time to control the current pandemic, the information will highly impact the way we deal with next coronavirus outbreaks in the future.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Coronavirus disease 2019 (COVID-19) triggered by infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been widely pandemic all over the world.', 'The aim of this study was to analyze the influence factors of death risk among 200 COVID-19 patients.', 'Two hundred patients with confirmed SARS-CoV-2 infection were recruited.', 'Demographic data and clinical characteristics were collected from electronic medical records.', \"Biochemical indexes on admission were measured and patient's prognosis was tracked.\", 'The association of demographic data, clinical characteristics and biochemical indexes with death risk was analyzed.', 'Of 200 COVID-19 patients, 163 (81.5%) had at least one of comorbidities, including diabetes, hypertension, hepatic disease, cardiac disease, chronic pulmonary disease and others.', 'Among all patients, critical cases, defined as oxygenation index lower than 200, accounted for 26.2%.', 'Severe cases, oxygenation index from 200 to 300, were 29.7%.', 'Besides, common cases, oxygenation index higher than 300, accounted for 44.1%.', 'At the end of follow-up, 34 (17%) were died on mean 10.9 day after hospitalization.', 'Stratified analysis revealed that older ages, lower oxygenation index and comorbidities elevated death risk of COVID-19 patients.', 'On admission, 85.5% COVID-19 patients were with at least one of extrapulmonary organ injuries.', 'Univariable logistic regression showed that ALT and TBIL, two indexes of hepatic injury, AST, myoglobin and LDH, AST/ALT ratio, several markers of myocardial injury, creatinine, urea nitrogen and uric acid, three indexes of renal injury, were positively associated with death risk of COVID-19 patients.', 'Multivariable logistic regression revealed that AST/ALT ratio, urea nitrogen, TBIL and LDH on admission were positively correlated with death risk of COVID-19 patients.', 'Older age, lower oxygenation index and comorbidities on admission elevate death risk of COVID-19 patients.', 'AST/ALT ratio, urea nitrogen, TBIL and LDH on admission may be potential prognostic indicators.', 'Early hospitalization is of great significance to prevent multiple organ damage and improve the survival of COVID-19']}\n", - "{'sentences': [\"[{'text': 'The outbreak of COVID-19 has now become a global pandemic and it continues to spread rapidly worldwide, severely threatening lives and economic stability.\", 'Making the problem worse, there is no specific antiviral drug that can be used to treat COVID-19 to date.', 'SARS-CoV-2 initiates its entry into human cells by binding to angiotensin-converting enzyme 2 (human cells by binding to angiotensin-converting enzyme 2) via the receptor binding domain (RBD) of its spike protein.', 'Therefore, molecules that can block SARS-CoV-2 from binding to human cells by binding to angiotensin-converting enzyme 2 may potentially prevent the virus from entering human cells and serve as an effective antiviral drug.', 'Based on this idea, we designed a series of peptides that can strongly bind to SARS-CoV-2 RBD in computational experiments.', 'Specifically, we first constructed a 31mer peptidic scaffold by linking two fragments grafted from human cells by binding to angiotensin-converting enzyme 2 (a.a. 22-44 and 351-357) with a linker glycine, and then redesigned the peptide sequence to enhance its binding affinity to SARS-CoV-2 RBD.', 'Compared with several computational studies that failed to identify that SARS-CoV-2 shows higher binding affinity for human cells by binding to angiotensin-converting enzyme 2 than SARS-CoV, our protein design scoring function, EvoEF2, makes a correct identification, which is consistent with the recently reported experimental data, implying its high accuracy.', 'The top designed peptide binders exhibited much stronger binding potency to human cells by binding to angiotensin-converting enzyme 2']}\n", - "{'sentences': ['Objective: To analyze the clinical characteristics of 2019 novel coronavirus (2019-nCoV) pneumonia and to investigate the correlation between serum inflammatory cytokines and severity of the disease.', 'Methods: 29 patients with 2019-ncov admitted to the isolation ward of Tongji hospital affiliated to Tongji medical college of Huazhong University of Science and Technology in January 2020 were selected as the study subjects.', 'Clinical data were collected and the general information, clinical symptoms, blood test and CT imaging characteristics were analyzed.', 'According to the relevant diagnostic criteria, the patients were divided into three groups: mild (15 cases), severe (9 cases) and critical (5 cases).', 'The expression levels of inflammatory cytokines and other markers in the serum of each group were detected, and the changes of these indicators of the three groups were compared and analyzed, as well as their relationship with the clinical classification of the disease.', 'Results: (1) The main symptoms of 2019-nCoV pneumonia was fever (28/29) with or without respiratory and other systemic symptoms.', 'Two patients died with underlying disease and co-bacterial infection, respectively.', '(2) The blood test of the patients showed normal or decreased white blood cell count (23/29), decreased lymphocyte count (20/29), increased hypersensitive C reactive protein (hs-CRP) (27/29), and normal procalcitonin.', 'In most patients,serum lactate dehydrogenase (LDH) was significantly increased (20/29), while albumin was decreased(15/29).', 'Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (Tbil), serum creatinine (Scr) and other items showed no significant changes.', '(3) CT findings of typical cases were single or multiple patchy ground glass shadows accompanied by septal thickening.', 'When the disease progresses, the lesion increases and the scope expands, and the ground glass shadow coexists with the solid shadow or the stripe shadow.', '(4) There were statistically significant differences in the expression levels of interleukin-2 receptor (IL-2R) and IL-6 in the serum of the three groups (P<0.05), among which the critical group was higher than the severe group and the severe group was higher than the mildgroup.', 'However, there were no statistically significant differences in serum levels of tumor necrosis factor-alpha (TNF-α), IL-1, IL-8, IL-10, hs-CRP, lymphocyte count and LDH among the three groups (P>0.05).', 'Conclusion: The clinical characteristics of 2019-nCoV pneumonia are similar to those of common viral pneumonia.', 'High resolution CT is of great value in the differential diagnosis of this disease.', 'The increased expression of IL-2R and IL-6 in serum is expected to predict the severity of the 2019-nCoV']}\n", - "{'sentences': ['All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.27.20040816 doi: medRxiv preprint', 'Phosphorus is an important element in the body, which participates in the synthesis and energy metabolism of adenosine triphosphate (ATP', 'Some studies have found that the incidence of hypophosphatemia in critically ill patients can be as high as 44.8% 9 .', 'In our study, serum phosphorus levels were lower than normal in 50% of the severe/critical patients, and the level of serum phosphorus in severe / critical patients was lower than that in normal patients.', 'This may be due to the decrease of the level of glycerol 2,3-diphosphate in erythrocytes under the condition of hypophosphatemia, which leads to the left shift of the oxygen dissociation curve, the decrease of oxygen release and the disorder of oxidative phosphorylation process, and finally leads to tissue hypoxia due to the decrease of ATP energy supply 10 .', 'At the same time, the disturbance of lung water absorption is closely related to the metabolic disorder of phosphorus, the lack of phosphorus aggravates the inflammatory level of lung tissue, the ratio of ventilation and blood flow of edematous lung tissue is maladjusted, and the oxygenation function decreases, which can induce fatigue caused by hypoxia in intercostal muscle and diaphragm.', 'At the same time, the production of pulmonary surfactant is reduced, pulmonary alveoli are trapped, and respiratory failure is further aggravated 11 .', 'Some studies have confirmed that timely correction of hypophosphatemia in patients with hypophosphatemia can reverse the above symptoms and improve the prognosis [12] [13] .', 'The level of serum phosphorus is related to the severity of elderly patients with ventilator-associated pneumonia (VAP) and has predictive value for the prognosis of elderly patients with VAP', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', \"https://doi.org/10.1101/2020.03.27.20040816 doi: medRxiv preprint Pathological anatomy of a patient with COVID-19 revealed that the patient's lymphocytes were over-activated, and the highly pro-inflammatory CCR4 + CCR6 + Th17 cells increased, which partially explained the severe immune damage to the lung of neocoronary pneumonia 17 .\", 'In this study, 85% of patients with severe/critical type had lymphocyte absolute value lower than the reference range, and the lymphocyte level of patients with severe/critical type was lower than that of patients with normal patients.', 'Studies have shown that the immune function of elderly patients with severe pneumonia is significantly lower than that of their healthy peers, while the immune function of patients with hypophosphatemia is lower and generally in the state of immunosuppression.', 'Studies have found that serum phosphorus in elderly patients with severe pneumonia is positively correlated with the ratio of CD4+ / CD8+ 18 .', 'Our study also showed that there was a positive correlation between the absolute value of lymphocyte and the level of serum phosphorus, so the timely treatment with phosphorus supplementation for severe patients with low phosphorus may improve their immune level and promote their recovery.', 'The decrease of blood phosphorus level in clinical practice is commonly seen in chronic diseases such as fasting, malnutrition, parenteral nutrition 19 , metabolic or respiratory alkalosis, diabetic ketoacidosis, alcoholism, chronic alcohol withdrawal, and inadequate phosphorus intake without timely supplementation [20] [21] .', 'Most of the severe/critical COVID-19 patients mentioned in our study were middle-aged, with an overweight BMI and few underlying diseases, and a decrease in blood phosphorus levels was detected 1-10 days after admission.', 'It is more likely that novel coronavirus invades human body, causing a strong stress response and the release of inflammatory factors.', 'On the one hand, gastrointestinal function decline or gastrointestinal mucosal cell integrity and barrier function is impaired, resulting in a reduction in phosphorus intake from food.', 'On the other hand, stress response leads to increased secretion of epinephrine, glucagon, etc., and severely reduced utilization of intracellular phosphorus, leading to the migration of a large amount of phosphorus into the cell to participate in energy metabolism 22 .', 'In addition to following the treatment of COVID-19 (trial version fifth), we also treated patients with hypophosphatemia with phosphorus supplementation.', 'With the recovery of the disease and the transformation of the viral nucleic acid, the blood phosphorus level and the absolute value of lymphocytes in the majority of severe/critical patients returned to normal.', 'In this process, is it caused by exogenous supplement or redistribution of phosphorus inside All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.27.20040816 doi: medRxiv preprint and outside cells with the gradual recovery of immune system?', 'More scientific basic or clinical research is needed in the future.', 'In our study, after the patients met the discharge standards of the current COVID-19 treatment scheme (trial version fifth) 8, there were still four patients with absolute value of lymphocytes and two patients with blood phosphorus level not returning to normal.', 'Will these patients have viral nucleic acid conversion to positive again after discharge?', 'There is an urgent need for more clinical research on how to follow up these patients.', 'In summary, hypophosphatemia was associated with the severity of COVID-19.', 'It is significant to improve the prognosis to strengthen the monitoring of blood phosphorus level in patients with COVID-19 severe/critical type and correct hypophosphatemia in time.', \"Limitations of this study: 1) the first emergency ward of Taiyuan fourth people's Hospital is a ward for the treatment of severe/critical COVID 19 patients in Shanxi\", 'The small number of samples may affect the statistics and analysis of the results.', '2) In the face of sudden outbreaks and life-threatening diseases, no one can use a placebo as a control, so we cannot make sense of exogenous phosphorus supplementation.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 / COVID-19) pandemic is a worldwide emergency.', 'An increasing number of diarrhea cases is reported.', 'Here we investigate the epidemiology, clinical presentation, molecular mechanisms, management, and prevention of SARS-CoV-2 associated diarrhea.', ': We searched on PubMed, EMBASE, and Web of Science up to March 2020 to identify studies documenting diarrhea and mechansism of intestinal inflammation in patients with confirmed diagnosis of SARS-CoV-2 infection.', 'Clinical studies show an incidence rate of diarrhea ranging from 2% to 50% of cases.', 'It may precede or trail respiratory symptoms.', 'A pooled analysis revealed an overall percentage of diarrhea onset of 10.4%.', 'SARS-CoV uses the the angiotensin-converting enzyme 2 (ACE2) and the serine protease TMPRSS2 for S protein priming.', 'ACE2 and TMPRSS2 are not only expressed in lung, but also in the small intestinal epithelia.', 'ACE2 is expressed furthermore in the upper esophagus, liver, and colon.', 'SARS-CoV-2 binding affinity to ACE2', 'Conclusion: Diarrhea is a frequent presenting symptom in patients infected with SARS-CoV-2.', 'Increasing evidence indicates possible fecal oral transmission, indicating the need for a rapid and effective modification of the screening and diagnostic algorithms.', 'The optimal methods to prevent, manage, and treat diarrhea in COVID-19 infected patients are subjects of intensive research.']}\n", - "{'sentences': ['Although coronaviruses are under extensive mutagenesis, some key proteins, especially replication-related enzymes, are highly conserved [8] .', 'Because the mutation in key proteins are often lethal to the virus [9] , drugs that target conservative protease are usually capable of preventing the replication and proliferation of the virus and exhibit broad spectrum.', 'Besides, they can reduce the risk of mutation mediated drug-resistance.', 'In the current study, based on the results from bioinformatics analysis, the structure of SARS-CoV 5n5o protein was selected as a homologous target for molecule screening.', 'Then, in silico high throughput screening strategy and automatic pipeline have been established by using classic docking software and our in-house program, which greatly accelerates the screening process.', 'Among the four molecules identified in this study, Prulifloxacin is a chemotherapeutic fluoroquinolone antibiotic with broad-spectrum activity, it has been approved for the treatment of uncomplicated and complicated urinary tract infections, community-acquired respiratory tract infections in Italy and gastroenteritis, including infectious diarrheas, in Japan [10] .', 'Unfortunately, Prulifloxacin is reported as a prodrug, which is rapidly metabolized to ulifloxacin in vivo [11] .', 'But it can be used as a lead compound that provide guidance for our later structural modification and optimization to design more effective main protease inhibitors.', 'Tegobuvir is a novel author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.01.28.922922 doi: bioRxiv preprint non-nucleoside inhibitor (NNI', 'Our results clearly showed that all the four molecules showed reasonable binding conformations with the viral main protease.', 'Among them, Prulifloxacin exhibited three binding sites with main protease, two of which were the same as Nelfinavir and', 'Further, molecule Prulifloxacin, Tegobuvir and Bictegravir are preferable to Nelfinaviras confirmed by affinity and physical-chemical properties analysis using SeeSAR.', \"Based on the pockets' functions of target protein, it suggested that these molecules should possess the abilities to block the active sites or interrupt the dimer formation of viral protein.\", 'Therefore, they may sever as promising candidates for drug repurpose and development against 2019-nCoV. The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.01.28.922922 doi: bioRxiv preprint']}\n", - "{'sentences': ['The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro']}\n", - "{'sentences': ['Background An ongoing outbreak of pneumonia associated with a novel coronavirus was reported in Wuhan city, Hubei province, China.', 'Affected patients were geographically linked with a local wet market as a potential source.', 'No data on person-to-person or nosocomial transmission have been published to date.', 'In this study, we report the epidemiological, clinical, laboratory, radiological, and microbiological findings of five patients in a family cluster who presented with unexplained pneumonia after returning to Shenzhen, Guangdong province, China, after a visit to Wuhan, and an additional family member who did not travel to Wuhan.', 'Phylogenetic analysis of genetic sequences from these patients were done.', 'Findings From Jan 10, 2020, we enrolled a family of six patients who travelled to Wuhan from Shenzhen between Dec 29, 2019 and Jan 4, 2020.', 'Of six family members who travelled to Wuhan, five were identified as infected with the novel coronavirus.', 'Additionally, one family member, who did not travel to Wuhan, became infected with the virus after several days of contact with four of the family members.', 'None of the family members had contacts with Wuhan markets or animals, although two had visited a Wuhan hospital.', 'Five family members (aged 36-66 years) presented with fever, upper or lower respiratory tract symptoms, or diarrhoea, or a combination of these 3-6 days after exposure.', 'They presented to our hospital (The University of Hong Kong-Shenzhen Hospital, Shenzhen) 6-10 days after symptom onset.', 'They and one asymptomatic child (aged 10 years) had radiological ground-glass lung opacities.', 'Older patients (aged >60 years) had more systemic symptoms, extensive radiological ground-glass lung changes, lymphopenia, thrombocytopenia, and increased C-reactive protein and lactate dehydrogenase levels.', 'The nasopharyngeal or throat swabs of these six patients were negative for known respiratory microbes by point-of-care multiplex RT-PCR, but five patients (four adults and the child) were RT-PCR positive for genes encoding the internal RNA-dependent RNA polymerase and surface Spike protein of this novel coronavirus, which were confirmed by Sanger sequencing.', \"Phylogenetic analysis of these five patients' RT-PCR amplicons and two full genomes by nextgeneration sequencing showed that this is a novel coronavirus, which is closest to the bat severe acute respiatory syndrome (SARS)-related coronaviruses found in Chinese horseshoe bats.\", 'Interpretation Our findings are consistent with person-to-person transmission of this novel coronavirus in hospital and family settings, and the reports of infected travellers in other geographical regions.']}\n", - "{'sentences': ['The recent outbreak of coronavirus disease caused by SARS-CoV-2 31 infection in Wuhan, China has posed a serious threat to global public health.', 'To 32 develop specific anti-coronavirus therapeutics and prophylactics, the molecular 33 mechanism that underlies viral infection must first be confirmed.', 'Therefore, we herein 34 used a SARS-CoV-2 spike (S) protein-mediated cell-cell fusion assay and found that 35 SARS-CoV-2 showed plasma membrane fusion capacity superior to that of 36 SARS-CoV. We solved the X-ray crystal structure of six-helical bundle (6-HB) core 37 of the HR1 and HR2 domains in SARS-CoV-2 S protein S2 subunit, revealing that 38 several mutated amino acid residues in the HR1 domain may be associated with 39 enhanced interactions with HR2 domain.', 'We previously developed a pan-coronavirus 40 fusion inhibitor, EK1, which targeted HR1 domain and could inhibit infection by 41 divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. We 42 then generated a series of lipopeptides and found that the EK1C4 was the most potent 43 fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and 44 pseudovirus infection with IC 50 s of 1.3 and 15.8 nM, about 241-and 149-fold more 45 potent than that of EK1 peptide, respectively.', 'EK1C4 was also highly effective 46 against membrane fusion and infection of other human coronavirus pseudoviruses 47 tested, including SARS-CoV and MERS-CoV, as well as SARSr-CoVs, potently 48 inhibiting replication of 4 live human coronaviruses, including SARS-CoV-2.', '49 Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected 50 mice from infection, suggesting that EK1C4 could be used for prevention and 51 treatment of infection by currently circulating SARS-CoV-2 and emerging 52 SARSr-CoVs.', '53 including 2,618 deaths, were reported in China and 27 other countries 11 , posing a 70 serious threat to global public health and thus calling for the prompt development of 71 specific anti-coronavirus therapeutics and prophylactics for treatment and prevention 72 of COVID-19.', '73 Coronaviruses (CoVs), the largest RNA viruses identified so far, belonging to the 74 Coronaviridae family, are divided into 4 genera, α-, β-, δ-and γ-coronaviruses, while 75 the β-coronaviruses are further divided into A, B, C, and D lineages.', 'The seven CoVs 76 that can infect humans (HCoVs) include HCoV-229E and HCoV-NL63 in the 77 α-coronaviruses, HCoV-OC43 and HCoV-HKU1 in the β-coronaviruses lineage A, 78 SARS-CoV and SARS-CoV-2 in the β-coronaviruses lineage B (β-B coronaviruses), 79 and MERS-CoV in the β-coronaviruses lineage C 6 .', \"To develop specific SARS-CoV-2 80 fusion inhibitors, it is essential to study the fusion capacity of SARS-CoV-2 compared 81 to that of SARS-CoV. Particularly, the spike (S) protein S2 subunit of SARS-CoV-2, We have solved the X-ray crystal structure of SARS-CoV-2's 6-HB core and 111 identified several mutated amino acid residues in HR1 domain responsible for its 112 enhanced interactions with HR2 domain.\", 'By conjugating the cholesterol molecule to 113 the EK1 peptide, we found that one of the lipopeptides, EK1C4, exhibited highly 114 potent inhibitory activity against SARS-CoV-2 S-mediated membrane fusion and PsV 115 infection, about 240-and 150-fold more potent than EK1 peptide, respectively.', '116 EK1C4 is also highly effective against in vitro and in vivo infection of some live 117 HCoVs, such as SARS-CoV-2, HCoV-OC43 and MERS-CoV, suggesting potential for 118 further development as pan-CoV fusion inhibitor-based therapeutics and prophylactics 119 for treatment and prevention of infection by the currently circulating SARS-CoV-2 120 and MERS-CoV, as well as future reemerging SARS-CoV and emerging 121 SARSr-CoVs.', '122 Results 123 The capacity of SARS-CoV-2 S protein-mediated membrane fusion 124 From the GISAID Platform (https://platform.gisaid.org), we obtained the 125 full-length amino-acid sequence of SARS-CoV-2 (BetaCoV 2019-2020) S protein 126 (GenBank: QHD43416).', 'Through alignment with SARS-CoV and SL-CoVs S 127 proteins, we located the functional domains in SARS-CoV-2 S protein, which 128 contains S1 subunit and S2 subunit with the cleavage site at R685/S686 15 .', 'S1 subunit 129 is located within the N-terminal 14-685 amino acids of S protein, containing 130 N-terminal domain (NTD), receptor binding domain (RBD), and receptor binding 131 motif (RBM).', 'S2 subunit contains fusion peptide (FP), heptad repeat 1 (HR1), heptad 132 repeat 2 (HR2), transmembrane domain (TM) and cytoplasmic domain (CP', 'Recent biophysical and structural evidence showed that SARS-CoV-2 S protein 134 binds hACE2 with 10-fold to 20-fold higher affinity than SARS-CoV S protein, 135 suggesting the higher infectivity of the new virus 12 .', 'Unlike other β-B coronaviruses, 136 S protein of SARS-CoV-2 harbors a special S1/S2 furin-recognizable site, indicating 137 that its S protein might possess some unique infectious properties.', 'Indeed, in live 138 author/funder.', 'All rights reserved.', 'No reuse allowed without permission.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Objective: To raise awareness about 2019 novel coronavirus pneumonia (NCP) and reduce missed diagnosis rate and misdiagnosis rate by comparing the clinical characteristics between RNA positive and negative patients clinically diagnosed with NCP.', 'From January 2020 to February 2020, 54 patients who were newly diagnosed with NCP in Wuhan Fourth Hospital were included in this study.', 'RT-PCR method was used to measure the level of 2019-nCov RNA in pharyngeal swab samples of these patients.', 'The patients were divided into RNA positive and negative group, and the differences of clinical, laboratory, and radiological characteristics were compared.', 'Results: There were 31 RNA of 2019-nCov positive cases, and 23 negative cases.', 'Common clinical symptoms of two groups were fever (80.64% vs. 86.96%) , chills (61.29% vs.52.17%) , cough (80.64% vs.95.65%) , fatigue (61.30% vs.56.52%) , chest distress (77.42% vs.73.91%) .', 'Some other symptoms were headache, myalgia, dyspnea, diarrhea, nausea and vomiting.', 'The laboratory and radiological characteristics of two groups mainly were lymphopenia, increased erythrocyte sedimentation rate, increased C-reactive protein, increased lactate dehydrogenase, decreased oxygenation index, normal white blood cell count and bilateral chest CT involvement.', 'There was no statistically significant difference in other clinical characteristics except for dyspnea between two groups.', 'Conclusions: RNA positive and negative NCP patients shared similar clinical symptoms, while RNA positive NCP patients tended to have dyspnea.', 'Therefore, we should improve the understanding of NCP to prevent missed diagnosis and misdiagnosis; In addition, more rapid and accurate NCP']}\n", - "{'sentences': ['Our prospective longitudinal study describes the psychological impact and mental health of the general population in a country that was first affected by the COVID-19 outbreak.', 'Although the number of confirmed cases of COVID-19 increased sharply from the first-to the second-survey recruitment, there were no significant changes in the mean DASS-stress, anxiety and depression scores.', 'Although the mean IES-R scores were above the cut-off score for PTSD symptoms in both surveys, a statistically but not clinically significant temporal reduction in the mean IES-R scores was observed during the study period.', 'The reduction in IES-R score could be due to the delicate balancing between controlling the spread of COVID-19 through lockdown and establishing confidence in public health measures.', 'The important unexpected finding of our study is the stable levels of stress, anxiety and depression despite sharp increases in the number of COVID-19 cases between the two surveys as well as statistically but not clinically significant reduction in the psychological impact on the general population.', 'We believe that decisive and rapid measures imposed by the Chinese government were instrumental in reducing further spread of the virus 20 but could safeguarded mental health in the general public.', 'Nevertheless, prolonged lockdown had several adverse impacts on mental health, especially among the second-survey respondents aged 12-21·4 years who demonstrated a higher psychological impact of COVID-19.', 'This age group mainly comprised of students who were affected by prolonged school closure, requiring online education support and uncertainty about examinations and matriculation arrangements.', 'Respondents from both surveys who were parents with children younger than 16 years of age were not associated with higher IES-R or DASS-21 scores.', 'This finding corresponds to the emerging pattern of resilience to severe outcomes of COVID19 in children 21 and parents were less worried as a result.', 'During the initial outbreak, 15.04%, 9.42% and 5.62% of respondents reported one, two or three somatic symptoms respectively.', 'The presence of somatic symptoms prompt researchers to consider the psychoneuroimmunological (PNI', 'COVID-19 can cause acute respiratory syndrome with consequent release of pro-inflammatory cytokines, including interleukin (IL)-1β and IL-6 from the respiratory tract.', '22 These cytokines were commonly found to be increased in major depressive disorder 23, 24 and functional somatic syndromes 25 .', 'COVID-19, depression and functional somatic syndrome share the same PNI framework.', 'Antidepressants (e.g. fluoxetine) was found to reduce pro-inflammatory cytokines by attenuating the behavioural and neuroendocrine effects of immune activation.', '26 Further research is required to study the effectiveness of antidepressants as part of the antiinflammatory strategies against COVID-19 by reducing depression and somatic symptoms.', 'Our study highlights some public health implications.', 'First, the strong association between physical symptoms and the psychological impact of COVID-19 outbreak supports importance of developing a rapid diagnostic test for COVID-19 with widespread availability to alleviate the psychological impact and psychiatric symptoms experienced by general population.', 'Second, providing proper and repeated, yet simple, health education via the Internet and media is important for inculcating good hygiene practices.', 'We observed that significantly higher proportion (10·8%) of the second-survey respondents did not know that COVID-19 could be transmitted by droplets, which might reduce the acceptability of certain precautionary measures.', 'Third, the dissemination of health information via radio was associated with higher levels of anxiety and depression in both surveys.', 'This observation may help the Governments and health authorities worldwide to modify the current methods of increasing public awareness.', 'Perhaps, increased use of television (with participation by celebrities) and Internet (for detailed information with visual graphics and videos) to disseminate important health information might be more effective methods to change knowledge, attitude and practices among the general public.', 'Fourth, mask-wearing, as a prevention method to reduce pathogen exposure 27 Our study has some limitations.', 'The general population sampled during the two surveys were not the same respondents.', 'Although the anonymity of the questionnaire made this sampling unavoidable, 333 respondents completed both the first and second surveys.', 'However, owing to the anonymous nature of the data collection, we could not pair respondents at the 2time intervals.', 'Another limitation is due to the self-reporting of the levels of psychological impact, anxiety, depression and stress, which may not always be aligned with objective assessment by mental health professionals.', 'Nevertheless, psychological impact, anxiety, depression and stress are based on personal feelings, and self-reporting was paramount during the COVID-19 pandemic.', '19 In the same vein, we could not rule out the possibility that some of the respondents might have been infected with COVID-19.', 'There were only 0.9% of the firstsurvey respondents and 0.5% of second-survey respondents who received testing on COVID-19.', 'Due to low prevalence of testing, the number of respondents who were tested positive for COVID-19 was even lesser.', 'Nevertheless, we could not rule out the possibility that some respondents were asymptomatic carriers with mild COVID-19 symptoms.', 'Finally, the understanding of COVID-19 was limited when we first designed this study.', 'We did not measure neurological symptoms (e.g. loss of smell or taste) that were recently discovered to be associated with COVID-19.']}\n", - "{'sentences': ['This study showed that most patients with COVID-19 had pneumonia, and the most common symptoms at onset of illness were fever, dry cough, myalgia or fatigue.', 'Less common symptoms were diarrhea, headache, sore throat, upper airway congestion and a small number of severe patients developed chest tightness and dyspnea, indicating that the target cells might be located in the lower airway.', 'This was consistent with the results of previous studies(7-10, 13-15).', 'There were no significant differences in initial clinical symptoms between in Hubei province and outside Hubei province.', 'These nonspecific symptoms are shared by winter respiratory diseases caused by bacteria and viruses, especially influenza.', 'Influenza are usually characterized by fever, myalgia, headache and dry cough, most of which are self-limiting but may also progress to severe conditions, such as pneumonia, myocarditis and death (16, 17) .', 'In addition, severe acute respiratory syndrome corona virus (SARS-CoV) and Middle East respiratory syndrome corona virus (MERS-CoV', 'The copyright holder for this preprint (which was not peer-reviewed) is .', '22.20040782 doi: medRxiv preprint This report demonstrated that the incidence of dry cough in confirmed group was significantly higher than that in unconfirmed group, but the clinical symptoms of patients with COVID-19 were nonspecific.', 'Therefore, clinical symptoms alone were difficult to distinguish from winter respiratory diseases.', 'Our study showed that the white blood cell count and the absolute value of lymphocytes in confirmed group was significantly lower than that in unconfirmed group.', 'Qin et al demonstrated that lymphocytes counts in most severe COVID-19 patients was reduced, which suggests that SARS-CoV2 might impaired immune system and mainly damaged lymphocytes, especially T lymphocytes (20) .', 'This was similar to SARS-CoV, which spread through the respiratory mucosa and infect other cells, triggering a series of inflammatory responses and cytokine storm, resulting in changes in lymphocytes (21) .', 'Therefore, the reduced white blood cell count and lymphocytes could be used as a reference index for clinical diagnosis of COVID-19.', 'In addition, the ESR of the confirmed group was significantly higher than that of unconfirmed group, while there was no statistical difference in CRP and procalcitonin between the two groups.', 'Therefore, ESR could help clinicians distinguish between COVID-19 and winter respiratory diseases.', 'Although previous studies had shown that some patients with confirmed COVID-19 had abnormal alanine aminotransferase (ALT), aspartate aminotransferase (AST', 'The copyright holder for this preprint (which was not peer-reviewed) is .', '22.20040782 doi: medRxiv preprint coagulation activation, myocardial injury were common in critically ill and severe cases.', 'This result was contrary to a recent study.', 'Zhao et al showed that the levels of liver function associated markers (ALT, AST and LDH) were significantly higher in confirmed group than in unconfirmed group, but the sample size of the study was very small (11) .', 'Therefore, these laboratory indicators might not provide reference for the differential diagnosis of COVID-19 outside Hubei province.', 'The CT imaging features of COVID-19 are diversity.', 'SARS-Cov-2 belongs to β coronavirus family, which causes pneumonia with similar imaging features to other coronavirus pneumonia, such as SARS and Middle East respiratory syndrome (MERS', 'were peripherally distributed multifocal GGO with predominance in the lower lung lobe.', 'However, it still had specific imaging characteristics, especially compared to that of influenza A and influenza B. While the manifestations of seasonal influenza are small patch GGO and consolidation with subpleural and/or peribronchial distribution on chest CT(24).', 'Our study indicated that the proportion of GGO, crazy-paving pattern, air bronchogram, and pleural thickening in the confirmed group was significantly higher than that in the unconfirmed group.', 'In terms of the distribution of lesions, the proportion of bilateral, subpleural, lower lung distribution and multi-lobe involvement in the confirmed group was significantly higher than that of the unconfirmed group.', 'Considering the high incidence of seasonal influenza, a recent study showed that the most common etiology in all suspected cases was influenza virus infection (25) .', 'Therefore, chest CT could become an effective clinical diagnostic tool for screening All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is (6, 26) .', 'In this study, 4 cases with asymptomatic infections of the 62 confirmed COVID-19 patients were first detected by chest CT scan and finally confirmed by RT-PCR.', 'Therefore, it could not only be possible to identify patients with negative results of RT-PCR but highly suspicious of COVID-19 for clinicians, but also to screen patients with a clear history of epidemiological exposure but asymptomatic infection.', 'In addition, chest CT was helpful for monitoring the dynamic therapeutic effect of patients during treatment (27) .', 'It was worth noting that 9 of the 62 confirmed COVID-19 patients in this study had no abnormal lesions in chest CT.', 'Therefore, suspected cases with epidemiological history, clinical manifestations and abnormal laboratory tests should be diagnosed combined with the results of RT-PCR test.', 'Our advantage was that this was the first multi-center study to compare the clinical and imaging features between confirmed and unconfirmed groups.', 'Comparison of the clinical and imaging features between the two groups may help clinicians to differentiate COVID-19 from other pathogen infections and then to screen patients with highly suspected cases.', 'There are several limitations in our study.', 'First, although the RT-PCR test is the current gold standard for the diagnosis of COVID-19, it might still present a certain false-negative rate after repetitions.', 'This is mainly due to the fact that the test samples are mostly pharynx swabs rather than bronchoalveolar lavage fluid (BALF', 'The copyright holder for this preprint (which was not peer-reviewed) is .', '22.20040782 doi: medRxiv preprint was easily degraded.', 'Second, we did not complete the tests of influenza A virus, influenza B virus, parainfluenza virus, mycoplasma pneumoniae, chlamydia pneumoniae, respiratory syncytial virus, adenovirus, coxsackie virus, the nucleic acid of influenza viruses A and B and microbial culture in all patients.', 'We could not clearly distinguish the specific pathogen infections in patients with unconfirmed group.', 'Therefore, we did not further compare the differences between COVID-19 and specific pathogen infections.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Risk indicators viral load (ORF1ab Ct), lymphocyte percentage (LYM%), C-reactive protein (CRP), interleukin-6 (IL-6), procalcitonin (PCT) and lactic acid (LA', 'However, the predictive effects of those indicators on disease classification and prognosis remains largely unknown.', 'We dynamically measured those reported indicators in 132 cases of COVID-19 patients including the moderate-cured (moderated and cured), severe-cured (severe and cured) and critically ill (died).', 'Our data showed that CRP, PCT, IL-6, LYM%, lactic acid and viral load could predict prognosis and guide classification of COVID-19 patients in different degrees.', 'CRP, IL-6 and LYM% were more effective than other three factors in predicting prognosis.', 'For disease classification, CRP and LYM% were sensitive in identifying the types between critically ill and severe (or moderate).', 'Notably, among the investigated factors, LYM% was the only one that could distinguish between the severe and moderate types.', 'Collectively, we concluded that LYM% was the most sensitive and reliable predictor for disease typing and prognosis.', 'During the COVID-19 pandemic, the precise classification and prognosis prediction are critical for saving the insufficient medical resources, stratified treatment and improving the survival rate of critically ill patients.', 'We recommend that LYM% be used independently or in combination with other indicators in the management of COVID-19.', 'Given the worldwide prevalence of COVID-19, disease typing and prognostic indicators are of great significance in guiding classified treatment, preventing medical runs and saving critical patients.', 'In this study, we selected several reported risk factors for prognosis of COVID-19 patients and further validated their predictive roles in disease outcome and classification.', 'This is the first study reporting CRP, PCT, IL-6, lactic acid, ORF1ab Ct and LYM% as indicators for different types of patients with COVID-19.', 'We validated that the LYM% could be a permissible predictor to identify critically ill, severe and moderate cases.', 'Previous studies also supported the conclusion that lymphocyte count and function were closely related to the disease status of COVID-19 [11, 19] .', 'Patients with insufficient immunity, including the elders and people with immunodeficiency, always presented a lower level of lymphocytes and a worse prognosis after infected with .', 'CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'In the present study, basing on the information of 132 patients with COVID-19, we analyzed the predictive power of several reported indicators for disease severity and prognosis in a descriptive manner.', 'We found that CRP, PCT, IL-6, LYM%, lactic acid and viral load could predict prognosis and guide classification of COVID-19 patients in different degrees.', 'CRP, IL-6 and LYM% were more effective than other three factors in predicting prognosis.', 'CRP and LYM% were sensitive in identifying the types between critically ill and severe (or moderate).', 'Notably, among the investigated factors, LYM% was the only one that could distinguish between the severe and moderate types.', 'Collectively, we concluded that LYM% was the most sensitive and reliable predictor for disease typing and prognosis.', 'We recommend that LYM% be used independently or in combination with other indicators in the management of COVID-19.']}\n", - "{'sentences': ['In this paper, we collected these measures systematically and made respective descriptions.', 'Our purpose is to tell the reader that COVID-19 is spreading globally at an alarming speed, and an outbreak in any environment could bring very serious consequences for each country.', 'Some countries in Europe still take vague attitudes about this outbreak, such as \"herd immunity\".', 'People refuse to wear facemasks and so on.', \"China's experience has shown that non-pharmacology interventions can reduce or even stop transmission in some cases successfully.\", \"Even in the face of widespread transmission -what China's experiences have shown was that if we keep calm, take action immediately with global, and implement systematic identification case and contact tracing, we would change the course of the epidemic, prevent people from getting sick and prevent the most vulnerable from dying.\", 'To the best of our knowledge, the main strategy of \"Four early\": \"early identification, early report, early isolation and early treatment\" was put forward and concentrating patients, medical experts, and medical resources into special centers to improve the .', 'CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.']}\n", - "{'sentences': ['COVID-19 has quickly become a worldwide pandemic, which has significantly impacted the economy, education, and social interactions.', 'Understanding the humoral antibody response to SARS-CoV-2 proteins may help identify biomarkers that can be used to detect and treat COVID-19 infection.', 'However, no immuno-proteomics platform exists that can perform such proteome-wide analysis.', 'To address this need, we created a SARS-CoV-2 proteome microarray to analyze antibody interactions at amino acid resolution by spotting peptides 15 amino acids long with 5-amino acid offsets representing full-length SARS-CoV-2 proteins.', 'Moreover, the array processing time is short (1.5 hours), the dynamic range is ~2 orders of magnitude, and the lowest limit of detection is 94 pg/mL. Here, the SARS-CoV-2 proteome array reveals that antibodies commercially available for SARS-CoV-1 proteins can also target SARS-CoV-2 proteins.', 'These readily available reagents could be used immediately in COVID-19 research.', 'Second, IgM and IgG immunogenic epitopes of SARS-CoV-2 proteins were profiled in the serum of ten COVID-19 patients.', 'Such epitope biomarkers provide insight into the immune response to COVID-19 and are potential targets for COVID-19 diagnosis and vaccine development.', 'Finally, serological antibodies that may neutralize viral entry into host cells via the ACE2 receptor were identified.', 'Further investigation into whether these antibodies can inhibit the propagation of SARS-CoV-2 is warranted.', 'Antibody and epitope profiling in response to COVID-19 is possible with our peptide-based SARS-COV-2 proteome microarray.', 'The data gleaned from the array could provide invaluable information to the scientific community to understand, detect, and treat COVID-19.']}\n", - "{'sentences': ['Epidémie au nouveau coronavirus (SARS-CoV-2) et prescription de la clozapine: Quelles mesures?Pourquoi?']}\n", - "{'sentences': ['The SARS-CoV-2 pandemic has demonstrated the need for antiviral drugs with broad activity against a range of viruses.', 'Whether treating SARS-CoV-2 in this current pandemic or the next unknown viral pathogen, we must attempt to have validated antiviral drugs that are ready at the first signs of an outbreak.', 'Many FDA approved drugs have been found to have antiviral activity and since these are extensively used in humans for other conditions, they could be streamlined for rapid approval for alternative use as antivirals.', 'We previously performed a screen of 290 FDA approved drugs and found a subset of these to have antiviral activity against SARS-CoV and MERS-CoV (4).', 'We prioritized testing these for antiviral activity against SARS-CoV-2.', 'From multiple independent screens performed with two MOI, we found that 17 of our 20 tested compounds display significant antiviral activity at non-cytotoxic concentrations.', 'Many of the compounds have IC50 values under 10µM and these will be the source of follow up testing on additional cell lines and in mouse models of SARS-CoV-2.', 'We have further tested .', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.25.008482 doi: bioRxiv preprint hydroxychloroquine and chloroquine phosphate for antiviral activity at the level of inhibiting viral mRNA (using N and RdRp) and infectious viral particle production (measured by TCID50 assay).', 'Both drugs showed inhibitory properties, but hydroxychloroquine had greater antiviral activity.', 'These data should be used to inform future planned human to assess antiviral activity of chloroquine or derivative drugs.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.25.008482 doi: bioRxiv preprint change for drug treated to vehicle control was calculated (dotted line to denote a fold change of 1 which is no change over control).', 'Data are from 2 independent infections performed on triplicate wells, the fold change was calculated in each independent experiment and the mean fold change is plotted with error bars displaying standard deviation.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.25.008482 doi: bioRxiv preprint .', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.25.008482 doi: bioRxiv preprint The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.25.008482 doi: bioRxiv preprint The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.25.008482 doi: bioRxiv preprint']}\n", - "{'sentences': ['Therapeutic Application of Chloroquine in Clinical Trials for COVID-19', \"[{'text': 'The corona virus disease -2019 (COVID-19) pandemic has caused a massive global public health havoc.\", 'Recent published clinical trials show conflicting data for use of chloroquine/hydroxychloroquine for COVID-19', 'Modern and robust scientific interventions at national and international level for prevention, containment and treatment has protected mankind from various deadly diseases like Ebola, Severe Acute Respiratory Syndrome, Middle East Respiratory Syndrome, etc.', 'in the contemporary parameters.', 'The Spanish flu about one hundred years ago claimed about up to 50 million lives (21) as modern scientific knowledge were contemporarily lacking and limited.', 'As predicted, in the absence of these measures, if 60% of global population were infected as forecasted by experts, and approximately 20% required treatment of chloroquine phosphate or hydroxychloroquine sulphate (22) , the cost could range tens of thousands USD per million population (Table 3) .', '(Table 4) .', 'Thus more studies are warranted to confirm the efficacy and safety for use of these medications.', 'In spite of that, continued efforts to try different dosages in ethically valid clinical trials is required for the assessment of effective and safe dosage administration.', 'This can importantly contribute to guide the medical professionals for prescribing the accurate interventions and also contribute to pharmaceutical companies for deciding appropriate manufacturing pathways.', 'While hydroxchloroquine has low dosage requirements and lesser side effects, the comparative price for complete prescribed treatment is more than five times of chloroquine phosphate (24) .', 'While malaria is endemic in poor parts of the world, the prevalence is still too less than the panic and feared caused by prevalence of COVID-19 prompting pharmaceuticals for scaling up for the production of chloroquine.', 'As chloroquine has significant adverse events, effective short-course dosing is very important.', 'Moreover, both of these drugs are prescribed for weeks to months for various indications (8,11) and the interventions for short disease course (2 weeks for mild and 3-4 weeks for severe and critical cases) (22) of COVID-19 may not significantly hamper treatment.', 'Other antiviral drugs in pipeline may not be very useful as their productions and supplies to the developing countries may require lengthy timeframe whereas mass production of chloroquine and hydroxychloroquine is already in place in malaria endemic developing countries.', \"Evaluating the potentially favorable benefit-risk balance, without any choice of valid therapeutic options left, chloroquine and hydroxychloroquine could be applicable for the management of COVID-19 in the present context of outbreak, however the respective national guidelines and clinician's evaluation and decision is recommended.\", 'In conclusion, chloroquine and hydroxchloroquine might have therapeutic potential for the medication of COVID-19 in the current context of pandemic situation.', 'However, the corroborating evidences from these undergoing clinical trials are definitely demanded to make the ultimate decision on COVID-19 treatment.', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.05.20031591 doi: medRxiv preprint Table 3 shows the main management strategies, comorbid conditions, and clinical outcomes of all the COVID-19 patients.', 'In the AMI group, in addition to antiviral and antibiotic therapies, cardioprotective medications such as amiodarone and cedilla were used by four patients to improve the cardiac function.', 'However, the non-definite AMI patients with and without cardiac markers abnormalities did not use cardioprotective medication.', 'All the 53 patients were administered nasal cannula oxygen therapy during admission for respiratory support; non-invasive ventilation or high-flow nasal cannula oxygen therapy was performed for five AMI and three non-definite AMI patients with cardiac marker abnormalities.', 'Notably, in the AMI group, invasive mechanical ventilation was used in three patients and ECMO in one patient due to extremely severe ARDS.', 'ARDS occurred in all the six AMI patients and four non-definite AMI patients with cardiac marker abnormalities.', 'Hypoxemia was a common complication that affected 19 (35.85%) of the 53 study patients, with a significant difference in the number of affected patients between the AMI (n=6, 100%) and non-definite AMI with cardiac marker abnormalities (n=10, 41.67%) groups and the without cardiac marker abnormalities group (n=3, 13.04%; p<0.001).', 'Moreover, a total of five AMI patients had AKI, and four of them used continuous renal replacement therapy.', 'Importantly, all the six AMI patients had critically severe NCP and needed care in intensive care unit (ICU).', 'However, half of the patients with cardiac marker abnormalities (n=13, 54.17%) had the common NCP type, with only two (8.33%) of them having critically severe NCP needing ICU', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.05.20031591 doi: medRxiv preprint patients (n=21, 91.30%) in the without cardiac marker abnormalities group had the common NCP type (Figure 2) .', 'Regarding clinical outcomes, in the AMI group, three patients died, two were still in admission, and one was discharged from hospital.', 'Conversely, a majority of non-definite AMI patients with (n=20, 83.33%) and without (n=21, 91.30%) cardiac marker abnormalities were discharged, with no case of death.']}\n", - "{'sentences': ['This retrospective, single-center study included a total of 221 SARS-CoV-2 pneumonia cases from Jan 2 to Feb 10, 2020.', 'Only 8 (3.6%) of patients had a history of exposure to the Huanan Seafood Market, while a majority of patients without the exposure history indicate the rapid human-to-human transmission.', 'Based on a recent review, the estimated All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.02.20030452 doi: medRxiv preprint 13 mean R0, an indicator of virus transmissibility, for the SARS-CoV-2 is around 3.28, which is higher than the WHO estimated at 1.95.', '16 , and is also higher than that of the SARS-CoV outbreak in 2003, with R0 approximately at 3.0.', '17 Clinical characteristic analysis shows a significantly increased age as well as elevated numbers of underlying comorbidities in severe patients than those in non-severe patients, indicating that the age and comorbidity may be important risk factors for poor outcome.', 'Contradictory to the previous report showing a higher incidence of COVID-19 in male patients, 5 recent data including ours, consistently showed a similar proportion of male and female patients with COVID-19.', '11 The patients with COVID-19 also demonstrated a decreased lymphatic count comparing to healthy people, and it was significantly decreased in severe patients compared to those in non-severe patients.', 'Our data show that lymphocytopenia occurred in more than 80% author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.02.20030452 doi: medRxiv preprint and IL-10 may be mediated in T cell pro-apoptosis.', '21 In addition, abnormal laboratory findings in the severe patients also included prolonged thrombin time, increased AST/AST, hypersensitive troponin I and serum creatine, suggesting aberrant coagulation pathway, hepatic injury, myocardial injury, and kidney injury, respectively.', 'The levels of PCT, a marker suggesting the bacterial infection, were not elevated in the patients with COVID-19, suggesting the viral-mediated pneumonia rather than bacteria.', 'These laboratory abnormalities are similar to those previously observed in patients with MERS-CoV 22 and']}\n", - "{'sentences': ['Objective To analysis the clinical characteristics and experiences in diagnosis and treatment of the patients with novel coronavirus pneumonia (NCP).', 'Methods Clinical data of 28 patients with NCP in Nanning', \"Fourth People's Hospital from January 22 to February 5 in 2020 were collected.\", 'The clinical manifestations, epidemiological history, laboratory tests, imaging examinations and treatments of patients were analyzed retrospectively.', 'Results The 28 patients with confirmed viral pneumonia included 11 males and 17 females, ranging from 11 to 68 years.', 'They all had history of epidemiological exposure and were all positive for 2019-nCoV nucleic acid in throat swabs.', 'There were one mild case, 25 ordinary cases and two severe cases.', 'There were four groups of family clusters.', 'The illness onset ranged from 1 to 12 days after exposure, and the time from the symptom onset to the positive result of the nucleic acid test was 0 to 13 days.', 'The clinical symptoms were mainly fever and cough, which progressed rapidly in a short period of time.', 'Since the onset of illness, the peak values of axillary temperature of the 28 patients were 36.6~39.5 ℃, while five patients had no fever throughout the course of the disease with the peak temperature of ≤37 ℃. There were two patients presented with decreased white blood cell counts, five patients with elevated C reactive protein, six patients with abnormal alanine aminotransferase, three patients with abnormal aspartate aminotransferase,10 patients with elevated creatine kinase, three patients with elevated creatine kinase isoenzyme, four patients with elevated lactate dehydrogenase, and all with normal procalcitonin levels.', 'The chest computed tomography examinations showed that the common features were ground glass shadows (21 cases), blurred edges (18 cases), speckles and patchy shadows (17 cases), thickening and disorder of some lung textures (cases), and visible band shadows), and visible band shadows (cases), and visible band shadows).', 'Pulmonary lesions often progressed rapidly.', 'One 11-year-old child was treated with alpha-interferon alone, and 27 patients were treated with alpha-interferon inhalation plus lopinavir/ritonavir with 4 withdrawal due to adverse reactions.', 'Up to February 12, nine patients had been discharged from the hospital, who were ordinary cases, without death cases.', 'Conclusions The NCP']}\n", - "{'sentences': [\"2019 novel coronavirus was an batacoronavirus which was transmitted by droplets and direct contact with a patient's body fluids, other ways of it transmission was unclear 8, 9 .\", 'Until 16 February 2020, the number of COVID-19 patients was more than 70 000, yet the number of infections was still rising 5 .', 'However, there are still no effective treatment for COVID-19, the main treatment is symptomatic and supportive therapy to alleviate symptoms and maintain organ function in severe diseases 10 .', 'Although some studies have reported that some drugs can be used against the 2019-nCov, these drugs still in the research stage 11 .', 'Our 128 case series by laboratory-diagnosed that all of them comeback from Wuhan, or had contacted with people from Wuhan, or close contacted with diagnosed patients.', 'However, there are unavoidable misdiagnosis through laboratory-confirmed by real-time quantitative fluorescence PCR detection of 2019-nCov due to sampling deviation.', 'In our study, the aged over 50 years patients accounted for over half of the diagnosed patients (53.9%).', 'Fever (89.8%) and cough(67.2%) were common symptoms, yet sore throat (14.1%) was rare.', 'Chest computed tomography scan showing ground glass opacity of diagnosed patients account for 63.3%, whereas the severe pneumonia up to 76.2%, these were inconsistent with other studies 12 data suggested that gender may not be an influence factor in 2019-nCov infection, yet advanced age was a risk factor for viral infection and poor prognosis.', 'Our data of laboratory detection indicated that the white blood cells and C-reactive protein level were elevated in severe case series and the lymphocytes were decreased.', 'The results suggested that severe pneumonia may be accompanying bacterial infection and immune deficiency may be also a risk factor for unfavourable prognosis in patients 13 .', 'In addition, alanine transaminase (ALT), aspartate transaminase (AST) and creatinine (CR', 'In summary, our data provide more information that advanced age, lower lymphocytes levels at the diagnosed COVID-19 patients may be a risk factor for unfavourable prognosis.', 'The white blood cells and C-reactive protein level elevated in severe COVID-19 patients may be accompanying bacterial infection.', '2019-nCov may be carries a risk factor of impaired liver and kidney function.']}\n", - "{'sentences': ['Chloroquine and hydroxychloroquine are widely used anti-malarial drugs with immunomodulatory properties that are approved for use in a number of rheumatological diseases.', 'Their anti-viral effects were discovered in 1960, and are related to their ability to limit viral replication by increasing the J o u r n a l P r e -p r o o f Journal Pre-proof 1 (AAK1) is a key regulator of endocytosis.', 'Baricitinib seems to inhibit AAK1 and binding cyclin G-associated kinase (GAK', 'Rheumatologists not only know the effectiveness of these drugs, but also the vital aspect of their safety.', 'Although there is an imperative need to discover treatments that can save human lives from this infection, it is also necessary to consider their possible adverse effects.', 'J o u r n a l P r e -p r o o f Journal Pre-proof']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Niclosamide has traditionally been used to treat tapeworm infections for many years, and it\\nis inexpensive and well tolerated in vivo with an extremely high acute oral\\nLD50 value of >5000 mg/kg in rats (niclosamide ethanolamine salt).10 In human medicines, single oral doses of 0.5, 1, and 2 g of niclosamide are\\nrecommended for children under 2 years, children between 2 and 6 years, and children older\\nthan 6 years and adults, respectively, to treat infections with Taenia\\nsolium, T. saginata, and Diphyllobothrium\\nlatum.10 Human infections with rat tapeworm\\nHymenolepis diminuta were eliminated by 5–7 daily doses of 2 g of\\nniclosamide each, while the treatment of Hymenolepis nana infection\\nrequires one or several 5–7 day courses of niclosamide treatment.', 'One 7 day course\\nregimen for adults is 2 g of niclosamide on day 1 followed by 1 g daily for 6\\ndays.10,55 When\\ntreating human volunteers each with a single oral dose of 2000 mg of niclosamide, the\\nmaximum serum concentration of niclosamide was equivalent to 0.25–6.0 μg/mL\\n(0.76–18.3 μM).', 'The wide concentration range was caused by the intraindividual\\nabsorption differences.', 'Niclosamide is only partially absorbed from the intestinal tract,\\nand the absorbed part is rapidly eliminated by the kidneys with no cumulative toxic effects\\nin human.10 Through a series of drug repurposing screening campaigns,\\nniclosamide was found to be effective against a variety of human conditions such as cancer\\nand viral infections.', 'Currently, there are four ongoing human clinical trials of niclosamide\\nin ulcerative colitis, prostate carcinoma, and colorectal cancer in the ClinicalTrails.gov\\nclinical trials registry.56 Of note, niclosamide has several weaknesses\\nsuch as unneglectable cytotoxicity and limited aqueous solubility as well as relatively low\\nabsorption and oral bioavailability (F = 10%), which may hamper its\\nextensive clinical development as an antiviral agent.57 Our group has\\nmade substantial efforts in medicinal chemistry based on niclosamide as a lead compound and\\ndiscovered a series of O-alkylamino-tethered derivatives as potent and\\norally bioavailable anticancer agents with improved aqueous solubility16\\nand diversified salicylamide derivatives as potent anti-HAdV inhibitors with increased\\npotency (submicromolar IC50s) and significantly decreased cytotoxicity likely by\\ntargeting different steps in the HAdV life cycle.58', 'The ester derivative\\nprodrug of niclosamide was also reported to increase its systemic drug exposure and extend\\nthe duration of exposure.59 The development of nanobased formulations is\\nanother useful strategy for improving the pharmacological and pharmacokinetic properties of\\nniclosamide and maximizing its therapeutic potential for clinical\\napplications.60−62', 'The outbreak of COVID-19 has been declared to be a public health emergency of international\\nconcern by the WHO, and the development of effective therapies for fast-spreading fatal\\nCOVID-19 is in an urgent need.', '3CL protease is a key enzyme that is responsible for\\nproteolytic processing and is indispensable for viral replication and the infection\\nprocess.6 Recently, the high-resolution crystal structure of SARS-CoV-2\\n3CL protease has been solved by Zihe Rao and Haitao Yang (PDB ID: 6LU7, Figure 2), and this may significantly facilitate the discovery of potent\\nsmall-molecule inhibitors of COVID-19 by targeting SARS-CoV-2 3CL protease via\\nhigh-throughput virtual screening of compound libraries or existing drug libraries for drug\\nrepurposing.', 'In addition, Wrapp et al. have determined a cryo-EM structure of the SARS-CoV-2\\nspike (S', 'It is reported that some existing drugs or drug candidates such as remdesivir, an\\nRNA-dependent RNA polymerase (RdRp']}\n", - "{'sentences': ['The COVID-19 had a high R0, a long incubation period, and a short serial interval.', '\\uf06c The COVID-19 had a general low CFR, but much higher in patients with comorbidities.', '\\uf06c The spike protein binding to ACE2 may explain the high R0 of COVID-19.', '\\uf06c Autopsy showed more exudative lesions, and less fibrosis and consolidation.', '\\uf06c Remdesivir, chloroquine, tocilizumab, and convalescent plasma may be effective.', 'Abstract: Background: The rapid spread of the coronavirus disease 2019 (COVID-19), caused by a zoonotic beta-coronavirus entitled 2019 novel coronavirus (2019-nCoV), has become a global threat.', 'Awareness of the biological features of 2019-nCoV should be updated in time and needs to be comprehensively summarized to help optimize control measures and make therapeutic decisions.', 'Methods: Based on recently published literatures, official documents and selected up-to-date preprint studies, we reviewed the virology and origin, epidemiology, clinical manifestations, pathology and treatment of 2019-nCoV infection, in comparison with severe acute respiratory syndrome coronavirus (SARS-CoV) and middle east respiratory syndrome coronavirus (MERS-CoV) infection.', 'Results: The genome of 2019-nCoV partially resembled SARS-CoV and MERS-CoV, and indicating a bat origin.', 'The COVID-19 generally had a high reproductive number, a long incubation period, a short serial interval and a low case fatality rate (much higher in patients with comorbidities) than SARS and MERS.', 'Clinical presentation and pathology of COVID-19', 'Conclusion: The initial experience from the current pandemic and lessons from the previous two pandemics can help improve future preparedness plans and combat disease progression.']}\n", - "{'sentences': ['Safety of Ibuprofen in Patients With COVID-19 Causal or Confounded?']}\n", - "{'sentences': ['Three leading infectious disease experts in China were invited to share their bedside observations in the management of COVID-19 patients.', 'Professor Taisheng Li was sent to Wuhan to provide frontline medical care.', 'He depicts the clinical course of SARS-CoV-2 infection.', 'Furthermore, he observes the significant abnormality of coagulation function and proposes that the early intravenous immunoglobulin and low molecular weight heparin anticoagulation therapy are very important.', 'Professor Hongzhou Lu, a leader in China to try various anti-viral drugs, expresses concern on the quality of the ongoing clinical trials as most trials are small in scale and repetitive in nature, and emphasizes the importance of the quick publication of clinical trial results.', 'Regarding the traditional Chinese medicine, Professor Lu suggests to develop a creative evaluation system because of the complicated chemical compositions.', \"Professor Wenhong Zhang is responsible for Shanghai's overall clinical management of the COVID-19 cases.\", 'He introduces the team approach to manage COVID-19 patients.', 'For severe or critically ill patients, in addition to the respiratory supportive treatment, timely multiorgan evaluation and treatment is very crucial.', 'The medical decisions and interventions are carefully tailored to the unique characteristics of each patient.']}\n", - "{'sentences': ['This retrospective cohort study identified several risk factors for death in adults in Wuhan who were hospitalised with COVID-19.', 'In particular, older age, d-dimer levels greater than 1 μg/mL, and higher SOFA score on admission were associated with higher odds of in-hospital death.', 'Additionally, elevated levels of blood IL-6, high-sensitivity cardiac troponin I, and lactate dehydrogenase and lymphopenia were more commonly seen in severe COVID-19 illness.', 'Sustained viral detection in throat samples was observed in both survivors and non-survivors.', 'Previously, older age has been reported as an important independent predictor of mortality in SARS and MERS.', '14, 15 The current study confirmed that increased age was associated with death in patients with COVID-19.', 'Previous studies in macaques inoculated with SARS-CoV found that older macaques had stronger host innate responses to virus infection than younger adults, with an increase in differential expression of genes associated with inflammation, whereas expression of type I interferon beta was reduced.', '16 The age-dependent defects in T-cell and B-cell function and the excess production of type 2 cytokines could lead to a deficiency in control of viral replication and more prolonged proinflammatory responses, potentially leading to poor outcome.', '17 SOFA score is a good diagnostic marker for sepsis and septic shock, and reflects the state and degree of multi-organ dysfunction.', '18, 19 Although bacterial infections are usually regarded as a leading cause of sepsis, viral infection can also cause sepsis syndrome.', 'Previously, we determined that sepsis occurred in nearly 40% of adults with community-acquired pneumonia due to viral infection.', '20 In the current study, we found that more than half of patients developed sepsis.', 'Additionally, we found that more than 70% of patients had white blood cell count below 10·0 × 10⁹ per L or procalcitonin below 0·25 ng/mL, and no bacterial pathogens were detected in these patients on admission.', 'Sepsis was a common complication, which might be directly caused by SARS-CoV-2 infection, but further research is needed to investigate the pathogenesis of sepsis in COVID-19 illness.', 'Cardiac complications, including new or worsening heart failure, new or worsening arrhythmia, or myocardial infarction are common in patients with pneumonia.', 'Cardiac arrest occurs in about 3% of inpatients with pneumonia.', '21 Risk factors of cardiac events after pneumonia include older age, pre-existing cardiovascular diseases, and greater severity of pneumonia at presentation.', '22 Coronary heart disease has also been found to be associated with acute cardiac events and poor outcomes in influenza and other respiratory viral infections.', '[22] [23] [24] In this study, increased high-sensitivity cardiac troponin I during hospitalisation was found in more than half of those who died.', 'The first autopsy of a 53-year-old woman with chronic renal failure in Jinyintan Hospital showed acute myocardial infarction (data not published; personal communication with a pathologist from the Chinese Academy of Science).', 'About 90% of inpatients with pneumonia had increased coagulation activity, marked by increased d-dimer concentrations.', '25 In this study, we found d-dimer greater than 1 µg/mL is associated with fatal outcome of COVID-19.', 'High levels of d-dimer have a reported asso ciation with 28-day mortality in patients with infection or sepsis identified in the emergency department.', '26 Contri butory mechanisms include systemic pro-inflammatory cytokine responses that are mediators of atherosclerosis directly contributing to plaque rupture through local inflammation, induction of procoagulant factors, and haemodynamic changes, which predispose to ischaemia and thrombosis.', '[27] [28] [29] In addition, angiotensin converting enzyme 2, the receptor for SARS-CoV-2, is expressed on myocytes and vascular endothelial cells, 30, 31 so there is at least theoretical potential possibility of direct cardiac involvement by the virus.', 'Of note, interstitial mononuclear inflammatory infiltrates in heart tissue has 32 The level and duration of infectious virus replication are important factors in assessing the risk of trans mission and guiding decisions regarding isolation of patients.', 'Because coronavirus RNA detection is more sensitive than virus isolation, most studies have used qualitative or quantitative viral RNA tests as a potential marker for infectious coronavirus.', 'For SARS-CoV, viral RNA was detected in respiratory specimens from about a third of patients as long as 4 weeks after disease onset.', 'Similarly, the dura tion of MERS-CoV RNA detection in lower respiratory specimans persisted for at least 3 weeks, 34, 35 whereas the duration of SARS-CoV-2 RNA detection has not been well characterised.', 'In the current study, we found that the detectable SARS-CoV-2 RNA persisted for a median of 20 days in survivors and that it was sustained until death in nonsurvivors.', 'This has important implications for both patient isolation decision making and guidance around the length of antiviral treatment.', 'In severe influenza virus infection, prolonged viral shedding was associated with fatal outcome and delayed antiviral treatment was an independent risk factor for prolonged virus detection.', '36 Similarly, effective antiviral treatment might improve outcomes in COVID-19, although we did not observe shortening of viral shedding duration after lopinavir/ritonavir treatment in the cur rent study.', 'Ran domised clinical trials for lopinavir/ritonavir (ChiCTR2000029308) and intravenous remdesivir (NCT04257656, NCT04252664) in treatment of COVID-19 are currently in progress.', 'Our study has some limitations.', 'First, due to the retrospective study design, not all laboratory tests were done in all patients, including lactate dehydrogenase, IL-6, and serum ferritin.', 'Therefore, their role might be underestimated in predicting in-hospital death.', 'Second, patients were sometimes transferred late in their illness to the two included hospitals.', 'Lack of effective antivirals, inadequate adherence to standard supportive therapy, and high-dose corticosteroid use might have also contributed to the poor clinical outcomes in some patients.', 'Third, the estimated duration of viral shedding is limited by the frequency of respiratory specimen collection, lack of quantitative viral RNA detection, and relatively low positive rate of SARS-CoV-2 RNA detection in throat-swabs.', '37 Fourth, by excluding patients still in hospital as of Jan 31, 2020, and thus relatively more severe disease at an earlier stage, the case fatality ratio in our study cannot reflect the true mortality of COVID-19.', 'Last but not least, interpretation of our findings might be limited by the sample size.', 'However, by including all adult patients in the two designated hospitals for COVID-19, we believe our study population is representative of cases diagnosed and treated in Wuhan.', 'To the best of our knowledge, this is the largest retrospective cohort study among patients with COVID-19 who have experienced a definite outcome.', 'We found that older age, higher SOFA score, and elevated d-dimer at admission were risk factors for death of adult patients with COVID-19.', 'The prolonged viral shedding provides the rationale for testing novel coronavirus antiviral interventions in efforts to improve outcomes.', 'Evidence before this study We searched PubMed on Feb 23, 2020, for articles that documented the risk factors of mortality and viral shedding in patients with coronavirus disease 2019 (COVID- 19) , resulting from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), using the search terms (\"novel coronavirus\" OR \"SARS-CoV-2\" OR \"COVID-19\") AND (\"death\" OR \"mortality\" OR \"viral shedding\") with no language or time restrictions.', 'Age, comorbidities, lymphocytopenia and elevated alanine aminotransferase, d-dimer, creatine kinase, high-sensitivity cardiac troponin I, prothrombin time, and disease severity were reported to be associated with intensive care unit admission.', 'However, no published works were found about the risk factors of mortality for adult patients with COVID-19.', 'One study compared the sensitivity of SARS-CoV-2']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['To the best of our knowledge, this is the first study to evaluate per-allele viral proteome presentation across a wide range of HLA alleles using MHC-peptide binding affinity predictors.', 'This study also introduces the relationship between coronavirus sequence conservation and MHC class I antigen presentation.', 'We show that individual HLA, haplotype, and full genotype variability likely influence the capacity to respond to SARS-CoV-2 infection, and we note certain alleles in particular (e.g. HLA-B*46:01) that could be associated with more severe infection, as previously shown with SARS-CoV (1) .', 'Indeed, we further compare SARS-CoV and SARS-CoV-2 peptide presentation and note a high degree of similarity between the two across HLA types.', 'Finally, this is the first study to report global distributions of HLA types and haplotypes with potential epidemiological ramifications in the setting of the current pandemic.', 'We found that in general, there is no correlation between the HLA allelic frequency in the population and allelic capacity to bind SARS-CoV or SARS-CoV-2 peptides, irrespective of estimated timing of peptide production during the viral replication cycle.', 'While we are not aware of any studies explicitly reporting the relationship between human coronavirus epitope abundance and immune response, there is data in vaccinia virus that suggests that early peptide antigens are more likely to generate CD8+ T-cell responses while antibody and CD4+ T-cell responses are more likely to target later mRNA expression with higher peptide abundance in the virion (53) .', 'We note, however, several limitations to this our work.', 'First and foremost, while we note that a handful of our binding affinity predictions were borne out in experimentally validated SARS-CoV peptides (Supplementary Table S4 ), we acknowledge that this is an entirely in silico study.', 'As we are unable to obtain individual-level HLA typing and clinical outcomes data for any real-world COVID-19 populations at this time, the data presented is theoretical in nature, and subject to many of the same limitations implicit to the MHC binding affinity prediction tool(s) upon which it is based.', 'As such, we are unable to assess the relative importance of HLA type compared to known disease-modifying risk factors such as age and clinical comorbidities (5-10) .', 'We further note that peptide-MHC binding affinity is limited as a predictor of subsequent T-cell responses (54-56) , and we do not study T-cell responses herein.', 'As such, we are ill-equipped to explore phenomena such as original antigenic sin (57-59) , where prior exposure to closely related infection(s) may trigger T-cell anergy (60-62) or immunopathogenesis (63) in the setting of a novel infection.', 'We explored only a limited set of 145 well-studied HLA alleles, but note that this analysis could be performed across a wider diversity of genotypes (49) .', 'Additionally, we did not assess genotypic heterogeneity or in vivo evolution of SARS-CoV-2, which could modify the repertoire of viral epitopes presented, or otherwise modulate virulence in an HLA-independent manner (64, 65) ( https://nextstrain.org/ncov ).', 'We also do not address the potential for individual-level genetic variation in other proteins (e.g. angiotensin converting enzyme 2 [ACE2] or transmembrane serine protease 2 [TMPRSS2], essential host proteins for SARS-CoV-2 priming and cell entry (66) to modulate the host-pathogen interface.', 'Unless and until the findings we present here are clinically validated, they should not be employed for any clinical purposes.', 'However, we do at this juncture recommend integrating HLA testing into clinical trials and pairing HLA typing with COVID-19 testing where feasible to more rapidly develop and deploy predictor(s) of viral severity in the population, and potentially to tailor future vaccination strategies to genotypically at-risk populations.', 'This approach may have additional implications for the management of a broad array of other viruses.']}\n", - "{'sentences': ['Over the last two months, more than 156,000 cases of a new infectious disease have been confirmed in China and other countries in Asia, Pacific, Europe, Africa, and the Americas [22, 23, [42] [43] [44] .', 'The COVID-19 is an emerging condition that primarily threatens the preparedness and biosecurity conditions of all countries on this planet [45] .', 'Preparedness at different levels, facing a new clinical disease, demands efforts in epidemiological, diagnostic, therapeutic, and preventive fields during a potential pandemic [46] , that threatens to spread to new territories (> 115) and areas with the risk of epidemics.', 'Clinical, laboratory, image findings, as well as the factors associated with evolution of the disease and outcomes, constitute critical knowledge that should be carefully studied when a new infectious disease emerges.', 'Recently, in this context of the COVID-19 outbreak, several questions have been raised, including what is the full spectrum of disease severity (which can range from asymptomatic, to symptomaticbut-mild, to severe, to requiring hospitalization, to fatal)?', 'In this systematic review and random-effects meta-analysis, we tried to initially summarize clinical data on COVID-19 confirmed cases that were published during the first weeks of the outbreak.', 'We managed to analyze more than 780 patients for major clinical manifestations and up to half of them for their associated significant laboratory findings.', 'Our findings are robust due to the pooled results after combining all the studies, which can be seen in forest plots for each of the variables.', 'We used a random-effects meta-analysis model.', 'This involves an assumption that the effects being estimated in the different studies are not identical, but follow some distribution.', 'For random-effects analyses, the pooled estimate and 95%CIs refer to the center of the distribution of pooled prevalence but do not describe the width of the distribution.', 'Often the pooled estimate and its 95%CI are quoted in isolation as an alternative estimate of the quantity evaluated in a fixed-effect metaanalysis, which is inappropriate.', 'The 95%CI from a random-effects meta-analysis describes uncertainty in the location of the mean of systematically different prevalence in the different studies [38, 39] .', 'As expected from initial observations in China [4, 5, 11] , COVID-19 patients presented predominantly with fever and cough, which appears to be more frequent in adults than children, as well as dyspnea, and myalgia, among other clinical features.', 'This was consistently found not only in the studies meta-analyzed here but also in the case reports included in this systematic review.', 'Fever frequency is similar in SARS and MERS, but the cough frequency is higher in SARS and COVID-19 than MERS (< 50%) [28, 48, 49] .', 'In SARS and MERS, diarrhea is reported in 20-25% of patients [50] , here we found it in less than 7%, at the studies ( Table 6 ) and case reports (Table 7) .', 'Of note, in the case reports, myalgia was the third most common reported symptom after fever and cough.', \"Most patients required hospitalization, often attributed to the patient's comorbidities, as observed in a third of the cases.\", 'We found To et al. that approximately 20% of those hospitalized needed to be admitted to ICU for critical management.', 'Unlike SARS, with it is well-characterized two-stage clinical course of the disease, COVID-19, still needs further definition [48] .', 'The first week of the condition is also similar, coinciding with recent data of the viral load during this stage [51] .', 'However, case-control studies and cohort studies are necessary to define the clinical evolution of disease better.', 'A second stage, as occurs in SARS, might also be seen in COVID-19, with the lower respiratory tract bilateral compromise, observed in more than 72% of the patients across nine studies with more than 500 patients, also experiencing a dry cough, and dyspnea [5, 48, 52] and with chest X-ray images of groundglass opacity frequently observed in two-thirds of patients -this is also seen in SARS [53] .', 'The laboratory abnormalities predominantly found included hypoalbuminemia, elevated inflammatory markers, such as C-reactive protein, LDH, and ESR, among others.', 'Also, lymphopenia is consistently present in more than 40% of the patients across eight studies with more than 500 patients.', 'Data from the 2002-2003 outbreak indicate that SARS may be associated with lymphopenia, leukopenia, and thrombocytopenia, elevated levels of LDH, alanine transaminase (ALT', 'With regard to complications and death, a third of patients presented with ARDS, but also, albeit in a lower frequency, acute cardiac injury, acute kidney injury, and shock, eventually followed by multiple organ failure.', 'Therefore, early identification and timely treatment of critical cases are of crucial importance [4] .', 'We observed a CFR of over 13% in 7 studies describing 632 hospitalized patients.', 'In two studies in China (n = 41, n = 99), the case fatality rates were 15% [5] and 11% [4] , respectively.', 'Crude surveillance data [42] , indicated that till March 14, 2020, from 156,106 reported cases, 5,829 patients have died (3.73%), with > 52% of the deaths occurring in China (3,085), followed by Italy with 24.', 'This differs from the CFR found in our systematic review and may be explained by the fact that cases requiring medical attention in hospitals were the patients included in the studies selected for analysis, and that consequently they consulted with an advanced stage of disease leading to hospitalization.', 'Even, from the crude epidemiological data reported by the countries, some of them have reported a higher proportion of deaths, as is the case of Australia (3.75%), China (3.86%), Iran (4.8%), Italy (6.81%, 1,441 deaths/ 21,157 cases), Argentina (8.33%), and Iraq (10.0%).', 'Thus, the CFR in different settings needs further reassessment.', 'More studies are needed to elucidate the risk factors for severe illness and death.', 'This will allow for the identification of groups most likely to have poor outcomes so that we can focus on prevention and treatment efforts?', 'After the development of this systematic review (SR', 'Comparing their findings [58] with ours, they found fever in 89.8% (95%CI 81.8-94.5%) of patients, this SR found 88.7% (95%CI 84.5-92.9%), but we assessed differences, as mentioned above, between adults and children, and they did not.', 'For cough, based on the 95%CI, there were not significant differences too, between that SR and the current, 72 [58] , we were able to do it for eight of the studies included in this systematic review.', 'Both reviews are clear and consistent in that more than 80% of the patients presented with fever, more than half with cough, and more than a third with fatigue.', 'That SR did not assess any laboratory findings, but evaluated the frequency of patients presenting ADRS which was found to be 14.8% (95%CI 4.6-29.6%), which was also consistent with our study, 32.8% (95%CI 13.7-51.8%), which Our results showed that there is still a need for more comprehensive clinical studies, including short and long -term follow-up cohort assessments.', 'More studies from outside China, where there are more than 100 patients diagnosed with COVID-19, as is the case of South Korea, Italy, and Japan [59, 60] , will contribute to the growing volume of data, in addition to the growing number of studies appearing from China.', 'Even more, the situation with the cruise ship Diamond Princess, docked in Yokohama, Japan, with 3711 passengers, approximately 20% of the infected, with 7 deaths, is also a valuable chance to better characterize COVID-19.', 'Clinical evidence synthesized in this review is mainly derived from China, although for case reports, ten of the thirty-two countries with confirmed cases [7, 12, 29, 30] , have published some of them (Table 7) .', 'Further clinical data is crucial to elucidate the clinical spectrum of the disease.', 'The clinical experience stemming from countries now dealing with an ever increasing number of cases such as Italy [61] , Singapore, Hong Kong, Nepal [7] , Iran, and Malaysia in the form of case reports, case series, or large observational studies will be most important.', 'Up to now, regardless whether of report type (cross-sectional studies or case reports) the clinical findings are consistent, but more data are needed to define the risk factors for admission in ICU and for fatal outcomes.', 'However, data suggest that older age and comorbidities play a vital role in influencing severe disease and negative clinical outcomes.', 'These data would be useful to guide patient risk groups management in the current epidemic, especially in those countries about to receive cases, as is the situation in Latin America.', 'COVID-19 cases have been confirmed in Brazil, Mexico, and in all the countries of South America, and in most of the Central America and the Caribbean subregions, as of the time of proofs correction (March 14, 2020) [62] .', 'In these and other resource-constrained settings, e.g. Africa, supplies chains, including those for drugs, masks and personal protection equipment, will be challenged.', 'The results of this systematic review highlight the clinical, laboratory, and imaging findings that may assist clinicians anywhere in the globe in suspecting the possibility of COVID-19 infection in those with recent travel to areas with ongoing transmission or among contacts of confirmed cases.', 'Early recognition of cases will allow clinicians to ensure adequate clinical monitoring, institution of supportive interventions, and preventing further transmission by implementing infection control measures [29, 56, 63] .', 'There is a need for prospective studies to evaluate the epidemiology, pathogenesis, duration of viral shedding, and the clinical spectrum of disease associated with this emerging viral infection [29, 56, 63] .', 'To effectively protect populations and healthcare workers in the face of arrival and spreading of this emerging viral pathogen, constant evaluation of available evidence is essential to guide clinical suspicion, diagnosis, management, and mitigation of transmission of COVID-19.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['In this study, we described the use of several adjuvant treatments in preventing severe pneumonia development in COVID-19 patients.', 'Hypertensive patients who received ACEI/ARB therapy had a lower risk of developing severe pneumonia compared with those on non-ACEI/ARB antihypertensive therapy, which suggested that ACEI/ARB therapy may be protective from severe pulmonary injury for hypertensive patients.', 'However, these results should be interpreted with caution owing to potential bias and residual confounders in this observational study.', 'Consistent with earlier reports and clinical experience around the world, our cohort confirmed that .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'that older age and hypertension without ACEI/ARB therapy were independently associated with developing severe pneumonia in COVID-19.', '2, 3, 22 The association between age and severe pneumonia may be attributed to the accumulation of medical comorbidities with age or decline in immune function over time.', 'Given the close collinearity between age and hypertension, our study adjusted for age by multivariate regression analysis and revealed that hypertension remained an independent risk factor for disease progression irrespective of age for patients without receiving ACEI/ARB therapy.', 'Our study examined the controversial topic of COVID-19 and ACEI/ARB therapy in hypertensive patients.', 'We found that hypertensive patients on ACEI/ARB therapy were less likely to develop severe pneumonia, although we acknowledged that the analysis was conducted in limited sample size -with only 16 of 82 patients on ACEI/ ARB therapy.', 'The dynamic profile of laboratory and radiological findings further showed that in patient on ACEI/ARB therapy, lactose dehydrogenase and CT lung score were lower in than those on non-ACEI/ARB therapy at about 3 days after admission.', 'Together, these findings were suggestive that ACEI/ ARB therapy may be protective in hypertensive patients with COVID-19.', 'COVID-19 patients with hypertension may endure worse outcomes due to decreased ACE2 levels.', 'ACE2, an important component of the renin-angiotensin-aldosterone system (RAAS), is highly expressed in both the lung and myocardium and converts angiotensin II (AII', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'SARS-CoV-2 can gain entry into the host cell through binding of the S-protein to the membrane-bound ACE2 aminopeptidase, which then is cleaved by serine proteases to allow for membrane fusion and invasion.', 'Following infection, there is a reduction in pulmonary ACE2, either through internalization with viral entry and/or downregulation of ACE2 enzyme during this process.', 'Hence this may exacerbate the lower baseline ACE2 function in hypertensive patients to lead to the accumulation of AII and reduced angiotensin 1-7 and subsequently worse immune-related cytolysis and lung injury, which was validated by the linear association between elevated plasma AII level and viral load or lung injury in COVID-19 patients.', '29 The use of ACEI or ARB likely promotes feedback upregulation of ACE2 expression in hypertension, although there are animal and human studies which have also found either no effect or downregulation of ACE2 level in the setting of diabetes, hypertension or cardiovascular disease, with or without ACE/ARB therapy.', '25, [30] [31] [32] [33] Nonetheless, this may explain our finding that ACEI/ARB therapy can be protective in SARS-CoV-2 infection.', 'Further evidence that would support this come from earlier studies in which ACEI/statins were protective in severe pneumonia, recombinant ACE2 protected mice from lung injury following SARS-CoV infection, and RAAS blockade reduced acute lung injury in rats injected with SARS-CoV S-protein.', '34, 35 Currently, there is still no specific treatment for COVID-19 except for supportive care.', 'In our cohort, 94.2% of non-severe patients received nonspecial antiviral therapy from just after admission.', 'The combination protocol and medication dose varied in different hospitals.', 'However, our results did not support any single or combined antiviral treatments to limit the progression of COVID-19.', 'In addition, none of 25 patients treated with chloroquine developed severe pneumonia, though without statistical significance.', 'This is unfortunately limited by the degree of heterogeneity .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'in our cohort and relatively small size.', 'Chloroquine is known to block virus infection by increasing endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of cellular receptors of coronavirus, which has been confirmed to inhibit SARS-CoV-2 in vitro.', '[36] [37] [38] A recent open label non randomized clinical trial reported that hydroxychloroquine combined with azithromycin is significantly associated with viral load reduction/disappearance in COVID-19 patients.', '39 Even so, more RCTs to assess the therapeutic effects of chloroquine on COVID-19 need to be conducted.']}\n", - "{'sentences': ['Although a positive PCR result cannot confirm the presence of live viruses, because of the novel nature of this new virus and disease and the fact that studies have confirmed that SARS can be transmitted through aerosols, 9 treating nucleic acid-positive PCR results in stool as evidence of continued infection would be prudent.', 'Because children show less susceptibility to SARS-CoV 10 and have milder symptom than adults, evaluating the stool PCR results of children is an important step in controlling infection.', 'Our report presents a number of limitations.', 'Because we only presented eight patients with mild to moderateinfection, the data obtained may not be generalizable to all cases, especially severe ones.', 'Second, lopinavir/ritonavir was used only in adult patients; as such, its role in children cannot be determined.', 'Third, we cannot estimate the exact time at which the patients were exposed to the virus and when they began to shed the virus in their feces.', 'Such data are urgently needed to understand the SARS-CoV-2 virus better and implement the necessary control strategies as early as possible.', 'The results of the present study revealed the novel finding that SARS-CoV-2 can be shed in the stool of some convalescent-phase patients.', 'Thus, discharge criteria should be carefully evaluated, especially among children.', 'Discharge of patients still infected with SARS-CoV-2 could increase the risk of infection to the public.', 'Thus, patients should be released only after all their specimens are negative to reduce possible infection.', 'Our results enhance the current knowledge on this emerging infectious disease and offer implications for clinical diagnostics and infection control.', 'This study found viral shedding in the feces of eight patients with SARS-CoV-2 infection, six of whom were children.', 'Thus, we first sought to determine whether patients shed SARS-CoV-2 in stool.', 'Coronaviruses are a large family of viruses.', 'To date, six CoVs are known to cause human infection.', 'Of these CoVs, Table 1 General information of the eight patients included in this study.', 'two zoonotic viruses, SARS-CoV and MERS-CoV, were responsible for serious outbreaks in China in 2002e2003 and MERS-CoV, were responsible for serious outbreaks in China in 2002e2003 (SARS-CoV and MERS-CoV, were responsible for serious outbreaks in China in 2002e2003) and in the Middle East in 2012 (MERS-CoV).', 'The 2019-nCoV virus is closely related to SARS-CoV and MERS-CoV, were responsible for serious outbreaks in China in 2002e2003', 'Next, we sought to determine why the shedding time of the virus in feces is longer in children than in adults.', 'One reason that can explain why the shedding time of the virus in feces is longer in children than in adults is that the former often have poorer hand hygiene practices than the latter.', 'Poor hygiene can cause contamination of the gastrointestinal tract by repeated touching with hands containing the virus or its fragments.', 'For example, we described earlier the case of a boy who showed no symptoms after close contact with his father and had repeated negative results for all of his airway specimens.', 'However, the stool results of this same boy were positive 3 weeks after contact.', 'Second, when SARS broke out in 2003, angiotensinconverting enzyme 2 (ACE2) was confirmed to be a functional receptor for SARS-CoV. Interestingly, subsequent findings indicated that 2019-nCoV also uses ACE2 as an entry receptor.', '6 Previous studies demonstrated that ACE2 is abundantly present in humans in the epithelia of the lungs and small intestine 7 and, especially, in proximal and distal enterocytes.', 'Animal studies have also shown that ACE2 has different distributions in the lung in different genders and ages and that ACE2 expression in rat lung decreases with age.', 'Therefore, we believe that the expression of ACE2', 'Third, children often cough weakly but they are prone to silent aspiration.', 'Thus, virus in the sputum or saliva may enter the gastrointestinal tract through swallowing, which could explain why children shed virus in their stool.']}\n", - "{'sentences': ['Human coronaviruses can remain infectious on inanimate surfaces at room temperature for up to 9 days.', 'At a temperature of 30 C or more the duration of persistence is shorter.', 'Veterinary coronaviruses have been shown to persist even longer for 28 d. Contamination of frequent touch surfaces in healthcare settings are therefore a potential source of viral transmission.', 'Data on the transmissibility of coronaviruses from contaminated surfaces to hands were not found.', 'However, it could be shown with influenza A virus that a contact of 5 s can transfer 31.6% of the viral load to the hands [9] .', 'The transfer efficiency was lower (1.5%) with parainfluenza virus 3 and a 5 s contact between the surface and the hands [10] .', 'In an observational study, it was described that students touch their face with their own hands on average 23 times per h, with contact mostly to the skin (56%), followed by mouth (36%), nose (31%) and eyes (31%', 'No data were found to describe the frequency of hands becoming contaminated with coronavirus, or the viral load on hands either, after patient contact or after touching contaminated surfaces.', 'The WHO recommends to preferably apply alcohol-based hand rubs for the decontamination of hands, e.g. after removing gloves.', 'Two WHO recommended formulations (based on 80% ethanol or 75% 2-propanol) have been evaluated in suspension tests against SARS-CoV and MERS-CoV, and both were described to be very effective [14] .', 'No in vitro data were found on the efficacy of hand washing against coronavirus contaminations on hands.', 'In Taiwan, however, it was described that installing hand wash stations in the emergency department was the only infection control measure which was significantly associated with the protection from healthcare workers from acquiring the SARS-CoV, indicating that hand hygiene can have a protective effect [15] .', 'Compliance with hand hygiene can be significantly higher in an outbreak situation but is likely to remain an obstacle especially among physicians [16e18] .', 'Transmission in healthcare settings can be successfully prevented when appropriate measures are consistently performed [19, 20] .', 'Human coronaviruses can remain infectious on inanimate surfaces for up to 9 days.', 'Surface disinfection with 0.1% sodium hypochlorite or 62e71% ethanol significantly reduces coronavirus infectivity on surfaces within 1 min exposure time.', 'We expect a similar effect against the SARS-CoV-2.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Background: The outbreak of coronavirus disease 2019 (COVID-19) in Wuhan City, China spreads rapidly since December, 2019.', 'Most patients show mild symptoms, but some of them develop into severe disease.', 'There is currently no specific medication.', 'The purpose of this study is to to explore changes of markers in peripheral blood of severe COVID-19 patients, which may be of value in disease monitoring.', 'Methods Clinical data of patients with nonsevere and severe type COVID-19 diagnosed by laboratory test in our institution were collected.', 'The relationship between peripheral blood cells and cytokines, clinical manifestation and outcome was analyzed.', 'Results A total of 69 severe type COVID-19 patients were included.', 'On admission, the median age of severe cases was 56-year old, with 52.17% female patient.', 'The most common symptoms were fever (79.72%), cough (63.77%), shortness of breath (57.97%) and fatigue (50.72%).', 'Diarrhea is less common.', 'The most common comorbidity is hypertension.', 'Upon admission, the proportion of bilateral pulmonary involvement and interstitial abnormalities evidenced by chest computed tomography (CT) imaging in severe cases was 60.87% and 27.54%, respectively.', 'Compared with patients with nonsevere disease, those with severe disease showed obvious lymphocytopenia.', 'Elevated level of lactate dehydrogenase (LDH), C-reactive protein (CRP), ferritin and D-dimer was found in most cases.', 'Two patients (2.9%) needed transfer to the intensive care unit.', 'Baseline immunological parameters and most of the inflammatory parameters were basically within the normal range.', 'However, baseline interleukin-6 (IL-6) was significantly increased in severe type, which was closely related to the maximal body temperature during hospitalization and to CT findings.', 'Baseline IL-6 was also significantly related to the increase of baseline level of CRP, LDH, ferritin and D-dimer.', 'The increase of baseline IL-6 level suggests that it may positively correlate with the severity of COVID-19.', 'Among the 30 severe type patients whose IL-6 was assessed before and after treatment, significant decrease in IL-6 and improved CT assessment was found in 25 patients after treatment.', 'Whereas the IL-6 level was further increased in 3 cases, which was closely related to disease progression.', 'It is suggested that IL-6 may be used as a marker for disease monitoring in severe COVID-19 patients.', 'Conclusions On admission, the baseline level of IL-6, CRP, LDH and ferritin was closely related to the severity of COVID-19, and the elevated IL-6 was significantly related to the clinical manifestation of severe type patients.', 'The decrease of IL-6 was closely related to treatment effectiveness, while the increase of IL-6 indicated disease exacerbation.', 'Collectively, the dynamic change of IL-6 level can be used as a marker for disease monitoring in patients with severe COVID-19']}\n", - "{'sentences': ['The current COVID-19 pandemic has led to a dramatic shortage of masks and other personal protective equipment (PPE) in hospitals around the globe [1] .', 'One component of PPE', 'We studied Cobalt-60 ( 60 Co) gamma irradiation as a method of effective sterilization without inducing mask degradation.', 'Significant literature exists supporting the use of gamma radiation as a sterilization method, with viral inactivation of SARS-CoV reported at doses of at most 10 kGy [3] , with other studies supporting 5 kGy for many types of viruses [4] .', 'However, concerns have been raised about the radiation damaging the fiber material within the mask, specifically by causing cross-linking of polymers, leading to cracking and degradation during fitting and/or deployment [5, 6] .', \"A set of 3M 8210 and 9105 masks were irradiated using MIT's 60 Co irradiator.\", 'Three masks of each type received 0 kiloGray (kGy), 10 kGy and 50 kGy', \"Following this sterilization procedure, the irradiated masks passed a OSHA Gerson Qualitative Fit Test QLFT 50 (saccharin apparatus) [7] when donned correctly, performed at the Brigham and Women's Hospital, in a blinded study repeated in triplicate.\", \"However, the masks' filtration of 0.3 µm particles was significantly degraded, even at 10 kGy.\", 'These results suggest against gamma, and possibly all ionizing radiation, as a method of disposable N95 sterilization.', 'Even more importantly, they argue against using the qualitative fit test alone to assess mask integrity.']}\n", - "{'sentences': ['J o u r n a l P r e -p r o o f', 'CUIDADO RESPIRATORIO EN COVID-19', 'Resumen Antecedentes: El COVID-19, hace parte de la familia de los virus conocida como Coronaviridae, el nuevo patógeno β-coronavirus del subgénero Sarbecovirus se denomino inicialmente como el nuevo coronavirus (2019-nCoV); identificado en un brote de neumonía en Wuhan; desarrollando alteraciones en el sistema respiratorio llevándolos a neumonía severa, edema pulmonar, síndrome de dificultad respiratoria agudo (SDRA). Objetivo: Revisar la evidencia científica disponible relacionada con el cuidado del sistema respiratorio, estableciendo pautas generales de tratamiento. Métodos: Revisión narrativa de la literatura. Se realizó una búsqueda, selección y revisión de artículos originales y secundarios escritos en inglés o español, en las diferentes bases de datos: NCBI, CENTRAL, MEDLINE y EMBASE publicados hasta marzo del 2020. Resultados: no se ha definido un tratamiento especifico ante la nueva enfermedad, teniendo como principal medida terapéutica el control sintomático. Utilizar elementos de bioseguridad: gafas, gorros, guantes, bata larga impermeable, tapabocas alta eficiencia en personal sanitario (FFP2 o N95), en paciente sintomático utilizar tapabocas quirúrgico, jabón hospitalario, toallas de papel, y alcohol al 70% o isopropilico. Utilizar oxígeno mediante sistemas de bajo flujo. En ventilación mecánica programar modos VCP o VCV, Vt: 4-6 ml/Kg, Fr: ≤ 35, FiO2: para PaO2=60 mmHg o SpO2: 92-96%, PEEP: 12-17 cmH2O, Ventilación prono si PAFI ≤ 150 con relación 16/8 o 18/6, óxido nítrico: 5-20 ppm. Conclusiones: Usar equipos de bioseguridad con el fin de interrumpir la transmisión, en hipoxemia usar sistemas de oxigenoterapia bajo flujo. Usar estrategias de protección pulmonar, disminución de volúmenes corrientes, presiones de plateau y frecuencias respiratorias, implementación de valores de PEEP elevados, bajos valores de presión de conducción y ventilación en prono, los cuales han demostrado mejoraría en la hipoxemia y la sobrevida en pacientes con SDRA.', 'Background: COVID-19 is part of the family of viruses known as Coronaviridae.', 'The new pathogen βcoronavirus of the subgenus Sarbecovirus was initially named as a novel coronavirus (2019-nCoV), identified in a pneumonia outbreak in Wuhan.', 'Patients developed alterations in the respiratory system leading to severe pneumonia, pulmonary oedema, and acute respiratory distress syndrome (ARDS', 'Objective: To review the available scientific evidence related to the care of the respiratory system in order to establish general treatment guidelines.', 'Methods: Narrative review of the literature was carried out that included a search, selection, and review of original and secondary articles written in English or Spanish in the different databases: NCBI, CENTRAL, MEDLINE and EMBASE published up to March 2020.', 'No specific treatment for the new disease has been defined, with symptomatic control as the main therapeutic measure.', 'The use of biosecurity elements, such as goggles, hats, gloves, long waterproof aprons, high efficiency masks for healthcare personnel (FFP2 or N95) is recommended.', 'In symptomatic patients use surgical masks, hospital soap, paper towels, and 70% alcohol or isopropyl alcohol.', 'Use oxygen through low flow systems.', 'A mechanical ventilation program in VCP or VCV modes, Vt: 4-6 ml/Kg, Fr: ≤ 35, FiO2: for PaO2 = 60 mmHg or SpO2: 92-96%, PEEP: 12-17 cmH2O, Prone ventilation if PAFI ≤ 150 with ratio16/8 or 18/6, nitric oxide: 5-20 ppm.', 'Conclusions: Use biosecurity equipment in order to prevent transmission.', 'In hypoxaemia use low flow oxygen therapy systems.', 'Use lung protection strategies, decrease in tidal volumes, plateau pressures and respiratory rates, plus implementation of high PEEP values, low conduction pressure values and prone ventilation.', 'These have been shown to improve hypoxaemia and survival in patients with ARDS.', 'Palabras clave: nuevo coronavirus 2019, 2019-nCoV; enfermedad respiratoria; neumonía; enfermedades infecciosas; ventilación mecánica; oxigeno terapia; bioseguridad.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': [\"[{'text': 'We firstly reported a case of acute myelitis in a SARS-CoV-2-infected patient.\", 'A 66-year-old man with COVID-19 was admitted with acute flaccid paralysis of bilateral lower limbs and urinary and bowel incontinence.', 'All serum microbiological studies were negative except for SARS-CoV-2 nucleic acid testing.', 'Clinical findings could be ascribed to a post-infectious acute myelitis.', 'He was receiving treatment with ganciclovir, lopinavir/ritonavir, moxifloxacin, dexamethasone, human immunoglobulin and mecobalamin.', 'With a diagnosis of post-infectious acute myelitis and comprehensive treatment, paralysis of bilateral lower extremities ameliorated.', \"After two times negative novel coronavirus RNA nasopharyngeal swabs tests, he was discharged and transferred to a designated hospital for isolation treatment and rehabilitation therapy.', 'cite_spans': [], 'ref_spans': [], 'section': 'Abstract'}]\", 'Our study firstly reported a post-infectious myelitis case in the world, indicating acute myelitis might be the neurological complication of 2019-nCov.', 'It had been demonstrated that microbes including mycoplasma pneumoniae, EBV, CMV, rhinovirus and measles were implicated in postinfectious acute myelitis [11] [12] [13] .', 'Mycoplasma pneumoniae was thought to be one of the most recognized infections.', 'Probable hypothesis was that infectious organism was targeted against by immunologic system which also attacked central nervous system (CNS', 'CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'Based on our study, acute paralysis was the novel neurological symptom of COVID-19.', 'Analysis of the clinical characteristics of 1099 patients with COVID-19 showed that the common symptoms at the onset of disease were fever (43.8% of the patients appeared on admission, while 88.7% of the patients occurred after admission), cough (67.8%), and neurological symptoms were rare 2 .', 'However, severe patients with COVID-19 were likely to have neurological symptoms (such as headache, dizziness, hypogeusia, and neuralgia) and complications including acute cerebrovascular diseases, impaired consciousness and skeletal muscular injury 15 .', 'According to the laboratory testing, we found that lymphopenia and eosinopenia happened in the early stage of COVID-19.', 'The decrease of red blood cell and hemoglobin showed that bone marrow hematopoietic system was affected by SARS-CoV-2, which was expected to be further confirmed by large-scale retrospective analysis.', 'It had been reported that ACE2 was expressed in hepatic bile duct cells and proximal renal tubules 7, 8 , hepatic and renal dysfunctions were also detected in the patients with COVID-19 16 .', 'Liver function of this patient in this study was obviously damaged with normal renal function, the elevated levels of alanine aminotransferase and aspartate aminotransferas reached the peak on the 15th day after the onset of disease, and then recovered gradually.', 'At the same time, the level of total protein, albumin and HDL-C significantly decreased with the process of the disease, suggesting that metabolic abnormalities contributed to the pathogenesis of COVID-19.', 'However, the renal function was normal in this study, which was inconsistent with previous study.', 'It had been reported that the decreased level of serum iron in patients with pneumonia was an independent risk factor for hospital death 17 .The mechanism may be related to the influence of pathogenic microorganism infection on iron uptake.', 'In this patient, on the 7th day of the onset of the disease, the level of serum iron was only 1.8 umol/L, and gradually increased with the treatment.', 'The level of serum iron returned to normal when the nucleic acid test of 2019-nCov turned into negative.', 'The possible role of serum iron in the 2019-nCov infection deserved further research in the future.', 'We believed that overactive inflammation response and immune damage occurred in COVID-19 for the high level of C-reactive protein, SAA, IL-6 and ferritin in the patient.', 'Immune damage and cytokines released by inflammatory storms at the early stage of COVID might interpret and explain why spinal cord was implicated in the disease.']}\n", - "{'sentences': ['One of the unique sides of our study is to look at the impact of medications on MERS infection.', 'To our knowledge, this is the first study to look at the association of patient’s medication history and the risk of infection.', 'We found that many medications include those for chronic diseases are not associated with the increase or decrease the likelihood of MERS infection.', 'Although many diabetic patients were on metformin, our analysis shows that it has no effect on MERS infection.', 'Similarly, sulfonylureas were not associated with an increase or decrease in the likelihood of the infection.', 'Of the diabetic medication, patient on DDP-4 inhibitors was less likely to have MERS infection.', 'The entry receptor for MERS-CoV was identified as a dipeptidyl peptidase receptor.', 'DDP-4 is expressed on the surface of human airway and the blockage of this enzyme may interfere with the virus transmission.', 'In a similar study looked at the demographics of patients with MERS infection, many studies suggested that the infection is more common in patients with comorbidities, primarily diabetes, and chronic kidney diseases.', 'Moreover, the severity of the infection and the increased risk of mortality is likely with older patients and patients with diabetes and chronic kidney diseases.', 'These findings suggest the benefit of screening suspected infection and may suggest future preventive therapy.', 'The limitations of this study include the following.', 'First, there were some missing data on some demographics data which limit the analysis to draw a better understanding of the infection.', 'Second, this was a retrospective analysis which has an inherited flow by its nature.', 'Finally, the outcome of infection and the severity of disease were not reported in the study.', 'In this study, we evaluated the characteristics of confirmed MERS infection.', 'As reported on smaller studies, age, male sex and comorbidities are likely to be associated with the infection (Aleanizy et al., 2017, Chen et al., 2017, Guery et al., 2013).', 'Other variables are less likely to suggest MERS infection.', 'In term of medication history, of the analyzed sample we found no statical differences that suggest increase or decrease the likelihood of the MERS infection, however, all subjects on received DiPeptidyl Peptidase-4 (DPP-4) inhibitors tested negative which may suggest an underlying mechanism that prevents the transmission of the virus.', 'Other medications include metformin, angiotensin-converting-enzyme inhibitors (ACE inhibitors', 'Like other studies that suggested that MERS infection is predominance in male, we found a statistical association that confirmed this (Aleanizy et al., 2017, Chen et al., 2017, Guery et al., 2013).', 'Although, our study has a large female representation in our sample and which can be due to the likelihood of the sharp increase in health care workers- which likely to be female, screening upon exposure to a patient with a possible history of MERS infection.', 'The other reason is many health care institutions became very strict with screening and testing any suspected cases to prevent MERS infection outbreaks which increase the female detection.', 'Our study suggests that gender difference is associated with an increase in the likelihood of MERS infection.', 'Also, our study suggests diabetic patient are more likely to have a confirmed MERS infection compared to nondiabetic patients which have been also reported previously in the literature (Zumla et al., 2015).']}\n", - "{'sentences': ['Severe acute respiratory syndrome coronavirus 2 (2019-nCoV), which first broke out in 1 Wuhan (China) in December of 2019, causes a severe acute respiratory illness with a mortality 2 ranging from 3% to 6%.', 'To better understand the evolution of the newly emerging 2019-nCoV, in this 3 paper, we analyze the codon usage pattern of 2019-nCoV. For this purpose, we compare the codon 4 usage of 2019-nCoV with that of other 30 viruses belonging to the subfamily of orthocoronavirinae.', '5 We found that 2019-nCoV shows a rich composition of AT nucleotides that strongly influences its 6 codon usage, which appears to be not optimized to human host.', 'Then, we study the evolutionary 7 pressures influencing the codon usage and evolutionary rates of the sequences of five conserved 8 genes that encode the corresponding proteins (viral replicase, spike, envelope, membrane and 9 nucleocapsid) characteristic of coronaviruses.', 'We found different patterns of both mutational bias 10 and nature selection that affect the codon usage of these genes at different extents.', 'Moreover, we 11 show that the two integral membrane proteins proteins (matrix and envelope) tend to evolve slowly 12 by accumulating nucleotide mutations on their genes.', 'Conversely, genes encoding nucleocapsid 13 (N), viral replicase and spike proteins are important targets for the development of vaccines and 14 antiviral drugs, tend to evolve faster as compared to other ones.', 'Taken together, our results suggest 15 that the higher evolutionary rate observed for these two genes could represent a major barrier in the 16 development of antiviral therapeutics 2019-nCoV. 18 20 genome of coronavirus (mouse hepatitis virus -MHV), a positive sense, single-stranded RNA virus, 21 was first reported in 1949.', 'It belongs to the family Coronaviridae and ranges from 26.4 (ThCoV 22 HKU12) to 31.7 (SW1) kb in length [10], making it the largest genomes among all known RNA viruses, 23 with G + C contents varying from 32% to 43% [20].', 'The coronavirinae family consists of four genera 24 based on their genetic properties, including genus: Alphacoronavirus, Betacoronavirus (subdivided in 25 subgroups A, B, C and D), Gammacoronavirus and Deltacoronavirus.', 'Coronavirus can infect humans 26 and many different animal 2 of 20 bats, rabbits, ferrets, mink, snake, and other wildlife animals.', 'To date, 30 CoVs genomes have been 28 identified.', 'Only seven CoVs have been identified that infect humans, including Human CoV-229E 29 (HCoV-229E), Human coronavirus NL63 (HCoV-NL63), HumanCoV-OC43 (HCoV-OC43), Human 30 CoV-HKU1 (HCoV-HKU1), Human SARS related coronavirus (SARSr-CoV), Middle East Respiratory 31 Syndrome (MERS-CoV) and SARS CoV 2 ( nCoV) [26].', '32 Severe acute respiratory syndrome CoV 2 (2019-nCoV), which first broke out in Wuhan (China) in 33 December of 2019, causes a severe acute respiratory illness with a mortality rate from 3% to 6%.', '34 The newly sequenced virus genome encodes two open reading frames (ORFs), ORF1a and ORF1ab, 35 the latter encodes replicase polyproteins, and four structural proteins [19], [9]: the spike-surface 36 glycoprotein (proteins [19], [9]: the spike-surface 36 glycoprotein), the small envelop protein (protein S), the small envelop protein), the matrix protein (M), and the 37 nucleocapsid protein (N).', '38 The phenomenon of codon usage bias (CUB) exists in many genomes including RNA genomes and 39 it is actually determined by mutation and selection [1].', 'As it is well-known, the non-random choice 40 of synonymous codons varies among species that are potential host for viruses [11] [? ].', 'It is then 41 important to study patterns of common codon usage in coronaviruses because CUB can be related to 42 the driving forces that shape the evolution of small RNA viruses.', 'Mutational bias has been considered 43 as the major determinant of codon usage variation among RNA viruses [13].', 'Indeed, RNA viruses 44 show an effective number of codons (ENC) that is quite high (ENC>45) pointing to a quite random 45 codon usage, whereas if one uses the adaptive index CAI then the viral CUB is consistent with that of 46 the host, as observed in the Equine infectious anemia virus (EIAV) or Zaire ebolavirus (ZEBOV', 'We compared the codon usage of 2019-nCoV with that of the other coronavirus genomes.', 'For 66 this purpose, we used the RSCU which is a biologically relevant metric of distance between the codon 67 usage in the protein-coding sequences of these genomes.', 'In Fig. 1 , we report the heatmap of the RSCU 68 values associated with the coronavirus.', 'The RSCU values of the majority of the codons scored between 69 0 and 3.1 (see legend in Figure 1).', \"Interestingly, analysis of codon bias in coronavirus genomes reveal 70 that the newly identified coronavirus 2019-nCoV Wuhan-Hu-1 sequence has a clear origin from other 71 beta-CoV's and is closer, specifically, to SARSr-CoV, consistent with their phylogenetic relationships 72 (Figure A3).\", 'In line with previous observations, we show that the mean CpG relative abundance in the 73 author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'coronavirus genomes is markedly suppressed [27].', 'Specifically, GGG, GGC, CCG (pyrimidine-CpG) 74 and ACG (purine-CpG) present a very low frequence of occurrence, probably due to the relative tRNA 75 abundance of the host.', 'In fact, in human the abundance of tRNA in codons GGG, GGC, CCG and 76 ACG are respectavely: 0, 0, 4 and 7.', 'In 2019-nCoV, the most frequently used codons are CGU (arginine, 2.34 times) and GGU (glycine, 78 2.42), whereas the least used codons are GGG (glycine) and UCG (serine).', 'We also note the most 79 frequently used codons for each amino acid, ended in either U or A. [5] 80 157 divergence.', 'Each point in Forsdyke plots measures the divergence between pairs of orthologous genes 158 in the two species, as projected along with the phenotypic (protein']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Several amino acid substitutions in RBD were identified in the SARS-CoV-2 RBD compared to Bat-SARS-CoVs and SARS-CoV. Mutations in the spike protein could change the tropism of a virus, including new hosts or increasing viral pathogenesis (Shang et al., 2020[13]).', 'HIV infection is a good model of change in viral tropism by mutations in the envelope proteins.', 'These mutations switch co-receptor use (CCR5 to CXCR4) increasing the viral pathogenesis (Mosier 2009[7]).', 'Interestingly, our data showed that these changes are not only related to the ability of interaction with the human ACE2 receptor but also for improving this receptor recognition.', 'The presence of two loops around the RBD of SARS-CoV-2 might be promoting the interaction with the ACE2 receptor, improving the binding to this receptor by increasing the number of atoms involved (Tables 1(Tab.', '1) and 2(Tab.', 'The amino acid substitutions and the longer capping loops could explain the increase in binding affinities in SARS-CoV-2 compared to SARS-CoV (Table 1(Tab.', 'Higher affinity values might be related to the dynamic of infection and the rapid spread observed for this virus.', 'The origin of the SARS-CoV-2 has been not fully elucidated.', 'While this study was in course, another study of Wong et al. (2020[18]), showed a high similarity at protein level in the RBD among the coronaviruses isolated from the recent outbreak (SARS-CoV-2), those isolated from pangolin and Rhinolophus affinis (RaTG13).', 'The authors also suggest that Pangolin might be the intermediate host, with a 98 % identity with the human virus, at the receptor binding motif, between the bat and human.', 'The spike model of RaTG13 is quite similar to that obtained from SARS-CoV and SARS-CoV-2 and the loops in the RBD are also present (data not shown).', 'The protein sequence of the receptor binding motif, has 5 important amino acids.', 'When comparing the sequence of SARS-CoV-2 with that of the isolated viruses of pangolin and Rhinolophus affinis, 1 and 4 differences are observed respectively in the amino acids considered key for the union with ACE2 (Yan et al., 2020[20]; Wong et al., 2020[18]).', 'These differences should mean slightly less favorable binding energies between these viruses with ACE2 compared to the SARS-CoV-2, shown in this study.', 'Thus, the loops observed in the spike protein of SARS-CoV-2 could play an important role together with the amino acid substitutions, being an interesting clue to determine the host receptor specificity for the viral spike protein.', 'Altogether, structural changes and residues composition in the viral spike protein could be associated with increased infection kinetics and viral spreading.', 'Comparative studies to determine the impact in vitro of the mutation and loops in RBD of SARS-CoV and SARS-CoV-2 are required in order to predict possible zoonotic event in the future.']}\n", - "{'sentences': ['wo US biotech firms have positioned themselves as front-runners fighting the novel coronavirus, called SARS-CoV-2.', 'On Feb. 25, the US National Institutes of Health (NIH) said it had begun a Phase II clinical trial of remdesivir, an experimental small-molecule drug made by Gilead Sciences, for treatment of those infected with SARS-CoV-2.', 'On the same day, Moderna said it had shipped its experimental coronavirus vaccine to the NIH']}\n", - "{'sentences': ['The intensity of human interactions with Earth systems has accelerated in recent decades, because of urban development, population growth, industrialization, deforestation, construction of dams, etc., with changes in physical, biological, and chemical processes in soils and waters.', \"In particular, human activity, driven by a high level of world population that is about eight billion (U. S. Census Bureau 2020), has induced changes to Earth's surface, cryosphere, ecosystems, and climate that are now so great and rapid, advancing the geological epoch of Anthropocene (Crutzen and Stoermer, 2000; Foley et al., 2013) .\", 'The beginning of the Anthropocene at around 1780 AD marks the beginning of immense rises in human population and carbon emissions as well as atmospheric CO 2 levels (Ellis et al., 2013) .', 'The scale of carbon emissions associated with industrial activity is leading to a rise in atmospheric greenhouse gases at a rate unprecedented and gradual rise in carbon dioxide (Glikson, 2013; Coccia, 2014a) .', 'In this era of Anthropocene, the health effects of air pollution have been subject to intense study in recent years.', 'Exposure to airborne particulate matter and ozone has main health effects associated with increases in mortality and hospital admissions for respiratory and cardiovascular diseases (Kampa and Castanas, 2008; Hoek et al., 2013) .', 'The idea that air pollution episodes have a detrimental effect on health is now rarely contested, and acute .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.06.20055657 doi: medRxiv preprint 41 | P a g e Coccia M. (2020) Two mechanisms for accelerated diffusion of COVID-19 outbreaks in regions with high intensity of population and polluting industrialization: the air pollution-to-human and human-to-human transmission dynamics exposures to high concentrations of air pollutants exacerbate cardiopulmonary disorders in human population worldwide (Langrish and Mills, 2014) .', 'This study shows that factors determining the diffusion of epidemics similar to COVID-19 are due to manifold elements, in addition to human-to-human transmission, given by:', 'General factors that are the same for all locations and associated with innate biological characteristics of the viruses, incubation time, effects on infected and susceptible people, etc.', 'Specific factors that are different for each location and even for each individual, such us level of air pollution over time and space, meteorological conditions of specific location, season, density of areas, economic wealth, cultural characteristics (religious habits, food culture, etc, organization and efficiency of healthcare sector, facilities and equipment in health sector, immune system of people, average age of population, sex of people, etc.', 'The main results of the study here, based on case study of COVID-19 outbreak in Italy, are: o Hinterland cities with higher number of average days exceeding the limits set for PM10 have a very high number of infected people on 1 st April, 2020 (arithmetic mean is about 2,000 infected, with average polluted days more than 80), than coastal cities also having days of exceeding the limits set for PM10 or ozone (arithmetic mean about 700 infected, with average polluted days about 60).', 'In fact, coastal cities have an average higher intensity of wind speed (about 12 km/h) than hinterland cities (8 km/h) and statistical analysis reveals a negative coefficient correlation between number of infected and intensity of wind speed (r= \\uf02d28 to \\uf02d38%, p-value .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.06.20055657 doi: medRxiv preprint 42 | P a g e Coccia M. (2020) Two mechanisms for accelerated diffusion of COVID-19 outbreaks in regions with high intensity of population and polluting industrialization: the air pollution-to-human and human-to-human transmission dynamics <0.05): in fact, wind speed and other elements clean air from pollutants that are associated with transmission dynamics of viral infectivity.', 'o Air pollution in cities under study seems to be a more important predictor in the initial phase of transmission dynamics (on 17 th March 2020, b1 = 1.27, p<0.001) than human-to-human transmission (b2 = 0.31, p<0.05).', \"In the second phase of the transmission dynamics of viral infectivity, air pollution reduces intensity (on 1 st April, 2020 b'1 = .85, p<0.001) also because of indirect effect of lockdown and human-to-human transmission slightly increases (b'2 = 0.34, p<0.01): This result reveals that accelerated transmissions dynamics of COVID-19 is due to mainly air pollution-to-human transmission in addition to human-to-human transmission.\", 'o To minimize future epidemics similar to COVID-19, the max number of days per year in which Italian provincial capitals can exceed the limits set for PM10 (particulate matter 10 micrometers or less in diameter) or for ozone, considering their meteorological conditions, is about 45 days.', 'Hence, high concentration of nitrogen dioxide, a noxious gas, particulate air pollutants emitted by motor vehicles, power plants, and industrial facilities in North Italy seems to be a platform to support diffusion of viral infectivity (Groulx et al., 2018) , increase hospitalizations for respiratory virus bronchiolitis (cf., Carugno et al., 2018; Nenna et al., 2017) , increase asthma incidence (Liao et al., 2011) and damage to the immune system of people (Glencross et al., 2020) .', 'Beelen et al. (2013) report the need to draw attention to the continuing effects of air pollution on health.', 'A socioeconomic strategy to prevent future epidemics similar to the COVID-19 is also the reduction of pollution with fruitful environmental and health effect by the rationalization of manufacturing industry in a perspective of sustainable development, de-industrializing polluting activities in the geographical development of current capitalism.', 'De-industrialization of polluting industries and sustainable development impose often huge social costs in the short term on people, households, and families but they have long-run benefits for human societies.', 'Studies show that public and environmental health policy interventions are necessary and have the potential to reduce morbidity and mortality across Europe (cf., Raaschou-Nielsen et al., 2013) .', 'In fact, the improvements in air quality have been .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.06.20055657 doi: medRxiv preprint 43 | P a g e Coccia M. (2020) Two mechanisms for accelerated diffusion of COVID-19 outbreaks in regions with high intensity of population and polluting industrialization: the air pollution-to-human and human-to-human transmission dynamics accompanied by demonstrable benefits to human health.', 'Pope et al. (2009) reported that PM2.5 concentrations fell by a third from the early 1980s to the late 1990s across major US metropolitan areas, with each 10 μg/m 3 reduction associated with an increase in life expectancy of 0.61 years.', 'Because of health problems of polluting industrialization, Wei et al. (2020) suggest different air pollution regulations in regions having varied geographical and climatic conditions, and different bio aerosol pollution.', 'In particular, Wei et al. (2020) suggest that different air quality strategies should be applied in inland and coastal cities, e.g., coastal cities also need start bio aerosol risk alarm during moderate pollution when severe pollution occurs in inland cities.', 'Guo et al. (2019) argue that in recent years, haze pollution is a serious environmental problem affecting cities, proposing implications for urban planning to improve public respiratory health.', 'In short, the long-term benefits of sustainable economic development are basic for the improvement of environment, atmosphere, air quality and especially health of populations (Blackaby, 1978; Bluestone and Harrison, 1982; Pike, 2009 ).', 'Overall, the, these findings here are consistent with correlational studies and indicate that health effects of air pollution exposure can span decades and extend beyond cardiopulmonary systems affecting diffusion of epidemics similar to COVID-19.', 'Hence, it is important to reinforce evidence related to air pollution and inter-related factors of the transmission dynamics of virus similar to COVID-19, and helps policy makers to develop proactive regulations for the control of environment, air pollution, polluting industrialization and prevention of the diffusion of viral infectivity.', 'The complex problem of epidemic threats has to be treated with an approach of dissolution: it means to redesign the strategies and protocols to cope with future epidemics in such way as to eliminate the conditions that caused accelerated diffusion of COVID-19, thus enabling advanced nations to do better in the future than the best it can do today (Ackoff and Rovin, 2003, pp.', '9-10; Bundy et al., 2017) .', 'This study revels interesting results of transmission dynamics of COVID-19 given by the mechanism of air pollution-to-human transmission that in addition to human-to-human transmission seems to have accelerated diffusion of epidemics in Italy.', 'However, these conclusions are tentative.', 'There are several challenges to such studies, particularly in real time.', 'Sources may be Coccia M. 2008 .', 'Spatial mobility of knowledge transfer and absorptive capacity: analysis and measurement of the impact within the geoeconomic space, The Journal of Technology Transfer, vol.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Objective: To understand the clinical characteristics, change of liver function, influencing factors and prognosis in hospitalized patients with coronavirus disease-19 (COVID-19) combined with liver injury.', 'Methods: The general conditions, biochemical indicators of liver, blood clotting mechanism, routine blood test, UGT1A1 * 28 gene polymorphism and other data of 40 cases with COVID-19 admitted to the isolation ward of Tangdu Hospital were retrospectively analyzed.', 'The clinical characteristics, influencing factors and prognosis of liver injury in patients with liver injury group and those with normal liver function group were compared.', 'The mean of two samples in univariate analysis was compared by t-test and analysis of variance.', 'The counting data was measured by χ(2) tests.', 'The non-normal distribution measurement data were described by the median, and the non-parametric test was used.', 'Statistically significant influencing factors were used as the independent variables in univariate analysis.', 'Multiple logistic regression analysis was used to analyze the main influencing factors of liver injury.', 'Results: Of the 40 cases, 25 were male (62.5%) and 15 were female (37.5%), aged 22 to 83 (53.87 ± 15.84) years.', 'Liver injury was occurred in 22 cases (55%) during the course of the disease.', 'Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level was initially increased (4.4 to 3.5 times of the normal value) along with decrease of albumin in the second week, and the difference was statistically significant (P < 0.001).', 'Ten cases (43.5%) had highest abnormal total blood bilirubin (54.1 μmol/ L).', 'There was no correlation between the increase in transaminase and the increase in total blood bilirubin (R = -0.006, P = 0.972).', 'Three cases had prothrombin activity (PTA) of ≤ 50%, 10 cases had elevated FDP, and 13 cases had elevated D-dimer, all of whom were severe or critically ill.', 'Liver function injury was more likely to occur in patients who used many types of drugs and large amounts of hormones (P = 0.002, P = 0.031), and there was no correlation with the TA6TA7 mutation in the UGT1A1 * 28 gene locus.', 'Multiple regression analysis showed that the occurrence of liver injury was only related to critical illness.', 'The liver function of all patients had recovered within one week after conventional liver protection treatment.']}\n", - "{'sentences': ['It has remained incompletely understood if sex might significantly impact the All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.26.20043943 doi: medRxiv preprint outcomes of COVID-19 patients.', 'Here, our study indicated the proportion of severe patients is less in females than that of males.', 'Additionally, the clinical outcomes of female patients were better than that of male patients, which is in accordance with recent studies 1, 2, 9, 10 .', 'Apparently, sexual dimorphisms account for differences in severity and outcomes of infectious diseases between females and males.', 'Previous study has indicated that menstruation status and hormonal fluctuation may affect disease symptom severity 11 .', 'Our study as presented here showed that menstrual cycles and volumes are associated with the clinical severity and outcomes.', 'But if age was considered as an adjust variable, the significance was reduced, even when the regular and irregular groups were merged into one non-menopause group.', 'Interestingly, postmenopausal patients have longer length of hospital stays than do non-menopausal females, when considering age and severity.', 'Accordingly, psychiatric hospitalizations for women are significantly greater within 5 days of their last menstrual period 12 .', 'Normal menstruation regularity may be an important protective factor for COVID-19 patients.', 'However, menstruation is often affected by many factors, such as medication, environment and anxiety, aside from the periodic fluctuation of sex hormones.', 'Sex-specific disease outcomes following virus infections are attributed to sexdependent production of steroid hormones, different copy numbers of immune response X-linked genes, and the presence of disease susceptibility genes in males and females 13 .', 'Our data showed that E2 and AMH are positively correlated with the disease severity.', 'E2 is primarily produced in ovaries and considered as the most prevalent and potent form of circulating estrogen.', 'Estrogens are thought to protect non-menopausal women from hepatitis C virus and other pathogens 14, 15 .', 'Also, All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.26.20043943 doi: medRxiv preprint ovariectomized and estrogen receptor antagonist treated female mice were more susceptible to SARS-CoV, which may be due to the protective effects of estrogen receptor signaling in SARS-CoV infection 13 .', 'AMH changes slightly with menstrual cycle and drugs and serves as the optimal marker for ovarian reserve and function.', 'AMH levels were positively associated with the number of oocytes retrieved, ovarian response, E2 and testosterone 16 .', 'Logistics regression analyses showed that the levels of E2 and AMH in non-severe group are higher than that of the severe group, which may play vital roles in the progression of COVID-19.', 'In this study, non-severe females have higher levels of testosterone than do severe patients.', 'Previous studies have shown that testosterone has suppressive effects on immune system, such as on cytokine production and lymphocyte proliferation 17 .', 'However, after adjusted by age, the significance became unobvious.', 'In the disease progression of COVID-19, testosterone may work by suppressing immune storms.', 'Our results also indicated that E2 has a stronger protective effect against the potential negative effects from testosterone.', 'Previous studies have suggested that high doses of E2 may inhibit the production of inflammatory cytokines (e.g., IL-1β, TNF-α), whereas stimulation with E2 at its physiological level enhances their production 18, 19 .', 'After viral infection, proinflammatory cytokines/chemokines secreted by macrophages induced various antiviral mechanisms.', 'Several clinical studies reported that levels of proinflammatory cytokines/chemokines, including IL-6, IL-8, IFN-γ, MCP-1, and IP-10, are highly increased in patients with SARS, some of which were correlated with ARDS, respiratory syncytial virus infections and human infection by avian influenza viruses 20, 21 .', 'In our study, the levels of IL6 and IL8 were negatively related to both disease severity and composite end points, and IL2R and IL10 were related to composite end All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.26.20043943 doi: medRxiv preprint points, consistent with a recent study 22 .', 'E2 has also been shown to regulate host immune response 17,23-25 .', 'Our results indicated that E2 is negatively associated with C3 in follicular phase, and IL2R, IL6,']}\n", - "{'sentences': ['Our observation shows that patients with hypertension who had previously taken ACEI/ARB drugs for antihypertensive treatment have an increased tendency to develop severe pneumonia after infection with SARS-COV-2.', 'Hypertensive patients may need to .', 'CC-BY-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.06.20054825 doi: medRxiv preprint adjust medications to be eliminate ACEI/ARB drugs to reduce the risk of severe pneumonia.', 'Mechanistically, the increase in the zinc metallopeptidase ACE2 might help SARS-COV-2 enter the cells and accelerate its replication.', 'ACE2 is the only known human homologue of the key regulator of blood pressure, angiotensin-converting enzyme (ACE', 'Since its discovery in 2000, ACE2 has been implicated to play an important role in the preservation of heart function, and the balance of blood pressure, with its effects being mediated, in part, through its ability to convert angiotensin II (Ang II', 'Unexpectedly, ACE2 also serves as the cellular entry point for the severe acute respiratory syndrome (SARS) virus and the enzyme is therefore a prime target for pharmacological intervention on coronavirus-related diseases 9 .', 'In 2003, ACE2 was identified as the receptor for severe acute respiratory syndrome coronavirus (SARS-CoV), which mediates the infection and transmission of SARS-CoV. This effect does not rely on the protease activity on ACE 10 .', 'Structural analysis showed that the spinous protein of SARS-CoV was in contact with the head-end of the ACE2 catalytic domain subunit I, did not involve subunit II, and did not block the active region.', 'Once SARS-CoV is connected to ACE2, the extracellular part of ACE2 will be lysed, and the transmembrane part will be transferred into the cell, which mediates further fusion of the virus particles and host cells 11 .', 'Through next-generation sequencing technology, the entire genome sequence of COVID-19 has been successfully determined 12 .', 'Compared with the genomic sequences of previous coronaviruses, it is found that SARS-COV-2 has 79% similarity with SARS-CoV', 'It is worth noting that ACEI/ARB drugs that are administered to hypertensive patients have resulted in an increased expression of ACE2 in the lungs.', 'The role of ACE2 is opposite .', 'CC-BY-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.06.20054825 doi: medRxiv preprint to that of ACE.', 'ACE2 can hydrolyze angiotensin I (Ang I', 'However, some scholars believe that the down-regulation of ACE2 expression after a neo coronavirus challenge aggravates lung injuries.', 'This opinion mainly comes from animal model studies in multiple laboratories and a small sample clinical study.', 'Studies have shown that ACE2 expression decreases after viral infection, causing acute lung injury; exogenous supplementation with ACE2 could alleviate acute lung injury 15 .', 'Human recombinant ACE 2 (rhuACE2) and angiotensin II type 2 receptors protect mice from severe acute lung injuries induced by acid aspiration or sepsis 16 .', 'It was found that patients with acute respiratory distress syndrome (ARDS) who were treated with rhuACE2 injections had rapidly decreasing levels of Ang II and increasing levels of Ang1-7 17 .', 'The down-regulation of ACE2 caused the imbalance of ACE/Ang II and ACE2 and the activity of Ang II in the renin-angiotensin-aldosterone system (RAAS', 'However, we cannot directly conclude that COVID-19 patients taking ACEI/ARB antihypertensive drugs will have more severe pneumonia than those not taking ACEI/ARB drugs because many confounding factors such as coexisting diseases have not yet been excluded.', 'Our survey shows that the population with hypertension does not seem to be more susceptible to COVID-19 comparing with the non-hypertension population.', 'Previously, a large sample study of 1099 patients showed that hypertension is a coexisting disease in only .', 'CC-BY-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint Our research has the following limitations:', 'First, our survey only focused on Hankou Hospital in Wuhan, and the number of patients included was small; larger sample size and multi-center clinical data will be needed to support our conclusions in a future study.', 'Second, our investigation included all clinically confirmed cases.', 'Many patients were not tested because of the lack of nucleic acid test kits at the beginning of the outbreak.', \"Further, there were some patients were suspected to have COVID-19 but were excluded from our study because they tested negative in the hospital; however, based on the exact epidemiological history, the patient's signs and symptoms, and chest CT examination results, we trust the reliability of the COVID-19 diagnosis in these patients.\", 'Third, due to the urgent data collection, we had a shorter follow-up time for some patients.', 'The shortest hospital stay for patients is only > 14 days.', 'This may interfere with the final prognosis and lead to the failure to analyze survival times.', 'Fourth, we did not analyze the comorbidities such as shock and ARDS, because our focus is to analyze the risk associated with hypertension to provide evidence for the issue of COVID-19 prevention and treatment guidelines.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['ABSTRACTThe newly identified 2019 novel coronavirus (2019-nCoV) has caused more than 800 laboratory-confirmed human infections, including 25 deaths, posing a serious threat to human health.', 'Currently, however, there is no specific antiviral treatment or vaccine.', 'Considering the relatively high identity of receptor binding domain (RBD) in 2019-nCoV and SARS-CoV, it is urgent to assess the cross-reactivity of anti-SARS-CoV antibodies with 2019-nCoV spike protein, which could have important implications for rapid development of vaccines and therapeutic antibodies against 2019-nCoV. Here, we report for the first time that a SARS-CoV-specific human monoclonal antibody, CR3022, could bind potently with 2019-nCoV RBD (KD of 6.3 nM).', 'The epitope of CR3022 does not overlap with the ACE2 binding site within 2019-nCoV RBD.', 'Therefore, CR3022 has the potential to be developed as candidate therapeutics, alone or in combination with other neutralizing antibodies, for the prevention and treatment of 2019-nCoV infections.', 'Interestingly, some of the most potent SARS-CoV-specific neutralizing antibodies (e.g., m396, CR3014) that target the ACE2 binding site of SARS-CoV failed to bind 2019-nCoV spike protein, indicating that the difference in the RBD of SARS-CoV and 2019-nCoV has a critical impact for the cross-reactivity of neutralizing antibodies, and that it is still necessary to develop novel monoclonal antibodies that could bind specifically to 2019-nCoV RBD']}\n", - "{'sentences': ['A novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) was identified from respiratory illness patients in Wuhan, Hubei Province, China, which has recently emerged as a serious threat to the world public health.', 'Hower, no approved drugs have been found to effectively inhibit the virus.', 'Since it has been reported that the HIV-1 protease inhibitors can be used as anti-SARS drugs by tegarting SARS-CoV 3CLpro, we choose six approved anti-HIV-1 drugs to investigate their binding interactions between 3CLpro, and to evaluate their potential to become clinical drugs for the new coronavirus pneumonia (COVID19) caused by SARS-CoV-2 infection.', 'The molecular docking results indicate that, the 3CLpro of SARS-CoV-2 has a higher binding affinity for all the studied inhibitors than its SARS homologue.', 'Two docking complexes (indinavir and darunavir) with high docking scores were futher subjected to MM-PBSA binding free energy calculations to detail the molecular interactions between these two proteinase inhibitors and the 3CLpro.', 'Our results show that darunavir has the best binding affinity with SARS-CoV-2 and SARS-CoV 3CLpro among all inhibitors, indicating it has the potential to become an anti-COVID-19 clinical drug.', 'The likely reason behind the increased binding affinity of HIV-1 protease inhibitors toward SARS-CoV2 3CLpro than that of SARS-CoV were investigated by MD simulations.', 'Our study provides insight into the possible role of structural flexibility during interactions between 3CLpro and inhibitors, and sheds light on the structure-based design of anti-COVID-19 drugs targeting the SARS-CoV-2 3CLpro.']}\n", - "{'sentences': ['The outbreak of the novel coronavirus disease COVID-19, caused by the SARS-CoV-2 virus has spread rapidly around the globe during the past 3 months.', 'As the virus infected cases and mortality rate of this disease is increasing exponentially, scientists and researchers all over the world are relentlessly working to understand this new virus along with possible treatment regimens by discovering active therapeutic agents and vaccines.', 'So, there is an urgent requirement of new and effective medications that can treat the disease caused by SARS-CoV-2.', 'The research includes the study of drugs that are already available in the market and being used for other diseases to accelerate clinical recovery, in other words repurposing of existing drugs.', 'The vast complexity in drug design and protocols regarding clinical trials often prohibit developing various new drug combinations for this epidemic disease in a limited time.', 'Recently, remarkable improvements in computational power coupled with advancements in Machine Learning (ML) technology have been utilized to revolutionize the drug development process.', 'Consequently, a detailed study using ML for the repurposing of therapeutic agents is urgently required.', 'Here, we report the ML model based on the Naïve Bayes algorithm, which has an accuracy of around 73% to predict the drugs that could be used for the treatment of COVID-19.', 'Our study predicts around ten FDA approved commercial drugs that can be used for repurposing.', 'Among all, we suggest that the antiretroviral drug Saquinavir (DrugBank ID -DB01232) would probably be one of the most effective drugs based on the selected criterions.', 'Our study can help clinical scientists in being more selective in identifying and testing the therapeutic agents for COVID-19 treatment.', 'In our study, we have taken those drugs for docking purpose which show protease inhibition activity.', 'The docking of SARS protein with the approved drug Saquinavir (DrugBank ID -DB01232), has a global energy of around -53.62eV which confirms that it had numerous steric clashes with the adjoining strands and thus highlight its potential to inhibit novel SARS coronavirus.', 'Saquinavir is a small molecule antiretroviral drug (Figure 2b the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is In addition to the docking of the above drug, we have also docked several other approved drugs available in the Drug Bank, which are predicted by our ML model with a confidence level of above 95% and also shows the activity of protease inhibition.', 'With reference to that, we have found that the other drugs predicted by the model with the inclusion of all the parameters taken under consideration can also be quite effective.', 'The rapid identification of active therapeutic agents against SARS-CoV-2 is a major challenge.', 'Analyzing the available knowledge on their safety profiles, and in some cases, efficacy against other coronaviruses and repurposing existing antiviral drugs is a potentially crucial short-term strategy to tackle COVID-19.', 'Under the current scenario, it takes more than 15 years to bring a drug from the investigational stages to market availability.', 'It is because of the trial and error process or the so-called Edisonian Approach, where one keeps on analyzing several compounds to find the best possible one.', 'These days with the inclusion of digital medicine, this time span has been reduced to a great extent and people are able to approach in a rational manner for the drug discovery process.', 'Here, we have targeted for the repurpssed drugs towards the development of effective treatment of COVID-19', 'to speed up clinical trial.', 'We have found that ML model created on the basis of the Naive Bayes algorithm is the most effective one with the accuracy of almost equal to 73%.', 'The drugs predicted by this model is further verified by the docking process.', 'So, We speculate can expect that our predicted the drugs show immense potential for treatment of the COVID-19.', 'Considering the ongoing efforts to prevent the spread of COVID-19 all over the world, we are optimistic that the outbreak may subside in a few months like SARS and MERS.', 'However, the outbreak has stressed the urgent need for renewed efforts towards the development of braod-spectrum therapeutic agents to combat coronaviruses which are repeatedly found to be a realistic threat of this century till now.', 'Our this findinging will provide a base for further enhanced drug discovery programs.', 'All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.04.05.20054254 doi: medRxiv preprint']}\n", - "{'sentences': ['This is an extended descriptive study on the epidemiology and clinical characteristics of the 2019nCoV, including data on 99 patients who were transferred to Jinyintan Hospital from other hospitals across Wuhan.', 'It presents the latest status of the 2019nCoV infection in China and adds details on combined bacterial and fungal infections.', 'Human coronavirus is one of the main pathogens of respiratory infection.', 'The two highly pathogenic viruses, SARSCoV and MERSCoV, cause severe res piratory syndrome in humans and four other human corona viruses (HCoVOC43, HCoV229E, HCoVNL63, HCoVHKU1) induce mild upper respiratory disease.', 'The major SARSCoV outbreak involving 8422 patients occurred during 2002-03 and spread to 29 countries globally.', '9,10 MERSCoV emerged in Middle Eastern countries in 2012 but was imported into China.', '11, 12 The sequence of 2019nCoV is relatively different from the six other coronavirus subtypes but can be classified as betacoronavirus.', 'SARSCoV and MERSCoV can be transmitted directly to humans from civets and dromedary camels, respectively, and both viruses origi nate in bats, but the origin of 2019nCoV needs further investigation.', '[13] [14] [15] 2019nCoV also has enveloped virions that measure approximately 50-200 nm in diameter with a single positivesense RNA genome.', '16 Clubshaped glycoprotein spikes in the envelope give the virus a crownlike or coronal appearance.', 'Transmission rates are unknown for 2019nCoV; however, there is evidence of humantohuman transmission.', 'None of the 99 patients we examined were medical staff, but 15 medical workers have been reported with 2019nCoV infection, 14 of whom are assumed to have been infected by the same patient.', '17 The mortality of SARSCoV has been reported as more than 10% and MERSCoV at more than 35%.', '5, 18 At data cutoff for this study, mortality of the 99 included patients infected by 2019nCoV was 11%, resembling that in a previous study.', '3 However, additional deaths might occur in those still hospitalised.', 'We observed a greater number of men than women in the 99 cases of 2019nCoV infection.', 'MERSCoV and SARSCoV have also been found to infect more males than females.', '19, 20 The reduced susceptibility of females to viral infections could be attributed to the protection from X chromosome and sex hormones, which play an important role in innate and adaptive immunity.', '21 Additionally, about half of patients infected by 2019nCoV had chronic underlying diseases, mainly cardiovascular and cerebrovascular diseases and diabetes; this is similar to MERSCoV. 19 Our results suggest that 2019nCoV is more likely to infect older adult males with chronic comorbidities as a result of the weaker immune func tions of these patients.', '[19] [20] [21] [22] Some patients, especially severely ill ones, had co infections of bacteria and fungi.', 'Common bacterial cultures of patients with secondary infections included A baumannii, K pneumoniae, A flavus, C glabrata, and C albicans.', '8 The high drug resistance rate of A baumannii can cause difficulties with antiinfective treatment, leading to higher possibility of developing septic shock.', \"23 For severe mixed infections, in addition to the virulence factors of pathogens, the host's immune status is also one of the important factors.\", 'Old age, obesity, and presence of comorbidity might be associated with increased mor tality.', '24 When populations with low immune function, such as older people, diabetics, people with HIV infection, people with longterm use of immuno suppressive agents, and pregnant women, are infected with 2019nCoV, prompt administration of antibiotics to prevent infection and strengthening of immune support treatment might reduce complications and mortality.', 'In terms of laboratory tests, the absolute value of lymphocytes in most patients was reduced.', 'This result suggests that 2019nCoV might mainly act on lympho cytes, especially T lymphocytes, as does SARSCoV. Virus particles spread through the respiratory mucosa and infect other cells, induce a cytokine storm in the body, generate a series of immune responses, and cause changes in peripheral white blood cells and immune cells such as lymphocytes.', 'Some patients progressed rapidly with ARDS and septic shock, which was eventually followed by multiple organ failure.', 'Therefore, early identification and timely treatment of critical cases is of crucial importance.', 'Use of intra venous immunoglobulin is recommended to enhance the ability of antiinfection for severely ill patients and steroids (methylprednisolone 1-2 mg/kg per day) are recommended for patients with ARDS, for as short a duration of treatment as possible.', \"Some studies suggest that a substantial decrease in the total number of lymphocytes indicates that coronavirus consumes many immune cells and inhibits the body's cellular immune function.\", 'Damage to T lymphocytes might be an important factor leading to exacerbations of patients.', '25 The low absolute value of lymphocytes could be used as a reference index in the diagnosis of new coronavirus infections in the clinic.', 'In general, the characteristics of patients who died were in line with the early warning model for predicting mortality in viral pneumonia in our previous study: the MuLBSTA score.', 'The MuLBSTA score system contains six indexes, which are multilobular infiltration, lympho penia, bacterial coinfection, smoking history, hyper tension, and age.', 'Further investigation is needed to explore the applicability of the MuLBSTA score in predicting the risk of mortality in 2019nCoV infection.', 'This study has several limitations.', 'First, only 99 patients with confirmed 2019nCoV were included; suspected but undiagnosed cases were ruled out in the analyses.', 'It would be better to include as many patients as possible in Wuhan, in other cities in China, and even in other countries to get a more comprehensive understanding of 2019nCoV. Second, more detailed patient information, particularly regarding clinical outcomes, was unavailable at the time of analysis; however, the data in this study permit an early assess ment of the epidemiological and clinical characteristics of 2019nCoV pneumonia in Wuhan, China.', 'In conclusion, the infection of 2019nCoV was of clustering onset, is more likely to infect older men with comorbidities, and can result in severe and even fatal respiratory diseases such as ARDS.', 'Contributors NC, XD, FG, YH, YQ, JW, YL, YW, JX, TY, and LZ collected the epidemiological and clinical data and processed statistical data.', 'NC and MZ drafted the manuscript.', 'JQ and XZ revised the final manuscript.', 'XZ is responsible for summarising all data related to the virus.', 'LZ is responsible for summarising all epidemiological and clinical data.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Severe acute respiratory syndrome coronavirus 2 (Severe acute respiratory syndrome coronavirus 2) emerged in Wuhan, China, in December 2019 and has spread globally with sustained human-to-human transmission outside China.', 'To report the initial experience in Singapore with the epidemiologic investigation of this outbreak, clinical features, and management.', 'Descriptive case series of the first 18 patients diagnosed with polymerase chain reaction (PCR)–confirmed Severe acute respiratory syndrome coronavirus 2 infection at 4 hospitals in Singapore from January 23 to February 3, 2020; final follow-up date was February 25, 2020.Confirmed Severe acute respiratory syndrome coronavirus 2 infection.', 'Clinical, laboratory, and radiologic data were collected, including PCR cycle threshold values from nasopharyngeal swabs and viral shedding in blood, urine, and stool.', 'Clinical course was summarized, including requirement for supplemental oxygen and intensive care and use of empirical treatment with lopinavir-ritonavir.', 'Among the 18 hospitalized patients with PCR-confirmed Severe acute respiratory syndrome coronavirus 2 infection (median age, 47 years; 9 [50%] women), clinical presentation was an upper respiratory tract infection in 12 (67%), and viral shedding from the nasopharynx was prolonged for 7 days or longer among 15 (83%).', 'Six individuals (33%) required supplemental oxygen; of these, 2 required intensive care.', 'There were no deaths.', 'Virus was detectable in the stool (4/8 [50%]) and blood (1/12 [8%]) by PCR but not in urine.', 'Five individuals requiring supplemental oxygen were treated with lopinavir-ritonavir.', 'For 3 of the 5 patients, fever resolved and supplemental oxygen requirement was reduced within 3 days, whereas 2 deteriorated with progressive respiratory failure.', 'Four of the 5 patients treated with lopinavir-ritonavir developed nausea, vomiting, and/or diarrhea, and 3 developed abnormal liver function test results.', 'Among the first 18 patients diagnosed with Severe acute respiratory syndrome coronavirus 2']}\n", - "{'sentences': ['SummaryA novel coronavirus, named SARS-CoV-2, emerged in 2019 from Hubei region in China and rapidly spread worldwide.', 'As no approved therapeutics exists to treat Covid-19, the disease associated to SARS-Cov-2, there is an urgent need to propose molecules that could quickly enter into clinics.', 'Repurposing of approved drugs is a strategy that can bypass the time consuming stages of drug development.', 'In this study, we screened the Prestwick Chemical Library® composed of 1,520 approved drugs in an infected cell-based assay.', '90 compounds were identified.', 'The robustness of the screen was assessed by the identification of drugs, such as Chloroquine derivatives and protease inhibitors, already in clinical trials.', 'The hits were sorted according to their chemical composition and their known therapeutic effect, then EC50 and CC50 were determined for a subset of compounds.', 'Several drugs, such as Azithromycine, Opipramol, Quinidine or Omeprazol present antiviral potency with 2 37.3 C or respiratory symptoms were considered as suspected cases and were referred to the emergency department for evaluation.', 'This assessment included routine serum chemistry tests and a complete blood count, C-reactive protein level, procalcitonin level, computed tomography of the chest and pharynx, and SARS-CoV-2 nucleic acid testing to rule out SARS-CoV-2 infections.', 'These suspected or confirmed cases were not brought into the dialysis treatment area, but rather were transferred to the isolation ward of the specialty hospital and received dialysis treatment in an isolation room until the SARS-CoV-2 nucleic acid test was negative.', 'SARS-CoV-2 is transmitted in most instances from person to person, either through inhalation or through deposition on mucosal surfaces of large respiratory droplets.', 'Dialysis facility staff adhered to infection control measures recommended by European Centre for Disease Prevention and Control, 15 including use of a waterproof disposable gown, cap, gloves, face shields, and an N95 face mask.', 'After each hemodialysis treatment, the dialyzer and all blood tubing were discarded as infectious waste.', \"The dialysis machine was disinfected using sodium hypochlorite solution according to the manufacturer's instruction.\", 'The dialysis machine was kept in a room in the COVID-19 isolation ward between dialysis sessions and was only used for patients who had contracted COVID-19 infection.', 'Because of these rigorous practices by medical staff, they were allowed to continue to work and return home per their usual routines.', 'In summary, we describe a hemodialysis patient with COVID-19 pneumonia.', 'This particular patient had a relatively mild course despite multiple comorbid conditions including chronic hepatitis B virus infection and type 2 diabetes.', 'With appropriate infection control measures, the staff who cared for this patient were not infected.', 'Lopinavir/ritonavir therapy was used in this patient; whether this resulted in less severe disease remains uncertain but warrants further study.', 'Last, through rigorous triage measures, we were able to limit the transmission of disease to other patients.', '337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 Case Report 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560', 'In this report, we describe the clinical course of a hemodialysis patient who developed COVID-19 infection.', 'The clinical presentation of the patient was similar to patients with atypical symptom COVID-19 infection.', 'Although the patient did not have many of the typical symptoms, including fever, sore throat, nasal congestion, malaise, headache, or myalgia, he had cough, dyspnea, and typical changes of bilateral multiple ground-glass opacities on computed tomographic images of the chest.', 'According to the Chinese criteria for diagnosis of pneumonia caused by novel coronavirus (trial version 6), 6 suspected cases can be divided into 2 case definitions: the first requires epidemiologic history of likely exposure and any 2 clinical criteria (fever and/or respiratory symptoms, imaging characteristics of pneumonia, and normal or decreased total number of white blood cells or lymphocytes in early onset), and the second requires no clear epidemiologic history of exposure but presents with at least 3 of the clinical manifestations described.', 'Confirmation requires a positive SARS-CoV-2 nucleic acid test result.', 'Because hemodialysis patients have disorders of B-and T-cell function, 7,8 patients may have atypical presentations.', 'Lymphopenia is common in patients with COVID-19 infection and might be a critical factor associated with disease severity and mortality in general patients.', '9 Cao and colleagues Q4 reported that the most common laboratory abnormalities were depressed total lymphocytes, prolonged prothrombin time, and elevated lactate dehydrogenase levels in COVID-19 pneumonia.', '10 Given low lymphocyte counts in hemodialysis patients chronically, lymphopenia likely is not helpful for identifying individuals with SARS-CoV-2 virus infection.', 'Procalcitonin has similar limitations, with levels chronically elevated in hemodialysis patients even in the absence of severe acute illness.', '11 Given these limitations and the high prevalence of comorbid conditions, COVID-19 pneumonia diagnosis in hemodialysis patients is dependent on clinical epidemiology, radiographic findings, and viral nucleic acid testing.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Anti-hypertensive Angiotensin II receptor blockers associated to mitigation of disease severity in elderly COVID-19 patients', 'Summary Background The novel coronavirus (CoV) severe acute respiratory syndrome (SARS)-CoV-2 outbreak started at the end of 2019 in Wuhan, China, and spread over 100 countries.', 'SARS-CoV-2 uses the membrane protein Angiotensin I converting enzyme 2(ACE2) as a cell entry receptor.', 'Indeed, it was reported that the balance of Renin-Angiotensin System (RAS), regulated by both ACE and ACE2, was altered in COVID-19 patients.', 'It is controversial, however, whether commonly used anti-hypertensive drugs Angiotensin I converting enzyme inhibitor (ACEI) and Angiotensin II receptor blocker (ARB) shall be continued in the confirmed COVID-19 patients.', 'This study was designed to investigate any difference in disease severity between COVID-19 patients with hypertension comorbidity.', 'The included COVID-19 patients used ACEI, ARB, calcium channel blockers (CCB), beta blockers (BB), or thiazide to treat preexisting hypertension prior to the hospital were compared to patients who did not take any of those drugs.', 'Methods In this multicentre retrospective study, clinical data of 511 COVID-19 patients were analyzed.', 'Patients were categorized into six sub-groups of hypertension comorbidity based on treatment using one of anti-hypertension drugs (ACEI, ARB, CCB, BB, thiazide), or none.', 'A meta-analysis was performed to evaluate the use of ACEI and ARB associated with pneumonia using published studies.', 'Findings Among the elderly (age>65) COVID-19 patients with hypertension comorbidity, the risk of COVID-19-S (severe disease) was significantly decreased in patients who took ARB drugs prior to hospitalization compared to patients who took no drugs (OR=0.343, 95% CI 0.128-0.916, p=0.025).', 'The meta-analysis showed that ARB use has positive effects associated with morbidity and mortality of pneumonia.', 'Interpretation Elderly (age>65) COVID-19 patients with hypertension comorbidity who are taking ARB']}\n", - "{'sentences': ['The unprecedented pandemic of COVID-19 has created worldwide shortages of personal protective 10 equipment, in particular respiratory protection such as N95 respirators 1 .', 'SARS-CoV-2 transmission is 11 frequently occurring in hospital settings, with numerous reported cases of nosocomial transmission 12 highlighting the vulnerability of healthcare workers 2-4 .', 'In general, N95 respirators are designed for single 13 use prior to disposal.', 'Several groups have addressed the potential for re-use of N95 respirators from a 14 mechanical or from a decontamination perspective (for a full literature overview see Supplementary 15 Appendix).', 'Here, we analyzed four different decontamination methods -UV radiation (260 -285 nm), 70ºC heat, 18 70% ethanol and vaporized hydrogen peroxide (VHP', 'Quantitative fit tests showed that the filtration performance of the N95 respirator was not markedly 29 reduced after a single decontamination for any of the four decontamination methods ( Figure 1B ).', 'Subsequent rounds of decontamination caused sharp drops in filtration performance of the ethanol-treated 31 masks, and to a slightly lesser degree, the heat-treated masks.', 'The VHP-and UV-treated masks retained 32 comparable filtration performance to the control group after two rounds of decontamination, and 33 maintained acceptable performance after three rounds.', '34 35 for use under a CC0 license.', ': medRxiv preprint Taken together, our findings show that VHP treatment exhibits the best combination of rapid inactivation 36 of SARS-CoV-2 and preservation of N95 respirator integrity, under the experimental conditions used here 37 (Figure 1C).', 'UV radiation kills the virus more slowly and preserves comparable respirator function.', '70ºC 38 dry heat kills with similar speed and is likely to maintain acceptable fit scores for two rounds of 39 decontamination.', 'Ethanol decontamination is not recommended due to loss of N95 integrity, echoing 40 earlier findings 5 .', '41 42 All treatments, particularly UV and dry heat, should be conducted for long enough to ensure that a 43 sufficient reduction in virus concentration has been achieved.', 'The degree of required reduction will 44 depend upon the degree of initial virus contamination.', 'Policymakers can use our estimated decay rates 45 together with estimates of degree of real-world contamination to choose appropriate treatment durations 46 (see Appendix).', 'Our results indicate that N95 respirators can be decontaminated and re-used in times of shortage for up to 49 three times for UV and HPV, and up to two times for dry heat.', 'However, utmost care should be given to 50 ensure the proper functioning of the N95 respirator after each decontamination using readily available 51 qualitative fit testing tools and to ensure that treatments are carried out for sufficient time to achieve 52 desired risk-reduction.', '53 for use under a CC0 license.', ': medRxiv preprint 54 55 Figure 1.', 'Decontamination of SARS-CoV-2 by four different methods.', 'A) SARS-CoV-2 on N95 fabric 56 and stainless steel surface was exposed to UV, 70 ºC dry heat, 70% ethanol and vaporized hydrogen 57 peroxide (VHP).', '50 µl of 10 5 TCID 50 /mL of SARS-CoV was applied on N95 and stainless steel (SS).', '58 Samples were collected at indicted timepoints post exposure to the decontamination method for UV, heat 59 and ethanol and after 10 minutes for VHP.', 'Viable virus titer is shown in TCID 50 /mL media on a 60 logarithmic scale.', 'All samples were quantified by end-point titration on Vero E6 cells.', 'Plots show 61 estimated mean across three replicates (dots and bars show the posterior median estimate of this mean and 62 the posterior inter-quartile range, or IQR).', 'Lines show predicted decay of virus titer over time (lines; 50 63 random draws per replicate from the joint posterior distribution of the exponential decay rate, i.e. negative 64 for use under a CC0 license.', 'of the slope, and intercept, i.e. initial virus titer).', 'Black dashed line shows maximum likelihood estimate 65 titer at the Limit of Detection (LOD']}\n", - "{'sentences': ['In December 2019, a novel coronavirus (SARS-CoV-2) caused infectious disease, termed COVID-19, outbroke in Wuhan, China.', 'COVID-19 patients manifested as lung injury with complications in other organs, such as liver, heart, gastrointestinal tract, especially for severe cases.', 'However, whether COVID-19 causes significant acute kidney injury (AKI) remained controversial.', 'Methods: We retrospectively analyzed the clinical characteristics, urine and blood routine tests and other laboratory parameters of hospitalized COVID-19 patients in Wuhan Union Hospital.', 'Findings: 178 patients, admitted to Wuhan Union hospital from February 02 to February 29, 2020, were included in this study.', 'No patient (0 [0%]) presented increased serum creatinine (Scr), and 5 (2.8%) patients showed increased blood urea nitrogen (BUN), indicating few cases with kidney dysfunction.', 'However, for patients (83) with no history of kidney disease who received routine urine test upon hospitalization, 45 (54.2%) patients displayed abnormality in urinalysis, such as proteinuria, hematuria and leukocyturia, while none of the patients was recorded to have acute kidney injury (AKI']}\n", - "{'sentences': ['Excitement around hydroxychloroquine for treating COVID-19 causes challenges for rheumatology']}\n", - "{'sentences': ['Antiviral therapy was given to 21 cases (87.5%) as initiated therapy, in which, one case also received antibiotics therapy, antifungal therapy plus immunoglobin therapy;', 'and immunoglobin therapy was also given to 2 cases.', 'All these cases were treated with interferon atomization.', 'None of the cases developed severe pneumonia, requiring systemic corticosteroids treatment, mechanical ventilation, or admission to ICU, and none died ( Table S1 ).', 'As of Feb 18, 2020, a total of 18 cases (75.0%) had the virus cleared (2 continuous negatives of nucleic acid tests), among whom 9 cases were discharged from the hospital while the rest 9 were kept in hospital for further observation.', 'Six cases (Case 3, 8, 13, 16, 19 and 23) had nucleic acid tests reversed to positive after one negative result.', 'Of particular concern, Case18 showed positive again even after the continuous negative of nucleic acid tests.', 'Five cases (Case 7, 9, 11, 14 and 24) had the virus cleared within a short time.', 'The communicable period, defined as the interval from the first day of positive nucleic acid tests to the first day of continuous negative tests, ranged from 1 to 21 days (median: 9.5 days, IQR, All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.02.20.20025619 doi: medRxiv preprint 9 3.5-13.0 days, Figure S4 , Table S1 ).', 'Due to the censored data of 6 cases and the indeterminate date of the exact first infection, the communicable period was underestimated.']}\n", - "{'sentences': ['Let’s take inventory on the therapies that are being developed for the coronavirus epidemic.', 'Here is a very thorough list of at Biocentury, and I should note that (like Stat and several other organizations) they’re making all their Covid-19 content free to all readers during this crisis.', 'I’d like to zoom in today on the potential small-molecule therapies, since some of these have the most immediate prospects for use in the real world.', 'The ones at the front of the line are repurposed drugs that are already approved for human use, for a lot of obvious reasons.', 'The Biocentury list doesn’t cover these, but here’s an article at Nature Biotechnology that goes into detail.', 'Clinical trials are a huge time sink – they sort of have to be, in most cases, if they’re going to be any good – and if you’ve already done all that stuff it’s a huge leg up, even if the drug itself is not exactly a perfect fit for the disease.', 'So what do we have?', 'The compound that is most advanced is probably remdesivir from Gilead, at right.', 'This has been in development for a few years as an RNA virus therapy – it was originally developed for Ebola, and has been tried out against a whole list of single-strand RNA viruses.', 'That includes the related coronaviruses SARS and MERS, so Covid-19 was an obvious fit.', 'The compound is a prodrug – that phosphoramide gets cleaved off completely, leaving the active 5-OH compound GS-44-1524.', 'It mechanism of action is to get incorporated into viral RNA, since it’s taken up by RNA polymerase and it largely seems to evade proofreading.', 'This causes RNA termination trouble later on, since that alpha-nitrile C-nucleoside is not exactly what the virus is expecting in its genome at that point, and thus viral replication is inhibited.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['This study conclusively demonstrates that genome-wide codon usage bias in SARS-CoV-2 coding sequences are similar to what was found in most studied RNA viruses.', 'However, mutation pressure is not the main force acting to shape the CUB in SARS-CoV-2, in contrast to what was observed in other RNA viruses (e.g. Hepatitis A virus and Influenza A virus).', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.01.019463 doi: bioRxiv preprint either A or U end nucleotides with the absence of G and C ones.', 'Furthermore, some genes such as Nucleocapsid phosphoprotein, ORF7a protein, and Surface glycoprotein had slightly high CAI values which may indicate for selection force acting on their codon usage, as they play important roles in viral assembly and may help viruses avoid the host immune system.', 'Overall, there was no significant differences in the patterns of codon usage bias between the tested 13 SARS-CoV-2 isolates from different geo-locations, except for the isolate from Pakistan that might be slightly different, reflecting small evolutionary changes between them.', 'The findings of the present study may help in understanding the underlying factors involved in the evolution of SARS-CoV-2 viruses and the interactions with their host.', 'Also, it may aid in vaccine design strategies.', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.01.019463 doi: bioRxiv preprint Table 1:', 'The table shows the average ENc and CAI values for the 13 SARS-CoV-2 isolates.', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.01.019463 doi: bioRxiv preprint Table2: RSCU values for all the 13 isolates in each country, and the RSCU > 1.6 are marked.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'Figure 3 .', 'Cluster analysis (Heat map) of RSCU values in 13 SARS-CoV-2 isolates coding regions.', 'The heat map represents the RSCU values divided into 3 ranges; <1 (Green color), 1-1.6 (Dark red), and >1.6 (Distinct red).', 'Euclidean distance and complete-linkage methods were used to produce the clusters.']}\n", - "{'sentences': ['Question What are the risk factors for severe patients with corona virus disease 2019 ?', 'Findings First in this review and meta-analysis, we found that elderly male patients with a high body mass index, high breathing rate and a combination of underlying diseases were more likely to develop into critically ill patients.', 'second, compared with ordinary patients, severe patients had more significant symptom such as fever and dyspnea.', 'Last, we also found that the laboratory test results of severe patients had more abnormal than non-severe patients.', 'Meaning This review summaried the risk factors of severe COVID-19 patients and aim to provide a basis for early identification of severe patients by clinicians.', 'Importance: With the increasing number of infections for COVID-19, the global health resources are deficient.', \"At present, we don't have specific medicines or vaccines against novel coronavirus pneumonia (NCP) and our assessment of risk factors for patients with severe pneumonia was limited.\", 'In order to maximize the use of limited medical resources, we should distinguish between mild and severe patients as early as possible.', 'Objective: To systematically review the evidence of risk factors for severe corona virus disease 2019 (COVID-19) patients.', 'We conducted a comprehensive search for primary literature in All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', ': medRxiv preprint both Chinese and English electronic bibliographic data bases including China National Knowledge Infrastructure (CNKI), Wanfang, Weipu, Chinese Biomedicine Literature Database (CBM-SinoMed), MEDLINE (via PubMed), EMBASE, Cochrane Central Register, and Web of science.', 'The American agency for health research and quality (agency for health research and quality', 'Results: 20 articles (N=4062 participants) were eligible for this systematic review and meta-analysis.', 'First in this review and meta-analysis, we found that elderly male patients with a high body mass index, high breathing rate and a combination of underlying diseases (such as hypertension, diabetes, cardiovascular disease, and chronic obstructive pulmonary disease) were more likely to develop into critically ill patients.', 'second, compared with ordinary patients, severe patients had more significant symptom such as fever and dyspnea.', 'Besides, the laboratory test results of severe patients had more abnormal than non-severe patients, such as the elevated levels of white-cell counts, liver enzymes, lactate dehydrogenase, creatine kinase, c-reactive protein and procalcitonin, etc, while the decreased levels of lymphocytes and albumin, etc.', 'Interpretation: This is the first systematic review investigating the risk factors for severe corona virus disease 2019 (COVID-19']}\n", - "{'sentences': ['No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial']}\n", - "{'sentences': ['Common laboratory abnormalities in COVID-19 patients include decreased white blood cell, lymphocyte, and platelet counts, and an increased LDH, CK, and CRP levels 7,8,9,10,11.', 'Suspected cytokine storms and a series of immune responses induced by SARS-CoV-2 have also been suggested 11.', 'Our data echoed the same findings of lymphopenia and elevated LDH levels during the second week after symptom onset.', 'Major complications, including arrhythmias, shock, ARDS, and multiple organ failure were not present.', 'Less than half of patients (40%) required low-flow oxygen therapy, and none of the patients needed invasive ventilation or extracorporeal membrane oxygenation.', 'In this cohort, no patients were admitted to the ICU or died; 50% were discharged, and 50% remained hospitalized.', 'For those who were discharged (n = 5), the median hospital stay was 20 days (IQR:19-21).', 'We believe that early diagnosis and adequate supportive treatment may have positive effects on stabilizing the patients.', 'Noticeably, the median duration from Macau arrival to admission was only 3 days, that early detection of imported cases may be contributed to the effective quarantine policy organized by the Macau government, and may minimize the spread of local outbreak in Macau as no new diagnosed cases from February 4th to 27th,2020 1.', 'About 75% of cases of COVID-19 have been reported with bilateral pneumonia 11, while bilateral pneumonia was noted in 80% of our cases.', 'The primary findings in CT images of COVID-19 patients were as follow 7,12 : ground glass opacities (GGO', 'Currently, there is no medications for COVID-19 approved by FDA.', 'Antiviral therapies such as ritonavir and lopinavir, with or without ribavirin, have shown some success in the treatment of SARS 14, and an early report suggests that it might have similar efficacy in the treatment of COVID-19 15.', 'Meanwhile, phase III trials of remdesivir, ritonavir and lopinavir had been initiated 16.', 'In this cohort, all our patients received lopinavir/ritonavir.', 'Although it is impossible to draw any conclusion of its efficacy before having the results from the trials, the side effects were well tolerated to all patients and the empirical use may be justified under the circumstances of epidemic.', 'Although the use of corticosteroids is controversial 17, three patients had received methylprednisolone for a short duration due to clinical and radiological exacerbations.', 'We believe that this is still advisable for patients who have severe illness, based on the hypothesis of reducing cytokine storm and inflammation-mediated lung injury.', 'The settlement of this debate still requires further high-quality studies to justify or against the use of corticosteroids, and also to determine the optimal timing, dosage and duration of administration.', 'NPS remains a mainstay sampling method for diagnosing SARS-CoV-2 infections; it is especially supported by recent data on SARS-CoV-2 viral loads in upper respiratory specimens with higher viral loads detected in the nasal area than in the throat 18.', 'Of our cases, 90% were diagnosed by RNA signals in NPS specimens.', 'Interestingly, patient 5 was diagnosed via the detection of viral RNA in sputum after one negative and one inconclusive result from NPS specimens.', 'All five NPS specimens taken six days after symptom onset remained negative or inconclusive by qRT-PCR in patient 5.', 'In contrast, fecal samples were subsequently collected and virus RNA were detectable in 90% of our patients from their first sample by qRT-PCR.', 'In addition, in patient 1, SARS-CoV-2 RNA was detected in feces till 14 days after the onset of symptoms.', 'This echoes the result from the first case in the U.S. that featured positive virus RNA in the stool 9, but is in contrast to a case series reported by Chan et al\\n8.', 'A recent study has shown that cell receptor angiotensin converting enzyme II was also expressed in absorptive enterocytes in the ileum and colon 19.', 'Based on our data on viral shedding in stool and the possibility of a lag in viral detection in NPS specimens, it is not unreasonable to perform additional testing of both stool and respiratory specimens to enhance the detection sensitivity and minimize the \"escape\" of infected individuals.', 'Although virus RNA shedding in feces was common in our patients, the question of whether it is a potential transmission route of SARS-CoV-2 deserves further evaluation since the viability of SAR-CoV-2 in feces is uncertain.', 'Thus, we advocate that we should consider a combined assessment of both fecal and respiratory specimens for all patients during hospitalization.', 'Furthermore, it is worth questioning the current discharge policy which is based on the clinical, radiological condition and twice negative results from qRT-PCR in respiratory specimens 5.', 'Our data suggested some patients may have the delay of virus RNA conversion in the stool sample.', 'Patients with negative NPS and positive stool samples may be undergoing the convalescent phase and their infectivity during this phase remained unknown.', 'We believed that the discharge of those patients should require additional considerations.', 'For example, transferring those with low medical demands from hospital to another isolation facilities or extending the isolation period at home with strict infection control and follow-up may be considered before more data available against this transmission route, especially when healthcare resource is in scarcity during the outbreak.', 'Notably, some recovered patients were reported to have virus RNA reappeared in respiratory samples after discharge 20.', 'We believed that false-negative RT-PCR test results, virus RNA residues or/and re-activation may be contributed to this phenomenon.', 'Whether these patients are contagious or not, we should take a more cautious approach unless proven otherwise.', 'Serial qRT-PCR tests and home isolation for discharged patients could provide a safety net to block the potential transmission.', 'In our cohort, 70% of cases were imported that it was difficult to follow their conditions when they returned home in Mainland China, but they were advised to be followed in local medical institutions.', 'A report suggested that 10% of patients present with diarrhea and nausea initially 7.', 'Another study of 1099 patients in China found that nausea or vomiting (5.0%) and diarrhea (3.8%) were uncommon 21.', 'While our data was contrary to these reports that diarrhea (80%) and nausea (50%) were more common in this cohort.', 'The exact reason for these discrepancies has not been identified yet.', \"However, given the fact that virus RNA was found in all our patients' stool specimens and they had fewer respiratory symptoms with none of them using mechanical ventilation, there may be two different subtypes of COVID-19 manifestations as “gut-tropism” and “lung-tropism” speculatively.\", 'However, the impact of other confounding factors such as side effects of antiviral or antibiotics may need to be considered.', 'Further studies on the impact of individual genetic variability in response to the virus may reveal a clearer picture of this issue.', 'During the SARS outbreak, a report stated that three hospital cleaners were infected by possible fomite transmissions without direct patient contact 22.', 'Under these circumstances, measures including strict precautions, adequate protective devices, and infection control training should be implemented for all hospital workers, especially assistants and cleaners who handle the excreta of these patients and toilet disinfection.', 'Moreover, public education on toilet hygiene, such as closing the toilet lid before flushing, avoiding low water levels of sewage U-traps, and reiterating the importance of hand hygiene, may minimize the risk of community outbreaks 23.', 'Adequate infection control training for all medical staff and provision of personal protection equipment such as masks, face shields, goggles, and protective clothes are recommended by the WHO 24.', 'Nevertheless, the Macau Health Bureau played a crucial role in coordinating all parties to ensure sufficient logistic support that achieved most of the recommendations from WHO during the outbreak of SARS-CoV-2.', 'Although C.H.C.S.J is the only hospital designated for COVID-19 patients in Macau, no in-hospital transmission has been noted so far.', 'This study has several limitations.', 'First, the number of patients in this study was relatively small and as such, it is hard to draw a definite conclusion.', \"Second, evaluation of viremia from patient's serum was not available in this study.\", 'Third, virus isolation from different specimens was not performed.', \"Hence, it was impossible to determine whether RNA shedding in specimens correlated to the virus's viability.\", 'Finally, half of the enrolled patients are still hospitalized at the time of the submission of this paper.', 'Therefore, there may have been bias regarding the prognosis of the patients.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Therapeutic effects of dipyridamole on COVID-19 patients with coagulation dysfunction', 'The human coronavirus HCoV-19 infection can cause acute respiratory distress syndrome 47 (ARDS), hypercoagulability, hypertension, extrapulmonary multiorgan dysfunction.', 'Effective 48 antiviral and anti-coagulation agents with safe clinical profiles are urgently needed to improve the 49 overall prognosis.', 'We screened an FDA approved drug library and found that an anticoagulant agent 50 dipyridamole (DIP) suppressed HCoV-19 replication at an EC50 of 100 nM in vitro.', 'It also elicited 51 potent type I interferon responses and ameliorated lung pathology in a viral pneumonia model.', 'In 52 analysis of twelve HCoV-19 infected patients with prophylactic anti-coagulation therapy, we found 53 that DIP supplementation was associated with significantly increased platelet and lymphocyte counts 54 and decreased D-dimer levels in comparison to control patients.', 'Two weeks after initiation of DIP 55 treatment, 3 of the 6 severe cases (60%) and all 4 of the mild cases (100%) were discharged from the 56 hospital.', 'One critically ill patient with extremely high levels of D-dimer and lymphopenia at the time 57 of receiving DIP passed away.', 'All other patients were in clinical remission.', 'In summary, HCoV-19 58 infected patients could potentially benefit from DIP adjunctive therapy by reducing viral replication, 59 suppressing hypercoagulability and enhancing immune recovery.', 'Larger scale clinical trials of DIP']}\n", - "{'sentences': ['Dose prediction of lopinavir/ritonavir for 2019-novel coronavirus (2019-nCoV', 'At present, lopinavir/ritonavir is widely used for possible treatment of 2019-nCoV infection in countries that the emerging infection exists.', 'Here, the authors used a mathematical modelling theoretical approach to predict the expectedproper dosage of lopinavir/ritonavir for possible treatment of 2019-nCoV infection.', 'The protocol for mathematical modeling in this work is the same as previous report by Wiwanitkit et al[5].', 'Briefly, the primary agreement was there had to be a specific amount of required energy for reaction between lopinavir/ritonavir and its target enzyme and this energy is a specific constant for the reaction.', 'Based on bonding theory, the required amount of lopinavir/ritonavir was varied to the two substrates, lopinavir/ritonavir and target, protease.', 'Here, the simple equation ‘A + B ?', 'C where A was the target enzyme, B was lopinavir/ritonavir and C was end product’ could be written.']}\n", - "{'sentences': ['Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial']}\n", - "{'sentences': ['The New Coronavirus Pneumonia (NCP, also named as COVID-19 by WHO on Feb 11 2020, is now causing a severe public health emergency in China since.', 'The number of diagnosed cases is more than 40,000 until the submission of this manuscript.', 'Coronavirus has caused several epidemic situations world widely, but the present contagious disease caused by 2019 new Coronavirus is unprecedentedly fulminating.', 'The published cohorts of 2019 new Coronavirus (n-Cov) are single-center studies, or retrospective studies.', 'We here share the therapeutic experiences of NCP treatment with literature review.', \"Combination of Ribavirin and Interferon-α is recommended by the 5(th) edition National Health Commission's Regimen (review.\", \"Combination of Ribavirin and Interferon-α is recommended by the 5(th) edition National Health Commission's Regimen) because of the effect on MERS (Middle East Respiratory Syndrome), and the effectiveness of Lopinavir/Ritonavir and Remdisivir needs to be confirmed by randomized controlled trial (RCT), given the situation of no specific antivirus drug on NCP is unavailable.\", \"Systemic glucocorticosteroid is recommended as a short term use (1~2 mg.kg(-1).d(-1), 3~5d ) by the 5(th) edition National Health Commission's Regimen (review.\", \"Combination of Ribavirin and Interferon-α is recommended by the 5(th) edition National Health Commission's Regimen\"]}\n", - "{'sentences': ['INTRODUCTION: The role of laboratory parameters in screening of COVID-19 cases has not been definitely established.', 'This study aimed to evaluate the accuracy of laboratory parameters in predicting cases with positive RT-PCR for COVID-19.', 'METHODS: This diagnostic accuracy study was conducted on suspected COVID-19 patients, who presented to Behpooyan Clinic Medical center in Tehran (Iran) from 22 February to 14 March, 2020.', 'Patients were divided into two groups based on the results of real time reverse transcriptase‐polymerase chain reaction (RT-PCR) for COVID-19, and the accuracy of different laboratory parameters in predicting cases with positive RT-PCR was evaluated using area under the ROC curve (AUC).', 'RESULTS: Two hundred cases with the mean age of 41.3± 14.6 (range: 19-78) years were studied (0.53% male).', 'The result of RT-PCR for COVID-19 was positive in 70 (35%) cases.', 'Patients with positive RT-PCR had significantly higher neutrophil (NEU) count (0.0001) and serum albumin level), and C-reactive protein (CRP) (p = 0.04), lactate dehydrogenase (LDH) (0.0001) and serum albumin level), aspartate aminotransferase (AST) (= 0.0001), aspartate aminotransferase (AST)), alanine aminotransferase (ALT) (0.0001) and serum albumin level), and Urea (= 0.0001), aspartate aminotransferase (AST)) levels in serum.', 'In addition, patients with positive RT-PCR had lower white blood cell (WBC) count (0.0001) and serum albumin level) and serum albumin level (0.0001) and serum albumin level) compared to others.', 'ALT (AUC = 0.879), CRP (AUC = 0.870), NEU (AUC = 0.858), LDH (AUCAUC = 0.835), and Urea (AUCAUC = 0.835) had very good accuracy in predicting cases with positive RT-PCR for COVID-19, respectively.', 'CONCLUSION: Our findings suggest that level of LDH, CRP, ALT and NEU']}\n", - "{'sentences': [\"[{'text': 'The spread of the novel coronavirus (SARS-CoV-2) has triggered a global emergency, that demands urgent solutions for detection and therapy to prevent escalating health, social and economic impacts.\", 'The spike protein (S) of this virus enables binding to the human receptor ACE2, and hence presents a prime target for vaccines preventing viral entry into host cells 1 .', 'The S proteins from SARS-CoV-1 and SARS-CoV-2 are similar 2 , but structural differences in the receptor binding domain (RBD) preclude the use of SARS-CoV-1-specific neutralizing antibodies to inhibit SARS-CoV-2 3 .', 'Here we used comparative pangenomic analysis of all sequenced Betacoronaviruses to reveal that, among all core gene clusters present in these viruses, the envelope protein E shows a variant shared by SARS and SARS-Cov2 with two completely-conserved key functional features, an ion-channel and a PDZ-binding Motif (PBM).', 'These features trigger a cytokine storm that activates the inflammasome, leading to increased edema in lungs causing the acute respiratory distress syndrome (ARDS) 4-6 , the leading cause of death in SARS-CoV-1 and SARS-CoV-2 infection 7,8 .', 'However, three drugs approved for human use may inhibit SARS-CoV-1 and SARS-CoV-2 Protein E, either acting upon the ion channel (Amantadine and Hexamethylene amiloride 9,10 ) or the PBM (SB203580 5 ), thereby potentially increasing the survival of the host, as already demonstrated for SARS-CoV-1in animal models.', 'Hence, blocking the SARS protein E inhibits development of ARDS', 'Therapies to combat the spread of SARS-CoV-2 and the lethality caused by the resulting COVID-2019 are currently focusing primarily on S, the viral spike protein 3,25,26 .', 'However, despite high similarities between proteins S between SARS-CoV-1 and SARS-CoV-2 viruses, existing neutralizing antibodies are ineffective against SARS-CoV-2 3 .', 'Hence, new antibodies that bind specifically to the SARS-CoV-2 spike protein need to be developed, tested and approved for human use, which would be a time-consuming process.', 'Our pangenomic analysis suggests that the protein E of all SARS viruses preserves its critical motifs used for pathogenesis.', 'Hence, we predict that the readily available and approved inhibitors (Amantadine, Hexamethylene amiloride and SB203580), that proved efficient for alleviating ARDS in SARS-CoV-1-infected animal models should also be effective against SARS-CoV-2.', 'While not preventing future spreading of the virus, these inhibitors might reduce the mortality rate while effective vaccines are being developed.', 'We used a pangenome approach to explore the genome of SARS-CoV-2 (MN985325 and related isolates) in comparison to other Betacornaviruses, including SARS and MERS.', 'Previous approaches 11 proceeded by extracting individual genes, aligning them, and then establishing a phylogeny.', 'Our approach differs in that we first cluster all sequences to then calculate the alignment.', 'This approach, based on using panX 12 , allows us to achieve a higher sensibility in the detection of gene clusters.', 'The resulting pangenome including all core and accessory gene clusters, interactive trees and alignments from 24 Betacoronavirus genomes, including 4 isolates from SARS-CoV-2, is available at https://pangenomedb.cbrc.kaust.edu.sa/.', 'There are five essential genes in coronaviruses, the Spike protein (S), Membrane glycoprotein (M), Nucleocapsid (N), envelope protein (E) and the Orf1ab (a large polyprotein known as replicase/protease), all required to produce a structurally complete viral particle 13 .', 'These five genes define the core pan-genome.', 'However, panX 12 only retrieved four of these (S, M, N and the ORF1ab) as components of the core pan-genome ( Figure 1 ).', 'However, the fifth gene in the Betacoronavirus core genome, the envelope protein (E), varied among genomes, defining three distinct subclusters within the envelope protein E of Betacoronaviruses ( Figure 2 ).', 'One of these E clusters comprises only SARS-CoV-1 (AY274119), SARS-CoV-2 and two Bat Coronaviruses (MG772933 and KF63652).', 'Among the other two protein E gene clusters, one includes MERS (JX869059 and KC164505) and several coronaviruses from different animals, while the third cluster includes coronaviruses from two Rousettus bats.', \"To validate the conservation and specificity of the SARS E cluster, we compared the SARS-CoV-2 E sequence with all known sequences in NCBI's non redundant (NR) protein database.\", 'This comparison showed, consistent with our pan-genome analysis, that the subcluster of the protein E gene appearing in SARS-CoV-2, SARS and two bat coronaviruses, is defined by the same essential functional features, which are exactly conserved (100% similarity) between bats and SARS-CoV-2, but differ slightly (95% similarity with one deletion and three substitutions) from SARS ( Figure 2B and supplementary figure 7) .', 'A recent study compared genomes and gene families of all alpha, beta, delta and gamma coronaviruses, but did not explore the variability present within the protein E', 'We found five accessory gene clusters (15% of the accessory genome of genus Betacoronavirus) common to SARS-like coronaviruses, including SARS-CoV-2, out of 33 total accessory gene clusters.', 'Four of these gene clusters (ORF3a, ORF6, ORF7a, and ORF8, Fig. 1A ), appear only in SARS-CoV-2, bat-SL-CoVZC45 and the SARS virus.', 'A gene cluster annotated as ORF10 appeared to be unique to SARS-CoV-2 ( Fig. 1) .', \"However, a blast-based search against the DNA of all sequences in NCBI's NT database showed that the ORF10 sequence matches with 100% coverage in DNA of other SARS-like genomes, but there is no open-reading frame predicted for those genomes in the matching region ( Fig 1A) .\", 'Hence, the apparent uniqueness of ORF10 might simply be an artifact of the GeneBank annotation pipeline that did not predict an ORF for this gene in other matching genomes.', 'However, for completeness, we report a functional analysis of ORF10 as Supplementary material (Supplementary material 1) since at present there is no experimental evidence available against or in favor of this being a real gene.', 'Compared to the essential genes S, M, N, E and ORF1ab, other genes such as ORF3a and ORF7a are poorly characterized, according to GenBank annotations (https://www.ncbi.nlm.nih.gov/genome/proteins/86693?genome_assembly_id=760344).', 'Our bioinformatic protein structural analysis confirmed that SARS-CoV-2 ORF3a (cluster 12), also known as viroporin, and ORF7a (cluster 12), also known as viroporin, and ORF7a', 'The remaining two accessory gene clusters, ORF6, ORF8, present in SARS-CoV-2, SARS and bat-SL-CoVZC45 are functionally uncharacterized.', 'All are very short polypeptides (61, 121 and 38 residues for ORF6 and 8, respectively) with a large percentage of hydrophobic residues (62%, 56%, respectively).', 'None of the proteins have trans-membrane regions, but ORF8 has an N-terminal sec-pathway signal peptide with a cleavage site after residues 15, suggesting that it is secreted into the extracellular space ( Supplementary Figures 5,6 ).', 'Following signal peptide cleavage, the ORF8 protein core is predicted to consist largely of b-strands and features 7 cysteines.', 'We predict that this protein adopts a cysteine disulfide-bond stabilized b-sandwich structure similar to the soluble domain of ORF7a (Supplementary Figures 5,6 ), inferring that ORF8 also functions as ligand binding module.', 'ORF6 consists of a long amphipathic helical region, followed by an acidic tail.', 'Our deep-learning-based annotation (DeepGOPlus 18 ) suggested that ORFs 6, 7, 8 are involved in the regulation of molecular functions, either in response to stimuli (ORFs 8), or in cellular component biogenesis and organization (ORF6) (Suppl.', 'Figure 2-4) .', 'Collectively, our analysis suggested no major function or gene cluster to be unique to SARS-CoV-2.', 'Moreover, our analysis is in agreement with ORFs 3a, 6, 7a, 8 and The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.02.17.952895 doi: bioRxiv preprint being accessory non-essential proteins, that would be inefficient targets for COVID-2019 therapy.', 'The S protein binds to the host receptor ACE2, and hence presents a prime target for preventing viral entry into host cells 1 .', 'The S proteins from SARS-CoV-1 and SARS-CoV-2 are similar 2 , but structural differences in the receptor binding domain (RBD', 'The SARS-Cov-1 protein E has ion channel (IC) activity and features a postsynaptic density-95/discs large/zona occludens-1 (PDZ)-binding motif (PBM).', 'Both IC and PBM were required for SARS-CoV to induce virulence in mice 14 .', 'The protein E from SARS-CoV-2 differs from that of SARS-CoV-1 only by three substitutions and one deletion (Figure 2A Studies on SARS-CoV-1 demonstrated that the E protein uses the IC and PBM to trigger a cytokine storm that activates the inflammasome, leading to increased edema in lungs.', 'Ultimately these events result in ARDS 4-6 , a leading cause of death in SARS-CoV-1 and SARS-CoV-2 infection 7, 8 .', 'However, the drugs Amantadine, Hexamethylene amiloride and also BIT225 (BIT225 is in clinical trials) completely block the IC activity of SARS-CoV-1 9,10 and restrict its reproduction, leading to better survival of the animal host.', 'The high level of conservation of the IC and PBM within clade 2, including SARS-CoV-1 and SARS-CoV-2, strongly suggests that the available inhibitors for the E protein of SARS-CoV-1 should also be active on SARS-CoV-2.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Objective: To analyze the clinical characteristics of patients with novel coronavirus pneumonia in Kunming City, and to study the correlation between nutritional status and immune function.', \"Methods: Clinical data of 36 patients with novel coronavirus pneumonia in isolation area of Kunming Third People's Hospital from January 31 to February 15, 2020 were collected, and the basic situation, clinical characteristics, laboratory examination and CT imaging characteristics were analyzed.\", 'Serum albumin (ALB), prealbumin (PAB), hypersensitive c-reactive protein (hs-crp', '(1) The patients with new coronavirus pneumonia in Kunming were mainly of common type.', \"(2) 50% of the patients' first symptoms were fever and cough; (3) The total number of white blood cells in peripheral blood was normal or decreased in 23 cases (79%), and the lymphocyte count decreased in 5 cases (13.89%), without anemia.\", 'Hypersensitive c-reactive protein increased in 19 (52.78%) cases, and procalcitonin increased in 1 case.', 'Albumin decreased in 5 cases (13.89%), proalbumin decreased in 15 cases (41.67%), alanine transaminase increased slightly in 4 cases (11.11%), alanine transaminase increased slightly in 4 cases), alanine transaminase increased slightly in 4 cases (11.11%), alanine transaminase increased slightly in 4 cases', 'group were significantly lower than those in the normal control group, and the hypersensitive c-reactive protein was higher than that in the normal control group.', '(5) The levels of PAB in the serum of the patients were linearly correlated with hs-crp, CD3 T cells, CD4 T cells and CD8 T cells, and the correlation coefficients were -0.474, 0.558, 0.467 and 0.613, respectively, showing statistical differences.', 'Conclusion: The clinical characteristics of the novel coronavirus pneumonia in Kunming are different from those in Wuhan.', 'The changes of serum proalbumin and T cell subsets are relatively obvious.', 'Changes in serum proalbumin may contribute to the early warning of novel coronavirus pneumonia.', 'The nutritional status of patients with common and mild pneumonia should be considered.']}\n", - "{'sentences': ['New therapeutic opportunities for COVID-19 patients with Tocilizumab: Possible correlation of interleukin-6 receptor inhibitors with osteonecrosis of the jaws']}\n", - "{'sentences': ['Vascular leak is a key driver of organ injury in diseases such as Acute Respiratory Distress Syndrome caused by viruses, including COVID-19.', 'Strategies that reduce enhanced permeability and vascular inflammation are promising therapeutic targets.', 'Activation of the Angiopoietin-1 (Angpt1)-Tie2 tyrosine kinase signaling pathway is an important regulator of vascular quiescence.', 'Here we describe the design and construction of a new soluble ANGPT1 mimetic that is a potent activator of endothelial Tie2 in vitro and in vivo.', 'Using a chimeric fusion strategy, we replaced the extracellular matrix (ECM) binding and oligomerization domain of ANGPT1 with a heptameric scaffold derived from the C-terminus of serum complement protein C4-binding protein α (C4BP', 'All rights reserved.', 'No reuse allowed without permission.', 'In summary, we designed and constructed a new C4BP-ANG1 fusion as a new candidate ANGPT1 mimetic therapy.', 'The fusion displays remarkable stability with high multimericity that can potently activate Tie2 and is suitable for systemic administration.', 'Furthermore, the study validated a general strategy to use a C4BP scaffold in drug design when high degree of oligomeric states is desired.', 'Here we sought to develop a \"bio-better\" analog of ANGPT1 as pharmaceutical candidate using a rational recombinant engineering design.', 'Our overall strategy was to overcome a key therapeutic limitation of native ANGPT1, which is nonspecific sequestration by the ECM and easy to aggregate, while still to preserve a high degree of oligomerization.', 'We chose a protein scaffold segment from C4BP, an abundant serum complement protein complex, which is characterized by seven functional polypeptide chains extending from an intertwined scaffold (28) .', 'We constructed several variants of C4BP-ANG1 fusion proteins and showed all formed stable heptamers when expressed in HEK293 and CHO cells.', 'Intradermal, intravenous, intraperitoneal and intravitreal injections of mice and rabbits all showed longlasting activity and protection from a variety types of inflammatory vascular leak.', 'In recent years, there have been major advances in drug development that specifically target the Angpt-Tie pathway.', 'Strategies include ANGPT1 mimetics, ANGPT2 neutralizing antibodies, bi-specific, doubletargeting antiangiogenic antibodies or affinity traps linking ANGPT2 with VEGF, or similarly, ANGPT2 with Tie2, and small molecule inhibitors of VEPTP or Tie2 catalytic activities, among others (2) .', 'With the exception of Tie2 kinase inhibitors, all these therapies are designed to elevate the activity and function of Tie2 to promote vascular stabilization and reduce vascular response to inflammatory signals.', 'Theoretically, these activities should counteract VEGF-induced neovascularization and inflammatory leakage that is characteristic of many human diseases.', 'Many clinical studies have demonstrated an association between elevated expression of circulating ANGPT2 and poor clinical outcome in diseases characterized by vascular leakage and tissue damage (2, 29) .', 'While it remains unclear if these elevated levels of ANGPT2 antagonizing Tie2 activity during inflammation are causal, agonistic ANGPT1 mimetic treatment with C4BP-ANG1 is predicted to ameliorate vascular destabilization that occurs in severe infectious conditions such as pneumonia from flu or coronavirus.', 'Indeed, several clinical studies confirm that the ratio of circulating ANGPT1/ANGPT2 is predictive of patient outcome (30, 31) .', 'Prior to this study, ANGPT1-mimetic therapies have been designed and tried where the N-terminus domains of the ANGPT1 analogs have been removed and replaced with less \"sticky\" structures.', 'These strategies include BowAng1, which contains a dimerization Fc domain and a tandem arrangement of the FLD, achieving a multimericity of 2x2=4.', 'A second strategy fused the FLD of ANGPT1 to the short coiled-coil domain of cartilage oligomeric matrix protein (COMP']}\n", - "{'sentences': ['There is an emergent need to search for possible medications.', 'Method: Utilization of the available sequence information, homology modeling, and in slico docking a number of available medications might prove to be effective in inhibiting the COVID-19 two main drug targets the spike glycoprotein and the 3CL protease.', 'Results: Several compounds were determined from the in silico docking models that might prove to be effective inhibitor for the COVID-19.', 'Several antiviral medications: Zanamivir, Indinavir, Saquinavir, and Remdesivir show potential as and 3CL PRO main proteinase inhibitors and as a treatment of COVID-19.', 'Conclusion: Zanamivir, Indinavir, Saquinavir, and Remdesivir are among the exciting hits on the 3CL PRO main proteinase.', 'It is also exciting to uncover that Flavin Adenine Dinucleotide (FAD', 'The COVID-19 has now been declared a global emergency by the World Health Organization.']}\n", - "{'sentences': ['Since 2002, beta coronaviruses (CoV) have caused three zoonotic outbreaks, SARS-CoV in 2002, MERS-CoV in 2012, and the recent outbreak of SARS-CoV-2 late in 2019 (also named as COVID-19 or novel coronavirus 2019 or nCoV2019.', 'Spike(S) protein, one of the structural proteins of this virus plays key role in receptor (ACE2) binding and thus virus entry.', 'Thus, this protein has attracted scientists for detailed study and therapeutic targeting.', 'As the 2019 novel coronavirus takes its course throughout the world, more and more sequence analyses are been done and genome sequences getting deposited in various databases.', 'From India two clinical isolates have been sequenced and the full genome deposited in GenBank.', 'We have performed sequence analyses of the spike protein of the Indian isolates and compared with that of the Wuhan, China (where the outbreak was first reported).', 'While all the sequences of Wuhan isolates are identical, we found point mutations in the Indian isolates.', 'Out of the two isolates one was found to harbour a mutation in its Receptor binding domain (RBD', 'replaced by isoleucine (a hydrophobic amino acid that is also a C-beta branched amino acid).', 'This mutation has been seen to change the secondary structure of the protein at that region and this can potentially alter receptor ding of the virus.', 'Although this finding needs further validation and more sequencing, the information might be useful in rational drug designing and vaccine engineering.', 'All rights reserved.', 'No reuse allowed without permission.', 'For the isolate 166 of India, we found a different mutation at position 930 of the spike protein ( Figure 2C) .', 'Here there was a substitution of A (alanine) to V (valine) at position 930 (A930V).', 'Since both the amino acids are hydrophobic in nature, any change that might occur due to this mutation might get masked upon tertiary structure formation A B', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.07.029132 doi: bioRxiv preprint and thus not imposing a functional change in the protein i.e. a conservative mutation.', 'Despite this possibility, valine has some unique characteristics.', 'Valine is one of the Cbeta branched amino acids like threonine and isoleucine.', 'C beta branched amino acids are bulkier towards the main chain and it is difficult for them to attain alpha helical conformations.', 'Such amino acids have restricted conformations, are destabilizing in nature causing distortion in local helix backbone [9] .', 'S protein if SARS-CoV2 has two domains: S1 and S2 [8] .', 'While S1 has the RBD and in involved in receptor binding, knowledge about progression of infection and disease severities will help correlating the significance of these mutation with respect to virus evolution and virulence.', 'Such information will further help in strategic designing of drug targets.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.07.029132 doi: bioRxiv preprint Figure 4A : Secondary structure prediction of spike protein of Wuhan isolate.', 'The area marked in red box has helix (H', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.07.029132 doi: bioRxiv preprint Figure 4B : Secondary structure prediction of spike protein of Indian isolate 29.', 'The area marked in red box that had helix (H', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.07.029132 doi: bioRxiv preprint', 'SARS-CoV-2 sequence data is expanding rapidly in the databases as the virus spreads worldwide.', 'Although many sequences from various countries have been deposited, limited full genome sequences are available from most of the countries.', 'This virus has infected people in various countries like China, Italy, Spain, USA, Germany, France, United Kingdom, India and many more and the data gets updated almost regularly by the World Health Organization (WHO', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.07.029132 doi: bioRxiv preprint', 'To compare the Indian isolates, we aligned the S protein sequences of these isolates with Wuhan isolates and a sequence from Italy.', 'While Wuhan and Italian isolates matched completely, we found few mutations in case of Indian isolates 29 and 166 as shown in Figure 2 .', 'We observed that isolate 29 had two mutations, a deletion mutation where Y (tyrosine) at position 144 was absent as compared to Wuhan and Italian isolates.', 'Due to deletion of the amino acid residues in position 144 in the protein structure there is a change in the beta sheets ( Figure 3 ).', 'This alteration may change the orientation of the molecule and also the stability of the protein itself.', 'Ramachandran plot of this structure show slight shifts of angle in the β sheet configuration.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.07.029132 doi: bioRxiv preprint Tertiary structure analyses showed that there because of the mutation there is an introduction of additional oxygen molecule to the next residue.', 'The protein stability score drops sharply (-4.08) and the thereby its electrostatic force.', 'Such a condition makes the protein flexible and might affect interaction with the receptor.', 'Alteration to the structure will cause shift in the hydrogen bonds and also the bond angle, two main pre-requisite for strong interaction with the receptor.', 'The hydrogen potential tends to increase from 10 to 13.2 in case of mutation.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Background Since December 2019, novel coronavirus (SARS-CoV-2)-infected pneumonia (COVID-19) occurred in Wuhan, and rapidly spread throughout China.', 'This study aimed to clarify the characteristics of patients with refractory COVID-19.', 'Methods In this retrospective single-center study, we included 155 consecutive patients with confirmed COVID-19 in Zhongnan Hospital of Wuhan University from January 1st to February 5th.', 'The cases were divided into general and refractory COVID-19 groups according to the clinical efficacy after hospitalization, and the difference between groups were compared.', 'Results Compared with general COVID-19 patients (45.2%), refractory patients had an older age, male sex, more underlying comorbidities, lower incidence of fever, higher levels of maximum temperature among fever cases, higher incidence of breath shortness and anorexia, severer disease assessment on admission, high levels of neutrophil, aspartate aminotransferase (AST), lactate dehydrogenase (LDH']}\n", - "{'sentences': ['Acetazolamide, Nifedipine and Phosphodiesterase Inhibitors: Rationale for Their Utilization as Adjunctive Countermeasures in the Treatment of Coronavirus Disease 2019 (COVID-19', 'Effective treatments for Coronavirus Disease 2019 (COVID-19) outbreak are urgently needed.', 'While anti-viral approaches and vaccines are being considered immediate countermeasures are unavailable.', 'The aim of this article is to outline a perspective on the pathophysiology of COVID-19 in the context of the currently available clinical data published in the literature.', 'This article appreciates clinical data published on COVID-19 in the context of another respiratory illness - high altitude pulmonary edema (HAPE).', 'Both conditions have significant similarities that portend pathophysiologic trajectories.', 'Following this potential treatment options emerge.', 'Both COVID-19 and HAPE exhibit a decreased ratio of arterial oxygen partial pressure to fractional inspired oxygen with concomitant hypoxia and tachypnea.', 'There also appears to be a tendency for low carbon dioxide levels in both as well.', 'Radiologic findings of ground glass opacities are present in up to 86% of patients with COVID-19 in addition to patchy infiltrates.', 'Patients with HAPE also exhibit patchy infiltrates throughout the pulmonary fields, often in an asymmetric pattern and CT findings reveal increased lung markings and ground glass-like changes as well.', 'Widespread ground-glass opacities are most commonly a manifestation of hydrostatic pulmonary edema.', 'Similarly, elevated fibrinogen levels in both conditions are likely an epiphenomenon of edema formation rather than coagulation activation.', 'Autopsy results of a COVID-19 fatality revealed bilateral diffuse alveolar damage associated with pulmonary edema, pro-inflammatory concentrates, and indications of early-phase acute respiratory distress syndrome (ARDS).', 'HAPE itself is initially caused by an increase in pulmonary capillary pressure and induces altered alveolar-capillary permeability via high pulmonary artery hydrostatic pressures that lead to a protein-rich and mildly hemorrhagic edema.', 'It appears that COVID-19 and HAPE both discretely converge on ARDS.', 'In light of this, a countermeasure that has been shown to be effective in the analogous condition of HAPE is Acetazolamide.', 'Acetazolamide has a myriad of effects on different organ systems, potently reduces hypoxic pulmonary vasoconstriction, improves minute ventilation and expired vital capacity.', 'Other therapeutics to consider that are also directed towards decreased pulmonary pressure include Nifedipine and Phosphodiesterase inhibitors.', 'This review describes COVID-19 in parallel to HAPE.', 'Deranged respiratory parameters that are present in both conditions are highlighted.', 'The utilization of medications found to be effective in HAPE, for the treatment of COVID-19', 'This review describes COVID-19 in parallel to HAPE.', 'Deranged respiratory parameters that are present in both conditions are highlighted.', 'The utilization of medications found to be effective in HAPE for the treatment of COVID-19 is proposed.', 'Given the medical emergency of a growing contagion and the thousands of lives at stake, expedient attempts to improve survival are needed.', 'Acetazolamide, Nifedipine and Phosphodiesterase inhibitors may present an opportunity for countermeasure development.']}\n", - "{'sentences': ['All patients received antiviral treatment.', 'All received Arbidol.', 'Lopinavir/ Ritonavir was administered to in 7 patients alongside with Darunavir/ Cobicistat in 3 patients, and alongside with Oseltamivir in 3 patients.', 'Four patients were given empirical antibiotic treatment, 3 patients were given systematic corticosteroid treatment, and 3 patients were given All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.28.20040097 doi: medRxiv preprint oxygen support via nasal cannula.', 'Five patients were treated with traditional Chinese Medicine (TCM', 'As shown in table 4, none of the patient was ever admitted to intensive care unit (ICU', 'The median MuLBSTA score was 4.5(IQR, 0-5; range from 0 to 5).', 'Here, we report clinical data from ten passengers with laboratory-confirmed COVID-19 after having been on a flight.', 'As far as we know, this is the first reported case series of in-flight transmission of COVID-19.', 'The clinical characteristics of these patients with All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.28.20040097 doi: medRxiv preprint SARS-CoV-2 transmission on aircraft were similar to those without in-flight history, as previously reported [4, 7, 14] .', 'Notably, the symptoms of COVID-19 patients infected in this flight were relatively mild, outcomes were inclined to be better, and the risk to passengers was higher compared with transmission of SARS on aircraft [15-17].', 'The imaging manifestations of these patients with COVID-19 transmission on aircraft were similar to those without in-flight history, as previously reported [12] .', 'Pleural effusion was rarely seen amongst COVID-19 patients [18, 19] .', 'In this case, for the first time we report small volumes of pleural effusion in both lungs in a non-severe patient of COVID-19.', 'Moreover, 9 patients were tested RT-PCR positive at admission while only 5 patients were chest CT scan positive at admission, indicating that RT-PCR has a higher sensitivity than chest CT scans in diagnosing COVID-19 in our study.', 'Patients in our cohort received antiviral treatment, but the types of medicine prescribed varied between patients based on their conditions.', 'All of them received Arbidol.', 'Use of Lopinavir combined with Ritonavia were considered to be beneficial because they had the potential to treat SARS [20] .', 'All the rate of antibiotics, corticosteroid, and TCM use were less than half.', 'TCM was considered to play a crucial role of treating All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.28.20040097 doi: medRxiv preprint COVID-19 patients in China, especially in the early mild period [21] .', 'Some patients were treated with oxygen support of nasal cannula when oxygen saturations were below 93% without oxygen support and recovered.', 'Currently, there is no widely recognized effective drug treatment exists.', 'As, to date, no results of randomized controlled studies on these drugs in COVID-19 patients have been conducted, it was unclear whether their improvement were due to these individual drugs or some combination of them.', 'All ten patients had no risk factors known to be associated with a worse outcome such as comorbidity or advanced age author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the None of the nine flight attendants were symptomatic or tested to be infected although they interacted with the ill passengers during this flight, perhaps largely because of their use of masks.', 'Therefore, we strongly suggest that mask-wearing and hand hygiene should be the imperative All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.28.20040097 doi: medRxiv preprint measures taken by passengers, flight attendants, and pilots.', 'These measures must abide to before boarding, during the flight and after disembarkation while the global pandemic of COVID-19 is occurring.', 'Our study is limited by the retrospective method and sample size.', 'Several issues should be taken into consideration when reading the results.', 'Firstly, we tried to obtain the passenger rosters, their seats assignments, and contact information during this flight from the Scoot airline in Singapore, as well as from the Health Commission and CDC of Hangzhou, but failed.', 'Therefore, we could not confirm that whether the transmission of COVID-19 amongst passengers occurred before boarding (having a feature that patients being randomly distributed throughout the aircraft) or while on board in the aircraft (having a feature that clustered patients were seated in the same row or within two rows in front of or behind index patient).', 'The WHO working definition of a contact on a flight is any passenger seated in the same row of seats or within two seats in front of or behind the index patient, or any flight attendant.', '[30] Secondly, there were two asymptomatic patients reported in our study.', 'We agreed that more asymptomatic carriers might be found out if all the other passengers and crew members were tested with RT-PCR assay for SARS-CoV-2 before they were released from quarantine.', 'It was reported that presymptomatic and symptomatic patients are equally effective in All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.28.20040097 doi: medRxiv preprint spreading COVID-19.', '[3, 31] A possible explanation for this aircraft transmission is there was a presymptomatic or asymptomatic flight attendant who mediated transmission between passengers, although we believe it was less likely as the flight attendants were wearing masks.', 'Thirdly, information about the physical proximity to the index patient were unavailable, therefore we could not quantify the exact risk of in-flight transmission, especially whether degree of illness in passengers was consistent with the physical proximity to the index patient(s).']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Tocilizumab treatment in severe COVID-19 patients attenuates the inflammatory storm incited by monocyte centric immune interactions revealed by single-cell analysis']}\n", - "{'sentences': ['This review provides updated information about COVID-19.', 'SARS-CoV-2 can affect patients of all ages.', 'COVID-19 can present as asymptomatic carriage, ARD, and pneumonia.', 'Severe cases are more likely to be older and to have increased underlying comorbidities compared to mild cases.', 'Age and disease severity can be correlated with the outcomes of COVID-19.', 'To date, effective treatment for SARS-CoV-2 is lacking; however, two trials investigating the clinical efficacy of remdesivir are underway in China.', 'Currently, effective infection control intervention is the only way to prevent the spread of SARS-CoV-2.']}\n", - "{'sentences': ['To identify safe and effective medical countermeasures (e.g., antivirals/antibodies) to address the current outbreak of a novel coronavirus Methods: Comprehensive literature searches were developed by an experienced librarian for MEDLINE, EMBASE, the Cochrane Library, and biorxiv.org/medrxiv.org; additional searches for ongoing trials and unpublished studies were conducted in clinicaltrials.gov and the Global Infectious Diseases and Epidemiology Network (Global Infectious Diseases and Epidemiology Network', 'Results: 54 studies were included in the review: three controlled trials, 10 cohort studies, seven retrospective medical record/database studies, and 34 case reports or series.', 'These studies included patients with severe acute respiratory syndrome (SARs, n=33), middle east respiratory syndrome (MERS patients, one cohort study, n=16), COVID-19 (n=3), and unspecified coronavirus (n=2).', 'The most common treatment was ribavirin (n=41), followed by oseltamivir (n=10) and the combination of lopinavir/ritonavir (n=7).', 'Additional therapies included broad spectrum antibiotics (n=30), steroids (n=39) or various interferons (n=12).', 'No eligible studies examining monoclonal antibodies for COVID-19 were identified.', 'One trial found that ribavirin prophylactic treatment statistically significantly reduced risk of MERS patients, one cohort study infection in people who had been exposed to the virus.', 'Of the 21 studies reporting rates of ICU admission in hospitalized study (MERS) and one retrospective study or MERS patients, one cohort study patients, none reported statistically significant results in favour of or against antiviral therapies.', 'Of the 40 studies reporting mortality rates in hospitalized study (MERS) and one retrospective study or MERS patients, one cohort study patients, one cohort study (MERS patients, one cohort study) and one retrospective study (study (MERS) and one retrospective study', 'The Public Health Agency of Canada commissioned a rapid review to address the urgent question of the effectiveness and safety of antiviral or antibody therapies in the treatment of coronavirus.', 'A comprehensive literature search of both electronic databases and grey literature sources resulted in 54 studies of various antiviral treatments in patients diagnosed with COVID-.', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.03.19.20039008 doi: medRxiv preprint 19, SARS, or MERS; however, no animal or human studies of monoclonal antibodies could be found.', 'Overall the results of the included studies proved inconclusive on the effectiveness of antiviral drugs in treating coronavirus infections and prevent any particular treatments from being recommended for use.', 'There is a low quality of available evidence that largely consists of case reports and case series, with few observational studies, and even fewer trials.', 'There were however important safety signals identified in the included studies, particularly the possible development of anemia and altered liver function in patients receiving ribavirin treatment.', 'It is similarly difficult to recommend a particular antiviral drug as a promising candidate for further investigation due to the variable quality and inconclusive results of the current evidence.', 'This review does show however that the existing body of evidence is weighted heavily towards studies of ribavirin which has shown no particular efficacy in treating coronavirus and may in fact cause harmful adverse effects.', 'Future investigations into potential antiviral therapies for coronavirus may be best served by pointing their attention to other drug candidates.', 'There are several limitations to the review methods employed here, single screening and abstraction for example, however they were selected to thoughtfully tailor our methods according to our knowledge user needs and the urgent nature of the request to provide timely results.', 'The current evidence for the effectiveness of antiviral therapies for coronavirus is not conclusive and suffers from a lack of well-designed prospective trials or observational studies.', 'None of the interventions examined in this review can be recommended for use in patients with coronavirus.', 'Similarly, no firm recommendations can be made for or against these interventions from a safety perspective due to a lack of conclusive evidence.', 'Some important safety signals potentially related to ribavirin use were identified (anemia, altered liver function) but also require further investigation to clarify their relation to the drug.', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint']}\n", - "{'sentences': [\"[{'text': 'The emergence of COVID-19 as a pandemic has resulted in the need for urgent development of vaccines and drugs and the conduction of clinical trials to fight the outbreak.\", 'Because of the time constraints associated with the development of vaccines and effective drugs, drug repurposing and other alternative treatment methods have been used to treat patients that have been infected by the SARS-CoV-2 virus and have acquired COVID-19.', 'In this systematic review, we provide an overview of the molecular mechanism of action of repurposed drugs or alternative treatment medicines used to attenuate COVID-19 disease.', 'The research articles or grey literature, including theses, government reports, and official news online, were identified from 4 databases and 1 search engine.', 'The full content of a total of 160 articles that fulfilled our inclusion criteria was analyzed and information about 6 drugs (ritonavir, lopinavir, oseltamivir, remdesivir, favipiravir, and chloroquine) and 3 traditional Chinese medicines Injection and Qing Fei Pai Du Tang) were extracted.', 'All of the drug treatment options depend on the ability of the drug to inhibit the proliferation of the SARS-CoV-2 virus by binding to enzyme active sites, viral chain termination, or triggering of the molecular pathway, whereas traditional Chinese medicine has a pivotal role in triggering the inflammation pathway, such as the neuraminidase blocker, to fight the SARS-CoV-2 virus.', \"This review provides an insight to experimental validation of drugs and alternative medicine used for the treatment and control of COVID-19.', 'cite_spans': [], 'ref_spans': [], 'section': 'Abstract'}]\", 'The treatment of COVID-19 with repurposed drugs is dependent on the ability of the drug to inhibit the proliferation by binding to the enzyme active sites, viral chain termination, and triggering of molecular pathways.', 'For instance, ritonavir and lopinavir are believed to bind at the enzyme active site and are used together to inhibit the replication of SARS-CoV-2 because lopinavir alone is susceptible to oxidation metabolism by the cytochrome P450 enzyme, whereas the addition of ritonavir and oseltamivir can inhibit P450 3A4 enzyme activity.', 'Therefore, the combination of ritonavir and lopinavir are essential to maintain the drug efficacy for the treatment of COVID-19.', 'Remdesivir and favipiravir attenuated replication through premature termination of RNA transcription.', 'Chloroquine shows a potential antiviral effect in vitro, however, there is a lack of in vivo data to support therapeutic treatment for SARS-CoV-2 infection.', 'In contrast to the 6 drugs mentioned above, the TCMs discussed in this review were initially used to treat influenza and SARS by triggering the inflammation pathway such as upregulating IL6 instead of RNA chain termination.', 'New drugs that are effective for the treatment COVID-19 are still in development or in clinical trials.', 'In this review we provide a framework for better understanding of the mechanism of action of repurposed drugs and TCM and their involvement in the molecular pathway for inhibiting viral replication such as SARS or MERS.', 'We hope this will provide insights into the molecular pathway for effective drug development to treat COVID-19 in the future.', 'However, further experimental validation is needed to provide more concrete evidence.', 'CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', '(which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101 /2020.04.10.20060376 doi: medRxiv preprint .', 'CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', '(which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101 /2020.04.10.20060376 doi: medRxiv preprint .', 'CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', '(which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101 /2020.04.10.20060376 doi: medRxiv preprint .', 'CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', '(which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101 /2020.04.10.20060376 doi: medRxiv preprint .', 'CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', '(which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101 /2020.04.10.20060376 doi: medRxiv preprint Ding, Y, Dou, J, Teng, Z, Yu, J, Wang, T, Lu, N, Wang, H and Zhou, C. 2014 . .', 'CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': [\"[{'text': 'COVID-19 is caused by SARS-CoV-2, and has become a global pandemic.\", 'There is no highly effective medicine or vaccine, most of the patients were recovered by their own immune response, especially the virus specific IgG and IgM responses.', 'However, the IgG/ IgM responses is barely known.', 'To enable the global understanding of SARS-CoV-2 specific IgG/ IgM responses, a SARS-CoV-2 proteome microarray with 18 out of the 28 predicted proteins was constructed.', 'The microarray was applied to profile the IgG/ IgM responses with 29 convalescent sera.', 'The results suggest that at the convalescent phase 100% of patients had IgG/ IgM responses to SARS-CoV-2, especially to protein N, S1 but not S2.', 'S1 purified from mammalian cell demonstrated the highest performance to differentiate COVID-19 patients from controls.', 'Besides protein N and S1, significant antibody responses to ORF9b and NSP5 were also identified.', 'Indepth analysis showed that the level of S1 IgG positively correlate to age and the level of LDH (lactate dehydrogenase), especially for women, while the level of S1 IgG negatively correlate to Ly% (Lymphocyte percentage).', \"This study presents the first whole picture of the SARS-CoV-2 specific IgG/ IgM responses, and provides insights to develop precise immuno-diagnostics, effective treatment and vaccine.', 'cite_spans': [], 'ref_spans': [], 'section': 'Abstract'}]\"]}\n", - "{'sentences': ['SARS-CoV-2, an evolutionary perspective of interaction with human ACE2 reveals undiscovered amino acids necessary for complex stability', \"[{'text': 'The emergence of SARS-CoV-2 has resulted in more than 200,000 infections and nearly 9,000 deaths globally so far.\", 'This novel virus is thought to have originated from an animal reservoir, and acquired the ability to infect human cells using the SARS-CoV cell receptor hACE2.', 'In the wake of a global pandemic it is essential to improve our understanding of the evolutionary dynamics surrounding the origin and spread of a novel infectious disease.', 'One way theory predicts selection pressures should shape viral evolution is to enhance binding with host cells.', 'We first assessed evolutionary dynamics in select betacoronavirus spike protein genes to predict where these genomic regions are under directional or purifying selection between divergent viral lineages at various scales of relatedness.', 'With this analysis, we determine a region inside the receptor-binding domain with putative sites under positive selection interspersed among highly conserved sites, which are implicated in structural stability of the viral spike protein and its union with human receptor hACE2.', 'Next, to gain further insights into factors associated with coronaviruses recognition of the human host receptor, we performed modeling studies of five different coronaviruses and their potential binding to hACE2.', 'Modeling results indicate that interfering with the salt bridges at hot spot 353 could be an effective strategy for inhibiting binding, and hence for the prevention of coronavirus infections.', 'We also propose that a glycine residue at the receptor binding domain of the spike glycoprotein can have a critical role in permitting bat variants of the coronaviruses to infect human cells.', 'In order to detect branches and sites under positive/negative selection, two datasets were explored.', \"The first ('closer' dataset) harbors the most similar genomes to Wuhan-Hu-1 coronavirus (SARS-CoV-2) (MN908947).\", 'For this dataset, several genomes were excluded from the analysis because they showed minimal variation to other sequences.', 'We used a preliminary phylogeny to select a representative isolate of each clade (Table 1 ) in order to exclude highly similar sequences.', \"The second dataset ('broad' dataset) includes some accessions of the first dataset plus isolates less related to SARS-CoV-2, like SARS-like coronavirus isolates from different countries (see methods).\", 'We compare the results of two dataset because the phylogenetic distance between orthologues in a given dataset has been demonstrated to alter the ability to detect selection in PAML and MEME (McBee et al., 2015) .', 'In both datasets, we observed evidence of purifying selection in the majority of nodes of the tree.', \"Specifically, in the 'closer' dataset we identified 38 nodes with evidence of negative selection, and 4 under positive selection when free ratios model of CODEML model was applied.\", 'To confirm the four nodes under positive selection we use LTR test for contrasting hypothesis using branch free, branch neutral and M0 models of CODEML.', 'Using these approximations, any node predicted by free ratios model with ω>1 was significantly different to the purifying (ω<1) or neutral (ω=1', 'To complement our analyses looking for evidence of selection among lineages, we specifically analyzed for patterns of selection across sites in the S-protein genes, we used the sites models available in CODEML and HyPhY. Model M2 of CODEML detected 0.133 % of sites under positive selection (ω>1) and models M1 and M2 detected 85% of sites under purifying selection (ω<1).', 'Model M2 explains the significant data better (p=7e-4) than M1 model, that takes in account only sites with neutral and purifying selection.', 'To resolve these ambiguities in positive selection sites we calculate putative selection sites with CODEML (using Bayes Empirical Bayes from M2 and M8 models) and FUBAR with different datasets reflecting the addition of novel sequences to online repositories (broad, closer, closer without MN996532 and MT084071 and closer without MT084071) and we obtain different results.', 'It is becoming increasingly clear that predictions of positive selected sites are highly influenced simply by the diversity of the individual sequences included in the datasets.', 'In any case, the majority of predicted sites converge in the region between 439 to 508, a section of the RBD.', 'Additionally, we used TreeSaap to detect important biochemical amino acid properties changes over regions and/or sites along betacoronavirus S-protein.', 'Using a sliding window size of 20 (increasing by 1) we detect that the region between 466 to 500 (using SARS-COV-2 S-protein as a reference) have drastic amino acid changes for alpha-helical tendencies.', 'In addition, the section between 448 to 485 residues registers radical changes in amino acids implicated in the equilibrium constant (ionization of COOH).', 'In the structural analysis we performed, the section between 472 to 486 forms a loop that is not present in certain S-proteins of coronavirus isolated in bats.', 'This loop extends the interaction area between RBD of S-protein and human ACE2, in fact, the lack of these loop decreases the negative energy of interaction (increasing the binding) among these two molecules (see Table 2 ).', 'These results obtained from independent analysis strongly highlight the importance of 439 to 508 section.', 'Additionally, important hACE2-binding residues in the RBD from SARS-COV-2 obtained from the crystallography and structure determination performed by Shang et al. (2020) are also present in the section we highlight here.', 'We propose that this region is the most probable to contain the sites under positive selection due to predictions by our CODEML and FUBAR models.', 'In that sense, we refer to this section as Region under Positive Selection (RPS).', 'It is important to additionally clarify that even inside the RPS', 'Interestingly, the RPS of the pangolin coronavirus isolate MP789 differs only in one amino acid with the homologous region of SARS-CoV-2, whereas in contrast the bat coronavirus RaTG13', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.21.001933 doi: bioRxiv preprint (the overall most similar isolate to SARS-CoV-2 sequenced at the moment) shows 17 differences in the same region.', 'Several explanations could derive from this observation.', 'The hypothesis of recombination inside the pangolin between a native coronavirus strain and a bat coronavirus (like RaTG13) is congruent with our observation.', 'This scenario was proposed and discussed as the origin of SARS-CoV-2 by (Lam et al., 2020; Wong et al., 2020; Xiao et al., 2020) , however, other explanations are possible.', 'If the SARS-CoV-2, RaTG13 and pangolin coronavirus MP789 isolate are closely related as shown in the tree of the Figure 1 , we are observing the ancestral sequence of RPS in human and pangolin coronaviruses, and a mutated version in bat virus.', 'Elucidating the origin of SARS-CoV-2 is beyond the scope of this work, nevertheless sequencing of new coronavirus isolates in the near future could resolve this question.', 'With a list of broader observations related to the role of selection across viral genomes we aimed to specifically understand how these regions could affect virus/host interactions.', 'To understand more in deep the importance of RPS in the evolution of SARS-COV-2, we quantified the relative importance of this region in the interaction between RBD and hACE2.', 'In that sense, MD simulations were run for five complexes (listed in methods).', 'In all cases the systems were stable with Root Mean Square Deviations (RMSD', \"Next we estimated the free energies of binding of the coronaviruses' RBDs to hACE2 and the results of these evaluations are summarized in Table 2 .\", 'These calculations show that the SARS2, SARS and Rs4231 viruses are predicted to favorably bind to the human hACE2 receptor, while the Rm1 and SARS2-MUT variants present unfavorable free energies of binding.', \"The fact that the bat's coronavirus Rs4231, in addition to SARS and SARS2, presents favorable interaction with hACE2 is in accordance with the previous observation that it is able to infect human cells expressing this protein (Hu et al., 2017) .\", 'To get more insights into the contribution of the receptor and the RBDs to the binding process, we performed energy decomposition experiments.', 'The contribution of each residue in the studied coronaviruses that interact with the hACE2 receptor are shown in Table 3 .', 'Rows are presented in such a way that each of them contains the residues occupying the same position in the viruses RBDs structures as in the SAR2 RBD .', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.21.001933 doi: bioRxiv preprint structure.', 'From here on, residues numeration will take that of SARS2 as reference.', 'In general, most RBDs residues show negative values of contribution to the free energies of binding to the human receptor.', 'All studied RBDs, except that of the Rm1 coronavirus, have amino acids with large favorable contributions to the free energies of binding that directly interact with hACE2: K417 of SARS2 and SARS2-MUT, R426 in SARS and R480 in Rs4231.', 'On the other hand, the G476D mutation (D463 present in bat coronavirus strains) have a negative contribution to the binding of the RDB to hACE2.', 'This site was predicted to be under purifying selection by FUBAR analyses, and is located within the RPS.', 'Strikingly, the G496D mutation (SARS2 numeration) has a large negative influence in the free energy of binding in the two complexes that contain it.', 'It is also worth noting that the three aspartic acid substitutions present in all systems negatively contribute to the systems stability.', 'Taking into account that the only difference between SARS2 and SARS2-MUT is the G496D mutation, we postulate that this RBD position is critical for the human receptor recognition by coronaviruses.', 'To the best of our knowledge, no coronavirus having aspartic acid at this position .', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.21.001933 doi: bioRxiv preprint is able to infect human cells.', 'This result supports the prediction from FUBAR analyses indicating that the site G496D is under purifying selection.', 'Combined, our results strongly suggest that the mutation of the D496 residue present in the coronaviruses from bats is critical for their RBDs to recognize the human hACE2 receptor.', 'Additionally, it shows the importance of sites under purifying selection in RPS for the RBD evolution.', 'To better interpret the influence of the key interactions between the coronaviruses RBDs and their hACE2 receptor, their interactions were analyzed.', 'To select the representative structure of each system the MD snapshots employed for MM-PBSA calculations were clustered.', 'Then, the representative structure of a system was selected as the centroid of the most populated cluster.', 'The predicted RBD-hACE2 complexes for SARS2, SARS and SARS2-MUT are depicted in Figure 2 .', 'Many studies have focused on coronaviruses mutations that favor adaptations for human hosts infections.', 'For example, it has been shown that specific substitutions at positions 455, 486, 483, 494 and 501 (442, 472, 479, 480 and 487 in SARS) of the RBD of SARS favors the interaction between the RBD of SARS and hACE2 (Cui et al., 2019) .', 'Likewise, homology modeling studies found favorable interactions between the residues occupying these positions in the SARS2 RBD and the human receptor .', 'The cornerstone of these favorable interactions is the complementarity of the RBDs with hot spots 31 and 353.', 'These are salt bridges between K31 and E35 and between D38 and K353 of ACE2 which are buried in a hydrophobic environment (see Figure.', 'In the cases of SARS2 and SARS, Q493 (N479 in SARS) and N501 (T487 in SARS) add support to the hot spots according to these previous studies.', 'These observations should also hold for the Rs4231 strain, however the N501A change in the later compared to SARS2 (A488 in Rs4231) add little support to hot spot 353.', 'In this case, to continue permitting human infection, the large favorable contribution of R480 in Rs4231 to the free energy of binding could compensate the weak support provided by A488 to hot spot 353.', 'Interestingly, K353 is the residue forming the largest network of contacts with the analyzed RBDs among those belonging to both hot spots.', 'Our simulations also show that in SARS2 and SARS the RBD amino acids with the largest contribution to the free energy of binding, K417 and R426 (see Table 3 ) respectively, do not interact with any hot spot residue.', 'Instead, they interact with D30 of hACE2 in the SARS2 complex and with E329 of the human receptor in the SARS complex.', 'This could indicate that interactions additional to those previously identified with the hACE2 hotspots could be critical for the stabilization of the RDB-human receptor complexes.', 'Finally, we analyzed the possible reasons for the predicted negative impact that the G496D mutation has on the predicted free energies of binding of the RBD to hACE2.', 'As depicted in Figure 2 , G496 directly interacts with K353 in hot spot 353 and its mutation interferes with the D38-K353 salt bridge.', 'Specifically, D496 of the RDB point to D38 of hACE yields a high electric repulsion between these amino acids.', 'Consequently, this portion of the RBD is pushed to a position further from hACE2 than that observed in the wild type receptor, resulting in the reduction of its network of contacts with K353.', 'As a result, the binding of the RBD to hACE2 is considerably inhibited and unlikely to occur.', 'A priority in ongoing research is to better understand coronavirus evolution, with specific interests in understanding the role of selection pressures in viral evolution, and clarifying how viral strains can infect novel hosts.', 'Our experiments suggest that there are sites under positive selection in the S-protein gene of SARS-CoV-2 and other betacoronaviruses, particularly in a region that we called RPS (Region under Positive Selection) inside of the RBD.', 'However, we have identified that by in large, sites in this region (and overall, in the S-protein gene) are under purifying selection.', 'Particularly, for the site D496G, the presence of aspartic acid seems indispensable for the interaction with the hACE2.', 'Additionally, we performed MD simulations and free energies of binding predictions for five different complexes of coronaviruses that do and do not infect human cells.', 'Our results suggest that as long as no disrupting interference occur with both salt bridges at hot spots 31 and 353 coronaviruses are able to bind with hACE2.', 'Modeling results suggest that interference with the hot spot 353 could be and effective strategy for inhibiting the recognition of the RBD of the SARS-COV-2 spike protein by its human host receptor ACE2 and hence prevent infections.', 'Although additional simulations and experiments are required, all evidence suggests that the mutation of D496 in the bat variants of the coronaviruses permit infection of human cells.', 'Giving the large contribution of SARS2 K417 to the free energy of binding of the RBD to hACE2 we propose that blocking its interaction with the receptor D30 could be a promising strategy for future drug discovery efforts.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial', 'However, evidence regarding its effects in patients is limited.', 'This study aims to evaluate the efficacy of hydroxychloroquine (HCQ', 'Main methods: From February 4 to February 28, 2020, 62 patients suffering from COVID-19 were diagnosed and admitted to Renmin Hospital of Wuhan University.', 'All participants were randomized in a parallel-group trial, 31 patients were assigned to receive an additional 5-day HCQ (400 mg/d) treatment, Time to clinical recovery (TTCR', 'Key findings: For the 62 COVID-19 patients, 46.8% (29 of 62) were male and 53.2% (33 of 62) were female, the mean age was 44.7 (15.3) years.', 'No difference in the age and sex distribution between the control group and the HCQ group.', 'But for TTCR, the body temperature recovery time and the cough .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'Despite our small number of cases, the potential of HCQ in the treatment of COVID-19 has been partially confirmed.', 'Considering that there is no better option at present, it is a promising practice to apply HCQ to COVID-19 under reasonable management.', 'However, Large-scale clinical and basic .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', '22.20040758 doi: medRxiv preprint research is still needed to clarify its specific mechanism and to continuously optimize the treatment plan. .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The Abbreviations: HCQ, hydroxychloroquine.', 'Figure 1 : Study flow diagram.']}\n", - "{'sentences': ['In addition to SARS-CoV-2, our work suggests that CADs could be considered for further pre-clinical investigation for other pathogens including those yet-to-emerge which do not have an effective therapy or vaccine.', 'Indeed, many CADs including those we have not studied here, such as tamoxifen, are being increasingly noted for their inhibitory effects on various infectious agents even in vivo (59-61).', 'To our knowledge, this is the first meta-analysis of genome-wide screens in human cells to identify consensus host factors important to human pathogens.', 'Most genome-wide screens in human cells with pathogens have focused on poorly characterized genes rather than potentially universally important ones.', 'Identifying \"universal\" host factors such as sphingolipid metabolism and the COG and GARP complexes is important in light of the recently put forth Omnigenic model (62) .', 'This model states that most genes contribute to human disease, though \"core\" genes contribute the most.', \"There isn't a clear understanding of what might be a core gene for most diseases.\", 'Our work suggests sphingolipid metabolism and the COG and GARP complexes represent potential core host response genes for diverse human pathogens.', 'There are several potential reasons related to membrane biology that may explain why CADs and sphingolipids are particularly important in host responses to pathogens: 1) Sphingolipids are a key part of lipid rafts (63) , which are a common point of entry for many pathogens (64) .', 'For example, SARS-CoV-1 requires sphingolipids in lipid rafts for binding to ACE2 (65); 2) Once inside the cell, pathogens are also susceptible to the unique chemical properties of sphingolipids and CADs.', 'For example, ceramides are non-swelling amphiphiles implying that they cannot give rise to micelles or other aggregates (66) .', 'Though understudied, this would seem to modulate the membranes of inclusion bodies, which are used by many pathogens to evade their destruction (67) .', 'Also, some pathogens need the ER to make more of themselves (68) .', 'Considering CADs associate with membranes (69) potentially in the ER, this could explain why CADs are effective against these types of pathogens; 3) CADs potentiate the effects of many anti-pathogen drugs.', 'For example, zinc is an anti-viral when used in combination therapies (70) .', 'The internalization of zinc ions is largely limited by their incompatibility with the cell membrane chemistry.', \"Chloroquine is a zinc ionophore which increases zinc's uptake by cells thereby promoting its biological effects (71) .\", 'There are several limitations from our analysis: 1) Like chloroquine, myriocin is an immunosuppressant (72) .', \"This suggests if myriocin eventually becomes considered as a treatment against pathogens, it might make a patient's situation worse.\", 'Consistent with this, in preclinical studies myriocin has been shown to promote host infection by herpes simplex (73) and dengue viruses (74); 2) We only compared genome-wide mutagenesis screens where cell fitness had been used as the phenotype.', 'We acknowledge reporter-based screens can yield important information we might be missing.', 'However, we used cell fitness because it is robust, and more importantly, because it enabled us to make apples-to-apples comparisons between screens.', \"This is critical for comparing screens using different mutagenesis strategies (CRISPR, CRISPRi, haploid, RNAi) and different types of perturbations (small molecules and pathogens) as we've done here; 3) Our results suggest CADs inhibit SPT thereby inhibiting sphingolipid biosynthesis and ceramide production.\", 'Previous studies with antidepressants demonstrated that CADs act on sphingolipid catabolism, in particular on acid sphingomyelinase (24) , which also generates ceramide.', 'We cannot rule out that CADs decrease ceramide levels both at the level of anabolic and catabolism processes.', 'However, our screens strongly suggest the former.', 'Prions are a type of pathogen we did not include in our analysis because a genome-wide screen in human cells has not yet been done with one.', 'Considering prions or other misfolded pathogenic proteins such as amyloid and tau also engage autophagy (75), we hypothesize sphingolipid biosynthesis and the COG and GARP complexes would also score strongly in a genome-wide screen with such proteins.', \"There is growing evidence that infectious agents might be an important causative factor in Alzheimer's disease (AD) (76) .\", 'Infectious agents and misfolded proteins are both by definition, pathogens.', 'In the future, it will be interesting to assess CADs for their effects on the interrelations of both types of pathogens in the development of AD or other neurodegenerative conditions.', 'Figure 1 : Genome-wide screens in human cells reveals inhibition of serine palmitoyltransferase as a potential mechanism of action for diverse CADs.', '(a) Chemical structures and properties of several FDAapproved cationic amphipathic drugs (CADs) and non-CADs.', 'The following CADs: sertraline, nortriptyline, fluoxetine, verapamil, amiodarone, chloroquine and non-CADs: alendronate, metformin, atorvastatin are shown.', 'CADs have relatively high partition coefficients (cLogP) and acid dissociation constants (pKa).', 'A cLogP of ~4-5 is relatively hydrophobic.', 'A pKa value of ~9-10 is weakly basic.', '(b) Schematic of the genome-wide screening process.', 'A mutagenesis approach using CRISPR interference (CRISPRi) was used for CADs at GI50 concentrations of drug.', 'GI50 refers to the concentration of drug that inhibits cell fitness by 50% relative to untreated cells.', '(c) Meta-analysis of CAD screens.', 'Mutagenesis type \"h\" refers to haploid gene-trap (77) .', 'Mutagenesis type \"i\" refers to CRISPRi (14) .', 'Zolendronate_v1 and v2 refer to biological replicates.', 'V1 was previously published (2) .', 'Pooled variance (PV) is the absolute value of the aggregated phenotype strength/effect size for a gene knockdown with all CADs that were tested.', \"P-values for individual screens were 'combined' by FDR-adjusting for multiple comparisons.\", \"18,191 human genes were analyzed, though 4,187 genes were not plotted because they have 0 values and the log of 0 doesn't exist.\", 'GI50 drug concentrations of CADs used in CRISPRi screens were as follows: fluoxetine 30 µM, nortriptyline 30 µM, chloroquine 100 µM, verapamil 250 µM, amiodarone 50 µM, sertraline 9µM. Individual screen results are provided in Table S1 .', '(d) Scoring of CAD top hits in each CAD and non-CAD screen.', \"Comparisons of the phenotype scores for the 19 genes that had PV > 2.5 for all six CADs we tested vs. their PV's with 10 non-CADs (alendronate, lovastatin, simvastatin, phenformin, HHT, PF8503, imatinib, ponatinib, zoledronate).\", 'Dotted lines reflect thresholds of PV > 2.5 and a FDR-adjusted p-value < 3.3E-4 for all six screens having individual p-values < 0.05.', '(e) Initial steps in the sphingolipid biosynthesis pathway and the design of a synthetic interaction experiment involving a combination of myriocin and a CAD.', 'Serine palmitoyltransferase is the known site of action for myriocin and is our hypothesized site of action for CADs.', '(f) Synthetic interaction testing between SPT and CADs.', 'The synthetic interaction strength between SPT and CADs was tested with 100nM myriocin, which inhibits all three SPTs (SPTLC1, SPTLC2, SPTLC3).', 'Non-CAD and CAD doses used minimally inhibit cell fitness on their own based on data in Figure S1a .', 'Doses used are as follows: non-CADs -100µM alendronate, 50µM phenformin; CADs -amiodarone 15µM, verapamil 60µM, chloroquine 20µM, sertraline 11µM. * P-value < 0.05, two-way ANOVA for all controls vs. experimental samples comparing single agents (myriocin or CAD) vs. their combination (or CAD) vs. their combination).', 'Detailed information on statistical tests and exact p-values for each comparison are provided in Table S1 .', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', '72 hour treatment.', 'mRNA levels were assessed by RT-qPCR.', '* P-value < 0.05, ANOVA for all controls vs. experimental samples.', 'One-way or two-way ANOVA was performed for mRNA expression or ATP analysis, respectively.', 'Detailed information on statistical tests and exact p-values for each comparison are provided in Table S1 .', 'Table S1 : Data related to Figure 1 .', 'The following tables related to Figure 1 and Figure S1 are included in Table S1 : All genome-wide screen results from this work; Further chemical property information for CADs and non-CADs; Details on previously published genome-wide small molecules screens that were included in our analysis; Statistical analysis performed in Figure 1 and S1 including exact p-values.', 'Figure 1D for their phenotypes with the non-CADs and CADs.', 'The 80% overlap between pathogen and CAD screen hits was determined by assessing how many of the top 30 pathogen screen hits scored with a PV > 2.5 with at least two CADs.', 'As one can visualize from the Figure 2C heatmap, 24 out of 30 genes met this criteria.', 'Table S2 :', 'Details on each pathogen genome-wide screens analyzed.', 'Enrichr-determined Gene ontology categories for the genes identified as most commonly scoring across the 14 pathogen screens.', 'Table S3 .', '(e) Dose dependency of SERPINE1/PAI-1 expression with CADs and non-CADs.', 'Cells were treated as in (a).', '* P-value < 0.05, unpaired t-test corrected for multiple comparisons by the Holm-Sidak method comparing untreated vs. each CAD dose.', 'Detailed information on statistical tests and exact p-values for each comparison are provided in Table S3 .', 'Table S3 : Data related to Figure 3 .', 'The following tables related to Figure 3 are included in Table S3 :', 'Full RNA-Seq data with CADs and non-CADs.', 'Enrichr-determined gene ontology provided for genes 5X or more enriched with all CADs', 'These results are important in light of novel coronavirus SARS-CoV-2 and COVID-19 because each CAD we tested is already FDA approved.', 'One of the CADs we screened, amiodarone, has shown efficacy in vitro against SARS-CoV-1 (55) .', 'Another CAD we screened, verapamil, was recently identified by Gordon et al. using proteomics analysis as possibly being relevant to SARS-CoV-2 (56) (not yet peer reviewed).', 'This suggests amongst the drugs Gordon et al. discovered, verapamil might potentially be prioritized for further pre-clinical investigation.', 'Lastly, azithromycin has shown promise in combination with chloroquine against SARS-CoV-2 (57) .', \"This is interesting considering azithromycin's pKa (8.5) and cLogP (2.6) and ability to promote phospholipidosis in vivo (58) , which suggests it might also be acting as a CAD in this context.\", 'Some COVID-19 patients are responding well to chloroquine whereas others are not.', 'As the pandemic continues it will be important to better understand who responds to treatment.', 'We established that genome-wide screening in cells can identify key genetic determinants that predict bad outcomes from taking bisphosphonates (1).', 'A similar cellular analysis with SARS-CoV-2 treatments should be considered as soon as there are clear frontrunners.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['During a pandemic such as COVID-19, mitigating the spread of infections is essential in the absence of a vaccine and limited critical care resources.', 'In this study, we have shown that face mask use in the general population can have a beneficial impact in reducing the total number of .', 'CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'cases and deaths, and that this impact naturally increases with mask effectiveness.', 'The benefits of mask deployment are apparent even with low effectiveness and limited resources.', 'In such cases, though mask deployment may not have a large impact on total cases and deaths, indirect benefits for outbreak management are achieved by delaying the epidemic peak.', 'Importantly, however, the overall impact of mask deployment hinges on appropriate distribution strategies.', 'We consistently observed that the random distribution of masks throughout the general population is a suboptimal strategy.', 'In contrast, prioritizing the elderly population, and retaining a supply of masks for identified infectious cases generally leads to a larger reduction in total infections and deaths than a naïve allocation of resources.', 'While there remains much uncertainty around the true effectiveness of face masks -especially when factoring in differences in mask types, levels of adherence and patterns of human behavior -there is evidence to suggest that masks can provide a measure of protection and containment for respiratory viruses, likely a greater degree of the latter than the former.', 'The more effective a mask is, the fewer masks are required to suppress an epidemic.', 'Under a strategy in which masks are retained for infectious persons, this is particularly important.', 'As a higher proportion of infectious persons -both symptomatic and asymptomatic (and possibly unaware of their status as a carrier) -are wearing masks offering a high level of containment, a smaller number of onward transmissions occur, requiring fewer masks to be provided for newly diagnosed individuals.', 'While mask use can help to mitigate transmission, the supply & demand model suggests that panic buying at the very early phase of an epidemic can be detrimental, and that managing demand in the early stages of the outbreak could be beneficial.', 'In Taiwan, the government implemented such a resource management strategy in early February 2020, limiting the number of masks each person can buy per week with their National Health Insurance cards [25] .', 'As human behavior and compliance are a significant component of how effective mask use is, it is essential that public health recommendations concerning face masks in the general population occur in tandem with clear education on proper use and application, such that limited resources are used as effectively as possible.', 'During a pandemic such as COVID-19, optimizing the deployment of resources is essential.', 'Our models concern the distribution of resources in the general population, under the assumption that healthcare workers and key personnel have adequate protection -clearly it is essential that this subpopulation should have prioritized access to protective equipment.', 'However, if production can be increased such that face masks may be available to the general population, an optimized deployment of these resources can limit spread.', 'While we considered the elderly population in our model, we did not explicitly consider other vulnerable subpopulations, such as immunocompromised persons or those with other respiratory conditions.', 'Such persons with increased risk of suffering severe infections, and perhaps more importantly, those interacting with them, should belong to the prioritized subpopulation we considered in the resource allocation.', 'In addition, we did not consider heterogeneity in population mixing.', 'In reality, there are clusters of particularly vulnerable persons (e.g. hospitals, nursing homes, long term care facilities, prisons, homeless shelters) which pose an elevated risk; failing to protect such communities could lead to rapid and highly localized spread.', 'It is likely that face mask use is also more beneficial in populations with higher contact rates.', 'Future modeling work could consider meta-populations of different population densities to optimize resource deployment in urban vs. rural settings.', 'The use of face masks in mitigating the spread of a pandemic disease such as COVID-19 is one of many strategies that are being implemented simultaneously, including social distancing, travel restrictions and self-isolation.', 'Even during lockdown measures in which people are only rarely leaving their homes, many still face high exposure settings (e.g. conducting essential work, trips to the supermarket) albeit less frequently.', 'Face mask use could be a particularly important component of transmission mitigation once social distancing measures are relaxed, and potential exposures rapidly increase.', 'Preparing an adequate supply of face masks for such a transitionary period could help to prevent a potentially costly second peak.']}\n", - "{'sentences': ['Direct-acting antivirals are effective tools to control viral infections.', 'SARS-CoV-2 is a coronavirus associated with the epidemiological outbreak in late 2019.', 'Previous reports showed that HIV-1 protease inhibitors could block SARS-CoV main protease.', 'Based on that and using an in silico approach, we evaluated SARS-CoV-2 main protease as a target for HIV-1 protease inhibitors to reveal the structural features related to their antiviral effect.', 'Our results showed that several HIV inhibitors such as lopinavir, ritonavir, and saquinavir produce strong interaction with the active site of SARS-CoV-2 main protease.', 'Furthermore, broad library protease inhibitors obtained from PubChem and ZINC (www.zinc.docking.org) were evaluated.', 'Our analysis revealed 20 compounds that could be clustered into three groups based on their chemical features.', 'Then, these structures could serve as leading compounds to develop a series of derivatives optimizing their activity against SARS-CoV-2 and other coronaviruses.', 'Altogether, the results presented in this work contribute to gain a deep understanding of the molecular pharmacology of SARS-CoV-2 treatment and validate the use of protease inhibitors against SARS-CoV-2.', 'Other antivirals have been evaluated in SARS-CoV-2 as the polymerase inhibitor remdesivir, a nucleotide analog (currently in clinical trials against Ebola virus and SARS-CoV-2), alone or in combination with chloroquine, an inhibitor of lysosome acidification, with interesting results (Wang et al., 2020[18]; de Wit et al., 2020[2]).', 'Therefore, proposing a combinatory therapy against SARS-CoV-2 could be a feasible approach.', 'The starting therapeutic scheme could include remdesivir, with the disadvantage of its intravenous administration, and HIV-1 protease inhibitors such as Lopinavir or Saquinavir.', 'Nevertheless, more pre-clinical and clinical data are required to support the development of new therapies against SARS-CoV-2.', 'Due to the rapid spread of SARS-CoV-2, affecting more than 70 countries, therapeutic alternatives are urgently required.', 'Viral main protease plays a pivotal role in coronavirus replication.', 'This enzyme is responsible for the cleavage of the polyprotein, producing functional proteins that will be packed into the virion.', 'The molecular study of SARS-CoV-2 protease showed that this virus has high homology with SARS-CoV protease.', 'Previous data suggest the use of protease inhibitors as potential inhibitors of SARS-CoV protease, in special some of those used for HIV-1 therapy.', 'HIV-1 protease is an aspartyl protease, while in coronavirus it is a cysteine protease.', 'However, the inhibition by protease inhibitors could be driven by a similar mechanism.', 'HIV-1 is one of the best-studied models in antiviral research, their targets are well characterized and its inhibition by drugs has been broadly studied.', 'Protease inhibitors play a main role in HIV-1 therapy.', 'Furthermore, these compounds have shown inhibitory effects over proteases from pathogens such as Leishmania and malaria (Valdivieso et al., 2010[16]; Sonoiki et al., 2016[15]; de Wilde et al., 2014[1]).', 'Thus, the use of protease inhibitors in other viral species could be supported by these non-specific protease inhibitions.', 'Previous reports showed the inhibition of SARS-CoV protease by protease inhibitors used in HIV-1 therapy, being an interesting pharmacological target to treat SARS-CoV-2.', 'Previously, scientific reports showed that some HIV-1 protease inhibitors could decrease SARS-CoV replication (Savarino, 2005[13]).', 'Nevertheless, not all of the protease inhibitors showed the same efficacy against this virus (Jenwitheesuk and Samudrala, 2003[3]).', 'Based on that, in this work, we established an in silico approach to validate the inhibition of SARS-CoV-2 protease by HIV-1 protease inhibitor.', 'The results showed that the main protease inhibitors used in HIV-1 therapy could produce a decrease in the protease activity in coronavirus enzyme.', 'The compound with the highest binding affinity was saquinavir.', 'Preliminary reports are showing that patients infected with SARS-CoV-2 and treated with lopinavir could achieve viral clearance (Lim et al., 2020[6]).', 'Our study suggests that drugs such as SQV and LPV have shown slightly higher, but comparative binding energies against the SARS-CoV-2, than HIV-1 protease.', 'Thus, based on their safety profiles, SQV and LPV could be used as therapy and/or pre-exposure prophylaxis to reduce new infections by SARS-CoV-2.', 'Additionally, the data obtained from prior outbreaks, the clinical results obtained by using protease inhibitors in patients infected with SARS-CoV-2, and the results shown here, support the use of protease inhibitors to treat SARS-CoV-2.', 'In addition, to contribute to further development of antiviral drugs against SARS-CoV-2, in this work experimental compounds against the SARS-CoV-2 protease were evaluated by virtual screening.', 'Some compounds showed comparable binding energy values to the SARS-CoV-2 protease than to those observed for SQV, LPV and RTV.', 'ADME (for Absorption, Distribution, Metabolism, and Excretion) parameters estimation for new drugs, significantly helps to reduce the pharmacokinetics-related failure in clinical phases.', 'These results evidence that these compounds could be suitable for further medicinal chemistry optimization to produce the second generation of inhibitors more specific and potent against SARS-CoV-2.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['In this study we reported a top down data integration approach by combining both machine learning and statistical analysis techniques, followed by web-lab experimental validation, to identify potential drug candidates for treating SARS-CoV-2 infection.', 'We showed that the PARP1 inhibitor CVL218 discovered by our in silico drug repurposing framework may have the therapeutic potential for the treatment of COVID-19.', 'Although we mainly conducted in vitro assays to experimentally validate the anti-SARS-CoV-2 effects of olaparib and CVL218 due to limited time, it is natural to speculate that other PARP1 inhibitors may also have antiviral activities against SARS-CoV-2 infection, based on our computational prediction and experimental validation results.', 'Based on the data present in this study and the previously known evidences reported in the literature, we propose several potential mechanisms to help understand the involvement of PARP1 inhibitors in the treatment of COVID-19 ( Figure 6 ).', 'First, during the life cycle of the coronavirus, PARP1 inhibitors may inhibit the viral growth through suppressing viral replication and impeding the binding of the nucleocapsid protein to viral RNAs [31, 34, 35, 36] , which can also be supported by our molecular docking results (see Section 2.6).', 'Second, PARP1 inhibitors have been previously reported to play a critical role in regulating inflammatory response by modulating the expression of pro-inflammatory factors such as NF-κB, AP-1, IL-6 and downstream cytokines and chemokines [37, 38, 39, 40] .', 'Also, it has been shown that the overactivation of PARP1 promotes energy (NAD + /ATP) consumption and drives cell death, exacerbating the inflammation response [37, 38, 39, 41] .', 'PARP1 inhibitors thus may repress the NF-κB-mediated pro-inflammatory signals, and reduce energy failure and subsequent cell death induced by necrosis, thus providing a clinical potential for attenuating the cytokine storm and inflammatory response caused by SARS-CoV-2 infection.', 'Third, ADP-ribosylation is a conserved post-translational modification on the nucleocapsid proteins across different coronavirus lineages, implying that it may have an important regulatory role for the structure packing of viral genome.', 'Several previous studies have demonstrated that PARP1 is critical for viral replication [35, 42, 43] .', 'For example, PARP1 has been reported to interact with hemagglutinin (HA) of influenza A virus (IAV', 'Considering the pro-inflammatory role of PARP1, the therapeutic effects of PARP1 inhibitors in inflammatory-mediated diseases have been extensively studied over past two decades [45, 46] .', 'PJ-34, the early generation PARP1 inhibitor, has been suggested in previous studies to have neuroprotective effects in stroke model and protect mice from necroptosis-associated liver injuries by repressing the IL-33 expression [47, 48] .', 'In addition, the FDA-approved PARP1 inhibitor, olaparib, has been reported to protect against the LPS (Lipopolysaccharide)-induced acute lung and kidney injuries in a NF-κB-dependent manner in mice [49] .', 'Numerous pre-clinical studies demonstrated that PARP1 inhibitors play an essential role in a range of inflammatory injuries and related diseases, especially the lung inflammatory disorders including ARDS (Acute Respiratory Distress Syndrome), COPD (Chronic Obstructive Pulmonary Disease) and asthma [40, 46, 50, 51] .', 'All these studies suggest that PARP1 inhibitors are of high relevance to the treatment of the novel pneumonia caused by SARS-CoV-2 infection, possibly via their roles in modulating inflammatory response.', 'Notably, current pathological studies have shown that the severe patients infected by SARS-CoV-2 generally have higher plasma levels of IL-2, IL-6, IL-10, TNFα, IFN-γ [25, 27, 28, 29] , implying a high risk of the inflammatory-associated cytokine storm after viral infection.', 'In addition, reduction and functional exhaustion of T cells have also been observed in COVID-19 patients [27] .', 'Therefore, blocking the overactive inflammatory response may be an effective strategy for the treatment of COVID-19, particularly for those ICU patients infected by SARS-CoV-2.', 'Recently, tocilizumab, a monoclonal anti-13 author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.11.986836 doi: bioRxiv preprint body drug targeting IL-6, has been recommended for the treatment of COVID-19 in the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7) promulgated by the Chinese government (http://www.nhc.gov.cn/yzygj/s7653p/20', 'e964.pdf), which also highlights the vital role of anti-inflammatory response in current therapeutics against SARS-CoV-2.', 'Our in vitro study has showed that CVL218 can effectively inhibit the IL-6 production induced by CpG in PBMCs ( Figure 3 ).', 'This finding indicates that CVL218 may also possess the IL-6 specific anti-inflammatory effect that is applicable to those severe patients infected by SARS-CoV-2.', 'PARP1 inhibitors are originally used for targeting homologous recombination repair defects in cancers, and mainly categorized as oncology drugs.', 'Thus, it would generally need more safety data to justify any repurposing of PARP1 inhibitors for non-oncology indications.', 'Fortunately, there are numerous existing pre-clinical and clinical studies on repurposing PARP1 inhibitors into non-oncological diseases, including the aforementioned acute diseases (e.g., acute respiratory distress syndrome (ARDS), stroke) [52] and chronic diseases (e.g., rheumatoid arthritis and vascular diseases) [52, 53] .', 'All these evidences indicate the possibility of repurposing PARP1 inhibitors as a safe therapeutic agent to treat the current acute lung disease caused by SARS-CoV-2 infection.', 'In addition, our pharmacokinetic and toxicokinetic data in rats and monkeys shown in our study indicate that CVL218 may have a relatively acceptable safety profile to be repositioned for the antiviral purpose.', 'Moreover, CVL218 has been approved to enter Phase I clinical trial in 2017 by National Medical Products Administration (NMPA', 'Our pharmacokinetic examination in rats has shown that CVL218 has the highest 14 author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.11.986836 doi: bioRxiv preprint level distribution in the lung tissue, 188-fold higher concentration compared to that in plasma.', 'Such a tissue specific enrichment in lung may bring an extra advantage for CVL218 to be used for the anti-SARS-CoV-2 purpose, as lung is the therapeutically targeted tissue for COVID-19.', 'Moreover, high level distribution in lung may also suggest that only low dosage is needed in order to ensure the therapeutic efficacy of CVL218 against SARS-CoV-2, which may further reduce the risk of adverse events.', 'Thus, CVL218 may have great potential to be repurposed as an effective therapeutic agent to combat SARS-CoV-2 and prevent future epidemic outbreak.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.11.986836 doi: bioRxiv preprint 4.']}\n", - "{'sentences': ['The COVID-19 is a new pandemic.', 'We empirically observed that malaria free countries have a higher incidence of COVID-19 among different countries.', 'Currently we can offer no exact explanation of our findings.', 'Such strong statistical association All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.03.20052563 doi: medRxiv preprint 8 as observed is unlikely to be a chance association.', 'Malarial transmission may give some protection against COVID-19.', 'One explanation may be community level use of drugs such as chloroquine or hydroxychloroquine in malaria-endemic countries and relative non-use of them in malaria-free countries.', 'Interestingly chloroquine has been shown to be effective in reduction of viral replications including COVID-19.', '8, 9 Hydroxychloroquine has some immunomodulatory action and after the outbreak, studies have shown some activity of this drug.', '10 Viral inhibition from possibly higher blood level in malaria-endemic countries is one postulation.', 'The second possible mechanism seems to be immunological.', 'With increasing effort to eliminate and finally eradicate malaria long-term changes may occur in the human immune system.', 'Possible link between filarial elimination and increased autoimmunity has previously been reported.', '11 Whether elimination of parasites leads to permanent changes in the human immune system should be investigated.', 'Prior BCG vaccination had an apparent paradoxical effect.', 'In the overall analysis lower BCG coverage was associated with lower number of COVID-19 cases.', 'However this effect is probably related to geographic locale of the countries.', 'In European and American countries, where natural tubercular infection rate was low, higher BCG coverage was associated with decreased COVID-19 mortality.', 'In these countries higher BCG coverage was also associated with numerically lower COVID-19 incidence.', 'On the other hand, in the African, Asian and Australasian continent, where natural TB incidence is higher, increased BCG coverage appeared to have author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.03.20052563 doi: medRxiv preprint 9', 'The relationship of case fatality rate of COVID-19 with malaria incidence was complex and a quartic equation was needed for adequate modeling.', 'In the equation the even powers have negative weights and the odd powers have positive weights.', 'Thus in areas of non-zero low to very low malaria incidence, the effect of higher powers shall be overwhelmed by the linear terms and an increased COVID-19 case fatality is seen.', 'On the other hand in malaria-endemic countries the reverse is observed.', 'There are some limitations in this study.', 'Many other parasitic diseases could have been screened, which however due to lack of worldwide data could not be done.', 'Many factors like underreporting of cases might underwhelm this report.', 'Socioeconomics is an important factor, which is missing from the current analysis.', 'To summarize, malaria free countries, worldwide, are experiencing higher burden of COVID-19 pandemic.', 'Among the western countries, those, which have continued high BCG vaccination coverage, have an apparent mortality benefit from COVID-19 infection.', 'However, among the African, Asian and Australasian countries, continued high-level BCG vaccination was associated with increased incidence of and mortality from the COVID-19 infection.', 'From the COVID-19 case fatality analysis a lower mortality could be expected in malaria-endemic countries.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.03.20052563 doi: medRxiv preprint 1 0']}\n", - "{'sentences': ['The focused drug repurposing of known approved drugs (such as lopinavir/ritonavir) has been reported failed for curing SARS-CoV-2 infected patients.', 'It is urgent to generate new chemical entities against this virus.', 'As a key enzyme in the life-cycle of coronavirus, the 3C-like main protease (3CL pro or M pro ) is the most attractive for antiviral drug design.', 'Based on a recently solved structure (PDB ID: 6LU7), we developed a novel advanced deep Q-learning network with the fragment-based drug design (advanced deep Q-learning network with the fragment-based drug design) for generating potential lead compounds targeting SARS-CoV-2 3CL pro .', 'We obtained a series of derivatives from those lead compounds by our structure-based optimization policy (SBOP).', 'All the 47 lead compounds directly from our AI-model and related derivatives based on SBOP', 'All rights reserved.', 'No reuse allowed without permission.', ': bioRxiv preprint disease (COVID-19) worldwide.', '1 As of March 2, 2020, more than 90,000 people have been infected by SARS-CoV-2 and more than 3000 people have been reported dead according to Johns Hopkins Coronavirus map tracker.', '2 The numbers of infection and death are still increasing.', 'To face the considerable threat of SARS-CoV-2, it is urgent to develop new inhibitors or drugs against this deadly virus.', 'Unfortunately, since the outbreak of severe acute respiratory syndrome (SARS) eighteen years ago, there has been no approved treatment against the SARS coronavirus (SARS-CoV), 3 which is similar to SARS-CoV-2.', 'Repurposing potential drugs such as lopinavir and ritonavir also failed to SARS-CoV-2 injected patients.', '4 Structure-based antiviral drug design with a new artificial intelligence algorithm may represent a more helpful approach to get the SARS-CoV-2 targeted inhibitors or drugs.', 'Thanks to the prompt efforts of many researchers, we have several pieces of important information about this vital virus genome and protein structures.', 'We now know that the non-structural protein 5 (Nsp5) is the main protease (M pro ) of SARS-CoV-2 and it is a cysteine protease, which also been called \"3C-like protease\" (3CL pro ).', 'Moreover, we know that the 3D structure of 3CL pro is very similar to SARS-CoV with a sequence identity of >96% and 3D structure superposition RMSDCα of 0.44 Å as shown in Figures S1 and S2.', '3CL pro has been reported as an attractive target for developing anti-coronaviral drugs: 1) this protease is highly conserved in both sequences and 3D structures; 5 2) 3CL pro is a key enzyme for related virus (including SARS and SARS-CoV-2) replication; 3) it only exists in the virus, not in humans.', 'Developing specific antiviral drugs targeting 3CL pro of the specific virus has shown significant success; for example, both approved drugs lopinavir and ritonavir can completely occupy the substrate-binding site of 3CL pro to break down the replication of human immunodeficiency virus (HIV).', 'However, due to the large difference between HIV and SARS-CoV-2 3CL pro , lopinavir and ritonavir were validated ineffective for inhibiting SARS-Cov-2.', '4 On the other hand, the substrate-binding site of 3CL pro is almost the same between the SARS-CoV-2 and SARS']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Challenges of methadone maintenance treatment during the COVID-19 epidemic in China: policy and service recommendations']}\n", - "{'sentences': ['Corona virus disease 2019 SARS-CoV-2 (COVID-19) is a zoonotic virus causing a variety of severe of respiratory diseases.', 'SARS-CoV-2 is closest to SARS-CoV and MERS-CoV in structure.', 'The highly prevalence of COVID-19 is due to the lack onset of symptoms.', 'Our study aimed to present an overview of the virus in terms of structure, epidemiology, symptoms, treatment, and prevention.', 'Conduct the differences of whole genome sequence and some viral proteins to determine the gap and the change alternation of nucleotides and amino acids sequences.', 'We evaluate 11 complete genome sequence of different coronavirus using BAST and MAFFT software.', 'We also selected 7 types of structural proteins.', 'We were conclude that COVID-19', 'Corona virus disease 2019 SARS-CoV-2 (COVID-19) is a zoonotic virus causing a variety of severe of respiratory diseases.', 'SARS-CoV-2 is closest to SARS-CoV and MERS-CoV in structure.', 'The highly prevalence of COVID-19 is due to the lack onset of symptoms.', 'Our study aimed to present an overview of the virus in terms of structure, epidemiology, symptoms, treatment, and prevention.', 'Conduct the differences of whole genome sequence and some viral proteins to determine the gap and the change alternation of nucleotides and amino acids sequences.', 'We evaluate 11 complete genome sequence of different coronavirus using BAST and MAFFT software.', 'We also selected 7 types of structural proteins.', 'We were conclude that COVID-19']}\n", - "{'sentences': ['Here we present a comprehensive immunogenicity map of the SARS-CoV-2 virus (Table S1), highlighting 65 B and T cell epitopes (Tables 1, S1 and S2) from a diverse sampling of viral domains across all 9 SARS-CoV-2 genes.', 'Based on our computational algorithm, we expect that the highest scoring peptides will result in safe and immunogenic T cell epitopes, and that B cell epitopes should be evaluated for safety and efficacy using methods previously reported (Wang et al., 2016) .', 'mRNA vaccines have been shown to be safe and effective in preclinical studies (Richner et al., 2017) , with nucleoside RNAs shown to be effective without triggering RNA-induced immunogenicity (Pardi et al., 2017) , while DNA vaccines have also been shown to be safe and protective (Dowd et al., 2016) .', 'Both DNA and mRNA vaccines are capable of being rapidly and efficiently manufactured at large scales.', 'We suggest that a multivalent construct composed of the SARS-CoV-2 minigenes (presented in Tables 1, S2, and S3) can be used in a DNA on mRNA vaccine for expression in antigen-presenting cells.', 'These epitopes can be used in tandem with a TLR agonist such as tetanus toxoid (Zanetti, Ferreira, de Vasconcelos, & Han, 2019) to drive activation of signals 1 and 2 in antigen presenting cells.', 'Constructs can be designed to contain a combination of optimal B and T cell epitopes, or deployed as a construct consisting of the top scoring T cell epitopes to be used in combination with the vaccines currently being developed targeting the Spike protein in order to drive the adaptive memory response.', 'DNA vaccine sequences can also be codon optimized to increase CpG islands such as to increase TLR9 activation (Krieg, 2008) .', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'The methods described here provide a rapid workflow for evaluating and prioritizing safe and immunogenic regions of a viral genome for use in vaccination.', 'With the third epidemic in the past two decades underway, and all originating from a coronavirus family virus, these viruses will continue to threaten the human population, and necessitate the need for prophylactic measures against future outbreaks.', 'A subset of the epitopes selected here are derived from viral regions sharing a high degree of homology with other viruses in the family, and thus we expect these evolutionarily conserved regions to be essential in the infectivity and replicative lifecycle across the coronavirus family, suggesting that an immune response against the epitopes listed herein may provide more broadly protective immunity against other coronaviruses.', 'Additionally, we describe epitopes containing the newly acquired features of SARS-CoV-2 that confer evolutionary advantages in viral spread and infectivity.', 'In addition, the immunogenicity map provided in Table S1 can be used to customize epitopes based on the HLA frequencies of specific populations.', 'Though here we suggest the use of 33mers based on optimal MHC presentation across the population, these methods can be applied to evaluate k-mers of various sizes depending on desired application.', 'Antigenic burden from epitopes that do not contribute to viral protection can cause autoimmune reactions, reactogenicity, detract from the efficacy of the virus, or result in ADE.', 'To mitigate these effects a priori, we selected maximally immunogenic epitopes with the highest degree of dissimilarity to the self-proteome such as to minimize the potential of cross-reactivity that can lead to adverse reaction or minimize the efficacy of the virus.', 'In addition to the predicted safety of these epitopes stemming from lack of potentially cross-reactive normal proteins, we expect that a greater author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'repertoire of viral antigen-specific T cells will exist due to lack of negative thymic selection.', 'We prioritize epitopes with maximal dissimilarity from the human proteome, however, many other SARS-CoV-2 peptides show identical or nearly identical peptides presented on MHC derived from normal proteins, suggesting their use in vaccination could result in an autoimmune response.', 'The 65 epitopes presented here can be expressed in a ~6.3kb construct and coupled with the safe and rapid production of synthetic DNA, mRNA, and peptide vaccines.', 'As SARS-CoV-2 has precipitated the need to develop novel approaches to rapidly deploy vaccines in pandemic situations (Lurie, Saville, Hatchett, & Halton, 2020) , we suggest that this comprehensive analysis can be incorporated into a process that can be rapidly deployed when future novel viral pathogens emerge.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.31.018978 doi: bioRxiv preprint compared to previous coronaviruses.', 'Using our analysis, we identify a high-ranking vaccine epitope (red) within the receptor binding domain.', '2) SARS-CoV-2 has acquired a novel furin cleavage site RRAR, along for increased infectivity due to improved membrane fusion (epitope containing the novel furin cleavage site highlighted in orange).', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'Table 1 .', 'List of highest scoring viral epitopes suggested for vaccination based on MHC class I population-scale presentation, MHC class II population presentation, similarity score, and homology score across 9 mammal species and 1,024 human SARS-CoV-2 cases.', 'Last column represents total score across all parameters, highlighting epitope S_462 in S protein containing novel receptor binding sites (Shang et al., 2020) .', '0 2 0 3 , 0 2 0 5 , 0 2 0 5 , 0 2 0 6 , 0 2 0 7 , 0 2 1 1 , 0 2 1 1 , 0 2 1 2 , 0 2 1 6 , 0 2 1 7 , 0 2 1 7 , 0 2 1 9 , 0 3 0 1 , 1 1 0 1 , 2 3 0 1 , 2 4 0 3 , 2 4 0 3 , 2 5 0 1 , 2 6 0 1 , 2 6 0 2 , 2 6 0 3 , 2 9 0 2 , 3 0 0 1 , 3 0 0 2 , 3 2 0 1 , 3 2 0 1 , 3 2 0 7 , 6 6 0 1 , 6 6 0 1 , 6 8 0 1 , 6 8 0 1 , 6 8 0 2 , 6 8 2 3 , 6 8 2 3 , 6 9 0 1 , 8 0 0 1 H L A -B : 0 8 0 1 , 0 8 0 2 , 0 8 0 3 , 1 5 0 1 , 1 5 0 2 , 1 5 0 3 , 1 5 0 3 , 1 5 0 9 , 1 5 1 7 , 3 5 0 1 , 3 5 0 1 , 3 5 0 3 , 3 8 0 1 , 3 8 0 1 , 4 0 1 3 , 4 5 0 6 , 4 6 0 1 , 4 8 0 1 , 5 1 0 1 , 5 3 0 1 , 5 8 0 1 , 5 8 0 2 , 7 3 0 1 , 8 3 0 1 8 2 . ', '1 % 2 4 H L A -D R B 1 : 0 1 0 1 , 0 4 0 1 , 0 4 0 2 , 0 4 0 3 , 0 4 0 4 , 0 4 0 5 , 0 8 0 1 , 0 9 0 1 , 1 0 0 1 , 1 1 0 1 , 1 3 0 1 , 1 6 0 2 H L A -D P A 1 0 -D P B 1 0 : 1 0 3 -2 0 1 , 1 0 3 -4 0 1 , 1 0 3 -4 0 2 , 1 0 3 -6 0 1 , 2 0 1 -1 0 1 ,', 'H L A -C : 0 3 0 3 , 0 4 0 1 , 0 6 0 2 , 0 7 0 1 , 0 7 0 2 , 0 8 0 2 , 1 2 0 3 , H L A -D Q A 1 0 -D Q B 1 0 : 1 0 2 -6 0 2 , 5 0 1 -3 0']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['As both SARS-CoV and SARS-CoV-2 (2019-nCoV) have the same receptor for virus entry, potential biotherapeutics to prevent SARS entry could be extrapolated to use for SARS-CoV-2.', 'Among immunotherapy approaches to block the virus attachment or entry, monoclonal antibodies are preferred due to their specificity, purity, low risk of blood-borne pathogen contamination and safety compared to serum therapy and intravenous immunoglobulins preparations [3] .', 'The promising results in targeting spike protein in SARS-CoV and MERS-CoV by monoclonal antibodies encourages researchers to use them in fighting against 2019-nCoV. Monoclonal antibody cocktail or the combination of different monoclonal antibodies that recognizes different epitopes on the viral surface may increase the effectiveness of virus neutralizing [3] .', 'Other targets in immunotherapy for COVID-19 that seem to be Promising are cytokines.', 'Among cytokines, specificity of IL-6 in COVID-19 comes from that Elevated IL-6 is correlated with inflammatory cytokine storm severity.', 'Therefore targeting IL-6 and its receptor (IL6R) by Siltuximab and tocilizumab monoclonal antibodies (mAb', 'Despite major progress in the development of monoclonal antibodybased passive immunotherapy for coronavirus infection, there is no marketed monoclonal antibody.', 'What limits the use of antibodies is that large-scale production of monoclonal antibodies for clinical application is laborious, expensive and time-consuming.', 'So designing and developing advanced protein production platforms and expression systems is urgent to provide efficient monoclonal antibodies at the affordable cost in a short time [3] .', 'Although no research has been tested, and there is no approved vaccines or anti-viral therapeutic agents to treat COVID-19 until now, the vaccines can be successful due to the specific structure of the virus.', 'Furthermore, existing evidence on immunotherapy for SARS-CoV and MERS-CoV holds the promise for using in 2019-nCoV.']}\n", - "{'sentences': ['Objective: To explore the clinical characteristics and prognosis of the new coronavirus 2019-nCoV patients combined with cardiovascular disease (CVD).', 'Methods: A retrospective analysis was performed on 112 COVID-19 patients with CVD admitted to the western district of Union Hospital in Wuhan, from January 20, 2020 to February 15, 2020.', 'They were divided into critical group (ICU, n=16) and general group (n=96) according to the severity of the disease and patients were followed up to the clinical endpoint.', 'The observation indicators included total blood count, C-reactive protein (CRP), arterial blood gas analysis, myocardial injury markers, coagulation function, liver and kidney function, electrolyte, procalcitonin (PCT), B-type natriuretic peptide (BNP), blood lipid, pulmonary CT and pathogen detection.', 'Results: Compared with the general group, the lymphocyte count (0.74×10(9) (0.34×10(9), 0.94×10(9/L vs. 0.99×10(9) (0.71×10(9), 1.29×10(9/L, P=0.03) was extremely lower in the critical group, CRP (106.98 (81.57, 135.76) mg/L vs. 34.34 (9.55,76.54) mg/L, P<0.001) and PCT (0.20 (0.15,0.48) μg/L vs. 0.11 (0.06,0.20)μg/L, P<0.001) were significantly higher in the critical group.', 'The BMI of the critical group was significantly higher than that of the general group (25.5 (23.0, 27.5) kg/m(2) vs. 22.0 (20.0, 24.0) kg/m(2), P=0.003).', 'Patients were further divided into non-survivor group (17, 15.18%) group and survivor group (95, 84.82%).', 'Among the non-survivors, there were 88.24% (15/17) patients with BMI> 25 kg/m(2), which was significantly higher than that of survivors (18.95% (was significantly higher than that of survivors (18.95%), P<0.001).', 'Compared with the survived patients, oxygenation index (130 (102, 415) vs. 434 (410, 444), P<0.001) was significantly lower and lactic acid (1.70 (1.30, 3.00) mmol/L vs. 1.20 (1.10, 1.60) mmol/L, P<0.001) was significantly higher in the non-survivors.', 'There was no significant difference in the proportion of ACEI/ARB medication between the critical group and the general group or between non-survivors and survivors (all P>0.05).', 'Conclusion: COVID-19 patients combined with CVD are associated with a higher risk of mortality.', 'Critical patients are characterized with lower lymphocyte counts.', 'Higher BMI are more often seen in critical patients and non-survivor.', 'ACEI/ARB use does not affect the morbidity and mortality of COVID-19 combined with CVD']}\n", - "{'sentences': ['Since rRT-PCR tests serve as the gold standard method to confirm the infection of SARS-CoV-2, false-negative results could hinder the prevention and control of the epidemic, particularly when this test plays a key reference role in deciding the necessity for continued isolated medical observation or discharge.', 'Regarding the underlying reasons for false-negative rRT-PCR results, a previous published study suggested that insufficient viral specimens and laboratory error might be responsible (3).', 'We speculated from these two cases that infection routes, disease progression status (specimen collection timing and methods), and coinfection with other viruses might influence the rRT-PCR test accuracy, which should be further studied with more cases.', 'False-negative rRT-PCR results were seen in many hospitals.', 'By monitoring data collected at our hospital from January 21 to 31, 2020, two out of ten negative cases shown by the rRT-PCR test were finally confirmed to be positive for COVID-19, yielding an approximately 20% false-negative rate of rRT-PCR.', 'Although the false-negative estimate would not be accurate until we expand the observational time span and number of monitored cases, the drawback of rRT-PCR was revealed.', 'Clinical manifestations, laboratory examination results, and chest CT features of patients with COVID-19 were also of great value in helping the detection and diagnosis.', 'Thus, an integrated criterion should be established for the diagnosis of SARS-CoV-2 infection.', 'In addition to the epidemiological information, we focused on two aspects of information: chest CT features and laboratory examination results.', 'Of note, approximately 96% of patients with COVID-19 presented with chest CT abnormalities, such as multiple bilateral and peripheral ground-glass opacities and consolidation (34), making chest CT features essential in recognizing COVID-19.', 'The National Health Commission of China revised the diagnostic criteria in the Hubei province, where a severe epidemic occurred (5).', 'A new diagnostic type called “Clinical diagnosis” was set according to the presence of pneumonia on chest CT, regardless of rRT-PCR results.', 'To some extent, CT features and rRT-PCR results were complimentary in the diagnosis of COVID-19.', 'From a clinical perspective, CT features could be utilized as the first and immediate reference for doctors to screen the highly suspected cases and to take necessary actions while rRT-PCR serves as a confirmation tool, the results of which could be utilized later to decide the subsequent action of continuing isolated treatment or discharge.', 'Notably, our hospital was facilitated with a DL-based computer-aided diagnostic system (InferRead CT Pneumonia, Infervision, Beijing, China) for pneumonia, which greatly improved the detection efficiency for patients highly suspected with COVID-19 by alarming the technician within 2 minutes when any suspected cases was found after CT examination.', 'The automatic lesion segmentation on CT was also helpful to evaluate the progression of COVID-19 quantitatively.', 'With an integrated approach of DL, CT features, and rRT-PCR results, the screening and treatment of COVID-19 would be more effective.', 'Furthermore, we observed conflicting laboratory examination results in these two patients.', 'Patient in Case 2 was infected only by SARS-CoV-2 and presented decreased lymphocytes and elevated C-reactive protein, consistent with the typical tendency found in the COVID-19 cohort.', 'In contrast, the patient in Case 1 was coinfected with influenza A and presented with increased lymphocytes and elevated C-reactive protein.', 'The difference in laboratory examination results could be a potential indicator of a different infection status, including SARS-CoV-2 infection alone or coinfection with other viruses, which, however, should be further validated with more cases.', 'In conclusion, we reported two false-negative results of rRT-PCR for SARS-CoV-2 infection and mentioned the possible tandem approaches for clinical practices to ensure an early and accurate diagnosis of COVID-19.', 'In addition, the potential role of laboratory examination results in differentiating the infection status was revealed as well.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': [\"The current global pandemic of the novel coronavirus Covid-19 created two epicenters first at Hubei Province in People's Republic of China and presently in Europe.\", 'SARS-CoV-2, like its close relatives SARS-CoV and MERS-CoV, is also pathogenic but with a higher infectivity rate.', 'The increasing number of cases and wide spread disease raise grave concerns about the future trajectory of the pandemic and thus, a better understanding regarding the molecular divergence of viral strains and pathogenesis, is utmost important.', 'The present study attempted to categorize COVID affected countries based on molecular pathogenesis.', 'Three important factors were considered, i.e, number of mutations during evolution, rarity of the allelic substitution and functional alteration of the non-synonymous mutations.', 'We screened and compared extent of mutations observed in genome sequence of SARS-CoV-2.', 'All reported genome sequences of 13 affected countries have been analyzed.', 'So far, studies indicated that there are only two strains, S, possibly the ancestral one and L, might be the lethal and more aggressive one.', 'The distinct clusters that we observed from our phylogenetic tree construction raise the assumption of existence of many more unknown strains (figure 5).', \"One interesting report substantiating our finding is from Shenzhen which showed possible generation of new strain which neither belongs to 'S' nor to 'L' subtype.\", '12 We evaluated the extent of molecular divergence by MSA and Pair-wise alignment and subsequently tried to decipher the protein alteration parallel to the mutations.', 'As a RNA virus, it was hypothesized that 2019-nCoV mutate faster than DNA virus.', '12 The genome-wide phylogenetic tree indicated that 2019-nCoV was closest to SARS-like coronavirus, with 96% sequence similarity.', '20,21 When we evaluated the SARS-CoV (2003) and SARS-CoV-2 (2020) from Italy, sequence identity was 79.4%, suggesting new mutations, might be deleterious in later strain.', 'Our first approach was to categorize the countries depending on number of mutations and type of mutation they had.', 'It was found that similar number of mutations does not correlate well with similar extent of fatality outcome.', 'Example, patients from Australia, Japan and Italy all show 3 mutations in the viral genome, but Australia has least fatality rate, while Italy has maximum.', 'Again, numbers of mutations are 5 in China, 6 in India and 7 in both Sweden and Spain.', 'The observations mentioned above strongly indicate that not the total number of mutation, but the nature of mutations finally guides the overall fatality outcome.', 'In the case of Italy, we found three deadly mutations in 2020 (i.e. 2269 A>T, very rare allele; 11083 G>A, very rare allele and .', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', '26144 G>T) with high disease outcome but the wild counterpart of these found in 2003 did not lead to any fatality, suggesting the significance of newly evolved mutations.', 'Although, 2269 A>T mutation does not alter amino acid (A668A), increasing number of evidences suggest that synonymous mutations could have effects on splicing, transcription, that ultimately alter the phenotype, disrupting their silence.', '22 Spain is also carrying a very rare allele transversion T>A, that occurs in orf1ab gene of virus.', 'Orf1ab gene transcribes into a polyprotein and cleaving by protease (3CLpro) and papain-like protease (PLpro', 'We assume, while some mutations are pathogenic, some will be favorable and will undergo positive selection pressure.', 'Herein, we tried to elucidate the possible interaction between ACE2 and spike glycoprotein.', 'It is well established that for virus entry, spike glycoprotein (S) present on the CoV can be a neutralization antibody and it binds to its receptor followed by membrane fusion.', 'It has been inferred that some favorable changes in viral glycoprotein may limit the increase of fatality.', 'This kind of favorable mutation was found in some strains of COVID-19 from India, Australia and Sweden.', 'Detailed screening depicted that Australian strain carry a rare allele transversion (T>G) which results into a NS mutation (S256R) on surface glycoprotein S1 domain which may affect the binding of hACE2 molecules, thus these strains become non-lethal to human.', 'In this study, only one tri-nucleotide deletion at S1 domain of surface glycoprotein has been found and that is found in Indian strains along with a NS mutation (R417I) in the Receptor Binding Domain (RBD', 'On the other hand, Brazilian strain acquires four common allelic transitions, of which only two non-synonymous mutations affect protein alteration.', 'Surprisingly, Swedish strain carry both extreme lethal (2717 G>A, very rare allele leading to G818S at Orf1ab polyprotein) and also favorable mutations (23952 T>G, rare allele leading to F806C at surface glycoprotein) and thus cumulatively lower the severity of the disease.', 'In summary, the present study reveals that the fatality rate increases with not only the number of mutations but also depending on its allelic rarity as well as functional alteration of protein.', 'Surface glycoprotein domain is very important for host-carrier interactions and hence the mutations affecting surface glycoprotein can be one of the important mechanisms which alter the viral entry and pathogenesis.', \"Future studies may uncover more genetic information at the molecular level as well as structural levels of the proteins, because without this knowledge it'll be difficult to identify drug target and prepare vaccine.\", 'We hope our work will help in that direction.']}\n", - "{'sentences': ['Currently there is no effective antiviral therapy for SARS-CoV-2 infection, which frequently leads to fatal inflammatory responses and acute lung injury.', 'Here, we discuss the various mechanisms of SARS-CoV-mediated inflammation.', 'We also assume that SARS-CoV-2 likely shares similar inflammatory responses.', 'Potential therapeutic tools to reduce SARS-CoV-2-induced inflammatory responses include various methods to block FcR activation.', 'In the absence of a proven clinical FcR blocker, the use of intravenous immunoglobulin to block FcR activation may be a viable option for the urgent treatment of pulmonary inflammation to prevent severe lung injury.', 'Such treatment may also be combined with systemic anti-inflammatory drugs or corticosteroids.', 'However, these strategies, as proposed here, remain to be clinically tested for effectiveness.']}\n", - "{'sentences': ['OBJECTIVE Most patients with Coronavirus Disease 2019 (COVID-19) were Mild or Moderate.', 'Severe patients progressed rapidly to Critical condition including multi-organ failure and even death.', 'Identification of early predictive factors is urgently necessary to facilitate appropriate intensive care.', 'METHODS We included all patient admitted to Wuhan Union Hospital and treated by the supportive medical team of Beijing Tongren Hospital as of March 20, 2020.', 'Indicators of injuries for multiple organs, including the heart, kidney and liver, and glucose homeostasis were specifically analyzed for predicting primary outcomes (an intensive care unit (ICU) or death).', 'RESULTS The data of 120 patients with a severity equal to or greater than Moderate, discharged or died were extracted.', 'After excluding patients with history of diabetes, chronic heart, kidney, and liver disease, 69 patients were included in the final analysis.', 'There were 26 cases with primary outcomes including 16 deaths.', 'Univariable analysis indicated that fasting blood glucose (FBG), lactate dehydrogenase (LDH), hydroxybutyrate dehydrogenase (HBDH), creatine kinase and creatinine were associated with primary outcomes and death.', 'Among patients with primary outcomes, although FBG levels were much higher on admission, they dramatically decreased subsequently, while in deceased patients they increased continuously.', 'Multivariable Cox regression indicated that FBG≥7mmol/L was the only independent predictor for death (HR = 3.75, 95% CI 1.26-11.15).', 'Cluster analysis found more proximities of FBG (at the time of admission) with LDH']}\n", - "{'sentences': ['Since the outbreak of COVID-19, there has been a pressing need for development of a prognostic tool that is easy for clinicians to use.', 'Recently, a Lancet publication showed that in a cohort of 191 patients with COVID-19, age, SOFA score and D-dimer measurements were associated with mortality.', 'No other publication involving prognostic factors or models has been identified to date.', 'In our cohorts of 444 patients from two hospitals, SOFA scores were low in the majority of patients on admission.', 'The relevance of D-dimer could not be verified, as it is not included in routine laboratory tests.', 'In this study, we have established a multivariable clinical prediction model using a development cohort of 299 patients from one hospital.', 'After backwards selection, four variables, including age, lymphocyte count, lactate dehydrogenase and SpO2 remained in the model to predict mortality.', 'This has been validated internally and externally with a cohort of 145 patients from a different hospital.', 'Discrimination of the model was excellent in both internal (c=0·89) and external (c=0·98) validation.', 'Calibration plots showed excellent agreement between predicted and observed probabilities of mortality after recalibration of the model to account for underlying differences in the risk profile of the datasets.', 'CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', '(which was not peer-reviewed)', 'The copyright holder for this preprint .']}\n", - "{'sentences': ['India is the second-largest population in the world, and developing nation, it is not well equipped 25 as compared to other developed countries like China, USA, Italy, Germany.', 'Hitherto, in the 26 scenario of the global pandemic, SARS-CoV-2 affected a hundred thousand people in 202 27 countries and territories, which could impart a devastating impact on the Indian population.', 'In 28 the absence of vaccines, the only way to respond against this critical condition is by practicing 29 large-scale social distancing.', 'Interestingly, China diminishes COVID-19 cases by forcefully 30 applying strict restrictions to isolate even mild symptomatic individuals; local authorities went 31 door to door for testing, increases the hospital facilities, including ventilators.', 'Likewise, India 32 also took a very bold decision to lock down the whole country for 21 days, starting from 24 33 March 2020 after detecting 571 positive COVID-19 confirmed cases.', 'However, till 1 April 2020, 34 SARS-CoV-2 positive cases were growing exponentially, which raises the concerns if the 35 number of reported and actual cases are similar.', 'Our analysis suggests that there is an urgent 36 need to take action to extend the period of lockdown and allocate enough resources, including 37 personnel, beds, and intensive care facilities, to manage the situation in the next few days and 38 weeks.', 'Otherwise, the outbreak in India can reach the level of the USA or Italy or could be worse 39 than these countries within a few days or weeks, given the size of the population and lack of 40 resources.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro']}\n", - "{'sentences': ['Objective: To study the effect of COVID-19 on pregnancy outcomes and neonatal prognosis in Hubei Province.', 'A retrospective comparison of the pregnancy outcomes was done between 16 women with COVID-19 and 45 women without COVID-19.', 'Also, the results of laboratory tests, imaging examinations, and the 2019-nCoV nucleic acid test were performed in 10 cases of neonatal deliverd from women with COVID-19.', 'Results: (1) Of the 16 pregnant women with COVID-19, 15 cases were ordinary type and 1 case was severe type.', 'No one has progressed to critical pneumonia.', 'The delivery method of the two groups was cesarean section, and the gestational age were (38.7±1.4) and (37.9±1.6) weeks, there was no significant difference between the two groups (P> 0.05).', 'Also, there wee no significant differences in the intraoperative blood loss and birth weight of the newborn between the two groups (all P>0.05).', '(2) Ten cases of neonates delivered from pregnant women with COVID-19 were collected.', 'The 2019-nCoV nucleic acid test were all negative.', 'There were no significant differences in fetal distress, meconium-stained amniotic fluid, preterm birth, and neonatal asphyxia between the two groups (all P>0.05).', '(3) In the treatment of uterine contraction fatigue, carbetocin or carboprost tromethamine was used more in cesarean section for pregnant women with COVID-19 (1.3±0.6), compared with Non-COVID-19 group (0.5±0.7), the difference was statistically significant (P=0.001).', 'Conclusions: If there is an indication for obstetric surgery or critical illness of COVID-19 in pregnant women, timely termination of pregnancy will not increase the risk of premature birth and asphyxia of the newborn, but it is beneficial to the treatment and rehabilitation of maternal pneumonia.', 'Preventive use of long-acting uterotonic agents could reduce the incidence of postpartum hemorrhage during surgery.', '2019-nCoV infection has not been found in neonates deliverd from pregnant women with COVID-19.']}\n", - "{'sentences': ['Structure-based drug discovery has been shown to be an advance approach for the 231 development of new therapeutics.', 'Many ongoing studies are developed to treat COVID-19 232 author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.06.977876 doi: bioRxiv preprint primarily targeting the spike protein, viral proteases (3C-like protease and papain-like protease).', 'However, there is little effective targeted therapeutic currently.', 'Recent studies demonstrated 234 that N proteins will be a good drug-targeting candidate in other CoVs since they process several 235 critical functions, such as RNA genomic packing, viral transcription and assembly, in the 236 infectious cell 10 .', 'However, the molecular basis of SARS-CoV-2 N protein is yet to be elucidated.', 'Here, we present the 2.7 Å crystal structure of SARS-CoV-2 N protein N-terminal domain, 238 revealing the specific surface charge distributions which may facilitate drug discovery specifically 239 to SARS-CoV-2 N protein ribonucleotide binding domain.']}\n", - "{'sentences': ['To avoid false-negative and false-positive results, coronavirus antibody tests should also be performed.', 'Antibodies can be used to determine whether coronavirus IgM and IgG antibodies are present in the body.', 'IgG is a protective antibody that is produced 2 weeks after infection with the virus.', 'Its production continues for a long time, and the antibody may be carried for life; its presence indicates infection with the virus.', 'A higher IgG value indicates a higher amount of antibodies in the patient and stronger resistance to the virus.', 'When both IgM and IgG are negative, no infection is present or no antibodies have been produced; when both are positive, the patient has recently been infected and viruses are present in the body.', 'When IgM is negative and IgG is positive, the patient has produced antibodies, is within the rehabilitation period, and is very safe.', 'When our patient was first discharged from the hospital, the negative nucleic acid test result might have been false-negative.', 'The virus might have been controlled at a low level, making it difficult to collect from the throat.', 'Before the protective antibodies were produced, the discontinuation of treatment may have contributed to a comeback of the virus.', 'The positive result of the nucleic acid test on the throat swab on 8 March basically ruled out the false-positive result, as assisted by the results of two nucleic acid tests from throat swabs on 17 and 20 March and viral antibody tests on 17 March ( Table 1) .', 'Instead of resurgence, the virus was in fact still present.', 'According to the explanation of positive test results in recovered patients with COVID-19 by academician Lanjuan Li in an interview, a small amount of residual virus remained in the deep regions of the lung, suggesting that TCM care such as Chinese herbal decoction, acupuncture and moxibustion, and Chinese Tuina massage during the rehabilitation period is also important.', 'Our patient was first discharged from the hospital according to the discharge standards at that time; these standards were based on consecutive negative nucleic acid test results together with remarkable alleviation of respiratory symptoms, a decrease in body temperature, and improvement of chest CT results.', 'The throat swab test is convenient and therefore very common.', 'However, an anal test and virus antibody test should be considered in future because such tests may help to rule out positive cases among discharged patients.', 'In particular, if IgM is negative and IgG is positive in a discharged patient with COVID-19, then protective antibodies have been produced and centralized isolation is not needed; this may greatly reduce medical costs.', 'In this patient with COVID-19, a positive nucleic acid test result on a throat swab was obtained 22 days after discharge from the hospital.', 'Whether this occurred because of recurrence of the disease, re-infection by the virus, or a false-positive result at discharge is worth further discussion.', 'After readmission, the patient had no discomfort except for throat itching and a cough; however, these symptoms were milder than before her first discharge from the hospital.', 'The CT scan showed improvement as evidenced by absorption of the lung opacities.', 'Additionally, the blood tests results were normal.', \"These findings indicate that the patient's positive nucleic acid test result after hospital discharge was not likely due to relapse; instead, it was more likely due to incomplete clearance of the virus.\", \"The nucleic acid test results on the patient's throat swabs were alternately negative and positive, which may be related to factors such as the sensitivity of nucleic acid testing or insufficient virus collection in throat swabs.\", \"The patient's nucleic acid test result on her throat swab was still positive more than 1 month (17 March) after her first discharge from the hospital (15 February), which may have been related to her thyroid cancer surgery in February 2018 and intermittent treatment with levothyroxine tablets.\", 'The virus was likely more slowly removed because of her impaired autoimmunity.', 'Additionally, whether the use of levothyroxine can cause false-positive results is unclear.', \"COVID-19 obviously injuries the patient's lung, and in TCM, the throat is the portal to the lungs.\", 'Therefore, throughout the entire respiratory tract with the exception of the lungs, coronavirus accumulates primarily in the throat; this is why many patients with COVID-19 in clinical practice have been found to have coughs caused by throat itching.', 'However, a simple chest radiograph or throat swab nucleic acid test is not enough to determine whether the virus has been completely removed.', 'The throat swab test results cannot truly reflect the amount of virus present in the throat and the lungs.', 'During treatment, the virus may be controlled and significantly reduced or removed from the upper respiratory tract; however, this does not mean that the virus in the lower respiratory tract has also been completely removed, but only that it cannot be detected through throat swab tests.', 'Similarly, the coronavirus may affect the heart, liver, spleen, and kidney.', '[6] [7] [8] [9] [10] If underlying diseases affecting any of these five viscera are present, virus removal will be more difficult.', 'Judging the condition of the lungs from the throat swab is in accordance with the TCM theory that the throat is the portal to the lungs.', 'Similarly, because the lung corresponds to the large intestine in TCM theory, it seems that an anal test should also be added to the diagnostic and cure criteria for COVID-19.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia', 'At the end of December 2019, a novel coronavirus (COVID-19) caused an outbreak in Wuhan, and has quickly spread to all provinces in China and 26 other countries around the world, leading to a serious situation for epidemic prevention.', 'So far, there is still no specific medicine.', 'Previous studies have shown that chloroquine phosphate (chloroquine) had a wide range of antiviral effects, including anti-coronavirus.', 'Here we found that treating the patients diagnosed as novel coronavirus pneumonia with chloroquine might improve the success rate of treatment, shorten hospital stay and improve patient outcome.', 'In order to guide and regulate the use of chloroquine in patients with novel coronavirus pneumonia, the multicenter collaboration group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus pneumonia developed this expert consensus after extensive discussion.', 'It recommended chloroquine phosphate tablet, 500mg twice per day for 10 days for patients diagnosed as mild, moderate and severe cases of novel coronavirus pneumonia and without contraindications to chloroquine']}\n", - "{'sentences': ['Over 100,000 cases of COVID-19 patients infected with the novel coronavirus SARS-COV-2 have been reported worldwide in approximately 2 months, resulting in over 3000 deaths.', 'Potential therapeutic strategies, including remdesivir, chloroquine phosphate, abidol, lopinavir/ritonavir, plasma, antibody, vaccine and stem cells are discussed in this review.', 'With the number of patients increasing daily, there is an urgent need for effective therapeutic intervention.', 'Currently, remdesivir appears to be the most promising drug for the treatment of pneumonia caused by COVID-19 pneumonia.', 'Many other agents or strategies are being tested for the treatment of patients with COVID-19.', 'However, double-blind, randomized controlled trials are required to investigate their safety and efficacy.']}\n", - "{'sentences': ['In this large prospective cohort study conducted in a tertiary teaching hospital with 3 branches in Wuhan, China, we observed a high prevalence of kidney disease in hospitalized patients with COVID-19.', 'More than 40% of them had evidence of kidney disease, with elevated serum creatinine and BUN values in over 13% of them.', 'Strikingly, the presence of kidney disease was associated with greater in-hospital mortality.', 'Multiple organ involvement including the liver, gastrointestinal tract, and kidney have been reported during the course of SARS in 2003 6 and very recently in patients with COVID-19.', '7 One possible explanation of the high prevalence of kidney involvement at hospital admission is that some the patients with COVID-19 had a past history of chronic kidney disease.', 'Such patients have a proinflammatory state with functional defects in innate and adaptive immune cell populations 8 and are known to have a higher risk for upper respiratory tract infection 9 and pneumonia.', 'Of note, the median time period between the first symptoms and signs of COVID-19 and hospital admission was slightly more than a week in our study.', 'An alternative explanation is that many patients with COVID-19 could not be admitted in the very early stage of disease outbreak because of the acutely increasing, large number of patients and limited availability of hospital beds in Wuhan.', 'Earlier admission to hospital might have helped to prevent disease spread and deterioration.', 'This is the first study showing an association between kidney involvement and poor outcome in patients with COVID-19.', 'We found that patients with elevated baseline serum creatinine were more likely to be admitted to the intensive care unit and to undergo mechanical ventilation, suggesting that kidney disease on admission represented a higher risk of deterioration.', 'It has been reported previously that kidney injury was associated with an increased risk of death in patients with influenza A virus subtype H1N1 and SARS.', '5, 11 In our study, e d i t o r i a l : s p e c i a l r e p o r t indicators of kidney involvement at admission were associated with a higher risk of in-hospital death even after adjustment for potential confounders.', 'This observation indicated poor prognosis regardless of initial COVID-19 severity and general physical condition.', 'Monitoring kidney function must therefore be emphasized even in patients with mild respiratory symptoms, and altered kidney function should be given particular attention after admission in clinical practice.', 'Early detection and treatment of renal abnormalities, including adequate hemodynamic support and avoidance of nephrotoxic drugs, may help to improve the vital prognosis of COVID-19.', 'AKI results from an abrupt loss of kidney function and is strongly associated with increased mortality and morbidity.', '12 We found that patients with elevated serum creatinine were more likely to develop AKI during hospitalization, which is consistent with study in SARS.', '5 It is therefore important to increase the awareness of AKI in those who entered the hospital with an elevated serum creatinine.', 'In our cohort, the detection rate of AKI in patients with COVID-19 was 5.1%, which is in keeping with recent reports of small sample size 1,4,7,13 and much higher than the 0.5% of a large observational study.', '14 This may be explained by an extremely high proportion of severely sick patients in a previous case series and only 15.7% in the large observational study.', 'In our cohort study, 42.7% of patients were severely ill, and this may explain the higher detection rate of AKI in clinic practice in Wuhan.', 'Importantly, the present method of detecting AKI is mainly based on acute changes in serum creatinine and the frequency of serum creatinine tests has a substantial impact on detection rate.', '15 In a nationwide crosssectional survey of hospitalize adult patients in China, the detection rate of AKI was only 0.99% by Kidney Disease: Improving Global Outcomes (Kidney Disease:', 'Improving Global Outcomes', 'The etiology of kidney disease involvement in patients with COVID-19 is likely to be multifactorial.', 'First, the novel coronavirus may exert direct cytopathic effects on kidney tissue.', 'This is supported by the detection of polymerase chain reaction fragments of coronavirus in blood and urine in both the patients with the 2003 SARS virus 18 and those with COVID-19.', '4 Recently, it has been shown that the novel coronavirus uses angiotensin converting enzyme 2 (ACE2', 'We compared the medications on the first day of admission and during the hospitalization in patients with AKI and non-AKI.', 'We found that patients with AKI were more likely to have higher proportion of glucocorticoid and lower proportion of antiviral drugs and reninangiotensin-aldosterone system inhibitors treatment on admission.', 'The difference in the use of glucocorticoids may be explained by the condition of patients with AKI that was more severe, thus physicians tended to use glucocorticoids in the most critically ill patients, even if there is a controversy on the use of glucocorticoids in patients with COVID-19.', '22, 23 However, the oral antiviral drugs, including umifenovir, oseltamivir, and lopinavir with ritonavir, were preferred in moderate patients on admission.', 'Given that ACE2 is a functional receptor for SARS-CoV-2, the safety and potential effects of renin-angiotensin-aldosterone system inhibitors in patients with COVID-19 should be carefully considered.', '24 These potentially harmful effects may account for the low proportion of renin-angiotensin-aldosterone system inhibitors used by physicians in our cohort, especially in patients with AKI who had higher level of creatinine on admission.', 'Due to the small number of patients with AKI and the bias in different therapy of patients with COVID-19, causal relationship between drug and AKI in patients with COVID-19 remains undetermined.', 'Even though this study included a large number of patients from a tertiary teaching hospital in Wuhan, it has several limitations.', 'First, an accurate baseline serum creatinine was not available, which may have led to an underestimation of AKI or erroneous associations.', 'Second, although we attempted to adjust for many confounders, other unmeasured or unknown confounders might have played a role.', 'Third, clinical data of patients after discharge were lacking, so we could not assess COVID-19 effects on long-term outcomes.', 'The precise impact of COVID-19 on kidney structure and function and the incidence of chronic kidney disease in these patients require further investigation.', 'In conclusion, the prevalence of kidney disease in patients with COVID-19 hospitalized in Wuhan, China, was high.', 'After adjustment for confounders, kidney disease on admission and AKI during hospitalization were associated with an increased risk of in-hospital death.', 'Clinicians should increase their awareness of kidney disease in hospitalized patients with COVID-19.', 'Early detection and effective intervention of kidney involvement may help to reduce deaths of patients with COVID-19.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Remdesivir and SARS-CoV-2: structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites', 'The rapid global emergence of SARS-CoV-2 has been the cause of significant health concern, highlighting the immediate need for antivirals.', 'Viral RNA-dependent RNA polymerases (RdRp) play essential roles in viral RNA synthesis, and thus remains the target of choice for the prophylactic or curative treatment of several viral diseases, due to high sequence and structural conservation.', 'To date, the most promising broad-spectrum class of viral RdRp inhibitors are nucleoside analogues (NAs), with over 25 approved for the treatment of several medically important viral diseases.', 'However, Coronaviruses stand out as a particularly challenging case for NA drug design due to the presence of an exonuclease (ExoN) domain capable of excising incorporated NAs and thus providing resistance to many of these available antivirals.', 'Here we use the available structures of the SARS-CoV RdRp and ExoN proteins, as well as Lassa virus N exonuclease to derive models of catalytically competent SARS-CoV-2 enzymes.', 'We then map a promising NA candidate, GS-441524 (the active metabolite of Remdesivir) to the nucleoside active site of both proteins, identifying the residues important for nucleotide recognition, discrimination, and excision.', \"Interestingly, GS-441524 addresses both enzyme active sites in a manner consistent with significant incorporation, delayed chain termination, and altered excision due to the ribose 1'-CN group, which may account for the increased antiviral effect compared to other available analogues.\", 'Additionally, we propose structural and function implications of two previously identified RdRp', 'This study highlights the importance of considering the balance between incorporation and excision properties of NAs between the RdRp and ExoN.']}\n", - "{'sentences': ['Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies']}\n", - "{'sentences': ['As the COVID-19 pandemic rapidly progresses worldwide, there is a dire need to identify new prophylactic and therapeutic strategies.', 'Based on recent data from analyses of inflammatory markers in COVID-19 (5, 6) and prior knowledge about inflammatory responses in other lethal viral lung infections, targeted immune-suppression is now appreciated as a potential strategy to prevent ARDS, fulminant myocarditis, organ failure, and mortality at advanced stages of the condition (9).', 'Accordingly, clinical trials for diverse immune-suppressants have been started around the world, including inhibitors of IL-6 and JAK/STAT signaling.', 'Here, we demonstrate a key role for the JAK1 kinase in driving cytokine storms and accompanying mortality in a mouse model of lethal anti-viral immune responses.', 'JAK1 is one of several JAK kinases required for mediating inflammatory signaling downstream of a large number of cytokines, including all three types of IFN signaling and IL-6 (25).', 'We show that eliciting the innate anti-viral immune response with TLR agonists is lethal in a sensitized mouse model carrying triplication of four of the six IFN receptors.', 'Within days, the Dp16 mice rapidly lose weight and die if unattended, concurrent with induction of many prominent cytokines linked to the severity of COVID-19-driven pathology, such as IL-6, TNF-α, IL-10, IP-10, MCP-1, and MIP-1α (6) .', 'Furthermore, Dp16 mice display exacerbated liver inflammation and pathology, which, together with stronger production of some cytokines, may converge into a pathological cascade leading to wasting and death.', 'Importantly, these phenotypes are blocked by JAK1 inhibition.', 'Based on these results, we propose here that JAK inhibitors are a valid therapeutic approach for attenuating the cytokine storm in COVID-19.', 'Four JAK inhibitors are currently FDA-approved for the treatment of diverse medical conditions: Jakafi/Ruxolitinib, a JAK1/2 inhibitor approved .', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.07.024455 doi: bioRxiv preprint for myelofibrosis, polycythemia vera, and graft-versus-host-disease; Xeljanz/Tofacitinib, a JAK1/3 inhibitor approved for rheumatoid arthritis, psoriatic arthritis and ulcerative colitis;', 'Olumiant/Baricitinib, a JAK1/2 inhibitor approved for rheumatoid arthritis; and Rinvoq/Upadacitinib, a JAK1 inhibitor also approved for rheumatoid arthritis.', 'Many JAK1specific inhibitors are currently being developed and tested in clinical trials for diverse inflammatory and autoimmune conditions, including the molecule used in this study,']}\n", - "{'sentences': ['The main purpose of this study was to generate a high-quality resource of metabolomic and lipidomic datasets associated with COVID-19 to help understand the pathogenesis of COVID-19.', 'For these COVID-19 patients, the metabolisms of main amino acids, nucleotides, organic acids and carbohydrates were significantly decreased.', 'Meanwhile, the lipids involved in glycerol metabolism pathway were upregulated, which maintain the balance of the energy metabolites of the body and are beneficial to the energy required for viral replication, suggesting that SARS-CoV-2 probably hijacks cellular metabolism like many other viruses (32).', 'And we hypothesize that the course of COVID-19 is closely associated with the alternations of host pyrimidine metabolic, purine metabolic, and glycerol phospholipid metabolic pathways.', 'Importantly, many of the altered metabolites and lipids, including the proposed biomarkers L-malic acid, Xu-5-P, Carbamoyl phosphate, Glycerol-3-phosphate, PC, LPC, etc., correlate well with the progress and severity of COVID-19 and are closely associated with hepatic functions.', 'Moreover, the downregulations of L-malic acid and Carbamoyl phosphate probably cause the abnormal accumulation of ammonia (i.e. hyperammonemia), which may in turn result in disease deterioration.', 'In addition, the metabolisms of purine and thyroid hormones were significantly altered in the fatality group.', 'Purine metabolism mainly occurs in human liver, and the thyroid hormone can affect hepatic protein synthesis and glycogen decomposition.', 'Therefore, our findings show that the development of COVID-19 can cause hepatic impairment in these 14 patients, which is consistent with the observations that a large number of COVID-19 patients showed liver function abnormalities (Table S13) (6) .', 'Besides, our data show that the metabolic pathway of glycerophospholipids has been significantly changed, and glycerophospholipids are closely related with cardiovascular diseases.', 'However, we did not find obvious pattern or significant difference of underlying diseases, such as hypertension, cardiac disease, diabetes, cerebrovascular disease, chronic hepatitis, and cancer, in the medical records of all the patient groups involved in this study.', 'Therefore, this finding suggests that the fatality caused by COVID-19 might be related with cardiac impairment.', 'Interestingly, COVID-19 has been recently reported to probably cause the loss of the smell and taste sense (https://www.npr.org/sections/goatsandsoda/2020/03/26/821582951/is-loss-of-smelland-taste-a-symptom-of-covid-19-doctors-want-to-find-out), and the KEGG analysis also showed that the taste transduction pathway is affected.', 'The metabolomic and lipidomic analyses also show that, although the patients in both the severe and mild symptom groups had met the official hospital discharge criteria as their COVID-19 nucleic acid tests turned negative consecutively twice and major clinical signs disappeared, many of their fundamental metabolites and lipids failed to return to normal.', 'This finding indicates that these discharged patients, regardless of the severity of their previous symptoms, had not been fully recovered from the disease in the aspect of metabolism, particularly hepatic functions.', 'Therefore, even after the clearance of SARS-CoV-2 from patient bodies, these convalescent COVID-19 patients All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.04.05.20053819 doi: medRxiv preprint 15 still need better nutrition and care that would be very helpful for their faster and full recovery from the disease.', 'The metabolomic and lipidomic alterations in patient plasma mainly reflect the systematic responses of the metabolisms of diverse cell types and organ systems that were affected by COVID-19.', 'Therefore, the interpretations of the datasets should be integrated with other types of system studies, such as the transcriptome and proteome of specific tissue and body fluid samples, as well as clinical observations and laboratory examinations, to have a clearer and more comprehensive picture of the development of this disease.', 'Moreover, such an integration would help us better understand the impacts of COVID-19 to specific cells and/or tissues infected by SARS-CoV-2.', 'In summary, the metabolomic and lipidomic datasets of the cohort of COVID-19 patients under different symptomatic conditions are highly valuable resources for better understanding the host metabolic responses associated with COVID-19, which expands our knowledge about the pathogenesis of COVID-19, accelerates identification of disease biomarkers and development of diagnostic assays, and provides hints of potential therapeutic strategies.', 'All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['2 3 Halim Maaroufi 4 Institut de biologie intégrative et des systèmes (Institut de biologie intégrative et des systèmes).', 'Canada 5 Halim.maaroufi@ibis.ulaval.ca 6 7 ABSTRACT The novel betacoronavirus (SARS-CoV-2) is highly contagious and can cause 8 serious acute respiratory illness syndromes, often fatal, called covid-19.', 'It is an urgent priority to 9 better understand SARS-CoV-2 infection mechanisms that will help in the development of 10 prophylactic vaccines and therapeutics that are very important to people health and socioeconomic 11 stability around the world.', 'The surface coronavirus spike (S) glycoprotein is considered as a key 12 factor in host specificity because it mediates infection by receptor-recognition and membrane 13 fusion.', 'Here the analysis of CoV-2 S protein revealed in S1subunit a B56-binding LxxIxE-like 14 motif that could recruit the host protein phosphatase 2A (PP2A).', 'This motif is absent in SARS-15 CoV and MERS-CoV. PP2A is a major family of serine/threonine phosphatases in eukaryotic cells.', '16 Phosphatases and kinases are big players in the regulation of pro-inflammatory responses during 17 pathogenic infections.', 'Moreover, studies have shown that viruses use multiple strategies to target 18 PP2A']}\n", - "{'sentences': ['This is the first mental health investigation in the wake of the coronavirus epidemic in Wuhan, China that aims, in part, to explore the demand for mental healthcare services in this context.', 'When cities are struck by deadly, large-scale disasters of various types, the characteristics of mental health problems that arise can differ across different periods (Shioyama et al., 2000) .', 'We therefore chose to survey a set of people (health care providers) in the discrete window of time soon after the initiation of a chaotic event (the outbreak of coronavirus infections).', 'To conduct a comprehensive analysis, we used multiple different scales to evaluate the mental health of medical staff.', 'Our study has revealed the limits in the availability of mental healthcare services provided by psychologists and psychiatrists and thus the limits in access points for psychological care for distressed individuals, including less personalized sources of support such as publication-style psychological materials and psychological resources available from media.', 'These latter methods can nonetheless contribute positively to alleviating mental health problems and physical discomfort caused by risk factors such as the exposure of close contacts to COVID-19.', 'Such exposure is known to be mentally injurious in epidemic settings: when the SARS epidemic hit, not only did the direct exposure of the work environment affect the mental health of medical staff, but the infection of friends or close relatives generated psychological trauma (Wu et al., 2009) .', 'We found that subthreshold and mild mental health disturbances accounted for a large proportion of disturbances.', 'People with such levels of disturbances may be more likely than those with more severe disturbances to take action and be motivated to learn the necessary skills and to adapt in productive ways to respond to diverse challenges.', 'These skills have been shown in previous retrospective studies to be protective for later mental health (Maunder et al., 2006) .', 'In addition, we note that people with subthreshold and mild mental health disturbances want to find ways to better help others, which is beneficial for health care teams.', 'In terms of physiology, positive coping has been seen to increase immune function when victimized subjects report high mental demands, leading to a better state of response (Sakami et al., 2004) .', 'However, there are negative consequences of stimulation caused by pressure, as acute psychological stress is known to activate the sympathetic adrenal medulla system and hypothalamus-pituitary adrenal axis, and this two-component stress response impacts physical and mental health and has disease consequences (Turner et al., 2020) .', 'In summary, continuous mental healthcare services are necessary even for subthreshold and mild psychological reactions during this epidemic to attenuate the possibility of escalating complications.', 'Multiple features were found for the group of untreated clinical L. Kang, et al. Brain, Behavior, and Immunity xxx (xxxx) Fig. 1 .', 'In this model, the solid line represents a significant relationship between the two, while the dotted line represents the relationship is not significant.', 'Kang, et al. Brain, Behavior, and Immunity xxx (xxxx) xxx-xxx personnel who had serious psychological problems.', 'First, compared to less severely affected groups, they had accessed fewer printed psychological advice materials (e.g., office brochures) and had accessed less psychological guidance publicized through digital media.', 'Second, they were more likely to desire personalized, one-on-one counseling as a therapy option.', 'One might speculate a cause-and-effect relationship wherein more frequent exposure of the other groups to the noted materials in some way protected them from reaching the most severely impacted category, but our cross-sectional results are, by nature, correlational.', 'This study limitation does not detract, however, from the importance of widely implementing prevention and monitoring strategies; mildly to moderately impacted personnel expressed interest in having access to psychological guidance materials, which provides evidence of the importance of prevention strategies.', 'The number of people suffering from mental health impacts after a major event is often greater than the number of people who are physically injured, and mental health effects may last longer.', 'Nonetheless, mental health attracts far fewer personnel for planning and resources (Allsopp et al., 2019) .', \"Thus, the Lancet Global Mental Health Commission's observation that the use of nonprofessionals and digital technologies can provide a range of mental health interventions may indicate an opportunity (Patel et al., 2018) .\", 'Our data are consistent with a model in which psychological advice and guidance in print resources and disseminated in the media can provide a level of protection for medical and nursing staff, improving mental health by reducing the stress impacts caused by high risk of infection.', 'Clearly, there is a role, nonetheless, for therapist-driven sessions, as previous research showed that a convenient group course intervention for doctors reduced depersonalization, improved views on the meaning of work, and achieved sustained results (West et al., 2014) .', 'We anticipate similar benefit for COVID-19 staff in Wuhan based on our findings contained herein.', 'Interestingly, previous studies on medical staff and other infectious agents have repeatedly emphasized that mental health impacts are related to department and occupation (Hawryluck et al., 2004; Wu et al., 2009) .', 'Health care workers with professional knowledge about differences in the relative exposure patterns and transmission of different infectious diseases could gain some degree of comfort and control over their situations (Chowell et al., 2015) .', 'For example, over the decades, although hepatitis viruses and HIV have often caused lethal infections, radiologists, pathologists and nurses knew that their risk of exposure was low as long as they exercised caution in their contact with bodily fluids.', 'The situation has been different in Wuhan due to the pernicious characteristics of COVID-19.', 'Many infected individuals exhibit minimal or no symptoms while contagious, for example, early in the course of infection (Bai et al., 2020) .', 'These individuals may thus visit a variety of different hospital departments in an infectious but asymptomatic state, unknowingly spreading the disease directly through aerosolized droplets or indirectly through skin contact with handled surfaces.', 'These features of the infectivity of coronavirus involve a substantial risk of exposure for medical workers, regardless of their hospital department, job title or building location; thus, any workerwhether doctor or nurse, specialist or generalistis at substantial risk.', 'The resultant stress due to concerns about infection risk thus indiscriminately affects large numbers of personnel.', 'There is a need to better recognize mental health needs as an important component of mobilizing a large-scale therapeutic response to sudden city-scale crisis scenarios.', 'A large rapid response team in crisis situations should include mental healthcare workers.', 'Local medical and nursing staff at the epicenter of a crisis are pivotal to the overall response, and care for these caregiverswhether through face-to-face counseling or comparable support through digital platforms such as cell phone interfacesis essential in efforts to extend their immediate efficiency and to better protect their mental health in the long term.', 'Our research also has some limitations.', 'First, compared with faceto-face interviews, self-reporting has certain limitations.', 'Second, the study is cross-sectional and does not track the efficacy of psychological services.', 'Due to changes in posttraumatic mental health, dynamic observation is necessary.', 'A randomized prospective study could better determine correlation and causation.', 'Third, a larger sample size is needed to verify the results.', 'In summary, the results demonstrate that a strikingly large portion of health care providers in virus-plagued Wuhan are suffering from mental health disturbances.', 'They would benefit from greater availability of personalized mental health care from psychotherapists and psychiatrists, wherein different mental health groups could focus on providing specialized mental healthcare services.', \"Among the steps needed to better prepare for future infectious disease outbreaks would be a greater investment in the mental health tools in society's medical arsenal to protect and care for future medical and nursing staff who find themselves unexpectedly on the dangerous front lines of disease response.\"]}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Cannabidiol as prophylaxis for SARS-CoV-2 and COVID-19?', 'Unfounded claims versus potential risks of medications during the pandemic']}\n", - "{'sentences': ['We analysed the serial viral load, antibody kinetics, and viral genome of patients with COVID-19 in Hong Kong.', 'For most patients, the viral load of SARS-CoV-2 was very high at presentation and declined steadily.', 'Despite develop ment of antibodies against surface and internal proteins of SARS-CoV-2, viral RNA could still be detected in posterior oropharyngeal (deep throat) saliva samples from a third of patients for 20 days or longer.', 'Peak viral load correlated positively with age.', 'Most patients had an antibody response at 10 days or later after onset of symptoms.', 'Viral whole-genome sequencing of paired samples from four patients did not identify any single nucleotide poly morphisms.', 'A high viral load on presentation of COVID-19 was recorded in our cohort, even for patients who were hospitalised shortly after symptom onset.', 'Using nasal swab and throat swab, Zou and colleagues 8 have also reported a high viral load shortly after symptom onset.', 'However, in that study, only cycle threshold values (not exact viral loads) were reported, and no statistical or correlative analysis was done with clinical variables such as age, comorbidities, disease severity, and antibody response.', 'The viral load profile of SARS-CoV-2 is similar to that of influenza, which peaks at around the time of symptom onset, but contrasts with that of SARS-CoV at around 10 days and that of MERS-CoV at the second week after symptom onset.', '4, 16, 17 The high viral load on presentation suggests that SARS-CoV-2 can be transmitted easily, even when symptoms are relatively mild.', 'This finding could account for the efficient person-to-person transmission noted in community and health-care settings.', 'Clusters in families, workplaces, religious gatherings, and food premises have been widely reported.', 'The viral load profile is important for guiding antiviral treatment.', 'Since viral load had already peaked around the time of hospital admission, the risk of emergence of antiviral resistance could be similar to that of single-drug treatment of influenza by adamantanes, acid polymerase inhibitors, and neuraminidase inhibitors.', 'However, our previous clinical trial of influenza treatment showed that a triple antiviral combination could significantly improve the clinical outcome and viral load profile and could reduce emergence of resistant virus quasispecies.', '19 Currently, no standard treatment is available for Figure 3 : Relation between viral load and age or disease severity Correlation between age and peak viral load (A).', 'Comparison of initial (B) and peak (C) viral load between severe and mild cases.', 'Comparison of initial (D) and peak (E) viral load between patients with comorbidities and those without comorbidities.', 'For SARS-CoV infection, our previous treatment study showed that a combination of lopinavirritonavir and ribavirin led to significantly fewer compli cations (eg, acute respiratory distress syndrome) or deaths than reported with historical controls treated with ribavirin.', '5 Lopinavir-ritonavir or interferon beta 1b also reduced lung damage and decreased viral load in a nonhuman primate model of MERS-CoV. 20 Lopinavir is a protease inhibitor with in-vitro activity against SARS-CoV and MERS-CoV. However, the idea that SARS-CoV 3C-like protease was the antiviral target of lopinavir was based purely on binding in computational modelling.', '21 Other protease inhibitors and nucleotide analogues (eg, remdesivir [Gilead Sciences, Foster City, CA, USA]) are potential candidates for treatment.', 'Combination treatment with virus-targeting and host-targeting agents to improve clinical outcome should be investigated.', 'Studies for SARS-CoV have shown that a high initial viral load was associated with death.', '22 However, our study only showed that the median viral load was 1 log 10 higher in severe cases than in mild cases, and the difference was not significant.', 'But, older age was associated with a higher peak viral load.', 'In a previous study of patients infected with SARS-CoV, older age was an independent factor associated with higher viral load, 23 as expected for immunosenescence, which impairs our innate and adaptive immune responses.', 'SARS-CoV-2 RNA could be detected for 20 days or longer in a third of patients who survived in our cohort, and one patient had SARS-CoV-2 RNA detected for 25 days.', 'Prolonged detection of viral RNA of 20 days or longer was also commonly seen for patients with MERS-CoV or SARS-CoV infections.', '4, 16 Prolonged detection of viral RNA represents a challenge for the limited availability of hospital isolation facilities because patients might not be discharged until viral RNA is undetectable in respiratory specimens.', 'Further studies are warranted to ascertain whether patients are shedding live virus, by viral culture of the prolonged RT-PCR-positive specimens obtained from patients with concomitant seropositivity when shedded virions are coated with host antibodies which render them non-infectious.', 'A criterion for discontinuation of transmission-based precautions is a negative RT-qPCR result from two sets of nasopharyngeal and throat swab specimens.', 'In the current study, one patient with complete symptom resolution tested positive for SARS-CoV-2 again after 2 days of negative findings.', 'Our results suggest that SARS-CoV-2 might be excreted at low levels despite clinical recovery.', 'Thus, both serial viral load monitoring and antibody response should be considered when making decisions about infection control measures, because viral load seemed to be related inversely to serum antibody response in this study.', 'The antibody profile is vital for timing requests for serological assays and interpretation of antibody test results.', 'Serological diagnosis is important for patients who present late with a very low viral load, below the detection limit of RT-PCR assays.', 'Because most patients have rising antibody titres 10 days after symptom onset, collection of serial serum samples in the convalescent phase would be more useful.', 'Serum IgG amounts can rise at the same time or earlier than those of IgM against SARS-CoV-2.', 'By comparison with findings of a study on IgM and IgG EIA, in which more patients were seropositive for IgG than IgM at day 0 and day 5 of hospital admission, 24 a higher Anti-NP IgG', 'Anti-NP IgM proportion of patients in the current study also had earlier IgG than IgM seroconversion.', 'However, this finding could also be accounted for by a lower sensitivity of the IgM EIA, which warrants investi gations with more patients.', 'Serum antibody levels were not correlated with clinical severity.', 'Notably, one patient with severe disease had an early antibody response 6 days after symptom onset.', 'Deceased patients infected with SARS-CoV developed faster peak anti-spike antibody responses when compared with patients who recovered 25 and had subsequent reduced B-cell immunity with impaired neutralising ability.', 'In a SARS-CoV macaque model, anti-spike IgG stimulated pulmonary proinflammatory responses and caused acute lung injury.', '26 The detrimental effect of antispike IgG was attributable to the effect on wound-healing macrophages, which was mediated via the Fcγ receptor.', 'Our findings showing correlation between antibody level detected by EIA and virus neutralisation titre are especially important for design of vaccine studies, and use of convalescent plasma or therapeutic monoclonal antibodies, which could improve clinical outcome or paradoxically cause immuno pathological damage to the recipient.', 'Whole-genome sequencing on paired samples from four patients was successful and showed no differences in individually paired genome sequences.', 'However, single nucleotide polymorphisms were shown to emerge during hospitalisation for MERS-CoV infection, using a targeted sequencing approach.', '27 Further studies in more patients with samples obtained at longer intervals could be more informative.', 'A high viral load in throat wash and saliva (up to 10⁸ copies per mL of SARS-CoV RNA) was reported in 17 patients with SARS.', \"28 In a Chinese macaque model of SARS-CoV, salivary gland ducts were early targets of SARS-CoV and, therefore, were a likely source of the virions found in patients' saliva, particularly early in infection.\", '29 Because of these important findings, our study used posterior oropharyngeal saliva brought up by a throat-clearing manoeuvre to ascertain the temporal viral load profile.', 'The posterior oropharynx is the meeting point between secretions coming from the posterior nasopharynx and the salivary glands and respiratory secretions swept up from the tracheal-bronchial tree.', 'Testing of saliva could show viral shedding from both the salivary glands and the upper and lower respiratory tract.', 'Moreover, because of greater patient acceptability for posterior oropharyngeal saliva samples than for nasopharyngeal or throat swabs, we obtained 7·5 respiratory specimens per patient for testing.', 'Thus, our temporal viral load profile can be analysed by statistics, unlike previous clinical studies of viral kinetics of infections by highly pathogenic betacoronaviruses.', '8, 16 Further studies are needed to ascertain whether the salivary glands can be infected by SARS-CoV-2.', 'Our study has several limitations.', 'First, we could only include a few patients, and viral load and antibody titre data were not available everyday.', 'This limitation is a common problem in studies of emerging infections such as SARS-CoV and MERS-CoV. 16 The few patients enrolled does not allow for adjustment for potential confounding factors that could affect viral load or antibody response.', 'Second, 48% of patients enrolled had chronic medical illness, which is a higher proportion than that reported in a large clinical series (24%).', '30 Although a lower anti-RBD IgG level was noted among patients with comorbidities, further studies are warranted with more patients.', 'Third, posterior oropharyngeal saliva samples cannot differentiate whether the virus is coming from the nasopharynx or from secretions from the lower respiratory tract; thus, our study cannot indicate whether SARS-CoV-2 has a predilection for both upper and lower respiratory tract.', 'Moreover, some patients might not clear the throat effectively to cough out saliva from deep in the throat, which could decrease test sensitivity when compared with that of nasopharyngeal swabs, particularly in patients with predominant upper respiratory involvement or mild symptoms.', 'Finally, the most abundantly expressed internal NP might have some cross-antigenicity between SARS-CoV-2 and SARS-CoV (90% amino acid homology) and, occasionally, OC43-CoV (38% amino acid homology).', '31 Thus, the less abundantly expressed surface spike protein RBD, which is specific for SARS-CoV-2 and is the direct target for neutralising antibodies, was used to guard the specificity of our dual antibody assays.', '32 COVID-19 is an emerging infection with many unknowns.', 'This study has shed light on viral kinetics and antibody response in patients and provides scientific evidence for guiding infection control policies and therapeu tics.', 'Further virological and immunological studies are needed to understand SARS-CoV-2 infection; infection control measures should be reviewed with the rapidly evolving epidemiology of COVID-19.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2', 'BACKGROUND: The Severe Acute Respiratory Syndrome Coronavirus 2 (Severe Acute Respiratory Syndrome Coronavirus 2) first broke out in Wuhan (China) and subsequently spread worldwide.', 'Chloroquine has been sporadically used in treating Severe Acute Respiratory Syndrome Coronavirus 2 infection.', 'Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions.', 'We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late-phase in critically ill Severe Acute Respiratory Syndrome Coronavirus 2 infected patients.', 'Currently, there is no evidence to support the use of hydroxychloroquine in Severe Acute Respiratory Syndrome Coronavirus 2 infection.', 'METHODS: The pharmacological activity of chloroquine and hydroxychloroquine was tested using Severe Acute Respiratory Syndrome Coronavirus 2 infected Vero cells.', 'Physiologically-based pharmacokinetic models (PBPK) were implemented for both drugs separately by integrating their in vitro data.', 'Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen whilst considering the drug’s safety profile.', 'RESULTS: Hydroxychloroquine (EC(50)=0.72 μM) was found to be more potent than chloroquine (EC(50)=5.47 μM) in vitro.', 'Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for Severe Acute Respiratory Syndrome Coronavirus 2 infection, as it reached three times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance.', 'CONCLUSIONS: Hydroxychloroquine was found to be more potent than chloroquine to inhibit Severe Acute Respiratory Syndrome Coronavirus 2']}\n", - "{'sentences': ['Vaccine is one of the most important and extensively produced pharmaceutical products.', 'Millions of infants and people are getting vaccinated every year.', 'However, the development and research processes of vaccines are costly and sometimes, it takes many years to develop an appropriate vaccine candidate against a pathogen.', 'In modern .', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.13.039198 doi: bioRxiv preprint times, various tools and methods of immune-informatics, bioinformatics, and reverse vaccinology are extensively used for vaccine development, which save time and cost of the vaccine development process [8, 22] .', 'In current study, the physicochemical study revealed that surface glycoproteins QIA98583.1 and QHS34546.1 had the highest extinction co-efficient of 148960M-1 cm-1 and 147470 M-1 cm-1and lowest GRAVY value of -0.077 and -0.071.', 'In addition, both surface glycoproteins were highly stable (instability index of less than 40) and antigenic.', 'Antigenicity of the proteins was determined by VaxiJen V2.0 server.', 'If a compound had instability index of more than 40, then the compound is referred to be unstable [23] .', 'The extinction coefficient means the amount of light, that is absorbed by a compound at a certain wavelength [24, 25] .', 'The various physicochemical properties like number of amino acids, molecular weight, theoretical pI, extinction co-efficient, instability index, aliphatic index, GRAVY was determined by ProtParam (https://web.expasy.org/protparam/) server.', 'The two selected proteins performed quite similarly in the physicochemical property assessment.', 'In immune system, two of the major cells that functions are the T lymphocytic cell and B lymphocytic cell.', 'After recognized by an antigen presenting cell or APC (like macrophage, dendritic cell etc, the antigen is presented by the MHC class-II molecule present on the surface of these standard APCs, to the helper T cell.', 'Since, the helper T cell contains CD4+ molecule on its surface, it is also called as CD4+ T cell.', 'After activated by APC, the T-helper cell then activates the B cell and causes the production of antibody producing plasma B cell along with memory B cell.', 'The plasma B cell produces a large number of antibodies and the memory B cell functions as the immunological, long term memory.', 'However, macrophage and CD8+ cytotoxic T cell are also activated by the Thelper cell that destroys the target antigen [26] [27] [28] [29] [30] .', 'The possible B cell and T cell epitopes of the selected SARS-CoV-2 proteins were identified by the IEDB (https://www.iedb.org/) server.', 'The IEDB server generates and ranks the epitopes on the basis of their antigenicity scores (AS', 'Moreover, the cluster analysis of the MHC class-I alleles and MHC class-II alleles were also carried out to identify their relationship with each other and cluster them functionally on the basis of their predicted binding specificity [15] .', 'In the next step, the peptide-protein docking was carried out between the selected epitopes and the MHC alleles.', 'The MHC class-I epitopes were docked with the MHC class-I molecule (PDB ID: 5WJL) and the MHC class-II epitopes were docked with the MHC class-II molecule (PDB ID: 5JLZ) respectively.', 'The peptideprotein docking was performed to analyze the ability of the epitopes to bind with their respective MHC molecule.', 'Pre-docking was performed by UCSF-chimera and later on, we performed 3D structure generation of the epitopes.', 'The docking was carried out by PatchDock and FireDock servers also analysed by HPEPDOCK server based on global energy.', 'GVYFASTEK, and NFRVQPTESI generated the best scores in the peptide-protein docking respectively.', 'All the vaccine candidates were proved to be potentially antigenic and non-allergenic, for this reason they should not cause any allergenic reaction within the host body.', 'However, more in vitro and in vivo researches should do to finally confirm the safety, efficacy and potentiality of the predicted vaccines candidates.']}\n", - "{'sentences': ['The full spectrum of COVID-19 disease is still emerging, but several research studies have highlighted that patients suffering from COVID-19 tend to have high d-dimers, fibrinogen and fibrin degradation products [3, 7] .', 'Additional research has suggested that these patients may have a mortality benefit from anticoagulation [7] .', 'During the Severe Acute Respiratory Syndrome (SARS) outbreak in 2002-2003 and H1N1 influenza pandemic in 2009 case reports described concurrent PE with viral lung infections [8, 9] .', 'Data from murine models suggests that SARS-CoV may interact with urokinase to produce a hypercoagulable state observed in SARS', 'An association between COVID-19 and PE creates a diagnostic challenge for emergency medicine clinicians given the overlap in symptoms between the two clinical entities.', 'Elevated D-Dimer levels (>1.0 mg/dl) have been identified as a potential predictor of increased mortality, but are not specific to the diagnosis of VTE [11, 12] .', 'Reliance on D-dimer as a screening tool should be discouraged in this patient population and may lead to over utilization of Computed Tomography Angiography (CTA']}\n", - "{'sentences': ['The cases were confirmed by real-time PCR and the demographic, clinical, laboratory, radiological, and treatment data were collected and analyzed.', 'Prognosis was defined as hospitalization, discharged survivor and death, which was followed up until March 12, 2020.', 'Of the 258 hospitalized patients (63 with diabetes) with COVID-19, the median age was 64 years (range 23-91), and 138 (53.5%) were male.', 'No significant differences in age and sex were identified between patients with and without diabetes.', 'Common symptoms included fever (82.2%), dry cough (67.1%), polypnea (48.1%), and fatigue (38%).', 'Patients with diabetes had significantly higher leucocyte and neutrophil counts, and higher levels of fasting blood glucose, serum creatinine, urea nitrogen and creatine kinase isoenzyme MB at admission compared with those without diabetes.', 'COVID-19 patients with diabetes were more likely to develop severe or critical disease condition with more complications at presentation, and had .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', '/2020 higher incidence rates of antibiotic therapy, non-invasive and invasive mechanical ventilation, and death (11.1% vs. 4.1%).', 'Cox proportional hazard model showed that diabetes (adjusted hazard ratio [aHR]=3.64; 95% confidence interval [CI]: 1.09, 12.21) and fasting blood glucose (aHR=1.19; 95% CI: 1.08, 1.31) were associated with the fatality of COVID-19, adjusting for potential confounders.', 'Conclusions Diabetes mellitus is associated with greater disease severity and a higher risk of mortality in patients with COVID-19.', 'Primary and secondary prevention strategies are needed for COVID-19 patients with diabetes.']}\n", - "{'sentences': ['Considering the significance of this ongoing global public health emergency, although our conclusions are limited by the small sample size, we believe that the findings are important to understand the clinical characteristics and SARS-CoV-2 reactivation potential in COVID-19 patients.', 'We confirmed that in a significantly proportion of COVID-19 patients, SARS-CoV-2 reactivation developed after discharging from hospital (9%).', 'We reported clinical data from 5 patients with SARS-CoV-2 reactivation.', 'The clinical characteristics of these patients with SARS-CoV-2 reactivation were similar to those of nonreactivated patients with COVID-19 infection.', 'None of the 5 patients developed severe pneumonia or died, as of Feb. 24, 2020.', 'Notably, based on our findings in these 5 patients, there is currently evidence to suggest that a proportion of recovered COVID-19 patients could reactivate.', 'The reactivated patients included 1 asymptomatic patient and 4 symptomatic patients, which suggests the reactivation potential of asymptomatic or minimally symptomatic patients.', 'The time from SARS-CoV-2 negative to positive ranged from 4 to 17 days, suggesting that recovered patients still may be virus carriers and require additional round of viral detection and isolation.', 'We need better data to determine risk factors and mechanisms that cause SARS-CoV-2 reactivation.', 'The timing of onset of SARS-CoV-2 reactivation can be variable depending upon the host factors, underlying disease and the type of immunosuppressive therapies.', 'In our study, the recovered patients had positive RT-PCR test results 4-17 days later.', 'The key risk factors for reactivation would include 3 categories: (1) host status, (2) virologic factors and (3) type and degree of immunosuppression.', 'Host factors may include sex, older age, type of disease needing immunosuppression.', 'Although we could not identify risk factors for these host factors in the current study, the potential requires further large cohort confirmation.', 'The virologic factors associated with increased risk of reactivation include high baseline SARS-CoV-2 load and variable genotype.', 'SARS-CoV-2 viral load would also linked to treatment response, disease severity and progression.', '8 The association of SARS-CoV-2 genotypes and viral load with SARS-CoV-2 reactivation will be an important question to address.', 'In our study, all the patients received antiviral therapy (Oseltamivir or Arbidol).', 'These cases suggest that SARS-CoV-2 reactivation may occur whatever the antiviral therapy used.', 'These host and virologic factors are important considerations that may further increase the likelihood of SARS-CoV-2 reactivation.', 'Therefore, the assessment of host as well as virologic risk factors should be important caveats to help decide whether to initiate prophylactic therapy and immunosuppression.', 'Immunosuppressive therapies are the commonly used causative agents.', 'These agents have a general mechanism that inhibits many immune functions.', 'For example, steroid inhibits cellmediated immunity by suppressing interleukins production which is important for T and B cell proliferation.', '9 It is thus not surprising that these general immunosuppressive effects result in broad immune dysfunctions and potential SARS-CoV-2 reactivation.', 'SARS-CoV-2 reactivation will be a vexing and persistent problem.', 'Considering numerous patients infected or previously exposed to the virus, such a problem poses a major public health burden in terms of global morbidity and possibly mortality.', 'Currently, we did not find reliable markers in predicting the risk of SARS-CoV-2 reactivation, nor there are any validated tests to determine whether a particular drug or therapy is associated with SARS-CoV-2 reactivation.', 'The latter point was often determined by our empirical experience.', 'Although decades of the experiences helped us to identify important drugs and to manage these situations appropriately, we could not accurately evaluate the risk of the drugs prior to its clinical application.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Objective: To investigate the pathological characteristics and the clinical significance of novel coronavirus (2019-nCoV)-infected pneumonia (termed by WHO as corona virus disease 2019, COVID-19).', 'Methods: Minimally invasive autopsies from lung, heart, kidney, spleen, bone marrow, liver, pancreas, stomach, intestine, thyroid and skin were performed on three patients died of novel coronavirus pneumonia in Chongqing, China.', 'Hematoxylin and eosin staining (HE']}\n", - "{'sentences': ['The likely long-term impact of the recently emerged COVID-19 is a topic currently shrouded in uncertainty for countries worldwide.', 'At the time of writing, global cases are mounting, with evidence of community transmission for a growing number of countries.', 'In the absence of setting-specific data, an epidemiological understanding of related and unrelated co-circulating pathogens is prudent to guide preliminary estimates of who is at risk and when, and to develop research priorities pertaining to population susceptibility.', 'Epidemiological knowledge of seasonal human coronaviruses (sCoVs) is lacking for many settings due to an absence of inclusion in routine diagnostic testing.', 'Here, we described several key features of sCoVs', 'It is well known that sCoVs cocirculate endemically with other common respiratory viruses, and coinfections are frequently observed [11, 12, 16] .', 'In the West of Scotland, sCoVs typically peak .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', '18.20037101 doi: medRxiv preprint in winter months alongside influenza viruses and RSV, as previously described [12] .', 'The common occurrence of sCoVs during periods of high influenza activity highlights the importance of considering these viruses in the differential diagnosis of viral respiratory infections.', 'This is particularly pertinent in the context of COVID-19 emergence; cocirculating viruses are associated with a broad spectrum of clinical presentation overlapping that of COVID-19, raising the potential for a large number of undiagnosed or misclassified cases in settings lacking the capacity for multiplexed testing.', 'Currently in NHS Greater Glasgow and Clyde, Scotland, the majority of COVID-19 testing is being conducted in the hospital setting, where all cases of respiratory illness are simultaneously tested for influenza, RSV, adenovirus and mycoplasma pneumoniae using a multiplex panel, and severely ill patients receive a full multiplex that includes sCoVs.', 'Sex-specific numbers of sCoV differed by healthcare setting; we observed a trend towards female sCoV cases for primary care, but male sCoV cases for secondary/tertiary care.', 'This finding may reflect sex differences in healthcare seeking behaviors and/or illness severity.', 'In terms of sex differences in detection odds (a proxy for infection risk), a statistically significant sex effect was found for CoV-229E, with a greater odds among males than females.', 'This finding is consistent with previous reports of a male bias for CoV-OC43 and CoV-NL63 among the hospital setting [12] , and in relation to influenza hospitalizations and mortality in the context of acute respiratory infections more generally [22, 23] .', 'It has been proposed that differences in sex hormones may explain variation in respiratory infection susceptibility, with testosterone exerting an immunosuppressive effect in males, and with estrogen playing a protective role in females [24, 25] .', 'We note however our analyses do not control for potential confounding factors such as smoking or chronic obstructive pulmonary disease (COPD', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', '18.20037101 doi: medRxiv preprint A greater number of sCoV cases were observed in children under five years of age and the elderly, particularly among patients admitted to hospital.', 'This pattern is consistent with overall testing trends, and may therefore reflect the healthcare seeking behavior of concerned parents, clinician testing practices, and/or the burden of other respiratory agents, rather than a greater risk of infection.', 'However, it should be borne in mind that these analyses were based on a patient population; the true community burden of mild and/or asymptomatic infections is likely to be much higher [26] .', 'When aggregated into epidemiological groupings, age-specific probabilities of virus detection varied across sCoV types.', 'In contrast to that observed for sCoVs, there are relatively few COVID-19 cases thus far in children [27] .', 'In the context of our study population, COVID-19 is closely related to CoV-OC43 (both betacoronaviruses), the most prevalent sCoV detection among patients under five.', 'It is possible that pre-existing cross-immunity confers protection and/or attenuates the severity of COVID-19 leading to fewer tested/hospitalized children.', 'The comparatively lower proportion positive and detection odds for school-aged children compared to younger children may potentially reflect a sustained level of CoV-OC43 immune-mediated protection, whereas waned immunity is expected to leave adults more vulnerable to coronavirus infections [27] .', 'Assuming some degree of cross-immunity with COVID-19, our data are consistent with an expected fewer cases of COVID-19 in children but more cases among the adult population.', 'Immunosenescence may exacerbate low levels of protective immunity in the elderly [29, 30] .', 'Three key features of our data seemingly support the proposition of cross-immunity.', 'Firstly, the contrasting age patterns of detection probabilities between closely related CoV-229E and CoV-NL63 (both alphacoronaviruses) may reflect niche segregation.', 'Secondly, closely related CoV-229E and CoV-NL63 also displayed asynchronous seasonality, in contrast to CoV-OC43 and CoV-NL63, supporting a competition dynamic.', 'Although our data did not permit in depth .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.03.18.20037101 doi: medRxiv preprint 13 analysis of CoV-HKU1, others have reported differences in the timing of peak detections with CoV-OC43 (both betacoronaviruses) [12] .', 'Thirdly, coinfections among sCoVs were not recorded in this study population, although detected by others albeit at a very low frequency [12] .', \"More work is needed to establish whether low coinfection frequency among sCoVs supports an immune-mediated competition for hosts, or whether this reflects a limitation of diagnostic data which only captures a snapshot of an individual's infection.\", 'To our knowledge, evidence of immunological cross-protection between human coronaviruses is lacking, and reports of antigenic cross-reactivity are inconsistent.', 'The potential for serological cross-reactivity between SARS-CoV and sCoVs has been shown by some [28, 29] but not others [30] .', 'And although confinement of cross-reactivity at the coronavirus genus level is possible, consistent with the greater genetic relatedness of these viruses [31, 32] , more general cross-reactivity between CoV-OC43 and CoV-229E has also been found [33] .', 'Population serological surveys will be critical for establishing the true burden and age distribution of sCoV infections in the community and the potential for cross-protective immunity.', 'It should be borne in mind that the implications of population levels of cross-immunity are likely to vary according to the local epidemiological context.', 'We note the predominance of CoV-OC43 detections previously observed in a comparatively urban but different Scottish patient population [14], a pattern more generally consistent at the Scottish national level [27] .', 'Other trends observed within our study population are consistent with the Scottish national level, such as peak levels of CoV-229E detection in 2010 coinciding with low levels of CoV-NL63 and CoV-OC43 [27] .', 'A predominance of CoV-OC43 has also been observed in Sweden [16] , suggesting a potential consistency in sCoV dominance over wider geographical areas.', 'However, differences are also apparent; for example, the relatively common detection of CoV-HKU1 in a .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', '18.20037101 doi: medRxiv preprint different Scottish population [14] in contrast to ours, as also suggested in a recent report on respiratory virus detections in France [28] .', 'Our study also highlights the potential for interactions between sCoVs and other respiratory viruses.', 'In previous extensive analyses of virus-virus interactions, we found a strong signal of positive interactions at the within-host scale between human coronaviruses overall and respiratory syncytial virus (RSV), adenovirus (AdV) and parainfluenza viruses (combining types 1 and 3; human respirovirus genus) [6] .', 'Here, our more in-depth analysis corroborates positive interactions at the sCoV type level.', 'For CoV-OC43, the most prevalent in this study population, our results support our earlier findings of a higher propensity of coinfection with RSV, AdV and PIV3 than with other respiratory viruses.', 'Note, these analyses were based on routine diagnostic testing and therefore the directionality of effects could not be determined.', 'The association with RSV was not supported following a correction for multiple comparisons, although previous studies also report a high proportion of sCoV coinfections with RSV', 'Further work is needed to establish the role of viral coinfections in COVID-19 severity.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Although ACE2 is a chaperon for B 0 AT1, our focus is on ACE2 in this study.', 'With the stabilization by B 0 AT1, we elucidated the structure of the full-length ACE2, which provides important insight into the molecular basis for viral infection by SARS-CoV as well as 2019-nCoV.', 'There has been no report on the oligomerization state of ACE2.', 'Our structure reveals the assembly of a dimer of heterodimers between ACE2 and B 0 AT1.', 'B 0 AT1 is not involved in homo-dimerization, whereas the contacts between the Neck domains of ACE2 are extensive.', 'Therefore ACE2 likely exists as a homodimer even in the absence of B 0 AT1.', 'This analysis provides immediate clue to the molecular basis for viral infection by SARS-CoV or 2019-nCoV.', 'Cleavage of the S protein of SARS-CoV was reported to be facilitated by cathepsin L in endosomes, indicating a mechanism of receptor-mediated endocytosis (8) .', 'The discovery of ACE2 as a dimer and the compatibility of simultaneous binding of dimeric author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.02.17.951848 doi: bioRxiv preprint 9 ACE2 with trimeric S protein suggests possible clustering that may facilitate membrane invagination for endocytosis.', 'Further characterizations are required to examine the interactions between ACE2 and the viral particle as well as the effect of co-factors such as B 0 AT1 and integrin on this process.', 'For membrane fusion, cleavage of the C-terminal segment, especially residues 697 to 716 (Supplementary Figure 4) , of ACE2 by proteases, such as transmembrane protease serine 2 (TMPRSS2), can enhance S protein-driven viral entry (33, 34) .', 'In our present structure, residues of 697-716 form helix N3 and N4 in the Neck domain and map to the dimeric interface of ACE2.', 'Presence of B 0 AT1 may block the access of TMPRSS2', 'In addition to kidney and intestine, where B 0 AT1 is primarily expressed, ACE2 is expressed in lung and heart (26) .', 'It remains to be tested whether B 0 AT1 can suppress SARS-CoV infection by blocking ACE2 cleavage.', 'We started this work because of our serious concern with the COVID-19.', 'Therefore the focus of structural analysis is mainly on ACE2.', 'In fact, B 0 AT1, as an important nutrient importer, exhibits many interesting structural features that are different from other LeuT-fold transporters.', 'We will aim for structural determination of B 0 AT1 in more conformations and present structural analysis of B 0 AT1 in separate studies.', 'In summary, our structural reveals the high-resolution structures of full-length ACE2 in a dimeric assembly.', 'Modelling analysis suggests simultaneous binding of two S protein trimer of coronavirus to an ACE2 dimer.', 'The structure presents here serves as an important framework to dissect the mechanism of 2019-nCoV infection and may facilitate development of potential therapeutics.']}\n", - "{'sentences': ['The outbreak of COVID-19 has been rapidly spreading over the recent 2 months, causing enormous damage to China.', 'With nationwide dissemination, its epidemiological and clinical features have changed.', 'Accumulating evidences indicate the appearance of several unique characteristics distinct from Wuhan 8, 9, 32 , including higher rate of mild type, lower rate of severe/critical type and mortality and longer period of nuclear acid positivity 10, 11, 27, 33 .', 'Moreover, the increased transmission route of SARS-CoV-2 has been gradually unmasked, from previous recognition of respiratory transmission to through feces 34 and even tears and conjunctival secretions 35 All these data indicate the possibility of virus evolution during its spreading, towards the direction of decreased severity but increased transmissibility.', 'However, according to recently published virus sequencing results 18 Through analysis on 788 COVID-19 patients in Zhejiang province, we found that there existed mild and severe types of SARS-CoV-2.', \"Though we didn't currently have evidence to prove whether patients with mild COVID-19 are directly caused by virus mutation or other factors, we indeed found the significant difference between ZJ01 and other members of SARS-CoV-2.\", 'ZJ01 had relative high number of 37 mutations and its RSCU was closer to humans than most members of SARS-CoV-2.', 'More importantly, ZJ01 was the only TT type of total 54 strains in our C/T categorization system.', 'Though the sequence of ZJ01 was still close to Wuhan-Hu-1 (the earliest identified SARS-CoV-2) and its mutations were not sufficient to reach the threshold of forming an independent subtype, our evidence indicated ZJ01 may represent a specific evolution direction of SARS-CoV-2.', 'In this study, we first developed the C/T categorization system of SARS-CoV-2, which revealed the occurrence of possibly inheritable mutation at the very early stage of its evolution and the potential of continuing C/T subtype formation.', 'The TT type of ZJ01 was unique in our system.', 'Though a similar categorization system has been recently proposed 36 , they did not report such TT type in their 120 strains of SARS-CoV-2.', 'Besides, the C/T pattern could also be used to trace the route of virus infection and evolution.', 'For instance, we found 8 strains of T type with RaTG13 and MP789 both had 8824C/28247T/29198T, we could speculate that these 8 strains of 29198T appeared earlier than strains of 29198C.', 'Using this method, we reckoned that the earliest strains of SARS-CoV-2 was one patient admitted in Shenzhen hospital on 2020-1-10, whose entire type was 8824C/28247T/29198T/2682C/3812C/9606C/11125G/15667T/29808G.', 'Besides, the earliest strain in the USA was from Phoenix, Arizona on 2020-1-26, whose entire type was 8824C/28247T/29198T/2682C/3812C/9606T/11125G/15667C/ 29808G.', 'Patients with these two earliest strains both had exposure history to Wuhan.', 'Therefore, we surmised that the origin of SARS-CoV-9 was still in Wuhan, but the earliest virus was still vague due to lack of enough samples (Supplementary Figure 1) .', 'Furin is well recognized as an important serine protease, which has a minimum enzyme restriction site of Arg(R)-X-X-Arg (R', 'RaTG13 was the strain closest to SARS-CoV-2 with 96% sequence similarity 39 .', 'However, SRAS-CoV-2 had PRRA insertion in 690 amino acid site of S protein, with high conservation 40 .', 'This insertion may become critical point for the host of RaTG13 turning from animal to human.', 'Through sequence alignment, we found this inserted sequence may arise from the translocation between human coronavirus HKU1 and OC43 (Figure 4 ).', 'CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', '(which was not peer-reviewed)', 'The copyright holder for this preprint .', '10.20033944 doi: medRxiv preprint SARS-CoV-2 had three FCS (F1-3), where F1 hydrolyzes S protein to S1 and S2 and promotes virus-cell fusion, F2 hydrolyzes S2 and participates in virus pathogenicity after cell entry, while F3 functions through NTD and promotes adhesion between virus and cell surface.', 'However, whether F3 site really exists and what is the function need further investigation.', 'Furthermore, the target cell binding site of HKU1 and OC43 was on their S A segment of S protein while its corresponding site in SARS-CoV-2 was NTD.', 'Therefore, except for the potential interaction in F1 site, there also exists the possibility of interaction in NTD segment between SARS-CoV-2 and HKU1/OC43.', 'Viruses frequently undergo mutation and adjust its RSCU under evolutionary selection pressure to adapt to the host, facilitating better replication and dissemination 41 .', 'The choice of Furin cleavage site might be an outstanding marker for coronavirus evolution.', 'Meanwhile, we found that the mutation in ZJ01 may cause binding force change of FCS.', 'All these data indicate that Furin might play a pivotal role in the pathogenicity of SARS-CoV-2.', 'The evolution trends of increasing FCS in SARS-CoV-2 we found in this study are more prone to influenza-like clinical manifestations such as human HKU1 and OC43 42 .', 'Single cell sequencing analysis showed that Furin had higher expression level and wider organ distribution than ACE2, especially in salivary gland, lachrymal gland, colon, liver and kidney.', 'Therefore, SARS-CoV-2 might evolve to utilize this specific feature by increasing FCS to become more infectious on multi-organ levels.', 'Our hypothesis was in consistent with changed clinical characteristics of COVID-19 from published data and our observation, including detection of virus in feces 34 and conjunctival secretions 35 , decreased severity/fatality, increased liver/kidney damage and symptoms of gastrointestinal tract, increased transmissibility and prolonged period of nuclear acid positivity.', 'Since ACE2 expression was quite low in the whole body including lung, we speculated that, on one hand, it might be the inflammatory reaction whereas not the viral road itself triggering severe respiratory damage; on the other hand, the utilization of Furin may help scatter virus attack from lung to other organs, contributing to the phenomenon of decreased severity but increased liver/kidney dysfunction.', 'Nevertheless, all these speculations warrant further investigations.', 'To sum up, ZJ01 isolated form mild COVID-19 patient of Zhejiang province represents a potential branch in virus evolution.', 'SARS-CoV-2 may adopt a similar mechanism by depending on Furin for invasion as HJU1 and OC43.', 'Such potential evolution direction may promote the appearance of mild subtype of COVID-19.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Why tocilizumab could be an effective treatment for severe COVID-19?', 'A severe pneumonia-associated respiratory syndrome caused by a new coronavirus was identified in December 2019 (coronavirus was identified in December 2019), spread rapidly and has become a world-wide public health challenge.', 'About 25% of coronavirus was identified in December 2019 patients experienced severe complications including acute respiratory distress syndrome (ARDS), and even progressed into an intensive care unit (ICU) admission and died.', 'The exploration for the mortality causes and advancing novel therapeutic development of severe coronavirus was identified in December 2019 is crucial at the moment.', 'The biopsy samples analysis at autopsy suggested that increased alveolar exudate caused by aberrant host immune response and inflammatory cytokine storm probably impedes alveolar gas exchange and contributes to the high mortality of severe coronavirus was identified in December 2019 patients.', 'Our research has identified that pathogenic T cells and inflammatory monocytes incite inflammatory storm with large amount of interleukin 6, therefore monoclonal antibody that targets the IL-6 pathways may potentially curb inflammatory storm.', 'Moreover, Tocilizumab treatment that blocking IL-6 receptors showed inspiring clinical results including temperature returned to normal quickly and respiratory function improved.', 'Therefore, we suggest that Tocilizumab is an effective treatment in severe patients of coronavirus was identified in December 2019', 'All three coronaviruses, including SARS-CoV, MERS-CoV and SARS-CoV-2, induce aberrant non-effective host immune responses that are associated with severe lung pathology.', 'The new SARS-CoV-2 additionally causes serious alveolar mucus infiltration and multiple organ failure.', 'As the SARS-CoV-2 continues to spread, the numbers of fatal cases rise exponentially in many countries, advancing novel therapeutic development becomes crucial to minimize the number of deaths from COVID-19.', 'In the absence of specific antiviral drugs, existing host-directed therapies could potentially be repurposed to treat COVID-19.', 'China’s plan of Tocilizumab treatment has shown its remarkable effectiveness and safety in clinical practice over the past 2 months, hoping it will benefit other countries fighting the pandemic and reduce the mortality of severe COVID-19 as well.\\n']}\n", - "{'sentences': ['In this report we discuss our first 7 cases of COVID-19 infection in kidney transplant recipients from south London, United Kingdom.', 'Median age of transplant recipients was 54 years (range, 45-69 years) comprising 4 men, 3 women.', 'Of 7 patients, 2 were managed on an outpatient basis and stayed at home, with the remaining 5 (71%) requiring hospital admission.', 'Four among the latter required ITU admission, and 1 is being managed in the renal ward.', 'Of 4 patients sent to ITU, 2 needed intubation and ventilation; the other 2 were managed with oxygen through mask and noninvasive ventilation only.', 'There was 1 death in this small series of 7 patients (mortality rate of 14%).', 'All 3 patients with severe disease were female and also had diabetes.', 'Two patients presented within 3 months of kidney transplantation (1 within 2 weeks) while kidney transplant vintage was 12 months or more in the remaining 5 cases.', 'The patients were managed in 3 centers and the total number of prevalent transplant patients in these centers was 2082, with 32 patients transplanted from December 15, 2019, to March 15, 2020, during the developing pandemic.', 'Transplant patients are at higher risk due to immunosuppression, underlying chronic kidney disease, and other comorbidities, in particular diabetes and hypertension, which are now recognized as significant factors that influence outcomes in patients with COVID-19 infection.', '9 Three of our patients had chronic kidney disease stage 4 to 5, with 1 recovering at home and 1 requiring hospital admission but recovering without needing ITU admission.', 'The remaining 4 patients had chronic kidney disease stage 3, of which 2 had severe disease requiring intubation and ventilation and 1 of them died.', 'Both patients who had severe COVID-19 including the one who died had diabetes mellitus.', 'Managing immunosuppression in these patients is challenging and should take into account age, severity of COVID-19 infection, associated comorbidities, and time posttransplant.', 'In transplant patients with mild to moderate infections, the usual practice is to continue or make reductions in the dose of immunosuppressive drugs, but this approach might favor high mortality in patients admitted to hospital with COVID-19 infection.', 'While we acknowledge that firm recommendations are not possible based on the small sample size of this study, we suggest that antiproliferative agents (MMF and azathioprine) should be stopped at the time of admission to hospital, dose of prednisolone should be either unchanged or increased, and tacrolimus dose should be reduced.', 'In severe infections (requiring intubation and ventilation), an argument can be made for stopping calcineurin inhibitors completely while maintaining corticosteroid therapy.', 'The role of cytokine storm and inflammation due to antiviral immune response as a driver of severe respiratory disease and acute respiratory distress syndrome has been discussed since the outbreak of this disease in December 2019, prompting trials of anti-interleukin 6 monoclonal antibody tocilizumab and case for continuing steroids in infected patients.', 'A similar argument can be made for continuing low-dose tacrolimus, but more evidence is needed before drawing firm conclusions.', 'An obvious concern is risk of rejection with reduction in immunosuppression but given the high mortality rate of COVID-19 infection in hospitalized patients, clinicians should focus on keeping their patients alive with a careful case-by-case assessment of risks versus benefits of continuing immunosuppression.', 'With regard to induction treatment, it is likely that lymphocyte-depleting antibodies increase the risk; therefore, many centers in the United Kingdom have stopped performing transplants requiring induction with either Q20 antithymocyte globulin or alemtuzumab.', 'All patients in this series received basiliximab induction therapy at time of transplantations.', 'Five of the 7 patients presented here were receiving triple immunosuppression.', 'Two patients with mild illness who did not require hospital admission and recovered fully at home were on dual immunosuppression (1 on azathioprine plus prednisolone and 1 on tacrolimus plus MMF).', 'With regard to concomitant therapy with angiotensin-converting enzyme inhibitors/ angiotensin receptor blockers, in line with current UK Renal Association and European Society of Cardiology recommendations, these therapies were not discontinued.', 'One of our 7 patients died, which is a mortality rate of 14%, although it is too soon to comment on likely mortality rates in this group of patients.', 'Two of our patients presented within 3 months after transplantation and 1 presented within 2 weeks.', 'UK National Health Service Blood and Transplant Organ Donation and Transplantation have since produced guidelines on COVID-19 screening in deceased donors and the transplant units are risk stratifying donors and recipients before considering kidney transplantation.', 'Transplantation is a high-risk procedure during this pandemic due to the risk of transmitting COVID-19 infection from the donor to the recipient as well as risk of recipient developing severe disease under higher levels of immunosuppression in the first 3 months posttransplant.', 'We suggest that apart from carefully selecting donor-recipient pairs, transplantation is not advisable during this pandemic, especially for older recipients with comorbidities, in particular diabetes.', 'We have stopped performing living donor transplants and are in discussions to suspend deceased donor program.', 'In addition to significant concerns about the effect of COVID-19 on immunosuppressed patients, increasing worries about access to ITU in the coming weeks and redistribution of staff to critical care to provide support for increasing number of COVID-19 patients, it is likely that deceased donor program will be suspended within most of the UK centers soon.', 'AKI has been described with COVID-19 infections in up to 15% patients, and occurrence of proteinuria or hematuria has been reported.', 'In our series, the observation that 4 of 7 patients had AKI (57%) may be an early signal that transplant patients are at higher risk of AKI with COVID-19 infection, compared with 29% AKI in critically ill patients of general population in Wuhan, China']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Case of the Index Patient Who Caused Tertiary Transmission of Coronavirus Disease 2019 in Korea: the Application of Lopinavir/Ritonavir for the Treatment of COVID-19 Pneumonia Monitored by Quantitative RT-PCR']}\n", - "{'sentences': ['Objective: To describe the characteristics of clinical manifestations and epidemiology of children with 2019 novel coronavirus (2019-nCoV) infection.', \"Methods: All 34 children with laboratory-confirmed 2019-nCoV infection by quantitative real-time reverse transcription-PCR through nasopharyngeal swab specimens were admitted to the Third People's Hospital of Shenzhen from January 19 to Febuary 7, 2020.\", 'Clinical data and epidemiological history of these patients were retrospectively collected and analyzed.', 'Results: Among the 34 cases, 14 were males, and 20 were females.', 'The median age was 8 years and 11 months.', 'No patients had underlying diseases.', 'There were 28 children (82%) related with a family cluster outbreak.', 'There were 26 children (76%) with a travel or residence history in Hubei Province.', 'These patients could be categorized into different clinical types, including 22 (65%) common cases, 9 (26%) mild cases and 3 (8.8%) asymptomatic cases.', 'No severe or critical cases were identified.', 'The most common symptoms were fever (17 cases, 50%) and cough (13 cases, 38% ).', 'In the 34 cases, the white blood cell counts of 28 cases (82%) were normal.', 'Five cases had white blood cell counts more than 10×10(9)/L. One case had white blood cell counts less than 4×10(9)/L. Neutropenia and lymphopenia was found in one case, respectively.', 'C-reactive protein levels and erythrocyte sedimentation rates were elevated in 1 and 5 case, respectively.', 'Elevated procalcitonin was found in 1 case and D-Dimer in 3 cases.', 'The levels of lactic dehydrogenase (LDH) were more than 400 U/L in 10 cases.', 'The CT images of these patients showed bilateral multiple patchy or nodular ground-glass opacities and/or infiltrating shadows in middle and outer zone of the lung or under the pleura.', 'Twenty patients were treated with lopinavir and ritonavir.', 'Glucocorticoids and immunoglobulin were not used in any cases.', 'All the cases improved and were discharged from hospital.', 'Further following up was need.', 'Conclusions: The clinical manifestations in children with 2019-nCoV infection are non-specific and are milder than that in adults.', 'Chest CT scanning is heplful for early diagnosis.', \"Children's infection is mainly caused by family cluster outbreak and imported cases.\", 'Family daily prevention is the main way to prevent 2019-nCoV']}\n", - "{'sentences': ['Although a number of antiviral agents have been evaluated for coronaviruses there are no approved drugs available.', 'To provide an overview of the landscape of therapeutic research for COVID-19, we conducted a review of registered clinical trials.', 'A review of currently registered clinical trials was performed on registries, including the Chinese (chictr.org.cn) and US (clinicaltrials.gov) databases to identify relevant studies up to March, 7 th 2020.', 'Out of the 353 studies identified, 115 clinical trials were selected for data extraction.', 'Phase IV trials were the most commonly reported study type (n=27, 23%).', 'However, 62 trials (54%) did not describe the phase of the study.', 'Eighty percent (n=92) of the trials were randomized with parallel assignment and the median number of planned inclusions was 63 (IQR, 36-120).', 'Open-label studies were the most frequent (46%) followed by double-blind (13%) and single blind studies (10%).', 'The most frequently assessed therapies were: stem cells therapy (n=23 trials), lopinavir/ritonavir (n=15), chloroquine (n=11), umifenovir (n=7), hydroxychloroquine (n=7), plasma treatment (n=7), favipiravir (n=7), methylprednisolone (n=5), and remdesivir (n=5', 'Numerous clinical trials have been registered since the beginning of the COVID-19 outbreak, however, a number of information regarding drugs or trial design were lacking.', 'Based on the evidence available up to March 7 th , 2020, stem cells therapy and lopinavirritonavir were the most frequently evaluated candidate therapies in terms of number of trials (23 and 15 trials respectively), whereas remdesivir was associated with the highest median number of planned inclusions per trial (400, IQR 394-453 for 5 trials only.', 'This review of ongoing clinical trials assessing COVID-19 treatments shows the important amount of research that is currently being conducted on this topic.', 'However, although the number of trials identified is high, there are a number of caveats.', 'First, numerous treatments have been selected based on various levels of supporting preclinical data.', 'Most of the agents evaluated in clinical trials have shown an in vitro antiviral activity, sometimes including coronaviruses.', 'Lopinavir/ritonavir is tested in 15 clinical trials in this review.', 'This combination has shown an in vitro activity against SARS-CoV in several studies 15 and appears to have activity against MERS-CoV in animal studies 16 .', 'The use of this agent for treatment of COVID-19 has been described in case reports 17, 18 and in a case series of patients infected with SARS-CoV-2 in Singapore.', '19 We found 18 clinical trials evaluating hydroxychloroquine or chloroquine, whose mechanism of action is similar.', '20 The in vitro antiviral activity of chloroquine has been known for a long time 21 and was described on a number of viruses including SARS-CoV. 22 However, chloroquine failed to demonstrate a benefit in the treatment of viral diseases such as influenza, dengue or chikungunya.', '[23] [24] [25] Regarding COVID-19, a recent publication reported an activity of chloroquine on SARS-CoV-2 26 and another encouraged the use of chloroquine for patients with COVID-19 on the basis of unreported clinical results.', '27 Experts in China have suggested the use of chloroquine for patients infected with SARS-CoV-2 but no clinical data has been provided yet to support this announcement.', '28, 29 Remdesivir is evaluated in 5 clinical trials but with the highest median number of planned inclusions per trial.', 'Studies in vitro in human airway epithelial cell assays demonstrated that remdesivir inhibits replication of coronaviruses, including MERS-CoV. 30 In mouse infection models, remdesivir had therapeutic efficacy against SARS-CoV and MERS-CoV. 30, 31 In a recent non-human primate study, remdesivir treatment initiated 12 hours post inoculation with MERS-CoV provided clinical benefit with a reduction in clinical signs, reduced virus replication in the lungs, and decreased presence and severity of lung lesions.', '32, 33 The rationale of using stem cell therapy is based on its immunomodulatory properties that could be interesting in severe COVID-19.', '34, 35 However, stem cell-based therapies have not demonstrated an effect in treating other viral diseases and the scientific background to test them is weak.', 'The fact that stem cell therapy, that has not shown any effect in antiviral diseases, was one of the most frequently assessed therapies is unexpected.', 'This highlights the fact that researchers should strive to conduct clinical trials with the most promising candidates, according to in vitro and preclinical in vivo scientific data.', 'Second, data is often lacking regarding study designs and on the treatment being assessed, such as the dose and duration.', 'This restricts the information available for researchers and potentially delay the finding of successful treatments.', 'Third, most of the trials planned including a low number of patients, which reduces the robustness of the future results of those clinical trials.', 'Although, these numbers should be taken with caution as they only represent an anticipated number of inclusions for each trial and not the actual number of patients included.', 'Fourth, primary outcomes were very heterogeneous in the clinical trials.', 'The use of clinical outcomes should be encouraged in a disease for which we do not know the association between viral clearance, radiological or immunological evolution and clinical status.', 'Due to the pandemic context associated with COVID-19, the number of clinical trials registered is increasing day after day.', 'A previous review conducted up to February 18 th , 2020 found 74 clinical trials evaluating antiviral agents or drugs.', '36 Our review adds to this evidence by screening a larger number of clinical trial registries and reporting the studies design, randomization, allocation, and number of planned inclusions as well as treatment dose, duration, disease severity, and primary outcomes used.', 'This important amount of work conducted by researchers is encouraging for the therapeutic research for this new disease.', 'However, care should be taken when designing a clinical trial in this complicated context as robust results are needed in order to be able to find the appropriate treatment.', 'Finding the best agents for rapid implementation in clinical trials for a new outbreak is challenging.', 'Our study underlines the need to register as much details as possible on clinical trials registries during outbreaks in order to inform the development of future trials.', 'The scientific background supporting the use of a treatment should be clear and detailed as much as possible.', 'The dose and duration of drugs evaluated, as well as details on the study design, the population of interest and the primary outcome, are crucial elements that have to be shared in the context of the epidemic response.', 'Reporting as much details as possible is key to have consistent clinical trials and to enhance the reproducibility of the results, especially as studies are more often associated with a low number of planned inclusions and composite or weak outcomes that can limit the efficacy assessment of the treatments.', 'That is why transparency and consistency are crucial when reporting clinical trials in order to improve statistical power by conducting, for example, meta-analyses.', 'The development of clinical trials during an outbreak is an adaptive process and new evidence is produced at an impressive rate.', 'A review of the strategies that are already registered in official clinical registries of clinical trials is an important asset for researchers and methodologists.', 'These results might inform the adaptation of existing clinical trials and the development of additional trials.', 'CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['The outbreak of the 2019-nCoV infection began in December 2019 in Wuhan, Hubei province, and rapidly spread to many provinces in China as well as other countries.', 'Here we report the epidemiological, clinical, laboratory, and radiological characteristics, as well as potential biomarkers for predicting disease severity in 2019-nCoV-infected patients in Shenzhen, China.', 'All 12 cases of the 2019-nCoV-infected patients developed pneumonia and half of them developed acute respiratory distress syndrome (ARDS).', 'The most common laboratory abnormalities were hypoalbuminemia, lymphopenia, decreased percentage of lymphocytes (LYM) and neutrophils (NEU), elevated C-reactive protein (CRP) and lactate dehydrogenase (LDH), and decreased CD8 count.', 'The viral load of 2019-nCoV detected from patient respiratory tracts was positively linked to lung disease severity.', 'ALB, LYM, LYM (%), LDH, NEU (%), and CRP were highly correlated to the acute lung injury.', 'Age, viral load, lung injury score, and blood biochemistry indexes, albumin (ALB), CRP, LDH, LYM (%), LYM, and NEU (%), may be predictors of disease severity.', 'Moreover, the Angiotensin II level in the plasma sample from 2019-nCoV infected patients was markedly elevated and linearly associated to viral load and lung injury.', 'Our results suggest a number of potential diagnosis biomarkers and angiotensin receptor blocker (ARB']}\n", - "{'sentences': [\"[{'text': 'RNA knockdown in vivo carries significant potential for disease modelings and therapies.\", 'Despite the emerging approaches of CRISPR/Cas9-mediated permanent knock out of targeted genes, strategies targeting RNA for disruption are advantageous in the treatment of acquired metabolic disorders when permanent modification of the genome DNA is not appropriate, and RNA virus infection diseases when pathogenic DNA is not available (such as SARS-Cov-2 and MERS infections).', 'Recently, Cas13d, a family of RNA-targeting CRISPR effectors, has been shown to accomplish robust down-regulation of cellular RNAs in mammalian cells in vitro.', 'Among the various Cas13d subtypes, CasRx (RfxCas13d) showed the most potent RNA knockdown efficiency in HEK293T cells.', 'However, the RNA-targeting activity of Cas13d still needs to be verified in vivo.', 'In this study, the CasRx system was demonstrated to efficiently and functionally knock down genes related to metabolism functions, including Pten, Pcsk9 and lncLstr, in mouse hepatocytes.', 'CasRx-mediated simultaneous knockdown of multiple genes was also achieved by sgRNA arrays, providing a useful strategy to modulate complex metabolism networks.', 'Moreover, the AAV (adeno-associated virus)-mediated delivery of CasRx and Pcsk9 sgRNAs into mouse liver successfully decreased serum PCSK9, resulting in significant reduction of serum cholesterol levels.', 'Importantly, CasRx-mediated knockdown of Pcsk9 is author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', ': bioRxiv preprint 3 reversible and Pcsk9 could be repeatedly down-regulated, providing an effective strategy to reversibly modulate metabolic genes.', \"The present work supplies a successful proof-of-concept trial that suggests efficient and regulatory knockdown of target metabolic genes for a designed metabolism modulation in the liver.', 'cite_spans': [], 'ref_spans': [], 'section': 'Abstract'}]\"]}\n", - "{'sentences': ['Fluxograma para atendimento e detecção precoce de COVID-19 em pronto atendimento UPA 24 horas e unidade hospitalar não definida como referência']}\n", - "{'sentences': ['Hydroxychloroquine and Azithromycin as a treatment of COVID-19: preliminary results of an open-label non-randomized clinical trial', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', '16.20037135 doi: medRxiv preprint For ethical reasons and because our first results are so significant and evident we decide to share our findings with the medical community, given the urgent need for an effective drug against SARS-CoV-2 in the current pandemic context.', 'We show here that hydroxychloroquine is efficient in clearing viral nasopharyngeal carriage of SARS-CoV-2 in COVID-19 patients in only three to six days, in most patients.', 'A significant difference was observed between hydroxychloroquine-treated patients and controls starting even on day3 post-inclusion.', 'These results are of great importance because a recent paper has shown that the mean duration of viral shedding in patients suffering from COVID-']}\n", - "{'sentences': ['Coalition: Advocacy for prospective clinical trials to test the post-exposure potential of hydroxychloroquine against COVID-19', 'Our coalition of public health experts, doctors, and scientists worldwide want to draw attention to the need for high-quality evaluation protocols of the potential beneficial effect of hydroxychloroquine (HCQ) as a post-exposure drug for exposed people, meaning people with close contact with positive tested patients, including home and medical caregivers.', 'We have reviewed the mechanisms of antiviral effect of HCQ, the risk-benefit ratio taking into consideration the PK/PD of HCQ', 'We have studied its use as an antimalarial, an antiviral, and an immunomodulating drug and concluded that the use of HCQ at does matching that of the standard treatment of Systemic Lupus erythematous, which has proven safety and efficacy in terms of HCQ blood and tissue concentration adapted to bodyweight (2,3), at 6mg/kg/day 1 (loading dose) followed by 5 mg/kg/day, with a maximum limit of 600 mg/day in all cases should swiftly be clinically evaluated as a post-exposure drug for exposed people.', 'J o u', 'r n a l P r e -p r o o f Journal Pre-proof epidemic.', 'However, its administration should be done under medical control to avo id potential side effects and to prevent an uncontrolled use leading to supply shortages.', 'J o u r n a l P r e -p r o o f Journal Pre-proof J o u', 'r n a l P r e -p r o o f Journal Pre-proof J o u', 'r n a l P r e -p r o o f Journal Pre-proof J o u', 'r n a l P r e -p r o o f Journal Pre-proof J o u', 'r n a l P r e -p r o o f Journal Pre-proof']}\n", - "{'sentences': ['Using pulmonary and cutaneous biopsy and autopsy samples from five individuals with severe COVID-19 we document that at least some SARS-CoV-2-infected patients who become critically ill suffer a generalized thrombotic microvascular injury.', 'Such pathology involves at least the lung and skin, and appears mediated by intense complement activation.', 'Specifically, we found striking septal capillary injury accompanied by extensive deposits of the terminal complement complex C5b-9 as well as C4d and MASP2 in the lungs of two cases examined, and a similar pattern of pauci-inflammatory complement mediated microthrombotic disease in the skin of three cases with retiform and purpuric lesions, with C5b-9 and C4d deposition in samples taken from both cutaneous lesions and normal-appearing skin.', 'Our histologic findings are consistent with emerging observations suggesting that COVID-19 has clinical features distinct from typical ARDS.', 'That is, COVID-19-related severe respiratory distress can be manifest by relatively well-preserved lung mechanics, despite the severity of hypoxemia, characterized by high respiratory compliance, high shunt fraction, and prolonged requirement for mechanical ventilation (10, 11) .', 'The pathology in these cases might therefore be expected to differ from the diffuse alveolar damage and hyaline membrane formation which are hallmarks of typical ARDS.', 'Albeit preliminary pathology studies of lungs from COVID-19 cases described DAD with edema, hyaline membranes, and inflammation, followed by type II pneumocyte hyperplasia, features characteristic of typical ARDS (8, 9) , the pulmonary abnormalities in our patients appear largely restricted to the alveolar capillaries, i.e., more of a thrombotic microvascular injury with few signs of viral cytopathic or fibroproliferative', 'An increase in the dead space fraction might be anticipated with this type of pathology,', 'i.e., respiratory failure accompanied by greater lung compliance and less pulmonary consolidation than is characteristic of typical ARDS.', 'Indeed, the histologic pattern of paucicellular terminal lung parenchymal injury with septal capillary damage we document resembles images captured in early case reports in the Chinese language literature of severe COVID-19', 'We now show that this pathologic pattern, atypical for classic ARDS, is accompanied by extensive deposition of AP and LP complement components within the lung septal microvasculature.', 'With such extensive complement involvement, membrane attack complexmediated microvascular endothelial cell injury and subsequent activation of the clotting pathway, leading to fibrin deposition, might be anticipated (17), as observed in our cases.', 'It is also consistent with the very high d-dimer levels found in the three cases in which it was assessed.', 'Vascular deposition of C5b-9 is a key feature of many microthrombotic syndromes, regardless of the particular syndromic complex, including catastrophic antiphospholipid antibody syndrome, atypical hemolytic uremic syndrome, purpura fulminans and severe multi-organ malignant atrophic papulosis, and they may respond to anti-complement therapies (18) (19) (20) (21) (22) (23) .', 'A pre-clinical model of SARS infection emphasizes the potential role of complement in the parenchymal lung injury of coronavirus infection (7) .', 'Mouse-adapted SARS-CoV MA15', 'infection of C3 -/mice led to significantly less weight loss and respiratory dysfunction than seen in wild-type mice, and this occurred despite equivalent viral loads in the lung (7).', 'Another feature reflective of a prominence of complement-mediated pathology rather than simply inflammation or vasculitis in our COVID-19 patients was the extent of septal and intra-alveolar neutrophilia.', 'It was present, but pauci-inflammatory.', 'SARS-CoV-infected wild-type mice also had higher levels of neutrophils in the lung than their C3 -/counterparts (7).', 'Tissue neutrophilia may be attributable to the neutrophil chemoattractant properties of complement.', 'Both neutrophils and complement are key sentinels of innate immunity and also modulate thrombogenic pathways, the latter thought related to C5a receptor/tissue factor cross-talk mediated by neutrophils (24) .', 'Neutrophilia in human SARS-CoV patients is associated with a poor outcome and could be an index of the extent of complement activation (7, 25) .', 'Peripheral neutrophilia is not a significant observation in limited series of COVID-19 patients from China (26) There may also be pathways apart from virus spike engagement by which LP and AP are activated.', 'First, MBL and ficolins bind to pathogen-associated molecular patterns present on injured cells, enabling complex formation with MASP2 (36) .', 'In addition, all three ARDS-linked coronaviruses use ACE2 as an entry point to cells (6) .', 'Angiotensin I and angiotensin II have been associated with inflammation, oxidative stress, and fibrosis, and ACE2 is involved in their deactivation (37) .', 'If overwhelming coronavirus infection, with binding to ACE2 on epithelial targets not only in the lung but in other tissues expressing these proteins, including the kidney, intestines, and brain, were to interfere with ACE2 activity, the resulting increases in angiotensin II could lead to reactive oxygen species formation and interference with anti-oxidant and vasodilatory signals such as NOX2 and eNOS, with further complement activation.', 'This has been demonstrated in a rat model of angiotensin II over-expression linked to other disorders (38) .', 'The potential loss of auto-vasoconstriction and regulation of lung blood flow through injured vascular segments would also lead to increased shunting and severe hypoxemia.', 'Fig. 10 summarizes the potential mechanisms of SARS-CoV2 associated complement activation, and its possible interaction with coagulation pathways.', 'Given these data, use of agents that block LP activation at MBL recognition domains, shows a significant degree of C4d and SARS-CoV2 co-localization, as revealed by intense yellow staining.', 'E-H: A similar pattern was observed using an anti-C5b-9 reagent whose image appears green, with a significant degree of C5b-9 and SARS-CoV2 co-localization, as revealed by intense yellow staining.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Reply to Gautret et al. 2020:', 'A Bayesian reanalysis of the effects of hydroxychloroquine and azithromycin on viral carriage in patients with COVID-19', 'hydroxychloroquine and azithromycin on viral load in the upper respiratory tract of severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) patients.', 'The authors report that hydroxychloroquine (HCQ) had significant virus reducing effects, and that dual treatment of both HCQ', 'assumes a positive effect, compared to a model of no effect.', 'We find that the statistical evidence is highly sensitive to these data variants.', 'Statistical evidence for the positive effect model ranged from strong for the original data (BF +0 ~11), to moderate when including patients who deteriorated (BF +0 ~4.35), to anecdotal when excluding untested patients (BF +0 ~2), and to anecdotal negative evidence if untested patients were assumed positive (BF +0 ~0.6).', 'To assess whether HCQ is more effective when combined with AZ, we performed the same tests, and found only anecdotal evidence for the positive effect model for the original data (BF +0 ~2.8), and moderate evidence for all other variants of the data (BF +0 ~5.6).', 'Our analyses only explore the effects of different assumptions about excluded and untested patients.', 'These assumptions are not adequately reported, nor are they justified in the original paper, and we find that varying them causes substantive changes to the evidential support for the main claims of the original paper.', 'This statistical uncertainty is exacerbated by the fact that the treatments were not randomised, and subject to several confounding variables including the patients consent to treatment, different care centres, and clinical decision-making.', 'Furthermore, while the viral load measurements were noisy, showing multiple reversals between test outcomes, there is greater certainty around other clinical outcomes such as the 4 patients who seriously deteriorated.', 'The fact that all of these belonged to the HCQ group should be assigned greater weight when evaluating the potential clinical efficacy of HCQ.', 'Randomised controlled trials are currently underway, and will be critical in resolving this uncertainty as to whether HCQ and AZ are effective as a treatment for COVID-19.', 'Warning: There have been reports of people self-administering chloroquine phosphate (intended for treatment of disease in aquarium fish) , which has led to at least one death and one serious illness.', 'We state that under no circumstances should people self-administer hydroxychloroquine, chloroquine phosphate, azithromycin, or anything similar-sounding, or indeed any other drug, unless approved by a medical doctor.', 'The FDA has issued a specific warning: https://www.fda.gov/animal-veterinary/product-safety-information/fda-letter-stakeholders-do-not-use-chloroquine-phosphate-intended-fis h-treatment-covid-19-humans .', 'CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', '(which was not peer-reviewed)', 'The copyright holder for this preprint .']}\n", - "{'sentences': [\"[{'text': 'Background: A novel coronavirus (2019-nCoV) causing an outbreak of pneumonia in Wuhan, Hubei province of China was isolated in January 2020.\", 'This study aims to investigate its epidemiologic history, and analyze the clinical characteristics, treatment regimens, and prognosis of patients infected with 2019-nCoV during this outbreak.', 'Methods: Clinical data from 137 2019-nCoV-infected patients admitted to the respiratory departments of the respiratory departments of nine tertiary hospitals in Hubei province from December 30, 2019 to January 24, 2020 were retrospectively collected, including general status, clinical manifestations, laboratory test results, imaging characteristics, and treatment regimens.', 'Results: None of the 137 patients (61 males, 76 females, aged 20-83 years, median age 57 years) had a definite history of exposure to Huanan Seafood Wholesale Market.', 'Major initial symptoms included fever (112/137, 81.8%), coughing (66/137, 48.2%), and muscle pain or fatigue (44/137, 32.1%), with other, less typical initial symptoms observed at low frequency, including heart palpitations, diarrhea, and headache.', 'Nearly 80% of the patients had normal or decreased white blood cell counts, and 72.3% (99/137) had lymphocytopenia.', 'Lung involvement was present in all cases, with most chest computed tomography scans showing lesions in multiple lung lobes, some of which were dense; ground-glass opacity co-existed with consolidation shadows or cordlike shadows.', 'Given the lack of effective drugs, treatment focused on symptomatic and respiratory support.', 'Immunoglobulin G was delivered to some critically ill patients according to their conditions.', 'Systemic corticosteroid treatment did not show significant benefits.', 'Notably, early respiratory support facilitated disease recovery and improved prognosis.', 'The risk of death was primarily associated with age, underlying chronic diseases, and median interval from the appearance of initial symptoms to dyspnea.', 'Conclusions: The majority of patients with 2019-nCoV pneumonia present with fever as the first symptom, and most of them still showed typical manifestations of viral pneumonia on chest imaging.', 'Middle-aged and elderly patients with underlying comorbidities are susceptible to respiratory failure and may have a poorer prognosis.']}\n", - "{'sentences': [\"Maria was distraught after reading about the 'potential' epidemic, yet to happen, and the horror stories on Facebook needing reassurance and certainty about what she should do.\", 'She requested an urgent appointment to review her treatment plan.', 'Maria was a 26-year-old woman with relapsing multiple sclerosis who had recently experienced brainstem relapse with double vision and ataxia despite treatment with pegylated interferon-beta for the last 18 months.', 'A brain MRI performed one month prior had shown 16 new T2 lesions, four of which were enhancing.', 'One of the enhancing lesions was at the pontomedullary junction and was certainly the cause of her relapse.', \"Treatment was to be escalated to ocrelizumab with the first dose in a week's time.\", 'In view of the emerging coronavirus pandemic, she was questioning whether or not she should go ahead with ocrelizumab.', 'This was despite only a handful of confirmed COVID-19 cases in the country and none in her town and region.', 'If this scenario sounds plausible what should neurologists do?', 'Human coronaviruses are predominantly associated with respiratory tract infections and includes those that cause severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS', 'In an uncertain world, where we do not have a clear evidence-base, you often have to default to scientific principles, rather than using the wisdom of the crowd.', 'Not surprising, with Italy being one of the epicentres of the COVID-19 epidemic, the Italian society of neurology or SIN (Società Italiana di Neurologia) broke cover first producing recommendations on the management of patients with MS during the COVID-19 epidemic (see Box 1).', 'The SIN guidelines provide relatively straightforward, and one could argue arbitrary, advice on how to manage patients with MS in the short-term, but do not address supervision of these patients in the intermediate or long-term especially those with highly active MS.', 'If the public health measures being taken flatten the peak of the epidemic, but extend its tail, the problem of community-acquired SARS-CoV2 infection and COVID-19 may be with us for many months and potentially years.', 'Are the SIN guidelines compatible with the best interests of our patients or a knee-jerk response to an undefined problem that may not be a problem at all?']}\n", - "{'sentences': ['SARS-CoV-2 is a newly emerged coronavirus responsible for the current COVID-23', '19 pandemic that has resulted in more than one million infections and 73,000 24 deaths 1,2 .', 'Vaccine and therapeutic discovery efforts are paramount to curb the 25 pandemic spread of this zoonotic virus.', 'The SARS-CoV-2 spike (S', 'Here we describe multiple monoclonal antibodies targeting SARS-CoV-2 S 28 identified from memory B cells of a SARS survivor infected in 2003.', 'One 29 antibody, named S309, potently neutralizes SARS-CoV-2 and SARS-CoV 30 pseudoviruses as well as authentic SARS-CoV-2 by engaging the S receptor-31 binding domain.', 'Using cryo-electron microscopy and binding assays, we show 32 that S309 recognizes a glycan-containing epitope that is conserved within the 33 sarbecovirus subgenus, without competing with receptor attachment.', 'Antibody 34 cocktails including S309 along with other antibodies identified here further 35 enhanced SARS-CoV-2 neutralization and may limit the emergence of 36 neutralization-escape mutants.', 'These results pave the way for using S309 and 37 S309-containing antibody cocktails for prophylaxis in individuals at high risk of 38 exposure or as a post-exposure therapy to limit or treat severe disease.', '39 40 author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', ': bioRxiv preprint 2 Coronavirus entry into host cells is mediated by the transmembrane spike (S) 41 glycoprotein that forms homotrimers protruding from the viral surface 3 .', 'The S 42 glycoprotein comprises two functional subunits: S1 (divided into A, B, C and D domains) 43 that is responsible for binding to host cell receptors and S2 that promotes fusion of the 44 viral and cellular membranes 4,5 .', 'Both SARS-CoV-2 and SARS-CoV belong to the 45 sarbecovirus subgenus and their S glycoproteins share 80% amino acid sequence 46 identity 6 .', 'SARS-CoV-2 S is closely related to the bat SARS-related CoV (SARSr-CoV', 'RaTG13 with which it shares 97.2% amino acid sequence identity 1 .', 'We and others 48 recently demonstrated that human angiotensin converting enzyme 2 (hACE2) is a 49 functional receptor for SARS-CoV-2, as is the case for SARS-CoV 1,6-8 .', 'The S domain 50 B (S B ) is the receptor binding domain (RBD) and binds to hACE2', 'possibly contributing to the current rapid SARS-CoV-2 transmission in humans 6,9 , as 52 previously proposed for SARS-CoV 10 .', 'As the coronavirus S glycoprotein mediates entry into host cells, it is the main 54 target of neutralizing antibodies and the focus of therapeutic and vaccine design 55 efforts 3 .', 'The S trimers are extensively decorated with N-linked glycans that are 56 important for protein folding 11 and modulate accessibility to host proteases and 57 neutralizing antibodies 12-15 .', 'Cryo-electron microscopy (cryoEM', 'CoV-2 S in two distinct functional states 6,9 along with cryoEM and crystal structures of 59 SARS-CoV-2 S B in complex with hACE2 16-18 revealed dynamic states of S B domains, 60 providing a blueprint for the design of vaccines and inhibitors of viral entry.', '61 Passive administration of monoclonal antibodies (mAbs) could have a major 62 impact on controlling the SARS-CoV-2 pandemic by providing immediate protection, 63 complementing the development of prophylactic vaccines.', 'Accelerated development 64 of mAbs in a pandemic setting could be reduced to 5-6 months compared to the 65 traditional timeline of 10-12 months (Kelley B., Developing monoclonal antibodies at 66 pandemic speed, Nat Biotechnol, in press).', 'The recent finding that ansuvimab 67 (mAb114) is a safe and effective treatment for symptomatic Ebola virus infection is a 68 striking example of the successful use of mAb therapy during an infectious disease 69 outbreak 19,20 .', 'We previously isolated potently neutralizing human mAbs from memory 70 B cells of individuals infected with SARS-CoV 21 or MERS-CoV 22 .', 'Passive transfer of 71 these mAbs protected animals challenged with various SARS-CoV isolates and SARS-72 related CoV (SARSr-CoV) 21,23,24 , as well as with MERS-CoV 22 .', 'Structural 73 characterization of two of these mAbs in complex with SARS-CoV S and MERS-CoV 74 author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', ': bioRxiv preprint 3 S provided molecular-level information on the mechanisms of viral neutralization 14 .', 'In 75 particular, while both mAbs blocked S B attachment to the host receptor, the SARS-76 CoV-neutralizing S230 mAb acted by functionally mimicking receptor-attachment and 77 promoting S fusogenic conformational rearrangements 14 .', 'Another mechanism of 78 SARS-CoV neutralization was recently described for mAb CR3022, which bound a 79 cryptic epitope only accessible when at least two out of the three S B domains of a S 80 trimer were in the open conformation 25,26 .', 'However, none of these mAbs neutralize 81 SARS-CoV-2.', '82 83 Identification of a potent SARS-CoV-2 neutralizing mAb from a SARS survivor 84 We previously identified a set of human neutralizing mAbs from an individual 85 infected with SARS-CoV in 2003 that potently inhibited both human and zoonotic 86 SARS-CoV isolates 21,23,27 .', 'To characterize the potential cross-reactivity of these 87 antibodies with SARS-CoV-2, we performed a new memory B cell screening using 88 peripheral blood mononuclear cells collected in 2013 from the same patient.', 'We 89 describe here nineteen mAbs from the initial screen (2004 blood draw) 21,23 and six 90 mAbs from the new screen (2013 blood draw).', 'The identified mAbs had a broad V 91 gene usage and were not clonally related (Table 1).', 'Eight out of the twenty five mAbs', 'CoV S 30 and SARS-CoV-2 S 6 ectodomain trimers.', 'None of the mAbs studied bound to 97 prefusion OC43 S or MERS-CoV S ectodomain trimers, indicating a lack of cross-98 reactivity outside the sarbecovirus subgenus (Extended Data Fig.1) .', 'MAbs S303, 99 S304, S309 and S315 recognized the SARS-CoV-2 and SARS-CoV RBDs.', 'In 100 particular, S309 bound with nanomolar affinity to both S B domains, as determined by 101 biolayer interferometry (Fig. 1c-d, Extended Data Fig. 2) .', 'Unexpectedly, S306 and 102 S310 stained cells expressing SARS-CoV-2 S at higher levels than those expressing 103 SARS-CoV S, yet it did not interact with SARS-CoV-2 or SARS-CoV S ectodomain 104 trimers and RBD constructs by ELISA.', 'These results suggest that they may recognize 105 post-fusion SARS-CoV-2 S, which was recently proposed to be abundant on the 106 surface of authentic SARS-CoV-2 viruses 31 (Fig. 1a-b and Extended Data Fig.3) .', ': bioRxiv preprint 4 To evaluate the neutralization potency of the SARS-CoV-2 cross-reactive 108 mAbs, we carried out pseudovirus neutralization assays using a murine leukemia virus 109 (MLV', 'To study the mechanisms of S309-mediated neutralization, we characterized 120 the complex between the S309 Fab fragment and a prefusion stabilized SARS-CoV-2 121 S ectodomain trimer 6 using single-particle cryoEM.', 'Similar to our previous study of apo 122 SARS-CoV-2 S 6 , 3D classification of the cryoEM data enabled identification of two 123 structural states: a trimer with one S B domain open and a closed trimer.', 'We determined 124 3D reconstructions of the SARS-CoV-2 S ectodomain trimer with a single open S B 125 domain and in a closed state (applying 3-fold symmetry), both with three S309 Fabs 126 bound, at 3.7 Å and 3.3 Å resolution, respectively (Fig. 2a-c, Extended Data Fig. 5 127 and Table 2 ).', 'In parallel, we also determined a crystal structure of the S309 Fab at 3.3 128 Å resolution to assist model building ( Table 3) .', 'The S309 Fab bound to the open S B 129 domain is weakly resolved in the cryoEM map, due to marked conformational variability 130 of the upward pointing S B domain, and was not modeled in density.', 'The analysis below 131 is based on the closed state structure.', '132 S309 recognizes a protein/glycan epitope on the SARS-CoV-2 S B , distinct from 133 the receptor-binding motif.', 'The epitope is accessible in both the open and closed S 134', 'states, explaining the stoichiometric binding of Fab to the S trimer (Fig. 2a-c) .', 'The 135 S309 paratope is composed of all six CDR loops that burie a surface area of ~1,050Å 2 136 at the interface with S B through electrostatic interactions and hydrophobic contacts.', 'The 20-residue long CDRH3 sits atop the S B helix comprising residues 337-344 and 138 also contacts the edge of the S B five-stranded b-sheet (residues 356-361), overall 139 accounting for ~50% of the buried surface area (Fig. 2d-e) .', 'CDRL1 and CDRL2 extend 140 the epitope by interacting with the helix spanning residues 440-444 that is located near 141 author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', ': bioRxiv preprint 5 the S 3-fold molecular axis.', 'CDRH3 and CDRL2 sandwich the SARS-CoV-2 S glycan 142 at position N343 through contacts with the core fucose moiety (in agreement with the 143 detection of SARS-CoV-2 N343 core-fucosylated peptides by mass-spectrometry 34 ) 144 and to a lesser extent with the core N-acetyl-glucosamine (Fig. 2d) .', 'These latter 145 interactions bury an average surface of ~170 Å 2 and stabilize the N343 oligosaccharide 146 which is resolved to a much larger extent than in the apo SARS-CoV-2 S structures 6,9 .', '147 The structural data explain the S309 cross-reactivity between SARS-CoV-2 and 148 SARS-CoV as 19 out of 24 residues of the epitope are strictly conserved (Fig. 2f and 149 Extended Data Fig. 6a-b) .', 'R346SARS-CoV-2, R357SARS-CoV-2, N354SARS-CoV-2 and 150 L441SARS-CoV-2 are conservatively substituted to K333SARS-CoV, K344SARS-CoV (except for 151', 'whereas K444SARS-CoV-2 is semi-conservatively substituted to T431SARS-CoV, in 153 agreement with the comparable binding affinities to SARS-CoV and SARS-CoV-2 S 154 (Fig. 1c) .', 'The oligosaccharide at position N343 is also conserved in both viruses and 155 corresponds to SARS-CoV N330, for which we previously detected core-fucosylated 156 glycopeptides by mass spectrometry 14 which would allow for similar interactions with 157 the S309 Fab.', 'Analysis of the S glycoprotein sequences of the 2,229 SARS-CoV-2 158 isolates reported to date indicates that several mutations have occurred with variable 159 frequency on the SARS-CoV-2 S ectodomain (Extended Data Fig. 7a-b) but no 160 mutations arose within the epitope recognized by S309 mAb.', 'Finally, S309 contact 161 residues showed a high degree of conservation across clade 1, 2 and 3 sarbecovirus 162 human and animal isolates 35 (Extended Data Fig. 7c) .', 'Collectively, the structural data 163 indicate that S309 could neutralize all SARS-CoV-2 isolates circulating to date and 164 possibly most other zoonotic sarbecoviruses.', 'The cryoEM structure of S309 bound to SARS-CoV-2 S presented here 168 combined with the structures of SARS-CoV-2 S B and SARS-CoV S B in complex with 169 ACE2 [16][17][18]36 indicate that the Fab engages an epitope distinct from the receptor-binding 170 motif and would not clash with ACE2 upon binding to S (Figure 3a-b) .', 'Biolayer 171 interferometry analysis of S309 Fab or IgG binding to the SARS-CoV-2 S B domain or 172 the S ectodomain trimer confirmed the absence of competition between the mAb and 173 ACE2 for binding to SARS-CoV-2 S (Figure 3c and Extended Data Fig. 8) .', ': bioRxiv preprint 6 To further investigate the mechanism of S309-mediated neutralization, we 175 compared side-by-side transduction of SARS-CoV-2-MLV in the presence of either 176 S309 Fab or S309 IgG. Both experiments yielded comparable IC50 values (3.8 and 3.5 177 nM, respectively), indicating similar potencies for IgG and Fab (Fig. 3d) .', 'However, The 178 S309 IgG reached 100% neutralization, whereas the S309 Fab plateaued at ~80% 179 neutralization (Fig. 3d) .', 'This result indicates that one or more IgG-specific bivalent 180 mechanisms, such as S trimer cross-linking, steric hindrance or aggregation of 181 virions 37 , may contribute to the ability to fully neutralize pseudovirions.', 'Fc-dependent effector mechanisms, such as NK-mediated antibody-dependent 183 cell cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) can 184 contribute to viral control in infected individuals.', 'We observed efficient S309-and 185 S306-mediated ADCC', 'Fc fragment relative to the FcgRIIIa receptors.', 'ADCC was observed only using NK 189 (effector) cells expressing the high-affinity FcgRIIIa variant (V158) but not the low-190 affinity variant (F158) (Fig. 3e) .', 'These results, which we confirmed using a FcgRIIIa 191 cell reporter assay (Fig. 3f) , suggest that S309 Fc engineering could potentially 192 enhance activation of NK cells with the low-affinity FcgRIIIa variant (F158) 38 .', '193 Macrophage or dendritic cell-mediated ADCP can contribute to viral control by clearing 194 virus and infected cells and by stimulating T cell response via presentation of viral 195 antigens 39,40 .', 'Similar to the ADCC results, mAbs S309 and S306 showed the strongest 196 ADCP response (Fig . 3g and Extended Data Fig. 8b) .', 'FcgRIIa signaling, however, 197 was only observed for S309 (Fig. 3h) .', 'These findings suggest that ADCP by 198 monocytes was dependent on both FcgRIIIa and FcgRIIa engagement.', 'Collectively, 199 these results demonstrate that in addition to potent in vitro neutralization, S309 may 200 leverage additional protective mechanisms in vivo, as previously shown for other 201 antiviral antibodies 41,42 .', 'To gain more insight into the epitopes recognized by our panel of mAbs, we 205 used structural information, escape mutants analysis 23,27,30 , and biolayer 206 inteferometry-based epitope binning to map the antigenic sites present on the SARS-207 author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', ': bioRxiv preprint 7 CoV and SARS-CoV-2 S B domains ( Fig. 4a and Extended Data Fig.10 ).', 'This analysis 208 identified at least four antigenic sites within the S B domain of SARS-CoV targeted by 209 our panel of mAbs.', 'The receptor-binding motif, which is targeted by S230, S227 and 210 S110, is termed site I. Sites II and III are defined by S315 and S124, respectively, and 211 the two sites were bridged by mAb S304.', 'Site IV is defined by S309, S109, and S303 212 mAbs.', 'Given the lower number of mAbs cross-reacting with SARS-CoV-2, we were 213 able to identify sites IV targeted by S309 and S303, and site II-III targeted by S304 and 214 S315 (Fig. 4b) .', 'Based on the above findings, we evaluated the neutralization potency of the site 216 IV S309 mAb in combination with either the site II S315 mAb or site II-III S304 mAb.', 'Although S304 and S315 alone were weakly neutralizing, the combination of either of 218 these mAbs with S309 resulted in an enhanced neutralization potency, compared to 219 single mAbs, against both SARS-CoV-2-MLV and authentic SARS-CoV-2 ( Fig. 4c-d 220 and Fig. 1e) .', 'A synergistic effect between two non-competing anti-RBD mAbs has 221 been already reported for SARS-CoV 43 and our data extend this observation to SARS-222', 'CoV-2, providing a proof-of-concept for the use of mAbs combinations to prevent or 223 control SARS-CoV-2.', 'In summary, our study identifies S309 as a human mAb with broad neutralizing 225 activity against multiple sarbecoviruses, including SARS-CoV-2, via recognition of a 226 highly conserved epitope in the S B domain comprising the N343-glycan (N330 in 227 SARS-CoV S).', 'Furthermore, S309 can recruit effector mechanisms and synergizes 228 with weakly neutralizing mAbs, which may mitigate the risk of viral escape.', 'Our data 229 indicate the potential to discover potently neutralizing pan-sarbecovirus mAbs, 230 highlight antigenic sites to include in vaccine design, and pave the way to support 231 preparedness for future sarbecovirus outbreaks.', 'As S309 bears the promise to be an 232 effective countermeasure to curtail the COVID-19 pandemic caused by SARS-CoV-2, 233', 'Fc variants of S309 with increased half-life and effector functions have entered an 234 accelerated development path towards clinical trials.', '235 236 237 238 author/funder.', 'All rights reserved.', 'No reuse allowed without permission.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['COVID-19 virus is the cause of a debilitating and life-threatening infectious 26 pulmonary disease that is now responsible for a global pandemic.', 'Currently, there are 27 no specific drugs or vaccines to contain this virus.', 'The main protease (M pro ) of COVID-28 19 virus is a key enzyme, which plays an essential role in viral replication and 29 transcription, making it an ideal drug target.', 'An FDA-approved antineoplastic drug, 30 carmofur, has been identified as an inhibitor that targets COVID-19 virus M pro', 'However, its inhibitory mechanism is unknown.', 'Here, we report the 1.6-Å crystal 32 structure of COVID-19 virus M pro in complex with carmofur.', 'The crystal structure 33 shows that carmofur contains an electrophilic carbonyl reactive group, which 34 covalently binds to C145, a member of the catalytic dyad.', 'As a result, its fatty acid tail 35 occupies the hydrophobic S2 subsite of M pro whilst its 5-fluorouracil head is cleaved as 36 product of the new covalent bond that has formed.', 'Carmofur is active in a cell based 37 antiviral assay with an EC50 of 24.87 μM. It is therefore a promising lead compound 38 for the development of new antivirals to target COVID-19.']}\n", - "{'sentences': ['The COVID-19 pandemic has created a high demand on personal protective equipment, including disposable N95 masks.', 'Given the need for mask reuse, we tested the feasibility of vaporized hydrogen peroxide (VHP), ultraviolet light (UV), and ethanol decontamination strategies on N95 mask integrity and the ability to remove the infectious potential of SARS-CoV-2.', 'FIT test data showed functional degradation by both ethanol and UV decontamination to different degrees.', 'We first investigated if decontamination strategies, 70% ethanol, ultraviolet light, or VHP, impacted N95 mask integrity.', 'We assessed N95 mask integrity through quantitative respirator fit testing ( Figure 1A) .', 'Depending on perspective, the high concentration of SARS-CoV-2 initially applied to N95 masks can be considered either a strength or a weakness.', 'Without access to sophisticated droplet or aerosol generating machines and to avoid unnecessary risk, SARS-CoV-2 containing media was applied directly to the mask samples with a pipette.', 'We intended to deliver the highest challenge possible to assess decontamination efficacy.', 'Sample from the 6 highest titer patients in our healthcare system to date were pooled, and 100uL of this concentrated SARS-CoV-2 containing media was directly infiltrated into the N95 masks with the attempt to expose the middle layer.', 'It is hard to imagine a scenario where healthcare workers would face this degree of mask inoculum.', 'Methods able to decontaminate N95 masks under these intense exposure conditions would likely be highly efficacious in actual practice.', 'However, methods that appear less effective in decontaminating SARS-CoV-2 in our experiment, such as UV, would almost certainly be more effective if masks were challenged in a more realistic exposure scenario.', 'Our data may therefore inadvertently underestimate the decontamination efficacy of some methods.', 'Reuse of disposable N95 masks after decontamination is not recommended, primarily because of concerns that decontamination would degrade the performance of respirators (2, 3, 7) .', 'Our study provides further support for these prior recommendations.', 'Nevertheless, we recognize that health care systems and front-line providers around the world are currently facing unprecedented shortages of protective respiratory devices and must make decisions that are not ideal.', 'We hope our data will help guide evidenced-based decisions and future experiments that will protect health care providers fighting SARS-CoV-2 and other pathogens.', 'In this study we investigated the effect of different decontamination methods on disposable N95 masks for virucidal effect on SARS-CoV-2 and on N95 mask integrity.', 'In order to be compatible with reuse, methods of N95 mask SARS-CoV-2 decontamination must remove the viral threat, be harmless to the mask user, and not compromise the integrity of the various mask elements.', 'The decontamination methods utilized, 70% ethanol, ultraviolet light, and vaporized hydrogen peroxide, have previously been demonstrated to be safe for mask users (3) (4) (5) 9) .', 'We found that any ethanol exposure significantly altered mask integrity, as previously reported (7) .', 'We also found that the impact of 70% ethanol on mask integrity appears time dependent.', 'In fact, thirty minutes after 70% ethanol application there was even a larger decline in function, even though the N95 masks feel dry to the touch.', 'Consistent with prior studies, we did observe a decline in SARS-CoV-2 infectivity (as assessed by Vero E6 culture) after certain decontamination strategies.', 'There are many limitations to this study.', 'First and foremost, experiments to measure SARS-CoV-2 RNA and infectivity were conducted only once.', 'Our project was initiated to inform decision makers about strategies for mask decontamination.', 'Due to limited resources including continued access to BSL3 laboratory space and risk of viral concentration, we were only able to complete a single SARS-CoV-2 decontamination experiment.', 'Another limitation is that clear variation exists between N95 mask type and decontamination efficacy.', 'This could be due to technical replicate variation.', 'However, a reasonable hypothesis to test is that N95 masks with a fluid-resistant coating (healthcare grade) relative to the 8511 (with a fluid-resistant coating (healthcare grade) relative to the 8511', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'uptake and are therefore more likely to be effectively decontaminated.', 'More work is needed to understand this relationship between N95 mask material and decontamination efficacy.', 'Notably, we did not test if ethanol, UV, or VHP impaired N95 fluid-resistant coating on healthcare grade masks.', 'Next, FIT testing, which is utilized by our healthcare system to determine N95 integrity, could in some instances underrepresent actual protection.', 'Likewise, it is also possible ethanol or UV may have resulted in internal mask degradation, producing particulate that may have overestimated the negative impact on N95 mask integrity.', 'While we believe our quantitative FIT testing provides a reasonable estimate of N95 mask function that can aid in comparing imperfect decontamination strategies, we did not conduct the plethora of gold-standard National Institute for Occupational Safety and Health assays required for validation.', 'Another limitation is we did not test how time alone impacts SARS-CoV-2 infectivity.', 'It is entirely possible that no decontamination, and allowing for decay of virus infectivity over time, is a preferable strategy when faced with no ideal options.']}\n", - "{'sentences': ['Receptor recognition is the first step of viral infection and is a key determinant of host cell and tissue tropism.', 'Enhanced binding affinity between SARS-CoV S and hACE2 was proposed to correlate with increased virus transmissibility and disease severity in humans (Li et al., 2005c) .', 'Indeed, SARS-CoV isolates from the three phases of the 2002-2003 epidemic were more efficiently transmitted among humans and more pathogenic than the isolates associated with the 2003-2004 re-emergence that caused only a few cases, in line with their binding affinities for hACE2 (Consortium, 2004; Kan et al., 2005; Li et al., 2005c) .', 'Moreover, the ability to engage ACE2 from different animal species appears to reflect host susceptibility to SARS-CoV infection and facilitated the jump of the virus from animals to humans (Li, 2008; Li et al., 2004) .', 'We report here that SARS-CoV-2 uses hACE2 as an entry receptor and recognizes it with a similar affinity to the 2002-2003 SARS-CoV isolates, which suggests it can spread efficiently in humans, in agreement with the numerous SARS-CoV-2 human-to-human transmission events reported to date.', 'Besides binding to host cell receptors, priming of the S glycoprotein by host proteases through cleavage at the S 1 /S 2 and the S 2 0 sites is another crucial factor modulating tropism and pathogenicity (Millet and Whittaker, 2015) .', 'For instance, entry of the MERS-CoV-related bat coronavirus HKU4 into human cells required addition of exogenous trypsin, indicating that S proteolytic activation of this bat virus did not occur in human cells (despite its ability to recognize human DPP4) Yang et al., 2014) .', 'Subsequent work suggested that a glycan present near the S 1 /S 2 boundary accounted for the lack of proteolytic priming of HKU4 S and that its removal enhanced pseudovirus entry in human cells (Yang et al., 2015b) .', 'The presence of a polybasic cleavage site, that can be processed by furin-like proteases, is a signature of several highly pathogenic avian influenza viruses and pathogenic Newcastle disease virus (Klenk and Garten, 1994; Steinhauer, 1999) .', 'Strikingly, SARS-CoV-2 S harbors a furin cleavage site at the S 1 /S 2 boundary, which is processed during biosynthesis.', 'The presence of a furin cleavage site sets SARS-CoV-2 S apart from SARS-CoV S (and SARSr-CoV S) that possesses a monobasic S 1 /S 2 cleavage site processed upon entry of target cells Bosch et al., 2008; Glowacka et al., 2011; Matsuyama et al., 2010; Millet and Whittaker, 2015; Shulla et al., 2011) .', 'We speculate that the almost ubiquitous expression of furin-like proteases could participate in expanding SARS-CoV-2 cell and tissue tropism, relative to SARS-CoV, as well as increasing its transmissibility and/or altering its pathogenicity.', 'We previously suggested that coronaviruses use conformational masking and glycan shielding to limit recognition by the immune response of infected hosts (Walls et al., 2016b; Walls et al., 2019; Xiong et al., 2018) .', 'Similarly to SARS-CoV S and MERS-CoV S (Gui et al., 2017; Kirchdoerfer et al., 2018; Pallesen et al., 2017; Song et al., 2018; Walls et al., 2019; Yuan et al., 2017) , we found that the SARS-CoV-2 S trimer exists in multiple, distinct conformational states resulting from S B opening at the trimer apex.', 'These structural changes are necessary for receptor engagement of these three viruses and lead to initiation of fusogenic conformational changes (Song et al., 2018; Walls et al., 2017b; Walls et al., 2019) .', 'In contrast, only closed S trimers have been detected for the four other human-infecting coronaviruses: HCoV-NL63 (Walls et al., 2016b) , HCoV-OC43 , HCoV-HKU1 (Kirchdoerfer et al., 2016) , and HCoV-229E .', 'As HCoV-NL63 and HCoV-229E are known to engage protein receptors through S B (Wong et al., 2017; Wu et al., 2009) , trimer opening is also expected to occur to expose their RBMs that are otherwise buried at the interface between protomers in the closed S trimers Walls et al., 2016b) .', 'Regardless of the nature of the receptor and the location of the receptor-binding domains, removal of the trimeric S 1 crown is expected to be necessary for all coronaviruses to allow the large-scale S 2 conformational changes leading to fusion of the viral and host membranes (Walls et al., 2017b) .', 'Collectively, these data underscore that S glycoprotein trimers found in highly pathogenic human coronaviruses appear to exist in partially opened states, while they remain largely closed in human coronaviruses associated with common colds.', 'Based on the aforementioned data correlating the binding affinity of SARS-CoV for hACE2 with the rate of transmissibility, viral replication in distinct species, and disease severity (Guan et al., 2003; Li et al., 2004; Li et al., 2005c; Wan et al., 2020) , we hypothesize that the most pathogenic coronaviruses will exhibit S glycoprotein trimers spontaneously sampling closed and open conformations, as is the case for SARS-CoV-2, SARS-CoV and MERS-CoV.', 'The striking structural similarity and sequence conservation among the SARS-CoV-2 S and SARS-CoV S glycoproteins emphasize the close relationship between these two viruses that recognize hACE2 to enter target cells.', 'This resemblance is further strengthened by our finding that SARS-CoV S elicited polyclonal Ab responses, potently neutralizing SARS-CoV-2 S-mediated entry into cells.', 'We surmise most of these Abs target the highly conserved S 2 subunit (including the fusion peptide region) based on its structural similarity across SARS-CoV-2 and SARS-CoV, the lack of cross-reactivity of several S B -directed Abs (Tian et al., 2020; Wrapp et al., 2020) , and previous reports showing that sera from SARS-CoV-infected individuals target this region (Zhang et al., 2004) .', 'We note that most SARS-CoV neutralizing Abs isolated to date target the S B domain and that several of them recognize the RBM and prevent receptor engagement (Hwang et al., 2006; Rockx et al., 2008; Rockx et al., 2010; Traggiai et al., 2004; Walls et al., 2019) .', 'As the SARS-CoV-2 and SARS-CoV S B domains share 75% amino acid sequence identity, future work will be necessary to evaluate whether any of these Abs neutralize the newly emerged coronavirus.', 'These findings also indicate that it might be difficult to distinguish exposure to SARS-CoV-2 from other SARSr-CoVs in serological studies using S ectodomain trimers and that specific assays will need to be designed.', 'Our results provide a structural framework to identify conserved and accessible epitopes across S glycoproteins that will support Italic font indicates the absence of a glycosylation sequon and deletions are indicated with periods.', 'Glycans observed in the SARS-CoV-2 S cryo-EM map are underlined.', 'See also Data S1.', 'Cell 180, 1-12, March 19, 2020 7 ongoing vaccine design efforts.', 'Finally, elicitation of diverse, polyclonal Ab responses might prove key in light of the diversity of viruses circulating in animal reservoirs and in preventing the possible emergence of viral neutralization escape mutants.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['evaluated the association between changes in the incidence of AKI and COVID-19 disease and clinical outcomes by using logistic regression models.', 'Results: A total of 287 patients, 55 with AKI and 232 without AKI, were included in the analysis.', 'Compared to patients without AKI, AKI patients were older, predominantly male, and were more likely to present with hypoxia and have pre-existing hypertension and cerebrovascular disease.', 'Moreover, AKI patients had higher levels of white blood cells, D-dimer, aspartate aminotransferase, total bilirubin, creatine kinase, lactate dehydrogenase, procalcitonin, C-reactive protein, a higher prevalence of hyperkalemia, lower lymphocyte counts, and higher chest computed tomographic scores.', 'The incidence of stage 1 AKI was 14.3%, and the incidence of stage 2 or 3 AKI was 4.9%.', 'Patients with AKI had substantially higher mortality.', 'Conclusions: AKI is an important complication of COVID-19.', 'Older age, male, multiple pre-existing comorbidities, lymphopenia, increased infection indicators, elevated D-dimer, and impaired heart and liver functions were the risk factors of AKI.', 'AKI patients who progressed to stages 2 or 3 AKI had a higher mortality rate.', 'A recent seminal work indicated that the COVID-19 uses the angiotensin converting enzyme II (ACE2) as a cell entry receptor, a cellular mechanism identical to that of the SARS-CoV [14, 15] .', 'In addition, a gain-of-function experiment found that the ACE2 could be used by a wildtype coronavirus of a bat origin to gain entry into cells [15, 16] .', 'ACE2 is not exclusively expressed in the respiratory organs but also in other human tissues.', 'Of note, the expression of ACE2 is almost 100-fold higher in kidney tissue importantly, SARS-CoV-2 nucleic acids have been found in the urine of patients with COVID-19 [2] .', 'Together, these multiple lines of evidence indicate that kidney impairment may be one of the major causes of morbidity among patients with COVID-19, and may contribute to multiorgan failure and death.', 'Our study investigated the incidence of AKI and risk factors for AKI in patients with COVID-19.', 'The study included 287 patients admitted from Hankou Hospital, Wuhan from February 8 to March 8, 2020.', 'The incidence of AKI among the patients in our study was substantially higher than the overall incidence of 0.5-7% reported in previous studies [2, 7] , and is comparable to that of critically ill patients hospitalized with other illnesses (29%) [3] .', 'The following reasons may explain the higher incidence of AKI observed in our study compared to previous studies:', 'First, most of the patients admitted to our hospital with COVID-19 had severe disease.', 'At the time of admission, 43% of the patients had severe .', 'CC-BY-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.06.20055194 doi: medRxiv preprint disease.', 'Although many patients had low pulse oxygen saturation when they were admitted to the hospital, the symptoms of dyspnea tended to be mild.', \"The reason might be that the patient's condition gradually deteriorated and the body adapted and compensated to some degree.\", 'The very high CT score and the rapid deterioration of many patients after admission also provide evidence of the severity of the disease among the patients in this study.', 'Second, the methods that we used to diagnose and stage AKI might have overestimated the incidence and severity.', 'Due to the outbreak of COVID-19 and the shortage of medical resources, many patients did not have a baseline serum creatinine test prior to admission, and had not had a creatinine test in the previous year.', \"Therefore, we could only estimate the baseline serum creatinine of such patients according to the patient's sex, weight, medical history and other related parameters.\", 'The incidence of AKI was determined based on baseline values and serum creatinine values within 7 days of admission.', 'In order to reduce the bias of our estimates of baseline values, the two methods, including average serum creatinine method [11] and eGFR 75 method [17], were used for comparison.', 'The AKI incidence rate was 25.8% according to the average serum creatinine method and 19.2% according to the eGFR75 method (Supplemental Table 2 ).', 'The calculated values of baseline serum creatinine estimated by the eGFR75 method were significantly different from those of some of the patients with baseline serum creatinine results available.', 'Imprecision and inaccuracies in estimated baseline value of serum creatinine might have caused an overestimation of the incidence of AKI in our study.', 'However, any overestimation of the incidence of AKI may not have directly affected our investigation of AKI risk factors.', 'We found that compared with non-AKI patients with COVID-19, older age, multiple pre-existing comorbidities, an increased white blood cell count, low lymphocyte count, and increased levels of PCT and CRP, were risk factors for AKI.', 'The prevalence of several of .', 'CC-BY-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.06.20055194 doi: medRxiv preprint the pre-existing comorbidities that we considered, including chronic lung diseases and diabetes mellitus, did not differ significantly between the patients with and without AKI, although this might be due to the relatively small number of cases of AKI in this study.', 'Lymphopenia indicates that decreased immunity might occur in patients with COVID-19, and an increased level of PCT and CRP suggest that some patients may have had secondary bacterial infections which caused excessive inflammatory responses.', \"Unfortunately, we did not conduct bacterial and fungal culture on the patients with respiratory coinfections detected on PCR because of the shortage of medical staff, and were unable to test patients' inflammatory factor profiles because the local hospital did not have inflammatory factor test kits.\", 'Previous studies [2] [3] [4] 7] have shown that patients with COVID-19 have significantly increased D-dimer levels, multiple organ damage, and electrolyte disturbances.', 'Our study revealed that these abnormalities were more pronounced in patients with AKI.', 'These results suggest that patients may experience severe hypoxia, resulting in aggravated multiple organs damage.', 'It should not be overlooked that SARS-CoV-2 might also directly attack multiple organs, especially the kidneys.', 'The occurrence and development of AKI often leads to the imbalance of blood volume and electrolytes, the accumulation of metabolites, the aggravation of multiple organ dysfunction, and creating a vicious cycle.', 'While, the majority of patients with stage 1 AKI recovered and were discharged, those who progressed to stage 2/3 AKI, had an extremely high mortality rate.', 'The underlying reason might be due to the limited treatment conditions in urgent breakout period of our country.', 'The study results suggest that early intervention after the occurrence of AKI is very important, and that continuous renal replacement should be considered to help alleviate the progress of AKI.', 'Our survey included all clinically confirmed COVID-19 cases because most suspected cases (also known as clinically confirmed cases) present an exact epidemiological history, and many patients .', 'CC-BY-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.06.20055194 doi: medRxiv preprint changed from mild to severe during home quarantine.', 'Due to the long observation time, many patients showed negative by RT-PCR assay when they were hospitalized.', 'In fact, there are still a few suspected cases turned positive after with two negative RT-PCR results and discharged, which should be recognized as laboratory-confirmed cases.', 'In addition, other laboratory tests such as infection-related indicators (PCT and CRP), common respiratory pathogen nucleic acid determination, and CT scanning can also help us to differentiate pneumonia.', 'Our research has the following shortcomings: First, due to the large number of patient populations and the shortage of medical staff and equipment, we did not perform blood gas analysis and blood lactate measurement on most patients.', \"Instead, we based on the patient's main complaint, pulse oxygen saturation monitoring and CT to indirectly judge the oxygenation.\", \"Second, we have not explored the impact of treatment on AKI, because our treatments are based on WHO's standardized procedure [18] .\", 'The antiviral drugs, antibacterial drugs and hormones have little effect on renal function.', 'Third, we did not exclude patients with chronic renal insufficiency.', 'Five patients had chronic renal insufficiency with 3 cases in AKI group and 2 in the non-AKI group.', 'These patients were related to hypertension (2 cases) and diabetes (3 cases) at admission, but showed normal creatinine level during the past year.', 'Fourth, due to the urgent collation of data, we have a shorter follow-up time for some patients, and the shortest hospital stay for patients is only over 14 days.', 'These may interfere with the final prognosis judgment and lead to the failure to analyze the survival time.', 'Fifth, we did not analyze the comorbidities of all patients such as shock and adult respiratory distress syndrome (ARDS', 'CC-BY-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.06.20055194 doi: medRxiv preprint']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['The global pandemic of COVID-19 cases caused by infection with SARS-CoV-2 is ongoing, with no approved antiviral intervention.', 'We describe here the effects of treatment with interferon-α2b in a cohort of confirmed COVID-19 cases in Wuhan, China.', 'In this retrospective study, 77 adults hospitalized with confirmed COVID-19 were treated with either nebulized IFN-α2b (5mU b.i.d, arbidol (200mg t.i.d or a combination of IFN-α2b plus arbidol.', 'Serial SARS-CoV-2 testing along with hematological measurements, including cell counts and blood biochemistry, serum cytokine levels, temperature and blood oxygen saturation levels were recorded for each patient during their hospital stay.', 'Treatment with IFN-α2b with or without arbidol significantly reduced the duration of detectable virus in the upper respiratory tract and in parallel reduced duration of elevated blood levels for the inflammatory markers IL-6 and CRP.', 'These findings suggest that IFN-α2b should be further investigated as a therapy in COVID-19 cases.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'This retrospective study provides several important and novel insights into COVID-19 disease.', 'Most importantly, IFN-α2b therapy appears to shorten duration of viral shedding.', 'Notably, reduction of markers of acute inflammation such as CRP and IL6 correlated with this shortened viral shedding, suggesting IFN-α2b acted along a functional cause-effect chain where virally induced inflammation represents a pathophysiological driver.', 'Taken together, these findings elevate the biological plausibility of IFN-α2b representing a therapy for COVID-19 disease.', 'As the SARS-CoV-2 pandemic takes an ever-increasing toll, the urgent search for effective prophylactic and therapeutic interventions is rapidly accelerating.', 'This includes lopinavir/ritonavir, 7,8 chloroquine, 9 remdesivir ,10 as well as interferon (IFN)-α 2 and arbidol (ARB) 4 and combinations of these.', 'Most of these antivirals only have in vitro data to support consideration for coronavirus targets prior to clinical testing; as such, while unfortunate, it is not surprising that there is a high chance of failure.', 'However, we had shown during the SARS-CoV-1 outbreak in Canada that IFN-α treatment could hasten resolution of coronavirus-mediated human disease.', '3 This prompted us to evaluate IFN-α therapy that was administered for COVID-19 disease in the early stages of the outbreak in Wuhan, Hubei province, China.', 'Indeed, our analysis suggests that inhaled IFN-α2b accelerated viral clearance from the respiratory tract and hastened resolution of systemic inflammatory processes when compared to ARB treatment alone.', 'While we recognize that these data are at best suggestive, given the urgency, the findings indicate that a follow-up randomized placebo controlled clinical trial (RCT', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.06.20042580 doi: medRxiv preprint 13 could not only benefit the individual infected patient but, by reducing duration of viral shedding even in moderate cases (such as this cohort), assist in slowing the population spread.', 'The reduction of the inflammatory biomarker IL-6 following inhaled IFN-α2b therapy not only supported a clinically relevant impact of this approach, but also hinted at likely functional connections between viral infection and host end organ damage.', 'IL-6 has been shown to provide prognostic value in acute respiratory distress syndrome (ARDS), which is the most severe form of COVID-19 disease.', '12 If this were indeed the case, then targeting interventions such as interleukin-6 (IL-6) receptor inhibitors (e.g. toclizumab or sarilumab) towards this axis may prove a useful therapeutic adjunct, at least in those most severely ill.', \"This form of therapy has recently been approved by China's National Health Commission 13 and is currently under consideration by the Italian Medical Agency.\", '14 The advantage of IFN-α2b over blocking IL-6 rests in IFN targeting the cause (SARS-CoV-2), not only the symptoms (IL-6', 'This retrospective study has several significant limitations.', 'Most obvious is the fact that the study cohort was small, non-randomized, with unbalanced demographics between treatment arms that were of unequal size.', 'However, we considered this an exploratory study only, with the objective of determining in as rapid a manner as possible if a full trial should be considered.', 'The results indicate that an IFN-α RCT is now warranted.', 'Furthermore, since the entire cohort consisted only of moderate cases of COVID-19 disease, our findings may not be indicative of what occurs in more severely ill patients; All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.06.20042580 doi: medRxiv preprint 14 such caution about generalizability is indeed further supported by the lack of impact of age, sex and comorbidities on the course of COVID-19 disease in our cohort, as all these have been shown to influence clinical course.', '15 Irrespective of these significant limitations, to our knowledge, the findings presented here are the first to suggest therapeutic efficacy in COVID-19 disease of IFN-α2b, an available antiviral intervention.', 'Furthermore, beyond clinical benefit to the individual patient, treatment with IFN-α2b may also benefit public health measures aimed at slowing the tide of this pandemic, in that duration of viral shedding appears shortened.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.06.20042580 doi: medRxiv preprint']}\n", - "{'sentences': ['A Systems Biology perspective lends itself well to combating the current COVID-19 pandemic and for future zoonotic outbreaks as they will likely require multiple solutions from different biological and epidemiological perspectives.', 'Here, our analyses advocate for a re-evaluation of the currently accepted view that the primary means of infection for the SARS-CoV-2 virus is via association with ACE2 in lung tissue.', 'A non-respiratory path of infection has important implications for selecting the best methods to prevent the spread of SARS-CoV-2.', 'If a major route of infection is nasal/oral that leads to strong author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.06.028712 doi: bioRxiv preprint intestinal colonization, and the poorer binding of SARS-CoV-2 Spike protein with ACE (compared to SARS-CoV-1), if any, results in delays in the colonization of lung tissue, this may explain why many people are considered asymptomatic as they do not display the traditional symptoms (cough, fever, pneumonia).', 'Such individuals could thus be shedding virus through feces and poor hygiene long before they display traditional symptoms (if ever).', 'A recent study indicates that fecalmediated viral aerosolization from toilets may be a source of infective viral particles found in the air of bathrooms (46) .', 'It appears that there may be sufficient expression of ACE2 in nasal passages for SARS-CoV-2 to establish low level colonization that can lead to viral shedding via sneezing, nose blowing and lack of subsequent hand hygiene.', 'Awareness of these routes of infection may offer ways to reduce the number and severity of COVID-19 cases.', 'Furthermore, the significant variation in ACE and ACE2 expression among organs is consistent with some of the symptomology being reported for COVID-19, e.g. gastrointestinal (11) , testes (13) , thyroid (fatigue (14, 15) ), brain epithelial cells (headache (14, etc.', 'In addition, there is wide variation in tissue-specific expression across the GTEx population, which may partially explain differences in susceptibility and severity of illness being observed in COVID-19.', 'It is possible that the variation of ACE2 expression in the population is associated with some of the comorbidities found to be associated with mortality in COVID-19, including hypertension, cardiovascular disease and obesity.', 'Furthermore, it is possible the fluid loss associated with diarrhea resulting from gastrointestinal colonization by SARS-CoV-2, may affect the RAS system as it tries to regulate blood volume in the body.', 'Even though we verified very weak binding of SARS-CoV-2 spike protein to ACE in our simulations, we urge that the hypothesis that ACE, which is highly expressed in lung tissue, is an alternative receptor for SARS-CoV-2 should be thoroughly tested experimentally in humans and potential zoonotic reservoirs.', 'Our analyses suggest that ACE could be a secondary receptor for SARS-CoV-1 in the absence of ACE2, and it may have played a subtle but important role for the SARS outbreak.', 'It could explain the lower incidence of respiratory distress in COVID-19 compared to SARS (47) .', 'The expression analysis of the BAL samples indicates that COVID-19 likely induces increases in type I and type II alveolar epithelial cells, ciliated cells, Club cells, and lymphatic endothelial cells in BAL samples.', 'There also seemed to be a significant repression of myeloid and lymphoid lineages, particularly CSFR1+ macrophages as well as their inflammatory signatures, which may be due to the induction of the Ang 1-7 receptor MAS by the virus as part of its strategy to escape detection.', 'We posit that COVID-19 actively destroys these cells or reprograms them to the point of being unrecognizable.', \"This apparent elimination of functional macrophages and the complete lack of activated cytokine signature in COVID-19 lung BAL samples would seem to indicate that SARS-CoV-2's net effect of causing a functional immune deficiency syndrome (COVID-19-FIDS) is a considerable component of its virulence.\", 'Along with the information of host proteins involved in infection, we provide an extensive structural analysis of the viral proteome, all of which is available as a web resource (https://compsysbio.ornl.gov/covid-19/covid-19-structome/) and in the Appendix section of Supplementary Material.', 'The collective analysis also informs the identification of promising drug, vaccine and diagnostic targets for COVID-19.', 'The workflow developed for this study can readily be implemented in future efforts against pathogen outbreaks.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.06.028712 doi: bioRxiv preprint author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.06.028712 doi: bioRxiv preprint author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.06.028712 doi: bioRxiv preprint']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': [\"As the novel coronavirus that emerged in Wuhan spreads worldwide (p. 610), China is facing criticism that its initial response was slow, and questions persist about officials' openness.\", 'People in and outside of China have praised an early warning about mysterious illnesses, sounded in a message sent 30 December 2019 by Li Wenliang, an ophthalmologist at a Wuhan hospital, to his medical school classmates.', 'On 3 January, however, local police summoned Li, chastised him for spreading socially disruptive rumors, and made him sign a letter of self-criticism.', 'He has since become infected and was hospitalized.', \"Last week, the country's highest court faulted Li's detention as overreach.\", 'China is waging a fierce battle against the virus; it built a new, 1000-bed hospital in Wuhan in just 10 days, and Chinese scientists have published several papers on the virus.', \"But in a 30 January statement leaked on social media, China's Ministry of Science and Technology urged researchers to pour their efforts into stopping its spread instead.\", \"Until the task of prevention and control is completed, the focus should not be on the publication of papers,” the statement says As the novel coronavirus that emerged in Wuhan spreads worldwide (p. [610][1]), China is facing criticism that its initial response was slow, and questions persist about officials' openness.\", 'People in and outside of China have praised an early warning about mysterious illnesses, sounded in a message sent 30 December 2019 by Li Wenliang, an ophthalmologist at a Wuhan hospital, to his medical school classmates.', 'On 3 January, however, local police summoned Li, chastised him for spreading socially disruptive rumors, and made him sign a letter of self-criticism.', 'He has since become infected and was hospitalized.', \"Last week, the country's highest court faulted Li's detention as overreach.\", 'China is waging a fierce battle against the virus; it built a new, 1000-bed hospital in Wuhan in just 10 days, and Chinese scientists have published several papers on the virus.', \"But in a 30 January statement leaked on social media, China's Ministry of Science and Technology urged researchers to pour their efforts into stopping its spread instead.\", 'Until the task of prevention and control is completed, the focus should not be on the publication of papers,” the statement says.', '> “Employees … are questioning whether they should post potentially life-saving info or check tweets first.', \"” > > A September 2019 email by a National Weather Service official , reported by The Washington Post, after superiors rebuked forecasters for contradicting the president's inaccurate tweets about Hurricane Dorian's path.\", '### Agriculture The largest plague of desert locusts ( Schistocerca gregaria ) in decades is advancing across the Horn of Africa, consuming crops and threatening famine.', 'The problem began in 2018 when unusually heavy rains on the Arabian Peninsula allowed populations to boom over several generations.', 'In October 2019, the locusts swarmed south into Ethiopia, Eritrea, and Somalia, and in late December, they spread to Kenya, causing the worst infestation there in 70 years.', 'Somalia—which last week declared a national emergency and asked for increased food aid—has already lost 100,000 hectares of crops and pasture.', 'Another generation of locusts will likely hatch this month and cause more damage.', 'The Food and Agriculture Organization of the United Nations called for $70 million to fight the outbreak with pesticides and help farmers.', '### Glaciology After dropping sensors and a torpedo-shaped robot through a 700-meter hole in the ice, scientists in Antarctica last week revealed the first direct evidence that warm ocean temperatures around the rapidly retreating Thwaites Glacier could destabilize the key ice sheet.', 'Researchers are worried because Thwaites—larger than the state of Illinois—helps block the ocean from reaching and warming the even bigger, unstable West Antarctic Ice Sheet, whose melting could eventually drive meters of sea level rise.', 'Battling 2 months of stormy conditions, the team measured ocean waters beneath Thwaites at more than 2°C above the freezing point.', \"The robot, Icefin (above, shown operating elsewhere in Antarctica), provided the first images of the glacier's grounding zone, the mysterious boundary where the floating coastal ice sheet attaches to bedrock.\", 'The project is part of the International Thwaites Glacier Collaboration, a multiyear effort by the United States and the United Kingdom that is wrapping up its first full field season.', \"### Leadership Some researchers in Colombia are calling for a little-known molecular biologist appointed as the country's first ever science minister to resign.\", 'They are outraged by reports that she treated cancer patients with a fungal extract, without running a formal clinical trial.', 'We can only regret that the course of how to do science in our country has been left in the hands of pseudoscience,” the Colombian Association of Medical Faculties wrote in a statement.', 'In December 2019, Mabel Gisela Torres Torres was appointed to lead the newly created Ministry of Science, Technology and Innovation.', 'In January, she told a newspaper she did not seek formal ethical, safety, and efficacy reviews of her work with patients because she believed the fungus posed no threat to human health.', 'Her Ph.D. adviser has defended her and notes that metabolites in the fungi Torres studied have shown potential as a cancer treatment in cell and mouse studies.', '### Environmental science !', \"[Figure][2] CREDITS: (GRAPHIC) J. BRAINARD/ SCIENCE ; (DATA) UNITED NATIONS UNIVERSITY INSTITUTE FOR WATER, ENVIRONMENT, AND HEALTH The world's growing flows of wastewater offer a largely untapped, potentially lucrative source of energy, agricultural fertilizers, and water for irrigation, a comprehensive study says.\", \"The opportunities will increase as the annual volume of wastewater—now 380 billion cubic meters—expands by an estimated 51% by 2050, as populations and incomes multiply, says a team led by researchers at United Nations University's Institute for Water, Environment, and Health.\", 'About 13% of global demand for fertilizer could be met by recovering nitrogen, phosphorus, and potash from wastewater; such use provides a bonus, diverting nutrients from waterways, where they can create harmful eutrophication.', 'Sewage also offers an alternative energy source.', 'The need to plan and finance such recovery efforts is greatest in “low- and middle-income countries, where most municipal wastewater still goes into the environment untreated,” says the study, published 27 January in Natural Resources Forum.', \"### Conservation A decision by South Africa's government to allow breeding and genetic research on more than 30 wild species—including rhinos, lions, and cheetahs—could considerably reduce their genetic diversity, scientists warned last week.\", \"The government's action has been interpreted to allow breeders to select for commercially desirable traits, such as longer horns or larger body size; that could create genetic bottlenecks by promoting a few stud lines, the researchers wrote in the South African Journal of Science.\", 'They added that it may prove expensive or impossible to keep the intensively bred animals from mating with wild counterparts.', 'A handful of game ranchers requested the policy, which South Africa announced in May 2019 without consulting the public or studying potential consequences.', 'Game ranching —for hunting, meat, and tourism—already occupies more than 15% of the country, and the government wants to expand the industry.', '### Funding The U.S. National Science Foundation (NSF) announced this week seven winners in its contest for “big ideas” to address societal problems.', 'Four winning teams will receive $26,000 each to develop ideas on topics ranging from using artificial intelligence for complex problem-solving to developing small-scale technologies that sequester carbon dioxide.', 'Three more teams earned $10,000 as runners-up.', 'The 2026 Idea Machine contest attracted almost 800 submissions, and although some high schoolers made it to the semifinals, all the winners work at research institutions.', 'NSF hopes to fund workshops and exploratory grants to further develop these and other ideas from contestants.', \"### Publishing A software company said last week it has teamed up with publishing giant Wiley to roll out in mid-2020 a tool that can signal whether findings in Wiley's scientific papers are reproducible.\", \"The software, called [Scite.ai][3], uses artificial intelligence to examine articles that cite a paper, and determines and displays whether they provide evidence supporting or contradicting the paper's findings.\", 'Users can browse and search the relevant text of the citing articles.', 'Scite CEO Josh Nicholson says the software allows users to home in on articles that attempted to reproduce a study; of every 100 citations analyzed, Scite has found that 94 merely note the paper cited.', \"The addition of Wiley's articles will expand Scite's current trove of more than 14 million papers from other publishers, most in the biomedical sciences.\", 'Nicholson expects his company to sign agreements with additional publishers to analyze their articles.', '### Biomedicine The Chan Zuckerberg Initiative (CZI) said this week it will award $13.5 million to 30 patient advocacy groups to support their work finding treatments for rare diseases.', 'Of an estimated 7000 rare diseases, fewer than 5% have treatments approved by the U.S. Food and Drug Administration.', \"Each group will receive $450,000 over 2 years as well as training and mentoring as part of the foundation's Rare As One Project, launched last year to help advocates develop networks of patients, clinicians, and scientists.\", 'Most of the diseases are autoimmune, neurodegenerative, and other inherited disorders, but the list of diseases also includes rare cancers.', \"CZI, founded by Facebook's Mark Zuckerberg and pediatrician Priscilla Chan, his wife, has made a few other awards to rare disease groups.\", 'The initiative expected to make just 10 Rare As One awards but tripled the number after receiving 275 applications.', '### Conservation The Trump administration proposed last week to end penalties on owners of open oil storage ponds and other industrial operations that kill birds accidentally.', 'The administration will instead encourage voluntary efforts to protect birds.', 'Conservation groups cried foul, saying the change to the Migratory Bird Treaty Act of 1918 will only embolden companies to take actions that threaten vulnerable species.', '### Brain Research through Advancing Innovative Neurotechnologies Initiative gets leader Since its launch in 2013, the U.S. Brain Research through Advancing Innovative Neurotechnologies (Brain Research through Advancing Innovative Neurotechnologies) Initiative has doled out about $1.3 billion to develop tools that map and manipulate the brain.', 'Until now, the multiagency effort has had no formal director.', 'But last week, neurobiologist John Ngai of the University of California, Berkeley, was named to take the helm in March.', '(A longer version of the interview is at > Q: Why is Brain Research through Advancing Innovative Neurotechnologies getting a director?', 'The initiative has been run day to day by a terrific team of senior program directors and staff with oversight from the 10 [U.S. National Institutes of Health (NIH)] institutes and centers that are involved in Brain Research through Advancing Innovative Neurotechnologies.', 'I think as enterprises emerge from their startup phase, the question is how do you translate this into a sustainable enterprise, and yet maintain this cutting-edge innovation?', 'The initiative really will benefit from somebody thinking about this 24/7.', '> Q: What distinguishes this second phase of Brain Research through Advancing Innovative Neurotechnologies?', 'In the first phase, there was a very intentional and concentrated focus on tool development.', 'As we learn more about how neural circuits drive behavior … we can start implementing that knowledge, in terms of treating human diseases.', 'I am hopeful that Brain Research through Advancing Innovative Neurotechnologies, with other efforts in NIH']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Recently, several studies focus on the immunologic characteristics and potential factors for monitoring disease severity in COVID-19 patients [12, 13, 14, 16, 17] .', 'However, knowledge about the role of clinical parameters involved in COVID-19 patients is still insufficient.', 'In this study, we evaluated the clinical and immunological characteristics of 43 confirmed COVID-19 patients admitted at Chongqing Public Health Medical Center, Chongqing.', 'And we further screened potential factors as All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org /10.1101 /10.', '/2020 effective indicators for disease progression, in order to provide appropriate treatment for severe patients early.', 'Compared to mild patients, severe patients were older and had higher frequencies to be co-infected with bacteria, which is consistent with previous reports that critically ill patients were more likely to be older and had co-infection of bacteria [9] .', 'Furthermore, severe patients were more likely to have chest distress and respiratory symptoms, such as anhelation and asthma.', 'The clinical symptoms of COVID-19 patients are similar to those reported by other studies [6, 9, 10] .', 'In terms of laboratory finding, IL6, IL10, ESR, CRP, APTT, D-D, ALB, AST, LDH and FIB were significantly higher in severe cases than mild cases, which indicate a degree of cardiac, live, coagulation function abnormality and infection, so more attention should be paid for these patients to avoid delayed treatment.', 'In our study, severe patients were more likely to develop lymphopenia (57.1%) than mild patients (34.5%), which is consistent with previous studies that severe patients have higher rates of lymphopenia [6, 10, 13, 18] .', 'Lymphopenia is also observed in SARS-CoV and MERS-CoV infected patients but with different mechanisms [19] .', 'Consistent with previous study [20] , we also observed the decreased absolute number of CD3 + T cells in severe and mild patients (85.7%vs51.7%); moreover, the number of both CD4 + and CD8 + T cells were markedly lower in severe patients than mild patients.', 'So far, the All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org /10.1101 /10.', '/2020 potential mechanisms of lymphopenia, particularly the decrease of CD4 + and CD8 + T cell counts in COVID-19 patients remain unclear, the SARS-CoV-2 might have a direct influence on lymphocytes or lymphatic organs, or through an indirect pathway [12, 13] .', 'The corresponding mechanisms warrant further investigation.', 'Previous studies of COVID-19 patients have demonstrated that cytokine storm syndrome (CRS) could happen in SARS-CoV-2 infected patients [9, 10] .', 'Cytokine storms, which can quickly induce organ failure and threaten the life of the patients, are regarded as an important cause of death in COVID-19 patients.', 'Recent studies have reported an increase in serum cytokine levels in COVID-19 patients, especially in severe patients, and suggest that cytokine storm is associated with disease severity [6, 13] .', 'In our study, more severe patients occurred with the elevated IL6 (64.3%) and IL10 (64.3%', 'Furthermore, the levels of IL6 and IL10 in severe group were significantly higher than mild group.', 'Further analysis demonstrated that the variations of IL6 were closely related to the disease progression of COVID-19 patients.', 'This result is consistent with a previous study, which suggests IL6 as an effective target for disease monitoring and treatment [14, 21] .', 'IL6, as an acute phase inflammatory cytokine, plays an important role in regulating inflammatory responses.', 'Elevated IL6 level is often observed in the patients with acute respiratory distress syndrome [22] All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org /10.1101 /10.', '/2020 and may be related with T lymphocyte damage.', 'However, the underlying mechanisms of IL6 and other cytokines involved in COVID-19 patients needs further investigation.', 'Our results indicated that, as an infection-related factor, ESR was also significantly higher in severe patients compared to mild patients, which is consistent with previous studies [9, 23] .', 'ESR is a simple laboratory test for evaluating the inflammatory or acute response state.', 'Previous studies have reported that symptoms and signs plus ESR can predict pneumonia effectively [24] .', 'ESR also can be used as a monitoring factor in diagnosis and management of Gemcitabine-induced pulmonary toxicity [25] .', 'Furthermore, ESR is reported as a powerful predictor for coronary heart disease [26, 27] .', 'However, the exact role of ESR in COVID-19 patients is still controversial, as a study from Gong et al. indicate that ESR is unrelated to the disease severity in patients with COVID-19 pneumonia [28] .', 'Early examination of risk factors in COVID-19 patients could distinguish severe patients from mild patients effectively and facilitate appropriate treatment.', 'Recent studies have reported several factors that may be related to the severity of COVID-19 patients, including IL6 [14] , lymphopenia [12] , NLR [17] and N8R [13] .', 'Although we also observed a higher frequency of occurrence of lymphopenia in severe patients, it was not a potential factor for predicting the severity of COVID-19 patients All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org /10.1101 /10.', '/2020 according to LASSO binary logistic regression analysis.', 'Liu et al. Have indicated that N8R has even better performance than NLR in the ROC curve analysis [13] .', 'In our study, N8R was also significantly higher in severe patients, unfortunately, we cut it out since there are no results in LASSO binary logistic regression analysis.', 'Our results demonstrated that the potential markers to identify severe patients were ESR, D-D, age, ALB and IL6 by LASSO binary logistic regression analysis and ESR had the best performance with a higher AUC value in the ROC curve analysis.', 'Therefore, ESR can be used as a powerful indicator to predict disease severity in SARS-CoV-2 infected patients.', 'In conclusion, this study provides a correlation between clinical parameters and disease severity of COVID-19 patients.', 'Our study of mild and severe patients demonstrates that these clinical parameters, including ESR, D-D, age, ALB and IL6 are closely related with the disease progression of COVID-19 patients.', 'Among these parameters, ESR has the best performance and can be used as an effective indicator to predict the severity of disease.', 'Our study may help to identify severe COVID-19 patients in early stage, in order to provide supportive treatment and reduce the mortality.']}\n", - "{'sentences': ['Characterisation of the transcriptome and proteome of SARS-CoV-2 using direct RNA sequencing and tandem mass spectrometry reveals evidence for a cell passage induced in-frame deletion in the spike glycoprotein that removes the furin-like cleavage site.', \"[{'text': 'Direct RNA sequencing using an Oxford Nanopore MinION characterised the transcriptome of SARS-CoV-2 grown in Vero E6 cells.\", 'This cell line is being widely used to propagate the novel coronavirus.', 'The viral transcriptome was analysed using a recently developed ORF-centric pipeline.', 'This revealed the pattern of viral transcripts, (i.e. subgenomic mRNAs), generally fitted the predicted replication and transcription model for coronaviruses.', 'A 24 nt in-frame deletion was detected in subgenomic mRNAs encoding the spike (S) glycoprotein.', 'This feature was identified in over half of the mapped transcripts and was predicted to remove a proposed furin cleavage site from the S glycoprotein.', 'This motif directs cleavage of the S glycoprotein into functional subunits during virus entry or exit.', 'Cleavage of the S glycoprotein can be a barrier to zoonotic coronavirus transmission and affect viral pathogenicity.', 'Allied to this transcriptome analysis, tandem mass spectrometry was used to identify over 500 viral peptides and 44 phosphopeptides, covering almost all of the proteins predicted to be encoded by the SARS-CoV-2 genome, including peptides unique to the deleted variant of the S glycoprotein.', 'Detection of an apparently viable deletion in the furin cleavage site of the S glycoprotein reinforces the point that this and other regions of SARS-CoV-2 proteins may readily mutate.', 'This is of clear significance given the interest in the S', 'This integrated analysis of the SARS-CoV-2 transcriptome and proteome revealed significant findings, in particular, the identification of an eight aa deletion in the SARS-CoV-2 S glycoprotein that potentially effects protein cleavage, cell tropism and infectivity.', 'The coronavirus S glycoprotein is made as a larger precursor that must be primed by cleavage using host cell proteases to enable subsequent viral entry.', 'For different coronaviruses, cleavage can occur at one or more sites (termed the S1/S2 and S2´ sites) depending on the amino acid consensus sequences present at each site and has major repercussions on host cell tropism and pathogenesis 19 .', 'The SARS-CoV S glycoprotein has a single arginine residue at the S1/S2 site (Figure 2b ), that facilitates cleavage by a number of proteases including trypsin, cathepsin L and TMPRSS11D 32-34 and a consensus sequence for trypsin and/or elastin cleavage at the S2´ site 35, 36 .', 'By comparison, SARS-CoV-2 has a four amino acid insertion (680SPRR683) in the S glycoprotein that results in the generation of a furin-like cleavage site (682RRAR685) at the S1/S2 boundary that is not present in other lineage B betacoronaviruses, including SARS-CoV and the highly related bat coronavirus RaTG13 23 .', 'Moreover, analysis of a cryo-EM structure of the S glycoprotein showed that the SPRR insertion creates a disordered solvent exposed loop 24 that protrudes from the trimer surface (Figure 3a ).', 'It has been proposed that this region is more available to host cell proteases for processing 24 .', 'The presence of a furin-like cleavage site at the S1/S2 boundary results in cleavage of the SARS-CoV-2 S glycoprotein before viral exit from the cell, whereas the S glycoprotein of coronaviruses such as SARS-CoV, lacking a S1/S2 furin cleavage site, exit the cells with the S glycoprotein largely uncleaved, necessitating cleavage prior to or during cell entry 20, 37, 38 .', 'CC-BY 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.22.002204 doi: bioRxiv preprint', 'The SARS-CoV-2 S glycoprotein deletion identified in this study removes the furin cleavage site, but also Arg685 (corresponding to SARS-CoV Arg667) required for cleavage of the SARS-CoV S glycoprotein.', 'However the sequence 694AY/T696 (numbering of undeleted S glycoprotein, cleavage shown by \"/\"; Figure 2b ) is still retained and has been identified as a second potential S1/S2 protease cleavage site for SARS-CoV downstream of the basic Arg667 residue 23 suggesting that either the deleted SARS-CoV-2 S glycoprotein could be cleaved at this site or only use the S2´ site for cleavage.', 'Recently pseudoviruses expressing the SARS-CoV-2 S-glycoprotein and the corresponding S glycoprotein with the furin cleavage site removed at the S1/S2 boundary (residues 680SPRR683 removed) were made and their ability to mediate entry to Vero E6 and BHK-21 cells expressing hACE2 compared 33 In addition to the S glycoprotein deletion we were also able to find an additional significant deletion, in high quality data recently deposited by Kim et al. 8']}\n", - "{'sentences': [\"[{'text': 'Background: The outbreak of novel coronavirus pneumonia in China began in December 2019.\", 'Studies on novel coronavirus disease (COVID-19) were less based on pediatric patients.', 'This study aimed to reveal the clinical characteristics of COVID-19 in children.', 'Method: This study retrospectively analyzed the clinical symptoms, laboratory results, chest CT, and treatment of children with laboratory-confirmed COVID-19(ie, with samples that were positive for 2019 novel coronavirus[2019-nCoV]) who were admitted to Result: Nine patients had no obvious clinical symptom.', '11 patients developed fever.', 'Other symptoms, including cough(in eleven of seventeen patients), rhinorrhea(in two), diarrhea(in two), vomiting(in two), were also observed.', 'A small minority of patients had lymphocytopenia.', 'Alanine transaminase or transaminase increased in three cases.', 'According to chest CT scan, 11 patients showed unilateral pneumonia, 8 patients had no pulmonary infiltration.', 'No serious complications such as acute respiratory syndrome and acute lung injury occurred in all patients.', 'Conclusion: The clinical characteristics of 2019-nCoV infection in children were different from adult.', 'The overall condition of children were mild and have a good prognosis.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Despite significant advances in next generation sequencing technologies, which have facilitated the discovery of thousands of novel animal-derived viruses, tools for downstream functional assessment of these novel sequences are lacking.', 'To gain traction on this ever-growing problem, we took a reductionist approach to coronavirus entry and developed a scalable, BSL2-compatible method for testing only the minimal region of the virus essential for interacting with the host receptor ( figure 1, figure s1a ).', 'Because most of these viruses have never been isolated, we resorted to synthetic biology and molecular engineering to reduce the burden of gene synthesis to just a small fragment.', 'Thus, the cost and synthesis production time for testing several spikes for entry in our system is dramatically reduced (figure s1d).', 'In theory, this approach to functional viromics should be applicable to a wide variety of virus-host proteins and interactions.', 'Coronavirus entry is a multi-step process involving multiple, distinct domains in spike that mediate virus attachment to the cell surface, receptor engagement, protease processing and membrane fusion 8 .', 'While the RBD:receptor interaction is most studied in this process, recent studies have highlighted the major role host protease processing plays as a species barrier 22, [25] [26] [27] .', 'Lineage C coronaviruses include MERS-CoV as well as distantly related viruses such as HKU4, HKU5 and PDF-2180 28, 29 .', 'Studies have shown that HKU4 can bind human DPP4 but requires addition of exogenous trypsin to facilitate cell entry and that HKU5 and PDF-2180 spikes can enter human cells through an unidentified receptor with protease treatment 22, 26 .', 'Analogous to these earlier studies of lineage C CoVs, we observed protease-enhanced entry of lineage B CoVs (figure 2, 3, 5).', 'While it has been shown that host proteases cleave spike, allowing for downstream author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.01.22.915660 doi: bioRxiv preprint membrane fusion, other evidence suggests that protease may act on the receptor as well to activate it 30 Therefore, further studies are needed to assess where trypsin is enhancing entry of coronaviruses: at the level of spike, the receptor, or both.', 'In the absence of exogenous protease, only clade 1 RBDs entered nonhuman primate, human and porcine cell lines ( figure 2a, b, s2a, b) .', 'These findings are in strong agreement with previous studies that have either isolated virus (WIV1) or rescued recombinant chimeric viruses (SHC014, Rs4231, Rs7237) 5,7,31 .', 'However, with trypsin, a subset of genetically-similar clade 2 RBDs gained entry in these cells, suggesting their barrier is at the level of protease processing ( figure 2a, b) .', 'The other spike from clade 2 and 3 did not enter the cells we tested, regardless of protease addition, suggesting an absent or incompatible receptor.', 'Surprisingly, the protease-dependent entry phenotype was consistent in the reverse spike chimeras in which we replaced the RBD in clade 2 or 3 spike with a clade 1 RBD (figure 5d), suggesting that either the protease site between S1/S2 is not compatible with the chimeric spike backbone or the protease is not expressed in these cells (figure s5).', 'Because clade 1 spikes enter cells expressing human ACE2 without addition of protease but clade2-clade1 chimeras require protease, our data suggests the spike protease cleavage site is adapted to the protease environment of the receptor-bound RBD (figure s5).', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.01.22.915660 doi: bioRxiv preprint None of the spike pseudotypes efficiently entered Rhinolophus cells, which has been observed in previous studies using these cells 32, 33 (figure 2c) .', 'Surprisingly, AJi cells were selectively permissive for only clade 2 entry following protease treatment, which suggests that clade 2 RBDs interact with a receptor that is distinct from clade 1 (figure 2c).', 'Our results show that, despite all being classified as the same virus species, most lineage B β-CoVs do not use currently known coronavirus receptors ( figure 1e, 3a, b) .', 'Critically, we did not observe any pseudotype entry in the presence of protease and absence of receptor, suggesting that lineage B cell entry is still receptor-dependent following protease treatment (figure 3b).', 'While our study was ongoing, a novel lineage B β-CoV was identified as the etiological agent behind an outbreak of pneumonia in Wuhan, Hubei, China (2019-nCoV).', 'The RBD for 2019-nCoV has residues and motifs found in all 3 clades but forms a distinct clade, so we tested it for receptor usage and observed entry only with human ACE2 but not other known coronavirus receptors (figure 3d).', 'Interestingly, within the backbone of SARS-CoV spike, cell entry of 2019-nCoV was similar to the other clade 1 spikes tested, including SARS-CoV. These finding suggests 2019-nCoV is capable of using human ACE2 as efficiently as SARS-CoV, which may help explain the human-to-human transmissibility of this virus.', 'More studies are needed with the full spike sequence and, ideally, a viral isolate.', 'The receptor binding motif (RBM', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.01.22.915660 doi: bioRxiv preprint insufficient to impart human ACE2 usage (figure 4c).', 'This is likely because the noncontact residues in the RBM play a supportive and structural role for these contact points, and indeed, these non-contact residues are different between the clades (figure s4).', 'In contrast to changing individual amino acids, our chimeric RBD constructs show that clade 2 and 3 RBD containing the clade 1 RBM are compatible with human ACE2.', 'Coronaviruses frequently undergo recombination, gaining large swaths of genetic material at once 34, 35 .', 'Taken together with our data, it is possible that recombination with a clade 1 virus will impart compatibility with human ACE2.', 'Interestingly, the 2019-nCoV RBD forms a clade that is distinct from the other 3 clades (figure s1c).', 'However, the 2019-nCoV RBD contains most of the contact points with human ACE2 that are found in clade 1 as well as some amino acid variations that are unique to clade 2 and 3 (figure s4b).', 'Taken together with our receptor assay results, it may be possible that 2019-nCoV arose from recombination between clade 1 and the other clades.', 'As we saw with the SARS-As6526 RBD (clade 2) spike chimera, full length As6526 spike entered cells following protease treatment, but BM48-31 (clade 3) spike did not (figure 2, 5c).', 'These data show that the chimeric spikes generally reproduce the entry phenotypes of full-length spikes.', 'Notably, the full length As6526 spike did not enter cells as efficiently as the SARS-As6526 chimera, suggesting that other human-cell adaptations are likely needed in As6526 spike.', 'The capacity to predict the zoonotic potential of newly detected viruses has been severely hindered by a lack of functional data for these novel animal virus sequences.', 'Here, we have developed a rapid and cost-effective platform to functionally test large groups of related viruses for zoonotic potential.', 'We found that several other lineage B author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.01.22.915660 doi: bioRxiv preprint coronaviruses are capable of entering human cells through an unknown receptor and that lineage B spike proteins can recombine to gain entry with a known host-receptor.', 'Taken together with the latest outbreak of 2019-nCoV in humans, these findings underscore the importance of continued surveillance of coronaviruses at the sequence and functional levels in order to better prepare for the next emerging virus.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.01.22.915660 doi: bioRxiv preprint replicates.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.01.22.915660 doi: bioRxiv preprint replicates.', 'c, Expression and pseudotype incorporation of SARS-S-2019-nCoV RBD chimeras.', 'd, Pseudotypes were used to infect cells expressing hACE2, hDPP4, hAPN, or empty vector, without protease treatment.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.01.22.915660 doi: bioRxiv preprint author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.01.22.915660 doi: bioRxiv preprint author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.01.22.915660 doi: bioRxiv preprint']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['The effect of the rapid accumulation of non-synonymous mutations on the pathogenesis of SARS-CoV-2 is not yet known.', 'To predict the impact of non-synonymous mutations and polyproline regions identified in ORF3a on the formation of B-cell epitopes and their role in evading the immune response, nucleotide and protein sequences of 537 available SARS-CoV-2 genomes were analyzed for the presence of non-synonymous mutations and polyproline regions.', 'Mutations were correlated with changes in epitope formation.', 'A total of 19 different non-synonymous amino acids substitutions were detected in ORF3a among 537 SARS-CoV-2 strains.', 'G251V was the most common and identified in 9.9% (n=53) of the strains and was predicted to lead to the loss of a B-cell like epitope in ORF3a.', 'Polyproline regions were detected in two strains (EPI_ISL_410486, France and EPI_ISL_407079, Finland) and affected epitopes formation.', 'The accumulation of non-synonymous mutations and detected polyproline regions in ORF3a of SARS-CoV-2 could be driving the evasion of the host immune response thus favoring viral spread.', 'Rapid mutations accumulating in ORF3a should be closely monitored throughout the COVID-19 pandemic.']}\n", - "{'sentences': ['Baricitinib for COVID-19: a suitable treatment?', \"– Authors' reply\"]}\n", - "{'sentences': ['Reports suggest a role for hydroxychloroquine treatment in reducing the viral load(6).', 'In our cohort, 19/20 patients received this drug although toxicity led to treatment withdrawal in one case.', 'Hydroxychloroquine and lopinavir/ritonavir may interact causing a prolongation of the cardiac QTc, interval however none of this series experienced this complication.', 'Preliminary data and understanding of the pathogenesis of the pneumonia secondary to SARS-CoV-2 infection suggest a central role of inflammatory cytokines in inducing the rapid clinical deterioration in association with worsening chest radiology and escalating oxygen requirement , observed in an average of 7-10 days from the symptom onset (7) .', 'In this context glucocorticoids and tocilizumab have been suggested to be a therapeutic strategy (8) .', 'Our subgroup of patients treated by this approach experienced a poor outcome, although encouraging signals in terms of potential beneficial effects were observed in the patients treated with tocilizumab: 50% reduced oxygen therapy requirement and 33% experiencing improvement of radiological changes.', 'Despite that, two patients died.', 'Our results are too preliminary and the sample size too small to draw firm conclusions.', 'The high mortality rate of this population suggests aggressive management is needed for kidney transplant patients with SARS-CoV2 infection, in particular early hospitalization should be considered in case of pneumonia; furthermore more effective treatment protocols need to be identified.', 'Our study has limitations: the sample size is small and the median follow-up short; findings are, therefore, preliminary and will need to be confirmed in bigger cohorts with longer followup.', 'Some strengths may be acknowledged as well and in particular the monocentric approach and the homogeneity of the clinical treatment employed.', 'In conclusion, kidney transplant patients with SARS-CoV2 pneumonia may present with an unfavourable disease course and a poor outcome; hospitalization is required and repeat chest', \"Clinical management needs to be improved in order to impact on these patients' prognosis.\", 'According to the Italian regulations, ethical approval for the study has been obtained.', 'SARS-CoV2 infection is challenging health care systems around the world.', 'The mortality of the disease has been proposed to be around the 2.3% with age and comorbidities such as cardiovascular diseases, diabetes, chronic respiratory diseases, hypertension and cancer being associated with worse prognoses (4, 5) .', 'Immunosuppression and CKD may represent The role of lopinavir/ritonavir in SARS-CoV2 management is debated, with some data supporting a greater benefit with early start compared to a delayed commencement (1); our cohort was started on antiviral therapy a median of 5.5 days after symptom onset.', 'Lopinavir/ritonavir may interact with CNIs impacting on their level: the four patients of our cohort with serial CNI monitoring confirmed that; of note none of these patients died and 3/4 have been discharged.']}\n", - "{'sentences': ['Although confirmed cases of COVID-19 have rapidly accumulated during the past 2 months, our understanding of the clinical spectrum and pathophysiological changes of this infection still remains very limited.', 'Nevertheless, no definite treatment has been identified, which makes clinical management extremely difficult.', 'Here we report a case series of patients with COVID-19, all of whom were successfully treated by high-dose IVIg at the early stage of clinical deterioration.', 'Based on these observations, a high dose of IVIg administered at the appropriate point could successfully block the progression of the disease cascade and improve the outcome of COVID-19.', 'The natural history of SARS-CoV-2 infection does not resemble that of any of the previously known coronaviruses.', 'To date, we have noticed quite a wide clinical spectrum of SARS-CoV-2 infection, including asymptomatic infection, mild upper respiratory tract illness, and pulmonary infiltrations.', 'A large proportion of reported symptomatic cases, including our patients and many others, followed a similar track of progression.', 'The infection often started with mild or moderate unspecific symptoms, including but not limited to low-grade fever, sore throat, coughing, fatigue, and malaise, similar to the symptoms of a common cold.', 'The initial symptoms would abate or persist for around 3–7 days, when high-grade fever developed and respiratory distress became quite prominent.', 'Some of these patients would also have gastrointestinal symptoms during this period.', 'However, if we look at the CT series shown here, which were quite typical of most COVID-19 patients, we would have a very strong impression that most of the lesions started from the periphery, especially the subpleural region when acute respiratory distress syndrome (ARDS', 'Based on these observations, we deduced that symptomatic COVID-19 mainly consists of 3 phases, including a starting phase, spanning the acquisition of the virus and subsequent viremia; and in many but not all patients an accelerating phase, when virus-induced secondary damage of targeting organs and tissue occurs, including the lungs, the heart, the gastrointestinal tract, and even an overall inflammatory storm.', 'The third phase is the final recovery phase.', 'This was demonstrated by not only the clinical features but also the laboratory dynamics, including progressive lymphocytopenia and elevated inflammation markers at the time of acceleration.', 'Therefore, strategies against COVID-19 should also be specified according to the course of infection.', 'The best timing of antivirals, if any are used, may lie in the phase before acceleration.', 'When clinical deterioration begins, the first few days of deterioration may present a critical point when potent suppression of the inflammatory cascade could save the patients from fatal immune-mediated injuries, as shown here.', 'Moreover, from the experiences of our patients, if the acceleration of the disease could be stopped, it seemed to work well even if no effective antiviral drugs were given.', 'As a result, high-dose IVIg at 0.3–0.5 g per kg weight per day for five days was used in our patients as a potent and safe immune modulator.', 'The dose of IVIg was determined based on well-established practice in immune modulation therapy for other diseases, including neuromuscular disorders, autoimmune thrombocytopenic purpura, etc.', '[6, 7], with a consideration of potential cardiac or renal impairment in severe COVID-19 patients.', 'None of the 3 patients reported any adverse events.', 'All patients were clinically improved shortly after the administration, with their temperature back to normal in 1–2 days and breathing difficulties alleviating in 3–5 days.', 'Confounding factors did exist, including the use of different antivirals in 2 of the 3 patients at various time points and a short course of steroids in patient 3.', 'Moreover, in patient 2, valsartan, an angiotensin receptor 1 blocker (AT1R), had been used for treating hypertension.', 'As angiotensin-converting enzyme 2 (ACE2) has been identified as the major receptor-binding domain of SARS-CoV-2 [8, 9], there has been a hypothesis that higher expression of ACE2 after being chronically medicated with AT1R', 'IVIg is a blood product containing polyclonal immunoglobulin G isolated and pooled from healthy donors, and it has been used for over 30 years.', 'As a complex preparation, it contains a large number of bioactive moieties, and the entirety of its effects is not yet fully understood.', 'IVIg of higher dose has been a choice of immunomodulatory therapy for autoimmune or inflammatory disease and for prophylaxis and treatment of severe infections, especially in immunocompromised patients [11, 12].', 'Several theories have been proposed to explain its potential immunomodulatory mechanisms, including Fc-mediated and Fab-mediated approaches [13, 14].', 'In previous studies of SARS and Middle East respiratory syndrome (MERS', 'Our report is limited by the small numbers of patients we included, and more evidence is needed to confirm the conclusions.', 'However, this report provides an important therapeutic clue to the current situation of rapid disease spreading.', 'The timing of IVIg administration is critical in practice.', 'Patients might not receive much benefit when systemic damage has already taken place.', 'Currently, a randomized controlled trial evaluating the efficiency of high-dose IVIg therapy in severe COVID-19 has been initiated (NCT 04261426), which will provide more evidence for IVIg use in treating such patients.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Case report of chloroquine therapy and hypoglycaemia in type 1 diabetes: What should we have in mind during the COVID-19 pandemic?', 'ORCID Maja Baretic https://orcid.org/0000-0002-7242-8407 DECLARATION Author of the paper has no competing interests and did not receive any financial resource for publication and authorship.', 'Patient has signed informed consent for the publication of particular material.', 'A type 1 diabetes patient experienced remission associated with chloroquine therapy while travelling to a malaria-endemic area.', 'Chloroquine has immunomodulatory and hypoglycaemic effects and may become more frequently used due to the COVID-19 pandemic.', 'Patients with type 1 diabetes treated with chloroquine should be monitored for hypoglycaemia, even after recovery.']}\n", - "{'sentences': ['Letter to the Editor: Case of the Index Patient', 'Who Caused Tertiary Transmission of Coronavirus Disease 2019 in Korea: the Application of Lopinavir/Ritonavir for the Treatment of COVID-19 Pneumonia Monitored by Quantitative RT-PCR']}\n", - "{'sentences': ['[{\\'text\\': \"This report highlights details on a pregnant case of COVID-19 who unfortunately did not survive.', \"This 27-yearold woman at her 30 and 3/7 weeks' gestation was referred to our center with fever, myalgia, and cough.\", 'The laboratory investigations showed leukopenia and lymphopenia as well as increased creatinine and CRP levels.', 'The first chest X-ray (faint bilateral patchy opacities) and CT scan (some faint subpleural ground-glass opacities associated with pleural thickening) were not typical for initial COVID-19 pulmonary infection, however, the treatment for COVID-19 was started.', 'Due to respiratory distress, she was intubated and put under mechanical ventilation.', 'After a while, the fetus was born with Apgar score of 0 and did not react to the neonatal cardiopulmonary resuscitation protocol.', 'Finally, due to deterioration in the clinical and imaging findings, the patient was expired as a result of multi-organ failure.', 'Following the death, autopsy was performed and the histopathologic evaluations of the lungs showed evidence of viral pneumonia (viral cytopathic effect and a mild increase in alveolar wall thickness) and ARDS (hyaline membrane).', 'Also, reverse transcription-polymerase chain reaction (RT-PCR', 'Since 2000, two other outbreaks of coronaviruses have occurred other than COVID-19: Severe Acute Respiratory Syndrome (SARS) [10] and Middle East Respiratory Syndrome (MERS) [11] .', 'Through the evaluations performed in the previous coronavirus outbreaks (SARS and MERS), pregnant women have been shown to be at increased risk of mortality, spontaneous miscarriage, preterm parturition, and intrauterine growth restriction.', 'As it has been evaluated, the fatality rate of SARS and MERS', 'Herein, we reported a case of COVID-19 in her late pregnancy who expressed atypical presentations in the mentioned imaging modalities.', 'According to the released data to that date and considering the imaging findings on COVID-19 patients, results belonging to this patient were nonspecific for early stages of COVID -19 pneumonia.', 'In the first CT scan, we found some small patchy ground glass opacities with subpleural distribution.', 'Regarding the early initiation epidemic of COVID-19 in Iran, we decided to consider COVID-19 pneumonia as the main diagnosis.', 'However, we also noticed a bilateral pleural thickening in the CT scan.', 'As it has been mentioned, pleural effusion or thickening might be detected in the subacute phase of the disease but not on initial investigations [9, 12] .', 'Although, regarding the clinical findings as well as patchy ground-glass opacities in CT scan, the patient received the antiviral therapy.', 'An early study mentioned that the mean time from onset to ICU admission and mechanical ventilation was about 10.5 days [13] .', 'However, unfortunately, a rapid progression to consolidative opacities and pleural effusion occurred in our patient that only took 30 h. Due to the worsening of results from clinical and imaging findings, it seems that the patient could be considered a \"radiographic deterioration\" as Shi et al. have presented [9] .', 'Some studies have mentioned pleural effusion as a pertinent negative finding [12] ; although, in some other studies, trace amounts or mild pleural effusion in the course of the disease has been noted in some patients [9, 14, 15] .', 'Our patient, on the other hand, had moderate amount of pleural effusion which could have been attributed to the worsening of pulmonary involvement.', 'Regarding the released radiologic findings on COVID-19 by the time our patient exhibited (especially about the presence of pleural effusion) and considering her fever, thrombocytopenia, proteinuria, suspicious bloody mucosal secretions, it was not easy to rule out serositis as one of the criteria of the collagen vascular disease for our internal team.', 'An early study has evaluated the outcome of nine pregnant patients with COVID-19 without any specific underlying diagnosed diseases (all gestational ages ≥36 weeks).', 'Among them, 78%, 44%, 33% and 11% had fever (on admission), cough, myalgia, and dyspnea, respectively.', 'Our patient on the other hand, presented all these symptoms at the same time.', 'In laboratory investigations, they found that none of their patients had leukopenia while 56% of them had only lymphopenia (< 10⁹ cells/L).', 'Also, elevated CRP, aspartate aminotransferase (AST)/ alanine aminotransferase (ALT', 'Another study evaluated 13 pregnant patients (two cases < and 11 cases≥ 28 week of gestation) diagnosed with COVID-19.', 'They claimed the most common presentation among them to be fever (77%).', 'Of these 13 patients, 23% were discharged before labor and they continued their pregnancy normally.', 'On the other hand, 77% undergone cesarean section due to several reasons including fetal distress (3/10), premature rupture of the membrane or PROM (1/10), and stillbirth (1/10', 'Also, a study has evaluated the risk factors related to the mortality among survivor and non-survivor patients diagnosed with COVID-19.', 'Authors have stated that sepsis, respiratory failure, ARDS, heart failure, septic shock, coagulopathy, acute cardiac injury, and acute kidney injury were significantly higher (p-values < 0.00001) in non-survivors compared to those discharged.', 'Also, they have shown that the administration of corticosteroids in non-survivors was significantly higher than in survivor group.', 'However, some other findings in their study such as non-invasive mechanical ventilation, high-flow nasal cannula oxygen therapy, and invasive mechanical ventilation were also significantly higher in non-survivors compared to the survivors (p-values < 0.00001).', \"It is clear that taking these actions are all necessary in critically ill patients with COVID-19 and doesn't represent the worse outcome due to their action [3] .\", 'Taken together, there is not enough published evidence on COVID-19 (especially in pregnant patients) which help us to find the exact cause of death in this patient.', 'Although, we have discussed the prominent findings of the patient (such as leukopenia, lymphopenia, elevated CRP, atypical imaging findings, and multi-organ failure) which have been known to associate with mortality in other published articles [3] .', 'Regarding the treatment plan, the only treatment which has been mentioned to relate to mortality was corticosteroids which data has been published only after our patient received this drug.', 'Although the low-dose corticosteroid therapy was a part of treatment strategy in our country, the intention beyond this treatment for the case was the clinical suspicion of a collagen-vascular disease.', 'Altogether, considering the multi-organ failure, it is difficult to identify the definite cause(s) of death in this case and it needs more investigations in such cases.']}\n", - "{'sentences': ['Bats have been recognized as a natural reservoir and vectors of a variety of coronaviruses, and these viruses have crossed species barriers to infect humans and many different kinds of animals, including avians, rodents, and chiropters [83 , 84] .', 'While the origin of COVID-19 is still being investigated, COVID-19 has features typical of the Coronaviridae family and was classified in the beta-coronavirus 2b lineage.', 'COVID-19 can be transmitted between humans.', 'Interventions, including intensive contact tracing followed by quarantine and isolation, can effectively reduce the spread of COVID-19, with the effect of travel restrictions.', 'Wearing masks, washing hands and disinfecting surfaces contribute to reducing the risk of infection.', 'Human coronaviruses can be efficiently inactivated within 1 min using surface disinfection procedures with 62-71% ethanol, 0.5% hydrogen peroxide or 0.1% sodium hypochlorite [85] .', 'Identification of the causative viral pathogens of respiratory tract viral infections is important to select an appropriate treatment, control the pandemic, and reduce the economic impact of COVID-19 on China and the world.', 'In acute respiratory infection, RT-PCR is routinely used to detect causative viruses from respiratory secretions.', 'The positive rate of PCR from oropharyngeal swabs is not very high.', 'In this situation, more swab testing is needed to clarify diagnosis.', 'Typical CT findings can help early screening of suspected cases and diagnosis of COVID-19.', 'The COVID-19 infection has a clustering onset and is more likely to affect older males (average age 51 years) with comorbidities [86] .', 'No evidence supports adverse birth outcomes, intrauterine infection, or vertical transmission of COVID-19 [87] .', 'However, viral infections can be acquired when the infant passes through the birth canal during vaginal delivery or through postpartum breastfeeding [88] .', 'The most common symptoms were fever, cough, expectoration, headache, myalgia or fatigue, diarrhea, and hemoptysis [89] .', 'Some people may experience severe acute respiratory distress syndrome.', 'Histological examination of lung biopsy samples showed bilateral diffuse alveolar damage with cellular fibromyxoid exudates [90] .', 'Other organs are also susceptible to COVID-19.', 'The single-cell RNA-seq data was used to analyse receptor ACE2 expression to reveal the potential risk of different human organs to COVID-19 infection [91] .', 'COVID-19 uses the same cell entry receptor as SARS-CoV, ACE2, which regulates both cross-species and human-to-human transmissions [80] .', 'Proximal tubular cells also express higher levels of the ACE2 receptor, which leads to susceptibility to COVID-19 [91] and induces kidney injury.', 'Data from 33 patients with a complete clinical course were analysed, and the levels of blood urea and creatinine were higher in non-survivors than in survivors [92] .', 'All patients with COVID-19-infected pneumonia received antibacterial agents, 90% received antiviral therapy, and 45% received methylprednisolone [92] .', 'Clinical trials are underway to investigate the efficacy of new antiviral drugs, convalescent plasma transfusion, and vaccines.', 'Most of the trials were initiated by investigators and the study period is 1 to 11 months.', 'Although the final results of these studies will take a long time to complete, the interim research data may provide some help for the current urgent demand for therapy [93] .', 'The COVID-19 pandemic is a public health emergency of international concern, and all countries need a coordinated international effort to fight COVID-19.', 'The transmission of pneumonia associated with SARS-CoV-2 has not yet been eliminated.', 'In the absence of vaccines and antivirals, isolation and quarantine are achieving remarkable results.', 'It is necessary to strengthen the monitoring of COVID-19 and to develop drugs and vaccines against the COVID-19 infection as soon as possible.']}\n", - "{'sentences': ['The 2019 Novel Corona virus infection (COVID 19) is an ongoing public health emergency of international significance.', 'There are significant knowledge gaps in the epidemiology, transmission dynamics, investigation tools and management.', 'In this article, we review the available evidence about this disease.', 'Every decade has witnessed the evolution of a new coronavirus epidemic since the last three decades.', 'The varying transmission patterns, namely, nosocomial transmission and spread through mildly symptomatic cases is an area of concern.', 'There is a spectrum of clinical features from mild to severe life threatening disease with major complications like severe pneumonia, ARDS, acute cardiac injury and septic shock.', 'Presence of bilateral ground glass opacity and consolidation on imaging in appropriate clinical background should raise a suspicion about COVID 19.', 'Poor prognostic factors include Multilobular infiltration on chest imaging, Lymphopenia, Bacterial co-infection, Smoking history, Chronic medical conditions like Hypertension and age >60 years (MuLBSTA score).', 'Diagnosis is confirmed with PCR based testing of appropriate respiratory samples.', 'Management is primarily supportive, with newer antivirals (lopinavir ritonavir and Remdesivir) under investigation.', 'Role of steroids is still inconclusive.', 'Standard infection control and prevention techniques should be followed.', 'Vigilant screening of suspected cases and their contacts is important.', 'Isolation of symptomatic cases and home quarantine of asymptomatic contacts is recommended.', 'To conclude, controlling this highly transmissible disease requires international co-ordination.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['In this study, we analyzed the whole genome and the CDS of several key proteins of 2019-nCoVs.', '2019-nCoVs are the pathogens that cause severe pneumonia in human in Wuhan recently.', 'It is found one of the isolates (EPI_ISL_403928) has obvious variations in whole genome and CDS of P, S and N proteins, which result in the substitution of several amino acids.', 'We also analyzed the nucleotide substitution rate in the whole genome level and the CDS of some proteins during their evolution process.', 'There is no variation in CDS of M and E proteins.', 'CDS of N protein has the highest rate of base substitution (1·05 × 10 -2 .', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.01.30.926477 doi: bioRxiv preprint substitutions/site/year) and whole genome has the lowest (1.65 × 10 -3 substitutions/site/year).', 'The divergence time of the viruses deduced is about 91-214 days before the submission of the first isolate.', 'Their earliest sampling time was 8 December, 2019, and 91-214 days before that day, the viruses infected human or host animals and began to diverge in the evolution process.', 'It is not clear if the viruses began to mutate before or after infecting human beings.', 'There is also a possibility there were two strains evolved coincidentally, one for human and one for host animals that evolved more adaptive to human and then infected human.', 'Our analysis indicates that the outbreak occurred a few months earlier than it was officially reported, and there might be recessive infection and underdetection in the population.', 'Therefore, the seafood market in Wuhan, which is believed to be the first spot of the outbreak, may or may not be the case.', 'Human recessive infection of Betacoronavirus does exist.', 'For example, it occurs in the population for HKU1, another member of β -CoVs.', \"HKU1 is related to a variety of children's and adult diseases and distributed globally [16] .\", 'In the United States, 0.5% were infected by HKU1 [18] ; in Southeast Asia, the positive rate of HKU1 was 1.1%', 'in 2060 adult acute respiratory samples from Malaysia in 2012-2013 [19] .', 'The positive detection rate was 1.9% in Japan and 4342 from 2010 to 2013, and 2.5% in Korea [20, 21] .', 'Recessive HKU1 infection was common and many patients with HKU1 infection were found in routine examinations [24] [25] .', 'Cases of recessive']}\n", - "{'sentences': ['Remdesivir inhibits renal fibrosis in obstructed kidneys', 'Aim: Kidney impairment is observed in patients with .', 'We aimed to demonstrate the effect of anti-COVID-19 agent remdesivir on renal fibrosis.', 'Methods: Remdesivir and its active nucleoside metabolite GS-441524 were used to treat TGF-β stimulated renal fibroblasts (NRK-49F) and human renal epithelial cells (HK2).', 'Cell viability was determined by CCK8 assay, and fibrotic markers were measured by Western blotting.', 'Vehicle or remdesivir were given by intraperitoneal injection or renal injection through the left ureter in unilateral ureteral obstruction (UUO', 'Intraperitoneal injection or renal injection of remdesivir attenuated renal fibrosis of UUO kidneys.', 'Renal and liver function were not changed in remdesivir treated UUO mice.', 'Remdesivir can not be detected, but two remdesivir metabolites were detected after injection.', 'Conclusion: Remdesivir inhibits renal fibrosis in obstructed kidneys.', 'All rights reserved.', 'No reuse allowed without permission.', 'The effect of remdesivir on renal fibrosis is currently unknown.', 'In the present study, we showed that remdesivir inhibits renal fibrosis.', 'First, treatment with remdesivir or its active metabolite GS-441524 inhibited fibrosis in two cellular models for renal fibrosis.', 'Second, systematic administration of remdesivir inhibited renal fibrosis as shown by Masson staining and Western blotting.', 'Third, local infusion of remdesivir into UUO kidneys further revealed the anti-fibrotic effect of remdesivir.', 'The limitation of this study is that UUO model is not suitable to study the pharmaceutical effect on renal function.', 'UUO model is a classic model to study renal fibrosis, although we did observe a slightly increase in Scr and BUN levels in UUO mice as compared with that in sham mice (21).', 'The renal and liver function were assessed in this study to exclude the potential toxic effect of remdesivir, and we show no effect of remdesivir on renal and liver function in this study.', 'The concentration of remdesivir was measured to assess the dosing efficacy.', 'However, we are not able to detect remdesivir in serum or kidneys in two different dosing regimens or at different time points.', 'This is probably due to the rapid turnover of remdesivir by esterases which are abundant in blood and tissues (17, 22) .', 'Next, we measured the concentration of two remdesivir metabolites, alanine metabolite (Ala-Met) and nucleoside metabolite (GS-441524) (17) .', 'GS-441524 and Ala-Met', 'GS-441524 was detected in the serum and kidney at 1 hour after renal injection but not at day 7 post-injection.', 'To prove the specificity of renal infusion of remdesivir, we author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.01.019943 doi: bioRxiv preprint further measured Ala-Met which can only be detected in kidneys but not in serum at 1 hour after renal injection, and it was not detectable at day 7 after renal injection.', 'In conclusion, we showed that remdesivir inhibits renal fibrosis in obstructed kidneys.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.01.019943 doi: bioRxiv preprint']}\n", - "{'sentences': ['Collapsing glomerulopathy is the most fulminant form of kidney disease in the APOL1 spectrum.', 'It is an aggressive form of glomerular injury that has been described in association with autoimmune disease, interferon therapy, and viral illnesses including HIV, cytomegalovirus, and parvovirus.', 'S6-S10 Regardless of the associated disease, approximately 70% of these patients with collapsing glomerulopathy are homozygous for APOL1 risk alleles.', 'The etiology of APOL1-associated nephropathy has not been definitively determined, although there are data to support the role of innate immune pathways upregulated in viral illnesses and autoimmune disease as key drivers.', 'S19 The Q4 renal biopsy findings in the case presented here are therefore concerning for an aggressive APOL1-associated collapsing glomerulopathy driven by a COVID-19-related cytokine storm.', 'However, it is also possible that the collapsing glomerulopathy is unrelated to the viral infection and was only brought to medical attention by the SARS-CoV-2 infection.', 'web 4C=FPO Figure 2 .', 'In situ hybridization for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).', '(a) Tissue quality was evaluated by performing RNAscope analysis for mRNA of the housekeeping gene peptidylprolyl isomerase B (PPIB).', 'Positive cytoplasmic staining confirms adequate quality.', 'Signal was detected using 3,3 0 -diaminobenzidine (DAB) (brown) chromogen.', '(periodic acid-Schiff counter stain; original magnification Â400).', '(b) RNAscope using probes directed against SARS-CoV-2', 'We present a case of collapsing glomerulopathy in an African American patient with COVID-19 who had rapid decline in renal function.', 'This case raises the possibility that African American individuals with high-risk APOL1 genotype could be at increased risk of kidney disease in the setting of COVID-19.', 'Additional investigation to determine if APOL1 risk alleles confer increased risk of morbidity and mortality deserves urgent study, as it could have important implications for this population (Table 3) .', 'DISCLOSURE Q8 All the authors declared no competing interests.', 'Possible mechanisms for kidney injury in COVID-19 include direct infection of the kidney as well as cytokine storm related to sepsis.', 'Direct infection of the renal parenchyma is possible because the renal proximal tubule cells highly express angiotensin-converting enzyme 2, the cellular entry receptor for the SARS-CoV-2 virus.', '6, 7 The virus likely gains access to the kidney through the bloodstream, as approximately 15% of patients were found to have RNAemia in one series.', '2 Cytokine storm has been described previously both in animal models and humans infected with other highly pathogenic human coronaviruses, including severe acute respiratory syndrome and Middle East respiratory syndrome.', '8, 9 ,S1 Evidence of cytokine storm has also been documented in patients with COVID-19.', '2,S2 This case report is the first renal biopsy report to our knowledge describing the renal biopsy findings 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 in a living patient with COVID-19.', 'A recent report of postmortem kidney tissue from 6 patients who died of COVID-19 showed acute tubular injury without glomerular abnormalities.', 'S3 The SARS-CoV-2 NP antigen was described in renal tubules by immunohistochemical analysis in this report when the renal tissue was reacted with a rabbit monoclonal antibody directed against the SARS-CoV-2 nucleoprotein (Clone ID: 019; Sino Biological, Beijing, China).', 'In our laboratory, immunohistochemical analysis of renal tissue using this antibody under numerous conditions showed nonspecific positive staining in the renal parenchyma of all kidneys.', 'In the case presented here, in situ hybridization analysis for SARS-CoV-2 failed to show evidence of viral RNA in the kidney, suggesting that direct infection of the kidney was not present.', 'However, we cannot exclude the possibility that the virus was present below the level of detection.', 'The biopsy from our patient is unique, as it demonstrates the presence of collapsing glomerulopathy.', 'Acute tubular injury is commonly present on biopsy in association with collapsing glomerulopathy, and, therefore, is not necessarily being driven by either direct viral infection of the kidney or cytokine storm.', 'The biopsy findings raise the question as to whether or not African American patients who contract COVID-19 are at increased risk of developing APOL1-related kidney disease.', 'The reports of kidney disease in patients with COVID-19 thus far are primarily limited to Chinese patients, and therefore might not be generalizable to other populations, such as the African American patient described here.', 'In fact, African American individuals have long been known to be at increased risk of developing kidney disease compared with other ethnicities without recent African ancestry.', 'S4 This increased risk has been shown to largely result from 2 risk alleles in the APOL1 gene, G1 and G2, that are mutually exclusive and very common.', 'S5 Approximately 39% of African American individuals possess one APOL1 risk allele and 13% are at increased risk of kidney disease as a result of homozygosity for APOL1 risk alleles.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': [\"[{'text': 'With our successful experience of treating COVID-19 patients, we 22 retrospectively found that routine clinical features could reliably predict severe 23 pneumonia development, thus provide quick and affordable references for 24 physicians to save the otherwise fatal patients with the limited medical 25 resource.\", 'Abstract 28 Approximately 15-20% of COVID-19 patients will develop severe 29 pneumonia, about 10 % of which will die if not properly managed.', 'Earlier 30 discrimination of the potential severe patients basing on routine clinical and 31 laboratory changes and commencement of prophylactical management will not 32 only save their lives but also mitigate the otherwise overwhelmed health care 33 burden.', 'In this retrospective investigation, the clinical and laboratory features 34 were collected from 125 COVID-19 patients, who were classified into mild (93 35 cases) or severe (32 cases) groups according to their clinical outcomes after 3 36 to 7-days post-admission.', 'The subsequent analysis with single-factor and 37 multivariate logistic regression methods indicated that 17 factors on admission 38 differed significantly between mild and severe groups, but that only comorbid 39 with underlying diseases, increased respiratory rate (>24/min), elevated C-40 reactive protein (CRP >10mg/liter), and lactate dehydrogenase 41 (LDH >250U/liter), were independently associated with the later disease 42 development.', 'Finally, we evaluated their prognostic values with the receiver 43 operating characteristic curve (ROC']}\n", - "{'sentences': ['The COVID-19 pandemic has caused a worldwide shortage of personal protective equipment including N95 and FFP3 respirators.', 'Reusable elastomeric respirators are suitable alternatives when used with compatible filters.', 'These filters may be difficult to source and elastomeric respirators are not recommended for surgical use as the exhaled air is not filtered.', 'Breathing system filters are routinely used in anaesthetic circuits to filter virus and bacteria.', 'In this study, we designed 3D printed adapters that allowed elastomeric respirators to utilise breathing system filters and made simple modifications to the respirators to filter exhaled breaths.', 'We then evaluated the performance and safety of our modified elastomeric respirators with quantitative fit tests.', 'We recruited 8 volunteers to perform quantitative fit tests.', 'Fit factors, respiratory rate and end-tidal carbon dioxide were recorded before and after wearing the modified respirators for 1 hour.', 'All 8 volunteers obtained fit factors of 200+, the maximum achievable, for all tests exercises in all fit tests.', 'The mean (range) end-tidal carbon dioxide was 4.5 (3.9-5.5) kPa and 4.6 (range 4.1-5.3) kPa before and after 1 hour of usage.', 'The mean (range) respiratory rate was 16.5 (11-24) min-1 and 17.4 (15-22) min-1 before and after 1 hour of usage.', 'Four (50%) did not experience any subjective discomfort while 2 (25%) reported pressure on the face, 1 (12.5%) reported exhalation resistance and 1) reported exhalation resistance and 1 (12.5%) reported exhalation resistance and 1']}\n", - "{'sentences': ['The entry of SARS-CoV-2 into host cells is dependent upon angiotensin-converting enzyme 2 (ACE2), which serves as a functional attachment receptor for the viral spike glycoprotein, and the serine protease TMPRSS2 which allows fusion of the viral and host cell membranes.', 'We devised a quantitative measure to estimate genetic determinants of ACE2 and TMPRSS2 expression and applied this measure to >2,500 individuals.', 'Our data show significant variability in genetic determinants of ACE2']}\n", - "{'sentences': ['Corona Virus Disease 2019 (COVID-19) has seriously affected the treatment of patients and social stability.', 'In the later stage of disease, some COVID-19 patients may develop into acute respiratory distress syndrome or even multiple organ failure.', 'However, one of the most important mechanism underlying the deterioration of disease is cytokine storm.', 'At present, some therapies such as interleukin-6 antibody blocker, stem cell therapy, and transfusion of convalescent plasma have been applied to counteract the cytokine storm and have made some progress.', 'This article reviews the influences of cytokine storm syndrome on the COVID-19']}\n", - "{'sentences': ['The nonspecific presentations of these two cases are consistent with early reports of COVID-19 from China.', '6, 7 Fever remains the most common complain.', \"Some cases didn't have cough, and upper respiratory tract infections (URI) symptoms such as rhinorrhea and sore throat were rare.\", 'Similar clinical manifestations have been reported in SARS, 8 since URI symptoms were uncommon and cough was not always present in SARS patients.', 'Although routine laboratory testing was not diagnostic, certain patterns of laboratory abnormalities were observed in COVID-19.', 'Leukopenia, lymphopenia, anemia, elevation of liver enzymes and lactate dehydrogenase, have been reported in different series.', '6, 7 Also, a similar observation has been made in SARS.', 'The clinical utility of CXR in the early diagnosis of COVID-19 is questionable.', 'In this report, initial CXR of both cases was non-diagnostic, and more evident radiological abnormalities were detected on day 6.', 'Similar findings were reported in the first case of COVID-19 in the United States, and pulmonary patch/consolidation was not detected by CXR until day 5 in hospital (day 9 of illness).', 'Similarly, in a case series of SARS patients from the Amoy Gardens housing estate, 29.3% (22/75) cases had normal CXR on admission, however four of 22 cases developed acute respiratory distress syndrome (ARDS', 'Another challenge is the surge of clinical needs of laboratory testing.', 'It is anticipated that there will be an overwhelming demand for the supply chain of testing reagents and laboratory equipment, and the availability of well trained and experienced staff during the outbreak.', 'There are several alternative diagnostic strategies under development.', 'Feng et al. proposed a CRISPR-based technique for the diagnosis of COVID-19 (https://www.', 'After RNA extraction, the test result could be read using a dipstick in less than an hour.', 'RNA-based metagenomic sequencing is another promising approach, and has been used to diagnose COVID-19 in the first cluster related to the Huanan Seafood Market in China.', '10 Currently, clinical management and treatment of COVID-19 is largely supportive.', 'In the cases of pneumonia, our diagnostic capacity could be hindered by the nature of isolation units.', 'For example, for the first COVID-19 case in the United States, only point-of-care laboratory testing was permitted initially.', 'The current rate of co-infection and distribution of coexisting organisms in the cases of COVID-19 remain undefined.', 'Of note, current evidence suggests that co-infection is not uncommon in the patients with community-acquired pneumonia.', '11 In a prospective study of 2259 patients with pneumonia and specimens submitted for comprehensive bacterial and viral testing, etiologic agents were detected in only 38% cases.', 'Among these cases, the percentages of co-infections were associated with the severity and geographic regions.', '11 Clinical guideline for the treatment of community-acquired pneumonia in Taiwan shall be considered for these cases.', '12 In conclusion, we reported the clinical features of two patients with COVID-19 in Taiwan, and highlight the nonspecific nature of clinical presentations of COVID-19 and the importance of laboratory-based diagnosis.']}\n", - "{'sentences': ['Is this study we examine the strategy of vertical confinement as currently debated in Brazil.', 'Since the fatality rate of COVID-19 appears to be higher among the elderly population, we studied how confinement of age bins (particularly 60 and beyond) affect the demand for hospital beds and intensive care beds.', 'Our model suggests that at the current rate of advance of the pandemics, Brazil should face collapse of the health care system by May 15th, with 300 000 ICU beds needed (10 times more than the current capacity), and 10 6 fatalities.', 'A decrease in the rate of confirmed cases is seen with respect to the rate of fatalities, which is indicative of the effect of the lockdown.', 'A 60% lockdown reduces the number of deaths to 400 000 due to COVID-19, still not avoiding overload of the health care system.', 'An increase in lockdown to 70% is needed to avoid the number of cases overcome the number of available critical care beds.', 'An exit strategy of confinement of individuals older than 60 years old by May 1st would see a second wave disproportionally affect the 50-60 age bin.', 'The ICU cases in this age range alone would bring the health care system to collapse and result in over 100 000 deaths.', 'Confinement by age group should consider the population over 50 years old as well.', 'However, the age range 50-60yrs is also a part of the workforce, and thus defeats the purpose of a confinement by age.', 'Moreover, we emphasize that our model assumes an idealized lockdown where the confined are perfectly insulated from contamination, while in reality there would be several practical barriers to it as the confined elderly would depend on the young for most essential activities, and a perfect lockdown would not be achieved in a multi-generational household, especially in close April 14, 2020 14/17 .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.09.20060053 doi: medRxiv preprint quarters such as found in the low and even middle income neighborhoods common in Brazil.', 'Our results therefore discourage confinement by age as the only exit strategy.', 'We urge Brazilian authorities to take action to prevent virus dissemination in the critical coming weeks.']}\n", - "{'sentences': ['with rapidly increasing the number of cases (namely .', 'Abnormal liver functions are frequently present in these patients, here we aimed to clarify the clinical features of COVID-19-related liver damage to provide some references for the clinical treatment.', 'A total of 148 cases were analyzed for clinical features, laboratory parameters (including liver function tests), medications and the length of stay.', 'Of 148 confirmed SARS-CoV-2-infected patients, 49.3% were females and 50.7% were males.', 'The median age was 50.5 years (interquartile range, 36-64).', 'Patients had clinical manifestations of fever (70.1%), cough (45.3%), expectoration (26.7%) at admission.', '75 patients (50.7%) showed abnormal liver functions at admission.', 'Patients (n = 75) who had elevated liver function index were more likely to have a moderate-high degree fever (44% vs 27.4%; p = 0.035) and significantly present in male patients (62.67% vs 38.36%; p = 0.005).', 'The numbers of CD4 + and CD8 + T cells were significantly lower in abnormal liver function group than those in normal liver function group.', 'There was no statistical difference in prehospital medications between normal and abnormal liver function groups, while the utilization rate of lopinavir/ritonavir after admission was significantly higher in patients with emerging .', 'CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', '(which was not peer-reviewed)', 'The copyright holder for this preprint .']}\n", - "{'sentences': ['The present study provides evidence that host cell entry of SARS-CoV-2 depends on the SARS-CoV receptor ACE2 and can be blocked by a clinically proven inhibitor of the cellular serine protease TMPRSS2, which is employed by SARS-CoV-2 for S protein priming.', 'Moreover, it suggests that antibody responses raised against SARS-CoV could at least partially protect against SARS-CoV-2 infection.', 'These results have important implications for our understanding of SARS-CoV-2 transmissibility and pathogenesis and reveal a target for therapeutic intervention.', 'The finding that SARS-2-S exploits ACE2 for entry, which was also reported by Zhou and colleagues (Zhou et al., 2020) while the present manuscript was in revision, suggests that the virus might target a similar spectrum of cells as SARS-CoV. In the lung, SARS-CoV infects mainly pneumocytes and macrophages (Shieh et al., 2005) .', 'However, ACE2 expression is not limited to the lung, and extrapulmonary spread of SARS-CoV in ACE2 + tissues was observed (Ding et al., 2004; Gu et al., 2005; Hamming et al., 2004) .', 'The same can be expected for SARS-CoV-2, although affinity of SARS-S and SARS-2-S for ACE2 remains to be compared.', 'It has been suggested that the modest ACE2 expression in the upper respiratory tract (Bertram et al., 2012; Hamming et al., 2004) might limit SARS-CoV transmissibility.', 'In light of the potentially increased transmissibility of SARS-CoV-2 relative to SARS-CoV, one may speculate that the new virus might exploit cellular attachment-promoting factors with higher efficiency than SARS-CoV to ensure robust infection of ACE2 + cells in the upper respiratory tract.', 'This could comprise binding to cellular glycans, a function ascribed to the S1 domain of certain coronaviruses (Li et al., 2017; Park et al., 2019) .', 'Finally, it should be noted that ACE2 expression protects from lung injury and is downregulated by SARS-S (Haga et al., 2008; Imai et al., 2005; Kuba et al., 2005) , which might promote SARS.', 'It will thus be interesting to determine whether SARS-CoV-2 also interferes with ACE2 expression.', 'Priming of coronavirus S proteins by host cell proteases is essential for viral entry into cells and encompasses S protein cleavage at the S1/S2 and the S2 0 sites.', 'The S1/S2 cleavage site of SARS-2-S harbors several arginine residues (multibasic), which indicates high cleavability.', 'Indeed, SARS-2-S was efficiently cleaved in cells, and cleaved S protein was incorporated into VSV particles.', 'Notably, the cleavage site sequence can determine the zoonotic potential of coronaviruses (Menachery et al., 2020; Yang et al., 2014 Yang et al., , 2015 , and a multibasic cleavage site was not present in RaTG13, the coronavirus most closely related to SARS-CoV-2.', 'It will thus be interesting to determine whether the presence of a multibasic cleavage site is required for SARS-CoV-2 entry into human cells and how this cleavage site was acquired.', 'The S proteins of SARS-CoV can use the endosomal cysteine proteases CatB/L for S protein priming in TMPRSS2 À cells (Simmons et al., 2005) .', 'However, S protein priming by TMPRSS2 but not CatB/L is essential for viral entry into primary target cells and for viral spread in the infected host (Iwata-Yoshikawa et al., 2019; Kawase et al., 2012; Zhou et al., 2015) .', 'The present study indicates that SARS-CoV-2 spread also depends on TMPRSS2 activity, although we note that SARS-CoV-2 infection of Calu-3 cells was inhibited but not abrogated by camostat mesylate, likely reflecting residual S protein priming by CatB/L. One can speculate that furin-mediated precleavage at the S1/S2 site in infected cells might promote subsequent TMPRSS2-dependent entry into target cells, as reported for MERS-CoV (Kleine-Weber et al., 2018; Park et al., 2016) .', 'Collectively, our present findings and previous work highlight TMPRSS2 as a host cell factor that is critical for spread of several clinically relevant viruses, including influenza A viruses and coronaviruses (Gierer et al., 2013; Glowacka et al., 2011; Iwata-Yoshikawa et al., 2019; Kawase et al., 2012; Matsuyama et al., 2010; Shulla et al., 2011; Zhou et al., 2015) .', 'In contrast, TMPRSS2 is dispensable for development and homeostasis (Kim et al., 2006) and thus constitutes an attractive drug target.', 'In this context, it is noteworthy that the serine protease inhibitor camostat mesylate, which blocks TMPRSS2 activity (Kawase et al., 2012; Zhou et al., 2015) , has been approved in Japan for human use, but for an unrelated indication.', 'This compound or related ones with potentially increased antiviral activity (Yamamoto et al., 2016) could thus be considered for off-label treatment of SARS-CoV-2-infected patients.', 'Convalescent SARS patients exhibit a neutralizing antibody response that can be detected even 24 months after infection (Liu et al., 2006) and that is largely directed against the S protein.', 'Moreover, experimental SARS vaccines, including recombinant S protein (He et al., 2006) and inactivated virus (Lin et al., 2007) , induce neutralizing antibody responses.', 'Although confirmation with infectious virus is pending, our results indicate that neutralizing antibody responses raised against SARS-S could offer some protection against SARS-CoV-2 infection, which may have implications for outbreak control.', 'In sum, this study provided key insights into the first step of SARS-CoV-2 infection, viral entry into cells, and defined potential targets for antiviral intervention.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Molecular Modeling Evaluation of the Binding Effect of Ritonavir, Lopinavir and Darunavir to Severe Acute Respiratory Syndrome Coronavirus 2 Proteases', 'Three anti-HIV drugs, ritonavir, lopinavir and darunavir, might have therapeutic effect on coronavirus disease 2019 .', 'In this study, the structure models of two severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteases, coronavirus endopeptidase C30 (CEP_C30) and papain like viral protease (PLVP), were built by homology modeling.', 'Ritonavir, lopinavir and darunavir were then docked to the models, respectively, followed by energy minimization of the protease-drug complexes.', 'In the simulations, ritonavir can bind to CEP_C30 most suitably, and induce significant conformation changes of CEP_C30; lopinavir can also bind to CEP_C30 suitably, and induce significant conformation changes of CEP_C30; darunavir can bind to PLVP suitably with slight conformation changes of PLVP.', 'It is suggested that the therapeutic effect of ritonavir and lopinavir on COVID-19 may be mainly due to their inhibitory effect on CEP_C30, while ritonavir may have stronger efficacy; the inhibitory effect of darunavir on SARS-CoV-2 and its potential therapeutic effect may be mainly due to its inhibitory effect on PLVP', 'All rights reserved.', 'No reuse allowed without permission.']}\n", - "{'sentences': [\"[{'text': 'COVID-19 has now been declared a pandemic.\", 'To date, COVID-19 has affected over 944,181 people worldwide, resulting in over 47,312 reported deaths.', 'Numerous preventative strategies and non-pharmaceutical interventions have been employed to mitigate the spread of disease including careful infection control, the isolation of patients, and social distancing.', 'Management is predominantly focused on the provision of supportive care, with oxygen therapy representing the major treatment intervention.', 'Medical therapy involving corticosteroids and antivirals have also been encouraged as part of critical management schemes.', 'However, there is at present no specific antiviral recommended for the treatment of COVID-19, and no vaccine is currently available.', 'Despite the strategic implementation of these measures, the number of new reported cases continues to rise at a profoundly alarming rate.', 'As new findings emerge, there is an urgent need for up-to-date management guidelines.', 'In response to this call, we review what is currently known regarding the management of COVID-19, and offer an evidence-based review of current practice.']}\n", - "{'sentences': ['This report, to our knowledge, is the largest case series to analyze died patients with COVID-19 in hospital.', 'As of February 15, 2020 COVID-19 is 1.4% [12] , some special population including the aged and individuals with All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.04.20031039 doi: medRxiv preprint underlying comorbidities may be vulnerable to SARS-CoV-2 infection.', 'In our cohort, the median age of non-survivors was 71 years, 81.19% of them combined with one or more underlying medical conditions including hypertension, cardiovascular disease, diabetes, chronic pulmonary disease, cerebrovascular disease, chronic kidney disease and malignancy.', 'This study suggested that patients aged over 70 years with chronic medical conditions were more likely to suffer a severe attack and death.', 'Common symptoms at onset of COVID-19 were fever, dry cough, myalgia, fatigue etc.', 'In our cohort, we observed that, besides fever and cough, dyspnea (58.42%) presented early in most non-survivors with confirmed COVID-19, similar finding has also been observed in critically ill patients reported by Yang etc.', 'In these nonsurvivors, featured complications during hospitalization including ARDS and respiratory failure, acute cardiac injury, AKI, acute liver injury and abnormal coagulation.', 'In terms of SARS, severe respiratory failure was the leading cause of mortality, with little other organ failure [15] .', 'It is surprised that we observed 52.48% and 22.77% non-survivors suffered heart failure and AKI, respectively.', 'Angiotensinconverting enzyme 2 (ACE2', 'The most common laboratory abnormalities observed in this study were elevated white blood cell count, neutrophil count, C-reactive protein, hsTnI, BUN and decreased oxygen saturation etc.', 'Compared with those survived 3 days of admission, nonsurvivors died within 3 days had numerous different findings including depressed percentages of lymphocyte, CD3 + and CD8 + cells, and elevated white blood cell count, All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.04.20031039 doi: medRxiv preprint hsTnI and BUN.', 'These evidences suggest that SARS-CoV-2 infection may be associated with cellular immune deficiency and lead to acute myocardial injury and kidney injury.', 'These results also support the described organ injury above.', 'In addition, the characteristic chest CT imaging of these non-survivors were evaluated by previous described method [19] .', 'The CT features demonstrated extensive infection and severe damage, regarded as \"white lung\", in five lobes, but no significant difference was found between the two groups.', 'These characteristics combined with above repented organ failure, laboratory abnormalities suggested that early organ dysfunction or failure were responsible for rapid progression of disease and death of the patients.', 'Up to now, no antiviral treatment has been recommended for coronavirus treatment except supportive care and organ support [5, 20] .', 'In current clinical practice, arbidol was used as an antiviral treatment for SARS-CoV-2 infected patients, but the efficacy remains to be proved.', 'Other antiviral medications including remdesivir, lopinavir and traditional Chinese medicine are still being verified in clinical trials.', 'Furthermore, application of intravenous immunoglobulin is recommended to enhance the ability of anti-infection for critically ill patients and steroids are recommended for patients with ARDS, for as short duration of treatment as possible [21] .', 'In this study, 96.04% patients received antiviral therapy, 98.02% received antibacterial therapy.', 'Application of glucocorticoid mainly depended on the severity of inflammatory response.', 'In the early outbreak of COVID-19, all the non-survivors received oxygen inhalation therapy including high flow oxygen inhalation (77.23%), but quite a low proportion of patients received machine ventilation partly due to limited medical resources against the steeply increasing number of patients at early outbreak.', 'All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.04.20031039 doi: medRxiv preprint', 'To explore the risk factors associated with the rapid progress of disease and death, multivariable regression analysis was performed.', 'In this study, 100 (99.01%), 53 (52.48%) and 23 (22.77%) non-survivors suffered respiratory failure, acute cardiac injury and acute kidney injury, respectively.', 'Univariable analysis indicated elevated hsTnI, myoglobin, creatine kinase-MB, BUN, lactate and decreased oxygen saturation were associated with increased risk of death within 3 days of admission.', 'Representative indicators associated with organs injury including hsTnI, BUN and oxygen saturation were selected and included in multivariable regression analysis.', 'Usually, the level of neutrophils is slightly elevated or normal in virus infections, but significantly elevated neutrophils were observed in this rapid death of patients in our study.', 'Viral infections may impair the immune system and facilitate opportunistic infection and neutrophils are crucial in protection of bacterial infections [22] .', 'So, neutrophil count was also included in our multivariable regression analysis.', 'The median age of 101 died patients with COVID-19 were 71 years (IQR, 59-80) which was older compared to recent report [5] .', 'We also included age in multivariable analysis although median age of patients died within 3 days and survived 3 days of admission did not have significant difference, because older age has been reported to be associated with poor outcomes in critically ill patients with COVID-19 [12] .', 'Multivariable regression analysis revealed that decreased oxygen saturation, increased neutrophil count and elevated hsTnI on admission were associated with increased odds of rapid death within 3 days of hospital admission.', 'Early detection of these factors could help physicians to identify rapid progress of disease and death of patients with COVID-19.', 'Several limitations existed in this study.', 'Firstly, evaluation of CT imaging features partly depended on the experience of clinicians and radiologists which may cause All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.04.20031039 doi: medRxiv preprint inaccuracy.', 'Secondly, in the early outbreak of COVID-19, relatively inadequate medical resources may affect the observation of the natural course of disease.', 'Finally, only 101 patients died with COVID-19 in one hospital were included in this study, further studies including multi-centers are still needed.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': [\"[{'text': 'Aims: Studies have indicated that chloroquine (CQ\", 'Despite our small number of cases, the potential of HCQ in the treatment of COVID-19 has been partially confirmed.', 'Considering that there is no better option at present, it is a promising practice to apply HCQ to COVID-19 under reasonable management.', 'However, Large-scale clinical and basic research is still needed to clarify its specific mechanism and to continuously optimize the treatment plan.', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint Abbreviations: HCQ, hydroxychloroquine.', 'Figure 1 : Study flow diagram.']}\n", - "{'sentences': ['Aim: The Coronavirus disease 2019 outbreak is a major threat to human beings.', 'Lung injury has been reported as the major outcome of COVID-19 infection.', 'However, liver damage has also been considered to occur in severe cases.', 'Current meta-analysis of retrospective studies was done to summarize available findings on the association between liver injury and severity of COVID-19 infection.', 'Online databases including PubMed, Scopus, Web of Science and Cochrane Library were searched to detect relevant publications up to 1 April 2020, using relevant keywords.', 'To pool data, a fixed-or random-effects model was used depending on the heterogeneity between studies.', 'Furthermore, publication bias test and sensitivity analysis were also done.', 'Results: In total, 20 retrospective studies with 3,428 COVID-19 infected patients (severe cases = 1,455 and mild cases = 1,973), were included in this meta-analysis.', 'Higher serum levels of Aspartate aminotransferase (weighted mean difference = 8.84 U/L, 95% CI = 5.97 to 11.71, P<0.001), Alanine aminotransferase (weighted mean difference = 7.35 U/L, 95% CI = 4.77 to 9.93, P<0.001), total Bilirubin (weighted mean difference = 2.30 mmol/L, 95% CI = 1.24 to 3.36, P<0.001) and lower serum levels of Albumin (weighted mean difference = -4.24 g/L, 95% CI = -6.20 to -2.28, P<0.001), were associated with a significant increase in the severity of COVID-19 infection.', 'Conclusions: The incidence of liver injury seems to be higher in patients with severe COVID-19', 'This finding could help physicians to identify patients with poor prognosis at an early stage.', 'Findings from this meta-analysis supported the hypothesis that liver injury is associated with severe outcomes in patients with COVID-19 infection.', 'To our knowledge, this study is the first systematic review and meta-analysis to assess the association between serum levels of AST, ALT, total Bilirubin and Albumin with severity of COVID-19 infection.', 'Our results are in agreement with previous narrative review 32 .', 'Previously, liver damage has been reported as an important risk factor for severe outcome and death in SARS and MERS 33-36 .', 'Mild cases of COVID-19 showed symptoms of dry cough, fever, fatigue, myalgia and diarrhea.', 'In severe cases, viral pneumonia, dyspnea and hypoxemia occurred 1 week after the onset of the disease, which may progress to acute respiratory distress syndrome, metabolic acidosis, septic .', 'CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https: //doi.org/10.1101 //doi.org/10.', '/2020 shock and even death 12 .', 'Previous studies have shown that the incidence of liver injury in severe COVID-19 patients ranged from 58% to 78% 37, 38 , mainly indicated by elevated AST, ALT and total Bilirubin levels accompanied by slightly decreased Albumin levels 12, 21, 24, 39 .', 'Currently, studies on the mechanisms of COVID-19 related liver dysfunction are limited.', 'COVID-19 uses the angiotensin converting enzyme 2 (ACE2) as the binding site to enter the host cell in lungs, kidneys and heart 40 .', 'Previous study showed that both liver and bile duct cells express ACE2', 'In addition, the ACE2 expression of bile duct cells is much greater than that of liver cells.', 'Bile duct epithelial cells are known to play important roles in initiation and regulation of immune responses and liver regeneration 42 .', 'So there is at least theoretical potential possibility of direct liver and bile duct involvement by the virus.', 'Serum concentrations of pro-inflammatory cytokines, including IL-1β, IL-6 and TNF-α increased in the majority of severe cases, suggesting cytokine storm syndrome might be associated with disease severity 43 .', 'Similarly, SARS and MERS were also characterized by exuberant inflammatory responses and end-organ damage 44, 45 .', 'Besides, the cytokine storm syndrome was observed in severe COVID-19 cases 43 , yet whether it results in liver injury in patients remains to be investigated.', 'Mild lobular and portal activity along with moderate microvascular steatosis were observed in liver biopsy specimens, which might be caused by either COVID-19 infection or drug-induced liver injury 46 .', 'Similar to the situation in SARS and MERS, steroids, antivirals and antibiotics are widely used for the treatment of COVID-19 patients [47] [48] [49] .', 'Although these drugs are potential causes of liver dysfunction, there is little evidence that currently available drug combinations impair liver function in patients with COVID-19 infection 24 .', 'Actually, a recent study showed .', 'CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', '1101 that the liver dysfunction might be caused by lopinavir/litonavir, which is used as antivirals for the treatment of COVID-19 patients 50 .', 'The present study has some limitations.', 'First, interpretation of our meta-analysis findings might be limited by the small sample size.', 'Second, there is a lack of reports that liver failure occurs in COVID-19 patients with chronic liver diseases and our meta-analysis did not include data such as chronic hepatitis B or C.']}\n", - "{'sentences': ['The COVID-19 pandemic, after it was reported in December, 2019, is a highly contagious and now spreading to over 190 countries, causing a severe public health burden.', 'Currently, there is no vaccine or specific drug to treat COVID-19, which is caused by a novel coronavirus, SARS-2-CoV. For this emergency, the FDA has approved Remdesivir and Hydroxychloroquine for treatment of COVID-19 as Emergency Use Authorization.', 'However, even after this pandemic, COVID-19 may still have a chance to come back.', 'Therefore, we need to come out with new strategies for drug discovery for combating COVID-19 in the future.', 'Journal Pre-proof effective for both viruses.', 'Third, both COVID-19 and SARS have cytokine storms resulting in severe pneumonia, causing the death of patients.', 'The control of the cytokine storm is also a very desirable treatment approach for patients in serious conditions for virus infection-induced pneumonia, such as COVID-19.', 'Journal Pre-proof J o u', 'r n a l P r e -p r o o f Besides, the viruses utilize cellular machineries for their replication, and those cellular machineries can be drug targets too.', 'Recently, an old drug, Nitazoxanide(NTZ), developed initially as an antiprotozoal agent, has been identified as broad anti-influenza A and B viruses and drug-resistant mutants 23 .', 'The results from phase II/III clinical trial are very suspicious.', 'NTZ depletes ATP-sensitive intracellular Ca 2+ stores as well as alteration of viral protein N-linked glycosylation and trafficking 24 .', 'The long-term efficacy and potential side effect(s) need to be evaluated in the future.', 'There is no approved antiviral therapy available for multiple viruses or multiple drug-resistant viruses that cause serious diseases.', 'Therefore, targeting host factors can be a plausible approach for developing COVID-19 therapeutics or other emerging viruses in the future.', 'Journal Pre-proof J o u', 'r n a l P r e -p r o o f']}\n", - "{'sentences': ['BACKGROUND: Since December 2019, the outbreak of the novel coronavirus has impacted nearly >90,000 people in more than 75 countries.', 'In this case report, we aim to define the chest computed tomography findings of 2019-novel coronavirus associated with pneumonia and its successful resolution after treatment.', 'A fifty-year-old female patient, who is a businesswoman, presented with chief complaints of “fever for one week, diarrhea, anorexia, and asthenia.', 'Initially, she was given Tamiflu.', 'The influenza A virus serology was negative.', 'Three days later, levofloxacin was started because the patient’s symptoms did not improve.', 'The novel coronavirus nucleic acid test was negative.', 'It was noted that before the onset of the disease, the patient went to Wuhan on a business trip.', 'Despite the given treatment, her body temperature rose to 39.2°C and she was referred to our clinic for further evaluation.', 'Then, chest computed tomography was performed and showed bilateral multifocal ground glass opacities with consolidation which suggested viral pneumonia as a differential diagnosis, and the subsequent 2019-novel coronavirus pneumonia nucleic acid test was positive.', 'CONCLUSION: Chest computed tomography offers fast and convenient evaluation of patients with suspected 2019-novel coronavirus pneumonia.']}\n", - "{'sentences': ['The FDA-approved gold drug Auranofin inhibits novel coronavirus (SARS-COV-2) replication and attenuates inflammation in human cells', 'SARS-COV-2 has recently emerged as a new public health threat.', 'Herein, we report that the FDA-approved gold drug, auranofin, inhibits SARS-COV-2 replication in human cells at low micro molar concentration.', 'Treatment of cells with auranofin resulted in a 95% reduction in the viral RNA at 48 hours after infection.', 'Auranofin treatment dramatically reduced the expression of SARS-COV-2-induced cytokines in human cells.', 'These data indicate that auranofin could be a useful drug to limit SARS-CoV-2 infection and associated lung injury due to its anti-viral, antiinflammatory and anti-ROS properties.', 'Auranofin has a well-known toxicity profile and is considered safe for human use.', 'All rights reserved.', 'No reuse allowed without permission.']}\n", - "{'sentences': ['The 2019-nCoV outbreak has become a global health risk.', 'Editing by host deaminases is an innate restriction process to counter viruses, and it is not yet known whether it operates against 15 coronaviruses.', 'Here we analyze RNA sequences from bronchoalveolar lavage fluids derived from two Wuhan patients.', 'We identify nucleotide changes that may be signatures of RNA editing:', 'Adenosine-to-Inosine changes from ADAR deaminases and Cytosine-to-Uracil changes from APOBEC ones.', 'A mutational analysis of genomes from different strains of human-hosted Coronaviridae reveals patterns similar to the RNA editing pattern observed in the 2019-nCoV 20 transcriptomes.', 'Our results suggest that both APOBECs and ADARs are involved in Coronavirus genome editing, a process that may shape the fate of both virus and patient.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Coronavirus disease 2019 (COVID-19) is a declared global pandemic.', 'There are multiple parameters of the clinical course and management of the COVID-19 that need optimization.', 'A hindrance to this development is the vast amount of misinformation present due to scarcely sourced manuscript preprints and social media.', 'This literature review aims to presents accredited and the most current studies pertaining to the basic sciences of SARS-CoV-2, clinical presentation and disease course of COVID-19, public health interventions, and current epidemiological developments.', 'The review on basic sciences aims to clarify the jargon in virology, describe the virion structure of SARS-CoV-2 and present pertinent details relevant to clinical practice.', 'Another component discussed is the brief history on the series of experiments used to explore the origins and evolution of the phylogeny of the viral genome of SARS-CoV-2.', 'Additionally, the clinical and epidemiological differences between COVID-19 and other infections causing outbreaks (SARS, MERS, H1N1) are elucidated.', 'Emphasis is placed on evidence-based medicine to evaluate the frequency of presentation of various symptoms to create a stratification system of the most important epidemiological risk factors for COVID-19.', 'These can be used to triage and expedite risk assessment.', 'Furthermore, the limitations and statistical strength of the diagnostic tools currently in clinical practice are evaluated.', 'Criteria on rapid screening, discharge from hospital and discontinuation of self-quarantine are clarified.', 'Epidemiological factors influencing the rapid rate of spread of the SARS-CoV-2 virus are described.', 'Accurate information pertinent to improving prevention strategies is also discussed.', 'The penultimate portion of the review aims to explain the involvement of micronutrients such as vitamin C and vitamin D in COVID19 treatment and prophylaxis.', 'Furthermore, the biochemistry of the major candidates for novel therapies is briefly reviewed and a summary of their current status in the clinical trials is presented.', 'Lastly, the current scientific data and status of governing bodies such as the Center of Disease Control (CDC) and the WHO on the usage of controversial therapies such as angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs) (Ibuprofen), and corticosteroids usage in COVID-19 are discussed.', 'The composite collection of accredited studies on each of these subtopics of COVID-19']}\n", - "{'sentences': ['Ideally, a new mask or respirator would be used for each individual to minimize the transmission of infectious diseases that are airborne or transmitted via respiratory droplets.', 'However, crises such as the current COVID-19 pandemic can create shortages that necessitate measures to conserve PPE.', 'Among potential methods for decontamination, previous work has suggested UVGI results in less physical deformation then bleach, microwave irradiation, and vaporized hydrogen peroxide.', 'Additionally, this and other investigations of UVGI for the purpose of N95 respirator decontamination was motivated by the ubiquity of UV lamp equipped biosafety cabinets, especially at large biomedical research institutions.', 'Various groups have therefore begun sterilizing respiratory protective equipment themselves using UVGI and \"homebrew\" setups.', 'For example, enterprising clinicians at the University of Nebraska Medical Center are stringing N95 respirators between two towers of UVGI bulbs placed on either side of a room in order to inactivate potential SARS-CoV-2 viral contaminants on the masks.', '12 From our measurements, normalized to the technical specifications of the manufacturer using a typical BSC, we conservatively estimate the time to sterilize N95 respirators using similar models is 20 min per side.', 'This recommendation represents the time required to deliver a UV dose that is ≈30 times higher than the previously reported dose to inactivate 90% of single-stranded RNA viruses.', '2 To scale this protocol to any BSC, we propose that a conservative scaling factor of 1.98 for spatial heterogeneity is likely conserved across BSCs, but the amount of power delivered to the BSC surface likely varies significantly between manufacturers.', 'Note that given the variance between the two BSCs we measured, the true worst-case scaling factor is likely slightly worse than what we measured, as there almost certainly exist BSCs with greater variation in UV radiation intensity.', 'We invite other scientists to add measurements from their own BSCs to our github repository to allow continued updating of this recommendation.', 'Therefore, to calculate a time for an arbitrary BSC model, we recommend using Equation 4:', \"Note that this equation assumes that the UV radiation output of the BSC matches the manufacturer's specification.\", 'Ideally, BSCs should be calibrated before being used for the purposes of sterilizing PPE.', 'In the future, it may be possible to design a technique that avoids the need to flip masks over and irradiate']}\n", - "{'sentences': ['The World Health Organization (WHO) was informed on December 2019 about a coronavirus pneumonia outbreak in Wuhan, Hubei province (China).', 'Subsequently, on March 12, 2020, 125,048 cases and 4,614 deaths were reported.', 'Coronavirus is an enveloped RNA virus, from the genus Betacoronavirus, that is distributed in birds, humans, and other mammals.', 'WHO has named the novel coronavirus disease as COVID-19.', 'More than 80 clinical trials have been launched to test coronavirus treatment, including some drug repurposing or repositioning for COVID-19.', 'Hence, we performed a search in March 2020 of the clinicaltrials.gov database.', 'The eligibility criteria for the retrieved studies were: contain a clinicaltrials.gov base identifier number; describe the number of participants and the period for the study; describe the participants’ clinical conditions; and utilize interventions with medicines already studied or approved for any other disease in patients infected with the novel coronavirus SARS-CoV-2 (2019-nCoV).', 'It is essential to emphasize that this article only captured trials listed in the clinicaltrials.gov database.', 'We identified 24 clinical trials, involving more than 20 medicines, such as human immunoglobulin, interferons, chloroquine, hydroxychloroquine, arbidol, remdesivir, favipiravir, lopinavir, ritonavir, oseltamivir, methylprednisolone, bevacizumab, and traditional Chinese medicines (TCM', 'Xiyanping is a TCM preparation with andrographolide as a principal component; it has significant antibacterial and antiviral effects (44).', 'We identified 24 clinical trials (Table 1), in which 19 studies were at clinical phases 2, 3, or 4.', 'The pharmaceutical interventions found for COVID-19 treatment include human immunoglobulin, interferons, chloroquine, hydroxychloroquine, arbidol, remdesivir, oseltamivir, favipiravir, carrimycin, methylprednisolone, bevacizumab, thalidomide, vitamin C, pirfenidone, bromhexine, fingolimod, danoprevir, ritonavir, darunavir, cobicistat, lopinavir, xiyanping, and traditional Chinese medicines (TCM', 'Darunavir, in combination with cobicistat, will be used in trial number NCT04252274 (45) in patients with COVID-19 pneumonia.', 'The United States Food and Drug Administration (FDA', 'Recombinant human interferon α2β is described to have inhibitory effects on MERS-CoV and SARS-CoV (48), and the purpose of the clinical trials found for this paper is to evaluate the efficacy and safety of recombinant human interferon α2β in treating patients with new coronavirus infection (49).', 'Thalidomide will be used in two trials against COVID-19 (49, 50).', 'Thalidomide has an anti-inflammatory action due to its ability to speed up the degradation of messenger RNA in blood cells and thus reduce tumor necrosis factor-α (TNFα', 'The corticosteroid methylprednisolone will be tested against COVID-19 (52).', 'Long et al. 2016 (53) reported that corticosteroid therapy (methylprednisolone, dexamethasone, and hydrocortisone) is beneficial in treating SARS-CoV patients; it significantly prolongs the survival time of clinical cases.', 'Nevertheless, other authors described the use of corticosteroids in the early stages of SARS infection with increasing values of viral load (54).', 'Furthermore, studies with corticosteroids in the adjuvant therapy of MERS-CoV infection were unable to prove efficacy because all patients died (55).', 'Methylprednisolone has already been used in COVID-19 patients in combination with antibiotics, oseltamivir, and oxygen therapy (56).', 'Finally, vitamin C (ascorbic acid), pirfenidone, bevacizumab, fingolimod, and bromhexine hydrochloride are going to be tested on COVID-19 (57-61).', 'Vitamin C has antioxidant activity and may reduce oxidative stress and inflammation (57,62), effects that improve vasopressor synthesis, enhance immune cell function, improve endovascular function, and provide epigenetic immunologic modifications.', 'Clinical trials have demonstrated promising data on mortality improvement in sepsis, but more extensive studies are necessary to validate these conclusions (63).', 'Pirfenidone has been used in the treatment of idiopathic pulmonary fibrosis diseases due to anti-inflammatory and anti-oxidant effects, namely by inhibiting IL-1β and IL-4 (58).', 'Trial NCT04282902 claimed (58) that anti-inflammatory effects may be helpful in SARS-CoV-2 infection.', 'Bevacizumab is a humanized monoclonal antibody that targets vascular endothelial growth factor (VEGF) (59,63), and it may reduce the levels of VEGF caused by hypoxia, severe inflammation, and upregulation of the infected respiratory tract epithelium, all of which might suppress the edema in patients with COVID-19 (63).', 'Fingolimod is a sphingosine-1-phosphate receptor regulator (FTY720) with an effective immunology modulator that is useful in multiple sclerosis (60).', 'According to some pathological findings of pulmonary edema and hyaline membrane formation, the use of immune modulators, together with ventilator support, should be considered for severe patients to prevent the development of acute respiratory distress syndrome (ARDS', 'In conclusion, the WHO declared an epidemic of pneumonia caused by the SARS-CoV-2 in 2020.', 'In this review, we found 24 clinical trials that have already started with the repositioning of more than 20 medicines for COVID-19 treatment, such as human immunoglobulin, interferons, chloroquine, hydroxychloroquine, arbidol, remdesivir, favipiravir, oseltamivir, thalidomide, methylprednisolone, bevacizumab, and TCM.', 'The Hydroxychloroquine-azithromycin combination was the first drug repurposed with excellent results in clinical trials against SARS-CoV-2, but further, more extended studies, with a higher number of patients, are needed to confirm these results.', 'Besides its limitations, repositioning clinical trials are still an attractive strategy: they may facilitate the discovery of new classes of medicines; they may reduce the costs and time to reach the market; there is an existing pharmaceutical supply chain for formulation and distribution; and there is the possibility of combinations with other drugs in treatments that are more effective than monotherapy.', 'Most of the studies found in this article are scheduled to end in 2020, and we hope these repositioning trials may help to find solutions for COVID-19 treatment by this year.', 'Chloroquine and hydroxychloroquine are antimalarial drugs.', 'They have antiviral effects against human immuno-deficiency virus (HIV), namely by inhibiting virus entry into host cells.', 'Another antiviral mechanism is related to the post-translation alteration of newly synthesized proteins via glycosylation inhibition (12).', 'Hydroxychloroquine is already being used in clinical trials on acquired immune deficiency syndrome (AIDS', 'Immunoglobulins are useful in several diseases, such as idiopathic thrombocytopenia purpura (ITP), Guillain-Barre Syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), Kawasaki disease, and in multiple neurological autoimmune disorders refractory to standard immunosuppressive treatments (17).', 'Broadly neutralizing antibodies can recognize a wide variety of glycoproteins (GPs) in virus surfaces or the protein shell of a non-enveloped virus.', 'However, HIV-1, dengue virus (DENV), influenza viruses, hepatitis C virus (HCV), and Ebola virus (EBOV) can mutate superficial GPs', 'Two clinical studies refer to the use of remdesivir in severe (20) or mild (21) respiratory infections by SARS-CoV-2.', 'Remdesivir is a nucleotide analog inhibitor of the EBOV RNA-polymerase RNA-dependent (RdRp).', 'Dyer et al. 2019 (22) described preliminary findings of a mortality rate of 33% in 499 patients treated with remdesivir against the EBOV disease in early infection stages.', 'The same authors noted a mortality rate of 75% (almost 1 900 people) of non-treated infected patients during the same epidemic period (22).', 'Wang et al. 2020 (23) presented data showing that remdesivir is effective against the 2019-nCoV in Vero E6 cells (EC90 1.76 μM).', 'The suggested mechanism for remdesivir involves the host cells’ post-entry stage (23).', 'Arbidol, also known as umifenovir, is approved in Russia and China for the treatment of influenza virus infections; it does not have significant adverse effects and is patented for SARS treatment (24).', 'As shown in Table 1, four clinical trials will be conducted for COVID-19 treatment: one with arbidol in comparison with the basic treatment (25), and the other three studies comparing effects with oseltamivir (26,27), lopinavir-ritonavir (27', 'The lopinavir-ritonavir combination is approved for AIDS treatment in several countries.', 'Both drugs are HIV protease inhibitors, but ritonavir is also a cytochrome P450 and GP inhibitor, a fact that endorses the lopinavir pharmacokinetic and pharmacodynamic activities against HIV (32).', 'Such a combination, plus β-1b interferon, is in phase 2 for the MERS treatment (33).', 'Several trials involve lopinavir-ritonavir treatment in comparison with the use of other drugs for COVID-19: arbidol (26,27), carrimycin (28), TCM (34,35), xiyanping (36,37), danoprevir-ritonavir (38) and interferon inhalation (34,38).', 'Nevertheless, one previous article argued that in a clinical trial with 199 patients with laboratory-confirmed SARS-CoV-2 infection, the lopinavir-ritonavir combination was not associated with clinical improvement comparing with standard care procedures (39).', 'Carrimycin is a macrolide antibiotic with effects against some gram-positive bacteria and in vitro effects on Mycobacterium tuberculosis (40).', 'Danoprevir is an HCV NS3 protease inhibitor approved in China for the treatment of non-cirrhotic genotype 1b chronic hepatitis C, in combination with ritonavir, peginterferon-a, and ribavirin (41).', 'Traditional Chinese medicine (TCM']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['BACKGROUND: At the end of 2019, a novel coronavirus outbreak emerged in Wuhan, China, and its causative organism has been subsequently designated the 2019 novel coronavirus (2019-nCoV).', 'The virus has since rapidly spread to all provinces and autonomous regions of China, and to countries outside of China.', 'Patients who become infected with 2019-nCoV may initially develop mild upper respiratory tract symptoms.', 'However, a significant fraction of these patients goes on to subsequently develop serious lower respiratory disease.', 'The effectiveness of adjunctive glucocorticoid therapy uses in the management of 2019-nCoV infected patients with severe lower respiratory tract infections is not clear, and warrants further investigation.', 'METHODS: The present study will be conducted as an open-labelled, randomised controlled trial.', 'We will enrol 48 subjects from Chongqing Public Health Medical Center.', 'Each eligible subject will be assigned to an intervention group (methylprednisolone via intravenous injection at a dose of 1-2mg/kg/day for 3 days) or a control group (no glucocorticoid use) randomly, at a 1:1 ratio.', 'Subjects in both groups will be invited for 28 days of follow-up which will be scheduled at 4 consecutive visit points.', 'We will use the clinical improvement rate as our primary endpoint.', 'Secondary endpoints include the timing of clinical improvement after intervention, duration of mechanical ventilation, duration of hospitalization, overall incidence of adverse events, as well as rate of adverse events at each visit, and mortality at 2 and 4 weeks.', 'DISCUSSION: The present coronavirus outbreak is the third serious global coronavirus outbreak in the past two decades.', 'Oral and parenteral glucocorticoids have been used in the management of severe respiratory symptoms in coronavirus-infected patients in the past.', 'However, there remains no definitive evidence in the literature for or against the utilization of systemic glucocorticoids in seriously ill patients with coronavirus-related severe respiratory disease, or indeed in other types of severe respiratory disease.', 'In this study, we hope to discover evidence either supporting or opposing the systemic therapeutic administration of glucocorticoids in severe coronavirus disease 2019 (COVID-19']}\n", - "{'sentences': ['Challenges of Convalescent Plasma Therapy on COVID-19']}\n", - "{'sentences': ['The recent emergence of the pathogenic SARS-CoV-2 initiated a worldwide health crisis.', 'The entry of the virus into cells is mediated by the binding of the viral Spike protein to the angiotensin-converting enzyme-2 (ACE2), followed by its priming by the TMPRSS2 serine protease, both present on the cellular membrane of the target cells.', 'In the respiratory tract, these targets are ciliated cells.', 'Interestingly, various reports indicate an association between SARS-CoV-2 infection and anosmia, suggesting an alteration not restricted to the respiratory tissue, but that might also include the olfactory sensory epithelium.', 'We explored this possibility by generating RNA-seq libraries from human neuroepithelium, in which we found significant expression of ACE2', 'All rights reserved.', 'No reuse allowed without permission.', 'By taking a combined approach, based both on our own RNA-seq data and on published scRNA-seq datasets, we demonstrate that olfactory sustentacular cells and other non-neuronal cell types in the olfactory neuroepithelium, but not olfactory sensory neurons, coexpress TMPRSS2 and ACE2, the two key players in the binding and entry of the SARS-CoV-2 into human cells.', 'A fair question is to ask how common TMPRSS2 and ACE2 coexpression is in human cells.', 'A first answer, although limited to the 26 nose cell types analyzed here, is provided in Figure 2 A: not often.', 'We also looked at various other human cell types using available scRNA-seq datasets, corresponding to various organs (data not shown) and in particular to neuronal tissue (Figure 3) , and found TMPRSS2 and ACE2 coexpression to be a very rare characteristic.', 'Naturally, much is still to be learned about the players involved in SARS-CoV-2 infection of human cells.', 'Thus, although ACE2 and TMPRSS2 are currently believed to represent the major players during cell entry, other molecules, such as CD147 in particular, may also play a significant role 24 .', 'How likely is it that the coexpression of TMPRSS2 and ACE2 in olfactory sustentacular cells is at the origin of the SARS-CoV-2-induced anosmia?', 'And why are horizontal basal cells that also coexpress TMPRSS2 and ACE2 not prime candidates?', 'First, given the slow rate of neuronal renewal in the main olfactory epithelium and the apparent rapid development of SARS-CoV-2-triggered anosmia, a perturbation of the stem cell pool constituted by the horizontal basal cells appears unlikely to represent an immediate disturbance to the system.', 'Second, the significant amounts of TMPRSS2 and ACE2 transcripts we observed in sustentacular cells are in the same range as the one observed in respiratory ciliated cells, suggesting at least that sustentacular cells play in the same league in terms of SARS-CoV-2 receptors.', 'Third, sustentacular cells are in direct contact with the olfactory cavity, and thus with anything that enters the nose.', 'Finally, a known and critical role is played by sustentacular cells in the maintenance of the olfactory neuroepithelium integrity: if they die, the whole neuroepithelium disaggregates, leading to anosmia.', 'Taken together, and despite the fact that one cannot exclude inflammation and the infection of other non-neuronal cell types in the olfactory neuroepithelium as an origin of the SARS-CoV-2-induced anosmia, the link between the viral molecular entry tools expressed by olfactory sustentacular cells and the chemosensory alteration appears quite credible.', 'Naturally, a next step would be the study of the olfactory epithelium of a mouse model expressing the human ACE2/TMPRSS2 in sustentacular cells, and nasal biopsies of human olfactory neuroepithelia just after SARS-CoV-2 infection.', 'The idea that viruses may affect directly or indirectly the integrity and function of the sensory part of the olfactory system is not new.', 'Viruses may indeed affect the neuroepithelium in different ways.', 'They often alter specific cell types, including neurons.', 'For example, olfactory sensory neurons and sustentacular cells were shown to be major portals of host entry of the Murid Herpesvirus-4 (MuHV-4', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.31.013268 doi: bioRxiv preprint by viruses matters, in particular to fight the infection.', 'For example, in the case of a MuHV-4 challenge, olfactory sensory neurons are not responsive to interferon treatment (IFNγ), while sustentacular cells are 27 .', 'Finally, SARS-CoV-2-infection has not only been linked to the loss of a single chemosensory ability.', 'Indeed, in addition to anosmia, ageusia -that is loss of tastehas been reported 8 .', 'Whether these reports truly reflect taste anomalies, or rather olfactory perturbations that may drastically affect the flavor of food, is unclear.', 'However, this potential double effect on two chemosensory systems that share nothing at the periphery may suggest a more central alteration, involving for example a direct infection of the brain by SARS-CoV-2.', 'Again, such viral migration to the central nervous system, and in particular from the olfactory neuroepithelium, would not be a first.', 'SARS-CoV particles (that is the virus responsible for the previous SARS epidemic in 2002) have in fact been found in the human brain 18-20 .', 'Adding to this idea is the observation that in a transgenic mouse model expressing the human ACE2 and infected with SARS-CoV, brain lesions were observed.', 'Moreover, a retrospective case study on 214 COVID-19 patients reported neurological manifestations possibly correlated with the severity of the disease (with the confounding factor that old people are more likely to be very sick) 28 .', 'However, in the present work we did not identify neuronal or non-neuronal cell types in the mouse or human brain that coexpressed the orthologs of the human ACE2 and TMPRSS2.', 'This lack of coexpression is also true for human olfactory sensory neurons, as shown in this work.', 'Moreover, significant brain damage in humans seems quite unlikely or at least rare, since no specific cognitive or other brain-related deficits resulting directly from SARS-CoV-2 infection in the central nervous system were reported.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.31.013268 doi: bioRxiv preprint']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Background: SARS-CoV-2 is the cause of the COVID-19 that has been declared a global pandemic by the WHO in 2020.', 'The COVID-19 treatment guidelines vary in each country, and yet there is no approved therapeutic for COVID-19.', 'The search terms included combinations of: COVID, SARS-COV-2, glucocorticoids, convalescent plasma, antiviral, antibacterial.', 'There were no restrictions on the type of study design eligible for inclusion.', 'As of March 26, 2020, of the initial manuscripts identified (n=449) articles.', 'Forty-one studies were included, of which clinical trials (n=3), (case reports n=7), case series (n=10), retrospective (n=11) and prospective (n=10) observational studies.', 'Thirtysix studies were conducted in China (88%).', 'The most common mentioned and reported medicine in this systematic review was corticosteroids (n=25), followed by Lopinavir (n=21) and oseltamivir (n=16).', 'This is the first up to date review related the therapeutics used in COVID-patients in a systematic manner.', 'As of March, twenty-sixth, 2020 and since the emergence of COVID-19, only forty-one research articles on COVID-19 and therapeutics were found eligible to be included in the current systematic review ( 2, 5, , of which only three were clinical trials; most were either case reports, case series or prospective and retrospective observational studies.', 'Systematic corticosteroid of different names and formulation was the most commonly mentioned, and used medication (n=25), followed by the antivirals Lopinavir (n=21), oseltamivir (n=16) and arbidol hydrochloride (n=8).', 'The Convalescent plasma therapy was mentioned in one multi-center retrospective observational study and was administered to six patients.', 'Abidol hydrochloride was the fourth most mentioned medicine in this review; it is a broad-spectrum inhibitor of influenza A and B virus, parainfluenza virus, and other types of viruses including hepatitis C virus.', 'It is used in Russia and China, yet not approved for use in other countries (52) .', 'However, no conclusive evidence of its efficacy for COVID-19 was reported.', 'In this review, it was reported together with favipiravir, which was approved recently for treatment of novel influenza on February 15, 2020 in China (52) .', 'Chloroquine phosphate and Hydroxychloroquine were reported in this review and showed favorable outcomes on the recovery of COVID-19 patients (6) (7) (57) (58) (59) (60) .', 'The mechanism of action on viruses for these two medicines is probably the same effect.', 'Chloroquine has been used for a long time to treat malaria and showed positive outcomes on patients.', 'Furthermore, Hydroxychloroquine showed a significant effectiveness to kill intracellar pathogens such as Coxiella burnetii, the agent of Q fever (22) .', 'The French open label non-randomized clinical trial was promising and the first clinical trial of these medication on COVID-19 patients.', 'The effect of Hydroxychloroquine was significant because it showed reduction in the viral load when it compared with the control group (22) .', 'Moreover, the effect of Hydroxychloroquine was significantly more effective when azithromycin was added to the patients according to their clinical needs.', 'However, clinical follow-up and occurrence of adverse effects were not discussed in the paper; further work should be done on these medicines to reduce the spread of .', 'Although these two medicines have shown promising activity against SARSCoV-2, there is a risk of arrhythmia associated with their requiring caution for use at higher cumulative dosages.', 'Therefore, it is recommended that their use in suspected/confirmed COVID-19 is to be restricted to hospitalized patients.', 'On March 30, 2020, has issued an emergency use authorization for chloroquine and hydroxychloroquine to treat patients hospitalized with .', 'The findings showed that convalescent plasma was administered to six patients and no transfusion reactions occurred; however, the study could not provide adequate information about the efficacy of convalescent plasma, due to limited sample sizes and lack of randomized controlled group (61) (62) .', 'Convalescent plasma treatment was mention once in this review, in a multi-center cohort research of 45 critically ill COVID-19 patients admitted to ICU in Wuhan.', 'In fact, convalescent plasma therapy could be a promising method of treatment for COVID-19 patients, in a very recent study conducted in China (case series), showed that five critically ill patients with laboratory confirmed COVID-19 who had acute respiratory distress syndrome; their body temperature was normalized within 3 days in 4 of 5 patients after receiving plasma transfusion of recovered COVID-19 patients, their viral loads also decreased and became negative within 12 days after the transfusion; 3 out of 5 patients, were discharged from the hospital and were in stable condition at 37 days after transfusion (63) .', 'On March 24, 2020 the US FDA has approved convalescent plasma treatment for investigational use under the traditional Investigational New Drug Applications (IND', 'Notably there are some potential risks and ethical issues associated with their used, including increased thrombotic event risk that occur at the same administration date (0.04 to 14.9%), the lack of high quality research in this particular area, and the selectivity of donors with high neutralizing antibody titers (65) .', 'This is the first systematic review up to date, related to the therapeutics used in COVID-19 patients.', 'Only 41 research articles on COVID-19 and therapeutics were found eligible to be included, most conducted in China, of which only three were clinical trials.', 'The anti-inflammatory medication corticosteroid was found to be the most mentioned and used medicine in these studies, despite the safety alert made by WHO and CDC, followed by antivirals medication Lopinavir, oseltamivir and arbidol hydrochloride.', 'Although further research is warranted as the amount of the evidence increases, but with the limited available data, this study presents the current picture of treatment modalities used for COVID-19.', 'Propelling developments in treatment of COVID-19 are needed to be characterized in future studies.', 'Y a n g W , C a o Q , Q i ', 'n L , W a n g X , C h e n g Z , P a n A , e t a l . ', 'C l i n i c a l c h a r a c t e r i s t i c s a n d i m a g ', 'i n g m a n i f e s t a t i o n s o f t h e 2 0 1 9 n o v ', 'e l c o r o n a v ', 'i r ', 'u s d i s e ', 'a s e ( C O V I ', 'D -1 9 ) : ', 'A m u l t i ', 'c e n t e r s t u d y i n W e n z h o u c i t y , Z h e j ', 'i ', 'a n g , C h i n a [ p u b l i s h e d o n l i n e a h e a d o f p ', 'r ', 'i n t , 2 0 2 0 ', 'F e b 2 6 ] .', 'J I n f e c t . ', 'S 0 1 6 3 -4 4 5 3 ( 2 0 ) 3 0 0 9 9 -2 . ', 'h t t p s : / / d o i . ', 'o r g / 1 0 . ', '1 0 1 c i ', 't e d o n 2 2 / 3 / 2 0 2 0 1 2 . ', 'C a o B , W a n g Y , W e n D , e t a l . ', 'A t r ', 'i a l o f l o p i n a v ', 'i ', 'r -r i ', 't o n a v i r ', 'i n a d u l t s h o s p ', 'i ', 't a l i z e d w ', 'i t h s e v e r e C o v ', 'i d -1 9 .', 'T h e .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint . .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'a n a g e m e n t o f s e v e r e a c u t e r e s p i ', 'r a t o r y i ', 'n f e c t i ', 'o n ( S A R I ) ', 'w h e n C O V I D -1 9 d i s e a s e i s s u s p e c t e d . ', 'I n t e r i m g u i d a n c e . ', '2 0 2 0 M a r 1 3 . ', 'F r o m W H O w e b s i t e . ', 'A c c e s s e d 2 0 2 0 M a r 1 9 . ', 'h t t p s : / / w w w . ', 'w h o . ', 'i n t / p ', 'u b l i ', 'c a t i ', 'o n s -d e t a i l / c l i n i ', 'c a l m a n a g e m e n t -o f -s e v e r e -a c u t e -r e s p i ', 'r a t o r y -i n f e c t i o n -w h e n -n o v e l -c o r o n a v ', 'i r u s -( n c o v ) ', 'i n f e c t i o n -i s -s u s p ', 'e c t e d 5 7 . .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint . .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint . .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['A total of 27 categorical variables were identified in univariate logistic regression analysis, namely: age, smoking, BMI, hypnotics, dyspnea, diabetes, malignancy, cardiovascular and cerebrovascular diseases, serum amyloid A, procalcitonin, hypersensitive troponin I, creatine kinase CMB, lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, creatinine, glucose, leukocyte count, neutrophil count, platelet count, rRT-PCR at diagnosis, clinical status at admission, bilateral GGO, crazy paving sign, diffuse patchy ground glass and air bronchogram, and multiple bilateral pulmonary consolidation and intralobular interstitial thickening (Table S2) .', 'Eight variables were demonstrated as independent risk factors based on the multivariate logistic regression model.', 'The results indicated that age (patients over 65 years) , smoking , critical disease designation , diabetes, abnormally higher hypersensitive troponin I (>0.04 pg/mL) , leukocyte count (>10x10 9 /L ) and neutrophil count (>75 x10 9 /L) were significantly associated with unfavorable clinical outcome, and hypnotics showed significant beneficial effects on clinical outcomes (p<0.001) (Figure 2A ).', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.03.25.20037721 doi: medRxiv preprint Patients in the non-severe group showed significantly better survival compared with those in the severe and critical groups ( Figure 2B ).', 'Patients given hypnotics showed significant favorable survival compared with the non-hypnotics ( Figure 2C ), and patients with positive rRT-PCR results showed significantly poorer survival compared with those with negative rRT-PCR ( Figure 2D ).', 'In contrast to a previous study, 12 most patients with COVID-19 in the severe group of our series showed favorable clinical outcomes, at approximately the same frequency as in non-severe cases (84.9% vs 86.8%), and survival analysis demonstrated consistently higher survival rates in nonsevere and severe cases than in critical cases.', 'Although previous studies failed to show that smoking was a risk factor for COVID-19, 9, 14 multivariate analysis in our study demonstrated that smoking was an independent risk factor for unfavorable outcome.', 'Otherwise, we confirmed findings from other studies 10,12,13 that age over 65 years and leukocytosis with left shift were associated with poorer clinical outcome.', 'Zopiclone, a commonly prescribed nonbenzodiazepine soporific, was significantly associated with improved clinical outcome.', 'Patients taking hypnotics showed better outcome at the same disease stage than those not taking hypnotics.', 'For patients in the more severe disease groups, the improvement effect was even more pronounced.', 'Also, in analyzing the effect of hypnotics on rRT-PCR-positive and rRT-PCR-negative patients separately, we found hypnotics had more striking effect on the former.', 'Moreover, hypnotics were identified as an independent factor in the risk model that contributed to better clinical outcomes.', 'Also, patients administered hypnotics had a better survival rate.', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.03.25.20037721 doi: medRxiv preprint Patients usually showed strong anxiety, sleep deficiency and oxygen insufficiency during disease progression, which will lead to the metabolic dysregulation 18, 19 and immune system abnormalities 20 .', 'Better sleep quality and stress reduction could be one partial reason for prescribing hypnotics to COVID-19 patients.', 'Dimitrov et al indicated that sleep can exert some immune-supportive effects and potentially enhance an effective T cell response, and it has high relevant with some specific sleep disorders or impaired sleep, such as depression and chronic stress.', 'In addition, the superior efficacy of zopiclone may be due to enhanced gamma aminobutyric acid (GABA) signaling.', 'That is, zopiclone can interact with GABAA, and GABAA receptor can magnify responses to GABA.', 'Up till now, several description studies have mentioned the non-effective function of current medication treatment no matter which stages or outcomes was 10, 12, 24 , and it was accord with our study analysis.', \"By specifically comparing the standard treatment effect at the same disease status for each treatment ( Figure S2 ), we didn't see any standard therapy could improve clinical outcome in the study.\", 'However, since only about 25% of patients in our study took hypnotics, we assume that self-healing could be the major reason for the high recovery rate of patients in the non-severe and severe disease groups.', 'That is, COVID-19 is most likely a selflimited disease in the majority of patients.', 'Both rRT-PCR-confirmed COVID-19 patients and clinically diagnosed patients who were rRT-PCR negative were included in this study.', 'Due to the burgeoning epidemic and high .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'Since all patients in our study were tested by the same experienced team using the same rRT-PCR protocol, we believe the major reason for the negative rRT-PCR results in our patient series was due to the low concentration of virus in the throat, which may indicate that patients with negative rRT-PCR test might be less likely to infect other people.', 'We found that only a small portion of patients (less than 10%) with negative rRT-PCR had unfavorable outcomes.', 'In performing follow-up rRT-PCR on patients in the severe disease group with abnormal CT, we found 23 cases whose first test was negative and later tests were positive.', 'We believe the .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.03.25.20037721 doi: medRxiv preprint inclusion of rRT-PCR-negative patients with clinically compatible presentation of COVID-19 will help guide clinicians in the care of such patients.', 'Higher BMI (\\uf0b330), hyperglycemia and diabetes, and cardiovascular disease were distinct risk factors for unfavorable clinical outcomes.', 'Angiotensin-converting enzyme-2 (ACE2), which serves as a cell-entry receptor for SARS CoV-2, 27 plays a protective role for both diabetes and cardiovascular diseases.', '28, 29 Kuba and colleagues demonstrated that SARS CoV downregulates ACE2', 'We found that abnormally high hypersensitive troponin I was an independent predictor for poor clinical outcome.', 'Increased troponin can enhance coagulation activation.', '31 In patients with COVID-19, immune damage to the hematopoietic system, ischemic hypoxia-reperfusion injury, and drugs can cause coagulation disorders.', \"8, [31] [32] [33] [34] We speculate that increased troponin will induce dysfunction of coagulation and thrombus formation with possible pulmonary embolism, which would further aggravate the patient's condition.\", 'There were some limitations in our study.', 'Incomplete laboratory test results in some patient records may have caused deviations in statistical analysis.', 'Except for hypnotics, we found that all treatments were ineffective and many treatments showed unwanted side effects, including liver injury.', '35-37 Although we did not conduct separate analysis for rRT-PCR-positive and rRT-PCR-negative patients, our multivariate analysis identified eight independent risk factors, which were independent of the rRT-PCR result.', 'Although the vast majority of patients recovered, approximately 20% of our hospitalized patient cohort had unfavorable clinical outcomes.', 'To what extent chronic respiratory insufficiency or other organ system sequelae occur in COVID-19 patients will require careful .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.03.25.20037721 doi: medRxiv preprint and prolonged follow-up studies.', 'So far, it seems there is no effective standard treatment.', 'However, we have found that using hypnotics could significantly improve clinical outcome of COVID-19.', 'We also found that some novel risk factors that could predict patient outcome, which can help in early decision making for improving treatment outcomes of COVID-19 patients.', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.03.25.20037721 doi: medRxiv preprint .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity. .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'year-old male patient, who progressed from the non-severe to critical disease group, and died.', 'A1 (day 1), A2 (day 4), A3 (day 9): below the pleura are scattered shadows of frosted glass, large sheet diffuse paving stones in both lungs, and extensive consolidation of both lungs with thickening of interlobular stroma repetitively.', 'B1-B3, CT images of a 44-year-old female patient, who progressed from the critical to non-severe disease group.', 'B1 (day 3) exhibiting extensive consolidation of both lungs; B2 (day 9) exhibiting frosted hyaline change and paving stone signs.', 'B3 (day 20) showing significant resolution of ground-glass opacities and subpleural cord changes.', 'The association of clinical outcome with three diagnosis status: Non-severe, Severe, and Critical under the treatment A)', 'Kaletra, B) Interferon, C) Invasive ventilation, D) Non-invasive ventilation.', 'The percentages are calculated by the number of each outcome group (Unfavorable or Favorable) divided by the total number at each diagnosis status with (Yes) using or not (No']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['The COVID-19 pandemic has affected hundreds of thousands of patients and poses a major health threat on an international scale.', 'The CV community will play a key role in the management and treatment of patients affected by this disease, and in addition in providing continuity of care to non-infected patients with underlying CVD.', 'In the coming months, efforts towards evaluating new therapies will be crucial to the treatment of this virus, and as this process develops, further appreciation of the intricate interplay between COVID-19, CVD, and the various stakeholders involved including patients, health care workers, and health care systems will be crucial to improving outcomes in at-risk and infected patients.', 'Prospective randomized clinical trials and cohort studies are ongoing and will be important to helping treat patients affected by this virus.', 'ACE2 inhibits production of angiotensin II, which is a potent pro-inflammatory agent in the lung and leads to lung injury.', 'RAAS blockers both directly inhibit production of angiotensin II and may also increase levels of ACE2, thereby indirectly inhibiting angiotensin II (bottom panel).', 'Only a few studies, with single center experience have presented data to date, which limits the generalizability of the findings, and the confidence in the point estimates.']}\n", - "{'sentences': ['The potential of low molecular weight heparin to mitigate cytokine storm in severe covid-19 patients: a retrospective clinical study', 'Background On March 11, 2020, the World Health Organization declared its assessment of COVID-19 as a global pandemic.', 'Effective therapeutic drugs are urgently needed to improve the overall prognosis of patients, but currently no such drugs are available.', 'Methods The basic information, complete blood count, coagulation profile, inflammatory cytokines and serum biochemical indicators in 42 patients with COVID-19 (21 of whom were treated with low molecular weight heparin (LMWH), and 21 without LMWH) were retrospectively analyzed to compare and evaluate the effect of LMWH treatment on disease progression.', 'Findings 42 patients with COVID-19 treated at the hospital between February 1 and March 15, 2020 were selected for the study, of which 21 underwent LMWH treatment (Heparin group), and 21 did not (Control), during hospitalization.', 'The changes in lymphocyte% in patients in the heparin group before and after LMWH treatment were significantly different to those in the control group (p=0.011).', 'The changes in D-dimer and fibrinogen degradation products (FDP) levels in the heparin group before and after LMWH treatment were significantly different to those in the control group (p=0.002;p=0.035).', 'In the heparin group, IL-6 levels were significantly reduced after LMWH treatment (p=0.006).', 'In addition, the changes in IL-6 levels in the heparin group before and after LMWH treatment were significantly different to those in the control group (p=0.031).', 'Interpretation In this study, we found that LMWH']}\n", - "{'sentences': ['While most patients having COVID-19 pneumonia will have a mild disease course, some patients will develop severe respiratory distress, sepsis, and septic shock.', 'Coagulopathy commonly occurs in sepsis and may predict outcomes in severe COVID-19 [4] .', 'Han et al. reported disturbed coagulation function in patients infected with SARS-CoV-2 as compared to healthy controls, including elevated D-dimer, fibrin/fibrinogen degradation products, and fibrinogen levels [5] .', 'Additionally, two different studies by Zhou et al. [6] and Tang et al. [7] recently reported a positive correlation between elevated D-dimer levels on admission and in-hospital COVID-19 mortality, raising questions regarding potentially unknown pulmonary embolism and outlining the possible role of CT pulmonary angiography in patients with COVID-19 and rapid clinical worsening.', 'On the other hand, taking the same patients to the CT suite several times to perform non-contrast and subsequently contrast-enhanced CT may be logistically challenging for radiology departments since time-consuming infection control measures are required.', 'Fig. 1 shows an example of a 75-year-old patient admitted at our institution due to low-grade fever, asthenia, chills, and odynophagia.', 'Upon physical examination, coarse end-inspiratory crackles were noted at the right lung base.', 'Respiratory rate was 16/min, and oxygen saturation 95% on room air.', 'Blood sampling showed leukopenia (3.3 G/ L), lymphopenia (0.79 G/L), thrombopenia (129 G/L), and normal hemoglobin levels (157 g/L).', 'Nasopharyngeal sampling was positive for SARS-CoV-2.', 'He suddenly developed dyspnea and tachypnea on day 4 after admission, prompting further investigation with CT pulmonary angiography.', 'The CT signs were those of multifocal ground-glass opacities predominantly located at the periphery of all five lobes, right basal subpleural fibrotic streaks, vacuolar sign, and vascular dilation sign consistent with COVID-19 pneumonia.', 'Still, the CT pulmonary angiography -an established diagnostic tool [8] -also revealed right middle lobar segmental acute pulmonary embolism.', 'The patient received prophylactic low molecular weight heparin (LMWH) from day 3 after admission (Enoxaparin 40 mg once daily by subcutaneous injection).', 'Even though the etiology of acute pulmonary embolism associated with COVID-19 pneumonia remains unclear, adequate treatment can be initiated immediately considering the outcome of untreated pulmonary embolism.', 'The incidence of acute pulmonary embolism in patients diagnosed with COVID-19 is currently unknown; however, the available biological and clinical data raise concerns about unsuspected pulmonary embolism and calls for research on this specific topic.', 'Perhaps the only report on SARS-CoV-2 infection and CT pulmonary angiography that has come out recently is by Chen et al., and clearly shows that patients with COVID-19 are at risk of acute pulmonary embolism [9] .', 'Given the large number of COVID-19 patients seeking medical care, the international society on thrombosis and haemostasis (international society on thrombosis and haemostasis) advocates the use of laboratory tests, including D-dimers, prothrombin time, and platelet count to stratify patients at risk of adverse outcome and who need hospital admission [10] .', 'According to the same interim guidance proposed by the international society on thrombosis and haemostasis, all in-patients should receive antithrombotic prophylaxis with LMWH', 'In summary, patients requiring hospital admission for COVID-19 pneumonia should receive prophylactic LMWH to prevent thromboembolism, in the absence of contraindication.', 'Furthermore, CT has quickly become a cornerstone in both the diagnostic workup and follow-up of SARS-CoV-2 infection and is usually performed without intravenous contrast agent injection.', 'Though, patients with known COVID-19 disease may have acute pulmonary embolism.', 'In the case of elevated D-dimer levels on admission or sudden clinical worsening, CT pulmonary angiography should be considered since pulmonary embolism is a life-threatening but potentially treatable condition.']}\n", - "{'sentences': ['In December 2019 a new form of pneumonia was observed in the Chinese province of Hubei.[1] The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was subsequently identified as responsible of this condition, defined coronavirus disease (COVID-19).[2] The virus has now spread outside Chinese borders with 82,297 cases and 2,804 deaths worldwide at the 26th of February.[3] After infection, symptoms appear after an incubation time of 3-5 days, with 80% of those infected developing a mild disease, 15% a severe disease and 5% will require support in intensive care unit (ICU).[4] Overall, the estimated case-fatality rate is comprised between 0.4% and 2.9% and the basic reproduction number is approximately 3.28.[4,5] SARS-CoV-2 is a new pathogen for humankind and any type of immune protection exist, thus everybody can be potentially infected.', 'Moreover, no primary prophylaxis measures (vaccination) nor effective treatments are available.', 'If the above represented percentages are applied to the worldwide populations, it appears clear why any measure should be considered to avoid a further diffusion of the virus and prevent the saturation and collapse of health systems and the most catastrophic pandemic since 1919 Spanish flu.', 'Isolation of those affected and the use of personal protective equipment (PPE) are the mainstay to block transmission of this pathogen, which is presumed through respiratory droplets.', 'A 14 days quarantine is applied to subjects coming from endemic areas or who had contact with confirmed cases.', 'It is assumed that, if in this period the subject does not develop any sign or symptoms compatible with COVID-19, he is not infected and thus the quarantine can be removed, and the subject returned to the community.', 'Domiciliary quarantine of 14 days since a positive test is applied also for patients with a diagnosed mild disease who did not need medical support.', 'These rules are effective in controlling infections in the community, but several doubts arise when it is necessary to transpose them in the hospital setting.', 'Hospitals are indeed a delicate place in epidemics: they collect fragile persons who can be exposed to the virus and are subsequently readmitted to the community thus spreading the infection.', 'Indeed, the ongoing outbreak in Northern Italy has been linked to a single infected patient who accessed to a community hospital where he transmitted the virus to several other patients and health-care operators.[6] Moreover, the isolation of patients in the hospital setting impose a significant burden in terms of PPE used by the health-care operators, space dedicated and time employed in their management.', 'Even more complex is the situation of patients in ICU, where viral spreading is facilitated by endotracheal tubes and manoeuvres performed on the respiratory tract.', 'Therefore, a clear definition of the infectiousness timing and intensity of viral spreading is mandatory to alleviate the burden on the health-care system.', 'Unfortunately, the data available on the topic are scarce and composed only of measurements of viral shedding, without an assessment of the infectivity.', 'Kim et al.[7] assessed the viral load kinetics of SARS-CoV-2 in upper and lower respiratory tract materials in the first two confirmed patients in Korea.', 'They employed real-time reverse transcriptase polymerase chain reaction (rRT-PCR) to detect SARS-CoV-2 and converted cycle threshold (CT) values of rRT-PCR into RNA copy number.', 'The detection limit of rRT-PCR was 2,690 copies/mL. Overall, viral load above detection limit was detected until 14 and 25 days after symptoms onset and for 13 and 11 days after the first detection, respectively.[7] Of note, both patients received treatment with lopinavir/ritonavir.', 'Instead, Zou and colleagues analysed viral load in repeated nasal and throat swabs obtained from the 17 symptomatic patients.[8] They also employed rRT-PCR and considered a CT']}\n", - "{'sentences': ['Objectives: Comorbidities have significant indications for the disease outcome of COVID-19, however which underlying diseases that contribute the most to aggravate the conditions of COVID-19 patients is still largely unknown.', 'SARS-CoV-2 viral clearance is a golden standard for defining the recovery of COVID-19 infections.', 'To dissect the underlying diseases that could impact on viral clearance, we enrolled 106 COVID-19 patients who were hospitalized in the Zhongnan Hospital of Wuhan University, Wuhan, China between Jan 5 and Feb 25, 2020.', 'Methodology: We comprehensively analyzed demographic, clinical and laboratory data, as well as patient treatment records.', 'Survival analyses with Kaplan-Meier and Cox regression modelling were employed to identify factors influencing the viral clearance negatively.', 'Results: We found that increasing age, male gender, and angiotensin-converting enzyme 2 (ACE2) associated factors (including hypertension, diabetes, and cardiovascular diseases) adversely affected the viral clearance.', 'Furthermore, analysis by a random forest survival model pointed out hypertension, cortisone treatment, gender, and age as the four most important variables.', 'Conclusions: We conclude that patients at old age, males, and/or having diseases associated with high expression of ACE2']}\n", - "{'sentences': ['Protocol for a randomized controlled trial testing inhaled nitric oxide therapy in spontaneously breathing patients with COVID-19', '[{\\'text\\': \"Introduction: the current worldwide outbreak of Coronavirus disease 2019 due to a novel coronavirus (SARS-CoV-2) is seriously threatening the public health.', 'The number of infected patients is continuously increasing and the need for Intensive Care Unit admission ranges from 5 to 26%.', 'The mortality is reported to be around 3.4% with higher values for the elderly and in patients with comorbidities.', 'Moreover, this condition is challenging the healthcare system where the outbreak reached its highest value.', 'To date there is still no available treatment for SARS-CoV-2.', 'Clinical and preclinical evidence suggests that nitric oxide (NO) has a beneficial effect on the coronavirusmediated acute respiratory syndrome, and this can be related to its viricidal effect.', \"The time from the symptoms' onset to the development of severe respiratory distress is relatively long.\", 'We hypothesize that high concentrations of inhaled NO']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Currently available intravenous immunoglobulin (Gamunex®-C and Flebogamma® DIF) contains antibodies reacting against SARS-CoV-2 antigens', 'Background: There is a critical need for effective therapies that are immediately available to control the spread of COVID-19 disease.', 'In this study, we assessed currently marketed intravenous immunoglobulin (IVIG', 'Methods: Gamunex ® -C and Flebogamma ® DIF (Grifols) IVIG were tested against several betacoronaviruses antigens using ELISA techniques: HCoV (undetermined antigen), HCoV-HKU1 (N protein), SARS-CoV (culture lysate), MERS-CoV (N protein; S1 protein/RBD; S protein), and SARS-CoV-2 (protein/RBD; S protein), and SARS-CoV-2', 'Gamunex-C and Flebogamma DIF IVIG contain antibodies reacting against SARS-CoV-2 antigens.', 'These preparations may be useful for immediate treatment of COVID-19 disease.', 'The need for readily available effective therapies to combat SARS-CoV-2 infection is compelling.', 'In this study, we considered whether IVIG treatment could contribute to COVID-19 disease management.', 'To test this hypothesis, known currently available IVIG products, Gamunex-C and Flebogamma DIF, were tested for cross-reactivity with SARS-CoV-2 and other coronaviruses, including SARS-CoV and MERS-CoV. We found significant cross-reactivity to components of all tested viruses including the S1 protein of SARS-CoV-2, the protein responsible for virion attachment to the host cell and neutralization [12] .', 'The consistency of our cross-reactivity results among the SARS-CoV-2, SARS-CoV and MERS-CoV viruses, is noteworthy.', 'This replicates with the new SARS-CoV-2, the cross-reactivity already reported for SARS-CoV / MERS-CoV with other human betacoronaviruses [8] [9] [10] .', 'Importantly, Gamunex-C and Flebogamma DIF were confirmed to contain antibodies reacting against SARS-CoV-2 antigens, which could be important in the quest for an immediate therapy for COVID-19.', 'ELISA results for the undetermined antigen of HCoV were also mostly positive.', 'This was in contrast to HCoV-HKU1, which had negative reactivity.', 'HCoV-HKU1 was discovered in 2005 in Hong Kong and, although it did not result in an outbreak and had only restricted spread, this virus is probably still circulating in the population [13, 14] .', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.07.029017 doi: bioRxiv preprint 6', 'However, negativity of an IVIG reaction using a single ELISA coronavirus kit does not mean that such IVIG does not contain antibodies against this pathogen.', 'ELISA sensitivity relies on factors such as the antigen used, the sequence, the organism used to produce it, and the amount of material coated.', 'ELISA results should only be compared qualitatively, since comparison of the results between different kits is difficult based on differences in sensitivity, and there is no gold standard for quantification.', 'In addition, there is scarcity of tests for common coronaviruses.', 'It has been observed that patients that develop a more severe clinical course of SARS-CoV-2 infection have higher plasma levels of proinflammatory cytokines, suggesting a possible cytokine storm associated with the disease severity [15] .', 'IVIG products have been demonstrated to be effective in the treatment of inflammatory disorders [16] .', 'To date, a number of possible mechanisms for the immunomodulatory and antiinflammatory effects of IVIG therapy have been described [17, 18] , including anticomplement effects [19] , anti-idiotypic neutralization of pathogenic autoantibodies [20] , immune regulation via an inhibitory Fc receptor [16, 21] , enhancement of regulatory T cells [22] and inhibition of Th17 differentiation [23] .', 'Thus, IVIG may mediate a wide variety of biological and immunomodulatory effects via various types of blood cells [23] .', 'Altogether, these known immunomodulatory effects of IVIG products could be beneficial in COVID-19 disease management.', 'Anecdotally, there was a case series report describing a positive effect of high dose IVIG in three patients with COVID-19 [24] .', 'It should be noted that IVIG products are generally deemed safe and welltolerated.', 'Most of their adverse effects are mild and transient [25] .', 'In conclusion, we consistently observed cross-reactivity of IVIG products with SARS-CoV-2, SARS-CoV and MERS-CoV using ELISAs from different manufactures.', 'This evidence supports the presence of anti-SARS-CoV-2 cross-reacting antibodies in these IVIG preparations.', 'These results together with the known immune properties of IVIG, suggest a potential positive contribution of currently available IVIG products to COVID-19 disease management.', 'Further steps to confirm the functionality of IVIG antibodies such are neutralization studies are warranted.', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.07.029017 doi: bioRxiv preprint']}\n", - "{'sentences': ['We have analyzed the cell-type-specific expression of the renin-angiotensin system (RAS) components across 141 cell types or subtypes as defined by single-cell RNA-seq (scRNAseq) analysis.', 'ACE2, one of the components of RAS, also facilitates SARS-CoV-2 entry into cells in cooperation with its associated protease TMPRSS2.', 'Therefore, our analysis also contributes to the understanding of SARS-CoV-2 infection, spreading of the virus throughout the body, and potential viral interference with RAS', 'The COVID-19 pandemic caused by SARS coronavirus 2 (SARS-CoV-2) has created a global health emergency with more than a million confirmed cases as of April 4, 2020 1 .', 'For cellular entry, SARS-CoV-2 relies on the interaction of its glycosylated viral spike (S) protein with the host membrane-bound aminopeptidase angiotensin-converting enzyme 2 (ACE2).', 'Subsequently, transmembrane protease serine 2 (TMPRSS2) cleaves S and/or ACE2 protein, which facilitates the fusion of viral and cellular membranes 2 .', 'The secreted and systemically distributed protease renin (REN) activates RAS by proteolytically cleaving plasma angiotensinogen (AGT) to produce the 10-amino-acid (aa) hormonal peptide, angiotensin I (Ang I).', 'Subsequently, Ang I is processed to the 8-aa Ang II by the metallopeptidase angiotensin-converting enzyme (ACE) present on the surface of pulmonary and kidney endothelial cells.', 'Ang II is the active peptide in RAS triggering vasoconstriction, sodium retention, and fibrosis and signals by binding to its receptor AGTR1 or AT1R.', 'ACE2, a metallopeptidase paralogous to ACE, counters the activity of ACE by digesting Ang II to the 7 aa']}\n", - "{'sentences': ['Here we report the isolation and characterization of two potently neutralizing single-domain 273 antibodies from a llama immunized with prefusion-stabilized MERS-CoV and SARS-CoV-1 274 spikes.', 'These VHHs bind to the spike RBDs with high affinity and are capable of neutralizing S 275 pseudotyped viruses in vitro.', 'To our knowledge, the isolation and characterization of SARS-276', 'CoV-1 S-directed VHHs have not been described before.', 'Several MERS-CoV S-specific VHHs Figure 7A ).', 'The epitope of SARS VHH-72 does 287 not significantly overlap with the epitopes of any previously described antibodies other than that 288 of the recently described CR3022, which is also capable of binding to the RBDs of both SARS-289', 'CoV-1 and SARS-CoV-2 S (Hwang et al., 2006; Pak et al., 2009; Prabakaran et al., 2006; Walls 290 et al., 2019; Yuan M, 2020) Figure 7B ).', 'However, unlike SARS VHH-72, CR3022 does not 291 prevent the binding of ACE2 and it lacks neutralizing activity against SARS-CoV-2 (Tian et al., 292 2020; Yuan M, 2020) .', 'Because SARS VHH-72 binds with nanomolar affinity to a portion of the 293 SARS-CoV-1 S RBD that exhibits low sequence variation, as demonstrated by its cross-294 .', 'CC-BY-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.26.010165 doi: bioRxiv preprint reactivity toward the WIV1-CoV and SARS-CoV-2 RBDs, it may broadly bind all S proteins 295 from SARS-CoV-like viruses.', 'We show that by engineering a bivalent VHH-72-Fc construct, we 296 are able to compensate for the relatively high off-rate constant of the monovalent SARS VHH-297 72.', 'This bivalent molecule expresses well in transiently transfected ExpiCHO cells (~300 mg/L) 298 and is capable of potently neutralizing SARS-CoV-2 S pseudoviruses in vitro.', 'Due to the inherent thermostability and chemostability of VHHs, they have been 300 Animal Experiments of the Vrije Universiteit Brussel (permit No. 13-601-1).', 'Blood was collected 351 5 days after the last immunization for the preparation of lymphocytes.', 'Total RNA from the 352 peripheral blood lymphocytes was extracted and used as template for the first strand cDNA 353 synthesis with oligo dT primer.', 'Using this cDNA, the VHH encoding sequences were amplified 354 by PCR and cloned between the PstI and NotI sites of the phagemid vector pMECS.', 'In the pMECS 355 vector, the VHH encoding sequence is followed by a linker, HA and His6 tag 356 (AAAYPYDVPDYGSHHHHHH).', 'Electro-competent E.coli TG1 cells were transformed with the 357 recombinant pMECS vector resulting in a VHH library of about 3 x 10 8 independent transformants.', 'The resulting TG1 library stock was then infected with VCS M13 helper phages to obtain a library 359 of VHH-presenting phages.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.26.010165 doi: bioRxiv preprint milk powder in PBS and 50 μL of the periplasmic extract was added to the wells.', 'Bound VHHs 409', 'were detected with anti-HA (1/2,000, MMS-101P Biolegend) mAb followed by horseradish 410 peroxidase (HRP)-linked anti-mouse IgG (1/2,000, NXA931, GE Healthcare).', 'Periplasmic 411 fractions, for which the OD450 value of the antigen coated wells were at least two times higher than 412 the OD450 value of the BSA coated wells, were considered to be specific for the coated antigen and 413 selected for sequencing.', 'The selected clones were grown in 3 mL of LB medium with 100 μg/mL 414 ampicillin.', \"The DNA of the selected colonies was isolated using the QIAprep Spin Miniprep kit 415 (Qiagen) and sequenced using the MP057 primer (5'-TTATGCTTCCGGCTCGTATG-3').\"]}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['To explore longitudinal change patterns of key laboratory tests in patients with COVID-19, and to identify independent prognostic factors by examining the associations between laboratory findings and outcomes of patients.', 'The multicenter study prospectively included 59 patients with COVID-19 treated at Jilin province from January 21, 2020 to May 5, 2020.', 'Laboratory tests were included haematological, biochemical, and immunological tests.', 'Laboratory findings, the characteristics of epidemiological and demographic data were extracted from electronic medical records.', 'Eosinopenia was shown in 52.6% cases at onset, and the average value of eosinophil continued to significantly increase thereafter.', 'Lymphopenia was found in 40.4% cases at onset, and the average value of lymphocyte was slowly elevated after day 5.', 'Thrombocytopenia was shown in 12.3% cases at onset, and the average value of mean platelet volume was decreased sharply after day 7.', 'The values of aspartate aminotransferase, lactate dehydrogenase, creatine kinase, creatinine kinase-muscle/brain activity, and cardiac troponin I, serum cardiac markers, were beyond the upper limit of RI from 6.1% to 30.6% at onset.']}\n", - "{'sentences': ['Abnormal lymphocyte variables were common among patients with the new respiratory illness known as SARS-COV-2, which has caused a pandemic worldwide.', 'Lymphopenia, the depletion of T lymphocyte subsets, and the PLD may be associated with disease severity linked to mortality.', 'Studies of its effect on various body systems are crucial to the understanding of this disease.', 'Due to one transferred patient 7 in the study who was from other hospital co-infected with influenza A virus on day 9 of the observation, all other nine patients were tested for 9 additional respiratory pathogens.', 'Patient 1-6 were already treated with oseltamivir and lopinavir/ritonavir at admission and all tested negative.', 'Patient 8 was tested positive IgM for influenza A virus and oseltamivir and lopinavir/ritonavir treatment were added on day 15 of All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', '18.20038513 doi: medRxiv preprint 10 observation.', 'Patient 1 and 2 were tested positive IgM and IgG for influenza A virus on day 25-30 of observation without treatment of antiviral therapy due to poor renal function.', 'The sensitivity of COVID-19 IgG and IgM assay tested on day 15-30 of the observation was 90% and 100% for non-survivors, suggesting that B cell function is still intact in non-survivors.']}\n", - "{'sentences': ['We identified 174 potential SARS-CoV-2 vaccine candidate peptides, out of which 48 have been previously deposited in IEDB following various studies (Qu et al. 2019; Blicher et al. 2005; Sylvester-Hvid et al. 2004; Harndahl et al. 2006; Sidney et al. 2006; Ishizuka et al. 2009 ) .', 'The majority of the previously deposited peptides were measured in one or multiple affinity assays and reached low Kd (<50 nM) values, indicating strong affinity.', 'Additionally, 9 of these peptides were previously measured in another stability assay and were recognised as stable binders , independently confirming our approach and measurements.', 'Of the 48 peptides deposited in IEDB, two (FLLPSLATV https://www.iedb.org/epitope/16743, FLNRFTTTL https://www.iedb.org/epitope/16786) have previously been assessed for their ability to provoke T cell responses, with negative T cell responses for both.', 'To further assess the potential of the SARS-CoV-2 epitopes we explored their overlap with T cell-confirmed epitopes from SARS that are deposited in the IEDB.', 'We identified 4 peptides within our candidates that are represented within these confirmed epitopes as partial motifs.', 'In conclusion, we make freely available the identities of 174 COVID-19 epitopes that we have predicted and validated in vitro to be HLA-binding.', 'We hope that this contribution will aid the development of a vaccine against SARS-CoV-2.', 'We performed a benchmark analysis of 20 tools on 777 peptides that were predicted by state-of-the-art prediction tools from netMHC to be binders, and revealed high false positive rates for all benchmarked tools.', 'We observed improved performance after training our own prediction tool PrdX 1.0 on allotype A*02:01 using in-house generated stability data.', 'Our findings suggest that the performance of current state-of-the-art epitope prediction tools are impacted by the varying quality of publicly available data.', 'Here we benchmark a number of tools to identify epitopes for SARS-CoV-2 virus, and validate via stability assay the binding of candidate epitopes to 10 allotypes of HLA class I and one allotype of HLA class II.', 'We find that the false positive rate is high for all tested tools when testing for predicted HLA-binding peptides from SARS-CoV-2 virus.', 'This creates a challenge for vaccine development efforts, especially for the design of epitope vaccines, where only a limited number of epitopes may be included.', 'Furthermore, it highlights the risk for failed vaccine design (for any pathogen or disease) if predicted HLA-binding protein regions in reality do not bind and allow immune presentation and response.', 'We observed, remarkably, that all tools tested performed poorly for HLA-A*02:01, which is the allotype with most training data available (Kim et al. 2014) .', 'Based on our observations we .', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', '/2020 hypothesise that publicly available training data is not of high enough quality.', 'This is supported by the fact that AUC and Spearman correlations indicate that performance seems to correlate with the allotypes and not the tools; thus suggesting that either the training data or the difficulty of modelling the allotype is responsible for poor predictions.', 'To test the hypothesis that training data is limiting for tool performance, we trained a vanilla NN on only 2,193 historic in-house stability measurements, and found that our model outperformed all tested prediction tools in this setting.', 'This observation could also be explained by more similar data distributions between test and training data for PrdX 1.0.']}\n", - "{'sentences': ['Since the Covid-2019 outbreak, several milestone papers have been published to examine the particularity of SARS-CoV-2 spike protein and its putative interaction with ACE2 as a receptor [20] .', 'In the current study, we focused our analysis on the interface segments of SARS-CoV-2 spike RBD interacting with ACE2 from different species by estimating interaction energy profiles.', 'We have studied the effect of eight variants of ACE2 in order to detect polymorphisms that may increase or decrease the virulence in the host.', 'We concluded that if ACE2 is the only route for the infection in humans, variants interacting physically with RBD are not likely to disrupt the formation of the complex and would have a marginal effect on the affinity.', 'Therefore, it is unlikely that any form of resistance to the virus, related to .', 'CC-BY-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.04.976027 doi: bioRxiv preprint the ACE2 gene, exists.', 'However, this analysis merits to be investigated in depth in different ethnic groups for a better assessment of the contribution of genetic variability in host-pathogen interaction.', 'The binding of SARS-CoV-2 RBD to different forms of ACE2 shows similar values compared to SARS-CoV which is in agreement with the ability of the virus to cross the species barrier.', 'However, although we estimated low Kd value between SARS-CoV RBD and Gallus gallus ACE2, there have been no reported cases of SARS-CoV isolated from chicken.', 'On the other hand, while Kd is high for SARS-CoV RBD interacting with porcine ACE2, there are only few reported cases of such type [15] .', 'Indeed, host-pathogen interaction is a complex process unlikely to be controlled only by the binding of the spike protein with ACE2 [3] .', 'For model animals where Kd values are very low, ACE2 analysis may play a key role in targeting the main animal reservoir of SARS-CoV-2.', 'For high Kd values, other factors might regulate the infection including the implication of different receptors or the response of the immune system but that does not mean that the infection is unlikely to occur.', 'Whole-genome phylogenetic analysis of the different isolates included in this study is consistent with previous works that place the Wuhan-Hu-1 isolate close to Bat-SL-CoVZC45 and Bat-SL-CoVZXC21 isolates [10, 17] within the Betacoronavirus genus.', 'The use of RBD sequences, however, places the virus in a clade that comprises SARS-CoV related homologs including isolates from Bat and Civet.', 'The clade swapping as seen in figure 1A , seems also to occur for RaTG13 and Rm1 isolated from bat.', 'This is expected as the use of different phylogenetic markers may considerably affect the topology of the tree.', 'However, given the functional implication of the spike RBD in host-pathogen infection, we have raised the question about where the virus obtained its RBD binding interface.', 'The binding of the spike glycoprotein to ACE2 receptor requires a certain level of affinity.', 'In the case where the RBD evolves from an ancestral form closer to that of Bat-SL-CoVZC45 and Bat-SL-CoVZXC21, we expected a decrease of the binding energy through the evolution process following incremental changes in the RBD.', 'In such a scenario, we presume that there are other intermediary forms of coronavirus that describe such variation of the binding energy to reach a level where the pathogen can cross the species barriers and infect .', 'CC-BY-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.04.976027 doi: bioRxiv preprint humans with high affinity toward hACE2.', 'On the other hand, our results show that the binding energy and the interface sequence of SARS-CoV-2 RBD are closer to SARS-CoV related isolates (either from Human or other species).', 'Therefore a recombination event involving the spike protein that might have occurred between SARS-CoV and an ancestral form of the current SARS-CoV-2 virus might be also possible.', 'This will allow for the virus to acquire a minimum set of residues for the interaction with hACE2.', 'The recombination in the spike protein gene has been previously suggested by Wei et al in their phylogenetic analysis [4] .', 'Thereafter, incremental changes in the binding interface segment will occur in order to reach a better affinity toward the receptor.', 'One of these changes may involve P499 residue which substitution to threonine seems to drastically destabilize the interface segment and has a distant effect.', 'Moreover, the decomposition of the interaction energy showed that 5 out of 6 hotspot amino acids in SARS-CoV-2 have their equivalent in SARS-CoV including N501.', 'Contrary to what Wan et al [17] have stated, the single mutation N501T does not seem to enhance the affinity.', 'Rather, the residue Q493 might be responsible for such higher affinity due to a better satisfaction of the Van der Waals by the longer polar side chain of asparagine.', 'Indeed, when we made the same analysis while mutating Q493 to N493, the favorable contribution decreases from -2.55 kcal/mol to a non significant value of -0.01 kcal/mol, thus supporting our claim.', 'No major divergence of the interaction interface of SARS-CoV-2 RBD with hACE2 was noticed from the similarity matrix analysis.', 'This suggests that the molecular elements required for the binding with the receptor might also be involved in the interaction with other orthologous forms of ACE2 and that these elements are not optimized specifically for the human form.', 'Therefore, it is unlikely that the interface of RBD from SARS-CoV-2 is a result of human intervention aiming to increase the affinity toward ACE2.', 'For example, residue E484 contributes unfavorably to the binding energy with 2.24 kcal/mol due to an electrostatic repulsion with E75 from hACE2.', 'This residue is an apparent choice for engineering a protein-protein complex with high affinity by substituting E484 with a polar residue.', 'It is, however, noteworthy that the lesser homogeneity of the nodes of SARS-CoV-2 group, in comparison to SARS-CoV, may suggest a higher tolerance .', 'CC-BY-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.04.976027 doi: bioRxiv preprint for the mutation of the new virus which would allow it to cross the species barrier more easily and to efficiently optimize the interaction in the host.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['This is a descriptive study on the clinical characteristics and obstetric and neonatal outcomes of pregnant women infected with COVID-19.', 'At present, few cases of infected pregnant women have been reported.', 'This study is one of the first to report the maternal, fetal, and neonatal outcomes of pregnant women with COVID-19 who are in their third trimesters.', 'We have presented seven cases of COVID-19 in late pregnancy with good outcomes for both mother and infant.', 'Human coronaviruses are among the most common pathogens that cause respiratory infection.', 'SARS-CoV-2 has enveloped virions that measure about 50-200 nm in diameter with a single positive-sense RNA genome.', '11 COVID-19 is transmitted through respiratory droplets, physical contact, and aerosols, and there is evidence of human-to-human transmission.', '[12] [13] None of our pregnant patients had a history of exposure to Huanan Seafood Wholesale Market, but all of them lived in the epidemic area.', 'In terms of clinical manifestations, the common symptoms of these pregnant women at the onset of COVID-19 were fever and cough, and the less common symptoms were diarrhoea and shortness of breath.', 'Laboratory tests showed that absolute lymphocyte counts were reduced, C-reactive protein, erythrocyte sedimentation rate, and D-dimer were increased, and leucocytes were normal in most of the seven pregnant patients.', 'In our study, these patients showed a pattern of clinical characteristics similar to those reported in non-pregnant adults with COVID-19.', 'Because COVID-19 is an emerging infectious disease, the optimal treatment for affected individuals has not yet been established.', 'In our study, most patients were treated with ribavirin, corticosteroids, and antibiotics.', 'Although remdesivir and other antiviral drugs have been used in the clinical treatment of patients with COVID-19, no data of their safety and efficacy as COVID-19 treatments have been published.', 'No safety concerns have been identified related to the use of traditional Chinese medicine in our study.', 'Five of our patients were treated with steroids (methylprednisolone 1-2 mg/kg per day); however, animal Apgar score (1 min) 8-9 8-9 8-9 8-9 8-9 8-9 8-9', 'Apgar score (5 min) 9-10 9-10 9-10 9-10 9-10 9-10 9-10 studies have shown that the use of large doses of corticosteroids during pregnancy might lead to fetal malformation, and some studies have shown that the easy passage of corticosteroids through the placenta might increase the incidence of low birthweight in infants.', 'Therefore, steroids were only used after caesarean section in this study.', 'Thus far, no complications related to the steroids have been recorded in the mothers and infants, but their safety still needs more data to draw conclusions.', 'Because of alterations in hormone levels and decreased lung volumes caused by increases in uterus size during pregnancy, patients might have a more rapid clinical deterioration.', 'Additionally, the influence of the virus itself and these antivirals and Chinese medicines on fetal development is unknown.', 'Therefore, for full-term pregnant women, after consultation with a multi disciplinary team, delivering as soon as possible might be a better choice for the sake of safety considerations.', 'Timely use of antibiotics to prevent secondary bacterial infections and strengthen immune support treatment can reduce complications and mortality, so antibiotics were used routinely after operation.', '15 COVID-19 pneumonia in pregnancy is a complicated clinical scenario, and a multidisciplinary team of medical personnel is needed to care for and treat these patients comprehensively.', 'Relevant specialty areas include obstetrics, infectious diseases, internal medicine, paediatrics, anaesthesia, psychology, and infection control.', 'No medical staff had SARS-Cov-2 infections during the whole treatment period.', 'The sequence similarity between SARS and SARS-CoV-2 is as high as 79%; 16 the mortality rate of SARS infection is 10%, 17 and the mortality rate of SARS in pregnant women was 25%.', '18 Studies have reported that the mortality rate of patients with COVID-19 is about 1·4%.', '19 In our study, the maternal, fetal, and neonatal outcomes of pregnant women with COVID-19 pneumonia are better than those with SARS infection.', 'This might be associated with our small number of cases and short delivery time (ie, as soon as possible after diagnosis).', 'Previous studies have shown no evidence of perinatal SARS infection in infants born to mothers who had SARS infection during pregnancy.', '18, 20 One neonate in our study was infected with COVID-19 36 h after birth.', 'However, the viral nucleic acid tests of the placenta and cord blood in this patient were negative for SARS-CoV-2, so intrauterine vertical transmission might not have occurred; thus, further study is needed.', 'However, this study has several limitations.', 'First, only seven pregnant women with COVID-19 were included in the analyses.', 'More infected pregnant women and comparative studies (eg, cohorts, case-control) should be analysed to get a more comprehensive understanding of COVID-19 in pregnancy.', 'Second, all enrolled patients were in the third trimester, so the effect of the virus infection on the fetus in the first or second trimester is unknown.', 'Third, due to the short time of the outbreak, the long-term out comes of the neonates and whether mother-to-child transmission exists require further study.', 'However, the data in this study permit an early assessment of the clinical characteristics and maternal and fetal outcomes of COVID-19 in late pregnancy in women in Wuhan, China.', 'In conclusion, the clinical characteristics of these patients with COVID-19 during late pregnancy are similar to those reported by non-pregnant adults with COVID-19.', 'The maternal, fetal, and neonatal outcomes of those pregnant women infected in late pregnancy appear very good, and these outcomes are achieved with intensive, active management, which might be the best practice in absence of more robust data.', 'Long-term outcomes and potential mother-to-child vertical transmission needs further study.']}\n", - "{'sentences': ['Potential benefits of precise corticosteroids therapy for severe 2019-nCoV pneumonia', 'Salvage corticosteroids treatment for critical patients with 2019-nCoV?', 'Corticosteroids are widely used to prevent lung injury caused by severe community-acquired pneumonia (sCAP) due to their excellent pharmacological effects on the suppression of exuberant and dysfunctional systematic inflammation5.', 'Some scholars may not support the corticosteroids treatment for novel coronavirus pneumonia (NCP']}\n", - "{'sentences': ['We present an analysis of some of the most relevant topological properties of the main protease of the SARS CoV-2.', 'Our approach is based on the representation of the three-dimensional structure of the protein as a residue network in which C α of every amino acid is represented by a node of the network and two nodes are connected if the corresponding C α are at no more than 7.0 Å. CoV-2 M pro differs only in 12 punctual mutations from CoV-1 M pro and the superposition of their three-dimensional skeletons gives an r. m. s. of only 0.53 Å. Then, it comes at no surprise that the difference between most of the topological properties of the PRNs representing both proteases differ in less than 5%.', 'If we exclude from the analysis the LR descriptors, then 70% of the topological descriptors shows only a small variation between the two proteases.', 'In this situation it is certainly remarkable that there are topological descriptors which change in about 300% from one protease to the other.', 'These are the cases of the LR subgraph centrality of the amino acids and of the LR communicability between pairs of them.', 'The increase of these parameters in about 300% for CoV-2 M pro relative to CoV-1 M pro means that the 12 punctual mutations that differentiate both proteases have created a huge increment in the efficiency of CoV-2 M pro in transmitting perturbations of any kind between the amino acids of the protein using all available routes of connection and allowing for long-distance transmission.', 'To make clearer what this sensitivity means we are going to use a simple example.', 'Let us consider a tiny perturbation on the structure of the proteases which prevent the interaction between the amino acids P9 and G11, which have been selected at random.', 'In CoV-1 M pro these amino acids are at 5.69 Å and in CoV-2 M pro they are 6.48 Å apart.', 'Thus, in both cases they are connected in the corresponding PRN.', 'Let us consider that the perturbation remove this edge from the PRN of both proteases.', 'The relative decrement of the average path length in CoV-2 M pro relative to CoV-1 M pro is almost imperceptible, i.e., 5.7%.', 'In the case of the subgraph centrality it is of the same order, i.e., 3.4%.', 'This means that according to these parameters CoV-2 M pro is as sensitive as CoV-1 M pro to perceive a structural change in its structure produced by a given perturbation.', 'However, when we consider the LR subgraph centrality this relative change is 316.8%.', 'That is, according to this topological parameter which takes into account long-range interactions, CoV-2 M pro is more than three times more sensitive to a tiny structural change than CoV-1 M pro .', 'This remarkable finding indicates that the 12 mutations produced in CoV-1 M pro makes the resulting CoV-2 M pro much more efficient in transmitting \"information\" through the protein skeleton using short and longrange routes.', 'The second remarkable finding of the current work is that the largest changes in the LR subgraph centrality occurring in CoV-2 M pro relative to CoV-1 M pro do not spread equally across the whole structure of the protease.', 'Instead, they 14 author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.03.023887 doi: bioRxiv preprint 15 author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.03.023887 doi: bioRxiv preprint are concentrated around a geometrical region which includes most of the amino acids involved in the binding site of the protease to inhibitors or close to it.', 'One of the amino acids which has increased more dramatically its sensitivity to long-range transmission of information in CoV-2 M pro is Cys-145, which is one of the two catalytic sites of the protease, and the one involved in interactions with the inhibitors, such as the ones analyzed here.', 'We have analyzed here three different inhibitors of CoV-2 M pro .', 'In the three cases we have observed a significant variation in the LR subgraph centrality of the amino acids which were previously observed to have increased their LR sensitivity in the free protease.', 'Therefore, these amino acids corresponds to those involved in the binding of these three inhibitors, showing that their increased topological role in the CoV-2 M pro also may play an important functional role in it.', 'The analysis of PRN is easier than the study of the whole protein structure.', 'In this sense the PRN represents a simplified model of the three-dimensional structure of the protein.', 'Typically, such simplification in the complexity of the representation of systems convey a loss in the structural information which is represented by the global system.', 'In this case, however, we have shown that the use of a network representation of the proteins reveals some hidden patterns in their structure that were escaping to the analysis by using the global structure.', 'To detect such important structural factors it is necessary to account for longrange interactions among the amino acids of the proteases, which are the ones revealing the their most important characteristics in terms of their sensitivity to tiny structural changes produced by local or global perturbations to the system.', 'Such LR interactions revealed here the main differences between the proteases of CoV-1 and CoV-2, as well as the most important amino acids for the interaction with inhibitors, which may produce therapeutic candidates against COVID-19.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Background Since Dec 2019, SARS-CoV-2 has caused about fifty thousand patients and over two thousand deaths in Wuhan, China.', 'We reported characteristics of patients with COVID-19 during epidemic ongoing outbreak in Wuhan.', 'Methods Data of COVID-19 patients with clinical outcome in a designated hospital in Wuhan, were retrospectively collected from electronic medical records.', 'Characteristics were compared between patients who died or recovered, and between patients with different disease severity.', 'Results By Feb 25, 2020, 403 patients were enrolled, 100 died and 303 recovered.', 'Most of non-survivors tended to be males, old aged, or with chronic diseases.', 'Duration from illness onset to admission was 9 (7-12) days.', 'Patients with severe or critical illness had more days from onset to admission compared to those with ordinary illness.', 'Lymphopenia, anemia, hypoproteinemia, and abnormal serum sodium were presented in 52.6%, 54.6%, 69.8%, and 21.8% cases, respectively.', 'Patients who died or with severe/critical illness showed increased white blood cell and neutrophil count, serum total bilirubin, creatinine, hypersensitive troponin I, D-dimer, procalcitonin, and C-reactive protein, and decreased red blood cell, lymphocyte, platelet count, and serum albumin on admission compared to those who recovered or with ordinary illness.', 'Complications of acute organ injury and secondary infection were common in patients with COVID-19, especially in non-survivors.', 'Conclusions Multiple homeostasis disturbances were common in patients with severe or critical illness at admission.', 'Early support should be provided, especially for old men with chronic disease, which is vital to control disease progression and reduce mortality of COVID-19 during epidemic ongoing outbreak.', 'To our knowledge, this report presented the largest sample of COVID-19 patients with clinical outcome.', 'Our results confirmed the findings by Chen that male gender, older age, and chronic disease contributed to death caused by SARS-CoV-2 infection.', '7 Patients with severe or critical illness on admission presented a more delay to admission, implying the effect of delayed admission on disease deterioration.', \"The ongoing outbreak of this epidemic incurred a sharply increased patients in Wuhan, China, and most of them couldn't be admitted to hospitals in time.\", 'Frequent visits to fever clinics, inappropriate home quarantine, and delayed hospitalization further aggravated the disease progression and transmission of the virus.', 'Multiple homeostasis disturbances, including lymphopenia, anemia, hypoproteinemia and abnormal serum sodium were observed on admission, especially in patients with severe or critical illness.', 'Many factors might contribute to these disturbances, such as eating less due to poor appetite for food, augment of organic consumption, and simultaneous gastrointestinal problems.', \"Insufficient nutrient intake and augmented consumption might deteriorate tissue metabolism and damage one's immunity to virus.\", 'Our study showed that multiple organ damage, such as ARDS, acute kidney injury, acute cardiac injury, and acute liver injury, were common complications in patients with COVID-19.', 'Previous studies have showed that angiotensin-convertion enzyme 2 (ACE2), the receptor for SARS-CoV-2, is expressed in organs including lung, heart, liver, and kidney.', 'By binding to ACE2', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.03.19.20033175 doi: medRxiv preprint which was consistent with the elevated serum pro-inflammatory cytokines observed in COVID-19 patients.', '13, 14 Meanwhile, serum levels of some laboratory indexes such as total bilirubin, creatinine and hypersensitive troponin I were increased in patients on admission.', 'This trend was more obvious in patients with severe or critical illness, indicating signs of organ damage.', 'Though the pathological mechanism of COVID-19 is yet to be defined, direct attacks from SARS-CoV-2 and organ damage caused by excessive inflammatory response (cytokines storm) might be responsible for the pathogenesis of disease progression.', '14 Secondary infection, another main complication in this study, appeared mostly in non-survivors, indicating an important booster of disease progression.', 'Comprehensive treatments were provided for patients in this study.', 'No antiviral treatment for coronavirus infection has been proven to be effective, however, antiviral agents were applied in almost (97.8%) patients with COVID-19.', 'The main agents used included abidol, oseltamivir, ribavirin, ganciclovir, and recombinant interferon.', 'Remdesivir and chloroquine are considered two promising agents for SARS-CoV-2 infection, 15 which were given to some patients in randomized, double-blind, placebo-controlled clinical trials.', \"However, it's hardly to assess the efficacy and safety of remdesivir and chloroquine until results of the trials are released.\", 'Short-term (3 to 5 days) application of glucocorticoids is suggested for severe patients with COVID-19 in the protocol issued by NHC.', '9 In this study, glucocorticoids were applied in 166 (41.2%) cases, most of whom were patients with severe or critical illness.', 'However, glucocorticoids use was found to be correlated with increased mortality in SARS patients and delayed virus clearance.', '16, 17 In this context, glucocorticoids are not routinely recommended in treatment of SARS-CoV-2 pneumonia.', '18 In this study, secondary infection appeared mostly in patients with glucocorticoids use and might contribute to death, which was indicated by its higher incidence in patients who died (58.0% vs. 6.3%, p<0.001).', 'And so, glucocorticoids should be used more cautiously in patients with COVID-19.', 'High-flow nasal cannula oxygen therapy (HFNC) and mechanical ventilation are recommended for patients with ARDS.', '19 Non-invasive positive pressure ventilation (NIPPV', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.03.19.20033175 doi: medRxiv preprint intensive care unit (ICU', 'Since Dec 2019, SARS-CoV-2 has infected about fifty thousand patients and caused over two thousand deaths in Wuhan, China.', 'With the strengthened support from central and local governments and national medical staffs, SARS-CoV-2 epidemic has been preliminary controlled in Wuhan, China at current.', 'Many other countries such as Italy, Iran, and Korea, however, are showing an ongoing outbreak, 4 which will inevitably bring about shortage of medical resources.', 'To learn characteristics of patients with COVID-19 in Wuhan, China, during ongoing outbreak of SARS-CoV-2 epidemic, is helpful for others to make appropriate strategies and thus to reduce mortality of COVID-19 globally.', 'In conclusion, findings of this study suggested multiple homeostasis disturbances in patients with severe or critical illness on admission, including lymphopenia, anemia, hypoproteinemia, abnormal serum sodium, and elevated inflammatory stress.', 'Acute organ injuries were common in non-survivors, which might cause by SARS-CoV-2 attacks and excessive inflammatory response.', 'Early supportive therapy should been provided to control disease progression and reduce the mortality of COVID-19.']}\n", - "{'sentences': ['Hydrogen Peroxide Vapor sterilization of N95 respirators for reuse', 'Reprocessing of used N95 respirators may ameliorate supply chain constraints during the COVID-19 pandemic and provide a higher filtration crisis alternative.', 'The FDA Medical Countermeasures Initiative previously funded a study of HP vapor decontamination of respirators using a Clarus C system (Bioquell, Horsham, PA) which normally is used to fumigate hospital rooms.', 'The process preserved respirator function, but it is unknown if HP vapor would be virucidal since respirators have porous fabric that may harbor virus.', 'We evaluated the virucidal activity of HP vapor using a BQ-50 system (Bioquell, Horsham, PA) after inoculating 3M 1870 N95 respirators (3M, St. Paul, MN) with 3 aerosolized bacteriophage that are a reasonable proxy for SARS-CoV-2.', 'Inoculation resulted in contamination of the respirator with 9.87e4 plaque forming units (PFU) of phage phi-6, 4.17e7 PFU of phage T7 and 1.35e7 PFU of phage T1.', 'Respirators were reprocessed with BQ-50 with a long aeration phase to reduce HP vapors.', 'Virucidal activity was measured by a standard plaquing assay prior to and after sterilization.', 'A single HP vapor cycle resulted in complete eradication of phage from masks (limit of detection 10 PFU', 'Use of a Bioquell machine can be scaled to permit simultaneous sterilization of a large number of used but otherwise intact respirators.', 'HP vapor reprocessing may ease shortages and provide a higher filtration crisis alternative to non-NIOSH masks.', 'CC-BY-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.03.24.20041087 doi: medRxiv preprint 3']}\n", - "{'sentences': ['Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection', 'The continued emergence of Middle East Respiratory Syndrome (MERS) cases with a high case fatality rate stresses the need for the availability of effective antiviral treatments.', 'Remdesivir (GS-5734) effectively inhibited MERS coronavirus (MERS-CoV) replication in vitro, and showed efficacy against Severe Acute Respiratory Syndrome (SARS)-CoV in a mouse model.', 'Here, we tested the efficacy of prophylactic and therapeutic remdesivir treatment in a nonhuman primate model of MERS-CoV infection, the rhesus macaque.', 'Prophylactic remdesivir treatment initiated 24 h prior to inoculation completely prevented MERS-CoV−induced clinical disease, strongly inhibited MERS-CoV replication in respiratory tissues, and prevented the formation of lung lesions.', 'Therapeutic remdesivir treatment initiated 12 h postinoculation also provided a clear clinical benefit, with a reduction in clinical signs, reduced virus replication in the lungs, and decreased presence and severity of lung lesions.', 'The data presented here support testing of the efficacy of remdesivir treatment in the context of a MERS', 'Human safety data are available for remdesivir.', 'It has been used on a compassionate basis in several unique cases of Ebola virus disease (21, 22), as well as on a large scale in the ongoing Ebola virus outbreak in the Democratic Republic of Congo (23), with around 400 treated patients.', 'In addition, its efficacy is currently being tested in a clinical trial in Ebola virus disease survivors with prolonged virus shedding (24, 25).', 'Although the efficacy of remdesivir was lower in the Ebola virus trial than that of the different antibody treatments tested, survival was increased as compared to overall survival rate in this outbreak.', 'Taken together, the data presented here on the efficacy of remdesivir in prophylactic and therapeutic treatment regimens, the difficulty of coronaviruses to acquire resistance to remdesivir (9), and the availability of human safety data warrant testing of the efficacy of remdesivir treatment in the context of a MERS clinical trial.', 'Our results, together with replication inhibition by remdesivir of a wide range of coronaviruses in vitro and in vivo (7), may further indicate utility of remdesivir against the novel coronavirus 2019-nCoV emerging from Wuhan, China (26).', 'Prophylactic remdesivir treatment prevented MERS-CoV−induced clinical disease and lung lesions in rhesus macaques inoculated with MERS-CoV, and strongly inhibited MERS-CoV replication in respiratory tissues.', 'Since nosocomial transmission accounts for approximately one-third of MERS-CoV cases (11), prophylactic remdesivir treatment of patients, contacts of patients, and healthcare personnel with high-risk exposure to a diagnosed MERS patient and at high risk of developing severe MERS due to underlying conditions (12) could be considered.', 'Therapeutic remdesivir treatment also provided a clear clinical benefit, with a reduction in clinical signs and virus replication, and the absence of lung lesions in two out of six remdesivir-treated animals and a reduction in lesion severity in three additional animals.', 'Absence of histologic lung lesions, as seen in two out of the six animals with therapeutic remdesivir treatment, has so far rarely been observed in studies testing the efficacy of MERS-CoV antivirals in nonhuman primate models (13–16); it has only been shown once before in one out of three common marmosets treated with hyperimmune plasma at 6 h after inoculation (17).', 'Thus, although it is hard to compare different studies due to the fact that different species were used and treatment was initiated at different time points after inoculation, remdesivir appears to be one of the most promising antiviral treatments tested in a nonhuman primate model to date.', 'Therapeutic remdesivir treatment was administered at 12 h after inoculation with MERS-CoV, and, although this may seem relatively early after inoculation, it is close to the peak of MERS-CoV replication in the rhesus macaque model (10).', 'A drug that inhibits virus replication may be of little use once virus replication has reached its peak, as was shown in vitro (9).', 'However, in a considerable number of severe cases of MERS, viral RNA and infectious virus can still be detected in respiratory tract samples several weeks after the onset of symptoms (18, 19), with this prolonged virus replication most likely due to the presence of underlying conditions such as diabetes mellitus (18).', 'Likewise, an increase in virus replication over a longer period of time was observed in immunocompromised rhesus macaques (20).', 'Thus, remdesivir treatment could not only be of benefit to patients diagnosed with MERS early after symptom onset but may also improve recovery in those patients with severe cases of MERS where prolonged virus replication occurs.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Of the markers we tested, cell-free DNA was most closely associated with traditional inflammatory markers used to track COVID-19 including C-reactive protein, D-dimer, and lactate dehydrogenase.', 'Notably, although cell-free DNA is not a highly specific marker for NETs, it was strongly correlated with absolute neutrophil count, as was the more specific marker of NETs, MPO-DNA.', 'Somewhat unexpectedly, Cit-H3 did not correlate well with the other two markers, but did associate strongly with platelet levels.', 'It is believed that the predominant driver of histone citrullination (i.e., production of Cit-H3) in NETs is the enzyme peptidlyarginine deiminase 4 (PAD4) (38) .', 'However, neutrophils can be triggered to undergo NETosis by a variety of stimuli, and in vitro studies demonstrate that not all pathways to NETosis are equally reliant on PAD4', 'NETs were first described in 2004 as a novel pathogen eradication strategy that could function as an alternative to phagocytosis (35) , but it is now recognized that NETs have double-edgedsword properties and likely exacerbate (and in some cases even initiate) autoimmune and vascular diseases (42) .', 'NETs present and stabilize a variety of oxidant enzymes in the extracellular space, including MPO, NADPH oxidase, and nitric oxide synthase (43) , while also serving as a source of extracellular histones that carry significant cytotoxic potential (44, 45) .', 'In light of these toxic cargo, it is not surprising that NETs play a role in a variety of lung diseases including cystic fibrosis (where they occlude larger airways) (46) , smoking-related lung disease All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.09.20059626 doi: medRxiv preprint (47) , and, with particular relevance here, pathogen-induced acute lung injury and ARDS (13, 48, 49) .', 'NETs have also been very well studied in the setting of cardiovascular disease where they infiltrate and propagate inflammation in the vessel wall (50) , and, when formed intravascularly, occlude arteries (51), veins (52) , and microscopic vessels (53) .', 'Early studies of COVID-19 suggest a high risk of morbid arterial events (54) , and one can speculate that the risk of venous thrombosis will increasingly reveal itself as more data become available (55) .', 'Severe COVID-19 appears to be defined by neutrophilia, as well as elevations in IL-1β, IL-6, and D-dimer (17), the latter suggesting hyperactivity of the coagulation system.', 'All these findings have significant potential for cross-talk with NETs.', 'NETs are linked to IL-1β (both upstream and downstream) in cardiovascular and pulmonary diseases (18) (19) (20) (21) , including as described by our group for venous thrombosis (8) .', 'The same is true for IL-6, either directly (22), or perhaps with IL-1β as an intermediary (23) .', 'Of course, as discussed above, examples of NETs as drivers of thrombosis are myriad, as intravascular NETosis is responsible for initiation and accretion of thrombotic events in arteries, veins, and-particularly pertinent to COVID-19the microvasculature, where thrombotic disease can drive end-organ damage in lungs, heart, kidneys, and other organs (56, 57) .', 'Mechanistically, NETs, via electrostatic interactions, activate the contact pathway of coagulation (58) , while also presenting tissue factor to activate the intrinsic pathway (59) .', 'Simultaneously, serine proteases in NETs dismantle natural brakes on coagulation such as tissue factor pathway inhibitor and antithrombin (60) .', 'Bidirectional interplay between NETs and platelets may also be critical for COVID-19-associated microvascular thrombosis as has been characterized in a variety of disease models (57, 58) .', 'Of interest, a recent small study performed in China suggested potential efficacy of the adenosine-receptor agonist, dipyridamole in severe cases of COVID-19 (61).', 'Dipyridamole is an FDA-approved drug that our group recently discovered to inhibit NET formation by activation of adenosine A2A receptors (6) .', 'In the aforementioned trial, patients with COVID-19-associated bilateral pneumonia were treated with oral dipyridamole for seven days, in additional to treatment with antiviral agents (61) .', 'As compared with controls, dipyridamole-treated patients demonstrated improvements in platelet counts and D-dimer levels (61) .', 'Given the urgent need for effective treatments of COVID-19, a randomized study to characterize the impact of dipyridamole on COVID-19-related NETosis, thrombo-inflammatory storm, and, of course, outcomes may be warranted.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.09.20059626 doi: medRxiv preprint Other approaches to combatting NETs have been reviewed (62, 63) , and include the dismantling of already-formed NETs (deoxyribonucleases) and strategies that might prevent initiation of NET release, including inhibitors of neutrophil elastase and PAD4.', 'While our study certainly has limitations including the use of serum (plasma is typically preferred by our group and others for measurement of NETs) and a relatively small sample size, we hope it will ignite further research into the role of neutrophil effector functions in the complications of COVID-19.', 'As a first step, future studies should investigate the predictive power of circulating NETs in wellphenotyped longitudinal cohorts.', 'Furthermore, given the dichotomy we found here between MPO-DNA and Cit-H3, investigators should be encouraged to continue to include diverse markers of NETosis in future studies.', 'As we await definitive antiviral and immunologic solutions to the current pandemic, we posit that anti-neutrophil therapies may be part of a personalized strategy for some individuals affected by COVID-19 who are at risk for progression to respiratory failure.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.09.20059626 doi: medRxiv preprint', 'Here, we report for the first time elevated levels of serum NETs in many hospitalized patients with COVID-19.', 'We measured three markers commonly used to detect NET remnants in blood (cell-free DNA, Cit-H3, and MPO-DNA), and found significant elevations in all three.', 'We also found that COVID-19 sera are potent stimulators of NETosis when added to control neutrophils.', 'Together, these data provide evidence that COVID-19, at least in hospitalized patients, is a pro-NETotic state.', 'The triggers of NETosis in COVID-19 are potentially myriad and will require further investigation.', 'Possibilities include virus-damaged epithelial cells (13, 29) , activated platelets (30, 31) , activated endothelial cells (32) , and inflammatory cytokines such as IL-1β (19, 33), IL-8 (34, 35) , granulocyte colony stimulating factor (36, 37) , and likely others (17) .']}\n", - "{'sentences': ['COVID-19 outbreak is still threatening the public health.', 'Therefore, in the middle of the pandemic, all kind of knowledge on SARS-CoV-2 may help us to find the solution.', 'Determining the 3D structures of the proteins involved in host-pathogen interactions are of great importance in the fight against infection.', 'Besides, post-translational modifications of the protein on 3D structure should be revealed in order to understand the protein function since these modifications are responsible for the host-pathogen interaction.', 'Based on these, we predicted O-glycosylation and phosphorylation positions using full amino acid sequence of S1 protein.', 'Candidate positions were further analyzed with enzyme binding activity, solvent accessibility, surface area parameters and the positions determined with high accuracy rate were used to design full 3D glycoprotein structure of the S1 protein using carbohydrate force field.', 'In addition, the interaction between the C-type lectin CD209L and α -mannose residues was examined and carbohydrate recognition positions were predicted.', 'We suggest these positions as a potential target for the inhibition of the initial binding of SARS-CoV-2 S1', 'protein to the host cell.', 'Determining the 3D structures of the proteins involved in host-pathogen interactions are of great importance in the fight against infection.', 'Besides, post-translational modifications of the protein on 3D structure should be revealed in order to understand the protein function since these modifications are responsible for the host-pathogen interaction.', 'Therefore, researchers primarily have focused on the S protein structure of SARS-CoV-2 virus and revealed the 3D structure with N-glycosylation positions.', 'But, the detailed structure of the N-glycan units in these sites and the O-glycosylation positions are not included in the current model [13] .', 'Also, it is known that the initial binding of other coronaviruses to host cell occurs via the alternative receptor C-type lectin CD209L besides ACE2 protein [5] .', 'Taken together, herein, we first demonstrated SARS-CoV-2 S1 protein high mannose N-glycan structure and its interaction with CD209L.', 'When 3D glycoprotein structure of S1 protein analysed, N-glycosylation positions were found to be located mainly on the N-Terminal Domain (NTD', 'Since the Receptor Binding Domain (RBD', 'Secondly, we identified O-GalNAc and O-GlcNAc modifications of SARS-CoV-2 S1 protein.', 'O-glycans are known to be involved in protein stability and function [19] .', 'The presence of Oglycans in some viral proteins has been demonstrated and suggested that glycans may play a role on biological activity of viral proteins.', 'In the comparative study on human SARS-CoV-2 and other coronaviruses S proteins have showed that Ser673, Thr678, and Ser686 are conserved O-glycosylated positions and have suggested that SARS-CoV-2 S1 protein may show O-glycosylation at these positions [20] .', 'In this study, S1 protein was found to be O-GalNAcylated at Thr632, Thr678 and O-β-GlcNAcylated at Thr323, Thr638, Ser686 .', 'CC-BY 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.25.007898 doi: bioRxiv preprint positions (Table 1) .', 'When compared our results with the previous study, SARS-CoV-2 S1', 'protein found not to be O-glycosylated at Thr673, but O-GalNAcylated at Thr678 and O-β-GlcNAcylated at Ser686.', 'Besides, we found additional O-glycosylation positions at Thr323, Thr632, and Thr638 on the S1 protein.', 'On the 3D glycoprotein structure, Thr323 was found to be located at RBD and Thr678 and Ser686 located near Furin Recognizing Site (FRS', 'Phosphorylation of viral proteins are catalyzed by host cell enzymes like glycosylation modifications [12, 22] .', 'In this study, phosphorylation modification of SARS-CoV-2 S1 protein was also examined and 36 positions of Ser/Thr residues were found to be phosphorylated on almost all domains of the protein ( Table 2) .', 'Davidson et al. have shown that S1 protein is phosphorylated at 7 positions [23].', 'Amongst them, Ser459, Ser637, Ser640 positions were found to be correlated with our results.', 'Phosphorylation modification regulates the protein activity and function in cooperation with glycosylation [24, 25] .', 'When we examined the phosphorylation and glycosylation locations of S1 protein on the 3D structure; the phosphorylation positions at Ser161 and Ser162 were found to be located close to glycosylation position Asn165.', 'Likewise, Thr109 with Asn234; Ser680 with Thr678 and FRS; Thr604 with Asn603; Thr630 with Thr632; Thr637 and Thr640 with Thr638; Ser659 with Asn657 were found to be located close to each other on the 3D structure ( Fig. 3) .', 'Thus, we suggest these sites as critical sites for S1 protein activity.', 'COVID-19 outbreak is still threatening the public health.', 'At this point, inhibiting the initial binding of virus to the host cell is crucial in order to find treatment.', 'Since post-translational modifications regulate the host-pathogen interaction, identifying SARS-CoV-2 S1 protein modifications may help us to inhibit initial binding of the virus.', 'Therefore, we focused on the CD209L lectin-α-D-mannose interaction of S1 protein and suggested Met282, Lys307, and Ser345 positions as targets for the initial binding.', 'Also, we found that phosphorylation and glycosylation positions where located at close sites may be critical for S1 protein activity.', 'CC-BY 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'bioRxiv preprint Therefore, we suggest that, these positions can be targeted for drug development against COVID-19.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['The current epidemic situation of corona virus disease-19 (COVID-19) still remained severe.', 'As the National Clinical Research Center for Infectious Diseases, the First Affiliated Hospital of Zhejiang University School of Medicine is the primary medical care center for COVID-19 inZhejiang Province.', 'Based on the present expert consensus carried out by National Health Commission and National Administration of Traditional Chinese Medicine, our team summarized and established an effective treatment strategy centered on \"Four-Anti and Two-Balance\" for clinical practice.', 'The \"Four-Anti and Two-Balance\"strategy included antivirus, anti-shock, anti-hyoxemia, anti-secondary infection, and maintaining of water, electrolyte and acid base balance and microecological balance.', 'Meanwhile, integrated multidisciplinarypersonalized treatment was recommended to improve therapeutic effect.', 'The importance of early viralogical detection, dynamic monitoring of inflammatory indexes and chest radiograph was emphasized in clinical decision-making.', 'Sputum was observed with the highest positive rate of RT-PCR results.', \"Viral nucleic acids could be detected in10% patients'blood samples at acute periodand 50% of patients had positive RT-PCR results in their feces.\", 'We also isolated alive viral strains from feces, indicating potential infectiousness of feces.', 'Dynamic cytokine detection was necessary to timely identifyingcytokine storms and application of artificial liver blood purification system.', 'The \"Four-Anti and Two-Balance\"strategyeffectively increased cure rate and reduced mortality.', 'Early antiviral treatment could alleviate disease severity and prevent illness progression, and we found lopinavir/ritonavir combined with abidol showed antiviraleffects in COVID-19.', 'Shock and hypoxemia were usually caused by cytokine storms.', 'The artificial liver blood purification system could rapidly remove inflammatory mediators and block cytokine storm.', 'Moreover, it also favoredthe balance of fluid, electrolyte and acid-base and thus improved treatment efficacy in critical illness.', 'For cases of severe illness, early and also short periods of moderate glucocorticoid was supported.', 'Patients with oxygenation index below 200 mmHg should be transferred to intensive medical center.', 'Conservative oxygen therapy was preferred and noninvasive ventilation was not recommended.', 'Patients with mechanical ventilation should be strictly supervised with cluster ventilator-associated pneumonia prevention strategies.', 'Antimicrobial prophylaxis should be prescribed rationally and was not recommended except for patients with long course of disease, repeated fever and elevated procalcitonin (PCT), meanwhile secondary fungal infection should be concerned.', 'Some patients with COVID-19 showed intestinal microbialdysbiosis with decreasedprobiotics such as Lactobacillus and Bifidobacterium.', 'Nutritional and gastrointestinal function should be assessed for all patients.', 'Nutritional support and application of prebiotics or probiotics were suggested to regulate the balance of intestinal microbiota and reduce the risk of secondary infection due to bacterial translocation.', 'Anxiety and fear were common in patients with COVID-19.', 'Therefore, we established dynamic assessment and warning for psychological crisis.', 'We also integrated Chinese medicine in treatment to promote disease rehabilitation through classification methods of traditional Chinese medicine.', 'We optimized nursing process for severe patients to promote their rehabilitation.', 'It remained unclear about viral clearance pattern after the SARS-CoV-2 infection.', \"Therefore, two weeks' quarantine for discharged patients was required and a regular following up was also needed.\", 'The Zhejiang experience above and suggestions have been implemented in our center and achieved good results.', 'However, since COVID-19 was a newly emerging disease, more work was warranted to improve strategies of prevention, diagnosis and treatment for COVID-19']}\n", - "{'sentences': ['The 2019 novel coronavirus (2019-nCoV) is currently causing a widespread outbreak centered on Hubei province, China and is a major public health concern.', 'Taxonomically 2019-nCoV is closely related to SARS-CoV and SARS-related bat coronaviruses, and it appears to share a common receptor with SARS-CoV (ACE-2).', 'Here, we perform structural modeling of the 2019-nCoV spike glycoprotein.', 'Our data provide support for the similar receptor utilization between 2019-nCoV', 'Compared to SARS-CoV, we identify an extended structural loop containing basic amino acids at the interface of the receptor binding (S1) and fusion (S2) domains, which we predict to be author/funder.', 'All rights reserved.', 'No reuse allowed without permission.']}\n", - "{'sentences': ['A combination regimen by lopinave/litonawe (LPV/r), emtricitabine and tenofovir alafenamide fumarate (FTC/TAF) for treatment of novel coronavirus pneumonia (FTC/TAF) for treatment of novel coronavirus pneumonia', 'Objective To explore the efficacy of a combination regimen by Lopinave/Litonawe (LPV/r), emtricitabine and tenofovir alafenamide fumarate (FTC/TAF) for the treatment of novel coronavirus pneumonia (NCP).', 'Methods We design the protocol as a real world study, which includes two groups: prospective intervention cohort (T1) and historical control group (T2).', 'For T1 group, ninety patients will be enrolled who are diagnosed as NCP.', 'All patients in T1 group will receive standard therapies following the recommendation in the guidelines of National Commission of Health, and they will be administered an anti-virus regimen includes LPV/r and FTC/TAF.', 'The T2 group will enroll patients who have received single regimen includes LPV/r.', 'The major outcome is the survival rate of patients.', 'Secondary outcomes are the time of seroconversion of RNA, ARDS progression rate and length of hospital stay.', 'Conclusions The results of this real world study might provide clinical practitioners a high efficiency and fast antivirus regimen for NCP']}\n", - "{'sentences': ['Objective: To evaluate the cardiovascular damage of patients with COVID-19, and determine the correlation of serum N-terminal pro B-type natriuretic peptide (NT-proBNP) and cardiac troponin-I (cTnI) with the severity of COVID-19, and the impact of concomitant cardiovascular disease on severity of COVID-19 was also evaluated.', 'Methods: A cross-sectional study was designed on 150 consecutive patients with COVID-19 in the fever clinic of Tongji Hospital in Wuhan from January to February in 2020, including 126 mild cases and 24 cases in critical care.', 'Both univariate and multivariate logistic regression were used to analyze the correlation of past medical history including hypertension, diabetes and coronary heart disease (CHD) , as well as the levels of serum NT-proBNP and cTnI to the disease severity of COVID-19 patients.', 'Results: Age, hypersensitive C-reactive protein(hs-CRP) and serum creatinine levels of the patients were higher in critical care cases than in mild cases(all P<0.05).', 'Prevalence of male, elevated NT-proBNP and cTnI, hypertension and coronary heart disease were significantly higher in critical cases care patients than in the mild cases(all P<0.05).', 'Univariate logistic regression analysis showed that age, male, elevated NT-proBNP, elevated cTnI, elevated hs-CRP, elevated serum creatinine, hypertension, and CHD were significantly correlated with critical disease status(all P<0.05).', 'Multivariate logistic regression analysis showed that elevated cTnI(OR=26.909, 95%CI 4.086-177.226, P=0.001) and CHD (OR=16.609, 95%CI 2.288-120.577, P=0.005) were the independent risk factors of critical disease status.', 'Conclusions: COVID-19 can significantly affect the heart function and lead to myocardial injury.', 'The past medical history of CHD and increased level of cTnI']}\n", - "{'sentences': ['The outbreak of the 2019 Novel Coronavirus (SARS-CoV-2) rapidly spread from Wuhan, China to more than 150 countries, areas or territories, causing staggering number of infections and deaths.', 'A systematic profiling of the immune vulnerability landscape of SARS-CoV-2, which can bring critical insights into the immune clearance mechanism, peptide vaccine development, and antiviral antibody development, is lacking.', 'In this study, we investigated the potential of the SARS-CoV-2 viral proteins to induce class I and II MHC presentation and to form linear antibody epitopes.', 'We created an online database to broadly share the predictions as a resource for the research community.', 'Using this resource, we showed that genetic variations in SARS-CoV-2, though still few for the moment, already follow the pattern of mutations in related coronaviruses, and could alter the immune vulnerability landscape of this virus.', 'Importantly, we discovered evidence that SARS-CoV-2, along with related coronaviruses, used mutations to evade attack from the human immune system.', 'Overall, we present an immunological resource for SARS-CoV-2 that could promote both therapeutic development and mechanistic research.', ': bioRxiv preprint Chinese and European populations.', '(c) The B cell epitope profiles of the SARS-CoV-2.', 'The Y axis shows the predicted B cell epitope score.', 'Only showing residues with predicted epitope score >0.6.', '(d) BLASTing the motif binding domain of the SARS-CoV-2 S protein and the SARS-CoV S protein.', '(e) The T cell and B cell epitope profiles of SARS-CoV. (f) The T cell and B cell epitope profiles of MERS-CoV.', 'Fig. 2 Genetic drifts in SARS-CoV-2 are influenced by host immune pressure.', '(a-c) The relative mutational rate profiles of the three coronaviruses: (a) SARS-CoV-2, (b) SARS-CoV, and (c) MERS-CoV. The relative mutational rates are calculated by the percentage of nucleotides (nts) from all strains of each virus (n=114 for SARS-CoV-2, 19 for SARS-CoV-, and 519 for MERS-CoV) in each 60-nt bin that are different from the reference genome.', 'The semi-transparent boxes mark the regions of high mutational rates due to artefacts of incomplete sequencing.', 'These regions are shielded from calculations of gain and loss of immunogenicity.', '(d-f) The \"lost\" immunogenicity and \"gained\" immunogenicity due to mutations in each SARS-CoV-2 isolate compared with the reference genome.', '(d) CD8 + T epitopes, (e', 'Fig. 2 The variation of T cell epitope profiles for SARS-CoV-2, SARS-CoV and MERS-CoV across populations.', 'The heatmap represents the number of immunogenic binding epitopes across the binned genomes (500bp) of (a) SARS-CoV-2, (b) SARS-CoV and (c) MERS-CoV for the major HLA-A alleles shown as examples (allele frequency larger than 1%) in the European American (EA) and Hongkong Chinese (HK) populations.', 'These major alleles are colored in black, blue or red if they are common to both EA and HK population, unique to EA population, or unique to HK population, respectively.', 'On the right, the band of strength represents the cumulative number of immunogenic peptides, and the bands of EA and HK represent the HLA allele frequency of EA and HK populations, respectively.', 'Fig. 3 Part of the multiple alignment results of all the SARS-CoV-2 strains.', 'Fig. 4 B cell epitope-encoding amino acids in contiguous stretches of >10 epitope-encoding amino acids.', '(a) SARS-CoV-2, (b) SARS-CoV, and (c', 'Fig. 5 The trend of immunogenicity to SARS-CoV-2 over time.', '(a) \"Gained/lost\" T cell immunogenicity (class I).', '(b) \"Gained/lost\" T cell immunogenicity (class II).', '(c) Changes in B cell immunogenicity (all epitope-encoding residues).', '(d) Changes in B cell immunogenicity (epitope-encoding residues in stretches of >10 epitope-encoding residues).', 'The strains were grouped according to their collection time of']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Previously, we have designed and synthesized peptidomimetic a-ketoamides as broadspectrum inhibitors of the main proteases of betacoronaviruses and alphacoronaviruses as well as the 3C proteases of enteroviruses .', 'The best of these compounds (11r; see Scheme 1) showed an EC50 of 400 picomolar against MERS-CoV in Huh7 cells as well as low micromolar EC50 values against SARS-CoV and a whole range of enteroviruses in various cell lines.', 'In order to improve the half-life and the solubility of the compounds in human plasma, and to reduce the binding to plasma proteins, we have modified the compound by hiding the P3 -P2 amide bond within a pyridone ring and by replacing the cinnamoyl group.', 'For a compound related to 11r but modified this way (compound 13a), the half-life in human plasma was increased by 50%, solubility was improved, and plasma protein binding was reduced from 99% to 94%.', 'There was no author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.02.17.952879 doi: bioRxiv preprint 7 sign of toxicity in mice.', 'In addition, 13a showed good metabolic stability using mouse and human microsomes, with intrinsic clearance rates Cl int_mouse = 32.00 µL/min/mg protein and Cl int_human = 20.97 µL/min/mg protein.', 'This means that after 30 min, around 80% for mouse and 60% for humans, respectively, of residual compound remained metabolically stable.', 'Pharmacokinetic studies in CD-1 mice using the subcutaneous route at 20 mg/kg showed that 13a stayed in plasma for up to only 4 hrs, but was excreted via urine up to 24 hrs.', 'The Cmax was determined at 334.50 ng/mL and the mean residence time was about 1.59 hrs.', 'Although 13a seemed to be cleared very rapidly from plasma, it was found at 24 hrs at 135 ng/g tissue in the lung and at 52.7 ng/mL in broncheo-alveolar lavage fluid (BALF', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.02.17.952879 doi: bioRxiv preprint 8 distance from His 172 and the lack of H-bonding interaction between Glu 166 and the P1 moiety of the inhibitor (see below, even though compound 13b is bound in the same mode as in molecule A. This phenomenon has also been observed, in a more pronounced form, with the SARS-CoV M pro (Yang et al., 2003) and is consistent with the half-site activity described for this enzyme (Chen et al., 2006) .', 'In all copies of the inhibited 2019-nCoV M pro , the inhibitor binds to the shallow substratebinding site at the surface of each protomer, between domains I and II (Fig. 2) .', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.02.17.952879 doi: bioRxiv preprint 9 Through the nucleophilic attack of the catalytic Cys 145 onto the a-keto group of the inhibitor, a thiohemiketal is formed in a reversible reaction.', 'This is clearly reflected in the electron density (Fig. 2) ; the stereochemistry of this chiral moiety is S in all three copies of compound 13b in these structures.', 'The oxyanion (or hydroxyl) group of this thiohemiketal is stabilized by a hydrogen bond from His 41 , whereas the amide oxygen of 13b accepts a hydrogen bond from the main-chain amides of Gly 143 , Cys 145 , and partly Ser 144 , which form the canonical \"oxyanion hole\" of the cysteine protease.', 'The P1 g-lactam moiety, designed as a glutamine surrogate (Dragovich et al., 1999; Tan et al., 2013) , is deeply embedded in the S1 pocket of the protease, where the lactam amide nitrogen donates a three-center (bifurcated) hydrogen bond to the main-chain oxygen of Phe 140 (3.20/3.10/3.28 Å; values for the structure in space group C2/space group P212121 molecule A/space group P212121 molecule B) and to the Glu 166 carboxylate (3.35/3.33/ -Å), and the carbonyl oxygen accepts a 2.57/2.51/2.81-Å H-bond from the imidazole of His 163 .', 'The P2 cyclopropyl methyl moiety is embraced by the S2 subsite, which has shrunk by 28.4 Å 3 compared to a complex between compound 13a with P2 = cyclohexyl methyl and the SARS-CoV M pro (LLZ et al., unpublished) .', \"The pyridone in the P3 position of the inhibitor occupies the space normally filled by the substrate's main chain, its carbonyl oxygen accepts a 2.89/2.99/3.00-Å hydrogen bond from the main-chain amide of residue Glu166.\", 'Further, the P3 amide donates a 2.83/2.96/2.87-Å H-bond to the mainchain oxygen of Glu 166 .', 'Embedded within the pyridone, the P2 nitrogen can no longer donate a hydrogen bond to the protein; however, our previous crystal structures showed that the P2 mainchain amide of the linear a-ketoamides does not make a hydrogen bond with the protein in all cases, so this interaction does not seem to be essential .', 'The Boc group does not occupy the canonical S4 site of the protease, but is located near Pro 168 (at a distance of author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.02.17.952879 doi: bioRxiv preprint 3.81/4.17/3.65 Å); due to this interaction, the latter residue is \"pushed\" by >2 Å (compared to the structure of the free enzyme).', 'This contact explains that removing the Boc group weakens the inhibitory potency of this compound by a factor of about 2.', 'Interestingly, there is a space between the pyridone ring of 13b, the main chain of residue Thr 190 , and the side-chain of Gln 189 , which is filled by a DMSO molecule in the C2 crystal structure and a water molecule in the P212121 structure.', 'This suggests that P3 moieties more bulky than pyridone may be accepted here.', 'As the next steps in the development of compound 13b towards a potential drug targeting 2019-nCoV or other coronaviruses, we will undertake tests in virus-infected cell cultures and in a small-animal model (once it will become available for 2019-nCoV).', 'Meanwhile, our crystal structures may be used by others for virtual screening and de-novo design of inhibitors.', 'The 1.75-Å crystal structure of the unliganded 2019-nCoV M pro (Fig. 1 ) reveals the high similarity to the SARS-CoV M pro that was to be expected from sequence comparisons (Zhou et al., 2020; Wu et al., 2020) .', 'deviation between the two free-enzyme structures is 0.53 Å for all Ca positions of the molecule but the isolated domains exhibit r.m.s.', 'deviations of only 0.31 Å (domains exhibit r.m.s.', 'deviations of only 0.31 Å) -0.42 Å (domains I, III) (comparison between the novel coronavirus M pro structure and SARS-CoV M pro , PDB entry 2BX4 (Tan et al., 2005) ).', 'The chymotrypsin-and picornavirus 3C protease-like domains I and II (residues 10-99 and 100-182, respectively) are six-stranded antiparallel b-barrels that harbor the substrate-binding site between them.', 'Domain III (residues 198-303), a globular cluster of five helices, is involved in the regulation of dimer formation of the M pro (Shi & Song, 2006) .', '2019-nCoV M pro forms a tight dimer (contact interface, predominantly between domains exhibit r.m.s.', 'deviations of only 0.31 Å of molecule A and the NH2-terminal residues of molecule B (\"N-finger\"): ~1394 Å 2 ), with the two molecules oriented perpendicular to one another ( Fig. 1) .', 'Dimerization of the enzyme is necessary for catalytic activity, because the N-finger of each of the two protomers interacts with Glu 166 of the other protomer and thereby helps shape the S1 pocket of the substrate-binding site (Anand et al., 2002) .', 'To reach this interaction site, the N-finger is squeezed in between domains II and III of the parent monomer and domains exhibit r.m.s.', 'deviations of only 0.31 Å', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.02.17.952879 doi: bioRxiv preprint protomer, and supported by a hydrophobic contact between the side-chain of Ile 286 and Thr 285 Cg2.', 'In 2019-nCoV, the threonine is replaced by alanine (indicated by the black sphere in Fig. 1 ), and the isoleucine by leucine.', 'It has previously been shown that replacing Ser 284 , Thr 285 , and Ile 286 by alanine residues in SARS-CoV M pro leads to a 3.6-fold enhancement of the catalytic activity of the protease, concomitant with a slightly closer packing of the two domains III of the dimer against one another (Lim et al., 2014) .', 'According to that study, this is accompanied by changes of the structural dynamics of the enzyme that transmit the effect of the mutation to the catalytic center.', 'Indeed, the Thr 285 Ala replacement observed in the 2019-nCoV M pro also allows the two domains III to approach each other a little closer (the distance between the Ca atoms of residues 285 in molecules A and B is 6.77 Å in SARS-CoV M pro and 5.21 Å in 2019-nCoV M pro and the distance between the centers of mass of the two domains III shrinks from 33.4 Å to 32.1 Å).', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.02.17.952879 doi: bioRxiv preprint the positions of Ala 285 of each of the two domains III (see text).', 'Chain termini are labeled N and C for molecule A (light blue) and N* and C* for molecule B (orange).', 'In the active site of 2019-nCoV M pro , Cys 145 and His 41 form a catalytic dyad.', 'Like in SARS-CoV M pro and other coronavirus homologues, a buried water molecule is found hydrogen-bonded to His 41 ; this could be considered the third component of a catalytic triad.', 'Scheme 1: Chemical structures of a-ketoamide inhibitors 11r, 13a, and 13b']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['CRISPR-Cas13 emerged as a natural bacterial defense against bacteriophages, a powerful antiviral system that is able to use sequence-specific crRNAs to protect host bacterial cells from infections 29 .', 'Here, we have repurposed the RNA-guided RNA endonuclease activity of Cas13d in mammalian cells against emergent viral targets, SARS-CoV-2 and IAV, in our PAC-MAN strategy.', 'This expands the applications of CRISPR-Cas13 systems in addition to their uses for diagnostics such as SHERLOCK and live-cell imaging [30] [31] [32] [33] .', 'Prior work showed Cas13a/b systems could inhibit ssRNA viruses including influenza, which is consistent with our observed high efficiency of SARS-CoV-2 reporter and IAV inhibition using the PAC-MAN approach 31 .', 'We demonstrated that Cas13d-based genetic targeting can effectively target and cleave the RNA sequences of SARS-CoV-2 fragments and IAV in lung epithelial cell cultures.', 'Our bioinformatics analysis also suggested a minimal pool of 6 crRNAs able to target over 90% of sequenced coronaviruses.', 'While this strategy is a proof-of-concept and will require further testing using replication-competent SARS-CoV-2 viruses and validation in animal models before clinical tests in humans, it represents a unique approach to implement a rapid and broad antiviral defense in humans against emerging pathogens for which there are no effective vaccines.', 'For both SARS-CoV-2 and IAV, we found highly conserved regions of the viral genomes to target with Cas13d.', 'In the case of SARS-CoV-2, these genome regions encode the RdRP and Nucleocapsid proteins, which are essential for coronavirus replication and function 13, 34 .', 'RdRP is responsible for catalyzing the replication of all viral mRNAs and Nucleocapsid binds to genomic RNA, protecting it and serving as one of the two main structural proteins in virions.', 'Targeted inhibition of these proteins could have an outsized effect on disabling virus production and function, in addition to reducing viral load through degradation of the viral genome itself.', 'For IAV, the crRNAs that showed the best viral inhibition target the conserved ends of the segment S6 that encodes Neuraminidase (NA', 'Notably, the SARS-CoV-2 RdRP gene and IAV NA gene that we targeted in our study are also the targets of two antiviral drugs, Remdesivir and Oseltamivir.', 'Remdesivir, created by Gilead Sciences (development code GS-5734), is an RdRP inhibitor that was developed to treat Ebola and Marburg virus infections and has been reported to have antiviral activity against MERS and SARS 36-38 .', 'Remdesivir is already administered for COVID-19 through compassionate use requests, and clinical trials for its use against COVID-19 have already started in the U.S.', '(clinical trial ID NCT04280705) and China.', 'Oseltamivir (also known as Tamiflu), is an antiviral medication for treating and preventing IAV that acts as an inhibitor of NA, thereby preventing the egress of new viral particles 39 .', 'It will be interesting to see if these drugs could be used in combination with Cas13d PAC-MAN to synergistically cripple viral function and replication.', 'While we demonstrate that the PAC-MAN system is able to exhibit strong repression of viral sequences in an in vitro setting, it must be coupled with an effective in vivo delivery system for therapeutic use.', 'There are several potential strategies that could be employed for transient in vivo expression of CRISPR components.', 'Cas13d and its cognate crRNAs could be delivered as RNAs within polymers or lipid nanoparticles, perhaps with chemical alterations to increase stability 40 .', 'In addition, a DNA-based liposomal delivery strategy, such as the recently developed HEDGES platform is also attractive 41 .', 'Yet another strategy would be to deliver a author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.13.991307 doi: bioRxiv preprint Development of CRISPR as a prophylactic strategy to combat novel coronavirus and influenza Abbott et al. Manuscript 13 ribonucleoprotein complex containing purified Cas13d assembled with crRNAs 42, 43 .', 'All of these could potentially be used both as a therapeutic and as a prophylactic measure.', 'If the delivery barriers are overcome and a strategy like this is able to be used therapeutically, there are many potential benefits over traditional vaccines.', 'Traditional vaccines rely on priming the immune system through exposure to viral proteins or peptides often derived from surface proteins that exhibit a high rate of mutation, which increased the chances of viral evasion of the host immune response 44 .', 'In contrast, here we have demonstrated a genetic strategy that is able to target highly conserved regions, which would be expected to make it much more unlikely for the virus to escape inhibition through mutation.', 'In addition, the ability of Cas13d to process its own crRNAs from a crRNA array means that multiple crRNAs targeting different regions (e.g. Fig. 3E , and PAC-MAN-T6 in Fig. 5A ) could be delivered simultaneously 9 , further reducing the chances of viral escape.', 'As a further advantage, we demonstrate a potential pan-coronavirus strategy to target not only viruses that circulate in humans, but also those that currently are found in animal reservoirs that might transfer to humans to cause disease.', 'If the crRNAs targeting these viruses can be tested and validated before they ever infect humans, we can greatly accelerate the development of countermeasures for future emergent threats.', 'In summary, our PAC-MAN strategy represents a potentially powerful new approach for inhibiting viral function and replication, and we envision it could be useful for a diverse array of circulating and emergent viral threats.']}\n", - "{'sentences': ['The current study illustrated the high prevalence of hypokalemia in the patients with COVID-19 and the positive association between the degree of hypokalemia and the severity of COVID-19.', 'The study also proved that hypokalemia was more attributable to renal loss of K + than gastrointestinal loss.', 'Previous literature has proved that sufficient and appropriate levels of plasma K + have a protective role in preventing myocardial failure through weakening cellular hyperpolarity and depolarization 10, 11 .', \"SARS-CoV-2 can result in heart dysfunction due to the intensively expressed ACE2 in the patients' myocardial cells that act as receptors for this virus.\", 'Therefore, it is beneficial to patients that plasma K + levels be frequently checked and maintained between 4.0 and 5.5 mmol/L or 4.5 and 5.5 mmol/L for serum K + as serum generally has more K+ than plasma 12 .', 'In the present study, hypokalemia was prevailing among the patients with COVID-19, up to 62% (108/175) patients having plasma K + that was under 3 mmol/L. Among 175 patients, only 10 patients had plasma K + of 4 mmol/L recommended for patients with myocardial dysfunction.', \"That strikingly low prevalence of optimal concentration of plasma K + implied a massive risk for the patients' heart to be affected by both hypokalemia and the virus.\", 'As an emerging infectious disease, the available data on serum K + levels is scanty.', 'Only one previous study on 41 patients reported 4.2 mmol/L as the mean serum K + , as well as higher K + in the ICU patients (mean, 4.6 important indices for hypokalemia, myocardial injury, and evaluation of disease.', 'We expected these arrangements of results might facilitate future studies.', 'Seeing that hypokalemia was prevalent among patients with COVID-19 and associated with the severity of the disease, elucidation of the mechanisms for hypokalemia was elementary for understanding and treatment of COVID-19.', 'In the current situation, two probable causes of hypokalemia are increased gastrointestinal loss and increased urinary loss 15 .', 'Both causes can find their way in the patients with COVID-19, as mentioned in the introduction section.', 'However, the present findings indicated that gastrointestinal loss might not contribute much to hypokalemia as based on the following reasons: only a small proportion of patients with hypokalemia showing gastrointestinal symptoms, e.g., 31% of patients with severe hypokalemia having diarrhea; among the patients with hypokalemia, no significant difference between those with and those without diarrhea; the average number of diarrhea onsets being 5 times/day and diarrhea ending in a short time, meaning that the diarrhea was mild.', 'Therefore, hypokalemia might principally result from increased urine loss.', 'This was proved in this study by the dramatically increased urine K + output in the hypokalemia group than the control group with normokalemia.', 'This finding that increased urine K + was the primary cause of hypokalemia was consistent with the pathogenesis of SARS-CoV-2.', 'This virus drives RAS towards enhanced ACE-Ang II (angiotensin II)-Ang II type 1 receptor (AT1', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org /10.1101 /10.', '/2020 to collecting tubule of the kidney and enhanced potassium secretion.', 'This effect is similar to the effect of aldosterone that stimulates water and sodium reabsorption and potassium excretion and thus increases body water and blood pressure 16 .', 'As hypokalemia has an adverse effect on myocardial functions, in-time treatment is required for achieving good outcomes.', 'However, the mechanism of hypokalemia in the present study hinted that it was challenging to achieve normokalemia in the presence of continuous renal loss of K + .', 'This worry was proved by the elevated amount of urine K + measured in umol/gram of creatinine ( Figure 1 ).', 'The continual K + supplements had very little effect on the return of normokalemia when the urine loss of K + persisted in the severe cases.', 'Interestingly, we found a noteworthy phenomenon in most patients who were cured of COVID-19.', 'As shown in Figure 1 , when patients were inclined to recovery, they responded well to K + supplement treatment and steadily returned to normokalemia.', 'This phenomenon indicated the end of urine loss of K + due to disordered RAS balance; in other words, the ACE2 function began to return.', 'This exciting finding suggested that return of normokalemia might be a reliable biomarker for monitoring ACE2 function.', 'Although COVID-19 causes injury to lungs, heart, liver, and kidney, our study showed the occurrence of abnormal indices related to heart, liver, and kidney was low, and oxygen saturation often returned to normal level upon oxygen inhalation in most patients ( Table 2 and Table 4 ).', 'Several laboratory indices, such as elevated CK, CK-MB, LDH, ALT and AST were usually came to normal level or substantially improved after relevant treatment.', 'The superficial mildness contradicted with the sudden progression of disease in some patients.', 'This contradiction might result from the fact that the biomarkers were not sensitive to reflect the whole progression of this disease.', 'Therefore, a more sensitive biomarker to monitor the ongoing condition is All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.02.27.20028530 doi: medRxiv preprint urgently needed for these patients.', 'As discussed above, 93% severe and critically ill patients had hypokalemia, showing that depletion of K + was prevailing.', 'Based on analysis of the trend in plasma K + and urine output of K + , the end of the depletion often suggested a good prognosis (Figure 1) .', 'Therefore, comprehensive analysis of K + depletion can be achieved by monitoring urine K + loss, plasma K + , and the response to K + supplement treatment.', 'Importantly, the information from this analysis related to hypokalemia directly reflects the very basis of the pathogenesis of SARS-CoV-2 and might be a reliable, int-time and sensitive biomarker to reflect the progression of COVID-19.', 'The present study had some limitations.', 'Most patients were still hospitalized.', 'Only a small proportion of cases were used to evaluate the treatment outcomes.', 'However, from several patients who had been cured, the principal results related to hypokalemia treatment were consistent, which could provide reliable information.', 'Since this life-threatening disease is still ongoing in China and is developing in several countries, we expect our findings can provide timely information about better understanding and treatment of COVID-19.', 'To summarize, the present study has identified the prevailing hypokalemia in patients with COVID-19.', 'The correction of hypokalemia is challenging because of continuous renal loss of potassium resulting from the degradation of ACE2 by the binding of SAR-CoV-2.', 'The end of loss of K + often indicates a good prognosis and may be a reliable, in-time, and sensitive biomarker that reflects the end of adverse effect on the RAS system by SAR-CoV-2.', \"Due to the possible injury to cardiovascular functions, neurohormonal activation, and other vital organs by hypokalemia, clinicians should pay great attention to hypokalemia and the patients' response to K + supplements.\", 'All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.02.27.20028530 doi: medRxiv preprint']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['The present study for the first time showed the relationship between plasma NT-proBNP level and risks of in-hospital death in severe COVID-19 patients.', 'Severe COVID-19 patients with higher NT-proBNP levels tended to be older with higher levels of cardiac injury markers and higher levels of systematic inflammation markers.', 'Patients with higher NT-proBNP (above 88.64 pg/mL) level had lower cumulative survival rate.', 'After adjusting for potential cofounders in separate modes, NT-proBNP presented as an independent risk factor of in-hospital death in patients with severe COVID-19.', 'All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.07.20031575 doi: medRxiv preprint Previous studies have found that NT-proBNP is a powerful and independent predictor of mortality in community-acquired pneumonia (CAP', 'However, in present study, the cutoff value of NT-proBNP to predict the adverse outcome of severe COVID-19 patients was far lower than the threshold to diagnose heart failure (450 pg/mL for <50 years, 900 pg/mL for 50-75 years and 1,800 pg/mL for >75 years) 11 .', 'It was suggested that the prognostic effect of plasma NT-proBNP in In present study, NT-proBNP was positively correlated to the makers of cardiac injury and systematic inflammation.', 'The levels of cardiac injury and inflammation also showed risks of in-hospital death by univariate Cox proportional-hazards regression All rights reserved.', 'No reuse allowed without permission.', 'the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'https://doi.org/10.1101/2020.03.07.20031575 doi: medRxiv preprint analyze.', 'However, in multiple regression analyses, the cardiac injury markers were not associated with the hazard ratios of in-hospital death under the affection of NT-proBNP.', 'Both NT-proBNP and inflammation showed independent effect of predicting inhospital death.', 'Considering these, the prognostic effect of NT-proBNP might be a comprehensive index of reflecting the overall state of the organism.', 'SARS-CoV-2 binds with ACE2, resulting the uncontrolled releasing of angiotensin 2 (ANGII', 'The copyright holder for this preprint (which was not peer-reviewed) is .', 'Abbreviations: NT-proBNP, N-terminal pro-brain natriuretic peptide; HP, hypertension; CHD, coronary heart disease; MYO, myoglobin; CK-MB, creatine kinase-MB; Hs-TnI, high-sensitivity troponin-I; WBC, white blood cell; LYM, lymphocytes; CRP, c-reactive protein; PCT, procalcitonin; HR, hazards ratio; 95%CI, 95% confidence interval.']}\n", - "{'sentences': ['A newly identified coronavirus, 2019-nCoV, has been posing significant threats to public health since December 2019.', 'ACE2, the host cell receptor for severe acute respiratory syndrome coronavirus (SARS), has recently been demonstrated in mediating 2019-nCoV infection.', 'Interestingly, besides the respiratory system, substantial proportion of SARS and 2019-nCoV patients showed signs of various degrees of liver damage, the mechanism and implication of which have not yet been determined.', 'Here, we performed an unbiased evaluation of cell type specific expression of ACE2 in healthy liver tissues using single cell RNA-seq data of two independent cohorts, and identified specific expression in cholangiocytes.', 'The results indicated that virus might directly bind to ACE2 positive cholangiocytes but not necessarily hepatocytes.', 'This finding suggested the liver abnormalities of SARS', 'An very recent epidemiologic study revealed that 43 out of 99 initial patients infected with 2019-nCoV had various degrees of liver function abnormality, with alanine aminotransferase (ALT) or aspartate aminotransferase (AST']}\n", - "{'sentences': ['Here we report the expression pattern of ACE2 in the human intestine at single-cell resolution.', 'Our data suggest that ACE2 is specifically expressed by colonocytes and positively associated with viral entry and egress, consistent with observations that the gastrointestinal tract is a potential route for 2019-nCoV infection.', 'In supportive of the view that ACE2 expression prevents intestinal inflammation [11, 12] , bioinformatic analysis suggested that genes regulating type I and type III innate immunity, NK and T cell mediated cytotoxicity and energy metabolism are positively associated with ACE2 expression.', 'By contrast, humoral immunity, phagocytosis All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.02.05.20020545 doi: medRxiv preprint 6 and complement activation are negatively associated with ACE2 expression.', 'These findings may facilitate concurrent and future investigations of the nature and function of the immune system at systemic and local levels in patients with 2019-nCoV pneumonia.', 'Notably, SARS-CoV spike protein engagement downregulates ACE2 expression and activates the RAS [6] .', 'Given that hypertension is common in severe 2019-nCoV pneumonia [1] , it is highly likely that the RAS is activated in the lungs of patients with severe pneumonia.', 'The Xa inhibitor Rivaroxaban [5]']}\n", - "{'sentences': ['Since the emergence of SARS-CoV-2 in December 2019, Coronavirus Disease-2019 has rapidly spread across the globe.', 'Epidemiologic studies have demonstrated that age is one of the strongest risk factors influencing the morbidity and mortality of COVID-19.', 'Here, we interrogate the transcriptional features and cellular landscapes of the aging human lung through integrative analysis of bulk and single-cell transcriptomics.', 'By intersecting these age-associated changes with prior experimental data on host interactions between SARS-CoV-2 or its relative SARS-CoV, we identify several age-associated factors that may contribute to the heightened severity of COVID-19 in older populations.', 'These analyses illuminate potential avenues for further studies on the relationship between the aging lung and COVID-19 pathogenesis, which may inform strategies to more effectively treat this disease.', 'Age is one of the strongest risk factors for severe outcomes among patients with COVID-19 1,2.', 'For instance, the case-fatality rate of patients 50-59 years old was reported to be 1.0% in Italy (as of March 17, 2020) and 1.3% in China (as of February 11, 2020) 3,4; in contrast, the case-fatality rate of patients ≥ 80 years old was 20.2% in Italy, and 14.8% in China during that same time frame (Figure 1a) .', 'Similarly, in the United States, the Center for Disease Control (CDC) estimated that from February 12 to March 16, 2020, the case-fatality rate of patients 55-64 years old was 1.4 -2%, and 10.4 -27.3% for patients ≥ 85 years old 5 (Figure 1a) .', 'Furthermore, a recent analysis of Chinese CDC', 'While the effects of age on COVID-19 are likely to be multifactorial, involving a complex blend of systemic and local factors, we hypothesized that tissue-intrinsic changes that occur with aging may offer valuable clues.', 'To explore possible mechanisms by which age influences the clinical manifestations of SARS-CoV-2 infection, here we investigate the transcriptomic features and cellular landscape of the aging human lung in relation to SARS-CoV-2.', 'We emphasize that our findings are not intended to direct clinical practice, but rather to generate hypotheses and to further guide research efforts that can improve our understanding of this disease.', 'We focused our analysis on the Genotype-Tissue Expression (GTEx) project10,11, a comprehensive public resource of gene expression profiles from non-diseased tissue sites.', 'As the lung is the primary organ affected by COVID-19, we specifically analyzed lung RNA-seq transcriptomes from donors of varying ages (20-79 years old) (Figure 1b) .', 'A total of 578 lung RNA-seq profiles were compiled, of which 31.66% were from women.', 'An initial hypothesis for why SARS-CoV-2 differentially affects patients of varying ages is that the expression of host factors essential for SARS-CoV-2 infection may increase with aging.', 'To assess this possibility, we examined the gene expression of ACE2, which encodes the protein angiotensin-converting enzyme 2 that is coopted as the host receptor for SARS- [12] [13] [14] [15] There was no statistically significant association between age and ACE2 expression levels (Kruskal-Wallis test, p = 0.92) (Figure 1c) .', 'While ACE2 is the direct cell surface receptor for SARS-CoV-2, transmembrane serine protease 2 (TMPRSS2) and cathepsin L (CTSL', 'Expression of the corresponding genes TMPRSS2 and CTSL was modestly associated with age (p = 0.0039 and p = 0.026, respectively) (Figure 1c) , but TMPRSS2 and CTSL expression levels tended to decrease with age.', 'Of note, biological sex was not significantly associated with expression of ACE2, TMPRSS2, or CTSL (Supplementary Figure 2a-c) , though it has been observed that males are more likely to be affected by COVID-19 than females16-18.']}\n", - "{'sentences': ['The coronavirus disease 2019 has become a global pandemic currently.', 'Many drugs showed potential for COVID-19 therapy.', 'However, genetic factors which can lead to different drug efficiency and toxicity among populations are still undisclosed in COVID-19 therapy.', 'We selected 67 potential drugs for COVID-19 therapy (DCTs) from clinical guideline and clinical trials databases.', '313 pharmaco-genes related to these therapeutic drugs were included.', 'Variation information in 125,748 exomes were collected for racial differences analyses.', 'The expression level of pharmaco-genes in single cell resolution was evaluated from single-cell RNA sequencing (scRNA-seq', 'Results: Pharmacogenes, including CYP3A4, ABCB1, SLCO1B1, ALB, CYP3A5, were involved in the process of more than multi DCTs.', '224 potential drug-drug interactions (DDIs', 'Racial discrepancy of common nonsynonymous mutations was found in pharmacogenes including: VDR, ITPA, G6PD, CYP3A4 and ABCB1 which related to DCTs including ribavirin, α -interferon, chloroquine and lopinavir.', 'Moreover, ACE2, the target of 2019-nCoV, was only found in parts of lung cells, which makes drugs like chloroquine that prevent virus binding to ACE2 more specific than other targeted drugs such as camostat mesylate.', 'This study firstly focused pharmacogenetics and provided clinical suggestions for precision medicine in COVID-19 treatment systematically.', '44 DCTs were showed to associated with at least one gene.', 'And drug-gene network highlighted multi drug related genes in COVID-19 treatment.', 'Meanwhile, inter-racial variances in drug efficacy were found related to nonsynonymous mutations among different races, which indicated that racial special strategy for COVID-19 therapy should be considered during the outbreak of COVID-19 worldwide.', 'Since nonsynonymous mutations and gene expression levels can both affect the DCTs efficacy and toxicity as mentioned above, optimized therapy strategies are needed to benefit these affected patients all over the world.', 'In this study, we give three suggestions for DCTs as follows.', 'Firstly, drugs in CPIC guideline including ribavirin, α -interferon, chloroquine and captopril should be utilized with genetic detections as guided.', 'In this situation, adequate gene detection kits should be prepared in Africa for COVID-19 therapy, as related genetic variation frequency is higher in AFRs than other countries.', 'Secondly, drug such as chloroquine whose efficacy and toxicity can be determined by nonsynonymous mutations, may be preferred in special population with lower frequency of risk alleles such as Finnish and Non-Finnish European.', 'Otherwise, alternative drug for chloroquine can be used in high risk populations.', 'Thirdly, for drugs that can inhibit the activity of CYP450, DDI should be prevented in COVID-19', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'treatment (Table 1) .', 'When inhibitors of CYP450 were utilized, the dosage of these drugs should be adjudged carefully to avoid overdosage.', 'Although precision medicine should be considered in COVID-19 treatment, there are still many challenges to face.', 'The first challenge is that pharmacogenes of many drugs for COVID-19 are still not clear, due to that many newly developed drugs are still under clinical trials, their pharmacogenes can hardly be fully identified currently.', 'A potential solution is to predict candidate pharmacogenes according to the chemical structure of a new drug by the artificial intelligence and machine learning algorithm [21, 22] .', 'Then related molecular biological studies can be conducted to validate these candidate pharmacogenes rapidly.', 'Then the period of pharmacogenes identification can be shorted.', 'The second challenge is that some serious nonsynonymous mutations can be hardly identified in current pharmacogenetics studies, due to the frequencies of many nonsynonymous mutations are lower than 1%.', \"That's why the nonsynonymous mutations we presented above are common variants.\", 'If there are only a few patients carried a serious nonsynonymous mutation, related study can hardly be conducted to identify this mutation because of the limited sample size.', 'However, as we indicated in Figure 3 , most of nonsynonymous mutations are rare variations.', 'Therefore, a reliable way to predict potential pharmacogenetic variation is also important to improve the efficacy or avoid serious toxicity [23] .', 'The third challenge is that a suitable strategy for precision medicine in COVID-19 treatment is still lack.', \"A well-designed gene detection panel is important to fully characterized the patients' genotypes which relate to the drug effects [24] .\", 'Then the best treatment regimen can be utilized for this patient, and both of the efficacy and the safety can be guaranteed.', 'In our study, feasible suggestions were given, and it still can be much improved with the development of some pharmacogenetic studies in the future.', 'Last but not least, the expression level of All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'pharmacogenes in patients can hardly be detected in single cell resolution during COVID-19 treatment, although the expression level of these genes can be associated with drug efficacy or toxicity.', 'A potential solution is to build a systematic pharmacogenes expression map in single cell level among different populations in different age stages [25] .', 'This map would be helpful for personalized medicine in the future.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': [\"Please cite this article as: B. Robson, COVID-19 Coronavirus spike protein analysis for synthetic vaccines, a peptidomimetic antagonist, and therapeutic drugs, and analysis of a proposed achilles' heel conserved region to minimize probability of escape mutations and drug resistance, Computers in Biology and Medicine (2020), doi: https://doi.\", 'This paper continues a recent study of the spike protein sequence of the .', 'It is also in part an introductory review to relevant computational techniques for tackling viral threats, using COVID-19 as an example.', 'Q-UEL tools for facilitating access to knowledge and bioinformatics tools were again used for efficiency, but the focus in this paper is even more on the virus.', \"Subsequence KRSFIEDLLFNKV of the S2' spike glycoprotein proteolytic cleavage site continues to appear important.\", \"Achilles' Heel, less likely to acquire resistance by mutation, as has happened in some early SARS vaccine studies discussed in the previous paper.\", 'Preliminary conformational analysis of the receptor (ACE2) binding site of the spike protein is carried suggesting that while it is somewhat conserved, it appears to be more variable than KRSFIEDLLFNKV.', 'However compounds like emodin that inhibit SARS entry, apparently by binding ACE2, might also have functions at several different human protein binding studies.', 'The enzyme 11β-hydroxysteroid dehydrogenase type 1 is again argued to be a convenient model pharmacophore perhaps representing an ensemble of targets, and it is noted that it occurs both in lung and alimentary tract.', 'Perhaps it benefits the virus to block an inflammatory response by inhibiting the dehydrogenase, but a fairly complex web involves several possible targets.']}\n", - "{'sentences': ['Amantadine disrupts lysosomal gene expression; potential therapy for COVID19', 'SARS-coronavirus 2 is the causal agent of the COVID-19 outbreak.', 'SARS-Cov-2 entry into a cell is dependent upon binding of the viral spike (S', 'We have conducted a high throughput drug screen gene expression analysis to identify compounds that would downregulate the expression of CTSL/CTSB.', 'One of the top significant results shown to downregulate the expression of the CTSL gene is Amantadine.', \"Amantadine was approved by the US Food and Drug Administration in 1968 as a prophylactic agent for influenza and later for Parkinson's disease.\", 'It is available as a generic drug..', 'Amantadine in addition to downregulating CTSL appears to further disrupt lysosomal pathway , hence interfering with the capacity of the virus to replicate.', 'It acts as a lysosomotropic agent altering the CTSL functional environment.', 'We hypothesize that Amantadine could decrease the viral load in SARS-CoV-2 positive patients and as such it may serve as a potent therapeutic decreasing the replication and infectivity of the virus likely leading to better clinical outcomes.', 'Clinical studies will be needed to examine the therapeutic utility of amantadine in COVID-19 infection.', 'All rights reserved.', 'No reuse allowed without permission.', 'Decreasing the expression of enzymes is likely a potential mechanism that would lower the capacity of the virus to exit the cell.', 'Another viable option is lysosomal dysfunction .that can interfere in many ways with viral replication because this is where the virus is going to get assembled and get ready for subsequent replication.', 'Given one is able to perturb the lysosomes, their function or microenvironment, you may offer protection from the virus or decrease the severity of the symptoms.', 'Having seen that amantadine does not only down-regulate Cathepsin L, but a number of key lysosomal enzymes, we can now hypothesize that lysosomal dysfunction induced by amantadine administration can be protective from viral entry and replication.', 'Our hypothesis that people with certain lysosomal storage diseases are resistant to one of these viruses.', 'Along these lines there is suggestive evidence for this to be true.', 'NPC1 (Neimman Pick type C, storage, cholesterol transport disorder) offers resistance to Ebola in patient cell lines 20 , 21 .', 'Even more interesting in the attached article, bats show selective sensitivity to Ebola versus Marburg viruses', 'Interfering with the lysosomal milieu can have protective effects from coronavirus which we know uses cathepsin L, a pH sensitive enzyme, to process the cleavage of the spike protein.', 'Amantadine would be predicted by physical and chemical properties to accumulate in the lysosomes and raise a the pH, likely enough to interfere with cathepsin L function.', 'The gene expression pattern reported in this paper suggests that a more general lysosomal program is down-regulated, likely through a common set of transcription factors.', 'Amantadine could hence be used as a potent agent to decrease viral load if administered early enough in the course of the COVID-19 infection.', 'Accumulation in lysosomes, If effective, could reduce viral load, may decrease intra-host organ spread and decrease associated disease severity and progression.', 'Further studies including clinical trials would be required in order to examine the role of amantadine administration as a treatment for COVID-19.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.04.05.026187 doi: bioRxiv preprint']}\n", - "{'sentences': ['Apparently, in addition to the drugs currently prescribed to treat COVID-19, Arbidol hydrochloride, interferon, and Thalidomide plus Methylprednisolone can also be used due to their effects reported in clinical studies.', 'However, more studies are needed to confirm the use of corticosteroids, as there are conflicting reports regarding their efficacy.', 'Also, potential drugs listed in Table 1, such as Remdesivir, Atazanavir, Saquinavir, and Formoterol, and Tocilizumab can be introduced as treatments for COVID-19 if they prove to be effective in animal and clinical studies.']}\n", - "{'sentences': ['Of chloroquine and COVID-19']}\n", - "{'sentences': ['Starting from December 2019, a novel coronavirus, named 2019-nCoV, was found to cause Severe Acute Respiratory (SARI', 'With the hope to identify candidate drugs for 2019-nCoV, we adopted a computational approach to screen for available commercial medicines which may function as inhibitors for the M pro of 2019-nCoV. Up to 10 commercial medicines that may form hydrogen bounds to key residues within the binding pocket of 2019-nCoV M pro were identified, which may have higher mutation tolerance than lopinavir/ritonavir and may also function as inhibitors for other coronaviruses with similar M pro binding sites and pocket structures.', 'Coronavirinae, are enveloped positive-stranded RNA viruses which have spikes of glycoproteins projecting from their viral envelopes, thus exhibit a corona or halo-like appearance (Masters and Perlman, 2013; Cui et al., 2019) Coronaviruses are the causal pathogens for a wide spectrum of respiratory and gastrointestinal diseases in both wild and domestic animals, including birds, pigs, rodents, etc (Dhama et al., 2014).', 'Previous studies have found that six strains of coronaviruses are capable to infect human, author/funder.', 'All rights reserved.', 'No reuse allowed without permission.']}\n", - "{'sentences': ['This multicenter case series describes 24 critically ill patients who presented with acute hypoxemic respiratory failure and laboratory-confirmed Covid-19 infection.', 'We included all patients with Covid-19 who were admitted to an ICU at nine Seattle-area hospitals between February 24 and March 9, 2020.', 'All the patients had acquired Covid-19 without known exposure to a returning traveler.', 'Coexisting lower respiratory bacterial infections were not identified in sputum and blood cultures obtained early in the clinical course.', 'Overall outcomes were poor in patients who received ICU care.', 'The patients in our series presented with respiratory symptoms similar to those of patients described in reports from China, which indicates a common host response to SARS-CoV-2.', 'Cough was the most common presenting symptom, as it was in reports from China, and the mean duration of symptoms before ICU admission was 1 week.13 Only half the patients had fever at the time of hospital admission, which suggests that fever may not be a useful criterion to determine the severity of illness and that diagnostic algorithms that require fever for Covid-19 testing may delay diagnosis.', 'The majority of patients had chronic illnesses before their admission to the ICU, most commonly diabetes mellitus and chronic kidney disease.', 'Lymphocytopenia was common on hospital admission, as it was in reports from China.13', 'The case fatality rate of 50% in this series (to date) is similar to that reported among critically ill patients in Chinese hospitals but lower than that in a single-center experience reported from our area.8,13 Although the case fatality rate was higher in persons 65 years of age or older, it was still substantial (37%) in persons younger than 65 years of age.', 'Our case fatality rate may be an underestimate, given that 3 patients remained intubated at the time data were censored.', 'Patients who received mechanical ventilation had high oxygen requirements soon after initiation of mechanical ventilation, with plateau pressures (mean, 25 cm of water) and driving pressures (mean, 12 to 13 cm of water) similar to those in populations of patients with ARDS enrolled in clinical trials.14,15 For example, the mean plateau pressure in the Reevaluation of Systemic Early Neuromuscular Blockade (Reevaluation of Systemic Early Neuromuscular Blockade', 'A large proportion of patients in this series presented with shock that required vasopressor support.', 'In patients who had an echocardiogram, myocardial dysfunction was uncommon.', 'The lack of bacterial or viral coinfection suggests that the observed shock was directly related to Covid-19.', 'In these preliminary data, Covid-19 infection appears to differ from seasonal influenza, which is commonly associated with bacterial coinfection due to pathogens that colonize the nasopharynx, such as staphylococcus and streptococcus.16 Regarding antiviral interventions, 7 patients received compassionate-use remdesivir, but we have insufficient information to report associated outcomes.', 'Bronchoscopy was performed in a minority of patients and did not appear to change clinical management.', 'Three patients with mild asthma had received systemic glucocorticoids within 1 week before ICU admission, as outpatients, for presumed asthma exacerbation while they had symptoms of Covid-19.', 'These 3 patients then presented to the hospital again, with severe respiratory failure requiring invasive mechanical ventilation.', 'Previous studies have shown that glucocorticoid treatment for phylogenetically similar viruses, SARS-CoV (2003) and Middle East respiratory syndrome coronavirus (MERS-CoV', 'Our study has several notable limitations.', 'First, some cases had incomplete documentation of clinical symptoms, missing laboratory testing, or both.', 'However, given the need to provide objective data and the urgent timeline, we did not approach patients to obtain additional history or biologic samples for laboratory measurement.', 'Second, 7 patients (29%) remained in hospitals at the time of data censoring on March 23, 2020; as a result, outcomes for those patients were not known.', 'Third, because of our focus on the critical care needs of patients with the greatest severity of illness, our sample size is small.', 'Finally, it is possible that critically ill patients with established goals of care that were not consistent with admission to an ICU were not included in this report.', 'Specifically, this includes patients who received care on the general medical ward that focused on comfort measures only.', 'This early experience of the Covid-19 pandemic in the United States resembles the experience in other countries, with high mortality for patients requiring care in the ICU.', 'Patients with coexisting conditions and older age are at risk for severe disease and poor outcomes after ICU admission.', 'Better information is needed to inform care for these challenging patients.', 'Our findings also highlight the importance of planning for mass critical care as the need for ICU care and ventilatory support to treat patients with Covid-19 grows rapidly in the United States.22,23']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Two proteins from the neomycin, kanamycin and gentamicin biosynthesis pathway resulted upregulated at 24 h after virus infection (Figure 1b) : HK1 (hexokinase 1) and HKDC1 (hexokinase domain containing 1), which are proteins related to glucose use and homeostasis 16, 17 .', 'Interestingly, HK has been previously associated with inflammatory response in autoimmune disorders, and, deoxy-D-glucose (2-DG), an inhibitor of HK, has been proposed to ameliorate autoimmune inflammation 18 .', 'Recently, 2-DG has been shown to inhibit SARS-CoV-2 replication in Caco-2 cells 10 and to inhibit rhinovirus infection and inflammation in a murine model 19 .', 'For all this, hexokinase link to SARS-CoV-2 infection and related inflammation response deserves further study.', 'In Figure 2a , the network formed by the DE proteins, excluding isolated nodes, is shown.', 'One of the subnetworks with a higher number of connections is the one formed by RANBP2 (E3 SUMO-protein ligase RanBP2) (Figure 2b ).', 'RANBP2 forms a complex at the nuclear pore with TRIM5α, a cytoplasmic restriction factor that blocks post-entry retroviral infection and is regulated by SUMO.', 'It has been demonstrated that loss of RANBP2 blocked SUMOylation of TRIM5α, suppressing its anti-retroviral activity 20 .', 'Here RANBP2 presented a statistically significant fold-change (log) of -1.295 at 24 h post-infection, therefore the role of RAMBP2-TRIM5α in coronavirus infection deserves further consideration.', 'In the same subnetwork as RANBP2, some proteins, which are interestingly related to cell cycle progression, also deserve further research ( Figure 2b) : AURKA, AURKB, SPC25 and STAG1 participate in the regulation of chromosome segregation during mitosis [21] [22] [23] [24] .', 'Interestingly, they were all found down-regulated at 24 h post-infection, except STAG1, which was strongly up-regulated.', 'In this subnetwork, closely related to AURKB, and also down-regulated, is UBE2C (Ubiquitin-conjugating enzyme E2 C), which is an essential factor of the anaphase promoting complex/cyclosome (APC/C', 'In parallel to re-analyzing the data with alternative tools, when taking a close look at the data we discovered a down-regulation trend over time of ACE2 ( Figure 3 ) that had not been highlighted by the original authors 10 .', 'Actually, at 24 h time ACE2 quantitation presented a fold-change (log) of -0.168 and a p-value of 0.01.', 'Coronavirus entry into target cells depends on binding of its spike (S) proteins to a cellular receptor, which facilitates viral attachment to the surface of target cells.', 'ACE2 was reported as the entry receptor for SARS-CoV 26 , another coronavirus closely related to SARS-CoV-2, playing a key role in SARS-CoV transmissibility 27 , and recently also for by SARS-CoV-2 7 .', 'ACE2 is also a peptidase in the reninangiotensin system, converting antiotensin I to angiotensin (1-9) and angiotensin II to angiotensin (1-7) , a vasodilator.', 'The protective role in lung injury is related to this cleavage of angiotensin II.', 'Regarding ACE2 and SARS-CoV, it was also reported that ACE2 expression protects from lung injury and is downregulated by SARS-CoV 8, 9 , which might promote lung injury, therefore worsening the prognosis of the disease.', 'Here we highlight that SARS-CoV2 seems to be also interfering with ACE2 expression, which could be related to a higher level of lung injury as it was demonstrated for SARS-Cov.', 'When inspecting the quantitative data for other proteins in the renin-angiotensin system, two other proteins were found to be downregulated 24 h post-infection cathepsin A (CTSA) and angiotensinogen (AGT', \"The significantly affected pathways were analyzed using iPathwayGuide software, which implements an 'impact analysis' approach, taking into consideration not only the over-representation of differentially expressed genes in a given pathway (i.e. enrichment analysis), but also topological information such as the direction and type of all signals in a pathway, and the position, role, and type of each protein 11 .\", 'Although six pathways were found to be significantly impacted at 24 h, and two at 6 h, the number of DE proteins in these pathways were low (ranging 2 to 6 proteins).', 'For instance, the pathway transcriptional misregulation in cancer, with 5 DE proteins out of the 38 included in the pathway; the proteoglycans in cancer pathway, with 6 DE proteins out of 96; or the axon guidance pathway, with 3 DE proteins out of a total of 64 proteins.', 'Thus, we consider the experimental evidence for having an actual effect of the virus over these mechanisms is relatively low.', 'However, still having a low number of DE proteins, the ratio of DE proteins to total proteins included in three other significant pathways was higher, and for that they deserve a closer look.', 'They are linoleic acid metabolism pathway; neomycin, kanamycin and gentamicin biosynthesis pathway; and neuroactive ligand-receptor interaction pathway.', 'Linoleic acid metabolism pathway is linked to arachidonic acid metabolism and eicosanoids pathway, and therefore it could play a role in the inflammatory response observed in stages II and III of COVID-19 patients 12 .', 'Actually, the two proteins found DE in this pathway at 24 h post-infection, PLA2G4A (cytosolic phospholipase A2) and PLA2G2A (phospholipase A2, membrane associated), are key components of the phospholipase A2 group, which have been previously suggested to participate in a key mechanism in the propagation of inflammatory reaction 13 , and it has been demonstrated its contribution to inflammation and eicosanoid .', 'CC-BY 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.26.009605 doi: bioRxiv preprint profile in arthritis 14 and in cardiovascular diseases 15 .', 'When checking the trend over the whole time course, both proteins share the same profile with a clear increase at 24 h after virus infection (Figure 1b ).', 'It will then be interesting to explore the potential of these two proteins as COVID-19 early systemic diagnosis biomarkers.']}\n", - "{'sentences': ['This project highlights the ability of a voluntary collaboration involving designers, engineers, material scientists, clinicians, local fabricators and concerned citizens to perform rapid-cycle iterative prototyping developing 3D-printed PPE that addresses severe shortages in a time of crisis.', 'The resulting BWH/PanFab Mk 1.0 face shield provides protection from spray in a reusable design that can be cleaned using standard hospital disinfectants.', 'Using a team that self-organized on-line in response to a request of hospital incident command, PanFab was able to proceed from project inception to implementation in three weeks.', 'Critically, using a clinical testing approach, we were able to introduce a nontraditionally manufactured product into a hospital supply chain.', 'To date, we have fabricated hundreds of face shields, all of which remain in use, and we expect to introduce an additional thousand face shields within the coming weeks.', 'Keys to successful integration of this face shield in the hospital setting included a dedicated liaison within incident command, the willingness of the IRB to work closely and quickly with designers, and the ability of the BWH legal and leadership teams to act quickly on policy issues.', 'With a design in hand, we expect that others can deploy the solution we describe in as little as two weeks, plus 2-3 days for clinical testing (if required).', 'In some cases, teams seeking to replicate our approach will need to modify the PanFab design due to shortages of raw materials or differences in fabrication capabilities.', 'Under these circumstances, additional user testing under an IRB protocol might be required.', 'We are currently pursing three follow-on activities.', 'First, we are developing designs that will make it possible to use injection molding as an alternative to 3D printing (see below).', 'Second, we intend to subject our final design (printed or molded) to testing and certification under ANSI/ISEA Z.87.1-2015.', 'We note however that design and testing standards are not freely available (they currently cost several hundred USD) and testing represents a substantial additional expense.', 'Nonetheless, having a set of tested and approved designs would increase resiliency during a public health emergency such as COVID-19.', 'Finally, we are testing various procedures for decontaminating and reusing face shields and similar PPE.', 'Preliminary results with ionized hydrogen peroxide sterilization (iHP; TOMI SteraMist™) 10 suggests that PanFab face shields can be successfully sterilized without suffering damage through at least five cycles.']}\n", - "{'sentences': ['The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15', 'Steroid compounds, which are expected to have dual functions in blocking host inflammation and MERS-CoV replication, were screened from a chemical library.', 'Within this library, ciclesonide, an inhaled corticosteroid, suppressed human coronavirus replication in cultured cells, but did not suppress replication of respiratory syncytial virus or influenza virus.', 'The effective concentration of ciclesonide to block SARS-CoV-2 (the cause of replication (EC 90 ) was 6.3 μ M. After the eleventh consecutive MERS-CoV passage in the presence of ciclesonide, a resistant mutation was generated, which resulted in an amino acid substitution (A25V) in nonstructural protein (NSP', 'Steroid compounds, which are expected to have dual functions in blocking both coronavirus replication and host inflammation, were screened from a chemical library.', 'The cytopathic effect caused by MERS-CoV infection was measured to evaluate viral replication.', 'Four steroid compounds, ciclesonide, mometasone furoate, mifepristone, and algestone acetophenide conferred a greater than 95% cell survival rate (Fig. S1 ).', 'Next, concentration-dependent viral growth suppression and drug cytotoxicity were assessed.', 'Ciclesonide exhibited low cytotoxicity and potent suppression of viral growth (Fig. 1a ).', 'Cortisone and prednisolone, which are commonly used for systemic steroid treatment, dexamethasone, which has strong immunosuppressant effects, and fluticasone, a commonly used inhaled steroid, did not suppress viral growth (Fig. 1a) .', 'The antiviral effects of steroids against various species of viruses were tested by quantifying propagated virus in culture medium.', 'Ciclesonide and mometasone also suppressed replication of other coronaviruses, HCoV-229E and SARS-CoV, but not replication of RS virus or influenza virus (Fig. S2 ).', 'In addition, ciclesonide slightly but significantly inhibited rubella virus (having positive strand RNA genome) replication (Fig. S2 ), suggesting that ciclesonide interacted with the replication site of positive-strand RNA virus intracellularly.', 'To identify the drug target of virus replication, we conducted 11 consecutive MERS-CoV passages in the presence of 40 μ M ciclesonide or 40 μ M mometasone.', 'A mutant virus that developed resistance ciclesonide was generated (Fig. 1b) , but no resistant virus to author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.11.987016 doi: bioRxiv preprint mometasone was generated.', 'Next-generation sequencing identified that an amino acid substitution at A25V (C19647T in the reference sequence NC_019843.3) in nonstructural protein 15 (NSP15', 'Next, the effect of ciclesonide on SARS-CoV-2 infection was evaluated.', 'VeroE6/TMPRSS2 cells(10) were infected with authentic SARS-CoV-2 in the presence of steroids or other inhibitors.', 'At 6 h post-infection, cellular RNA was isolated, and real-time PCR was conducted to quantify the amount of viral RNA (11).', 'Ciclesonide and mometasone suppressed viral replication with a similar efficacy to lopinavir (Fig. 2a) .', 'For comparison, viral cell entry inhibitors were tested.', 'E64d substantially reduced viral RNA levels, but nafamostat and camostat had only modest antiviral effects, suggesting that SARS-CoV-2 primarily utilized the cathepsin/endosomal pathway of cell entry rather than the TMPRSS2/cell surface pathway to enter TMPRSS2-expressing cells, consistent with a recent study (12).', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https: //doi.org/10.1101 //doi.org/10.', 'The copyright holder for this preprint (which was not peer-reviewed) is th .', 'https://doi.org/10.1101/2020.03.11.987016 doi: bioRxiv preprint a RNA copy (log 10 ) SARS-CoV-2 RNA in cell (6 hpi Cell viability (%', 'The copyright holder for this preprint (which was not peer-reviewed) is th .', 'https://doi.org/10.1101/2020.03.11.987016 doi: bioRxiv preprint']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['The need for a fast and reliable test for COVID-19 is paramount in managing the current pandemic.', 'A cost effective and efficient diagnostic tool as near to the point of care (PoC) as possible would be a game changer in current testing.', 'We tested reverse transcription loop mediated isothermal amplification (reverse transcription loop mediated isothermal amplification', 'Methods: This service improvement project piloted a research RT-LAMP method on nasal and pharyngeal swabs on 21 residents in a high dependency care home, with two index COVID-19 cases, and compared it to multiplex tandem reverse transcription polymerase chain reaction (RT-PCR).', 'We calculated the sensitivity, specificity, positive and negative predictive values of a single RT-LAMP swab compared to RT-PCR', 'The novel method accurately detected 8/10 PCR positive cases and identified a further 3 positive cases.', 'Eight further cases were negative using both methods.', 'Using repeated RT-PCR as a \"gold standard\", the sensitivity and specificity of the novel test were 80% and 73% respectively.', 'Positive predictive value (PPV) was 73% and negative predictive value (NPV', 'Interpretation: RT-LAMP testing for SARS-CoV-2 was found to be promising, fast, easy to use and to work equivalently to RT-PCR methods.', 'Definitive studies to evaluate this method in larger cohorts are underway.', 'RT-LAMP has the potential to transform COVID-19 detection, bringing rapid and accurate testing to the point of care.', 'This method could be deployed in mobile testing units in the community, care homes and hospitals to detect disease early and prevent spread.', 'CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', '(which was not peer-reviewed)', 'The copyright holder for this preprint .', 'There is urgent need of a rapid, robust and cost-efficient point-of-care test that can be used in care homes, community settings and away from centralised large-scale laboratories, without the need for skilled technicians.', 'Magnetic bead capture and RT-LAMP amplification and testing for SARS-CoV-2 was found to be promising, rapid, easy to use and to work equivalently to standard multiplex tandem PCR methods.', 'Definitive studies to evaluate this method in larger cohorts are underway.', 'RT-LAMP has the potential to transform COVID-19 detection, bringing rapid and accurate testing to the PoC.']}\n", - "{'sentences': ['Graphical Abstract Highlights d Pangolin-CoV is 91.02% identical to SARS-CoV-2 at the whole-genome level d Pangolin-CoV is the second closest relative of SARS-CoV-2 behind RaTG13 d Five key amino acids in the RBD are consistent between Pangolin-CoV and SARS-CoV-2 d Only SARS-CoV-2 contains a potential cleavage site for furin proteases SUMMARY An outbreak of coronavirus disease 2019 (COVID-19) caused by the 2019 novel coronavirus (SARS-CoV-2) began in the city of Wuhan in China and has widely spread worldwide.', 'Currently, it is vital to explore potential intermediate hosts of SARS-CoV-2 to control COVID-19', 'We found genomic and evolutionary evidence of the occurrence of a SARS-CoV-2-like CoV (named Pangolin-CoV) in dead Malayan pangolins.', 'Pangolin-CoV is 91.02% and 90.55% identical to SARS-CoV-2 and BatCoV RaTG13, respectively, at the wholegenome level.', 'Aside from RaTG13, Pangolin-CoV is the most closely related CoV to SARS-CoV-2.', 'The S1 protein of Pangolin-CoV is much more closely related to SARS-CoV-2 than to RaTG13.', 'Five key amino acid residues involved in the interaction with human ACE2 are completely consistent between Pangolin-CoV and SARS-CoV-2, but four amino acid mutations are present in RaTG13.', 'Both Pangolin-CoV and RaTG13 lost the putative furin recognition sequence motif at S1/S2 cleavage site that can be observed in the SARS-CoV-2.', 'Conclusively, this study suggests that pangolin species are a natural reservoir of SARS-CoV-2-like CoVs.']}\n", - "{'sentences': ['Abstract Background：Since December 2019, Severe acute respiratory syndrome coronavirus 2（SARS-CoV-2）-infected disease (Coronavirus Disease 2019，COVID-19) emerged in Wuhan , China，and rapidly spread throughout China，even throughout the world.', 'We try to describe the epidemiological and clinical characteristics of COVID-19 in non-Wuhan area，and explore its effective treatment.', 'Methods：Retrospective, single-center case series of the 51 hospitalized patients with confirmed COVID-19 at Chongqing University Three Gorges Hospital in Chongqing, China, from January 20 to February 3, 2020；The discharge time was from January 29 to February 11, 2020.', 'The main results and indicators of epidemiology, demography, clinical manifestation, laboratory examination, imaging data and treatment data of 51 patients with covid-19 were collected and analyzed.', 'The changes of blood routine and biochemical indexes at discharge and admission were compared.', 'Compare the clinical characteristics of severe patients (including severe and critical patients) and non- severe patients (general patients).', 'Results： Of 51 hospitalized patients with COVID-19, the median age was 45 years (interquartile range, 34-51; range, 16-68 years) and 32 (62.7%) were men.43（84.3%）patients had been to Wuhan or Other Hubei areas outside Wuhan，and 4（7.7%） patients had a clear contact history of COVID-19 patients before the onset of the disease, and 4（7.7%） patients had no clear epidemiological history of COVID-19.Common symptoms included fever (43 [84.3%]), cough (38 [74.5%]) and fatigue (22 [43.1%]).', 'Lymphopenia was observed in 26 patients (51.0%), and elevated C-reactive protein level in 32 patients (62.7%).', 'Ground-glass opacity was the typical radiological finding on chest computed tomography (41 [80.4%])，Local consolidation of pneumonia in some patients(17 [33.3%]).Most of the patients were treated with traditional Chinese medicine decoction (28 [54.9%])，all of them received aerosol inhalation of recombinant human interferon a-1b for injection and oral antiviral therapy with Lopinavir and Ritonavir tablets (51 [100%]); Most of the patients were given Bacillus licheniformis capsules regulated intestinal flora treatment (44 [86.3%]).', '10 patients (19.6%) received short-term (3-5 days) glucocorticoid treatment.', 'Compared with non-severe patients (n = 44), severe patients']}\n", - "{'sentences': ['Objective: We aimed to investigate clinical features and management of 55 COVID-19 patients in Wuxi, especially severe COVID-19.', 'Methods: Epidemiological, demographic, clinical, laboratory, imaging, treatment, and outcome data of patients were collected.', 'Follow-up lasted until April 6, 2020.', 'Results: All 55 patients included 47 (85.5%) non-severe patients and 8 (14.5%) severe patients.', 'Common comorbidities were hypertension and diabetes.', 'Common symptoms were fever, cough and sputum.', 'Lymphopenia was a common laboratory finding, and ground-glass opacity was a common chest CT feature.', 'All patients received antiviral therapy of α -interferon inhalation and lopinavir-ritonavir tablets.', 'Common complications included acute liver injury and respiratory failure.', 'All patients were discharged.', 'No death was occurred and no medical staff got infected.', 'Patients with severe COVID-19 showed significantly older age, decreased lymphocytes, increased C reactive protein, and higher frequency of bilateral lung infiltration compared to non-severe patients.', 'Significantly more treatments including antibiotic therapy and mechanical ventilation, longer hospitalization stay and higher cost were shown on severe patients.', 'Conclusions: Our study suggested that patients with severe COVID-19 may be more likely to have an older age, present with lymphopenia and bilateral lung infiltration, receive multiple treatments and stay longer in hospital.', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'To our knowledge, this report is the first retrospective study of all 55 COVID-19 patients in Wuxi, Jiangsu Province, China.', 'We described epidemiological, demographic, clinical, imaging features as well as treatment and outcomes of all patients.', 'All patients got recovery and discharged from hospital.', 'No death was occurred and no medical staff got infected.', 'In our study, the median age of patients with severe disease were significantly higher compared to patients with non-severe disease, suggesting that older patients may be more susceptible of getting severe disease than younger patients.', 'However, no significant sex difference was found between patients with non-severe and severe illness.', 'A majority (78.2%) of patients got infected due to epidemic clusters, mostly via familial and dining clusters, which provided the evidence of person-to-person transmission of SARS-CoV-2.', 'According to cluster investigation technical guidelines from the Chinese Epidemiology Working Group, epidemic clusters are divided into several subtypes, which refer to the cluster of family, dining, work unit, transportation and public place [12] .', \"Over half (52.7%) of patients had comorbidities, most of which were hypertension (30.9%) and diabetes (16.4%), whereas we didn't discover a significant difference of all comorbidities between patients with non-severe and severe disease other than diabetes.\", 'Similarly, recent studies showed that the prevalence of diabetes was averagely about two folds higher in severe cases [15] .', 'Common symptoms found in our study were fever, cough, sputum production, dyspnea, fatigue, chest distress and headache.', 'Interestingly, we found 18 (32.7%) patients had diarrhea, with a higher incidence than that in previous studies [11, 16] .', 'Four (7.3%) patients had no signs and symptoms during the onset and they only got the non-severe disease (data not shown).', 'The existence of asymptomatic infected individuals has been reported and they also had the ability of virus transmission to others [17] .', 'Particularly, patients with asymptomatic infection may not realize their illness and they could be important hidden sources of infection, which may bring potential danger to public health.', 'Therefore, it is of great significance for suspected patients to fully cooperate with self-isolation, supervision and screenings.', 'In laboratory findings, patients with severe disease had significantly lower levels of lymphocytes and decreased serum sodium concentration as well as higher levels of C reactive protein and procalcitonin than those with non-severe disease, implying these abnormalities could be a potential indicator for severe-type COVID-19.', \"However, unlike some other studies, we didn't find any major differences of leukocytes, neutrophils, D-dimer and liver enzymes between two groups [16, 18] .\", 'Our findings also suggested patients with severe disease were more likely to present with increased neutrophils and D-dimer.', 'The results of Chest CT showed a majority of patients had bilateral infiltration and ground-glass opacity, and both of them were presented in all patients with severe disease.', 'Moreover, a small portion of patients showed no obvious abnormalities on CT.', 'Currently, most of the treatments for COVID-19 are supportive therapy.', 'Till now, no specific drugs or vaccinations have been approved for treatment or prevention from infection with SARS-CoV-2.', 'In our study, all patients received the combination therapy of α -interferon and lopinavir-ritonavir.', 'α -interferon is responsible for broad antiviral effect and enhancement of immune response [19] .', 'Lopinavir, a human immunodeficiency virus type 1 aspartate protease inhibitor, was previously approved for treating SARS-CoV infection in 2003, and ritonavir is .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', '10.20060335 doi: medRxiv preprint combined with lopinavir to increase its plasma half-life through the inhibition of cytochrome P450 [20] .', 'Surprisingly, a recent small-scale clinical trial showed no clinical improvement was observed with lopinavir-ritonavir treatment beyond standard care for treating patients with severe disease [20] .', 'However, Deng et al. found that lopinavir-ritonavir combined with arbidol, another drug against SARS-CoV, might show benefit in delaying clinical progression of COVID-19 and attenuating viral transmissibility [21] .', 'Chloroquine is newly recognized as potential effect against SARS-CoV. In our study, chloroquine was used to treat four (7.3%) patients, mostly used on Overall, it needs to take a long time to identify or invent effective medicine for COVID-19.', 'From our data, patients with severe disease were more likely to be treated by antibiotic therapy, intravenous systemic corticosteroid, intravenous immune globulin, thymosin injection, probiotics tablets, LMWH injection, high-flow oxygen nasal cannula support and mechanical ventilation, which, to some extent, may explain the longer duration and higher cost of hospitalization in severe patients.', 'Our team also used new techniques to treat the critically severe patient, such as transfusion of convalescent plasma, ECMO, and even lung transplant.', 'No significant difference was found in the duration of conversion from the positive PCR test to the negative one after admission (Table 3 & Figure 3B ), however, patients with severe disease had the tendency to stay longer in hospital after the negative PCR test.', 'SARS-CoV-2, the coronavirus causing COVID-19, has been proved to bind the entry receptor of host cells called angiotensin-converting enzyme II (ACE2), the same as previous SARS-CoV and MERS-CoV[25].', 'ACE2 is a protein with 805 amino acids and diffusely expressed in heart, vessels, lung, kidney and gut.', 'It functions as the conversion of angiotensin I to angiotensin II, playing a pivotal role in renin-angiotensin-aldosterone system (RAAS', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'least 14 days.', 'Suspected patients would receive the nucleic acid PCR test and those who got a positive result would be admitted to hospital immediately.', 'Every confirmed patient with COVID-19 would be arranged in the negative pressure ward of a designated infectious hospital for treatment.', 'Those who got discharged still need the PCR test again two and four weeks after discharge, respectively.', 'Of all patients, one patient retested positive of stool samples.', 'Several limitations do exist in our study.', 'First, this study included only 55 cases thanks to good monitoring and screening in Wuxi, which may cause some statistical and selective bias of our results.', 'Second, no immune function test like serum T cells or cytokines and some other tests like serum lactate dehydrogenase were involved in the laboratory test.', 'As such their role might be underestimated in causing severe disease.', 'Third, this study was limited to the local investigation, and the findings may be inconsistent with nationwide or worldwide studies, which may decrease its credibility.', 'All patients received antiviral therapy of α -interferon inhalation and lopinavir-ritonavir tablets ( Table 3 ).', 'Significantly more patients with severe disease had respiratory failure than those with non-severe disease (100.0% vs 4.3%, p<0.001).', 'All patients were discharged from hospital and no death occurred.', 'The median duration of hospitalization among all patients was 16.0 days (IQR 5.0-10.0; Table 3 ) and patients with severe disease had longer hospitalization compared with those with non-severe disease (23.0 days vs 16.0 days, p=0.003; HR=0.37 [95% CI 0.21-0.65], p=0.0012; Figure 3A ).', 'Patients with severe disease also stayed significantly longer in hospital after negative PCR test (14.0 days vs 6.0 days, p=0.002; HR=0.38 [95% CI 0.21-0.66], p=0.0010; Figure 3C ).', 'The median hospitalization cost was 11472.67 yuan (IQR 8220.14-17509.40), in which patients with severe disease spent significantly more money than those with non-severe disease (71902.29 yuan vs 10589.70 yuan, p<0.001).']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['The pandemic outbreak of COVID-19 is rapidly spreading all over the world, resulting in over one hundred thousand global death due to no any well-established treatment.', 'To our knowledge, present study, a multicenter retrospective cohort study, is the first clinical research on the efficiency of IVIG treatment on critical COVID-19 patients and with the largest number of cases.', 'Patients received IVIG were in more severe condition.', 'However, for the critical COVID-19 patients, the results showed that IVIG has no effect on the 28-day mortality and 60day mortality.', 'Notably, multivariable regression showed that both classification of COVID-19 and IVIG using were the factors which related with hazards ratios of death.', 'Subgroup analysis showed that only in patients with critical type, IVIG could significantly reduce the 28-day mortality rate and prolong the survival time, decrease the inflammatory response and improve some organ functions (all P< 0.05), and IVIG had a more significantly curative effect by using IVIG in the early stage (admission≤ 7 days) and with high dose (>15 g/d).', 'These findings indicated that early and high dose of IVIG therapy may improve the prognosis of COVID-19 patients only in critical type, which provide the clinical basis for the choice of treatment population and method of IVIG therapy for the SARS-CoV-2 infection.', 'It is still controversial about the usage of immunoglobulin, but also when and how to use.', 'According to the pharmacological effect, immunoglobulin pulse therapy, based on high dose immunoglobulin intravenous injection, could form immunocomplex with infectious antigen and further clear the immunocomplex in circulation.', 'In addition, immunoglobulin showed antiviral and anti-inflammatory effect by increasing some cytokines secretion, such as IL-2, promoting T cell and B cell proliferation and differentiation.', 'Therefore, immunoglobulin has been widely used in virus infectious diseases and autoimmune disease treatment, especially in viral pneumonia [12, 13] .', 'Previous studies in SARS and MERS therapy also suggested that high dose immunoglobulin could be beneficial [16, 17] .', 'Since immunoglobulin was not the specific antibody to any virus and its clinical evidence was limited, some researchers held the oppose view about immunoglobulin effect on acute virus infection [18, 19] .', 'In both China and WHO COVID-19 treatment guidance, the recommendation on immunoglobulin usage was optional.', 'Similar with previous results, our data showed that IVIG did not improve the outcome when all critical COVID-19 patients were enrolled.', 'However, multivariable regression and subgroup analysis showed that IVIG only could improve the prognosis in the critical type patients.', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.11.20061739 doi: medRxiv preprint explanation was that mild cases with lower organ injury and mortality, which is similar with previous study.', 'The recommendation dose of immunoglobulin is 0.5 g/kg· d for 5 days.', 'However, in present study, the doses differed between each centers and physicians, ranging from 0.1 to 0.5 g/kg· d.', 'The treatment time ranged from 5 to 10 days, and it could be over 15 days in some critical cases.', 'We collected total dose in one day for analysis.', 'Due to the limitation of knowledge and drug unit, the usage of immunoglobulin was not in strict according with the body weight.', 'These issues not only suggested that usage of immunoglobulin was ill-formed, but also indicated that different dose might be another factor on the drug efficiency.', 'By subgroup analysis, we found that only the dose over 15 g/d (about 0.2-0.3g/kg) could show the efficiency, consisting with previous study, in which believed that immunoglobulin has no effect until the dose over 1.5-2g/kg.d [20] .', 'Generally, only high dose treatment could increase the immunoglobulin concentration by 3 to 6 times in rapidly and showed the antiviral and immune enhancement function.', 'Our results suggested that the dose of immunoglobulin should be over 15 g/d (>~0.3g/kg.d), providing a reference for the clinical treatment in COVID-19 infection.', 'For the timing of immunoglobulin treatment, it is considered that it should be employed in early stage.', 'Immunoglobulin affected the natural immune system and adapted immune system, and could bind to the antigen directly, which occurred in the virus infection early stage [21, 22, 23 ].', 'In addition, according to the knowledge of COVID-19 pathogenesis, in late stage, the organ dysfunction and poor prognosis was blamed to the excessive inflammatory response and vicious circle [8, 9] , in which the targeting of immunoglobulin was lacked.', 'Our data showed that immunoglobulin employed within 7 days could improve the prognosis.', 'In this multicenter retrospective study, we found that patients in IVIG group were in more severe condition, evidenced by higher APACHE II score, SOFA score, IL-6 and lactate concentration, and decreased lymphocyte count and oxygenation index.', 'This may due to the unknown factor of COVID-19, including the limited knowledge of pathogenesis, organ dysfunction discipline and risk factors.', 'Though lots of treatment protocol based on the cognition of SARS and MERS, researchers still found that COVID-19 showed some exceptionality, such as prolonged course of disease, potential asymptomatic hypoxia, severe lung injury, unexpected progress induced death [4, 5, 24] .', 'These unfamiliar performance lead to lots of treatment became exploratory attempts.', 'When it becomes more severe, more attempts were employed, and .', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', 'is the (which was not peer-reviewed)', 'The copyright holder for this preprint .', 'https://doi.org/10.1101/2020.04.11.20061739 doi: medRxiv preprint immunoglobulin was one of them.', 'Indeed, this might lead to the bias.', 'To clarify the influence of the bias, we took the regression analysis on the potential factors.', 'Univariate survival analysis showed that APACHE II and SOFA sore were the risk factor which related with the outcome.', 'In further analysis, we found APACHE II and SOFA score were relatively low in most our enrolled patients.', 'This is consisted with the characteristic of this disease, that is, only severe lung injury, with few other organ damage.', 'COX regression confirmed that critical type in COVID-19 patients showed poor prognosis and IVIG rescued these patients.', 'Though IVIG has no effect on the whole patients, it could be beneficial to the critical type patients.', 'In addition, COX regression also founded that lymphopenia was the risk of poor prognosis.', 'Previous study reported that 35%-83% COVID-19 patients showed lymphocyte count decreased, and persistent lymphopenia was related with the poor outcome [25], consist with our results.', 'However, subgroup analysis according to the lymphocyte counts did not show that IVIG could improve the patient outcome.', 'The explanation was not clear, potentially due to the limited cases or the unknown function of lymphocyte in this disease, and further researches are needed.', 'There are some limitations in present study.', 'Firstly, cases in these four clinical centers may not with enough representativeness.', 'Secondly, the dose and timing inconformity in each center was another limitation of present study.', 'Thirdly, the evaluation of immunoglobulin effect was limited, especially the direct evaluation index, such as viral load, lymphocyte activation etc.', 'With the developing recognition of COVID-19, large cases randomized control studies and more developed evaluation systems are needed to confirm the efficiency of IVIG on COVID-19 treatment.', 'In conclusion, present was the first clinical research on the efficiency of IVIG treatment on critical COVID-19 patients.', 'We found that early and high dose of IVIG therapy may improve the prognosis of COVID-19 patients with critical type.', 'These findings provide the clinical basis for the choice of treatment population and method of IVIG therapy for the COVID-19 infection and help to increase effective of treatment in this spreading disease.', 'CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Background: Recently, Coronavirus Disease 2019 (COVID-19', 'Objectives: To summary and analyze the clinical characteristics and identify the predictors of disease severity and mortality.', 'The PubMed, Web of Science Core Collection, Embase, Cochrane and MedRxiv databases were searched through February 25, 2020.', 'Meta-analysis of Observational Studies in Epidemiology (Meta-analysis of Observational Studies in Epidemiology', 'A total of 30 studies including 53000 patients with were included in this study, the mean age was 49.8 years (95% CI, 47.5-52.2 yrs) and 55.5% were male.', 'The pooled incidence of severity and mortality were 20.2% (95% CI, 15.1-25.2%) and 3.1% (95% CI, 1.9-4.2%), respectively.', 'The predictor for disease severity included old age (≥ 50 yrs, odds ratio [OR] = 2.61; 95% CI, 2.29-2.98), male (OR =1.348, 95% CI, 1.195-1.521), smoking (OR =1.734, 95% CI, All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.', ': medRxiv preprint 1.146-2.626) and any comorbidity (OR = 2.635, 95% CI, 2.098-3.309), especially chronic kidney disease (CKD, OR = 6.017; 95% CI,, chronic obstructive pulmonary disease (COPD, OR = 5.323; 95% CI, 2.613-10.847) and cerebrovascular disease (OR = 3.219; 95% CI, 1.486-6.972).', 'In terms of laboratory results, increased lactate dehydrogenase (LDH), C-reactive protein (CRP', 'To our knowledge, this is the first evidence-based medicine research to explore the risk factors of prognosis in patients with COVID-19, which is helpful to identify early-stage patients with poor prognosis and adapt effective treatment.', 'All rights reserved.', 'No reuse allowed without permission.', 'author/funder, who has granted medRxiv a license to display the preprint in perpetuity.']}\n", - "{'sentences': ['A total of 14 chemical neighbors were identified, 8 sharing the same scaffold of NHC [21] and 6 having a different isosteric scaffold.', 'Among those, there were three drugs, namely, cytarabine, azacytidine and adenosine (Figure 2 ).', 'Since some of the proteins interacting with those drugs are already known, an analysis of their pharmacologies will help defining the target landscape around NHC.', 'Accordingly, all known drug-target interactions, in both public and patent databases available in CLARITY, were extracted and compiled in Table 1 .', 'As can be observed, there is almost no overlap in their known interacting proteins.', 'This should not be too surprising if one considers that those molecules were most likely not tested consistently against the same panel of proteins [22] .', 'Among the few known common targets, all three drugs bind to members of the adenosine receptor family and two of them, cytarabine and adenosine, are known to be active against the transmembrane domain-containing protein TMIGD3.', 'In addition, cytarabine is also known to bind to four other proteins, namely, E3 ubiquitinprotein ligase Mdm2 (proteins, namely, E3 ubiquitinprotein ligase Mdm2), latent membrane protein 1 (LMP1), receptor-type tyrosine-protein kinase (LMP1), receptor-type tyrosine-protein kinase FLT3 ((LMP1), receptor-type tyrosine-protein kinase FLT3), and nuclear receptor coactivator 3 (NCOA3).', 'In turn, azacytidine is known to have affinity for DNA (cytosine-5)-methyltransferase 1 (DNMT1) and peptidyl-tRNA hydrolase (PTH).', 'Interestingly, chloroquine, one of the drugs being currently used against Covid-19, is also known to bind to a methyltransferase [23] , the histamine N-methyltransferase (HNMT).', 'Finally, adenosine is known to interact with The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.30.016485 doi: bioRxiv preprint multiple proteins, with most potent affinities for cAMP-dependent protein kinase type I alpha (PRKAR1A), growth hormone secretagogue receptor 1 (GHSR), dipeptidyl peptidase 4 (DPP4), and isoleucyl-tRNA synthetase (IleRS).', 'Altogether, these three drugs provide a list of 23 targets that could be relevant to any molecule within their chemical neighborhood, such as NHC.', 'Beyond the three drugs discussed above, there are two structurally close molecules that deserve consideration (Figure 3 ).', 'One of them is cytidine, the endogenous substrate of several nucleoside transporters [24] , such as the sodium/nucleoside cotransporter 1 (SLC28A1), the solute carrier family 28 member 3 .', 'CC-BY-NC-ND 4.0 International license author/funder.', 'It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.30.016485 doi: bioRxiv preprint (SLC28A3), and the equilibrative nucleoside transporter 1 (SLC29A1).', 'And the other one is N6-hydroxyadenosine (NHA), a known active molecule against tyrosyl-DNA phosphodiesterase 1 (TDP1) [25] and also shown to act as a potent antiviral [26] .', 'Again, further analysis of the chemical neighborhood of NHC identifies 4 additional targets and provides evidence of potent antiviral effects.', 'All metabolic transformations of a given molecule can be also considered part of its chemical neighborhood.', 'Therefore, NHC was processed with CLARITY that predicted two types of metabolic transformations ( Figure 4) : a hydrolytic deamination, leading to the formation of uridine (with 70% confidence) and a phosphorylation, resulting in the mono/di/tri-phosphate metabolites (with an average confidence of 34%).', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.30.016485 doi: bioRxiv preprint Beyond the three nucleoside transporters mentioned above that interact with cytidine, uridine binds to the sodium-dependent nucleobase transporter (SLC23A4), the equilibrative nucleoside transporter 2 (SLC29A2), and the equilibrative nucleoside transporter 3 (SLC29A2), and the equilibrative nucleoside transporter 3) [24] .', 'In addition, uridine is also the result of the catalytic activity of cytidine deaminase (CDA', 'In turn, uridine can also be transformed into uridine triphosphate that will then bind to several pyrimidinergic receptors, such as P2Y2 and P2Y4 [24] .', 'Finally, the structural similarity of adenosine to NHC will translate into its triphosphate metabolite (ATP) being also in the chemical neighborhood of NHCTP, with all derived consequences in biology.', 'ATP is the endogenous ligands for purinergic (P2X) and pyrimidinergic (P2Y', 'Following on the recent PHASE initiative [11, 12] , a list of likely protein targets of NHC was predicted using CLARITY and SEA ( Table 2 ).', 'The highest confidence prediction from CLARITY is for members of the adenosine receptor family, supported by a strong p-value from SEA.', 'This result is very much in line with the only common targets observed within the drug neighborhood (Table 1 ).', 'In contrast, NHC is most strongly predicted by SEA to bind to P2Y purinoreceptors, whereas no prediction is obtained from CLARITY.', 'A closer look at all results generated reveals that in fact CLARITY predicts those P2Y purinoreceptors not for NHC but for the NHC triphosphate metabolite generated ( Figure 4 ), in agreement with some of the targets known for the adenosine and uridine triphosphates (vide supra).', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.03.30.016485 doi: bioRxiv preprint']}\n", - "{'sentences': ['BACKGROUND: Medicines for the treatment of 2019-novel coronavirus (2019-nCoV) infections are urgently needed.', 'However, drug screening using live 2019-nCoV requires high-level biosafety facilities, which imposes an obstacle for those without such facilities or 2019-novel coronavirus (2019-nCoV).', 'This study aims to repurpose the clinically approved drugs for the treatment of coronavirus disease 2019 (COVID-19) in a 2019-nCoV related coronavirus model.', 'METHODS: A 2019-nCoV related pangolin coronavirus GX_P2V/pangolin/2017/ Guangxi was described.', 'Whether GX_P2X uses angiotensin-converting enzyme 2 (ACE2) as the cell receptor was investigated by using small interfering RNA (siRNA) -mediated silencing of ACE2.', 'The pangolin coronavirus model was used to identify drug candidates for treating 2019-nCoV infection.', 'Two libraries of 2406 clinically approved drugs were screened for their ability to inhibit cytopathic effects on Vero E6 cells by GX_P2X infection.', 'The antiviral activities and antiviral mechanisms of potential drugs were further investigated.', 'Viral yields of RNAs and infectious particles were quantified by quantitative real-time polymerase chain reaction (qRT-PCR) and plaque assay, respectively.', 'RESULTS: The spike protein of coronavirus GX_P2V shares 92.2% amino acid identity with that of 2019-nCoV isolate Wuhan-hu-1, and uses ACE2 as the receptor for infection just like 2019-nCoV. Three drugs-cepharanthine (CEP), selamectin and mefloquine hydrochloride exhibited complete inhibition of cytopathic effects in cell culture at 10 μmol/L. CEP demonstrated the most potent inhibition of GX_P2V infection, with a concentration for 50% of maximal effect [EC50] of 0.98 μmol/L. The viral RNA yield in cells treated with 10 μmol/L CEP was 15,393-fold lower than in cells without CEP treatment ([6.48 ± 0.02] × 10vs.', '1.00 ± 0.12, t = 150.38, P < 0.001) at 72 h post-infection (p.i.', 'Plaque assays found no production of live viruses in media containing 10 μmol/L CEP at 48 h p.i.', 'Furthermore, we found CEP has potent antiviral activities against both viral entry (1.00 ± 0.37 vs. 0.46 ± 0.12, t = 2.42, P < 0.05) and viral replication (1.00 ± 0.43 vs. [6.18 ± 0.95] × 10, t = 3.98, P < 0.05).', 'CONCLUSIONS: Our pangolin coronavirus GX_P2V is a workable model for 2019-nCoV research.', 'CEP, selamectin and mefloquine hydrochloride are potential drugs for treating 2019-nCoV infection.', 'Our results strongly suggest that CEP is a wide-spectrum inhibitor of pan-betacoronavirus, and clinical trial of CEP for treatment of 2019-nCoV']}\n", - "{'sentences': ['Does Hydroxychloroquine Combat COVID-19?', 'A Timeline of Evidence']}\n", - "{'sentences': ['medRxiv preprint Funding Information:', 'Health Commission of Hubei Province scientific research project (No. WJ2019Q048 to M.Z', 'We declare no conflict of interest.', 'Since SARS-CoV-2 infection was first identified in December 2019, it spread rapidly and a global pandemic of COVID-19 has occurred.', 'ACE2, the receptor for entry into the target cells by SARS-CoV-2, was found to abundantly express in testes, including spermatogonia, Leydig and Sertoli cells.', 'However, there is no clinical evidence about whether SARS-CoV-2 infection can affect male gonadal function so far.', 'In this study, we compared the sex-related hormones between 81 reproductive-aged men with SARS-CoV-2 infection and 100 age-matched healthy men, and found that serum luteinizing hormone (LH) was significantly increased, but the ratio of testosterone (T) to LH and the ratio of follicle stimulating hormone (FSH) to LH were dramatically decreased in males with COVID-19.', 'Besides, multivariable regression analysis indicated that c-reactive protein (CRP) level was significantly associated with serum T:LH']}\n", - "{'sentences': ['BACKGROUND: Cancer and transplant patients with COVID-19 have a higher risk of developing severe and even fatal respiratory diseases, especially as they may be treated with immune-suppressive or immune-stimulating drugs.', 'This review focuses on the effects of these drugs on host immunity against COVID-19.', 'METHODS: Using Ovid MEDLINE, we reviewed current evidence for immune-suppressing or -stimulating drugs: cytotoxic chemotherapy, low-dose steroids, tumour necrosis factorα (TNFα) blockers, interlukin-6 (IL-6) blockade, Janus kinase (JAK) inhibitors, IL-1 blockade, mycophenolate, tacrolimus, anti-CD20 and CTLA4-Ig.', 'RESULTS: 89 studies were included.', 'Cytotoxic chemotherapy has been shown to be a specific inhibitor for severe acute respiratory syndrome coronavirus in in vitro studies, but no specific studies exist as of yet for COVID-19.', 'No conclusive evidence for or against the use of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of COVID-19 patients is available, nor is there evidence indicating that TNFα blockade is harmful to patients in the context of COVID-19.', 'COVID-19 has been observed to induce a pro-inflammatory cytokine generation and secretion of cytokines, such as IL-6, but there is no evidence of the beneficial impact of IL-6 inhibitors on the modulation of COVID-19.', 'Although there are potential targets in the JAK-STAT pathway that can be manipulated in treatment for coronaviruses and it is evident that IL-1 is elevated in patients with a coronavirus, there is currently no evidence for a role of these drugs in treatment of COVID-19.', 'CONCLUSION: The COVID-19 pandemic has led to challenging decision-making about treatment of critically unwell patients.', 'Low-dose prednisolone and tacrolimus may have beneficial impacts on COVID-19.', 'The mycophenolate mofetil picture is less clear, with conflicting data from pre-clinical studies.', 'There is no definitive evidence that specific cytotoxic drugs, low-dose methotrexate for auto-immune disease, NSAIDs, JAK kinase inhibitors or anti-TNFα agents are contraindicated.', 'There is clear evidence that IL-6', 'The current literature does not give conclusive evidence for or against the use of NSAIDs in the treatment of COVID-19 patients, though there appears to be some evidence that corticosteroids may be beneficial in the treatment of SARS-CoV. However, it is important to note this is not specific to COVID-19.', 'It has been suggested that the pathogenesis of SARS-CoV is mediated by disproportional immune responses and the ability of the virus to circumvent innate immunity.', 'The COVID-19 infection has also been observed to induce pro-inflammatory cytokine generation and secretion of cytokines, such as IL-6, which dysregulates the local inflammatory responses that have been suggested as partially responsible for the devastating acute respiratory distress syndrome.', 'Moreover, it has been observed that COVID-19 induces high levels of IL-6 for at least 2 weeks after disease onset.', 'Children presented lower levels of cytokine production.', 'IL-6 has been suggested as a potential prognostic marker of COVID-19 disease severity.', 'Different molecules related with the IL6 pathway have been suggested as potential therapeutic targets such as ADAM-17, SARS-CoV ssRNA, DUSP1 and p38 MAPK.', 'Currently, there is no scientific evidence of the beneficial impact of IL-6 inhibitors in the modulation of the COVID-19 infection.', 'Further understanding of the role of IL-6 reduction will be forthcoming as the pandemic progresses and further clinical data becomes available.', 'In vitro treatment with glycopyrronium, formoterol and budesonide exerted additive inhibitory effects on viral titers and cytokine production human nasal and tracheal epithelial cells.', 'Overall, this review demonstrated that although it is evident that IL-1 is elevated in patients infected with a coronavirus, there is not at present evidence for an established role for IL-1 blockers in the treatment of COVID-19 in humans.', 'The literature did, however, suggest a potential role for low-dose corticosteroids to reduce levels of pro-inflammatory markers, such as IL-1, which are elevated as part of the immune response and may have a role in the severe lung damage associated with human coronaviruses.', 'Overall the small amount of literature available suggests a potential role of FK506 (tacrolimus) as a potent antiviral in the treatment of human coronaviruses.', 'It is important to note, however, that COVID-19 is a novel disease and may have different aetiology and mechanistic action compared to existing strains and to date, this immunosuppressive drug and its derivatives has not been tested in humans.', 'Further study is warranted, both in the clinical setting and laboratory.', 'The rapidly progressing SARS-CoV-2 pandemic has led to challenging decision-making about the treatment of critically unwell patients with the novel viral infection.', 'In parallel, doctors across multiple specialties are making clinical decisions about the appropriate continuation of treatments for patients with chronic illnesses requiring immune-suppressive medication.', 'This systematic review looks to provide guidance from the current available literature.', 'As the COVID-19 pandemic progresses, collective effort to capture data from prospective trials is required.', 'Sponsors of randomized controlled trials recruiting patients randomized to receive immune modulatory drugs that may be affected by COVID-19 should collect data about the disease outcomes and consider interim analysis of potential advantages and disadvantages associated with using one of these medications.', 'Low-dose prednisolone and tacrolimus therapy may have beneficial impacts on the course of SARS-CoV-2.', 'This observation requires further validation.', 'The mycophenolate mofetil picture is less clear, with conflicting data from pre-clinical studies.', 'There is no definitive evidence that specific cytotoxic drugs, low-dose methotrexate for auto-immune disease, NSAIDs, JAK kinase inhibitors or anti-TNFa biological agents are contraindicated.', 'There is evidence that IL-6 peak levels are associated with severity of pulmonary complications.', 'Ongoing studies of blockade of the IL-6 pathway are rational and will hopefully inform practice as the pandemic progresses.', 'Coronavirus strains were one of the most common viral pathogens identified in paediatric cancer patients undergoing chemotherapy.', 'Patients with pre-B acute lymphoblastic leukaemia and breast cancer who have undergone chemotherapy have reported cases of coronavirus infection.', 'Cytotoxic therapies used in cancer chemotherapy such as 6MP and 6TG have shown to be specific inhibitors for SARS coronavirus in in vitro studies.', 'However, further in vitro and in vivo studies are required to confirm this, especially in COVID-19.', 'Currently, there is no scientific evidence of the interaction between methotrexate and COVID-19.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': [\"[{'text': 'The infection of a novel coronavirus found in Wuhan of China (SARS-CoV-2) is rapidly spreading, and the incidence rate is increasing worldwide.\", 'Due to the lack of effective treatment options for SARS-CoV-2, various strategies are being tested in China, including drug repurposing.', 'In this study, we used our pre-trained deep learning-based drug-target interaction model called Molecule Transformer-Drug Target Interaction (MT-DTI) to identify commercially available drugs that could act on viral proteins of SARS-CoV-2.', 'The result showed that atazanavir, an antiretroviral medication used to treat and prevent the human immunodeficiency virus (HIV), is the best chemical compound, showing an inhibitory potency with Kd of 94.94 nM against the SARS-CoV-2 3C-like proteinase, followed by remdesivir (113.13 nM), efavirenz (199.17 nM), ritonavir (204.05 nM), and dolutegravir (336.91 nM).', 'Interestingly, lopinavir, ritonavir, and darunavir are all designed to target viral proteinases.', 'However, in our prediction, they may also bind to the replication complex components of SARS-CoV-2 with an inhibitory potency with Kd < 1,000 nM. In addition, we also found that several antiviral agents, such as Kaletra (lopinavir/ritonavir), could be used for the treatment of SARS-CoV-2.', 'Overall, we suggest that the list of antiviral drugs identified by the MT-DTI', 'In many cases, DTI prediction models serve as a tool to repurpose drugs to develop novel usages of existing drugs.', 'The application of DTI prediction in the present study may be useful to control unexpected and rapidly spreading infections such SARS-CoV, Middle East respiratory syndrome (MERS-CoV), and SARS-Cov-2 at the frontline of the disease control until better therapeutic measures are developed.', 'Several recent studies have identified promising drug candidates that may help reduce symptoms of COVID-19 by inhibiting some aspects of SARS-CoV-2.', 'For example, remdesivir and chloroquine showed inhibitory effects against SARS-CoV-2 in vitro (31) .', 'Another in-vitro study showed that hydroxychloroquine was found to be more potent than chloroquine for inhibiting SARS-CoV-2 (32).', 'Remdesivir and lopinavir/ritonavir (Kaletra) also reduced pneumonia-associated symptoms of some COVID-19 patients (33, 34) .', 'However, these studies are based on previous knowledge that these drugs showed some inhibitory effects on similar coronaviruses such as SARS-CoV and/or MERS-CoV. In contrast, our approach was truly based on a pre-trained MT-DTI deep-learning model that understands drug-target interactions without domain knowledge (12) .', 'In fact, MT-DTI successfully identified the epidermal growth factor receptor (EGFR)-targeted drugs that are used in clinics (in top-30 predicted candidates) among 1,794 chemical compounds registered in the DrugBank database in a previous study (12) , suggesting that 3D structural information of proteins and/or molecules is not necessarily required to predict drug-target interactions.', 'Our results showed the following intriguing findings that need to be tested experimentally and clinically in the near future.', 'First, MT-DTI generally showed similar results overall compared to the conventional 3D structure-based prediction model, AutoDock Vina, but some differences were observed.', 'For example, atazanavir, remdesivir, and efavirenz were the top three predicted drugs that may bind to the 3C-like proteinase of SARS-CoV-2.', 'This is while saquinavir, nelfinavir, and grazoprevir were the top three drugs identified by AutoDock Vina (Fig. 1) .', 'Secondly, when the search space was expanded to all FDA-approved drugs, some immunosuppressant drugs (rapamycin and everolimus) and a drug (tiotropium bromide) for asthma and chronic obstructive pulmonary disease (COPD', 'We hope our prediction results may support experimental therapeutic options for China and other countries suffering from the SARS-CoV-2 pandemic and align with recent clinical trials (35) .']}\n", - "{'sentences': ['Obviously there is an major concern globally regarding the emerging outbreak of COVID-19, with increasing cases confirmed in multiple countries currently.', 'The World Health Organization has upgraded its coronavirus risk assessment to \"very high\" at global level as COVID-19 continuously spread in more countries despite rigorous global containment and quarantine efforts.', 'Recent studies concerning the novel coronavirus provided evidence of the potential connection SARS-CoV-2 infection and acute cardiac injury [2, 4] .', 'We observed that the clinical symptoms of COVID-19 and other viral pneumonia were highly variable and overlap, whereas the most common symptoms were cough, fever and fatigue, with dizziness and diarrhea less common.', 'While typical symptoms like fever could be absent in the disease progression particularly in elderly, adversely, gastrointestinal discomfort and altered mental status presented more frequently.', 'High sensitivity cTnI tests were more inclined to perform on participants with older age and preexisting concomitants include hypertension, cardiovascular disease and atrial fibrillation.', 'Mortality rate was higher significantly in the older individuals, might explained by decaying organ systems，particularly respiratory tract, immune system and cardiovascular system and urinary system.', 'In addition, more remarkable laboratory abnormalities was observed within severe patients and those with poor outcomes.', 'The concentration of CRP was considerably higher among the deceased than the survived ones.', 'The average hemoglobin count was obviously lower than the survivors and over half deaths sustained with anemia， suggesting a relatively status of hypoxia and malnutrition.', 'The occurrence of leukocytosis might accompany with a secondary bacterial infection which has higher frequency in non-survivors.', 'Thrombocytopenia was revealed in more than half non-survivors whereas not to the degree of depletion, which provided extra evidence that the coagulation was highly activated.', 'We analyzed the coagulation marker as manifested by d-dimer, notably revealing that there were substantial coagulation abnormalities in COVID-19 patients, in addition, more profoundly among severe and fatal illness.', 'Most non-survivors underwent oxygen administration，which we unfortunately discovered whether noninvasive nor invasive mechanical ventilation could reverse the rapidly deterioration of multi-systemic damage.', 'The multivariate Cox regression model showed that elevation of hs-cInI and the levels of SpO2% and d-dimer were independent predictors of in-hospital prognosis of COVID-19.', 'Evidently, the elevation of hs-cT and D-dimer and decreased SpO2 was associated with higher risk of death.', 'Current reports suggest that majority of patients on admission for pneumonia underwent coagulation disorders, which included higher platelet aggregating activity, elevated levels of antithrombin and thrombin-antithrombin complex, decreased factor IX activity [7, 8] .', 'The association between SARS-CoV-2 infection and acute myocardial injury has been appreciated, likewise stronger when the infection is more severe.', 'Limited reports of autopsy detected cardiomyocytes necrosis and degeneration，with intercellular substance infiltrated with small amounts of monocytes ， lymphocyte and/or neutrophils, additionally, the occurrence of endoangiitis and thrombosis was noted [9] .', 'No evidence has shown that SARS-CoV-2 infected myocardium directly, despite the putative receptor of SARS-CoV-2, ACE2 [10] , same with SARS-CoV, as well as the documented reports state that the RNA of SARS-CoV has been identified within myocardium of affected patients [11] .', 'While confirmation of SARS-CoV-2-related myocarditis has been hampered by its heterogeneous clinical presentations and complexity of definitive diagnose, PCR technology have enabled detection of many other virus within the myocardium of affected patients [12] .', 'Hence, whether the virus exerted its pathogenic effects by transition to myocardium directly is yet to investigated.', \"Apart from that, it's likely the host response to infection is major determinants in COVID-19 patients that are complicated by myocardial injury [13] .\", \"It's estimated that pneumonia can affect the cardiovascular system by multiple mechanisms.\", 'The established pneumonia associated with SARS-CoV-2 accounted for the inciting infection, results in relative or severe hypoxemic state of the host, prompted by impaired gas exchange across the alveoli of inflamed lung parenchyma and ventilation-perfusion mismatching.', 'Moreover， inflammation increase the metabolic needs of peripheral tissues and organs, attributable to myocardial ischemia, may related either to: increasing heart rate which shortens the diastolic duration, coronary artery spasm or coronary microvascular dysfunction, without ruptured plaque within coronary atherosclerosis, therefore compromising coronary perfusion and exaggerating cardiac metabolic imbalance [7] .', 'The preexistent cardiovascular diseases and COVID-19 appears to accelerate the progression bidirectional.', 'On the other hand, circulating inflammatory factor and toxin mediated vasoconstriction adversely affect myocardial function，through which called cytokine storm.', 'The overall effect of the inflammatory response triggered by infection is dictated by the balance between pro-inflammatory (eg, IL-1, IL-6, TNF-α, IL-8) and anti-inflammatory (eg, IL-10,TGF-β) mediators [14] .', 'Sustained or uncontrolled release of cytokines secreted by various cell populations especially immune cells, inflicting excessive systemic inflammation which leads .', 'CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Objective To explore the clinical characteristics and prognosis of the new coronavirus 2019-nCoV patients combined with cardiovascular disease (CVD).', 'Methods A retrospective analysis was performed on 112 COVID-19 patients with CVD admitted to the western district of Union Hospital in Wuhan, from January 20, 2020 to February 15, 2020.', 'They were divided into critical group (ICU, n =16) and general group ( n =96) according to the severity of the disease and patients were followed up to the clinical endpoint.', 'The observation indicators included total blood count, C-reactive protein (CRP), arterial blood gas analysis, myocardial injury markers, coagulation function, liver and kidney function, electrolyte, procalcitonin (PCT), B-type natriuretic peptide (BNP), blood lipid, pulmonary CT and pathogen detection.', 'Results Compared with the general group, the lymphocyte count (0.74×10 9 (0.34×10 9 , 0.94×10 9 )/L vs. 0.99×10 9 (0.71×10 9 , 1.29×10 9 )/L, P =0.03) was extremely lower in the critical group, CRP (106.98 (81.57, 135.76) mg/L vs. 34.34 (9.55,76.54) mg/L, P <0.001) and PCT (0.20 (0.15,0.48) μg/L vs. 0.11 (0.06,0.20)μg/L, P <0.001) were significantly higher in the critical group.', 'The BMI of the critical group was significantly higher than that of the general group (25.5 (23.0, 27.5) kg/m 2 vs. 22.0 (20.0, 24.0) kg/m 2 , P =0.003).', 'Patients were further divided into non-survivor group (17, 15.18%) group and survivor group (95, 84.82%).', 'Among the non-survivors, there were 88.24% (15/17) patients with BMI> 25 kg/m 2 , which was significantly higher than that of survivors (18.95% (was significantly higher than that of survivors (18.95%), P <0.001).', 'Compared with the survived patients, oxygenation index (130 (102, 415) vs. 434 (410, 444), P <0.001) was significantly lower and lactic acid (1.70 (1.30, 3.00) mmol/L vs. 1.20 (1.10, 1.60) mmol/L, P <0.001) was significantly higher in the non-survivors.', 'There was no significant difference in the proportion of ACEI/ARB medication between the critical group and the general group or between non-survivors and survivors (all P >0.05).', 'Conclusion COVID-19 patients combined with CVD are associated with a higher risk of mortality.', 'Critical patients are characterized with lower lymphocyte counts.', 'Higher BMI are more often seen in critical patients and non-survivor.', 'ACEI/ARB use does not affect the morbidity and mortality of COVID-19 combined with CVD']}\n", - "{'sentences': ['bioRxiv preprint Serine Protease 2) in the host cell.', 'Importantly, beside respiratory symptoms, consistent with other common respiratory virus infection when patients become viraemic, a significant number of COVID-19 patients also develop liver comorbidities.', 'We explored if specific target cell-type in the mammalian liver, could be implicated in disease pathophysiology other than the general deleterious response to cytokine storms.', 'Here we employed single-cell RNA-seq (scRNA-seq', 'Importantly, we fail to detect the expression of ACE2 in hepatocyte or any other liver (immune and stromal) cell types.', 'These results indicated that in COVID-19 associated liver dysfunction and cell death, viral infection of TROP2 + progenitors in liver may significantly impaired liver regeneration and could lead to pathology.', '-EPCAM + Liver progenitors co-express ACE2 and TMPRSS2 -ACE2 and TMPRSS2 expression is highest in TROP2 high progenitors -ACE2 and TMPRSS2 cells express cholangiocyte biased fate markers -ACE2 and TMPRSS2 positive cells are absent in human fetal liver .']}\n", - "{'sentences': ['Nelfinavir was predicted to be a potential inhibitor of 2019-nCov main protease by an integrative approach combining homology modelling, molecular docking and binding free energy calculation', '2019-nCov has caused more than 80 deaths as of 27 January 2020 in China, and infection cases have been reported in more than 10 countries.', 'However, there is no approved drug to treat the disease.', '2019-nCov M pro is a potential drug target to combat the virus.', 'We built homology models based on SARS M pro structures, and docked 1903 small molecule drugs to the models.', 'Based on the docking score and the 3D similarity of the binding mode to the known M pro ligands, 4 drugs were selected for binding free energy calculations.', 'Both MM/GBSA and SIE methods voted for nelfinavir, with the binding free energy of -24.69±0.52 kcal/mol and -9.42±0.04 kcal/mol, respectively.', 'Therefore, we suggested that nelfinavir might be a potential inhibitor against 2019-nCov M pro .', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'After visualizing the docked complexes carefully, we selected 15 drugs (Table 2) for further analysis.', 'There are some differences between the conformations of the protein in the 3D similarity reference and 2GTB model.', 'Therefore, we modelled 10 new homology models using the proteins in 3D similarity reference as templates and we redocked the 15 drugs to the 10 new homology models.', '6 drugs (nelfinavir, pitavastatin, perampanel, praziquantel, zopiclone, and eszopiclone) show good docking scores and binding modes (Table 3) .', 'Because eszopiclone and zopiclone was used to treat insomnia in a low dosage which may not be suitable to treat pneumonia, we carried out further binding free energy calculation for the rest 4 drugs.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.01.27.921627 doi: bioRxiv preprint praziquantel-3V3M, were subjected to 5 ns molecular dynamics simulations using author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.01.27.921627 doi: bioRxiv preprint Amber 16.', 'To provide insight into their binding mechanisms, the binding free energies were calculated by MM/GBSA and SIE approaches.', 'In results of the MM/GBSA approach, the calculated binding free energies of nelfinavir-2GX4, pitavastatin-2GTB, perampanel-5NH0, and praziquantel-3V3M, are -24.69±0.52, -12.70±0.38, -14.98±0.34, and -6.51±0.21 kcal/mol, respectively (Table 4) , which highlight nelfinavir as the most active one.', 'In pitavastatin-2GTB, perampanel-5NH0, and praziquantel-3V3M, the van der Waals interaction (E vdw ) makes a more significant contribution than the electrostatic interaction (E ele ) (', '2019-nCov caused more than 80 deaths in China as of 27 January 2020 and is a potential threat to the global health.', 'However, there is no approved drug to treat the disease.', '2019-nCov M pro is a potential drug target to combat the virus, which shares 96% sequence similarity with the corresponding one in SARS.', 'We built 11 homology models of 2019-nCov M pro and docked 1903 approved small molecule drugs to the 2GTB model.', 'Based on the docking score and the 3D similarity of binding mode to 39 known M pro binders, 15 drugs were selected for further evaluation.', 'The 15 drugs were then docked to all the 11 homology models, leading to 4 drugs for binding energy calculations.', 'Both MM/GBSA and SIE calculations voted for nelfinavir, a HIV-1 protease inhibitor to treat HIV.', 'Therefore, we suggested that nelfinavir might be active against 2019-nCov M pro .', 'In addition, pitavastatin, perampanel, and praziquantel might author/funder.', 'All rights reserved.', 'No reuse allowed without permission.', 'The copyright holder for this preprint (which was not peer-reviewed) is the .', 'https://doi.org/10.1101/2020.01.27.921627 doi: bioRxiv preprint also have moderate activities against 2019-nCov.']}\n", - "{'sentences': ['Fatal toxicity of chloroquine or hydroxychloroquine with metformin in mice', \"[{'text': 'Guided by the principle of primum non nocere (first do no harm), we report a cautionary note on the potential fatal toxicity of chloroquine (CQ) or hydroxychloroquine (HCQ) in combination with anti-diabetic drug metformin.\", 'We observed that the combination of CQ or HCQ and metformin, which were used in our studies as potential anti-cancer drugs, killed 30-40% of mice.', 'While our observations in mice may not translate to toxicity in humans, the reports that CQ or HCQ has anti-COVID-19 activity, the use of CQ resulting in toxicity and at least one death, and the recent Emergency Use Authorization (EUA) for CQ and HCQ by the US Food and Drug Administration (FDA) prompted our report.', 'Here we report the lethality of CQ or HCQ in combination with metformin as a warning of its potential serious clinical toxicity.', 'We hope that our report will be helpful to stimulate pharmacovigilance and monitoring of adverse drug reactions with the use of CQ or HCQ']}\n", - "{'sentences': ['The epidemiological and clinical characteristics of heart transplant (HTx) recipients during the SARS-CoV-2 epidemic remains unclear.', 'We studied the characteristics of HTx recipients during Dec 20, 2019 and Feb 25, 2020 in an effort to understand their risk and outcomes.', 'All accessible HTx recipients were included in this single-center, retrospective study.', 'We collected information on the recipients using a web-based questionnaire as well as the hospital database.', 'We followed 87 HTx recipients (72.4% were men and average age was 51 years).', '79 recipients resided in Hubei, and 57 recipients had a Wuhan related history of travel or contact.', 'The majority took precautionary measures while in contact with suspicious crowds.', '96.6% of the families and communities undertook prevention and quarantine procedures.', '4 upper airway infection were reported, and 3 of them tested negative for SARS-CoV-2 (the 4 th recovered and was not tested).', 'All cases were mild and successfully recovered after proper treatment.', 'Laboratory results of 47 HTx cases within the last 2 months were extracted.', '21.3% recipients had pre-existing lymphopenia and 87.2% of recipients had therapeutic tacrolimus concentration (5-12ng/ml).', '5 and 6 recipients had liver and kidney insufficiency respectively.', 'HTx recipients that practiced appropriate prevention measures had a low rate of infection with SARS-CoV-2 and transition to COVID-19.', 'These early data will require confirmation as the pandemic establishes around the world.']}\n", - "{'sentences': ['Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro']}\n", - "{'sentences': ['OBJECTIVE: The SARS-CoV-2-infected disease (COVID-19) outbreak is a major threat to human beings.', 'Previous studies mainly focused on Wuhan and typical symptoms.', 'We analysed 74 confirmed COVID-19 cases with GI symptoms in the Zhejiang province to determine epidemiological, clinical and virological characteristics.', 'DESIGN: COVID-19 hospital patients were admitted in the Zhejiang province from 17 January 2020 to 8 February 2020.', 'Epidemiological, demographic, clinical, laboratory, management and outcome data of patients with GI symptoms were analysed using multivariate analysis for risk of severe/critical type.', 'Bioinformatics were used to analyse features of SARS-CoV-2 from Zhejiang province.', 'RESULTS: Among enrolled 651 patients, 74 (11.4%) presented with at least one GI symptom (nausea, vomiting or diarrhoea), average age of 46.14 years, 4-day incubation period and 10.8% had pre-existing liver disease.', 'Of patients with COVID-19 with GI symptoms, 17 (22.97%) and 23 (31.08%) had severe/critical types and family clustering, respectively, significantly higher than those without GI symptoms, 47 (8.14%) and 118 (20.45%).', 'Of patients with COVID-19 with GI symptoms, 29 (39.19%), 23 (31.08%), 8 (10.81%) and 16 (21.62%) had significantly higher rates of fever >38.5°C, fatigue, shortness of breath and headache, respectively.', 'Low-dose glucocorticoids and antibiotics were administered to 14.86% and 41.89% of patients, respectively.', 'Sputum production and increased lactate dehydrogenase/glucose levels were risk factors for severe/critical type.', 'Bioinformatics showed sequence mutation of SARS-CoV-2 with m(6)A methylation and changed binding capacity with ACE2.', 'CONCLUSION: We report COVID-19 cases with GI symptoms with novel features outside Wuhan.', 'Attention to patients with COVID-19 with non-classic symptoms should increase to protect health providers.']}\n" - ] - }, - { - "name": "stdout", - "output_type": "stream", - "text": [ - "{'sentences': ['Although recent studies have reported epidemiological and clinical features of COVID-19 [1] , this is the first study to characterize KTx recipients with COVID-19.', 'After the outbreak of COVID-19, we identified five infected KTx recipients.', 'While three patients had a suspected history of exposure, the incubation period concerning the other two patients was unclear (Fig. 1) .', 'However, these two patients were residents of Wuhan, the center of the outbreak, and their infection may have been due to exposure to undiagnosed, asymptomatic carriers of SARS-CoV-2.', 'Furthermore, specifically concerning patient 2, the patient was treated with methylprednisolone pulse therapy, which involves greater immunosuppression and could be a predisposing factor for SARS-CoV-2 infection.', 'Although SARS-CoV-2 nucleic acid reverse transcription polymerase chain reaction analysis using throat swab specimens can confirm COVID-19 infection, false negatives are possible due to the sampling techniques, viral load of the upper respiratory tract, and mutations of the virus gene.', 'For example, on illness day 21, the NAT result of patient 2 was not definitive, which suggests that trained technicians should conduct standard multisampling in strict accordance with protocols to improve the sensitivity of specimens.', 'Apart from lower respiratory tract sampling, whole genome sequencing and detection of serum antibodies should be considered to optimize diagnostic methods.', 'Concerning laboratory findings, lymphocytopenia developed in the five patients on admission.', 'Although we could not explain this, lymphocytes have been identified as primary targets of SARS-CoV injury [8] .', 'Notably, the absolute leukocyte and neutrophil value was increased in patient 2.', 'However, because bacterial culture results were not available, the presence of bacterial coinfections could not be confirmed.', 'It should also be noted that glucocorticoids, such as methylprednisolone, and acute rejection can contribute to increasing leukocytes and neutrophils on initiation [9] .', 'Thus, the use of the leukocyte differential could be helpful in determining whether an abnormal number of leukocytes and neutrophils are due to bacterial coinfections, acute rejection, or initiation of methylprednisolone.', 'Apart from symptomatic support therapy, no specific treatment for COVID-19 has been confirmed, although several ongoing clinical trials may identify some options E U R O P E A N U R O L O G Y X X X ( 2 0 1 9 ) X X X -X X X for D-dimer, 0-0.5 mg/l; for CRP, 0-8 mg/l; for ESR, 0-15 mm/h; for albumin, 35-55 g/l; for total bilirubin, 5.1-19.0 mmol/l; for direct bilirubin, 1.7-6.8 mmol/l; for ALT, 5-40 U/l; for AST, 8-40 U/l; for LDH, 109-245 U/l; for urea, 2.9-8.2 mmol/l; for creatinine, 44.0-133.0 mmol/l; for proteinuria, \"-\" indicates that protein excretion is <10 mg/dl, \"+\" indicates that protein excretion is between 30 and 100 mg/dl, and \"++\" indicates that protein excretion is between 100 and 300 mg/dl.', 'E U R O P E A N U R O L O G Y X X X ( 2 0 1 9 ) X X X -X X X [10] .', 'Even for KTx recipients infected with SARS and MERS, the treatment options are limited [3] [4] [5] .', 'Therefore, enhancing personal protection precautions, early identification, and timely management of affected cases are of crucial importance.', 'Despite the lack of evidence on clinical efficacy, each patient in this study received antiviral therapy, and patients 2 and 3 also received antibacterial agent and intravenous immunoglobulin, respectively.', 'Given the extent of lymphocytes shown to be consumed by SARS-CoV-2 [10] , MMF treatment was withdrawn in four patients.', 'Moreover, glucocorticoids and tacrolimus dosages were also adjusted.', 'There is no evidence to confirm the favorable effects of glucocorticoids in COVID-19 treatment [11] .', 'Furthermore, whether SARS-CoV-2 can be inhibited by tacrolimus is unclear, although replication of SARS-CoV was diminished after tacrolimus treatment [12] .', 'Notably, cyclosporine, another CNI drug, may be used as an option of hostdirected therapies for COVID-19 [13] .', 'Strikingly, no significant kidney impairment was detected except in patient 2, implying that reducing immunosuppressive therapy for a short period would not lead to acute rejection.', 'However, the long-term effect is uncertain.', 'For patient 5, immunosuppressant use was not changed because of the relatively mild symptoms.', 'The satisfactory clinical outcome of patient 5 suggested that an immunosuppressive maintenance dosage might not compromise the antiviral immune effect in relatively mild COVID-19 cases.', 'In addition, aggressive reduction or withdrawal of the immunosuppressant should be considered cautiously only for recipients with severe pneumonia or acute respiratory distress syndrome [14] .', 'More importantly, renal function should be monitored frequently because renal failure resulting from acute rejection could make treatment more difficult.', 'During hospitalization, symptoms of four patients were gradually controlled, whereas those of patient 2 got worse, which, in this case, might be related in part to former acute rejection.', 'Additionally, as COVID-19 progresses, kidney impairment in patients infected with SARS-CoV-2 might contribute to poor outcomes, similar to SARS-CoV where pathological findings concerning kidney specimens from patients with SARS-CoV shows acute tubular necrosis [15, 16] .', 'Moreover, based on recent studies [1] , old age and malignancy could be further risk factors for patient 2.', 'However, whether other factors may affect prognosis could not be determined due to the limited data available.', 'In conclusion, although the five KTx recipients were immunocompromised, severe COVID-19 was not found.', 'Mild COVID-19 in KTx recipients can be managed using symptomatic support therapy combined with adjusted maintenance immunosuppressive therapy.', 'Meanwhile, physicians should pay attention to the influence of comorbidities and the possibility of coinfections.', 'More data are needed to gain better understanding of KTx recipients infected with COVID-19.']}\n", - "{'sentences': ['Objective To investigate the diagnostic value of immunoglobulin M (IgM) and immunoglobulin G(IgG) antibodies to 2019 Novel Coronavirus (2019-nCoV) in 2019-nCoV infection.', 'Method This is a retrospective study.', 'Serum samples were collected from 284 patients including outpatients and inpatients in the Renmin Hospital of Wuhan University from January 20, 2020 to February 17, 2020.', \"Among them 205 cases were 2019-nCoV infected patients, including 186 cases confirmed with nucleic acid test and 19 cases diagnosed by clinical symptoms and CT characteristics according to 'the New Coronavirus Pneumonia Control Protocol (5th edition)' .\", 'A total of 79 subjects with other diseases but negative to 2019-nCoV infection were recruited as control group.', 'Serum IgM and IgG antibodies to 2019-nCoV were measured with fully automated immunoassay technology for all subjects.', 'Statistical significance between 2019-nCoV antibodies test and 2019-nCoV nucleic acid test was determined using the χ 2 tests.', 'Result The sensitivity of serum IgM and IgG antibodies to 2019-nCoV were 70.24%(144/205) and 96.10%(197/205) respectively and the specificity were 96.20%(76/79) and 92.41%(73/79) respectively.', 'The positive and negative predictive values of 2019-nCoV antibodies were 95.63%(197/206) and 91.03% (71/78) respectively, and the positive and negative predictive values of 2019-nCoV nucleic acid test were 100%(186/186) and 80.61%(79/98) respectively.', 'The total coincidence rate of diagnosing 2019-nCoV infection between antibody tests and nucleic acid test for 2019-nCoV were 88.03%(250/284).', 'Conclusion Joint detection of serum IgM and IgG antibodies to 2019-nCoV is an effective screening and diagnostic indicators for 2019-nCoV']}\n" - ] - } - ], - "source": [ + "%%capture \n", + "## this would stop the output from getting printed\n", "df_abs['pred'] = df_abs.sentences.apply(lambda x:claim_predictor.predict_json({'sentences': x}))\n", "df_abs['best_paths'] = df_abs.pred.apply(lambda x: model.crf.viterbi_tags(torch.FloatTensor(x['logits']).unsqueeze(0), \n", " torch.LongTensor(x['mask']).unsqueeze(0)))\n", @@ -1995,593 +383,54 @@ }, { "cell_type": "code", - "execution_count": 338, - "metadata": {}, + "execution_count": 19, + "metadata": { + "scrolled": true + }, "outputs": [], "source": [ "df_abs['claims']=df_abs.apply(lambda x: np.extract(x['p_claims'],x['sentences']),axis=1)\n", - "df_abs['claims_id']=df_abs.apply(lambda x:np.extract(x['p_claims'],x['sentence_id']), axis=1)" - ] - }, - { - "cell_type": "code", - "execution_count": 339, - "metadata": {}, - "outputs": [ - { - "data": { - "text/plain": [ - "(345,)" - ] - }, - "execution_count": 339, - "metadata": {}, - "output_type": "execute_result" - } - ], - "source": [ - "df_abs[df_abs['claims'].str.len()>0]['claims'].shape" + "# df_abs['claims_id']=df_abs.apply(lambda x:np.extract(x['p_claims'],x['sentence_bid']), axis=1)" ] }, { "cell_type": "code", - "execution_count": 340, - "metadata": {}, - "outputs": [ - { - "data": { - "text/plain": [ - "14" - ] - }, - "execution_count": 340, - "metadata": {}, - "output_type": "execute_result" - } - ], - "source": [ - "df_abs['claims'].str.len().max()" - ] - }, - { - "cell_type": "code", - "execution_count": 341, - "metadata": {}, - "outputs": [ - { - "data": { - "text/plain": [ - "array(['Modeling results indicate that interfering with the salt bridges at hot spot 353 could be an effective strategy for inhibiting binding, and hence for the prevention of coronavirus infections.',\n", - " 'We also propose that a glycine residue at the receptor binding domain of the spike glycoprotein can have a critical role in permitting bat variants of the coronaviruses to infect human cells.',\n", - " 'These results obtained from independent analysis strongly highlight the importance of 439 to 508 section.',\n", - " 'These calculations show that the SARS2, SARS and Rs4231 viruses are predicted to favorably bind to the human hACE2 receptor, while the Rm1 and SARS2-MUT variants present unfavorable free energies of binding.',\n", - " \"The fact that the bat's coronavirus Rs4231, in addition to SARS and SARS2, presents favorable interaction with hACE2 is in accordance with the previous observation that it is able to infect human cells expressing this protein (Hu et al., 2017) .\",\n", - " 'This result supports the prediction from FUBAR analyses indicating that the site G496D is under purifying selection.',\n", - " 'Combined, our results strongly suggest that the mutation of the D496 residue present in the coronaviruses from bats is critical for their RBDs to recognize the human hACE2 receptor.',\n", - " 'Additionally, it shows the importance of sites under purifying selection in RPS for the RBD evolution.',\n", - " 'This could indicate that interactions additional to those previously identified with the hACE2 hotspots could be critical for the stabilization of the RDB-human receptor complexes.',\n", - " 'Our experiments suggest that there are sites under positive selection in the S-protein gene of SARS-CoV-2 and other betacoronaviruses, particularly in a region that we called RPS (Region under Positive Selection) inside of the RBD.',\n", - " 'Our results suggest that as long as no disrupting interference occur with both salt bridges at hot spots 31 and 353 coronaviruses are able to bind with hACE2.',\n", - " 'Modeling results suggest that interference with the hot spot 353 could be and effective strategy for inhibiting the recognition of the RBD of the SARS-COV-2 spike protein by its human host receptor ACE2 and hence prevent infections.',\n", - " 'Although additional simulations and experiments are required, all evidence suggests that the mutation of D496 in the bat variants of the coronaviruses permit infection of human cells.',\n", - " 'Giving the large contribution of SARS2 K417 to the free energy of binding of the RBD to hACE2 we propose that blocking its interaction with the receptor D30 could be a promising strategy for future drug discovery efforts.'],\n", - " dtype='\n", - "\n", - "\n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " \n", - " 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cord_uidsentence_idsectionsentencew2vVectordrug_terms_usedclaim_flag
002q9y01102q9y0111022435RESULTS AND DISCUSSIONConclusion-The significance of the study stems...[0.10180759, -0.00600497, 0.0917831, 0.0254331...amino acids,glycine,protein c,tandem0.0
102q9y01102q9y0111022436RESULTS AND DISCUSSIONThis is the first step needed to justify scree...[0.00878348, -0.04307965, 0.09269622, -0.06150...amino acids,glycine,protein c,tandem0.0
202q9y01102q9y0111022437RESULTS AND DISCUSSIONMore work needs to be done, however, to unders...[-0.01625532, 0.02996597, 0.02187862, 0.030338...amino acids,glycine,protein c,tandem0.0
302q9y01102q9y0111022438RESULTS AND DISCUSSIONSome work with alpha coronaviruses suggest tha...[0.05328574, 0.00301708, 0.03859519, -0.061556...amino acids,glycine,protein c,tandem0.0
402q9y01102q9y0111022439RESULTS AND DISCUSSION13 However, studies with other (+)RNA viruses ...[0.01838331, -0.0495583, 0.07313509, -0.138604...amino acids,glycine,protein c,tandem0.0
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"\n", - " drug_terms_used claim_flag \n", - "0 amino acids,glycine,protein c,tandem 0.0 \n", - "1 amino acids,glycine,protein c,tandem 0.0 \n", - "2 amino acids,glycine,protein c,tandem 0.0 \n", - "3 amino acids,glycine,protein c,tandem 0.0 \n", - "4 amino acids,glycine,protein c,tandem 0.0 " - ] - }, - "execution_count": 349, - "metadata": {}, - "output_type": "execute_result" - } - ], - "source": [ - "df_merged.head()" - ] - }, - { - "cell_type": "code", - "execution_count": 350, + "execution_count": 23, "metadata": {}, "outputs": [], "source": [ - "df_merged.to_csv(\"../Output/claims_flag_each_cord_uid.csv\",index=False)" - ] - }, - { - "cell_type": "code", - "execution_count": 351, - "metadata": {}, - "outputs": [ - { - "data": { - "text/plain": [ - "(893, 2)" - ] - }, - "execution_count": 351, - "metadata": {}, - "output_type": "execute_result" - } - ], - "source": [ - "df_merged[['cord_uid','claim_flag']].drop_duplicates().shape" - ] - }, - { - "cell_type": "code", - "execution_count": 353, - "metadata": {}, - "outputs": [ - { - "data": { - "text/plain": [ - "345" - ] - }, - "execution_count": 353, - "metadata": {}, - "output_type": "execute_result" - } - ], - "source": [ - "df_merged[df_merged['claim_flag']==1].cord_uid.nunique()" - ] - }, - { - "cell_type": "code", - "execution_count": 357, - "metadata": {}, - "outputs": [ - { - "data": { - "text/plain": [ - "2.0" - ] - }, - "execution_count": 357, - "metadata": {}, - "output_type": "execute_result" - } - ], - "source": [ - "key=df_merged.cord_uid.unique()[2]\n", - "df_merged[df_merged['cord_uid']==key]['claim_flag'].sum()" - ] - }, - { - "cell_type": "code", - "execution_count": 358, - "metadata": {}, - "outputs": [ - { - "data": { - "text/plain": [ - "array([['The predominant pathological features of COVID-19 infection largely mimic those previously reported for SARS-CoV-1 infection.',\n", - " 0.0],\n", - " ['They include dry cough, persistent fever, progressive dyspnea, and in some cases acute exacerbation of lung function with bilateral pneumonia (30).',\n", - " 0.0],\n", - " ['Major lung lesions include several pathological signs, such as diffuse alveolar damage, inflammatory exudation in the alveoli and interstitial tissue, hyperplasia of fibrous tissue, and eventually lung fibrosis (43) (44) (45) .',\n", - " 0.0],\n", - " ['It has been shown by fluorescence in situ hybridization technique that SARS-CoV-1 RNA locates to the alveolar pneumocytes and alveolar space (46, 47) .',\n", - " 0.0],\n", - " ['Considering all these facts, it is not surprising that most histopathological analyses have been focused on distal parts of the respiratory airways, while the regions other than the alveolus have been less systematically studied.',\n", - " 0.0],\n", - " ['The copyright holder for this preprint (which was not peer-reviewed) is the .',\n", - " 0.0],\n", - " ['https://doi.org/10.1101/2020.04.13.038752 doi: bioRxiv preprint intermediate cells between goblet, ciliated, and club cells.',\n", - " 0.0],\n", - " ['If SARS-coronaviruses predominantly attack these cells, locating along the airway segments including the trachea, bronchi, and bronchioles until the last segment that is the respiratory bronchioles, it would be obvious that physiological protective mechanisms are severely affected.',\n", - " 0.0],\n", - " ['Defective mucosal protection and inefficient removal of pathogens due to viral infection may contribute to onset of severe bilateral pneumonia that is common for SARS-diseases (51) .',\n", - " 0.0],\n", - " ['This pathogenic mechanism is supported by previous findings, showing that early disease is manifested as a bronchiolar disease with respiratory epithelial cell necrosis, loss of cilia, squamous cell metaplasia, and intrabronchiolar fibrin deposits When we initiated the present study, we hypothesized that understanding better the transcriptional regulation of the ACE2 gene might help to explain the peculiar distribution pattern of ACE2 in tissues.',\n", - " 0.0],\n", - " ['Since upregulation of ACE2 would reflect an increased number of SARS-coronavirus receptors on cell surfaces, it could possibly help us to understand the mechanisms why certain patients (males more than females, old more than young, smokers more than non-smokers) are more susceptible for the most detrimental effects of the COVID-19 infection.',\n", - " 0.0],\n", - " ['In our study, the signals for ACE2 mRNA in the lung specimens did not vary much in different age groups nor did they show significant differences between males and females, which is in line with the previous findings (48) .',\n", - " 0.0],\n", - " ['Therefore, different expression levels of lung ACE2 may not explain the variable outcome of the disease concerning age groups and genders.',\n", - " 0.0],\n", - " ['To investigate the transcriptional regulation of ACE2 gene we made predictions for the binding sites of transcription factors within the proximal promoter region of the intestine-specific and lungspecific human ACE2 transcript promoters.',\n", - " 0.0],\n", - " ['Our findings introduced several putative binding sites in the ACE2 promoter for known transcription factors, which showed high levels of coexpression with ACE2 in several tissues including the ileum, colon, and kidney.',\n", - " 0.0],\n", - " ['The identified transcription factors .', 0.0],\n", - " ['CC-BY 4.0 International license author/funder.', 0.0],\n", - " ['It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .',\n", - " 0.0],\n", - " ['https://doi.org/10.1101/2020.04.13.038752 doi: bioRxiv preprint could represent potential candidate target molecules which regulate ACE2 expression.',\n", - " 0.0],\n", - " ['Two of our predictions, for HNF1A and HNF1B have been previously identified experimentally to drive ACE2 expression in pancreatic islet cells and insulinoma cells, respectively (36).',\n", - " 0.0],\n", - " ['Later work by the same group has shown that our prediction of FOXA binding sites in the ACE2 promoter are also likely correct (54) .',\n", - " 0.0],\n", - " ['It is of interest that ACE2 might be regulated by oxygen status.',\n", - " 0.0],\n", - " ['Zhang and coworkers previously demonstrated that ACE2 mRNA and protein levels increased during the early stages of hypoxia and decreased to near-baseline levels at later stages after hypoxia inducible factor (HIF)-1α accumulation (55) .',\n", - " 0.0],\n", - " ['Based on these findings ACE2 has been listed as a HIF1α-target gene (56), although it does not follow the typical HIF1α regulated expression pattern, nor is there any predicted HIF1α binding site in our analyses.',\n", - " 0.0],\n", - " ['The regulation of ACE2 expression remains an enigma and there may be multiple factors involved.',\n", - " 0.0],\n", - " ['There has been a concern that the use of ACE inhibitors and angiotensin receptor blockers could increase the expression of ACE2 and increase patient susceptibility to viral host cell entry (57) .',\n", - " 0.0],\n", - " ['Previous studies have suggested that both ACE inhibitor and angiotensin II receptor type I antagonist therapies increase ACE2 mRNA expression in the rat heart (58) .',\n", - " 0.0],\n", - " ['There has also been some evidence in humans showing increased expression of ACE2 in the heart, brain, and even in urine after treatment with angiotensin receptor blockers (57) .',\n", - " 0.0],\n", - " ['Since these drugs are widely used for treatment of hypertension and heart failure, it would be important to determine in COVID-19 patients whether these medications have any significant effects on symptoms or outcome of the disease.',\n", - " 0.0],\n", - " ['Gene ontology investigations revealed interesting novel data on potential physiological roles of ACE2.',\n", - " 0.0],\n", - " ['The five most significant gene ontology terms included angiogenesis, blood vessel morphogenesis, vasculature development, cardiovascular system development, and blood vessel development.',\n", - " 0.0],\n", - " ['Our analysis of single cell RNA-Seq data suggested that ACE2 is positively, though weakly, expressed in the endothelial cells.',\n", - " 0.0],\n", - " ['In another study, ACE2 expression was previously detected in blood vessels (25), and a recent study showed that SARS-CoV-2 is capable of directly infecting blood vessel cells (11) .',\n", - " 0.0],\n", - " ['Based on the present finding angiogenesis/blood vessel morphogenesis may be considered a putative function for ACE2 in addition to its classical role as the key angiotensin-(1-7) forming enzyme (59) .',\n", - " 0.0],\n", - " ['The copyright holder for this preprint (which was not peer-reviewed) is the .',\n", - " 0.0],\n", - " ['https://doi.org/10.1101/2020.04.13.038752 doi: bioRxiv preprint dataset we studied included neither the AT2 nor secretory3 cells that have been recently shown positive for ACE2 (48) .',\n", - " 0.0],\n", - " ['The results suggest that SARS-CoV infection may target the cell types that are important for the protection of airway mucosa and their damage may lead to deterioration of epithelial cell function, finally leading to a more severe lung disease with accumulation of alveolar exudate and inflammatory cells and lung edema, the signs of pneumonia recently described in the lung specimens of two patients with COVID-19 infection (60) .',\n", - " 1.0],\n", - " ['Gene ontology analysis suggested that ACE2 is involved in angiogenesis/blood vessel morphogenesis processes in addition to its classical function in renin-angiotensin system.',\n", - " 0.0],\n", - " ['The copyright holder for this preprint (which was not peer-reviewed) is the .',\n", - " 0.0],\n", - " ['https://doi.org/10.1101/2020.04.13.038752 doi: bioRxiv preprint Figure 2 .',\n", - " 0.0],\n", - " ['Immunohistochemical localization of ACE2 protein in selected human tissues.',\n", - " 0.0],\n", - " ['In the duodenum (A), the protein is most strongly localized to the apical plasma membrane of absorptive enterocytes (arrows).',\n", - " 0.0],\n", - " ['The goblet cells (arrowheads) show weaker apical staining.',\n", - " 0.0],\n", - " ['Intracellular staining is confined to the absorptive enterocytes.',\n", - " 0.0],\n", - " ['In the kidney (B), ACE2 shows prominent apical staining in the epithelial cells of the proximal convoluted tubules (arrows) and Bowman´s capsule epithelium (arrowheads).',\n", - " 0.0],\n", - " ['The distal convoluted tubules are negative (asterisk).', 0.0],\n", - " ['The testis specimen (C) shows strong immunostaining in the seminiferous tubules (arrows) and interstitial cells (arrowheads).',\n", - " 0.0],\n", - " ['The lung sample (D) is negative.', 0.0],\n", - " ['In the nasopharyngeal mucosa (E), ACE2 signal is very weak and only occasional epithelial cells show weak signals (arrows).',\n", - " 0.0],\n", - " ['Immunostained specimens were from Protein Expression Atlas (https://www.proteinatlas.org/).',\n", - " 0.0],\n", - " ['The copyright holder for this preprint (which was not peer-reviewed) is the .',\n", - " 0.0],\n", - " ['https://doi.org/10.1101/2020.04.13.038752 doi: bioRxiv preprint Figure 3 .',\n", - " 0.0],\n", - " ['Single cell RNA-Seq analysis of different cell types from the respiratory tract (mouse tracheal epithelium), derived from data from GEO dataset GSE103354 (37).',\n", - " 0.0],\n", - " ['Cell types were determined using markers as defined in the CellMarker database, as collected from the literature.',\n", - " 0.0],\n", - " ['ACE2 mRNA expression is shown for comparison in upper panel.',\n", - " 0.0],\n", - " ['UMAP dimensionality reduction plot was computed and visualized in ScanPy (40).',\n", - " 0.0],\n", - " ['CC-BY 4.0 International license author/funder.', 0.0],\n", - " ['It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .',\n", - " 0.0],\n", - " ['https://doi.org/10.1101/2020.04.13.038752 doi: bioRxiv preprint The copyright holder for this preprint (which was not peer-reviewed) is the .',\n", - " 0.0],\n", - " ['https://doi.org/10.1101/2020.04.13.038752 doi: bioRxiv preprint Figure 5 .',\n", - " 0.0],\n", - " ['Effect of age on ACE2 mRNA expression levels.', 0.0],\n", - " ['Data is extracted from the GTEx dataset as TPM.', 0.0],\n", - " ['In these organs, ANOVA revealed significant differences between age categories in tibial nerve (p=8.58 x 10 -6 ), minor salivary gland (p=0.002), and whole blood (p=0.005).',\n", - " 0.0],\n", - " ['In other tissues, the differences did not reach statistical significance.',\n", - " 0.0],\n", - " ['The highest TPM values are seen the small intestine, testis, and kidney.',\n", - " 0.0],\n", - " ['CC-BY 4.0 International license author/funder.', 0.0],\n", - " ['It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .',\n", - " 0.0],\n", - " ['https://doi.org/10.1101/2020.04.13.038752 doi: bioRxiv preprint Figure 6 .',\n", - " 0.0],\n", - " ['Effect of gender on ACE2 mRNA expression levels.', 0.0],\n", - " ['Data is extracted from the GTEx dataset as TPM.', 0.0],\n", - " ['The expression levels in males and females overlap in all tissue categories.',\n", - " 0.0],\n", - " ['Statistically significant differences studied by ANOVA analysis were determined in esophagusgastroesophageal junction (p=0.024) and whole blood (p=0.0002).',\n", - " 0.0],\n", - " ['The ACE2 mRNA expression levels in testis specimens are shown here for comparison.',\n", - " 0.0],\n", - " ['CC-BY 4.0 International license author/funder.', 0.0],\n", - " ['It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .',\n", - " 0.0],\n", - " ['https://doi.org/10.1101/2020.04.13.038752 doi: bioRxiv preprint Figure 7 .',\n", - " 0.0],\n", - " ['Prediction of transcription factor binding sites in the human ACE2 gene promoter regions of Ensembl transcripts ENST00000252519 and ENST00000427411 using TFBSfootprinter.',\n", - " 0.0],\n", - " ['A) Promoter region of the intestine specific ACE2 transcript.',\n", - " 0.0],\n", - " ['The results show putative binding sites for several transcription factors which have a strong correlation of expression with ACE2 in colon, kidney, and ileum.',\n", - " 1.0],\n", - " ['The predicted binding sites overlap regions of conservation in mammal species (Ensembl GERP), and cluster within 400 base pairs (bp) of the transcription start site.',\n", - " 0.0],\n", - " ['B) Promoter region of the lung specific ACE2 transcript.', 0.0],\n", - " ['The predicted binding sites cluster within 200 bp', 0.0],\n", - " ['CC-BY 4.0 International license author/funder.', 0.0],\n", - " ['It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .',\n", - " 0.0],\n", - " ['https://doi.org/10.1101/2020.04.13.038752 doi: bioRxiv preprint Figure 8 .',\n", - " 0.0],\n", - " ['Expression of ACE2 highly correlated other genes in single cell datasets of trachea and intestinal epithelia.',\n", - " 0.0],\n", - " ['Trachea expression data is taken from GSE103354 (37) and intestinal epithelia data is derived from GSE92332 (61) .',\n", - " 0.0],\n", - " ['Visualized in ScanPy (40).', 0.0],\n", - " ['Table 2 .', 0.0],\n", - " ['Gene ontology annotation results for the processes associated with genes strongly coexpressed (≥0.5) with ACE2 across all tissues in GTEx dataset.',\n", - " 0.0]], dtype=object)" - ] - }, - "execution_count": 358, - "metadata": {}, - "output_type": "execute_result" - } - ], - "source": [ - "df_merged[df_merged['cord_uid']==key][['sentence','claim_flag']].values" - ] - }, - { - "cell_type": "code", - "execution_count": 359, - "metadata": {}, - "outputs": [ - { - "data": { - "text/plain": [ - "array(['The results suggest that SARS-CoV infection may target the cell types that are important for the protection of airway mucosa and their damage may lead to deterioration of epithelial cell function, finally leading to a more severe lung disease with accumulation of alveolar exudate and inflammatory cells and lung edema, the signs of pneumonia recently described in the lung specimens of two patients with COVID-19 infection (60) .',\n", - " 'The results show putative binding sites for several transcription factors which have a strong correlation of expression with ACE2 in colon, kidney, and ileum.'],\n", - " dtype=object)" - ] - }, - "execution_count": 359, - "metadata": {}, - "output_type": "execute_result" - } - ], - "source": [ - "df_merged[(df_merged['cord_uid']==key)&(df_merged['claim_flag']==1)]['sentence'].values" + "df_merged.to_csv(\"../Output/claims_flag_each_cord_uid_200620.csv\",index=False)" ] }, { @@ -2608,7 +457,7 @@ "name": "python", "nbconvert_exporter": "python", "pygments_lexer": "ipython3", - "version": "3.6.10" + "version": "3.8.2" } }, "nbformat": 4,