Beneficial effects of Angiotensin II Receptor Blockers on Mortality in Patients with COVID-19: a Retrospective Study from 2019 to 2020 in China (preprint)

Background COVID-19 pandemic has become a serious global public health problem. Although the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor type 1 blockers (ARBs) has been recommended in patients with COVID-19 and cardiovascular diseases (CVDs), according to the results of some small-sample retrospective analyses; however, there is still a lack of sufficient evidence to validate their efficacy. This multicenter retrospective study investigated whether ACEI/ARB administration was beneficial in patients with COVID-19 and CVDs.Methods A total of 11,231 patients with confirmed COVID-19 and CVDs, from 138 hospitals in Hubei Province, were included in this multicenter retrospective study. We compared the clinical characteristics and outcomes between the ARB and non-ARB groups and analyzed the risk factors for in-hospital death using univariate and multivariate Cox regression analyses and Kaplan–Meier curves.Results In the multivariate Cox regression model, after adjusting for age, gender, comorbidities, and in-hospital medications, ARB use was associated with lower all-cause mortality (adjusted HR, 0.53; 95% CI, 0.38–0.73; P < 0.001). After propensity score-matched analysis, the adjusted HR for the use of ARB associated with all-cause mortality was 0.62 (95% CI, 0.40–0.88; P = 0.02). Further subgroup analyses found that the adjusted HRs for the use of ARB associated with all-cause mortality were 0.52 (95% CI, 0.30–0.89; P = 0.016), 0.37 (95% CI, 0.21–0.64; P < 0.001), 0.42 (95% CI, 0.28–0.64; P < 0.001), and 0.55 (95% CI, 0.37–0.84; P = 0.005) in patients with heart failure, diabetes, and hypercholesterolemia, and severe COVID-19, respectively.Conclusions ARB administration was significantly associated with a lower risk of all-cause mortality in patients with COVID-19 and CVDs.Trial registration ClinicalTrials.gov NCT05615792.

Psychological symptoms and correlates of Chinese healthcare professionals in the intensive care unit before and after the COVID-19 outbreak: A comparison of two cross-sectional studies.

BACKGROUND: The outbreak of COVID-19 disarranged lives across mainland China. No study has examined changes in psychological symptoms of healthcare professionals in the intensive care unit (ICU) before and after the outbreak of COVID-19. The aim of this study was to estimate changes in psychological symptoms of ICU healthcare professionals before and after the COVID-19 outbreak, and to analyze factors related to psychological symptoms. METHODS: Two waves' administrations were implemented between December 13 and December 14, 2018, and between April 5 and April 7, 2020, respectively. The symptom checklist-90 (SCL-90) were used to evaluate psychological symptoms. Multiple logistical regression was used to reveal the risk of psychological symptoms. RESULTS: A total of 3902 and 3908 ICU healthcare professionals took part in the first and second surveys. The mean total score of the SCL-90 was 179.27 (70.02) at wave 1 and 147.75 (58.40) at wave 2, respectively. The proportion of psychological symptoms was 55.6 % (95%CI = 54.0-57.1) at wave 1. But rates of psychological symptoms decreased to 36.6 % (95%CI = 35.1-38.2) at wave 2. ICU healthcare professionals with western economic belt and 6-10 years of work were more likely to develop psychological symptoms, while ICU healthcare professionals with the later survey and doctoral degree were less likely to develop psychological symptoms. CONCLUSION: Although COVID-19 period benefited psychological symptoms of ICU healthcare professionals, psychological symptoms still had a related high prevalence. Regular screening and appropriate interventions should still be implemented to decrease the risk for psychological symptoms among Chinese ICU healthcare professionals.

Impact of comorbidities on the serological response to COVID-19 vaccination in Taiwan (preprint)

Background/Aims Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the best policies to control COVID-19 pandemic. The serological response to COVID-19 vaccination in Taiwanese patients with different comorbidities is elusive. Methods Uninfected subjects who received 3 doses of mRNA vaccines (BNT162b2 [Pfizer-BioNTech, BNT] and mRNA-1273 [Moderna]), viral vector-based vaccines (ChAdOx1-S (AZD1222, AZ) or protein subunit vaccines (Medigen COVID-19 vaccine) were prospectively enrolled. The SARS-CoV-2-IgG spike antibody level was determined within three months after the 3rd dose of vaccination. The Charlson Comorbidity Index (CCI) was applied to determine the association between vaccine titers and underlying comorbidities. Results A total of 824 subjects were enrolled in the current study. The proportions of CCI scores of 0-1, 2-3 and >4 were 52.8% (n=435), 31.3% (n=258) and 15.9% (n=131), respectively. The most commonly used vaccination combination was AZ-AZ-Moderna (39.2%), followed by Moderna-Moderna-Moderna (27.8%). The mean vaccination titer was 3.11 log BAU/mL after a median of 48 days after the 3rd dose. Factors associated with potentially effective neutralization capacity included an age ≥60 years (odds ratio [OR]/95% confidence interval [CI], 0.49/0.34–0.72; P <0.001), female gender (OR/CI, 1.78/1.26–2.53; P =0.001), Moderna-based vaccination (compared to AZ-based vaccination; OR/CI, 6.49/3.90–10.82; P <0.001) and a CCI score ≥4 (OR/CI, 0.55/0.35–0.85; P =0.01). There was a decreasing trend in antibody titers with increasing CCI scores (trend P<0.001). Linear regression analysis revealed that AZ-based vaccination (β: 0.341, CI: 0.144, 0.21, P<0.001) and higher CCI scores (β: -0.055, CI: -0.096, -0.014, P=0.009) independently correlated with low IgG spike antibody levels. Conclusions Subjects with more comorbidities had a poor response to 3 doses of COVID-19 vaccination.

Impact Factors of COVID-19 Vaccination Hesitancy in patients after lung cancer surgery: an outpatients-based cross-sectional study (preprint)

Background The safety and efficacy of several vaccine candidates have been tested and found to be effective and safe against COVID-19. But, little is known about the actual level of people with lung cancer willing to accept a COVID-19 vaccine and the impact factors that affect acceptability. The survey aimed to determine the prevalence of vaccine hesitancy in lung cancer patients after surgery and characterize underlying factors contributing to reluctance.Methods An clinical survey was inducted from May 1, 2021, to August 20, 2021. Eligible participants were 18 years or older, were diagnosed with lung cancer, and received lung cancer surgery, including lobectomy, sublobectomy, and pneumonectomy. Data were collected on a self-administered questionnaire from 294 lung cancer patients after surgery.Results Among the final included 281 participants, 54.1% were female, and 93.6% were of Han ethnicity. 48.0% were in pathologic stage I, 36.3% in stage II, 10.3% in stage III, and 5.3% in stage IV. The vaccination hesitancy/refusal rate was 41.6%. In multivariable regression analysis, age over 60 years old, low educational level, duration of cancer (< 1 year), subjective health status, current cancer treatments use, presence of postoperative pain, and report of the items “ever hesitated or refused to get a vaccination,” “get negative information about getting the COVID-19 vaccine”, “worried about vaccine adverse reactions,” and “worried about the COVID vaccine interferes with cancer treatments” were independently associated with hesitant of the COVID-19 vaccine.Conclusions Vaccine hesitancy is common among lung cancer patients after surgery, related mainly to health status and concerns about side effects, worsens cancer prognosis, and interferes with cancer treatments. These results suggest that vaccination programs may need tailoring to specific populations’ hesitancy.

Observational Cohort of COVID-19 Patients in Hubei Province

Immunomolecular Assay Based on Selective Virion Capture by Spike Antibody and Viral Nucleic Acid Amplification for Detecting Intact SARS-CoV-2 Particles (preprint)

Background: Effective therapeutics and vaccines for coronavirus disease 2019 (COVID-19) are currently lacking because of the mutation and immune escape of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on the propagation characteristics of SARS-CoV-2, rapid and accurate detection of complete virions from clinical samples and the environment is critical for assessing infection risk and containing further COVID-19 outbreaks. However, currently applicable methods cannot achieve large-scale clinical application because of factors such as the high viral load, cumbersome virus isolation steps, demanding environmental conditions, and long experimental periods. In this study, we developed an immunomolecular detection method combining capture of the viral spike glycoprotein with monoclonal antibodies and nucleic acid amplification via quantitative reverse transcription PCR to rapidly and accurately detect complete virions. Results: : After constructing a novel pseudovirus, screening for specific antibodies, and optimizing the detection parameters, the assay achieved a limit of detection of 9 × 10 2 transduction units/mL of viral titer with high confidence (~95%) and excellent stability against human serum and common virus/pseudovirus. The coefficients of variation were 1.0–2.0% for intra-assay and inter-assay analyses, respectively. Compared with reverse transcription-PCR, the immunomolecular method more accurately quantified complete virions. SARS-CoV-2/pseudovirus was more stable on plastic and paper than on aluminum and copper in the detection of SARS-CoV-2 pseudovirus under different conditions, and complete virions were detected up to 96 h after they were applied to these surfaces (except for copper), although the titer of the virions was greatly reduced. Conclusions: : Convenient, inexpensive, and accurate complete virus detection can be applied in many fields, such as monitoring the infectivity of convalescent and post-discharge patients and assessing high-risk environments (isolation rooms, operating rooms, patient living environments, and cold chain logistics). This method can also be used to detect intact virions such as those of hepatitis B and C viruses, human immunodeficiency virus, influenza, and the partial pulmonary virus, which may further improve the accuracy of diagnoses and facilitate individualized and precise treatments.

Polymersomes as Stable Nanocarriers for a Highly Immunogenic and Durable SARS-CoV-2 Spike Protein Subunit Vaccine.

Multiple successful vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed to address the ongoing coronavirus disease 2019 (Covid-19) pandemic. In the present work, we describe a subunit vaccine based on the SARS-CoV-2 spike protein coadministered with CpG adjuvant. To enhance the immunogenicity of our formulation, both antigen and adjuvant were encapsulated with our proprietary artificial cell membrane (ACM) polymersome technology. Structurally, ACM polymersomes are self-assembling nanoscale vesicles made up of an amphiphilic block copolymer comprising poly(butadiene)-b-poly(ethylene glycol) and a cationic lipid, 1,2-dioleoyl-3-trimethylammonium-propane. Functionally, ACM polymersomes serve as delivery vehicles that are efficiently taken up by dendritic cells (DC1 and DC2), which are key initiators of the adaptive immune response. Two doses of our formulation elicit robust neutralizing antibody titers in C57BL/6 mice that persist at least 40 days. Furthermore, we confirm the presence of functional memory CD4+ and CD8+ T cells that produce T helper type 1 cytokines. This study is an important step toward the development of an efficacious vaccine in humans.

Total Infectomes Characterization of Respiratory Infections in pre-COVID-19 Wuhan, China (preprint)

At the end of 2019 Wuhan witnessed an outbreak of “atypical pneumonia” that later developed into a global pandemic. Metagenomic sequencing rapidly revealed the causative agent of this outbreak to be a novel coronavirus - SARS-CoV-2. Herein, to provide a snapshot of the pathogens in pneumonia-associated respiratory samples from Wuhan prior to the emergence of SARS-CoV-2, we collected bronchoalveolar lavage fluid samples from 408 patients presenting with pneumonia and acute respiratory infections at the Central Hospital of Wuhan between 2016 and 2017. Unbiased total RNA sequencing was performed to reveal their “total infectome”, including viruses, bacteria and fungi. Consequently, we identified 37 pathogen species, comprising 15 RNA viruses, 3 DNA viruses, 16 bacteria and 3 fungi, often at high abundance and including multiple co-infections (12.8%). However, SARS-CoV-2 was not present. These data depict a stable core infectome comprising common respiratory pathogens such as rhinoviruses and influenza viruses, an atypical respiratory virus (EV-D68), and a single case of a sporadic zoonotic pathogen – Chlamydia psittaci . Samples from patients experiencing respiratory disease on average had higher pathogen abundance than healthy controls. Phylogenetic analyses of individual pathogens revealed multiple origins and global transmission histories, highlighting the connectedness of the Wuhan population. This study provides a comprehensive overview of the pathogens associated with acute respiratory infections and pneumonia, which were more diverse and complex than obtained using targeted PCR or qPCR approaches. These data also suggest that SARS-CoV-2 or closely related viruses were absent from Wuhan in 2016-2017.

Impact of Glycosylation on SARS-CoV-2 Infection and Broadly Protective Vaccine Design (preprint)

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 167 million confirmed cases and over 3 million deaths so far. This global pandemic has led to great efforts directed toward the study of this virus and its infection mechanism as well as development of effective means to control this devastating infectious disease. Like many other viral surface proteins, the trimeric SARS-CoV-2 spike (S) protein is heavily glycosylated with 22 N- and 2 O-glycosites per monomer which are likely to influence S protein folding and evade host immune response. More than one million S protein sequences with over 1,000 sites of mutation in its 1,273 amino acids have been reported to the GISAID database, including the highly transmissible variant strains found in the UK and South Africa. This high frequency of transmission and mutation is a major challenge in the development of broadly protective vaccines to control the pandemic. We have studied the impact of glycosylation on receptor-ligand interaction through evaluation of ACE2 and S protein expressed in different cell lines. Of different S protein glycoforms, the one expressed from lung epithelial cells, the primary cells for infection, has more complex-type glycans and higher binding avidity to the receptor as compared with the S protein from HEK293T cells which have more high-mannose or hybrid-type glycoforms. We also found that most of the S protein glycosites are highly conserved and the glycosites at positions 801 and 1194 are essential for viral entry. In addition, the RBD of S1 and the HR regions of S2 contain most of highly conserved sequences, and removal of each glycosite on pseudotyped SARS-CoV-2 virus for evaluation of the impact on structure and function provides insights into the design of broadly protective vaccines. In an effort to develop such universal vaccines, we found that mice immunized with monoglycosylated S protein (Smg) elicited better antibody responses capable of neutralizing not only the wild type but also the variants from the UK and South Africa than those with the fully-glycosylated S protein (Sfg), and strikingly, Smg vaccination provides better survival for hACE2 transgenic mice when challenged with lethal dose of SARS-CoV-2. Moreover, using single B cell technology, we isolated a monoclonal antibody from Smg immunized mice which was also able to neutralize the wild type and variants, suggesting that removal of unnecessary glycans from S protein to better expose the highly conserved sequences is an effective approach to developing broadly protective vaccines against SARS-CoV-2 and variants.

Redefining NT-proBNP in predicting mortality of adult inpatients with COVID-19 (preprint)

NT-proBNP was much lower than the recommended threshold for heart failure in some adult COVID-19 inpatients with poor prognosis. NT-proBNP has different ranges of normal values for different age groups. NT-proBNP levels specific to age, defined as NT-proBNP ratio, were divided into quartiles and measured the hazard ratios (and 95% confidence intervals) for in-hospital death of COVID-19 patients. Higher NT-proBNP ratio was directly associated, in a dose-response manner, with a higher risk of all causes in-hospital death in the COVID-19 patients. Our study shows that NT-proBNP ratio is an independent predictor of the risk of in-hospital death of the adult patients with COVID-19. This implies that NT-proBNP levels specific to age in the COVID-19 patietns requires attention of healthcare workers.

The prevalence of psychiatric comorbidities during the SARS and COVID-19 epidemics: a systematic review and meta-analysis of observational studies.

The coronavirus disease 2019 (COVID-19) and Severe Acute Respiratory Syndrome (SARS) are associated with various psychiatric comorbidities. This is a systematic review and meta-analysis comparing the prevalence of psychiatric comorbidities in all subpopulations during the SARS and COVID-19 epidemics. A systematic literature search was conducted in major international (PubMed, EMBASE, Web of Science, PsycINFO) and Chinese (China National Knowledge Internet [CNKI] and Wanfang) databases to identify studies reporting prevalence of psychiatric comorbidities in all subpopulations during the SARS and COVID-19 epidemics. Data analyses were conducted using the Comprehensive Meta-Analysis Version 2.0 (CMA V2.0). Eighty-two studies involving 96,100 participants were included. The overall prevalence of depressive symptoms (depression hereinafter), anxiety symptoms (anxiety hereinafter), stress, distress, insomnia symptoms, post-traumatic stress symptoms (PTSS) and poor mental health during the COVID-19 epidemic were 23.9% (95% CI: 18.4%-30.3%), 23.4% (95% CI: 19.9%-27.3%), 14.2% (95% CI: 8.4%-22.9%), 16.0% (95% CI: 8.4%-28.5%), 26.5% (95% CI: 19.1%-35.5%), 24.9% (95% CI: 11.0%-46.8%), and 19.9% (95% CI: 11.7%-31.9%), respectively. Prevalence of poor mental health was higher in general populations than in health professionals (29.0% vs. 11.6%; Q=10.99, p=0.001). The prevalence of depression, anxiety, PTSS and poor mental health were similar between SARS and COVID-19 epidemics (all p values>0.05). Psychiatric comorbidities were common in different subpopulations during both the SARS and COVID-19 epidemics. Considering the negative impact of psychiatric comorbidities on health and wellbeing, timely screening and appropriate interventions for psychiatric comorbidities should be conducted for subpopulations affected by such serious epidemics.

Next generation vaccine platform: polymersomes as stable nanocarriers for a highly immunogenic and durable SARS-CoV-2 spike protein subunit vaccine (preprint)

Multiple successful vaccines against SARS-CoV-2 are urgently needed to address the ongoing Covid-19 pandemic. In the present work, we describe a subunit vaccine based on the SARS-CoV-2 spike protein co-administered with CpG adjuvant. To enhance the immunogenicity of our formulation, both antigen and adjuvant were encapsulated with our proprietary artificial cell membrane (ACM) polymersome technology. Structurally, ACM polymersomes are self-assembling nanoscale vesicles made up of an amphiphilic block copolymer comprising of polybutadiene-b-polyethylene glycol and a cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane. Functionally, ACM polymersomes serve as delivery vehicles that are efficiently taken up by dendritic cells, which are key initiators of the adaptive immune response. Two doses of our formulation elicit robust neutralizing titers in C57BL/6 mice that persist at least 40 days. Furthermore, we confirm the presence of memory CD4+ and CD8+ T cells that produce Th1 cytokines. This study is an important step towards the development of an efficacious vaccine in humans.

Insulin Treatment Increased Fatality in COVID-19 Patients with Diabetes (preprint)

Background: COVID-19 epidemic continues to spread rapidly around the world, causing severe multi-organ injury and high mortality in a subset of patients. Individuals with diabetes mellitus are at a higher risk of SARS-CoV-2 infection and worse outcomes than the general population without diabetes. While glucose control was observed to be associated with attenuated mortality, limited evidence is available to determine whether glucose control by insulin was beneficial for COVID-19 patients with diabetes.Methods: This retrospective study focused on a cohort of 689 COVID-19 patients from Wuhan, China, diagnosed with diabetes, and assessed the clinical outcomes associated with insulin treatment. Kaplan-Meier survival analysis and proportional Cox regression were employed to analyze the influence of insulin treatment on all cause death.Results: Among the 689 diabetic patients infected with COVID-19, 106 patients died (fatality was 15.4%). The fatality of COVID-19 patients with diabetes treated with insulin was significantly higher than those without insulin treatment (27.2% vs. 3.5%, p < 0.001). The HR was 6.57 (95% CI 3.09 to 13.99; p < 0.001) after adjustment for age, gender, coronary heart disease, COPD, chronic kidney disease, pulse, respiratory rate, SpO2, lymphocyte count, albumin, NT-proBNP and glucose. Further survival analysis in several subgroups and critically ill group showed the similar effect of insulin on adverse outcome in COVID-19 patients with diabetes.Conclusion: According to this retrospective study, insulin treatment increases the mortality in COVID-19 patients with diabetes. Thus, close observation especially glucose and vital signs monitoring are very important when COVID-19 patients with diabetes treated with insulin.Funding: This work was supported in part by projects from Ministry of Science and Technology of China (No. 2020YFC0844500), Nature Science Foundation of China (Nos. 31130031), Emergency project fund of Chinese Academy of Sciences (No. 2020YJFK0105) and Chinese Academy of Engineering and Ma Yun Foundation (No. 2020-CMKYGG-05). Conflict of Interest: The authors have declared that no competing interests exist.Ethical Approval: This study was approved by the institutional review board of Tongji Hospital (IRBID: TJ-IRB20200229). The written informed consent was waived by the Ethics Committee because of the retrospective and anonymous nature of the data.

Two Color Single Molecule Sequencing on GenoCare 1600 Platform to Facilitate Clinical Applications (preprint)

With the rapid development of precision medicine industry, DNA sequencing becomes increasingly important as a research and diagnosis tool. For clinical applications, medical professionals require a platform which is fast, easy to use, and presents clear information relevant to definitive diagnosis. We have developed a single molecule desktop sequencing platform, GenoCare 1600. Fast library preparation (without amplification) and simple instrument operation make it friendlier for clinical use. Here we presented sequencing data of E. coli sample from GenoCare 1600 with consensus accuracy reaches 99.99%. We also demonstrated sequencing of microbial mixtures and COVID-19 samples from throat swabs. Our data show accurate quantitation of microbial, sensitive identification of SARS-CoV-2 virus and detection of variants confirmed by Sanger sequencing.

Correlation Study of Chest CT Features of Severe/Critical type COVID-19 with Early Renal Damage and Clinical Prognosis (preprint)

Background: Among patients with confirmed severe/critical type COVID-19, we found that although the seurm creatinine (Cr) value is in normal range, patients might have occured early renal damage. For severe/critical type COVID-19 patients, whether some chest CT features can be used to predict the early renal damage or clinical prognosis.Methods: 162 patients with severe/critical type COVID-19 were reviewed retrospectively in 13 medical centers from China. According to the level of eGFR, 162 patients were divided into three groups, group A (eGFR < 60 ml/min/1.73m2), group B (60 ml/min/1.73m2 ≤ eGFR < 90 ml/min/1.73m2 group) and group C (eGFR ≥ 90 ml/min/1.73m2). All patients’ baseline clinical characteristics, laboratory data, CT features and clinical outcomes were collected and compared. The eGFR and CT features was assessed using univariate and multivariate Cox regression.Results: Baseline clinical characteristics showed that there were significant differences in age, hypertension, cough and fatigue among groups A, B and C. Laboratory data analysis revealed significant differences between the three groups of leukocyte count, platelet count, C-reactive protein, aspartate aminotransferase, creatine kinase. Chest CT features analysis indicated that crazy-paving pattern has significant statistical difference in groups A and B compared with group C. The eGFR of patients with crazy-paving pattern was significant lower than those without crazy-paving pattern (76.73 ± 30.50 vs. 101.69 ± 18.24 ml/min/1.73m2, p < 0.001), and eGFR (OR = 0.962, 95% CI = 0.940-0.985) was the independent risk factor of crazy-paving pattern. The eGFR (HR = 0.549, 95% CI = 0.331-0.909, p = 0.020) and crazy-paving pattern (HR = 2.996, 95% CI = 1.010-8.714, p = 0.048) were independent risk factors of mortality.Conclusions: In patients with severe/critical type COVID-19, the presence of crazy-paving pattern on chest CT are more likely occured the decline of eGFR and poor clinical prognosis. The crazy-paving pattern appeared could be used as an early warning indicator of renal damage and to guide clinicians to use drugs reasonably.

Risk Factors for ICU Admission, Mechanical Ventilation and Mortality in Hospitalized Patients with COVID-19 in Hubei, China. (preprint)

Purpose: To examine the risk factors for Intensive Care Unit (ICU) admission, mechanical ventilation and mortality in hospitalized patients with COVID-19. Methods: This was a retrospective cohort study including 432 patients with laboratory-confirmed COVID-19 who were admitted to three medical centers in Hubei province from January 1st to April 10th 2020. Primary outcomes included ICU admission, mechanical ventilation and death occurring while hospitalized or within 30 days. Results: Of the 432 confirmed patients, 9.5% were admitted to the ICU, 27.3% required mechanical ventilation, and 33.1% died. Total leukocyte count was higher in survivors compared with those who died (8.9 vs 4.8 x 109/l), but lymphocyte counts were lower (0.6 vs 1.0 x 109/l). D-dimer was significantly higher in patients who died compared to survivors (6.0ug/l vs 1.0ug/l, p<0.0001. This was also seen when comparing mechanically versus non-mechanically-ventilated patients. Other significant differences were seen in AST, ALT, LDH, total bilirubin and creating kinase. The following were associated with increased odds of death: age > 65 years (adjusted hazard ratio (HR 2.09, 95% CI 1.02-4.05), severe disease at baseline (5.02, 2.05-12.29), current smoker (1.67, 1.37-2.02), temperature >39o C at baseline (2.68, 1.88-4.23), more than one comorbidity (2.12, 1.62-3.09), bilateral patchy shadowing on chest CT or X-ray (3.74, 1.78-9.62) and organ failure (6.47, 1.97-26.23). The following interventions were associated with higher CFR: glucocorticoids (1.60, 1.04-2.30), ICU admission (4.92, 1.37-17.64) and mechanical ventilation (2.35, 1.14-4.82). Conclusion: Demographics, including age over 65 years, current smoker, diabetes, hypertension, and cerebrovascular disease, were associated with increased risk of mortality. Mortality was also associated with glucocorticoid use, mechanical ventilation and ICU admission. Take-Home Message: COVID-19 patients with risk factors were more likely to be admitted into ICU and more likely to require mechanical ventilation.

Extensive Genetic Diversity and Host Range of Rodent-borne Coronaviruses (preprint)

To better understand the genetic diversity, host association and evolution of coronaviruses (CoVs) in China we analyzed a total of 696 rodents encompassing 16 different species sampled from Zhejiang and Yunnan provinces. Based on the reverse transcriptase PCR-based CoV screening CoVs of fecal samples and subsequent sequence analysis of the RdRp gene, we identified CoVs in diverse rodent species, comprising Apodemus agrarius, Apodemus latronum, Bandicota indica, Eothenomys miletus, E. eleusis, Rattus andamanesis, Rattus norvegicus, and R. tanezumi. Apodemus chevrieri was a particularly rich host, harboring 25 rodent CoVs. Genetic and phylogenetic analysis revealed the presence of three groups of CoVs carried by a range of rodents that were closely related to the Lucheng Rn rat coronavirus (LRNV), China Rattus coronavirus HKU24 (ChRCoV_HKU24) and Longquan Rl rat coronavirus (LRLV) identified previously. One newly identified A. chevrieri-associated virus closely related to LRNV lacked an NS2 gene. This virus had a similar genetic organization to AcCoV-JC34, recently discovered in the same rodent species in Yunnan, suggesting that it represents a new viral subtype. Notably, additional variants of LRNV were identified that contained putative nonstructural NS2b genes located downstream of the NS2 gene that were likely derived from the host genome. Recombination events were also identified in the ORF1a gene of Lijiang-71. In sum, these data reveal the substantial genetic diversity and genomic complexity of rodent-borne CoVs, and greatly extend our knowledge of these major wildlife virus reservoirs.

Safety, Tolerability and Immunogenicity of a Recombinant Adenovirus Type 5 Vectored COVID-19 Vaccine in Healthy Adults in China: Preliminary Report of a First-In Human Single-Center, Open-Label, Dose-Escalating Clinical Trial (preprint)

Background: We aimed to assess the safety, tolerability and immunogenicity of a recombinant adenovirus type 5 (Ad5) vectored COVID-19 vaccine expressing the spike glycoprotein of a SARS-Cov-2 strain. This is the first-in-human study of a candidate vaccine against COVID-19.Methods: We conducted a single-center, open-label, dose-escalating clinical trial of Ad5 vectored COVID-19 vaccine. Healthy adults aged between 18-60 years were sequentially enrolled and allocated to receive a single intramuscular injection in one of three dose groups: 5 × 10^10, 1×10^11, and 1·5×10^11 viral particles. Safety was assessed over the next 28 days. Specific antibodies were measured on enzyme-linked immunosorbent assay (ELISA), and the neutralizing antibody responses induced by vaccination were detected by using SARS-CoV-2 virus neutralization and pseudovirus neutralization tests. T-cell responses were accessed by enzyme-linked immunospot (ELISpot) and flow-cytometry assays. Results: A total of 108 participants were recruited and received low dose, middle dose, or high dose vaccine, with 36 in each dose group. 30(83·3%), 30(83·3%), and 27(75·0%) recipients in the low dose, middle dose, and high dose groups reported at least one adverse reaction within the first 7 days after the vaccination. The most common injection-site adverse reaction was pain, the most commonly reported systematic adverse reactions were fever, fatigue, headache, and muscle pain. A majority of the adverse reactions that were reported in all dose groups were mild or moderate in severity. No serious adverse event was noted within 28 days post-vaccination. Both ELISA antibodies and neutralizing antibodies increased significantly at day 14, and peaked 28 days post-vaccination. Specific T cell response peaked at day 14 post-vaccination.Conclusions: The Ad5 vectored COVID-19 vaccine is tolerable and immunogenic. Humoral responses against SARS-CoV-2 peaked at day 28 post-vaccination in health adults, and rapid specific T cell responses were noted since day 14.Trial Registration: The study is registered with ClinicalTrials.gov, number NCT04313127. Funding Statement: National Key R&D Program of China (2020YFC10841400), National Science and Technology Major Project (2016ZX10004001, 2018ZX09201005), and CanSino Biotechnology Inc.Declaration of Interests: Mr. Gou report being employees of Tianjin CanSino Biotechnology Inc, No other potential conflict of interest relevant to this article was reported.Ethics Approval Statement: The protocol and informed consent were approved by the Institutional Review Board of the Jiangsu Provincial Center of Disease Control and Prevention. Written informed consents from all participants were obtained before screening. This study was undertaken by Jiangsu Provincial Center of Disease Control and Prevention, Hubei Provincial Center for Disease Control and Prevention and Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology in accordance with the Declaration of Helsinki and Good Clinical Practice.