Drug resistance revealed by in silico deep mutational scanning and mutation tracker (preprint)

As COVID-19 enters its fifth year, it continues to pose a significant global health threat, with the constantly mutating SARS-CoV-2 virus challenging drug effectiveness. A comprehensive understanding of virus-drug interactions is essential for predicting and improving drug effectiveness, especially in combating drug resistance during the pandemic. In response, the Path Laplacian Transformer-based Prospective Analysis Framework (PLFormer-PAF) has been proposed, integrating historical data analysis and predictive modeling strategies. This dual-strategy approach utilizes path topology to transform protein-ligand complexes into topological sequences, enabling the use of advanced large language models for analyzing protein-ligand interactions and enhancing its reliability with factual insights garnered from historical data. It has shown unparalleled performance in predicting binding affinity tasks across various benchmarks, including specific evaluations related to SARS-CoV-2, and assesses the impact of virus mutations on drug efficacy, offering crucial insights into potential drug resistance. The predictions align with observed mutation patterns in SARS-CoV-2, indicating that the widespread use of the Pfizer drug has lead to viral evolution and reduced drug efficacy. PLFormer-PAF's capabilities extend beyond identifying drug-resistant strains, positioning it as a key tool in drug discovery research and the development of new therapeutic strategies against fast-mutating viruses like COVID-19.

The Difference of COVID-19 Vaccination Attitude, Preventive Measures and Knowledge of SARS-COV-2 Between Diabetic Patients and Healthy Citizens in China.

Purpose: The outbreak of coronavirus disease has become an evolving global health crisis with wide-ranging implications. Clinical researches from several countries have reported greater morbidity and mortality from COVID-19 patients with diabetes. SARS-CoV-2/COVID-19 vaccines are currently the relatively effective means of prevention. The research was aimed to explore the attitudes of diabetic patients towards COVID-19 vaccine and the knowledge of COVID-19 related epidemiology and epidemic prevention. Methods: This case-control study was carried out in China via online and offline surveys. Knowledge questionnaire of COVID-19 and drivers of COVID-19 Vaccination Acceptance Scale (DrVac-COVID19S) were used to compare the difference of COVID-19 vaccination attitude, preventive measures, and knowledge of SARS-COV-2 between diabetic patients and healthy citizens. Results: The diabetic patients showed lower vaccination willingness and insufficient knowledge of the transmission route and common symptoms of COVID-19. Only 60.99% diabetic patients were willing to be vaccinated. Less than half of diabetics knew the COVID-19 spread by surface touch (34.04%) or aerosol (20.57%). The common symptoms like shortness of breath/ anorexia/ fatigue/ nausea/vomiting/diarrhea (34.04%) and panic and chest tightness (19.15%) were not well comprehend too. Diabetes patients shown lower report intentions when they contact a person infected with the virus (81.56%) or have any of the disease symptoms (74.47%). Values, knowledge, and autonomy assessed by the DrVac-COVID19S scale also showed negative attitude of vaccination in patients with diabetes. Also, patient with diabetes pay less attention to national (56.03%) and international (51.77%) COVID-19 updates. The willingness to attend COVID-19 lectures (27.66%) or read information leaflets (70.92%) was low. Conclusion: Vaccination is the effective available method for preventing the virus. Social and medical workers can increase the vaccination of diabetic patients through knowledge's popularization and patient's education based on the above differences.

Kinetics of SARS-CoV-2 neutralizing antibodies in Omicron breakthrough cases with inactivated vaccination: Role in inferring the history and duration of infection.

Background: The quantitative level and kinetics of neutralizing antibodies (NAbs) in individuals with Omicron breakthrough infections may differ from those of vaccinated individuals without infection. Therefore, we aimed to evaluate the difference in NAb levels to distinguish the breakthrough cases from the post-immunized population to identify early infected person in an outbreak epidemic when nasal and/or pharyngeal swab nucleic acid real-time PCR results were negative. Methods: We collected 1077 serum samples from 877 individuals, including 189 with Omicron BA.2 breakthrough infection and 688 post-immunized participants. NAb titers were detected using the surrogate virus neutralization test, and were log(2)-transformed to normalize prior to analysis using Student's unpaired t-tests. Geometric mean titers (GMT) were calculated with 95% confidence intervals (CI). Linear regression models were used to identify factors associated with NAb levels. We further conducted ROC curve analysis to evaluate the NAbs' ability to identify breakthrough infected individuals in the vaccinated population. Results: The breakthrough infection group had a consistently higher NAb levels than the post-immunized group according to time since the last vaccination. NAb titers in the breakthrough infection group were 6.4-fold higher than those in the post-immunized group (GMT: 40.72 AU/mL and 6.38 AU/mL, respectively; p<0.0001). In the breakthrough infection group, the NAbs in the convalescent phase were 10.9-fold higher than in the acute phase (GMT: 200.48 AU/mL and 18.46 AU/mL, respectively; p<0.0001). In addition, the time since infection, booster vaccination, and the time since last vaccination were associated with log(2)-transformed NAb levels in the breakthrough infection group. ROC curve analysis showed that ROC area was largest (0.728) when the cut-off value of log(2)-transformed NAb was 6, which indicated that NAb levels could identify breakthrough infected individuals in the vaccinated population. Conclusion: Our study demonstrates that the NAb titers of Omicron BA.2 variant breakthrough cases are higher than in the post-immunized group. The difference in NAb levels could be used to identify cases of breakthrough infection from the post-immunized population in an outbreak epidemic.

Immunosenescence, aging and successful aging

Aging induces a series of immune related changes, which is called immunosenescence, playing important roles in many age-related diseases, especially neurodegenerative diseases, tumors, cardiovascular diseases, autoimmune diseases and coronavirus disease 2019(COVID-19). However, the mechanism of immunosenescence, the association with aging and successful aging, and the effects on diseases are not revealed obviously. In order to provide theoretical basis for preventing or controlling diseases effectively and achieve successful aging, we conducted the review and found that changes of aging-related phenotypes, deterioration of immune organ function and alterations of immune cell subsets participated in the process of immunosenescence, which had great effects on the occurrence and development of age-related diseases.

Impact of COVID-19 social distancing on medical research from the perspective of postgraduate students: a cross-sectional online survey.

Objective: To investigate the impact of COVID-19 social distancing on medical research from the perspective of postgraduate students. Methods: A cross-sectional study using an online survey was conducted from October 31 to November 1, 2021. A questionnaire was used to assess the impact of COVID-19 social distancing on medical research among postgraduate students. The questionnaire included basic information, medical research information, and information about social distancing measures. Participants also completed the self-made Research Work Affected Scale of Postgraduates (RWAS-P; qualitative evaluation: very mildly 0-10; mildly 11-20; moderately 21-30; severely 31-40; very severely 41-50). Logistic regression was used to identify factors related to the impact of COVID-19 social distancing. Results: A total of 468 participants were analyzed; 95.2% of the participants adhered to social distancing measures. The median total RWAS-P score was 22. The median RWAS-P scores for earlier research data, current research projects, future research plans, paper publication, and graduation schedule were 2, 6, 6, 6, and 4, respectively (score range 0-10). The higher grade of students, experimental research, and existence of inappetence or sleeplessness were related to negative attitude towards COVID-19 social distancing (odd ratio = 6.35, 9.80, 2.31, 2.15, 1.95, respectively). Conclusions: Participants reported that social distancing had a moderate overall impact on their medical research. Social distancing had the greatest impact on current research projects, future research plans, and paper publications among postgraduate students. Higher grade level, experimental research type, inappetence, and sleeplessness were related to the impact of social distancing on their medical research.

No Differences in Wound Healing and Scar Formation Were Observed in Patients With Different COVID-19 Vaccination Intervals.

Background: Safety concerns are one of the most common reasons for COVID-19 vaccination refusal. In the field of plastic and reconstructive surgery, whether COVID-19 vaccination influences wound healing and scar formation is worthy of special attention. Methods: In this study, patients with adult trauma with subcutaneous sutures placed by a single plastic surgeon in a single center were included. The vaccination interval was defined as the interval between the last dose of the COVID-19 vaccine and when surgical sutures were introduced. The patients were categorized by vaccination interval into three groups of <1, 1-3, and ≥3 months. Wound healing and scar formation were rated according to the Wound Assessment Inventory (WAI) and Patient and Observer Scar Assessment Scale (POSAS) in the groups at 7 days and after a 3-month follow-up. Results: All total and individual scores of WAI and POSAS were not significantly different among the groups. Conclusion: No differences in wound healing and scar formation were observed in patients with different COVID-19 vaccination intervals. Thus, it is not necessary to postpone COVID-19 vaccination, as the vaccine does not affect wound healing and scar formation in patients undergoing surgery. This study aimed to eliminate concerns and hesitancy in receiving the COVID-19 vaccine.

Stem-cell-derived trophoblast organoids model human placental development and susceptibility to emerging pathogens.

Trophoblast organoids derived from placental villi provide a 3D model system of human placental development, but access to first-trimester tissues is limited. Here, we report that trophoblast stem cells isolated from naive human pluripotent stem cells (hPSCs) can efficiently self-organize into 3D stem-cell-derived trophoblast organoids (SC-TOs) with a villous architecture similar to primary trophoblast organoids. Single-cell transcriptome analysis reveals the presence of distinct cytotrophoblast and syncytiotrophoblast clusters and a small cluster of extravillous trophoblasts, which closely correspond to trophoblast identities in the post-implantation embryo. These organoid cultures display clonal X chromosome inactivation patterns previously described in the human placenta. We further demonstrate that SC-TOs exhibit selective vulnerability to emerging pathogens (SARS-CoV-2 and Zika virus), which correlates with expression levels of their respective entry factors. The generation of trophoblast organoids from naive hPSCs provides an accessible 3D model system of the developing placenta and its susceptibility to emerging pathogens.

Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine in Chinese adults: a randomised, double-blind, placebo-controlled, phase 1 trial.

BACKGROUND: Safe and effective vaccines are urgently needed to end the COVID-19 pandemic caused by SARS-CoV-2 infection. We aimed to assess the preliminary safety, tolerability, and immunogenicity of an mRNA vaccine ARCoV, which encodes the SARS-CoV-2 spike protein receptor-binding domain (RBD). METHODS: This single centre, double-blind, randomised, placebo-controlled, dose-escalation, phase 1 trial of ARCoV was conducted at Shulan (Hangzhou) hospital in Hangzhou, Zhejiang province, China. Healthy adults aged 18-59 years negative for SARS-CoV-2 infection were enrolled and randomly assigned using block randomisation to receive an intramuscular injection of vaccine or placebo. Vaccine doses were 5 µg, 10 µg, 15 µg, 20 µg, and 25 µg. The first six participants in each block were sentinels and along with the remaining 18 participants, were randomly assigned to groups (5:1). In block 1 sentinels were given the lowest vaccine dose and after a 4-day observation with confirmed safety analyses, the remaining 18 participants in the same dose group proceeded and sentinels in block 2 were given their first administration on a two-dose schedule, 28 days apart. All participants, investigators, and staff doing laboratory analyses were masked to treatment allocation. Humoral responses were assessed by measuring anti-SARS-CoV-2 RBD IgG using a standardised ELISA and neutralising antibodies using pseudovirus-based and live SARS-CoV-2 neutralisation assays. SARS-CoV-2 RBD-specific T-cell responses, including IFN-γ and IL-2 production, were assessed using an enzyme-linked immunospot (ELISpot) assay. The primary outcome for safety was incidence of adverse events or adverse reactions within 60 min, and at days 7, 14, and 28 after each vaccine dose. The secondary safety outcome was abnormal changes detected by laboratory tests at days 1, 4, 7, and 28 after each vaccine dose. For immunogenicity, the secondary outcome was humoral immune responses: titres of neutralising antibodies to live SARS-CoV-2, neutralising antibodies to pseudovirus, and RBD-specific IgG at baseline and 28 days after first vaccination and at days 7, 15, and 28 after second vaccination. The exploratory outcome was SARS-CoV-2-specific T-cell responses at 7 days after the first vaccination and at days 7 and 15 after the second vaccination. This trial is registered with www.chictr.org.cn (ChiCTR2000039212). FINDINGS: Between Oct 30 and Dec 2, 2020, 230 individuals were screened and 120 eligible participants were randomly assigned to receive five-dose levels of ARCoV or a placebo (20 per group). All participants received the first vaccination and 118 received the second dose. No serious adverse events were reported within 56 days after vaccination and the majority of adverse events were mild or moderate. Fever was the most common systemic adverse reaction (one [5%] of 20 in the 5 µg group, 13 [65%] of 20 in the 10 µg group, 17 [85%] of 20 in the 15 µg group, 19 [95%] of 20 in the 20 µg group, 16 [100%] of 16 in the 25 µg group; p<0·0001). The incidence of grade 3 systemic adverse events were none (0%) of 20 in the 5 µg group, three (15%) of 20 in the 10 µg group, six (30%) of 20 in the 15 µg group, seven (35%) of 20 in the 20 µg group, five (31%) of 16 in the 25 µg group, and none (0%) of 20 in the placebo group (p=0·0013). As expected, the majority of fever resolved in the first 2 days after vaccination for all groups. The incidence of solicited systemic adverse events was similar after administration of ARCoV as a first or second vaccination. Humoral immune responses including anti-RBD IgG and neutralising antibodies increased significantly 7 days after the second dose and peaked between 14 and 28 days thereafter. Specific T-cell response peaked between 7 and 14 days after full vaccination. 15 µg induced the highest titre of neutralising antibodies, which was about twofold more than the antibody titre of convalescent patients with COVID-19. INTERPRETATION: ARCoV was safe and well tolerated at all five doses. The acceptable safety profile, together with the induction of strong humoral and cellular immune responses, support further clinical testing of ARCoV at a large scale. FUNDING: National Key Research and Development Project of China, Academy of Medical Sciences China, National Natural Science Foundation China, and Chinese Academy of Medical Sciences.

Expression of plasma IFN signaling-related miRNAs during acute SARS-CoV-2 infection and its association with RBD-IgG antibody response.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a huge challenge worldwide. Although previous studies have suggested that type I interferon (IFN-I) could inhibit the virus replication, the expression characteristics of IFN-I signaling-related miRNAs (ISR-miRNAs) during acute severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and its relationship with receptor-binding domain (RBD) IgG antibody response at the recovery phase remain unclear. METHODS: Expression profiles of 12 plasma ISR-miRNAs in COVID-19 patients and healthy controls were analyzed using RT-qPCR. The level of RBD-IgG antibody was determined using the competitive ELISA. Spearman correlation was done to measure the associations of plasma ISR-miRNAs with clinical characteristics during acute SARS-CoV-2 infection and RBD-IgG antibody response at the recovery phase. RESULTS: Compared with the healthy controls, COVID-19 patients exhibited higher levels of miR-29b-3p (Z = 3.15, P = 0.002) and miR-1246 (Z = 4.98, P < 0.001). However, the expression of miR-186-5p and miR-15a-5p were significantly decreased. As the results shown, miR-30b-5p was negatively correlated with CD4 + T cell counts (r = - 0.41, P = 0.027) and marginally positively correlated with fasting plasma glucose in COVID-19 patients (r = 0.37, P = 0.052). The competitive ELISA analysis showed the plasma level of miR-497-5p at the acute phase was positively correlated with RBD-IgG antibody response (r = 0.48, P = 0.038). CONCLUSIONS: Our present results suggested that the expression level of ISR-miRNAs was not only associated with acute SARS-CoV-2 infection but also with RBD-IgG antibody response at the recovery phase of COVID-19. Future studies should be performed to explore the biological significance of ISR-miRNAs in SARS-CoV-2 infection.

Determinants of Vaccine Acceptance against COVID-19 in China: Perspectives on Knowledge and DrVac-COVID19S Scale.

Background: This study determined the knowledge and attitudes regarding COVID-19 and assessed the acceptance of the COVID-19 vaccine among the Chinese population. Methods: An online and offline cross-sectional study was conducted from 1 to 18 June 2021 among the Chinese population. Demographic characteristics, attitudes, knowledge, values, impact, and autonomy regarding the COVID-19 vaccine were collected using questionnaire. The variables in our study were analyzed by Mann-Whitney test and chi-square test. Results: A total of 93.8% participants were willing to be vaccinated, 2.7% refused, and 3.5% hesitated. In regards to knowledge about the COVID-19 vaccine, 94.3% citizens surveyed knew about the spread of droplets and 65% had knowledge about surfaces touched by an infected person. In addition, 93.8% of participants had knowledge of the common symptoms related to COVID-19, such as fever and cough (93.8%), shortness of breath/anorexia/fatigue/nausea/vomiting/diarrhea (80.2%), and panic and chest tightness (69.4%). Most participants had a strong self-prevention awareness, such as washing hands regularly (92.1%) and wearing a facemask (94.1%). Besides, over ninety percent of respondents would report exposure to SARS-CoV-2 (96.6%) and exposure to symptoms possibility related to COVID-19 (92.9%). If necessary, most respondents would agree to isolate at home (93.5%) or an isolation in hospital (96.3%). Knowledge of COVID-19, including transmission, symptoms, protective measures, and vaccines itself, is associated with vaccination attitude. Values, perceived impacts, knowledge, and autonomy, assessed by the scale of DrVac-COVID19S, have also been revealed as important determinants to vaccine acceptance. Conclusions: Almost 93% of Chinese people surveyed in this study showed a willing attitude toward COVID-19 vaccination. Based on the above results, government and social workers can take measures from these perspectives to improve the vaccination attitude, so as to increase vaccine immunization rates.

Targeting lysophospholipid acid receptor 1 and ROCK kinases promotes antiviral innate immunity.

Growing evidence indicates the vital role of lipid metabolites in innate immunity. The lipid lysophosphatidic acid (LPA) concentrations are enhanced in patients upon HCV or SARS-CoV-2 infection, but the function of LPA and its receptors in innate immunity is largely unknown. Here, we found that viral infection promoted the G protein­coupled receptor LPA1 expression, and LPA restrained type I/III interferon production through LPA1. Mechanistically, LPA1 signaling activated ROCK1/2, which phosphorylated IRF3 Ser97 to suppress IRF3 activation. Targeting LPA1 or ROCK in macrophages, fibroblasts, epithelial cells, and LPA1 conditional KO mice promoted interferon-induced clearance of multiple viruses. LPA1 was colocalized with the receptor ACE2 in lung and intestine. Together with previous findings that LPA1 and ROCK1/2 promoted vascular leaking or lung fibrosis, we propose that the current available preclinical drugs targeting the LPA1-ROCK module might protect from SARS-CoV-2 or various virus infections in the intestine or lung.

The safety and efficacy of mesenchymal stem cells in the treatment of COVID-19-associated pneumonia: a systematic review and meta-analysis (preprint)

Mesenchymal stem cells (MSCs) therapy is considered one of the most promising treatments in the context of the coronavirus disease 2019 (COVID-19) pandemic. However, the safety and effectiveness of MSCs in the treatment of COVID-19-associated pneumonia patients need to be systematically reviewed and analyzed. Two independent researchers searched for the relevant studies published between October 2019 and April 2021 in PubMed, Embase, Cochrane Library, WAN FANG, and CNKI databases. A total of 22 studies involving 371 patients were included in the present study. MSCs were administered in 247 participants, and MSCs were allogeneic from umbilical cord, adipose tissue, menstrual blood, placenta, Whartons jelly, or unreported sources. Combined results found that MSCs group significantly reduced the incidence of adverse events (OR = 0.43, 95%CI. = 0.22[~]0.84, P = 0.01) and mortality (OR = 0.17, 95%CI. = 0.06[~]0.49, P < 0.01), and the difference compared with control group was statistically significant. No MSCs treat-related serious adverse events were reported. The lung function and radiographic outcomes, and biomarker levels of inflammation and immunity all showed improvement trends. Therefore, MSCs therapy is an effective and safe method in the treatment of COVID-19-associated pneumonia and shows advantages in less adverse events and mortality. However, a standard and effective MSCs treatment program needs to be developed.

Impaired Cellular Immunity to SARS-CoV-2 in Severe COVID-19 Patients.

The high infection rate and rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) make it a world-wide pandemic. Individuals infected by the virus exhibited different degrees of symptoms, and most convalescent individuals have been shown to develop both cellular and humoral immune responses. However, virus-specific adaptive immune responses in severe patients during acute phase have not been thoroughly studied. Here, we found that in a group of COVID-19 patients with acute respiratory distress syndrome (ARDS) during hospitalization, most of them mounted SARS-CoV-2-specific antibody responses, including neutralizing antibodies. However, compared to healthy controls, the percentages and absolute numbers of both NK cells and CD8+ T cells were significantly reduced, with decreased IFNγ expression in CD4+ T cells in peripheral blood from severe patients. Most notably, their peripheral blood lymphocytes failed in producing IFNγ against viral proteins. Thus, severe COVID-19 patients at acute infection stage developed SARS-CoV-2-specific antibody responses but were impaired in cellular immunity, which emphasizes on the role of cellular immunity in COVID-19.

Incidence and Associated Factors for Neuraxial Anaesthesia-Related Hypotension in COVID-19 Parturients Undergoing Caesarean Delivery: A Multicenter Case-Control Study (preprint)

Background: COVID-19 continues to spread globally and results in additional challenges for perioperative management in parturients. The purpose of this study was to determine the incidence and identify associated factors for neuraxial anaesthesia-related hypotension in COVDI-19 parturients during caesarean delivery.Methods: We performed a multicenter case-control study at 3 medical institutions in Hubei province, China form 1th January to 30th May 2020. All ASA Physical Status II full termed pregnant women who received caesarean delivery under neuraxial anaesthesia were eligible for inclusion. The univariate analysis and binary logistic regression analysis were used to identified the independent predictors of neuraxial anaesthesia-related hypotension.Results: Present study included 102 COVID-19 parturients. The incidence of neuraxial anaesthesia-related hypotension was 58%. Maternal abnormal lymphocyte count (OR = 3.41, p = 0.03), full stomach (OR = 3.22, p = 0.04), baseline heart rate (OR = 1.04, p = 0.03), experience of anaesthetist (OR = 0.86, p = 0.02) and surgeon (OR = 0.76, p = 0.03), and combined spinal-epidural anaesthesia technique (OR = 3.27, p = 0.02) were associated with neuraxial anaesthesia-related hypotension. The area under the receiver operating characteristic curve achieved 0.83 which was significantly higher than 0.5 (p < 0.001). And the sensitivity, specificity and percentage correct were 75%, 79% and 75%, respectively. The Hosmer-Lemeshow test showed a good calibration of the model (H = 2.01, DF = 8, p = 0.98).Conclusions: Maternal abnormal lymphocyte count, full stomach, baseline heart rate, experience of anaesthetist and surgeon, and combined spinal-epidural anaesthesia technique were identified as the independent predictors of neuraxial anaesthesia-related hypotension.

Reductions in mortality resulting from COVID-19 quarantine measures in China.

BACKGROUND: To explore the impact of quarantine measures on the cause of death. METHODS: We use time series analysis with the data from death cause surveillance database of Suzhou from January 2017 to December 2019 to estimate the expected deaths from January to June 2020 and compare these expected deaths with the reported numbers of deaths. RESULTS: After the implementation of epidemic prevention measures in Suzhou in the first 3 months, overall number of all-cause deaths declined for 5.36, 7.54 and 7.02% compared with predicted numbers. The number of deaths from respiratory causes and traffic accidents declined shapely by 30.1 and 26.9%, totally. When quarantine measures were released (April-June), however, the observed numbers of total deaths exceeded the predicted deaths. People aged over 70 accounted for 91.6% of declined death number in respiratory causes and people aged over 60 accounted for 68.0% of declined death number in traffic accidents. Women over the age of 80 benefited the most from respiratory prevention (accounts for 41% of all reductions), whereas women aged over 60 benefited the most from traffic control (44%). CONCLUSIONS: Overall, the whole population benefited from the epidemic prevention measures especially elderly females. This study is a useful supplement to encourage the government to develop regular preventive measures under the era of normalized epidemic.

Glycemic control before admission is an important determinant of prognosis in patients with coronavirus disease 2019.

AIMS/INTRODUCTION: This study aimed to explore the association between glycemic control before admission with severity and mortality of coronavirus disease 2019, and tried to reveal the mechanism. MATERIALS AND METHODS: A total of 77 inpatients were grouped into sufficient control group (glycated hemoglobin [HbA1c] <6.5%, n = 49) and insufficient control group (HbA1c ≥6.5%, n = 28). Regression models were used to analyze the clinical data. RESULTS: Compared with patients with HbA1c <6.5, patients with HbA1c ≥6.5 showed higher heart rate (101 vs 89 b.p.m., P = 0.012), lower percutaneous oxygen saturation (93 vs 97%, P = 0.001), higher levels of multiple indicators of inflammation, such as white blood cell count (7.9 vs 5.9 × 109 /L, P = 0.019), neutrophil count (6.5 vs 4.1 × 109 /L, P = 0.001), high-sensitivity C-reactive protein (52 vs 30 mg/L, P = 0.025) and serum ferritin (1,287 vs 716 µg/L, P = 0.023), as well as lower levels of lymphocyte count (0.7 vs 0.8 × 109 /L, P = 0.049) at hospital admission. Thus, patients with HbA1c ≥6.5 were more likely to develop secondary respiratory infections (25 [89%] vs 33 [67%], P = 0.032) and acute respiratory distress syndrome (17 [61%] vs 14 [29%], P = 0.006) than patients with HbA1c <6.5, resulting in a higher proportion of critically ill patients (19 [68%] vs 18 [37%], P = 0.009) and non-survivors (13 [46%] vs 11 [22%], P = 0.029). After adjustment for potential risk factors, HbA1c was independently associated with in-hospital death. CONCLUSION: HbA1c was an independent risk factor for poor outcomes in coronavirus disease 2019 patients. Severe pulmonary infection and consequent acute respiratory distress syndrome might be the primary causes of death in insufficient glycemic control patients.

Triglyceride to High-Density Lipoprotein Cholesterol Ratio is an Important Determinant of Cardiovascular Risk and Poor Prognosis in Coronavirus Disease-19: A Retrospective Case Series Study.

BACKGROUND: Acute myocardial injury and heart failure characterized by elevated cardiac troponin and decreased heart pump function are significant clinical features and prognostic factors of coronavirus disease-19 (COVID-19). Triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio is an indicator of insulin resistance. This study aimed to explore the association of the TG/HDL-C ratio with cardiovascular risk and prognosis in COVID-19. METHODS: Ninety-eight laboratory-confirmed patients with COVID-19 admitted in a tertiary teaching hospital in Wuhan, China, were enrolled in this retrospective study. Regression models were used to investigate the association between TG/HDL-C ratio with myocardial injury, heart failure, severity, and mortality in COVID-19. RESULTS: Among the 98 patients, the mean age was 63.9±1.4 years, and male sex (58, 59%) was predominant. Forty-six patients (47%) were admitted to the intensive care unit (ICU), 32 (33%) and 46 (47%) patients suffered from myocardial injury and heart failure, respectively, and 36 (37%) patients died. The TG/HDL-C ratio was increased in patients with myocardial injury, heart failure, severe illness, and fatal outcome (P<0.05 for each). Baseline TG/HDL-C ratio significantly correlated with log transformed levels of plasma high-sensitivity cardiac troponin I (r=0.251, P=0.018), N-terminal brain natriuretic propeptide (r=0.274, P=0.008), glycated hemoglobin (r=0.239, P=0.038), and interleukin-6 (r=0.218, P=0.042). Multivariate logistic regression analysis showed that an increased TG/HDL-C ratio was independently associated with the risk of myocardial injury [odds ratio (OR)=2.73; P=0.013], heart failure (OR=2.64; P=0.019), disease severity (OR=3.01; P=0.032), and fatal outcome (OR=2.97; P=0.014). CONCLUSION: Increased TG/HDL-C ratio was independently associated with myocardial injury, heart failure, disease severity, and mortality in patients with COVID-19, and it may be a useful marker for early identification of patients with high risk and poor outcome.

In Silico Screening of Potential Spike Glycoprotein Inhibitors of SARS-CoV-2 with Drug Repurposing Strategy.

OBJECTIVE: To select potential molecules that can target viral spike proteins, which may potentially interrupt the interaction between the human angiotension-converting enzyme 2 (ACE2) receptor and viral spike protein by virtual screening. METHODS: The three-dimensional (3D)-coordinate file of the receptor-binding domain (RBD)-ACE2 complex for searching a suitable docking pocket was firstly downloaded and prepared. Secondly, approximately 15,000 molecular candidates were prepared, including US Food and Drug Administration (FDA)-approved drugs from DrugBank and natural compounds from Traditional Chinese Medicine Systems Pharmacology (TCMSP), for the docking process. Then, virtual screening was performed and the binding energy in Autodock Vina was calculated. Finally, the top 20 molecules with high binding energy and their Chinese medicine (CM) herb sources were listed in this paper. RESULTS: It was found that digitoxin, a cardiac glycoside in DrugBank and bisindigotin in TCMSP had the highest docking scores. Interestingly, two of the CM herbs containing the natural compounds that had relatively high binding scores, Forsythiae fructus and Isatidis radix, are components of Lianhua Qingwen (), a CM formula reportedly exerting activity against severe acute respiratory syndrome (SARS)-Cov-2. Moreover, raltegravir, an HIV integrase inhibitor, was found to have a relatively high binding score. CONCLUSIONS: A class of compounds, which are from FDA-approved drugs and CM natural compounds, that had high binding energy with RBD of the viral spike protein. Our work provides potential candidates for other researchers to identify inhibitors to prevent SARS-CoV-2 infection, and highlights the importance of CM and integrative application of CM and Western medicine on treating COVID-19.