The effect of the COVID-19 pandemic on life expectancy in 27 countries.

The expected year-on-year intrinsic mortality variations/changes are largely overlooked in the existing research when estimating the effect of the COVID-19 pandemic on mortality patterns. To fill this gap, this study provides a new assessment of the loss of life expectancy caused by COVID-19 in 27 countries considering both the actual and the expected changes in life expectancy between 2019 and 2020. Life expectancy in 2020 and the expected life expectancy in the absence of COVID-19 are estimated using the Lee-Carter model and data primarily from the Human Mortality Database. The results show that life expectancy in 21 of the 27 countries was expected to increase in 2020 had COVID-19 not occurred. By considering the expected mortality changes between 2019 and 2020, the study shows that, on average, the loss of life expectancy among the 27 countries in 2020 amounted to 1.33 year (95% CI 1.29-1.37) at age 15 and 0.91 years (95% CI 0.88-0.94) at age 65. Our results suggest that if the year-on-year intrinsic variations/changes in mortality were considered, the effects of COVID-19 on mortality are more profound than previously understood. This is particularly prominent for countries experiencing greater life expectancy increase in recent years.

A Clinical and Correlative Study of Elotuzumab, Carfilzomib, Lenalidomide, and Dexamethasone (Elo-KRd) for Lenalidomide Refractory Multiple Myeloma in First Relapse.

INTRODUCTION: Treatment of patients with multiple myeloma (MM) in first relapse remains a challenge. This phase II study combined elotuzumab (Elo) with carfilzomib, lenalidomide, and dexamethasone (KRd) for treatment of MM in first relapse with the aim of improving efficacy. METHODS: Enrolled patients received Elo-KRd induction for 4 cycles, and Elo-lenalidomide maintenance until progression. The primary endpoint was VGPR or better (≥VGPR) postinduction. Secondary endpoints were MRD by flow cytometry, OS, PFS, and safety. Correlatives included characterization of the impact of Elo-KRd on NK and T cell subsets via flow cytometry. Target accrual of 40 patients was not met due to COVID-19 pandemic. RESULTS: Of 15 patients enrolled, 10 (67%) had high-risk features (del17p, t[4;14], t[14;16], 1q gain/amplification, plasma cell leukemia, extramedullary MM, or functional high risk), 12 (80%) were lenalidomide-refractory, and 5 (33.3%) bortezomib-refractory. Postinduction ≥VGPR was 7/15 (46.7%) and MRD-negative (10-5) rate 20%. Overall response during study was 80%, including ≥VGPR as best response of 53.3%. At median follow-up of 28.2 (range, 3.8 to 44.2) months, the median PFS was 11.5 months (95% CI 1.9, 18), and median OS not reached (95% CI 10.1, NA). No new safety concerns were reported. Elo-KRd treatment did not augment NK cell distribution or activity in blood or bone marrow. Effector CD4+ and CD8+ T cells significantly decreased postinduction, with concomitant acquisition of T central memory phenotype, particularly at a high rate in ≥VGPR group. CONCLUSION: A short course of Elo-KRd induction followed by Elo-lenalidomide maintenance demonstrated activity in predominantly lenalidomide-refractory and / or high-risk MM. The results with this well-tolerated combination are comparable to other contemporary approved triplet combinations.

SARS-CoV-2 hijacks cellular kinase CDK2 to promote viral RNA synthesis.

The coronavirus disease 2019 (COVID-19) pandemic has devastated global health. Identifying key host factors essential for SARS-CoV-2 RNA replication is expected to unravel cellular targets for the development of broad-spectrum antiviral drugs which have been quested for the preparedness of future viral outbreaks. Here, we have identified host proteins that associate with nonstructural protein 12 (nsp12), the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 using a mass spectrometry (MS)-based proteomic approach. Among the candidate factors, CDK2 (Cyclin-dependent kinase 2), a member of cyclin-dependent kinases, interacts with nsp12 and causes its phosphorylation at T20, thus facilitating the assembly of the RdRp complex consisting of nsp12, nsp7 and nsp8 and promoting efficient synthesis of viral RNA. The crucial role of CDK2 in viral RdRp function is further supported by our observation that CDK2 inhibitors potently impair viral RNA synthesis and SARS-CoV-2 infection. Taken together, we have discovered CDK2 as a key host factor of SARS-CoV-2 RdRp complex, thus serving a promising target for the development of SARS-CoV-2 RdRp inhibitors.

The impact of mass gatherings on the local transmission of COVID-19 and the implications for social distancing policies: Evidence from Hong Kong.

Mass gatherings provide conditions for the transmission of infectious diseases and pose complex challenges to public health. Faced with the COVID-19 pandemic, governments and health experts called for suspension of gatherings in order to reduce social contact via which virus is transmitted. However, few studies have investigated the contribution of mass gatherings to COVID-19 transmission in local communities. In Hong Kong, the coincidence of the relaxation of group gathering restrictions with demonstrations against the National Security Law in mid-2020 raised concerns about the safety of mass gatherings under the pandemic. Therefore, this study examines the impacts of mass gatherings on the local transmission of COVID-19 and evaluates the importance of social distancing policies. With an aggregated dataset of epidemiological, city-level meteorological and socioeconomic data, a Synthetic Control Method (SCM) is used for constructing a 'synthetic Hong Kong' from over 200 Chinese cities. This counterfactual control unit is used to simulate COVID-19 infection patterns (i.e., the number of total cases and daily new cases) in the absence of mass gatherings. Comparing the hypothetical trends and the actual ones, our results indicate that the infection rate observed in Hong Kong is substantially higher than that in the counterfactual control unit (2.63% vs. 0.07%). As estimated, mass gatherings increased the number of new infections by 62 cases (or 87.58% of total new cases) over the 10-day period and by 737 cases (or 97.23%) over the 30-day period. These findings suggest the necessity of tightening social distancing policies, especially the prohibition on group gathering regulation (POGGR), to prevent and control COVID-19 outbreaks.

Clinical characteristics and risk factors for a prolonged length of stay of patients with asymptomatic and mild COVID-19 during the wave of Omicron from Shanghai, China.

BACKGROUND: This study aims to investigate the clinical characteristics and the length of hospital stay (LOS), as well as risk factors for prolonged LOS in a cohort of asymptomatic and mild COVID-19 patients infected with the Omicron variant. METHODS: A total of 1166 COVID-19 patients discharged from the inpatient ward of the largest makeshift hospital (May 8-10, 2022) in Shanghai, China, were included. The demographics, medical history, and the lowest and admission cycle threshold (Ct) values of the RT-PCR tests for SARS-CoV-2 genes of the open reading frame 1ab (Ct-ORF) and the nucleocapsid protein (Ct-N) during hospitalization were recorded. Patients with LOS > 7 days, or LOS ≤ 7 days were included in the Prolonged group or the Control group, separately. The clinical characteristics and LOS of the participants in the two groups were described and compared. Multivariate Logistic and linear regression analyses were applied to explore the risk factors for prolonged LOS. The diagnostic efficacy of the lowest and admission Ct values for the Prolonged group was tested via the receiver operating characteristic (ROC) curve analysis. RESULTS: The median LOS was 6 days in the total study population. The age was older (45.52 ± 14.78 vs. 42.54 ± 15.30, P = 0.001), while both the lowest and admission Ct-ORF (27.68 ± 3.88 vs. 37.00 ± 4.62, P < 0.001; 30.48 ± 5.03 vs. 37.79 ± 3.81, P < 0.001) and Ct-N (25.79 ± 3.60 vs. 36.06 ± 5.39, P < 0.001; 28.71 ± 4.95 vs. 36.95 ± 4.59, P < 0.001) values were significantly lower in the Prolonged group. There were more mild cases in the Prolonged group (23.8% vs. 11.5%, P < 0.001). The symptom spectrum differed between the two groups. In multivariate analyses, age, disease category, and the lowest Ct-N values were shown to be associated with prolonged LOS. Besides, both the lowest and admission Ct-ORF (AUC = 0.911 and 0.873) and Ct-N (AUC = 0.912 and 0.874) showed robust diagnostic efficacy for prolonged LOS. CONCLUSIONS: Our study firstly reports the clinical characteristics and risk factors for prolonged LOS during the wave of the Omicron epidemic in Shanghai, China. These findings provide evidence for the early identification of asymptomatic and mild COVID-19 patients at a high risk of prolonged hospitalization who may require early intervention, and long-term monitoring and management.

A Vicious Cycle: In Severe and Critically Ill COVID-19 Patients.

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, is one of the fastest-evolving viral diseases that has instigated a worldwide pandemic. Severe inflammatory syndrome and venous thrombosis are commonly noted in COVID-19 patients with severe and critical illness, contributing to the poor prognosis. Interleukin (IL)-6, a major complex inflammatory cytokine, is an independent factor in predicting the severity of COVID-19 disease in patients. IL-6 and tumor necrosis factor (TNF)-α participate in COVID-19-induced cytokine storm, causing endothelial cell damage and upregulation of plasminogen activator inhibitor-1 (PAI-1) levels. In addition, IL-6 and PAI-1 form a vicious cycle of inflammation and thrombosis, which may contribute to the poor prognosis of patients with severe COVID-19. Targeted inhibition of IL-6 and PAI-1 signal transduction appears to improve treatment outcomes in severely and critically ill COVID-19 patients suffering from cytokine storms and venous thrombosis. Motivated by studies highlighting the relationship between inflammatory cytokines and thrombosis in viral immunology, we provide an overview of the immunothrombosis and immunoinflammation vicious loop between IL-6 and PAI-1. Our goal is that understanding this ferocious circle will benefit critically ill patients with COVID-19 worldwide.

A survey of health status of healthcare providers in a square cabin hospital during the new corona omicron outbreak: A cross-sectional study

Background The coronavirus omicron variant outbroke in early 2022 in Shanghai. Although previous studies indicated that long working hours in a square cabin hospital might increase the risk of mental health among frontline healthcare providers, few studies have investigated whether the mental health risk could be reduced among well-trained professionals following the new guidelines. Objective This study aimed to investigate the health situation of frontline healthcare providers in Shanghai square cabin during the omicron variant circulation. Methods An online survey was used to evaluate those healthcare providers working in the square cabin hospitals from March 1, 2022, to May 31, 2022. The first online survey was conducted and emailed to the health providers on April 1. The second survey was conducted and sent to the nonrespondents on May 31. Overall, 142 frontline healthcare providers completed the online survey. Their mental health was assessed by the Insomnia Severity Index Scale, the Generalized Anxiety Disorder Scale, the Patient Health Questionnaire-9, and the Psychological Resilience Scale. We estimated multiple clinical systems and identified factors associated with those symptoms among participants. Multivariable logistic regression models were used to assess the risk factors of these symptoms. Results Overall, 66.20%, 45.07%, and 27.46% of frontline healthcare providers in Shanghai City reported symptoms of insomnia, depression, and anxiety, respectively. In addition, the most common symptoms included dry eyes (57.75%), lumbar muscle strain (47.18%), dry mouth (35.92%), itching (31.69%), headache (29.58%), and sore throat (28.87%) among the frontline healthcare providers. There was no statistical difference in symptoms by gender, age, personnel category, or job position (p > 0.05). Conclusion In the case of an unexpected pandemic, the mental health of healthcare providers is not optimistic. This situation still exists more than 2 years after the global outbreak of the COVID-19 pandemic. Therefore, the physical and mental health of long-term healthcare providers working in a square cabin hospital still needs monitoring.

IFITM3 Inhibits SARS-CoV-2 Infection and Is Associated with COVID-19 Susceptibility.

SARS-CoV-2 has become a global threat to public health. Infected individuals can be asymptomatic or develop mild to severe symptoms, including pneumonia, respiratory distress, and death. This wide spectrum of clinical presentations of SARS-CoV-2 infection is believed in part due to the polymorphisms of key genetic factors in the population. In this study, we report that the interferon-induced antiviral factor IFITM3 inhibits SARS-CoV-2 infection by preventing SARS-CoV-2 spike-protein-mediated virus entry and cell-to-cell fusion. Analysis of a Chinese COVID-19 patient cohort demonstrates that the rs12252 CC genotype of IFITM3 is associated with SARS-CoV-2 infection risk in the studied cohort. These data suggest that individuals carrying the rs12252 C allele in the IFITM3 gene may be vulnerable to SARS-CoV-2 infection and thus may benefit from early medical intervention.

Reducing Anxiety and Stress among Youth in a CBT-Based Equine-Assisted Adaptive Riding Program.

Reining in Anxiety (RiA) is a therapeutic program for youth with mild to moderate anxiety delivered in a therapeutic riding setting by Certified Therapeutic Riding Instructors. RiA was developed after a review of the evidence base for youth anxiety, is manualized, and includes five core CBT components: in vivo exposure, cognitive restructuring, youth psychoeducation, relaxation, and caregiver psychoeducation about anxiety. This study extended findings from a prior RCT that examined (1) the feasibility of collecting saliva samples from horses and children to measure stress (cortisol) and relaxation (oxytocin); (2) whether changes in stress and relaxation occurred both during each lesson and over the course of the 10-week intervention for horses and youth; (3) whether changes in anxiety symptoms, emotional regulation, and self-efficacy found in the first trial were comparable; and (4) if fidelity to the program was reliable. Youth participants (n = 39) ages 6-17 with caregiver-identified mild-to-moderate anxiety participated in a ten-week therapeutic intervention (RiA), which combined adaptive riding and components of CBT. Physiological data and self-report measures were taken at weeks one, four, seven, and ten for the youth and horses. Saliva assays assessed cortisol as a physiological marker of stress and anxiety, and oxytocin as a measure of relaxation. Fidelity data were recorded per session. Anxiety, as measured by caregiver self-reporting, significantly decreased from pre- to post-test, while emotional regulation scores increased. No significant changes in self-efficacy from pre- to post-test were observed. Saliva samples obtained from participants before and after riding sessions showed a consistent decrease in cortisol and a significant increase in oxytocin at two of the four timepoints (Week 1 and Week 7), but no overall pre- to post-test changes. Horse saliva data were collected using a modified bit; there were no significant changes in oxytocin or cortisol, suggesting that the horses did not have an increase in stress from the intervention. RiA may be a promising approach for reducing anxiety and stress among youth, as measured both by self-reported and by physiological measures. Collection of salivary assays for both youth and horses is feasible, and the intervention does not increase stress in the horses. Importantly, RiA can be delivered by adaptive/therapeutic horseback riding instructors in naturalistic (e.g., non-clinic-based) settings. As youth anxiety is a growing public health problem, novel interventions, such as RiA, that can be delivered naturalistically may have the potential to reach more youth and thus improve their quality of life. Further research is needed to examine the comparative value of RiA with other animal-assisted interventions and to assess its cost-effectiveness.

Repurposing of HIV/HCV protease inhibitors against SARS-CoV-2 3CLpro.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen that caused the global COVID-19 outbreak. The 3C-like protease (3CL^pro) of SARS-CoV-2 plays a key role in virus replication and has become an ideal target for antiviral drug design. In this work, we have employed bioluminescence resonance energy transfer (BRET) technology to establish a cell-based assay for screening inhibitors against SARS-CoV-2 3CL^pro, and then applied the assay to screen a collection of known HIV/HCV protease inhibitors. Our results showed that the assay is capable of quantification of the cleavage efficiency of 3CL^pro with good reproducibility (Z' factor is 0.59). Using the assay, we found that 9 of 26 protease inhibitors effectively inhibited the activity of SARS-CoV-2 3CL^pro in a dose-dependent manner. Among them, four compounds exhibited the ability to bind to 3CL^proin vitro. HCV protease inhibitor simeprevir showed the most potency against 3CL^pro with an EC₅₀ vale of 2.6 µM, bound to the active site pocket of 3CL^pro in a predicted model, and importantly, exhibited a similar activity against the protease containing the mutations P132H in Omicron variants. Taken together, this work demonstrates the feasibility of using the cell-based BRET assay for screening 3CL^pro inhibitors and supports the potential of simeprevir for the development of 3CL^pro inhibitors.

Risk spillover analysis of China’s financial sectors based on a new GARCH copula quantile regression model

This study employs a new GARCH copula quantile regression model to estimate the conditional value at risk for systemic risk spillover analysis. To be specific, thirteen copula quantile regression models are derived to capture the asymmetry and nonlinearity of the tail dependence between financial returns. Using Chinese stock market data over the period from January 2007 to October 2020, this paper investigates the risk spillovers from the banking, securities, and insurance sectors to the entire financial system. The empirical results indicate that (i) three financial sectors contribute significantly to the financial system, and the insurance sector displays the largest risk spillover effects on the financial system, followed by the banking sector and subsequently the securities sector;(ii) the time-varying risk spillovers are much larger during the global financial crisis than during the periods of the banking liquidity crisis, the stock market crash and the COVID-19 pandemic. Our results provide important implications for supervisory authorities and portfolio managers who want to maintain the stability of China’s financial system and optimize investment portfolios.

The associations between COVID-19 vaccination and psychological disorders among healthcare workers in China.

INTRODUCTION: COVID-19 has caused an unprecedented psychological affection that might impact the nationwide vaccination program in China. This study was to explore the association between COVID-19 vaccination and psychological disorders among healthcare workers. METHODS: The study included 1571 healthcare workers from an anonymous online survey. Participants' sociodemographic characteristics, uptake data for the COVID-19 vaccine, and scores of the Depression, Anxiety, and Stress Scale (DASS-21) were collected. Nonparametric tests were conducted to compare the mean scores of DASS-21 between different subgroups. The potential factors related to psychological disorders of healthcare workers were analyzed using logistic regression. RESULTS: The vaccination rate was 69.6 %, the incidence of vaccine-related adverse events was 35.13 %, and the prevalence of depression, anxiety, and stress were 24.8 %, 32 %, and 33.4 % in this study, respectively. Compared to vaccinated participants (single-dose and double-dose vaccines), unvaccinated participants got significantly higher mean scores of DASS-21 (p < 0.05 for all). Vaccinated participants who suffered no adverse events scored significantly lower than those who suffered 1-2 or ≥3 adverse events (p < 0.05 for all). Vaccination was negatively associated with higher depression, anxiety, and stress, however, the number of vaccine-related adverse events was positively associated with them. LIMITATIONS: As this is a cross-sectional study, we could only speculate on the causality. CONCLUSIONS: An obvious impact of the psychological disorders on the COVID-19 vaccine coverage and related adverse events was detected in this study. Public health agencies should attach great importance to the psychological states of our citizens before getting vaccinated.

Immunogenicity of a vaccinia virus-based severe acute respiratory syndrome coronavirus 2 vaccine candidate

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines provide essential tools for the control of the COVID-19 pandemic. A number of technologies have been employed to develop SARS-CoV-2 vaccines, including the inactivated SARS-CoV-2 particles, mRNA to express viral spike protein, recombinant spike proteins, and viral vectors. Here, we report the use of the vaccinia virus Tiantan strain as a vector to express the SARS-CoV-2 spike protein. When it was used to inoculate mice, robust SARS-CoV-2 spike protein-specific antibody response and T-cell response were detected. Sera from the vaccinated mice showed strong neutralizing activity against the ancestral Wuhan SARS-CoV-2, the variants of concern (VOCs) B.1.351, B.1.617.2, and the emerging B.1.1.529 (omicron). This finding supports the possibility of developing a new type of SARS-CoV-2 vaccine using the vaccinia virus vector.

A Vicious Cycle: In Severe and Critically Ill COVID-19 Patients

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, is one of the fastest-evolving viral diseases that has instigated a worldwide pandemic. Severe inflammatory syndrome and venous thrombosis are commonly noted in COVID-19 patients with severe and critical illness, contributing to the poor prognosis. Interleukin (IL)-6, a major complex inflammatory cytokine, is an independent factor in predicting the severity of COVID-19 disease in patients. IL-6 and tumor necrosis factor (TNF)-α participate in COVID-19-induced cytokine storm, causing endothelial cell damage and upregulation of plasminogen activator inhibitor-1 (PAI-1) levels. In addition, IL-6 and PAI-1 form a vicious cycle of inflammation and thrombosis, which may contribute to the poor prognosis of patients with severe COVID-19. Targeted inhibition of IL-6 and PAI-1 signal transduction appears to improve treatment outcomes in severely and critically ill COVID-19 patients suffering from cytokine storms and venous thrombosis. Motivated by studies highlighting the relationship between inflammatory cytokines and thrombosis in viral immunology, we provide an overview of the immunothrombosis and immunoinflammation vicious loop between IL-6 and PAI-1. Our goal is that understanding this ferocious circle will benefit critically ill patients with COVID-19 worldwide.

Clinical applications of machine learning in the survival prediction and classification of sepsis: coagulation and heparin usage matter.

BACKGROUND: Sepsis is a life-threatening syndrome eliciting highly heterogeneous host responses. Current prognostic evaluation methods used in clinical practice are characterized by an inadequate effectiveness in predicting sepsis mortality. Rapid identification of patients with high mortality risk is urgently needed. The phenotyping of patients will assistant invaluably in tailoring treatments. METHODS: Machine learning and deep learning technology are used to characterize the patients' phenotype and determine the sepsis severity. The database used in this study is MIMIC-III and MIMIC-IV ('Medical information Mart for intensive care') which is a large, public, and freely available database. The K-means clustering is used to classify the sepsis phenotype. Convolutional neural network (CNN) was used to predict the 28-day survival rate based on 35 blood test variables of the sepsis patients, whereas a double coefficient quadratic multivariate fitting function (DCQMFF) is utilized to predict the 28-day survival rate with only 11 features of sepsis patients. RESULTS: The patients were grouped into four clusters with a clear survival nomogram. The first cluster (C_1) was characterized by low white blood cell count, low neutrophil, and the highest lymphocyte proportion. C_2 obtained the lowest Sequential Organ Failure Assessment (SOFA) score and the highest survival rate. C_3 was characterized by significantly prolonged PTT, high SIC, and a higher proportion of patients using heparin than the patients in other clusters. The early mortality rate of patients in C_3 was high but with a better long-term survival rate than that in C_4. C_4 contained septic coagulation patients with the worst prognosis, characterized by slightly prolonged partial thromboplastin time (PTT), significantly prolonged prothrombin time (PT), and high septic coagulation disease score (SIC). The survival rate prediction accuracy of CNN and DCQMFF models reached 92% and 82%, respectively. The models were tested on an external dataset (MIMIC-IV) and achieved good performance. A DCQMFF-based application platform was established for fast prediction of the 28-day survival rate. CONCLUSION: CNN and DCQMFF accurately predicted the sepsis patients' survival, while K-means successfully identified the phenotype groups. The distinct phenotypes associated with survival, and significant features correlated with mortality were identified. The findings suggest that sepsis patients with abnormal coagulation had poor outcomes, abnormal coagulation increase mortality during sepsis. The anticoagulation effects of appropriate heparin sodium treatment may improve extensive micro thrombosis-caused organ failure.

SARS-CoV-2 spike protein-induced cell fusion activates the cGAS-STING pathway and the interferon response.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the unprecedented coronavirus disease 2019 (COVID-19) pandemic. Critical cases of COVID-19 are characterized by the production of excessive amounts of cytokines and extensive lung damage, which is partially caused by the fusion of SARS-CoV-2-infected pneumocytes. Here, we found that cell fusion caused by the SARS-CoV-2 spike (S) protein induced a type I interferon (IFN) response. This function of the S protein required its cleavage by proteases at the S1/S2 and the S2' sites. We further showed that cell fusion damaged nuclei and resulted in the formation of micronuclei that were sensed by the cytosolic DNA sensor cGAS and led to the activation of its downstream effector STING. Phosphorylation of the transcriptional regulator IRF3 and the expression of IFNB, which encodes a type I IFN, were abrogated in cGAS-deficient fused cells. Moreover, infection with VSV-SARS-CoV-2 also induced cell fusion, DNA damage, and cGAS-STING-dependent expression of IFNB. Together, these results uncover a pathway underlying the IFN response to SARS-CoV-2 infection. Our data suggest a mechanism by which fused pneumocytes in the lungs of patients with COVID-19 may enhance the production of IFNs and other cytokines, thus exacerbating disease severity.

Psychological Distress Was Still Serious Among Anesthesiologists Under the Post COVID-19 Era.

Purpose: This study aims to evaluate the psychological status and the attitudes toward the novel coronavirus disease 2019 (COVID-19) vaccine among anesthesiologists. We expected to analyze related factors and offer them some strategies to prevent and manage psychological issues under the post COVID-19 era. Methods: Based on the Checklist for Reporting Results of Internet E-Surveys (CHERRIES), an online survey was designed and conducted among anesthesiologists in Shaanxi, China. Participants were asked to complete a validated questionnaire voluntarily. The following tests were performed: Depression, Anxiety and Stress Scale (DASS-21), Primary Care Post-traumatic Stress Disorder Screen (PC-PTSD), and the attitudes toward COVID-19 vaccine. Results: A total of 795 anesthesiologists completed the survey, the majority of them were female, young and middle-aged, well educated, and married. The prevalence of depression, anxiety, and stress in this sample were 26.5%, 35.5%, and 19.9%, respectively. Longer daily working time, concomitant basic chronic disease, and COVID-19 exposure were extracted as risk factors for the psychological symptoms, while vaccination, elder age, and married status were negatively associated with them. An unsatisfied vaccination rate (71.9%) which might be linked with inadequate awareness and perception of the COVID-19 vaccine was also detected in this study. Conclusion: Anesthesiologists are still under rising pressure of psychological symptoms in the post COVID-19 era. It is imperative to afford continuous psychological support to them and ensure their mental health and professional performance.

Loss of life expectancy due to respiratory infectious diseases: findings from the global burden of disease study in 195 countries and territories 1990-2017.

Understanding of the patterns of and changes in mortality from respiratory infectious diseases (RID) and its contribution to loss of life expectancy (LE) is inadequate in the existing literature. With rapid sociodemographic changes globally, and the current COVID-19 pandemic, it is timely to revisit the disease burden of RID. Using the approaches of life table and cause-eliminated life table based on data from the Global Burden of Disease Study (GBD), the study analyses loss of LE due to RID in 195 countries/territories and its changes during the period 1990-2017. Results indicate that loss of LE due to RID stood at 1.29 years globally in 2017 globally and varied widely by age, gender, and geographic location, with men, elderly people, and populations in middle/low income countries/territories suffering a disproportionately high loss of LE due to RID. Additionally, loss of LE due to RID decreased remarkably by 0.97 years globally during the period 1990-2017 but increased slightly among populations older than 70 years and in many high income countries/territories. Results suggest that RID still pose a severe threat for population and public health, and that amid dramatic sociodemographic changes globally, the disease burden of RID may resurge. The study presents the first examination of the life-shortening effect of RID at the global and country/territory levels, providing new understanding of the changing disease burden of RID and shedding light on the potential consequences of the current COVID-19 pandemic.

5-Iodotubercidin inhibits SARS-CoV-2 RNA synthesis.

Coronavirus disease 2019 (COVID-19) is a newly emerged infectious disease caused by a novel coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The rapid global emergence of SARS-CoV-2 highlights the importance and urgency for potential drugs to control the pandemic. The functional importance of RNA-dependent RNA polymerase (RdRp) in the viral life cycle, combined with structural conservation and absence of closely related homologs in humans, makes it an attractive target for designing antiviral drugs. Nucleos(t)ide analogs (NAs) are still the most promising broad-spectrum class of viral RdRp inhibitors. In this study, using our previously developed cell-based SARS-CoV-2 RdRp report system, we screened 134 compounds in the Selleckchemicals NAs library. Four candidate compounds, Fludarabine Phosphate, Fludarabine, 6-Thio-20-Deoxyguanosine (6-Thio-dG), and 5-Iodotubercidin, exhibit remarkable potency in inhibiting SARS-CoV-2 RdRp. Among these four compounds, 5-Iodotubercidin exhibited the strongest inhibition upon SARS-CoV-2 RdRp, and was resistant to viral exoribonuclease activity, thus presenting the best antiviral activity against coronavirus from a different genus. Further study showed that the RdRp inhibitory activity of 5-Iodotubercidin is closely related to its capacity to inhibit adenosine kinase (ADK).

2-((1H-indol-3-yl)thio)-N-phenyl-acetamides: SARS-CoV-2 RNA-dependent RNA polymerase inhibitors.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of Coronavirus Disease 2019 (COVID-19) pandemic. Despite intensive and global efforts to discover and develop novel antiviral therapies, only Remdesivir has been approved as a treatment for COVID-19. Therefore, effective antiviral therapeutics are still urgently needed to combat and halt the pandemic. Viral RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 demonstrates high potential as a reliable target for the development of antivirals. We previously developed a cell-based assay to assess the efficiency of compounds that target SARS-CoV-2 RdRp, as well as their tolerance to viral exoribonuclease-mediated proof-reading. In our previous study, we discovered that 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides specifically targets the RdRp of both respiratory syncytial virus (RSV) and influenza A virus. Thus, we hypothesize that 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides may also have the ability to inhibit SARS-CoV-2 replication by targeting its RdRp activity. In this research, we test a compound library containing 103 of 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides against SARS-CoV-2 RdRp, using our cell-based assay. Among these compounds, the top five candidates strongly inhibit SARS-CoV-2 RdRp activity while exhibiting low cytotoxicity and resistance to viral exoribonuclease. Compound 6-72-2a is the most promising candidate with the lowest EC50 value of 1.41 µM and highest selectivity index (CC50/EC50) (above 70.92). Furthermore, our data suggests that 4-46b and 6-72-2a also inhibit the replication of HCoV-OC43 and HCoV-NL63 virus in a dose-dependent manner. Compounds 4-46b and 6-72-2a exhibit EC50 values of 1.13 µM and 0.94 µM, respectively, on HCoV-OC43 viral replication. However, higher concentrations of these compounds are needed to effectively block HCoV-NL63 replication. Together, our findings successfully identified 4-46b and 6-72-2a as promising inhibitors against SARS-CoV-2 RdRp.