A new generation Mpro inhibitor with potent activity against SARS-CoV-2 Omicron variants.

Emerging SARS-CoV-2 variants, particularly the Omicron variant and its sublineages, continually threaten the global public health. Small molecule antivirals are an effective treatment strategy to fight against the virus. However, the first-generation antivirals either show limited clinical efficacy and/or have some defects in pharmacokinetic (PK) properties. Moreover, with increased use of these drugs across the globe, they face great pressure of drug resistance. We herein present the discovery and characterization of a new generation antiviral drug candidate (SY110), which is a potent and selective inhibitor of SARS-CoV-2 main protease (Mpro). This compound displayed potent in vitro antiviral activity against not only the predominant SARS-CoV-2 Omicron sublineage BA.5, but also other highly pathogenic human coronaviruses including SARS-CoV-1 and MERS-CoV. In the Omicron-infected K18-hACE2 mouse model, oral treatment with SY110 significantly lowered the viral burdens in lung and alleviated the virus-induced pathology. Importantly, SY110 possesses favorable PK properties with high oral drug exposure and oral bioavailability, and also an outstanding safety profile. Furthermore, SY110 exhibited sensitivity to several drug-resistance Mpro mutations. Collectively, this investigation provides a promising new drug candidate against Omicron and other variants of SARS-CoV-2.

Constructing a diversified online neurology teaching model under the COVID-19.

Purpose: To construct a diversified and comprehensive network teaching model to provide highly qualified medical teaching in neurology under COVID-19 pandemic. Materials and methods: Published studies on medical education were systematically reviewed and summarized. Based on previous studies and our experience, we constructed a novel online neurology teaching model and applied it to real scene. Students taking traditional in class lessons and online lessons were asked to finish the test, respectively, to compare the efficiency of learning. Questionnaires were designed and assigned to get the feedback from students. Results: The average test score of students who take online class (84.27 ± 4.64) was significantly higher than those who take in class lessons (82.08 ± 6.17) (P < 0.01). According to the feedbacks from students, online classes were more attractive to students than the conventional one. Conclusion: Traditional single-mode teaching can no longer meet the needs of current medical education, especially under the rampant epidemic. This novel teaching mode, which orchestrates high-tech tools, diverse teaching methods and traditional teaching concepts, provides the solution to the challenge faced by traditional medical education. We believe that this novel online teaching mode will boost neurology education and inspire educators in other fields during this tough period.

Constructing a diversified online neurology teaching model under the COVID-19

Purpose To construct a diversified and comprehensive network teaching model to provide highly qualified medical teaching in neurology under COVID-19 pandemic. Materials and methods Published studies on medical education were systematically reviewed and summarized. Based on previous studies and our experience, we constructed a novel online neurology teaching model and applied it to real scene. Students taking traditional in class lessons and online lessons were asked to finish the test, respectively, to compare the efficiency of learning. Questionnaires were designed and assigned to get the feedback from students. Results The average test score of students who take online class (84.27 ± 4.64) was significantly higher than those who take in class lessons (82.08 ± 6.17) (P < 0.01). According to the feedbacks from students, online classes were more attractive to students than the conventional one. Conclusion Traditional single-mode teaching can no longer meet the needs of current medical education, especially under the rampant epidemic. This novel teaching mode, which orchestrates high-tech tools, diverse teaching methods and traditional teaching concepts, provides the solution to the challenge faced by traditional medical education. We believe that this novel online teaching mode will boost neurology education and inspire educators in other fields during this tough period.

Anti‐S2 Protection in COVID‐19 Infection and SARS‐CoV‐2 Spike Vaccination

The overall goal of this project is to define the magnitude, quality, and duration of the primary immune response elicited against SARS‐CoV‐2 Spike by measuring domain‐specific antibody abundance and binding characteristics in plasmas after infection and vaccination. This investigation has enabled initiation of the screening of convalescent plasma polyclonal antibody (pAb) abundance and specificity through the IMPACC (Immunophenotyping Assessment in a COVID‐19 Cohort) at Drexel U College of Medicine (DUCOM) in collaboration with Tower Health Hospitals. We measured the active concentration of pAbs specific for RBD, S1 and S2 domains using SPR (surface plasmon resonance) molecular interaction analysis. By adopting a kinetic format, a complementary SPR analysis step was optimized to determine the binding rates and affinities of elicited antibodies targeting each domain of the Spike using the same plasma dilution aliquot. Most importantly, we found that the abundance of S2 reactive antibodies was comparable to that of anti‐S1 and RBD in convalescent plasmas. Plasmas obtained up to 6 months post‐vaccination are also becoming available through the TTC (Vaccination TetraCore cohort) assessment at DUCOM, and screening for these has demonstrated that anti‐S2 pAbs are also elicited, though intriguingly in lower abundance than after infection. To assess the importance anti‐S2 antibodies from convalescent plasmas, we purified anti‐S2 fractions by an SPR‐based microaffinity method and used the recovered antibodies in pseudovirus infection inhibition assays of ACE2 expressing cells to measure neutralization activity. Evidence for sustained generation of S2 antibodies up to 6 months post‐infection and occurrence of neutralizing anti‐S2 pAbs has begun to emerge with the possibility that antibodies targeting the S2 domain of the SARS‐CoV‐2 spike protein complex could provide pan‐coronavirus protection against COVID‐19, emerging variants, and other coronaviruses with conserved spike structures. Targeting the more conserved fusion machinery in the virus spike ultimately can lead to therapeutic antibodies or small molecule inhibitors effective on escape variants that occur mainly in S1 as well as other coronaviruses.

Risk factors of severe and critical patients with COVID-19 in Hubei, China. (Special Issue: Spatio-temporal dynamics analysis, risk assessment and emergency management for COVID-19 epidemic.) [Chinese]

Objective: To investigate the risk factors of severe and critical patients with coronavirus disease 2019(COVID-19)in Hubei, China. Methods All patients with COVID-19 registered in the National Legal Infectious Disease Reporting System of Hubei Provincial Center for Disease Control and Prevention, as of March 18, 2020, were recruited. According to the symptoms, the patients were divided into two groups: mild/moderate patients and severe/critical patients. Their general characteristics were described, and the risk factors of severe and critical patients with COVID-19 were explored by using a Logistic regression model. Results A total of 48 814 cases were included, of which 38 730 were mild/moderate patients and 10 084 were severe/critical patients. The median age was 54(41, 65)years. Multivariate analysis showed that the elderly, male, home workers, people in Wuhan City, migrants, longer interval between onset and diagnosis, low temperature, higher concentrations of PM2.5/PM10/SO2/O3 increased the risk of severe/critical diagnosis in patients with COVID-19. Conclusion The elderly, male, home workers, people in Wuhan City, migrants, longer interval between onset and diagnosis, low temperature, and air pollution exposure are risk factors for severe/critical COVID-19 patients. More attention should be paid to people with these characteristics.

An Experimental Evaluation of Two Approaches for Improving Response to Household Screening Efforts in National Mail/Web Surveys.

Survey researchers have carefully modified their data collection operations for various reasons, including the rising costs of data collection and the ongoing Coronavirus disease (COVID-19) pandemic, both of which have made in-person interviewing difficult. For large national surveys that require household (HH) screening to determine survey eligibility, cost-efficient screening methods that do not include in-person visits need additional evaluation and testing. A new study, known as the American Family Health Study (AFHS), recently initiated data collection with a national probability sample, using a sequential mixed-mode mail/web protocol for push-to-web US HH screening (targeting persons aged 18-49 years). To better understand optimal approaches for this type of national screening effort, we embedded two randomized experiments in the AFHS data collection. The first tested the use of bilingual respondent materials where mailed invitations to the screener were sent in both English and Spanish to 50 percent of addresses with a high predicted likelihood of having a Spanish speaker and 10 percent of all other addresses. We found that the bilingual approach did not increase the response rate of high-likelihood Spanish-speaking addresses, but consistent with prior work, it increased the proportion of eligible Hispanic respondents identified among completed screeners, especially among addresses predicted to have a high likelihood of having Spanish speakers. The second tested a form of nonresponse follow-up, where a subsample of active sampled HHs that had not yet responded to the screening invitations was sent a priority mailing with a $5 incentive, adding to the $2 incentive provided for all sampled HHs in the initial screening invitation. We found this approach to be quite valuable for increasing the screening survey response rate.

Improved Durability to SARS-CoV-2 Vaccine Immunity following Coimmunization with Molecular Adjuvant Adenosine Deaminase-1.

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have demonstrated strong immunogenicity and protection against severe disease, concerns about the duration and breadth of these responses remain. In this study, we show that codelivery of plasmid-encoded adenosine deaminase-1 (pADA) with SARS-CoV-2 spike glycoprotein DNA enhances immune memory and durability in vivo. Coimmunized mice displayed increased spike-specific IgG of higher affinity and neutralizing capacity as compared with plasmid-encoded spike-only-immunized animals. Importantly, pADA significantly improved the longevity of these enhanced responses in vivo. This coincided with durable increases in frequencies of plasmablasts, receptor-binding domain-specific memory B cells, and SARS-CoV-2-specific T follicular helper cells. Increased spike-specific T cell polyfunctionality was also observed. Notably, animals coimmunized with pADA had significantly reduced viral loads compared with their nonadjuvanted counterparts in a SARS-CoV-2 infection model. These data suggest that pADA enhances immune memory and durability and supports further translational studies.

An orally available Mpro inhibitor is effective against wild-type SARS-CoV-2 and variants including Omicron.

Emerging SARS-CoV-2 variants continue to cause waves of new infections globally. Developing effective antivirals against SARS-CoV-2 and its variants is an urgent task. The main protease (Mpro) of SARS-CoV-2 is an attractive drug target because of its central role in viral replication and its conservation among variants. We herein report a series of potent α-ketoamide-containing Mpro inhibitors obtained using the Ugi four-component reaction. The prioritized compound, Y180, showed an IC50 of 8.1 nM against SARS-CoV-2 Mpro and had oral bioavailability of 92.9%, 31.9% and 85.7% in mice, rats and dogs, respectively. Y180 protected against wild-type SARS-CoV-2, B.1.1.7 (Alpha), B.1.617.1 (Kappa) and P.3 (Theta), with EC50 of 11.4, 20.3, 34.4 and 23.7 nM, respectively. Oral treatment with Y180 displayed a remarkable antiviral potency and substantially ameliorated the virus-induced tissue damage in both nasal turbinate and lung of B.1.1.7-infected K18-human ACE2 (K18-hACE2) transgenic mice. Therapeutic treatment with Y180 improved the survival of mice from 0 to 44.4% (P = 0.0086) upon B.1.617.1 infection in the lethal infection model. Importantly, Y180 was also highly effective against the B.1.1.529 (Omicron) variant both in vitro and in vivo. Overall, our study provides a promising lead compound for oral drug development against SARS-CoV-2.

Comparison of 19 major infectious diseases during COVID-19 epidemic and previous years in Zhejiang, implications for prevention measures.

BACKGROUND: The global pandemic of coronavirus disease 2019 (COVID-19) has attracted great public health efforts across the world. Few studies, however, have described the potential impact of these measures on other important infectious diseases. METHODS: The incidence of 19 major infectious diseases in Zhejiang Province was collected from the National Notifiable Infectious Disease Surveillance System from January 2017 to October 2020. The entire epidemic control phase was divided into three stages. The government deployed the first level response from 24 January to 2 March (the most rigorous measures). When the outbreak of COVID-19 was under control, the response level changed to the second level from 3 to 23 March, and then the third level response was implemented after 24 March. We compared the epidemiological characteristics of 19 major infectious diseases during different periods of the COVID-19 epidemic and previous years. RESULTS: A total of 1,814,881 cases of 19 infectious diseases were reported in Zhejiang from January 2017 to October 2020, resulting in an incidence rate of 8088.30 cases per 1,000,000 person-years. After the non-pharmaceutical intervention, the incidence of 19 infectious diseases dropped by 70.84%, from 9436.32 cases per 1,000,000 person-years to 2751.51 cases per 1,000,000 person-years, with the large decrease in the first response period of influenza. However, we observed that the daily incidence of severe fever with thrombocytopenia syndrome (SFTS) and leptospirosis increased slightly (from 1.11 cases per 1,000,000 person-years to 1.82 cases per 1,000,000 person-years for SFTS and 0.30 cases per 1,000,000 person-years to 1.24 cases per 1,000,000 person-years for leptospirosis). There was no significant difference in the distribution of epidemiological characteristic of most infectious diseases before and during the implementation of COVID-19 control measures. CONCLUSION: Our study summarizes the epidemiological characteristics of 19 infectious diseases and indicates that the rigorous control measures for COVID-19 are also effective for majority of infectious diseases.

Ambient air pollution and low temperature associated with case fatality of COVID-19: A nationwide retrospective cohort study in China.

The evidence for the effects of environmental factors on COVID-19 case fatality remains controversial, and it is crucial to understand the role of preventable environmental factors in driving COVID-19 fatality. We thus conducted a nationwide cohort study to estimate the effects of environmental factors (temperature, particulate matter [PM2.5, PM10], sulfur dioxide [SO2], nitrogen dioxide [NO2], and ozone [O3]) on COVID-19 case fatality. A total of 71,808 confirmed COVID-19 cases were identified and followed up for their vital status through April 25, 2020. Exposures to ambient air pollution and temperature were estimated by linking the city- and county-level monitoring data to the residential community of each participant. For each participant, two windows were defined: the period from symptom onset to diagnosis (exposure window I) and the period from diagnosis date to date of death/recovery or end of the study period (exposure window II). Cox proportional hazards models were used to estimate the associations between these environmental factors and COVID-19 case fatality. COVID-19 case fatality increased in association with environmental factors for the two exposure windows. For example, each 10 µg/m3 increase in PM2.5, PM10, O3, and NO2 in window I was associated with a hazard ratio of 1.11 (95% CI 1.09, 1.13), 1.10 (95% CI 1.08, 1.13), 1.09 (95 CI 1.03, 1.14), and 1.27 (95% CI 1.19, 1.35) for COVID-19 fatality, respectively. A significant effect was also observed for low temperature, with a hazard ratio of 1.03 (95% CI 1.01, 1.04) for COVID-19 case fatality per 1°C decrease. Subgroup analysis indicated that these effects were stronger in the elderly, as well as in those with mild symptoms and living in Wuhan or Hubei. Overall, the sensitivity analyses also yielded consistent estimates. Short-term exposure to ambient air pollution and low temperature during the illness would play a nonnegligible part in causing case fatality due to COVID-19. Reduced exposures to high concentrations of PM2.5, PM10, O3, SO2, and NO2 and low temperature would help improve the prognosis and reduce public health burden.

Population Movement, City Closure in Wuhan, and Geographical Expansion of the COVID-19 Infection in China in January 2020.

BACKGROUND: The unprecedented outbreak of corona virus disease 2019 (COVID-19) infection in Wuhan City has caused global concern; the outflow of the population from Wuhan was believed to be a main reason for the rapid and large-scale spread of the disease, so the government implemented a city-closure measure to prevent its transmission considering the large amount of travel before the Chinese New Year. METHODS: Based on the daily reported new cases and the population-movement data between 1 and 31 January, we examined the effects of population outflow from Wuhan on the geographical expansion of the infection in other provinces and cities of China, as well as the impacts of the city closure in Wuhan using different closing-date scenarios. RESULTS: We observed a significantly positive association between population movement and the number of the COVID-19 cases. The spatial distribution of cases per unit of outflow population indicated that the infection in some areas with a large outflow of population might have been underestimated, such as Henan and Hunan provinces. Further analysis revealed that if the city-closure policy had been implemented 2 days earlier, 1420 (95% confidence interval, 1059-1833) cases could have been prevented, and if 2 days later, 1462 (1090-1886) more cases would have been possible. CONCLUSIONS: Our findings suggest that population movement might be one important trigger for the transmission of COVID-19 infection in China, and the policy of city closure is effective in controlling the epidemic.

Rhabdomyolysis is Associated with In-Hospital Mortality in Patients with COVID-19.

PURPOSE: Rhabdomyolysis (RM) has been associated with many viral infectious diseases, and associated with poor outcomes. We aim to evaluate the clinical features and outcomes of RM in patients with coronavirus disease 2019 (COVID-19). METHOD: This was a single-center, retrospective, cohort study of 1,014 consecutive hospitalized patients with confirmed COVID-19 at the Huoshenshan Hospital in Wuhan, China, between February 17 and April 12, 2020. RESULTS: The overall incidence of RM was 2.2%. Compared with patients without RM, those with RM tended to have a higher risk of deterioration. Patients with RM also constituted a greater percentage of patients admitted to the intensive care unit (90.9% vs. 5.3%, P < 0.001) and a greater percentage of patients undergoing mechanical ventilation (86.4% vs. 2.7% P < 0.001). Moreover, patients with RM had laboratory test abnormalities, including the presence of markers of inflammation, activation of coagulation, and kidney injury. Patients with RM also had a higher risk of in-hospital death (P < 0.001). Cox's proportional hazard regression model analysis confirmed that RM indicators, including peak creatine kinase levels > 1,000 IU/L (HR = 6.46, 95% CI: 3.02-13.86) and peak serum myoglobin concentrations > 1,000 ng/mL (HR = 9.85, 95% CI: 5.04-19.28), were independent risk factors for in-hospital death. Additionally, patients with COVID-19 that developed RM tended to have delayed viral clearance. CONCLUSION: RM might be an important contributing factor to adverse outcomes in COVID-19 patients. The early detection and effective intervention of RM may help reduce mortality among COVID-19 patients.

Community evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission through air.

BACKGROUND: Nine COVID-19 (Corona Virus Disease, 2019) cases were observed in one community in Guangzhou. All the cases lived in three vertically aligned units of one building sharing the same piping system, which provided one unique opportunity to examine the transmission mode of SARS-CoV-2. METHODS: We interviewed the cases on the history of travelling and close contact with the index patients. Respiratory samples from all the cases were collected for viral phylogenetic analyses. A simulation experiment in the building and a parallel control experiment in a similar building were then conducted to investigate the possibility of transmission through air. RESULTS: Index patients living in Apartment 15-b had a travelling history in Wuhan, and four cases who lived in Apartment 25-b and 27-b were subsequently diagnosed. Phylogenetic analyses showed that virus of all the patients were from the same strain of the virus. No close contacts between the index cases and other families indicated that the transmission might not occur through droplet and close contacts. Airflow detection and simulation experiment revealed that flushing the toilets could increase the speed of airflow in the pipes and transmitted the airflow from Apartment 15-b to 25-b and 27-b. Reduced exhaust flow rates in the infected building might have contributed to the outbreak. CONCLUSIONS: The outbreak of COVID-19 in this community could be largely explained by the transmission through air, and future efforts to prevent the infection should take the possibility of transmission through air into consideration. A disconnected drain pipe and exhaust pipe for toilet should be considered in the architectural design to help prevent possible virus spreading through the air.

Predictive Model and Risk Factors for Case Fatality of COVID-19: A Cohort of 21,392 Cases in Hubei, China.

An increasing number of patients are being killed by coronavirus disease 2019 (COVID-19), however, risk factors for the fatality of COVID-19 remain unclear. A total of 21,392 COVID-19 cases were recruited in the Hubei Province of China between December 2019 and February 2020, and followed up until March 18, 2020. We adopted Cox regression models to investigate the risk factors for case fatality and predicted the death probability under specific combinations of key predictors. Among the 21,392 patients, 1,020 (4.77%) died of COVID-19. Multivariable analyses showed that factors, including age (≥60 versus <45 years, hazard ratio [HR] = 7.32; 95% confidence interval [CI], 5.42, 9.89), sex (male versus female, HR = 1.31; 95% CI, 1.15, 1.50), severity of the disease (critical versus mild, HR = 39.98; 95% CI, 29.52, 48.86), comorbidity (HR = 1.40; 95% CI, 1.23, 1.60), highest body temperature (>39°C versus <39°C, HR = 1.28; 95% CI, 1.09, 1.49), white blood cell counts (>10 × 109/L versus (4-10) × 109/L, HR = 1.69; 95% CI, 1.35, 2.13), and lymphocyte counts (<0.8 × 109/L versus (0.8-4) × 109/L, HR = 1.26; 95% CI, 1.06, 1.50) were significantly associated with case fatality of COVID-19 patients. Individuals of an older age, who were male, with comorbidities, and had a critical illness had the highest death probability, with 21%, 36%, 46%, and 54% within 1-4 weeks after the symptom onset. Risk factors, including demographic characteristics, clinical symptoms, and laboratory factors were confirmed to be important determinants of fatality of COVID-19. Our predictive model can provide scientific evidence for a more rational, evidence-driven allocation of scarce medical resources to reduce the fatality of COVID-19.

Environmental contamination of SARS-CoV-2 in healthcare premises.

OBJECTIVES: A large number of healthcare workers (HCWs) were infected by SARS-CoV-2 during the ongoing outbreak of COVID-19 in Wuhan, China. Hospitals are significant epicenters for the human-to-human transmission of the SARS-CoV-2 for HCWs, patients, and visitors. No data has been reported on the details of hospital environmental contamination status in the epicenter of Wuhan. METHODS: We collected 626 surface swabs within the Zhongnan Medical Center in Wuhan in the mist of the COVID-19 outbreak between February 7 - February 27, 2020. Dacron swabs were aseptically collected from the surfaces of 13 hospital function zones, five major objects, and three major PPE. The SARS-CoV-2 RNAs were detected by reverse transcription-PCR. RESULTS: The most contaminated zones were the intensive care unit specialized for taking care of novel coronavirus pneumonia (NCP) (31.9%), Obstetric Isolation Ward specialized for pregnant women with NCP (28.1%), and Isolation Ward for NCP (19.6%). We classified the 13 zones into four contamination levels. The most contaminated objects were self-service printers (20.0%), desktop/keyboard (16.8%), and doorknob (16.0%). Both hand sanitizer dispensers (20.3%) and gloves (15.4%) were the most contaminated PPE. CONCLUSION: Our findings emphasize the urgent need to ensure adequate environmental cleaning, strengthen infection prevention training, and improve infection prevention among HCWs during the outbreak of COVID-19.