Elucidating host cell response pathways and repurposing therapeutics for SARS-CoV-2 and other coronaviruses.

COVID-19, first reported in late 2019, is an ongoing pandemic that has been causing devastation across the globe. Although there are multiple vaccines that can prevent severe symptoms, effective COVID-19 therapeutics are still of importance. Using our proprietary in silico engine, we screened more than 22,000 unique compounds represented by over half a million gene expression profiles to uncover compounds that can be repurposed for SARS-CoV-2 and other coronaviruses in a timely and cost-efficient manner. We then tested 13 compounds in vitro and found three with potency against SARS-CoV-2 with reasonable cytotoxicity. Bortezomib and homoharringtonine are some of the most promising hits with IC50 of 1.39 µM and 0.16 µM, respectively for SARS-CoV-2. Tanespimycin and homoharringtonine were effective against the common cold coronaviruses. In-depth analysis highlighted proteasome, ribosome, and heat shock pathways as key targets in modulating host responses during viral infection. Further studies of these pathways and compounds have provided novel and impactful insights into SARS-CoV-2 biology and host responses that could be further leveraged for COVID-19 therapeutics development.

Determinants of Satisfaction With Hospital Online Appointment Service Among Older Adults During the COVID-19 Pandemic: A Cross-Sectional Study.

BACKGROUND: How did older adults who had to use online medical service during the COVID-19 pandemic bridge the "digital divide"? Taking Internet-based appointment service (IBAS) as an example, this study aimed to investigate the subjective feelings of older adults and evaluate their user-satisfaction. METHODS: This study was based on data from a questionnaire survey involving 325 outpatients 60 years old in shanghai during the COVID-19 pandemic. The satisfaction of IBAS was evaluated and compared from six domains including convenience, visiting time, correct identification of specialists, on-site assist service, COVID-19 prevention, and privacy protection. Logistic regression analysis was used to investigate the correlation between satisfaction and social factors. RESULTS: No significant difference between older adults with or without previous experience using IBAS in terms of overall satisfaction. In the domain of operation difficulty (81.9 vs. 97.5%) and precise medicine (88.1 vs. 96.9%), such as correctly identifying the specialist, the satisfaction of previous user group was significantly higher than that of first-time user group. However, there was no significant difference in the remaining four domains between the two groups. Among the first time IBAS users, the satisfaction was higher than the walk-in registration they used before. Logistic regression revealed that some "intention to use IBAS"-associated social factors such as distance from the hospital, living status, and frequency of hospital visit, were related to the satisfaction of older adults. CONCLUSIONS: Driven by the external pandemic and internal intention, older adults would choose and manage network medical resources with their high satisfaction, which essentially demonstrates not only behavioral adjustment but also inner acceptance in older adults. Our findings support the need for promoting the driving force of older adults in using Internet-based medical service as well as transforming the design factors and behavior patterns.

Associations of healthy lifestyle and socioeconomic status with mortality and incident cardiovascular disease: two prospective cohort studies.

OBJECTIVE: To examine whether overall lifestyles mediate associations of socioeconomic status (SES) with mortality and incident cardiovascular disease (CVD) and the extent of interaction or joint relations of lifestyles and SES with health outcomes. DESIGN: Population based cohort study. SETTING: US National Health and Nutrition Examination Survey (US NHANES, 1988-94 and 1999-2014) and UK Biobank. PARTICIPANTS: 44 462 US adults aged 20 years or older and 399 537 UK adults aged 37-73 years. EXPOSURES: SES was derived by latent class analysis using family income, occupation or employment status, education level, and health insurance (US NHANES only), and three levels (low, medium, and high) were defined according to item response probabilities. A healthy lifestyle score was constructed using information on never smoking, no heavy alcohol consumption (women ≤1 drink/day; men ≤2 drinks/day; one drink contains 14 g of ethanol in the US and 8 g in the UK), top third of physical activity, and higher dietary quality. MAIN OUTCOME MEASURES: All cause mortality was the primary outcome in both studies, and CVD mortality and morbidity in UK Biobank, which were obtained through linkage to registries. RESULTS: US NHANES documented 8906 deaths over a mean follow-up of 11.2 years, and UK Biobank documented 22 309 deaths and 6903 incident CVD cases over a mean follow-up of 8.8-11.0 years. Among adults of low SES, age adjusted risk of death was 22.5 (95% confidence interval 21.7 to 23.3) and 7.4 (7.3 to 7.6) per 1000 person years in US NHANES and UK Biobank, respectively, and age adjusted risk of CVD was 2.5 (2.4 to 2.6) per 1000 person years in UK Biobank. The corresponding risks among adults of high SES were 11.4 (10.6 to 12.1), 3.3 (3.1 to 3.5), and 1.4 (1.3 to 1.5) per 1000 person years. Compared with adults of high SES, those of low SES had higher risks of all cause mortality (hazard ratio 2.13, 95% confidence interval 1.90 to 2.38 in US NHANES; 1.96, 1.87 to 2.06 in UK Biobank), CVD mortality (2.25, 2.00 to 2.53), and incident CVD (1.65, 1.52 to 1.79) in UK Biobank, and the proportions mediated by lifestyle were 12.3% (10.7% to 13.9%), 4.0% (3.5% to 4.4%), 3.0% (2.5% to 3.6%), and 3.7% (3.1% to 4.5%), respectively. No significant interaction was observed between lifestyle and SES in US NHANES, whereas associations between lifestyle and outcomes were stronger among those of low SES in UK Biobank. Compared with adults of high SES and three or four healthy lifestyle factors, those with low SES and no or one healthy lifestyle factor had higher risks of all cause mortality (3.53, 3.01 to 4.14 in US NHANES; 2.65, 2.39 to 2.94 in UK Biobank), CVD mortality (2.65, 2.09 to 3.38), and incident CVD (2.09, 1.78 to 2.46) in UK Biobank. CONCLUSIONS: Unhealthy lifestyles mediated a small proportion of the socioeconomic inequity in health in both US and UK adults; therefore, healthy lifestyle promotion alone might not substantially reduce the socioeconomic inequity in health, and other measures tackling social determinants of health are warranted. Nevertheless, healthy lifestyles were associated with lower mortality and CVD risk in different SES subgroups, supporting an important role of healthy lifestyles in reducing disease burden.