A Comprehensive Survey of Prospective Structure-Based Virtual Screening for Early Drug Discovery in the Past Fifteen Years.

Structure-based virtual screening (SBVS), also known as molecular docking, has been increasingly applied to discover small-molecule ligands based on the protein structures in the early stage of drug discovery. In this review, we comprehensively surveyed the prospective applications of molecular docking judged by solid experimental validations in the literature over the past fifteen years. Herein, we systematically analyzed the novelty of the targets and the docking hits, practical protocols of docking screening, and the following experimental validations. Among the 419 case studies we reviewed, most virtual screenings were carried out on widely studied targets, and only 22% were on less-explored new targets. Regarding docking software, GLIDE is the most popular one used in molecular docking, while the DOCK 3 series showed a strong capacity for large-scale virtual screening. Besides, the majority of identified hits are promising in structural novelty and one-quarter of the hits showed better potency than 1 µM, indicating that the primary advantage of SBVS is to discover new chemotypes rather than highly potent compounds. Furthermore, in most studies, only in vitro bioassays were carried out to validate the docking hits, which might limit the further characterization and development of the identified active compounds. Finally, several successful stories of SBVS with extensive experimental validations have been highlighted, which provide unique insights into future SBVS drug discovery campaigns.

A rapid, high-throughput, and sensitive PEG-precipitation method for SARS-CoV-2 wastewater surveillance.

The effective application of wastewater surveillance is dependent on testing capacity and sensitivity to obtain high spatial resolution testing results for a timely targeted public health response. To achieve this purpose, the development of rapid, high-throughput, and sensitive virus concentration methods is urgently needed. Various protocols have been developed and implemented in wastewater surveillance networks so far, however, most of them lack the ability to scale up testing capacity or cannot achieve sufficient sensitivity for detecting SARS-CoV-2 RNA at low prevalence. In the present study, using positive raw wastewater in Hong Kong, a PEG precipitation-based three-step centrifugation method was developed, including low-speed centrifugation for large particles removal and the recovery of viral nucleic acid, and medium-speed centrifugation for the concentration of viral nucleic acid. This method could process over 100 samples by two persons per day to reach the process limit of detection (PLoD) of 3286 copies/L wastewater. Additionally, it was found that the testing capacity could be further increased by decreasing incubation and centrifugation time without significantly influencing the method sensitivity. The entire procedure uses ubiquitous reagents and instruments found in most laboratories to obtain robust testing results. This high-throughput, cost-effective, and sensitive tool will promote the establishment of nearly real-time wastewater surveillance networks for valuable public health information.

Exploring the driving forces and scenario analysis for China's provincial peaks of CO2 emissions

Understanding the drivers and peaks of CO2 emissions at the provincial level plays a crucial role in achieving the goals of China's CO2 emissions peak by 2030. This research combines the spatial-temporal Logarithmic Mean Division Index with scenario analysis to empirically explore the drivers and peaks of CO2 emissions in 30 provinces in China during 1997 and 2020, considering COVID-19 effects. The results show that the energy structure has replaced the energy intensity as the main factor of emission reduction in 2020. The CO2 emission driving mechanism at the provincial level is different from that at the country level. The population restrains the CO2 emissions in Heilongjiang, Sichuan, and Guizhou. The energy structure increases CO2 emissions in Hainan, Ningxia, Shanxi, and Xinjiang. The role of driving factors to CO2 emissions varies greatly among provinces. The population effect is strong in Shandong, Guangdong, and Henan. The economic effect is significant in Shanghai, Jiangsu, and Tianjin. The energy intensity effect is remarkable in Shanxi, Ningxia, and Inner Mongolia. The energy structure effect is profound in Shanxi, Inner Mongolia, and Henan. Based on our findings, China's CO2 emissions peak will occur in 2030 and 2025 under baseline and green development scenarios. Many provinces have already reached their peaks, including Chongqing, Yunnan, Beijing, Tianjin, Qinghai, Shanghai, Jilin, Hubei, Heilongjiang, Hebei, Sichuan, Anhui, Guizhou, and Henan. However, Xinjiang and Shanxi will not reach their peaks by 2030. Based on the findings, this paper put forward several policy implications.

Identifying conditions for a third dose intention of COVID-19 vaccination in college students: A fuzzy-set qualitative comparative analysis.

Background: During the pandemic, a third dose of the COVID-19 vaccine effectively reduces the proportion of severe cases in those infected, but vaccine hesitancy impedes this reasonable prevention method. Epidemic control in China is being tested due to the large population base, especially in crowded places like college campuses. This study aimed to explore the configuration paths of psychological antecedents for college students to receive a third COVID-19 vaccine. Methods: An anonymous cross-sectional survey was carried out in five universities in Wuhan using convenience sampling. A long version of the 5C 7-point Likert scale was used to measure college students' intention and psychological antecedents on the third dose of the COVID-19 vaccine. A fuzzy-set Qualitative Comparative Analysis (QCA) approach was performed to explore the configuration of conditions to the vaccination willingness. Results: 31.67% of respondents surveyed did not receive their third dose of the COVID-19 vaccine. The score of intention to get the vaccine for college students who did not receive the booster vaccine was 4.93 (±1.68). Average scores of 5.19 (±1.24), 4.35 (±1.75), 4.02 (±1.45), 5.84 (±1.23), and 4.61(±1.32) were reported for confidence, complacency, constraints, calculation, and collective responsibility in them. QCA showed high confidence and collective responsibility playing a central role in third dose vaccination intention. Meanwhile, low confidence and collective responsibility are the core conditions of low vaccination willingness. Conclusion: Eliminating vaccine hesitancy necessitates focusing on the psychological antecedents of vaccination intentions to identify critical targets for policy and interventions. This study identified trust and collective responsibility are core elements of the psychological antecedents of college students' intention to receive the booster vaccine for COVID-19. To achieve herd immunity as soon as possible, health administration and campus can start with vaccine confidence-building and collective responsibility cultivation to take appropriate actions and measures to improve coverage of the booster vaccination.

Potential mechanism of SARS-CoV-2-associated central and peripheral nervous system impairment.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is more than merely a respiratory disease, as it also presents with various neurological symptoms. SARS-CoV-2 may infect the central nervous system (CNS) and thus is neurotropic. However, the pathophysiological mechanism of coronavirus disease 2019 (COVID-19)-associated neuropathy remains unclear. Many studies have reported that SARS-CoV-2 enters the CNS through the hematogenous and neuronal routes, as well as through the main host neurological immune responses and cells involved in these responses. The neurological immune responses to COVID-19 and potential mechanisms of the extensive neuroinflammation induced by SARS-CoV-2 have been investigated. Although CNS infection with SARS-CoV-2 was shown to lead to neuronal impairment, certain aspects of this mechanism remain controversial and require further analysis. In this review, we discussed the pathway and mechanisms of SARS-CoV-2 invasion in the CNS, and associated clinical manifestations, such as anosmia, headache, and hyposmia. Moreover, the mechanism of neurological damage caused by SARS-CoV-2 may provide potential treatment methods for patients presenting with SARS-CoV-2-associated neuropathy.

Comparison of virus concentration methods and RNA extraction methods for SARS-CoV-2 wastewater surveillance.

Wastewater surveillance is a promising tool for population-level monitoring of the spread of infectious diseases, such as the coronavirus disease 2019 (COVID-19). Different from clinical specimens, viruses in community-scale wastewater samples need to be concentrated before detection because viral RNA is highly diluted. The present study evaluated eleven different virus concentration methods for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in wastewater. First, eight concentration methods of different principles were compared using spiked wastewater at a starting volume of 30 mL. Ultracentrifugation was the most effective method with a viral recovery efficiency of 25 ± 6%. The second-best option, AlCl3 precipitation method, yielded a lower recovery efficiency, only approximately half that of the ultracentrifugation method. Second, the potential of increasing method sensitivity was explored using three concentration methods starting with a larger volume of 1000 mL. Although ultracentrifugation using a large volume outperformed the other two large-volume methods, it only yielded a comparable method sensitivity as the ultracentrifugation using a small volume (30 mL). Thus, ultracentrifugation using less volume of wastewater is more preferable considering the sample processing throughput. Third, a comparison of two viral RNA extraction methods showed that the lysis-buffer-based extraction method resulted in higher viral recovery efficiencies, with cycle threshold (Ct) values 0.9-4.2 lower than those obtained for the acid-guanidinium-phenol-based method using spiked samples. These results were further confirmed by using positive wastewater samples concentrated by ultracentrifugation and extracted separately by the two viral RNA extraction methods. In summary, concentration using ultracentrifugation followed by the lysis buffer-based extraction method enables sensitive and robust detection of SARS-CoV-2 for wastewater surveillance.

Protective efficient comparisons among all kinds of respirators and masks for health-care workers against respiratory viruses: A PRISMA-compliant network meta-analysis.

BACKGROUND: There is no definite conclusion about comparison of better effectiveness between N95 respirators and medical masks in preventing health-care workers (HCWs) from respiratory infectious diseases, so that conflicting results and recommendations regarding the protective effects may cause difficulties for selection and compliance of respiratory personal protective equipment use for HCWs, especially facing with pandemics of corona virus disease 2019. METHODS: We systematically searched MEDLINE, Embase, PubMed, China National Knowledge Infrastructure, Wanfang, medRxiv, and Google Scholar from initiation to November 10, 2020 for randomized controlled trials, case-control studies, cohort studies, and cross-sectional studies that reported protective effects of masks or respirators for HCWs against respiratory infectious diseases. We gathered data and pooled differences in protective effects according to different types of masks, pathogens, occupations, concurrent measures, and clinical settings. The study protocol is registered with PROSPERO (registration number: 42020173279). RESULTS: We identified 4165 articles, reviewed the full text of 66 articles selected by abstracts. Six randomized clinical trials and 26 observational studies were included finally. By 2 separate conventional meta-analyses of randomized clinical trials of common respiratory viruses and observational studies of pandemic H1N1, pooled effects show no significant difference between N95 respirators and medical masks against common respiratory viruses for laboratory-confirmed respiratory virus infection (risk ratio 0.99, 95% confidence interval [CI] 0.86-1.13, I2 = 0.0%), clinical respiratory illness (risk ratio 0.89, 95% CI 0.45-1.09, I2 = 83.7%, P = .002), influenza-like illness (risk ratio 0.75, 95% CI 0.54-1.05, I2 = 0.0%), and pandemic H1N1 for laboratory-confirmed respiratory virus infection (odds ratio 0.92, 95% CI 0.49-1.70, I2 = 0.0%, P = .967). But by network meta-analysis, N95 respirators has a significantly stronger protection for HCWs from betacoronaviruses of severe acute respiratory syndrome, middle east respiratory syndrome, and corona virus disease 2019 (odds ratio 0.43, 95% CI 0.20-0.94). CONCLUSIONS: Our results provide moderate and very-low quality evidence of no significant difference between N95 respirators and medical masks for common respiratory viruses and pandemic H1N1, respectively. And we found low quality evidence that N95 respirators had a stronger protective effectiveness for HCWs against betacoronaviruses causative diseases compared to medical masks. The evidence of comparison between N95 respirators and medical masks for corona virus disease 2019 is open to question and needs further study.

Potential Anti-Coronavirus Agents and the Pharmacologic Mechanisms.

Severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) is an emerging pathogen, which is similar to previous SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) occurrences. However, we only get few understandings about the pathogenesis of SARS-CoV-2, which need to further be studied. The discovery of an agent that has a treatment efficacy against SARS-CoV-2 is very urgent. In this review, we briefly discuss the virology of this pathogen and focus on the available understanding of the pathogenesis and treatments of this pathogen including the uses of nucleoside analogues, protease inhibitors, interferons, and other small-molecule drugs, on the basis previous comprehensions of SARS and MERS. These reviewed concepts may be beneficial in providing new insights and potential treatments for COVID-19.

Optimal cut-off value of elevated cardiac troponin concentrations for myocardial injury predicts clinical outcomes in adult patients with COVID-19: a dose-response analysis protocol for systematic review.

INTRODUCTION: Acute myocardial injury in patients with COVID-19 infection has been recognised as one important complication associated with in-hospital mortality. The potential dose-response effect of cardiac troponin (cTn) concentrations on adverse clinical outcomes has not been systematically studied. Hence, we will conduct a comprehensive dose-response meta-analysis to quantitatively evaluate the relationship between elevated cTn concentrations and in-hospital adverse clinical outcomes in patients with COVID-19. METHODS: We will search PubMed, EMBASE, Cochrane Library and ISI Knowledge via Web of Science databases, as well as preprint databases (medRxiv and bioRxiv), from inception to October 2021, to identify all retrospective and prospective cohorts and randomised controlled studies using related keywords. The primary outcome will be all-cause mortality during hospitalisation. The secondary outcome will be major adverse event (MAE). To conduct a dose-response meta-analysis of the potential linear or restricted cubic spline regression relationship between elevated cTn concentrations and all-cause mortality or MAE, studies with three or more categories of cTn concentrations will be included. Univariable or multivariable meta-regression and subgroup analyses will be conducted to compare elevated and non-elevated categories of cTn concentration. Sensitivity analyses will be used to assess the robustness of our results by removing each included study at one time to obtain and evaluate the remaining overall estimates of all-cause mortality or MAE. ETHICS AND DISSEMINATION: In accordance with the Institutional Review Board/Independent Ethics Committee of Fuwai Hospital, ethical approval was waived for this systematic review protocol. This meta-analysis will be disseminated through a peer-reviewing process for journal publication and conference communication. PROSPERO REGISTRATION NUMBER: CRD42020216059.

Early outcomes of Stanford type A aortic dissection under the coronavirus disease 2019 (COVID-19) pandemic: a multicentre study from Hubei province.

OBJECTIVES: Our goal was to compare the short-term outcomes of Stanford type A aortic dissection (TAAD), during the coronavirus disease 2019 (COVID-19) pandemic with those during normal times and summarize our perioperative management experience of patients with TAAD in the context of COVID-19. METHODS: From 17 January 2020 to 8 March 2020, a total of 27 patients with TAAD were operated on in 8 cardiovascular surgery centres in Hubei Province (COVID-19 group). The data from 91 patients with TAAD from the same centres during the same period last year were extracted from the Hubei Cardiac Surgery Registration System (control group). A propensity score matched subgroup of 26 pairs (1:2) was identified. Perioperative data and short-term outcomes were assessed. RESULTS: Nine patients in the COVID-19 group were categorized as suspicious for the disease (9/27, 33.3%), and others were excluded (18/27, 66.7%). No one was laboratory confirmed preoperatively. The average waiting, cross-clamp and circulatory arrest times were longer in the COVID-19 group (22.9 ± 8.3 vs 9.7 ± 4.0 h, P < 0.001; 135 ± 36 vs 103 ± 45 min, P = 0.003; 24 ± 9 vs 17 ± 8 min, P < 0.001, respectively). The 30-day or in-hospital deaths were 3.8% in both groups (P = 1.0). The COVID-19 group was associated with longer ventilation and intensive care unit times (81 ± 71 vs 45 ± 19 h, P < 0.001; 7.4 ± 3.8 vs 4.5 ± 2.7 days; P < 0.001, respectively). There were no statistical differences between the 2 groups in the incidence of complications such as stroke, neurological deficit, acute kidney injury, pulmonary infection and reoperation. Serum antibody tests for those patients showed 7 out of 9 suspected cases were Immunoglobulin G positive. No cross-infection occurred in other patients or associated medical staff. CONCLUSIONS: With adequate preparation and appropriate protection, satisfactory early outcomes can be achieved after emergency operations for patients with TAAD during the COVID-19 pandemic.

The Urban-Rural Disparity in the Status and Risk Factors of Health Literacy: A Cross-Sectional Survey in Central China.

Health literacy is the ability of individuals to access, process, and understand health information to make decisions regarding treatment and their health on the whole; it is critical to maintain and improve public health. However, the health literacy of urban and rural populations in China has been little known. Thus, this study aims to assess the status of health literacy and explore the differences of its possible determinants (e.g., socio-economic factors) among urban and rural populations in Henan, China. A cross-sectional study, 78,646 participants were recruited from a populous province in central China with a multi-stage random sampling design. The Chinese Resident Health Literacy Scale was adopted to measure the health literacy of the respondents. In the participants, the level of health literacy (10.21%) in central China was significantly lower than the national average, and a big gap was identified between urban and rural populations (16.92% vs. 8.09%). A noticeable difference was reported in different aspects and health issues of health literacy between urban and rural populations. The health literacy level was lower in those with lower levels of education, and a significant difference was identified in the level of health literacy among people of different ages and occupations in both urban and rural areas. Note that in rural areas, as long as residents educated, they all had higher odds to exhibit basic health literacy than those uneducated; in rural areas, compared with those aged 15 to 24 years, residents aged 45 to 54 years (OR = 0.846,95% CI (0.730, 0.981)), 55 to 64 years (OR = 0.716,95% CI (0.614, 0.836)) and above 65 years (OR = 0.679, 95% CI (0.567, 0.812)) were 84.6%, 71.6%, and 67.9%, respectively, less likely to exhibit basic health literacy. Considering the lower health literacy among rural residents compared with their urban counterparts, a reorientation of the health policy-making for Chinese rural areas is recommended. This study suggests that urban-rural disparity about health literacy risk factors should be considered when implementing health literacy promotion intervention.