Identification of and Mechanistic Insights into SARS-CoV-2 Main Protease Non-Covalent Inhibitors: An In-Silico Study.

The indispensable role of the SARS-CoV-2 main protease (Mpro) in the viral replication cycle and its dissimilarity to human proteases make Mpro a promising drug target. In order to identify the non-covalent Mpro inhibitors, we performed a comprehensive study using a combined computational strategy. We first screened the ZINC purchasable compound database using the pharmacophore model generated from the reference crystal structure of Mpro complexed with the inhibitor ML188. The hit compounds were then filtered by molecular docking and predicted parameters of drug-likeness and pharmacokinetics. The final molecular dynamics (MD) simulations identified three effective candidate inhibitors (ECIs) capable of maintaining binding within the substrate-binding cavity of Mpro. We further performed comparative analyses of the reference and effective complexes in terms of dynamics, thermodynamics, binding free energy (BFE), and interaction energies and modes. The results reveal that, when compared to the inter-molecular electrostatic forces/interactions, the inter-molecular van der Waals (vdW) forces/interactions are far more important in maintaining the association and determining the high affinity. Given the un-favorable effects of the inter-molecular electrostatic interactions-association destabilization by the competitive hydrogen bond (HB) interactions and the reduced binding affinity arising from the un-compensable increase in the electrostatic desolvation penalty-we suggest that enhancing the inter-molecular vdW interactions while avoiding introducing the deeply buried HBs may be a promising strategy in future inhibitor optimization.

Qualitative descriptive study during the COVID-19 pandemic on the needs of informal caregivers of Chinese minors who underwent craniopharyngioma surgery.

PURPOSE: To determine the needs of informal caregivers during the long-term health management of minors who have undergone craniopharyngioma surgery. Design and methodology This is a qualitative and descriptive research study. Purposive sampling was used to select participants, and semi-structured interviews were conducted to explore the needs of 21 informal caregivers for postoperative minors. Due to the COVID-19 pandemic, the respondents were provided with the options of online video call or offline one-on-one interviews. Following this, a content analysis method was conducted. RESULTS: Four themes and 14 sub-themes were extracted from the results of the study, including needs for relieving psychological stress (including psychological pressure on both minors and on caregivers); requirement for on-campus assistance (physical activity, eliminating verbal violence in schools, special education needs for child, healthcare services provided by school hospitals); demands for medical help (acquiring medical knowledge, need for medication management, convenience and reliable access to medical services, need for technological development, expectations of multidisciplinary cooperation, the necessity of health review reminders); and the desire for financial aid (charity platform assistance, inclination of government policy). CONCLUSIONS: In China, informal caregivers of young patients with onset craniopharyngioma require both the multidisciplinary cooperation of medical institutions and the multi-departmental cooperation of society. Information and medical technology advancements may benefit families with young patients. Improving community hospitals' medical services and encouraging the practical use of online medical treatment and prescriptions are both necessary in the context of COVID-19. PRACTICE IMPLICATIONS: By identifying the needs of informal caregivers, medical professionals are able to develop care plans and interventions aimed at reducing the burden of care for minors who have undergone craniopharyngioma surgery.

Molecular characteristics of ambient organic aerosols in Shanghai winter before and after the COVID-19 outbreak.

During the global pandemic of COVID-19, the world adopted different strategies to avoid the human and economic loss, and so does China. The reduction of human activities during this time period caused reduction in PM emissions. This study adopted a HPLC-Q-TOF-MS to compare the chemical compositions of ambient aerosol samples collected in Shanghai winter before (2018, 2019) and after (2021) the COVID-19 outbreak. The identified compositions were classified into subgroups of CHO, CHN, CHON, CHONS, CHOS and CHN compounds. Results showed that CHO compounds and CHON compounds were dominating the organic compounds in ESI- and ESI+, respectively. The average percentages of CHO- compounds were 57.97 % in 2018, 58.98 % in 2019, and 43.93 % in 2021, respectively. The average percentages of CHON+ compounds were 52.74 % in 2018, 50.34 % in 2019, and 52.02 % in 2021, respectively. The proportion of aliphatic compounds increased gradually during the three years, especially in 2021, indicating that CHO compounds were less affected by aromatic precursors after the COVID-19 outbreak. The contribution of anthropogenic emissions in Shanghai was weakened compared with the previous years. In addition, there was an enhanced emission source containing hydroxyl for CHOS compound formation in 2021. The variations of atmospheric oxidation degree among the three years were not significant.

Medical emergency calls and calls for central nervous system symptoms during the COVID-19 outbreak in Hangzhou, China.

Background: Since January 2020, the continuous and severe COVID-19 epidemic has ravaged various countries around the world and affected their emergency medical systems (EMS). The total number of emergency calls and the number of emergency calls for central nervous system (CNS) symptoms during the 2020 COVID-19 outbreak in Hangzhou, China (January 20-March 20) were investigated, and it was investigated whether these numbers had decreased as compared with the corresponding period in 2019. Methods: The number of daily emergency calls, ambulance dispatches, and rescues at the Hangzhou Emergency Center (HEC) was counted. The CNS symptoms considered in this study included those of cerebrovascular diseases, mental and behavioral disorders, and other neurological diseases. Results: It was found that, during the 2020 study period, the number of emergency calls was 33,563, a decrease of 19.83% (95% CI: 14.02-25.41%) as compared to the 41,863 emergency calls in 2019 (P < 0.01). The number of ambulances dispatched was 10,510, a decrease of 25.55% (95 %CI: 18.52-35.11%) as compared to the 14,117 ambulances dispatched in 2019 (P < 0.01). The number of rescues was 7,638, a decrease of 19.67% (95% CI: 16.12-23.18%) as compared with the 9,499 rescues in 2019 (P < 0.01). It was also found that the number of emergency calls related to CNS symptoms, including symptoms of cerebrovascular diseases, mental and behavioral disorders, and other neurological diseases, was significantly reduced (P < 0.01). Conclusion: The total number of medical emergency calls and the number of emergency calls for CNS symptoms occurring in a large city in China decreased significantly during the COVID-19 epidemic.

Risk factors for pulmonary embolism in patients with COVID-19: a systemic review and meta-analysis.

PURPOSE: To detect the risk factors for pulmonary embolism (PE) in patients with COVID-19. METHODS: Studies were searched for in PubMed, Cochrane Library, Web of Science, and EMBASE. Two authors independently screened articles and extracted data. The data were pooled by meta-analysis and three subgroup analyses were performed. RESULTS: Of the 2210 articles identified, 27 studies were included. Pooled analysis suggested that males (odds ratio (OR) 1.49, 95% confidence interval (CI) 1.26-1.75, P = 0.000), obesity (OR 1.37, 95% CI 1.03-1.82, P = 0.033), mechanical ventilation (OR 3.34, 95% CI 1.90-5.86, P = 0.000), severe parenchymal abnormalities (OR 1.92, 95% CI 1.43-2.58, P = 0.000), ICU admission (OR 2.44, 95% CI 1.48-4.03, P = 0.000), and elevated D-dimer and white blood cell values (at two time points: hospital admission or closest to computed tomography pulmonary angiography) (P = 0.000) correlated with a risk for PE occurrence in COVID-19 patients. However, age and common comorbidities had no association with PE occurrence. Computed tomography pulmonary angiography, unclear-ratio/low-ratio, and hospitalization subgroups had consistent risk factors with all studies; however, other subgroups had fewer risk factors for PE. CONCLUSIONS: Risk factors for PE in COVID-19 were different from the classic risk factors for PE and are likely to differ in diverse study populations.

Strong displayed passion and preparedness of broadcaster in live streaming e-commerce increases consumers' neural engagement

Live streaming shopping, the streaming of real-time videos promoting products that consumers can purchase online, has recently been a booming area of e-commerce, especially during the COVID-19 pandemic. The success of live streaming e-commerce largely relies on the extent to which the broadcaster can get consumers engaged by the live stream. Thus, it is important to discover the antecedents of consumer engagement in such a context. Drawing on consumer engagement and neuroscience literature, this study used electroencephalography inter-subject correlation (EEG-ISC) to explore how broadcasters' entrepreneurial passion during live streaming videos influenced consumers' neural engagement as they watched the live streaming videos. We used the framework of displayed passion and preparedness from the entrepreneurial passion literature to predict consumer engagement. We found significant ISC for strong displayed passion, while preparedness had partially significant effects on the first, second, and summed components of ISC. The interaction effects of these two factors on the first and summed components of ISC were partially significant. Strong displayed passion and preparedness activated the left and right prefrontal regions of the consumers' brains. These findings indicate that broadcasters' displayed passion and preparedness can influence consumer engagement in live streaming e-commerce settings. Our findings suggest that a scientific approach could be used to improve a broadcaster's performance by testing ISC during rehearsals before live streaming.

Assessing the "negative effect" and "positive effect" of COVID-19 in China.

The COVID-19 pandemic lockdowns led to a sharp drop in socio-economic activities in China in 2020, including reductions in fossil fuel use, industry productions, and traffic volumes. China's economy suffered a serious negative effect from COVID-19. However, there is a "positive effect" on CO2 emissions reduction. Here, for the first time, this paper constructs a new model named "Weighted Multi-regional Hypothetical Extraction Method (WMHEM)" based on a multiregional input-output model. It not only solves the problems of traditional HEM methods such as improper use of assumptions, excessive reliance on industry intermediate input, but also accurately reflects the impact of external shocks on the inter-industry linkages. By using the monthly economic data of each provinces in China during COVID-19 (except Hong Kong，Macao and Taiwan) an the latest Multi-regional input-output tables, the "economic negative effect" and "CO2 emission positive effect" under COVID-19 in China are measured. Results show that COVID-19 lockdown was estimated to have reduced China's CO2 emissions substantially between January and March in 2020, with the largest reductions in February. With the spread of coronavirus controlled, China's CO2 emissions rebounded in April. In addition, key emission reduction sectors and key development encouraged sectors are selected by combining "economic negative effect" and "CO2 emission positive effect" during COVID-19. Therefore, policies recommendations are put forward based on forward and backward linkages respectively which are from two ends of the supply chain to turn pandemic-related CO2 emissions declines into firm climate action.

Safety and immunogenicity of a broad-spectrum mosaic vaccine as a booster dose against SARS-CoV-2 Omicron and other circulating variants (preprint)

BACKGROUNDThe rising breakthrough infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, especially Omicron and its sub-lineages, have raised an urgent need to develop broad-spectrum vaccines against coronavirus disease 2019 (COVID-19). We have developed a mosaic-type recombinant vaccine candidate, named NVSI-06-09, having immune potentials against a broad range of SARS-CoV-2 variants. METHODSAn ongoing randomized, double-blind, controlled phase 2 trial was conducted to evaluate the safety and immunogenicity of NVSI-06-09 as a booster dose in subjects aged 18 years and older from the United Arab Emirates (UAE), who had completed two or three doses of BBIBP-CorV vaccinations at least 6 months prior to the enrollment. The participants were randomly assigned with 1:1 to receive a booster dose of NVSI-06-09 or BBIBP-CorV. The primary outcomes were immunogenicity and safety against SARS-CoV-2 Omicron variant, and the exploratory outcome was cross-immunogenicity against other circulating strains. RESULTSA total of 516 participants received booster vaccination. Interim results showed a similar safety profile between NVSI-06-09 and BBIBP-CorV booster groups, with low incidence of adverse reactions of grade 1 or 2. For immunogenicity, by day 14 after the booster vaccination, the fold rises in neutralizing antibody geometric mean titers (GMTs) from baseline level elicited by NVSI-06-09 were remarkably higher than those by BBIBP-CorV against the prototype strain (19.67 vs 4.47-fold), Omicron BA.1.1 (42.35 vs 3.78-fold), BA.2 (25.09 vs 2.91-fold), BA.4 (22.42 vs 2.69-fold), and BA.5 variants (27.06 vs 4.73-fold). Similarly, the neutralizing GMTs boosted by NVSI-06-09 against Beta and Delta variants were also 6.60-fold and 7.17-fold higher than those boosted by BBIBP-CorV. CONCLUSIONSA booster dose of NVSI-06-09 was well-tolerated and elicited broad-spectrum neutralizing responses against SARS-CoV-2 prototype strain and immune-evasive variants, including Omicron and its sub-lineages. The immunogenicity of NVSI-06-09 as a booster vaccine was superior to that of BBIBP-CorV. (Funded by LIBP and BIBP of Sinopharm; ClinicalTrials.gov number, NCT05293548).

Explore the attitudes of children and adolescent parents towards the vaccination of COVID-19 in China.

BACKGROUND: With the increasing incidence of asymptomatic carriers or milder symptoms, children and adolescents are likely to become a silent source of infection. In view of the efficacy and safety of vaccines in the treatment of novel Coronavirus pneumonia, population-wide vaccination will be an inevitable trend to control the spread of COVID-19. However, there is no survey on the attitudes of Chinese parents of children and adolescents towards their children's COVID-19 vaccination. METHODS: We used online questionnaires to find out the attitudes of Chinese parents toward their children's immunization against COVID-19. Logistic regression was used to explore the influencing factors. RESULTS: A total of 2019 parents participated in the survey. Overall, 74.38% parents said they would actively get vaccinated, 8.90% refused to get vaccinated, 4.60% said they would delay vaccination and 12.12% were still undecided. CONCLUSIONS: In general, Chinese parents have a high desire to be vaccinated against COVID-19, and most parents have a positive attitude towards their children's vaccination. However, many people still hesitate or even refuse to be vaccinated. Education background, attitudes towards children's vaccination, children's age, recent illness and other factors have a certain impact on Chinese parents of children and adolescents towards their children's COVID-19 vaccination.

Mechanistic Origin of Different Binding Affinities of SARS-CoV and SARS-CoV-2 Spike RBDs to Human ACE2.

The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (RBDCoV2) has a higher binding affinity to the human receptor angiotensin-converting enzyme 2 (ACE2) than the SARS-CoV RBD (RBDCoV). Here, we performed molecular dynamics (MD) simulations, binding free energy (BFE) calculations, and interface residue contact network (IRCN) analysis to explore the mechanistic origin of different ACE2-binding affinities of the two RBDs. The results demonstrate that, when compared to the RBDCoV2-ACE2 complex, RBDCoV-ACE2 features enhanced dynamicsand inter-protein positional movements and increased conformational entropy and conformational diversity. Although the inter-protein electrostatic attractive interactions are the primary determinant for the high ACE2-binding affinities of both RBDs, the significantly enhanced electrostatic attractive interactions between ACE2 and RBDCoV2 determine the higher ACE2-binding affinity of RBDCoV2 than of RBDCoV. Comprehensive comparative analyses of the residue BFE components and IRCNs between the two complexes reveal that it is the residue changes at the RBD interface that lead to the overall stronger inter-protein electrostatic attractive force in RBDCoV2-ACE2, which not only tightens the interface packing and suppresses the dynamics of RBDCoV2-ACE2, but also enhances the ACE2-binding affinity of RBDCoV2. Since the RBD residue changes involving gain/loss of the positively/negatively charged residues can greatly enhance the binding affinity, special attention should be paid to the SARS-CoV-2 variants carrying such mutations, particularly those near or at the binding interfaces with the potential to form hydrogen bonds and/or salt bridges with ACE2.

Explore the attitudes of children and adolescent parents towards the vaccination of COVID-19 in China (preprint)

Background With the increasing incidence of asymptomatic carriers or milder symptoms, children and adolescents are likely to become a silent source of infection. In view of the efficacy and safety of vaccines in the treatment of novel Coronavirus pneumonia, population-wide vaccination will be an inevitable trend to control the spread of COVID-19. However, there is no survey on the attitudes of Chinese parents of children and adolescents towards their children's COVID-19 vaccination.Methods We used online questionnaires to find out the attitudes of Chinese parents toward their children's immunization against COVID-19. Logistic regression was used to explore the influencing factors.Results A total of 2019 parents participated in the survey. Overall, 74.38% parents said they would actively get vaccinated, 8.90% refused to get vaccinated, 4.60% said they would delay vaccination and 12.12% were still undecided.Conclusions In general, Chinese parents have a high desire to be vaccinated against COVID-19, and most parents have a positive attitude towards their children's vaccination. However, many people still hesitate or even refuse to be vaccinated. Education background, attitudes towards children's vaccination, children's age, recent illness and other factors have a certain impact on Chinese parents of children and adolescents towards their children's COVID-19 vaccination.

Air Quality During The COVID-19 Epidemic in China (preprint)

At the end of 2019, the COVID-19 emerged in Wuhan, China. It has since put global public health institutions on high alert. People reduced their traveling, and production has stopped nationwide during the epidemic. This paper explores the effect of these COVID-19-derived changes on the air quality in China. Air quality data of 367 cities around China were included. The daily air pollutants concentration (AQI,CO, O3, NO2, SO2, PM10, and PM2.5) were collected. We compared the air quality changes between three periods (23.1.2019-23.3.2019, 22.11.2019-22.1.2020, and 23.1.2020–23.3.2020). To compare, we calculated the daily average number of cities with pollution, and the trend in air quality index change. Furthermore, Air quality in the top 50 cities with confirmed cases and Wuhan was analyzed. During the period between 23.1.2020 and 23.3.2020, the number of cities with excellent air quality was significantly higher than that in another two periods. The concentrations of PM2.5, PM10, NO2, SO2, CO, and O3 decreased significantly during the COVID-19 epidemic. The most significant decreases were in PM10 and NO2. The number of cities with good air quality in the later period was significantly higher than that a year before. The air quality has improved significantly during the COVID-19 outbreak, The reason for this change may be human activities such as reduced transportation and production stoppage.

Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19：a meta-analysis.

BACKGROUND: The coronavirus disease (COVID-19) epidemic has not been completely controlled. Although great achievements have been made in COVID-19 research and many antiviral drugs have shown good therapeutic effects against COVID-19, a simple oral antiviral drug for COVID-19 has not yet been developed. We conducted a meta-analysis to investigate the improvement in mortality or hospitalization rates and adverse events among COVID-19 patients with three new oral antivirals (including molnupiravir, fluvoxamine and Paxlovid). METHODS: We searched scientific and medical databases, such as PubMed, Web of Science, Embase and Cochrane Library for relevant articles and screened the references of retrieved studies on COVID-19. RESULTS: A total of eight studies were included in this study. The drug group included 2440 COVID-19 patients, including 54 patients who died or were hospitalized. The control group included a total of 2348 COVID-19 patients, including 118 patients who died or were hospitalized. The overall odds ratio (OR) of mortality or hospitalization was 0.33 (95% confidence interval [CI], 0.22-0.49) for COVID-19 patients in the drug group and placebo group, indicating that oral antiviral drugs were effective for COVID-19 patients and reduced the mortality or hospitalization by approximately 67%. CONCLUSIONS: This study showed that three novel oral antivirals (molnupiravir, fluvoxamine and Paxlovid) are effective in reducing the mortality and hospitalization rates in patients with COVID-19. In addition, the three oral drugs did not increase the occurrence of adverse events, thus exhibiting good overall safety. These three oral antiviral drugs are still being studied, and the available data suggest that they will bring new hope for COVID-19 recovery and have the potential to be a breakthrough and very promising treatment for COVID-19.KEY MESSAGESMany antiviral drugs have shown good therapeutic effects, and there is no simple oral antiviral drug for COVID-19 patients.Meta-analysis was conducted for three new oral antivirals to evaluate the improvement in mortality or hospitalization rates and adverse events among COVID-19 patients.We focussed on three new oral Coronavirus agents (molnupiravir, fluvoxamine and Paxlovid) and hope to provide guidance for the roll-out of oral antivirals.

Mechanistic origin of different binding affinities of SARS-CoV and SARS-CoV-2 spike RBDs to human ACE2 (preprint)

The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein mediates viral entry into host cells through binding to the cell-surface receptor angiotensin-converting enzyme 2 (ACE2). It has been shown that SARS-CoV-2 RBD (RBDCoV2) has a higher binding affinity to human ACE2 than its highly homologous SARS-CoV RBD (RBDCoV), for which the mechanistic reasons still remain to be elucidated. Here, we used the multiple-replica molecular dynamics (MD) simulations, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations, and interface residue contact network (IRCN) analysis approach to explore the mechanistic origin of different ACE2 binding affinities of these two RBDs. The results demonstrate that, when compared to the RBDCoV2-ACE2 complex, the RBDCoV-ACE2 complex features the enhanced overall structural fluctuations and inter-protein positional movements and increased conformational entropy and diversity. The inter-protein electrostatic attractive interactions are a dominant force in determining the high ACE2 affinities of both RBDs, while the significantly strengthened electrostatic forces of attraction of ACE2 to RBDCoV2 determine the higher ACE2 binding affinity of RBDCoV2 than of RBDCoV. Comprehensive comparative analyses of the residue binding free energy components and IRCNs reveal that, although any RBD residue substitution involved in the charge change can significantly impact the inter-protein electrostatic interaction strength, it is the substitutions at the RBD interface that lead to the overall stronger electrostatic attractive force of RBDCoV2-ACE2, which in turn not only tightens the interface packing and suppresses the dynamics of RBDCoV2-ACE2, but also enhances the ACE2 binding affinity of RBDCoV2 compared to that of RBDCoV. Since the RBD residue substitutions involving gain/loss of the positively/negatively charged residues, in particular those near/at the binding interfaces with the potential to form hydrogen bonds and/or salt bridges with ACE2, can greatly enhance the ACE2 binding affinity, the SARS-CoV-2 variants carrying such mutations should be paid special attention to.