Combining virtual screening with cis-/trans-cleavage enzymatic assays effectively reveals broad-spectrum inhibitors that target the main proteases of SARS-CoV-2 and MERS-CoV.

The main protease (Mpro) of SARS-CoV-2 is essential for viral replication, which suggests that the Mpro is a critical target in the development of small molecules to treat COVID-19. This study used an in-silico prediction approach to investigate the complex structure of SARS-CoV-2 Mpro in compounds from the United States National Cancer Institute (NCI) database, then validate potential inhibitory compounds against the SARS-CoV-2 Mpro in cis- and trans-cleavage proteolytic assays. Virtual screening of ∼280,000 compounds from the NCI database identified 10 compounds with highest site-moiety map scores. Compound NSC89640 (coded C1) showed marked inhibitory activity against the SARS-CoV-2 Mpro in cis-/trans-cleavage assays. C1 strongly inhibited SARS-CoV-2 Mpro enzymatic activity, with a half maximal inhibitory concentration (IC50) of 2.69 µM and a selectivity index (SI) of >74.35. The C1 structure served as a template to identify structural analogs based on AtomPair fingerprints to refine and verify structure-function associations. Mpro-mediated cis-/trans-cleavage assays conducted with the structural analogs revealed that compound NSC89641 (coded D2) exhibited the highest inhibitory potency against SARS-CoV-2 Mpro enzymatic activity, with an IC50 of 3.05 µM and a SI of >65.57. Compounds C1 and D2 also displayed inhibitory activity against MERS-CoV-2 with an IC50 of <3.5 µM. Thus, C1 shows potential as an effective Mpro inhibitor of SARS-CoV-2 and MERS-CoV. Our rigorous study framework efficiently identified lead compounds targeting the SARS-CoV-2 Mpro and MERS-CoV Mpro.

Associations between brain gene expression perturbations implicated by COVID-19 and psychiatric disorders.

BACKGROUND: Currently, there is increasing evidence from clinic, epidemiology, as well as neuroimaging, demonstrating neuropsychiatric abnormalities in COVID-19, however, whether there were associations between brain changes caused by COVID-19 and genetic susceptibility of psychiatric disorders was still unknown. METHODS: In this study, we performed a meta-analysis to investigate these associations by combing single-cell RNA sequencing datasets of brain tissues of COVID-19 and genome-wide association study summary statistics of psychiatric disorders. RESULTS: The analysis demonstrated that among ten psychiatric disorders, gene expression perturbations implicated by COVID-19 in excitatory neurons of choroid plexus were significantly associated with schizophrenia. CONCLUSIONS: Our analysis might provide insights for the underlying mechanism of the psychiatric consequence of COVID-19.

Impacts of COVID-19 on a mathematics graduate programme

In this study, performance data from students on a mathematics graduate programme from Spring 2019 to Spring 2020 were collected and analysed. The results showed that, if the right course delivery method was implemented, the impact of the coronavirus pandemic (COVID-19) on students' performance could be minimal. Based on the study, some recommendations are made on how to improve students' performances in graduate-level mathematics courses.

Associations between brain gene expression perturbations implicated by COVID-19 and psychiatric disorders

Background Currently, there is increasing evidence from clinic, epidemiology, as well as neuroimaging, demonstrating neuropsychiatric abnormalities in COVID-19, however, whether there were associations between brain changes caused by COVID-19 and genetic susceptibility of psychiatric disorders was still unknown. Methods In this study, we performed a meta-analysis to investigate these associations by combing single-cell RNA sequencing datasets of brain tissues of COVID-19 and genome-wide association study summary statistics of psychiatric disorders. Results The analysis demonstrated that among ten psychiatric disorders, gene expression perturbations implicated by COVID-19 in excitatory neurons of choroid plexus were significantly associated with schizophrenia. Conclusions Our analysis might provide insights for the underlying mechanism of the psychiatric consequence of COVID-19.

Analysis of serum SARS-CoV-2 antibody IgG tests after booster vaccination of COVID-19 vaccine in 205 individuals

Objective To analyze IgG test results of serum SARS-CoV-2 antibody in people after booster vaccinations against SARS-CoV-2, and to provide a basis for the booster vaccination. Methods There were 314 healthy individuals who had been vaccinated with the COVID-19 vaccine. Depending on their inoculation situation, they were divided into three groups:the booster injection group(1 week to 2 months after booster vaccination)of 205 cases, <180 days after two doses group(<180 days after two doses of COVID-19 vaccine)of 49 cases, and >180 days after two doses group(>180 days after two doses of COVID-19 vaccine)of 60 cases. The positive rate of IgG in serum of the three groups was measured using the colloidal gold method. Results The serum COVID-19 antibody IgG positive rates were 83.9% in the booster injection group, 18.4% in the <180 days after two doses group, and 5.0% in the >180 days after two doses group, with statistically significant difference between any two groups(all P < 0.05). In the booster injection group, the serum COVID-19 antibody IgG positive rate was 85.2% in people who received a booster injection more than a month, while those who received a booster injection less than a month had a positive rate of 75.9%, and there was no significant difference between these two groups(P > 0.05). In the booster injection group, the positive rates of serum COVID-19 antibody IgG were 85.1% in males and 82.4% in females, with no significant difference(P > 0.05). In the booster injection group, people at the age of 18 and 50 had a positive serum COVID-19 antibody IgG rate of 86.0%, while those over 50 had a positive rate of 58.3%, and there was significant difference between them(P < 0.05). Conclusions Compared with two injections of the COVID-19 vaccine, the booster injection can significantly increase the positive rate of the antibody IgG of COVID-19, which results in a stronger immune response. There is a lower IgG positive rate of COVID-19 antibodies in those aged over 50 years following the booster dose of COVID-19 vaccine than in those aged 18- 50 years.

Effects of psychosocial function in pediatric-onset inflammatory bowel disease during the coronavirus disease 2019 pandemic.

Background and Aims: Research on the effect of the coronavirus disease 2019 (COVID-19) pandemic on psychosocial function in patients with pediatric-onset inflammatory bowel disease (PIBD) is limited. This study aimed to evaluate the psychological status of patients with PIBD before and during the pandemic, and the relationship between mental health and disease activity. Methods: This study was a retrospective cohort study. Statistical analyses were performed to assess the relationship between demographic, clinical data and psychological data (questionnaires) of PIBD patients before and during the epidemic. The anxiety and depression emotional status of the guardians during the pandemic were evaluated. Results: In the PIBD follow-up cohort, 42 patients(male 61.9%) were included. Female with PIBD had lower pediatric quality of life inventory(PedsQL) scores (P = 0.007) and higher spence children's anxiety scale(SCAS) scores (P = 0.038) than male. The pandemic did not have a substantial impact on PedsQL, pittsburgh sleep quality index(PSQI), SCAS, or children's depression inventory(CDI) in patients with PIBD. The self-rating anxiety scale(SAS) score, anxiety rate, self-rating depression scale(SDS) score, and depression rate of PIBD guardians were significantly higher than those of healthy controls (SAS, P = 0.008; SDS, P = 0.001). Conclusions: Female children with PIBD were more vulnerable to decreased QOL and increased anxiety than male children. The anxiety and depression status of PIBD guardians were significantly higher than those of healthy controls during the COVID-19 pandemic. But the COVID-19 pandemic did not significantly affect quality of life(QOL), sleep, anxiety, or depressive mood of patients with PIBD in our study.

Hybridoma-derived neutralizing monoclonal antibodies against Beta and Delta variants of SARS-CoV-2 in vivo.

Neutralizing monoclonal antibodies (mAb) are a major therapeutic strategy for the treatment of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. The continuous emergence of new SARS-CoV-2 variants worldwide has increased the urgency for the development of new mAbs. In this study, we immunized mice with the receptor-binding domain (RBD) of the SARS-CoV-2 prototypic strain (WIV04) and screened 35 RBD-specific mAbs using hybridoma technology. Results of the plaque reduction neutralization test showed that 25 of the mAbs neutralized authentic WIV04 strain infection. The 25 mAbs were divided into three categories based on the competitive enzyme-linked immunosorbent assay results. A representative mAb was selected from each category (RD4, RD10, and RD14) to determine the binding kinetics and median inhibitory concentration (IC50) of WIV04 and two variants of concern (VOC): B.1.351 (Beta) and B.1.617.2 (Delta). RD4 neutralized the B.1.617.2 variant with an IC50 of 2.67 â€‹ng/mL; however, it completely lost neutralizing activity against the B.1.351 variant. RD10 neutralized both variants with an IC50 exceeding 100 â€‹ng/mL; whereas RD14 neutralized two variants with a higher IC50 (>1 â€‹mg/mL). Animal experiments were performed to evaluate the protective effects of RD4 and RD10 against various VOC infections. RD4 could protect Adv-hACE2 transduced mice from B.1.617.2 infection at an antibody concentration of 25 â€‹mg/kg, while RD10 could protect mice from B.1.351 infection at an antibody concentration of 75 â€‹mg/kg. These results highlight the potential for future modifications of the mAbs for practical use.

Longitudinal Assessment of Chest CT Findings and Pulmonary Function after COVID-19 Infection.

Background Information on pulmonary sequelae and pulmonary function 2 years after recovery from SARS-CoV-2 infection is lacking. Purpose To longitudinally assess changes in chest CT abnormalities and pulmonary function in individuals after SARS-CoV-2 infection. Materials and Methods In this prospective study, participants discharged from the hospital after SARS-CoV-2 infection from January 20 to March 10, 2020, were considered for enrollment. Participants without chest CT scans at admission or with complete resolution of lung abnormalities at discharge were excluded. Serial chest CT scans and pulmonary function test results were obtained 6 months (June 20 to August 31, 2020), 12 months (December 20, 2020, to February 3, 2021), and 2 years (November 16, 2021, to January 10, 2022) after symptom onset. The term interstitial lung abnormality (ILA) and two subcategories, fibrotic ILAs and nonfibrotic ILAs, were used to describe residual CT abnormalities on follow-up CT scans. Differences between groups were compared with the χ2 test, Fisher exact test, or independent samples t test. Results Overall, 144 participants (median age, 60 years [range, 27-80 years]; 79 men) were included. On 2-year follow-up CT scans, 39% of participants (56 of 144) had ILAs, including 23% (33 of 144) with fibrotic ILAs and 16% (23 of 144) with nonfibrotic ILAs. The remaining 88 of 144 participants (61%) showed complete radiologic resolution. Over 2 years, the incidence of ILAs gradually decreased (54%, 42%, and 39% of participants at 6 months, 12 months, and 2 years, respectively; P < .001). Respiratory symptoms (34% vs 15%, P = .007) and abnormal diffusing capacity of lung for carbon monoxide (43% vs 20%, P = .004) occurred more frequently in participants with ILAs than in those with complete radiologic resolution. Conclusion More than one-third of participants had persistent interstitial lung abnormalities 2 years after COVID-19 infection, which were associated with respiratory symptoms and decreased diffusion pulmonary function. Chinese Clinical Trial Registry no. ChiCTR2000038609 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by van Beek in this issue.

Deep Learning for Detecting COVID-19 Using Medical Images.

The global spread of COVID-19 (also known as SARS-CoV-2) is a major international public health crisis [...].

The impact of COVID-19 on firm risk and performance in MENA countries: Does national governance quality matter?

This study investigated the impact of the COVID-19 crisis on firm risk and performance in different country-level governance qualities in the MENA region. Analyzing a sample of 739 non-financial listed firms in 12 MENA countries for the period 2011-2020, we found that the COVID-19 crisis negatively impacted the performance of firms, especially low-performance firms, in most industries, and increased firm risk in general. Moreover, we found that national governance quality plays an important role in mitigating the negative impact of the COVID-19 crisis on firm operations. Specifically, national governance quality reduces the negative impact of the COVID-19 crisis on firm performance and the positive impact of the crisis on firm risk. The results are consistent with our contention that national governance quality contributes to creating a positive environment for businesses activities and reducing economic shocks.

Systemic Lupus Erythematosus Risk: The Role of Environmental Factors.

Systemic lupus erythematosus (SLE) is a complex, chronic autoimmune disease. The etiology of SLE is multifactorial and includes potential environmental triggers, which may occur sequentially (the "multi-hit" hypothesis). This review focuses on SLE risk potentially associated with environmental factors including infections, the microbiome, diet, respirable exposures (eg, crystalline silica, smoking, air pollution), organic pollutants, heavy metals, and ultraviolet radiation.

Internet of medical things-enabled CRISPR diagnostics for rapid detection of SARS-CoV-2 variants of concern.

Previous studies have highlighted CRISPR-based nucleic acid detection as rapid and sensitive diagnostic methods for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we reported an optimized CRISPR-Cas12a diagnostic platform for the safe and rapid detection of SARS-CoV-2 variants of concern (VOCs). This platform, which was referred to as CALIBURN-v2, could complete the diagnosis on extracted RNA samples within 25 min in a closed-lid reaction mode and had 100-fold increase in detection sensitivity in comparison with previous platforms. Most importantly, by integrating a portable device and smartphone user interface, CALIBURN-v2 allowed for cloud server-based data collection and management, thus transforming the point-of-care testing (POCT) platform to internet of medical things (IoMT) applications. It was found that IoMT-enabled CALIBURN-v2 could achieve 95.56% (172 out of 180) sensitivity for SARS-CoV-2 wild type and 94.38% (84 out of 89) overall sensitivity for SARS-CoV-2 variants including Delta and Omicron strains. Therefore, our study provides a feasible approach for IoMT-enabled CRISPR diagnostics for the detection of SARS-CoV-2 VOCs.

Estimating the restraint of SARS-CoV-2 spread using a conventional medical air-cleaning device: Based on an experiment in a typical dental clinical setting.

OBJECTIVES: Droplets or aerosols loaded with SARS-CoV-2 can be released during breathing, coughing, or sneezing from COVID-19-infected persons. To investigate whether the most commonly applied air-cleaning device in dental clinics, the oral spray suction machine (OSSM), can provide protection to healthcare providers working in clinics against exposure to bioaerosols during dental treatment. METHOD: In this study, we measured and characterized the temporal and spatial variations in bioaerosol concentration and deposition with and without the use of the OSSM using an experimental design in a dental clinic setting. Serratia marcescens (a bacterium) and ΦX174 phage (a virus) were used as tracers. The air sampling points were sampled using an Anderson six-stage sampler, and the surface-deposition sampling points were sampled using the natural sedimentation method. The Computational Fluid Dynamics method was adopted to simulate and visualize the effect of the OSSM on the concentration spatial distribution. RESULTS: During dental treatment, the peak exposure concentration increased by up to 2-3 orders of magnitude (PFU/m3) for healthcare workers. Meanwhile, OSSM could lower the mean bioaerosol exposure concentration from 58.84 PFU/m3 to 4.10 PFU/m3 for a healthcare worker, thereby inhibiting droplet and airborne transmission. In terms of deposition, OSSM significantly reduced the bioaerosol surface concentration from 28.1 PFU/m3 to 2.5 PFU/m3 for a surface, effectively preventing fomite transmission. CONCLUSION: The use of OSSM showed the potential to restraint the spread of bioaerosols in clinical settings. Our study demonstrates that OSSM use in dental clinics can reduce the exposure concentrations of bioaerosols for healthcare workers during dental treatment and is beneficial for minimizing the risk of infectious diseases such as COVID-19.

Antiviral effects and tissue exposure of tetrandrine against SARS-CoV-2 infection and COVID-19.

Tetrandrine (TET) has been used to treat silicosis in China for decades. The aim of this study was to facilitate rational repurposing of TET against SARS-CoV-2 infection. In this study, we confirmed that TET exhibited antiviral potency against SARS-CoV-2 in the African green monkey kidney (Vero E6), human hepatocarcinoma (Huh7), and human lung adenocarcinoma epithelial (Calu-3) cell lines. TET functioned during the early-entry stage of SARS-CoV-2 and impeded intracellular trafficking of the virus from early endosomes to endolysosomes. An in vivo study that used adenovirus (AdV) 5-human angiotensin-converting enzyme 2 (hACE2)-transduced mice showed that although TET did not reduce pulmonary viral load, it significantly alleviated pathological damage in SARS-CoV-2-infected murine lungs. The systemic preclinical pharmacokinetics were investigated based on in vivo and in vitro models, and the route-dependent biodistribution of TET was explored. TET had a large volume of distribution, which contributed to its high tissue accumulation. Inhaled administration helped TET target the lung and reduced its exposure to other tissues, which mitigated its off-target toxicity. Based on the available human pharmacokinetic data, it appeared feasible to achieve an unbound TET 90% maximal effective concentration (EC90) in human lungs. This study provides insights into the route-dependent pulmonary biodistribution of TET associated with its efficacy.

Shortening the biologics clinical timeline with a novel method for generating stable, high-producing cell pools and clones.

Reducing drug development timelines is an industry-wide goal to bring medicines to patients in need more quickly. This was exemplified in the coronavirus disease 2019 pandemic where reducing development timelines had a direct impact on the number of lives lost to the disease. The use of drug substances produced using cell pools, as opposed to clones, has the potential to shorten development timelines. Toward this goal, we have developed a novel technology, GPEx® Lightning, that allows for rapid, reproducible, targeted recombination of transgenes into more than 200 Dock sites in the Chinese hamster ovary cell line genome. This allows for rapid production of high-expressing stable cell pools and clones that reach titers of 4-12 g/l in generic fed-batch production. These pools and clones are highly stable in both titer and glycosylation, showing strong similarities in glycosylation profiles.

Primary Care Physicians' and Patients' Perspectives on Equity and Health Security of Infectious Disease Digital Surveillance.

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic facilitated the rapid development of digital detection surveillance (DDS) for outbreaks. This qualitative study examined how DDS for infectious diseases (ID) was perceived and experienced by primary care physicians and patients in order to highlight ethical considerations for promoting patients' autonomy and health care rights. METHODS: In-depth interviews were conducted with a purposefully selected group of 16 primary care physicians and 24 of their patients. The group was reflective of a range of ages, educational attainment, and clinical experiences from urban areas in northern and southern China. Interviews were audio recorded, transcribed, and translated. Two researchers coded data and organized it into themes. A third researcher reviewed 15% of the data and discussed findings with the other researchers to assure accuracy. RESULTS: Five themes were identified: ambiguity around the need for informed consent with usage of DDS; importance of autonomous decision making; potential for discrimination against vulnerable users of DDS for ID; risk of social inequity and disparate care outcomes; and authoritarian institutions' responsibility for maintaining health data security. The adoption of DDS meant some patients would be reluctant to go to the hospital for fear of either being discriminated against or forced into quarantine. Certain groups (older people and children) were thought to be vulnerable to DDS misappropriation. CONCLUSIONS: These findings indicate the paramount importance of establishing national and international ethical frameworks for DDS implementation. Frameworks should guide all aspects of ID surveillance, addressing privacy protection and health security, and underscored by principles of social equity and accountability.Annals "Online First" article.