Relationship between cognitive dysfunction and the promoter methylation of PER1 and CRY1 in patients with cerebral small vessel disease.

Background and purpose: The prevalence of cerebral small vessel disease (CSVD) is increasing due to the accelerating global aging process, resulting in a substantial burden on all countries, as cognitive dysfunction associated with CSVD is also on the rise. Clock genes have a significant impact on cognitive decline and dementia. Furthermore, the pattern of DNA methylation in clock genes is strongly associated with cognitive impairment. Thus, the aim of this study was to explore the connection between DNA promoter methylation of PER1 and CRY1 and cognitive dysfunction in patients with CSVD. Methods: We recruited patients with CSVD admitted to the Geriatrics Department of the Lianyungang Second People's Hospital between March 2021 and June 2022. Based on their Mini-Mental State Examination score, patients were categorized into two groups: 65 cases with cognitive dysfunction and 36 cases with normal cognitive function. Clinical data, 24-h ambulatory blood pressure monitoring parameters, and CSVD total load scores were collected. Moreover, we employed methylation-specific PCR to analyze the peripheral blood promoter methylation levels of clock genes PER1 and CRY1 in all CSVD patients who were enrolled. Finally, we used binary logistic regression models to assess the association between the promoter methylation of clock genes (PER1 and CRY1) and cognitive dysfunction in patients with CSVD. Results: (1) A total of 101 individuals with CSVD were included in this study. There were no statistical differences between the two groups in baseline clinical data except MMSE and AD8 scores. (2) After B/H correction, the promoter methylation rate of PER1 was higher in the cognitive dysfunction group than that in the normal group, and the difference was statistically significant (adjusted p < 0.001). (3) There was no significant correlation between the promoter methylation rates of PER1 and CRY1 in peripheral blood and circadian rhythm of blood pressure (p > 0.05). (4) Binary logistic regression models showed that the influence of promoter methylation of PER1 and CRY1 on cognitive dysfunction were statistically significant in Model 1 (p < 0.001; p = 0.025), and it still existed after adjusting for confounding factors in Model 2. Patients with the promoter methylation of PER1 gene (OR = 16.565, 95%CI, 4.057-67.628; p < 0.001) and the promoter methylation of CRY1 gene (OR = 6.017, 95%CI, 1.290-28.069; p = 0.022) were at greater risk of cognitive dysfunction compared with those with unmethylated promoters of corresponding genes in Model 2. Conclusion: The promoter methylation rate of PER1 gene was higher in the cognitive dysfunction group among CSVD patients. And the hypermethylation of the promoters of clock genes PER1 and CRY1 may be involved in affecting cognitive dysfunction in patients with CSVD.

Adaptation of the infectious bronchitis virus H120 vaccine strain to Vero cell lines.

Infectious bronchitis virus (IBV) has restricted cell and tissue tropism. IBVs, except the Beaudette strain, can infect and replicate in chicken embryos, primary chicken embryo kidneys, and primary chicken kidney cells, only. The limited viral cell tropism of IBV substantially hinders in vitro cell-based research on pathogenic mechanisms and vaccine development. Herein, the parental H120 vaccine strain was serially passaged for five generations in chicken embryos, 20 passages in CK cells and 80 passages in Vero cells. This passaging yielded a Vero cell-adapted strain designated HV80. To further understand viral evolution, serial assessments of infection, replication, and transmission in Vero cells were performed for the viruses obtained every tenth passage. The ability to form syncytia and the replication efficiency significantly after the 50th passage (strain HV50). HV80 also displayed tropism extension to DF-1, BHK-21, HEK-293 T, and HeLa cells. Whole genome sequencing of viruses from every tenth generation revealed a total of 19 amino acid point mutations in the viral genome by passage 80, nine of which occurred in the S gene. The second furin cleavage site appeared in viral evolution and may be associated with cell tropism extension of HV80.

Low complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils.

The self-assembly of the Nucleocapsid protein (NCAP) of SARS-CoV-2 is crucial for its function. Computational analysis of the amino acid sequence of NCAP reveals low-complexity domains (LCDs) akin to LCDs in other proteins known to self-assemble as phase separation droplets and amyloid fibrils. Previous reports have described NCAP's propensity to phase-separate. Here we show that the central LCD of NCAP is capable of both, phase separation and amyloid formation. Within this central LCD we identified three adhesive segments and determined the atomic structure of the fibrils formed by each. Those structures guided the design of G12, a peptide that interferes with the self-assembly of NCAP and demonstrates antiviral activity in SARS-CoV-2 infected cells. Our work, therefore, demonstrates the amyloid form of the central LCD of NCAP and suggests that amyloidogenic segments of NCAP could be targeted for drug development.

Efficacy of SARS-CoV-2 vaccines and the dose-response relationship with three major antibodies: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: The efficacy of SARS-CoV-2 vaccines in preventing severe COVID-19 illness and death is uncertain due to the rarity of data in individual trials. How well the antibody concentrations can predict the efficacy is also uncertain. We aimed to assess the efficacy of these vaccines in preventing SARS-CoV-2 infections of different severities and the dose-response relationship between the antibody concentrations and efficacy. METHODS: We did a systematic review and meta-analysis of randomised controlled trials (RCTs). We searched PubMed, Embase, Scopus, Web of Science, Cochrane Library, WHO, bioRxiv, and medRxiv for papers published between Jan 1, 2020 and Sep 12, 2022. RCTs on the efficacy of SARS-CoV-2 vaccines were eligible. Risk of bias was assessed using the Cochrane tool. A frequentist, random-effects model was used to combine efficacy for common outcomes (ie, symptomatic and asymptomatic infections) and a Bayesian random-effects model was used for rare outcomes (ie, hospital admission, severe infection, and death). Potential sources of heterogeneity were investigated. The dose-response relationships of neutralising, spike-specific IgG and receptor binding domain-specific IgG antibody titres with efficacy in preventing SARS-CoV-2 symptomatic and severe infections were examined by meta-regression. This systematic review is registered with PROSPERO, CRD42021287238. FINDINGS: 28 RCTs (n=286 915 in vaccination groups and n=233 236 in placebo groups; median follow-up 1-6 months after last vaccination) across 32 publications were included in this review. The combined efficacy of full vaccination was 44·5% (95% CI 27·8-57·4) for preventing asymptomatic infections, 76·5% (69·8-81·7) for preventing symptomatic infections, 95·4% (95% credible interval 88·0-98·7) for preventing hospitalisation, 90·8% (85·5-95·1) for preventing severe infection, and 85·8% (68·7-94·6) for preventing death. There was heterogeneity in the efficacy of SARS-CoV-2 vaccines against asymptomatic and symptomatic infections but insufficient evidence to suggest whether the efficacy could differ according to the type of vaccine, age of the vaccinated individual, and between-dose interval (p>0·05 for all). Vaccine efficacy against symptomatic infection waned over time after full vaccination, with an average decrease of 13·6% (95% CI 5·5-22·3; p=0·0007) per month but can be enhanced by a booster. We found a significant non-linear relationship between each type of antibody and efficacy against symptomatic and severe infections (p<0·0001 for all), but there remained considerable heterogeneity in the efficacy, which cannot be explained by antibody concentrations. The risk of bias was low in most studies. INTERPRETATION: The efficacy of SARS-CoV-2 vaccines is higher for preventing severe infection and death than for preventing milder infection. Vaccine efficacy wanes over time but can be enhanced by a booster. Higher antibody titres are associated with higher estimates of efficacy but precise predictions are difficult due to large unexplained heterogeneity. These findings provide an important knowledge base for interpretation and application of future studies on these issues. FUNDING: Shenzhen Science and Technology Programs.

Real-World COPD Management Over 3 Years at the Community Health Service Center of Shanghai During the COVID-19 Pandemic in China.

Objective: To evaluate the real-world situation for the management of chronic obstructive pulmonary disease (COPD) and poorly controlled disease risk factors in the Chinese community. Methods: This retrospective multicentre study analysed data from COPDMICand MICHC in Shanghai Songjiang District, Shanghai, China. The differences in COPD Assessment Test (CAT), the modified Medical Research Council (mMRC) dyspnea scale, and the number of emergency cases, emergency visits, inpatient cases, and hospitalisations from January 2018 to December 2020 were analysed. The impact of coronavirus disease 2019 (COVID-19) on COPD management was also assessed. Results: For 2020 versus 2018, analysis of 468 COPD cases from COPDMIC matched with MICHC data showed significantly more patients with improved mMRC grades, significantly fewer emergency cases and emergency visits, and significantly fewer hospitalisation cases and hospitalisations. Differences in the number of emergency visits and hospitalisations per capita were statistically significant. Compared to GOLD 3-4, GOLD 1-2 patients showed significant improvements in CAT score, mMRC grade, the number of emergency visits and hospitalisations per capita. Treatment adherence from 2018 to 2020 was 25%, 29.1%, and 6.8%, and the proportion of medication regimens consistent with guidelines was 43.44%, 50.98%, and 71.87%, respectively. Higher treatment adherence resulted in significantly improved CAT scores and mMRC grades and fewer emergency department visits and hospitalisations per capita. Conclusion: Combined with remote management tools, patients with COPD achieved continuous improvement in symptoms and exacerbations over 3 years. In the context of COVID-19 prevention/control measures, improvements were significant for patients with GOLD 1-2 COPD but limited with GOLD 3-4. Pharmacologic treatment significantly improved clinical symptoms and reduced emergency visits and hospitalisations. Severe airflow limitation and poor adherence to pharmacologic treatment were important risk factors for lack of disease remission.

The impact of COVID-19 on online medical education: a knowledge graph analysis based on co-term analysis.

BACKGROUND: This study aims to identify the characteristics and future directions of online medical education in the context of the novel coronavirus outbreak new through visual analytics using CiteSpace and VOSviewer bibliometric methods. METHOD: From Web of Science, we searched for articles published between 2020 and 2022 using the terms online education, medical education and COVID-19, ended up with 2555 eligible papers, and the articles published between 2010 and 2019 using the terms online education, medical education and COVID-19, and we ended up with 4313 eligible papers. RESULTS: Before the COVID-19 outbreak, Medical students and care were the most frequent keywords and the most cited author was BRENT THOMA with 18 times. The United States is the country with the greatest involvement and research impact in the field of online medical education. The most cited journal is ACAD MED with 1326 citations. After the COVID-19 outbreak, a surge in the number of research results in related fields, and ANXIETY and four secondary keywords were identified. In addition, the concentration of authors of these publications in the USA and China is a strong indication that local epidemics and communication technologies have influenced the development of online medical education research. Regarding the centrality of research institutions, the most influential co-author network is Harvard Medical School in the United States; and regarding the centrality of references, the most representative journal to which it belongs is VACCINE. CONCLUSION: This study found that hey information such as keywords, major institutions and authors, and countries differ in the papers before and after the COVID-19 outbreak. The novel coronavirus outbreak had a significant impact on the online education aspect. For non-medical and medical students, the pandemic has led to home isolation, making it difficult to offer face-to-face classes such as laboratory operations. Students have lost urgency and control over the specifics of face-to-face instruction, which has reduced the quality of teaching. Therefore, we should improve our education model according to the actual situation to ensure the quality of teaching while taking into account the physical and psychological health of students.

Parameters and Morphological Changes of Erythrocytes and Platelets of COVID-19 Subjects: A Longitudinal Cohort Study.

Purpose: Information about dynamic changes occurring in the parameters and morphology of erythrocytes and platelets during the coronavirus disease 2019 (COVID-19) infection and convalescence is scarce. To explore potential associations between dynamic erythrocyte and platelet parameters, morphological changes, and the course or severity of the disease is essential. Patients and Methods: From January 17th, 2020, to February 20th, 2022, we followed up on 35 patients with non-severe and 11 patients with severe COVID-19 following their discharge. We collected clinical features, dynamic complete blood count (CBC), and peripheral blood smears (PBS) and analyzed parameter and morphological changes of erythrocytes and platelets depending on the course or severity of the disease. The course of the disease included four periods, namely onset (T1), discharge (T2), 1-year follow-up (T3), and 2-year follow-up (T4). Results: Red blood cell (RBC) counts and hemoglobin were the lowest in T2, followed by T1, and lower in T1 and T2 than in T3 and T4. Inversely, the red blood cell distribution width (RDW) was the highest in T2, followed by T1, and higher than in T3 and T4. Compared to non-severe patients, the platelet of severe patients was lower in T1 and T2. In contrast, the mean platelet volume (MPV) and platelet distribution width (PDW) tended to be higher in severe patients. Similarly, anisocytosis was more common in peripheral blood smears at early stages and in severe patients. Finally, large platelets were more common in severe patients. Conclusion: Anisocytosis of erythrocytes and large platelets are found in patients with severe COVID-19, these changes may help primary hospitals to identify patients with a high risk of severe COVID-19 at an early stage.

Exploring the factors that drive consumers to use contactless delivery services in the context of the continued COVID-19 pandemic

The spread of the COVID-19 pandemic has resulted in the launch of contactless delivery services. This research integrates resource matching, service quality evaluation, and perceived value theories to explore the factors that promote the use contactless delivery services. The data was obtained through questionnaire surveys, and research hypotheses were verified through the structural equation modelling approach. With the exception of convenience, the results show that privacy, reliability, security, and flexibility have a significantly positive effect on consumers' intention to use "contactless” delivery services through consumers' perceived value. This study contributes to the literature by introducing theoretical frameworks from various paradigms and enriches the academic research on existing theoretical structure models. It also helps optimize resource allocation and realize the social environment related to coexisting with the COVID-19 pandemic.

Antiviral drug design based on structural insights into the N-terminal domain and C-terminal domain of the SARS-CoV-2 nucleocapsid protein.

Nucleocapsid (N) protein plays crucial roles in the life cycle of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including the formation of ribonucleoprotein (RNP) complex with the viral RNA. Here we reported the crystal structures of the N-terminal domain (NTD) and C-terminal domain (CTD) of the N protein and an NTD-RNA complex. Our structures reveal a unique tetramer organization of NTD and identify a distinct RNA binding mode in the NTD-RNA complex, which could contribute to the formation of the RNP complex. We also screened small molecule inhibitors of N-NTD and N-CTD and discovered that ceftriaxone sodium, an antibiotic, can block the binding of RNA to NTD and inhibit the formation of the RNP complex. These results together could facilitate the further research of antiviral drug design targeting N protein.

15-Month Health Outcomes and the Related Risk Factors of Hospitalized COVID-19 Patients From Onset: A Cohort Study.

Objective: The long-term impact of COVID-19 on patient health has been a recent focus. This study aims to determine the persistent symptoms and psychological conditions of patients hospitalized with COVID-19 15 months after onset, that patients first developed symptoms. The potential risk factors were also explored. Methods: A cohort of COVID-19 patients discharged from February 20, 2020 to March 31, 2020 was recruited. Follow-ups were conducted using validated questionnaires and psychological screening scales at 15 months after onset to evaluate the patients' health status. The risk factors for long-term health impacts and their associations with disease severity was analyzed. Findings: 534 COVID-19 patients were enrolled. The median age of the patients was 62.0 years old (IQR 52.0-70.0) and 295 were female (55.2%). The median time from onset to follow-up was 460.0 (451.0-467.0) days. Sleep disturbance (18.5%, 99/534) and fatigue (17.2%, 92/534) were the most common persistent symptoms. 6.4% (34/534) of the patients had depression, 9.2% (49/534) were anxious, 13.0% (70/534) had insomnia and 4.7% (25/534) suffered from post-traumatic stress disorder (PTSD). Multivariate adjusted logistic regression analysis showed that glucocorticoid use during hospitalization (OR 3.58, 95% CI 1.12-11.44) was significantly associated with an increased risk of fatigue. The OR values for anxiety and sleep disorders were 2.36 (95% CI 1.07-5.20) and 2.16 (95% CI 1.13-4.14) in females to males. The OR value of PTSD was 25.6 (95% CI 3.3-198.4) in patients with persistent symptoms to those without persistent symptoms. No significant associations were observed between fatigue syndrome or adverse mental outcomes and disease severity. Conclusions: 15-month follow-up in this study demonstrated the need of extended rehabilitation intervention for complete recovery in COVID-19 patients.

Aerosol Transport Modeling: The Key Link Between Lung Infections of Individuals and Populations.

The recent COVID-19 pandemic has propelled the field of aerosol science to the forefront, particularly the central role of virus-laden respiratory droplets and aerosols. The pandemic has also highlighted the critical need, and value for, an information bridge between epidemiological models (that inform policymakers to develop public health responses) and within-host models (that inform the public and health care providers how individuals develop respiratory infections). Here, we review existing data and models of generation of respiratory droplets and aerosols, their exhalation and inhalation, and the fate of infectious droplet transport and deposition throughout the respiratory tract. We then articulate how aerosol transport modeling can serve as a bridge between and guide calibration of within-host and epidemiological models, forming a comprehensive tool to formulate and test hypotheses about respiratory tract exposure and infection within and between individuals.

COVID-19 lockdown policy and heterogeneous responses of urban mobility: Evidence from the Philippines.

Throughout 2020, national and subnational governments worldwide implemented nonpharmaceutical interventions (NPIs) to contain the spread of COVID-19. These included community quarantines, also known as lockdowns, of varying length, scope, and stringency that restricted mobility. To assess the effect of community quarantines on urban mobility in the Philippines, we analyze a new source of data: cellphone-based origin-destination flows made available by a major telecommunication company. First, we demonstrate that mobility dropped to 26% of the pre-lockdown level in the first month of lockdown and recovered and stabilized at 70% in August and September of 2020. Then we quantify the heterogeneous effects of lockdowns by city's employment composition. A city with 10 percentage points more employment share in work-from-home friendly sectors is found to have experienced an additional 2.8% decrease in mobility under the most stringent lockdown policy. Similarly, an increase of 10 percentage points in employment share in large and medium-sized firms was associated with a1.9% decrease in mobility on top of the benchmark reduction. We compare our findings with cross-country evidence on lockdowns and mobility, discuss the economic implications for containment policies in the Philippines, and suggest additional research that can be based on this novel dataset.

Structures of the Omicron spike trimer with ACE2 and an anti-Omicron antibody.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has become the dominant infective strain. We report the structures of the Omicron spike trimer on its own and in complex with angiotensin-converting enzyme 2 (ACE2) or an anti-Omicron antibody. Most Omicron mutations are located on the surface of the spike protein and change binding epitopes to many current antibodies. In the ACE2-binding site, compensating mutations strengthen receptor binding domain (RBD) binding to ACE2. Both the RBD and the apo form of the Omicron spike trimer are thermodynamically unstable. An unusual RBD-RBD interaction in the ACE2-spike complex supports the open conformation and further reinforces ACE2 binding to the spike trimer. A broad-spectrum therapeutic antibody, JMB2002, which has completed a phase 1 clinical trial, maintains neutralizing activity against Omicron. JMB2002 binds to RBD differently from other characterized antibodies and inhibits ACE2 binding.

Structure genomics of SARS-CoV-2 and its Omicron variant: drug design templates for COVID-19.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought an unprecedented public health crisis and persistently threatens to humanity. With tireless efforts from scientists around the world, understanding of the biology of coronavirus has been greatly enhanced over the past 2 years. Structural biology has demonstrated its powerful impact on uncovering structures and functions for the vast majority of SARS-CoV-2 proteins and guided the development of drugs and vaccines against COVID-19. In this review, we summarize current progress in the structural biology of SARS-CoV-2 and discuss important biological issues that remain to be addressed. We present the examples of structure-based design of Pfizer's novel anti-SARS-CoV-2 drug PF-07321332 (Paxlovid), Merck's nucleotide inhibitor molnupiravir (Lagevrio), and VV116, an oral drug candidate for COVID-19. These examples highlight the importance of structure in drug discovery to combat COVID-19. We also discussed the recent variants of Omicron and its implication in immunity escape from existing vaccines and antibody therapies.

[The Liver Injury and Coagulation Dysfunction in the Patients with Severe/Critical COVID-19].

AbstractObjective: To analyze the liver injury and coagulation dysfunction in COVID-19 severe/critical type patients. METHODS: The clinical data of 53 COVID-19 patients were collected from a single center in Wuhan from February 8, 2020 to March 25, 2020. The patients were divided into severe type group (38 patients) and critical type group (15 patients). The clinical characteristics, indexes of liver function, coagulation function and inflammatory markers were analyzed retrospectively. According to the degree of abnormal liver function in the process of diagnosis and treatment, the patients were divided into three groups: combined liver injury, mild abnormal liver function and normal liver function group. Statistical analysis was performed by using Student t test, Mann-Whitney U test, Kruskal-Wallis test and Chi-square test. RESULTS: Among the 53 patients, 29 were male (54.7%) and 24 were female (45.3%), the median age was 57(27－80) years old. The time from onset to admission was (11.5±7.7) days. The levels of AST, TBIL, DBIL, ALP, GGT, LDH, D-dimer, PCT and hsCRP in critical patients were higher than those in severe patients (P<0.05). The levels of Alb in critical patients was lower than those in severe patients (P<0.05). Among the 53 patients, 34 (64%) patients showed abnormal elevation of ALT, AST or TBIL, while 4 (7.5%) patients showed the criteria of COVID-19 with liver injury. After the patients were grouping according to the degree of liver dysfunction, the levels of ALP, GGT and D-dimer of the patients in the liver injury group were significantly higher than those in the normal liver function group, D-dimer levels of the patients in the liver injury group was significantly higher than those in the mild abnormal liver function group, while the levels of ALP and GGT in the mild abnormal liver function group were significantly higher than those in the normal liver function group, and the differences were statistically significant(P<0.05). CONCLUSION: In this group, the patients with COVID-19 severe/critical type have a certain proportion of liver injury accompanied by significantly increased D-dimer levels, critical type patients have more severe liver function and coagulation dysfunction, which may promote the progression of COVID-19.

Molecular basis for kinin selectivity and activation of the human bradykinin receptors.

Bradykinin and kallidin are endogenous kinin peptide hormones that belong to the kallikrein-kinin system and are essential to the regulation of blood pressure, inflammation, coagulation and pain control. Des-Arg10-kallidin, the carboxy-terminal des-Arg metabolite of kallidin, and bradykinin selectively activate two G protein-coupled receptors, type 1 and type 2 bradykinin receptors (B1R and B2R), respectively. The hyperactivation of bradykinin receptors, termed 'bradykinin storm', is associated with pulmonary edema in COVID-19 patients, suggesting that bradykinin receptors are important targets for COVID-19 intervention. Here we report two G protein-coupled complex structures of human B1R and B2R bound to des-Arg10-kallidin and bradykinin, respectively. Combined with functional analysis, our structures reveal the mechanism of ligand selectivity and specific activation of the bradykinin receptor. These findings also provide a framework for guiding drug design targeting bradykinin receptors for the treatment of inflammation, cardiovascular disorders and COVID-19.

Mask-Ematics: Modeling the Effects of Masks in COVID-19 Transmission in High-Risk Environments.

The COVID-19 pandemic has placed an unprecedented burden on public health and strained the worldwide economy. The rapid spread of COVID-19 has been predominantly driven by aerosol transmission, and scientific research supports the use of face masks to reduce transmission. However, a systematic and quantitative understanding of how face masks reduce disease transmission is still lacking. We used epidemic data from the Diamond Princess cruise ship to calibrate a transmission model in a high-risk setting and derive the reproductive number for the model. We explain how the terms in the reproductive number reflect the contributions of the different infectious states to the spread of the infection. We used that model to compare the infection spread within a homogeneously mixed population for different types of masks, the timing of mask policy, and compliance of wearing masks. Our results suggest substantial reductions in epidemic size and mortality rate provided by at least 75% of people wearing masks (robust for different mask types). We also evaluated the timing of the mask implementation. We illustrate how ample compliance with moderate-quality masks at the start of an epidemic attained similar mortality reductions to less compliance and the use of high-quality masks after the epidemic took off. We observed that a critical mass of 84% of the population wearing masks can completely stop the spread of the disease. These results highlight the significance of a large fraction of the population needing to wear face masks to effectively reduce the spread of the epidemic. The simulations show that early implementation of mask policy using moderate-quality masks is more effective than a later implementation with high-quality masks. These findings may inform public health mask-use policies for an infectious respiratory disease outbreak (such as one of COVID-19) in high-risk settings.