Search

We develop a game-theoretic model of strategic interdependence and tipping in public policy choices and show that the model can be estimated by probit and logit estimators. We test its validity and applicability by using daily data on state-level COVID-19 responses in the United States. Social distancing via shelter-in-place (SIP) strategies and wearing masks emerged as the most effective nonpharmaceutical ways of combatting COVID-19. In the United States, choices about these policies are made by individual states. We develop a game-theoretic model of such choices and test it econometrically, confirming strong interdependence in the implementation of these policies. If enough states engage in social distancing or mask wearing, others will be tipped to follow suit. Policy choices are influenced mainly by the choices of other states, especially those of similar political orientation and to a lesser degree by the number of new COVID-19 cases. The choice of mask-wearing policies is more sensitive to peer choices than the choice of SIP policies, and Republican states are much less likely than Democratic to introduce mask-wearing policies. The choices of policies are influenced more by political than public health considerations. These findings emphasize strategic interdependence in policy choice and offer an analytical framework for these complex dynamics., Competing Interests: Competing interests statement:The authors declare no competing interest.

Airborne pathogens represent a topic of scientific relevance, especially considering the recent COVID-19 pandemic. Air pollution, and particulate matter (PM) in particular, has been proposed as a possible risk factor for the onset and spread of pathogen-driven respiratory diseases. Regarding SARS-CoV-2 infection, exposure to fine PM (PM 2.5 , particles with an aerodynamic diameter < 2.5 μm) has been associated with increased incidence of the COVID-19 disease. To provide useful insights into the mechanisms through which PM might be involved in infection, we exposed human lung cells (A549) to PM 2.5 and SARS-CoV-2, to evaluate the toxicological properties and the molecular pathways activated when airborne particles are combined with viral particles. Winter PM 2.5 was collected in a metropolitan urban area and its physico-chemical composition was analyzed. A549 cells were exposed to SARS-CoV-2 concomitantly or after pre-treatment with PM 2.5 . Inflammation, oxidative stress and xenobiotic metabolism were the main pathways investigated. Results showed that after 72 h of exposure PM 2.5 significantly increased the expression of the angiotensin-converting enzyme 2 (ACE2) receptor, which is one of the keys used by the virus to infect host cells. We also analyzed the endosomal route in the process of internalization, by studying the expression of RAB5 and RAB7. The results show that in cells pre-activated with PM and then exposed to SARS-CoV-2, RAB5 expression is significantly increased. The activation of the inflammatory process was then studied. Our findings show an increase of pro-inflammatory markers (NF-kB and IL-8) in cells pre-activated with PM for 72 h and subsequently exposed to the virus for a further 24 h, further demonstrating that the interaction between PM and SARS-CoV-2 determines the severity of the inflammatory responses in lung epithelial cells. In conclusion, the study provides mechanistic biological evidence of PM contribution to the onset and progression of viral respiratory diseases in exposed populations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Monitoring the presence of RNA from emerging pathogenic viruses, such as SARS-CoV-2, in wastewater (WW) samples requires suitable methods to ensure an effective response. Genome sequencing of WW is one of the crucial methods, but it requires high-quality RNA in sufficient quantities, especially for monitoring emerging variants. Consequently, methods for viral concentration and RNA extraction from WW samples have to be optimized before sequencing. The purpose of this study was to achieve high coverage (≥ 90 %) and sequencing depth (at least ≥200×) even for low initial RNA concentrations (< 10 5 genome copies (GC)/L) in WW. A further objective was to determine the range of SARS-CoV-2 RNA concentrations that allow high-quality sequencing, and the optimal sample volume for analysis. Ultrafiltration (UF) methods were used to concentrate viral particles from large influent samples (up to 500 mL). An RNA extraction protocol using silica beads, neutral phenol-chloroform treatment, and a PCR inhibitor removal kit was chosen for its effectiveness in extracting RNA and eliminating PCR inhibitors, as well as its adaptability for use with large influent samples. Recovery rates ranged from 24 % to 63 % (N = 17) for SARS-CoV-2 naturally present in WW samples. 200 mL WW samples can be enough for UF concentration, as they showed high quality sequencing analyses with between 5 × 10 4 GC/L and 6 × 10 3 GC/L. Below 6 × 10 3 GC/L, high-quality sequencing was also achieved for ∼40 % of the samples using 500 mL of WW. Sequencing analysis for variant detection was performed on 200 mL WW samples with coverage of >95 % and sequencing depth of >1000×. Analyses revealed the predominance of variant EG.5, known as Eris (66 %-100 %). The use of UF methods in combination with a suitable RNA extraction protocol appear promising for sequencing enveloped viruses in WW in a context of viral emergence., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Isabelle Bertrand, Olivier Rohr, Nicolas Boudaud reports financial support was provided by ANRS. Isabelle Bertrand, Christophe Gantzer, Vincent Marechal, Nicolas Boudaud, Olivier Rohr reports a relationship with OBEPINE that includes: board membership. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The sign language interpreting service has undergone a tremendous change due to COVID-19 and remote interpreting has become a more frequent alternative to the face-to-face format. The aim of the study is to investigate how the interpreters perceive the organisation of remote interpreting in Sweden and how it has evolved since the COVID-19 pandemic., Method: Interviews with 26 experienced remote interpreters, representing 19 of Sweden's 21 counties, were analysed with qualitative content analysis., Results: Three themes were revealed in the analysis. The first theme was regulation. It was stated that directives and regulatory decisions concerning provision of remote interpreting services were varied and unclear. Several different platforms were used when interpreting remotely. Some of the services had conducted risk analyses, whereas others had not. The second theme was modification, including adjusting interactions to suit the preferences and capabilities of the users (both signing and speaking parties), as well as adjustments to work environments and workplaces. The third theme, evolution of remote interpreting, showed that support and training were rare and varied. Although the processes and organisation of remote interpreting are not yet fully established in Sweden, remote interpreting is here to stay., Conclusions: In Sweden, remote interpreting is a service that varies according to regulations and the type of assignments. The service would benefit from being more uniform and streamlined across Sweden, although consideration must be given to those involved with the service., Competing Interests: Declarations Ethics approval and consent to participate The Swedish Ethical Review Authority approved this study (Dnr. 2021–02182). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: With an emphasis on spatial health disparities, this study examines how COVID-19 has affected healthcare access and inequality in India. The study developed the Healthcare Access Index (HAI) and Healthcare Inequality Index (HII) to assess the pandemic's effects on healthcare. The study addresses spatial health disparities in healthcare access and inequality, filling gaps in the literature. The final aim of the study is to offer policy suggestions to lessen healthcare inequities in India, particularly in the context of COVID-19., Design/methodology/approach: The study incorporates secondary data from publicly accessible databases such as the National Family Health Survey, Niti-Ayog and Indian Census databases and employs a quantitative research design. The impact of the COVID-19 pandemic on healthcare access and healthcare inequality in India is examined using the HAI and the HII. The five dimensions of healthcare access - availability, accessibility, accommodation, cost and acceptability - were used in developing the HAI. The study uses a panel data analysis methodology to examine the HAI and HII scores for 19 states over the pre-COVID-19 (2015) and post-COVID-19 (2020) periods. In order to investigate the connection between healthcare access, healthcare inequality and the COVID-19 pandemic, the analysis employs statistical tests such as descriptive statistics, correlation analysis, factor analysis and visualization analysis., Findings: According to the study, COVID-19 impacted healthcare access and inequality in India, with notable regional inequalities between states. The pandemic has increased healthcare disparities by widening the gap between states with high and low HII ratings. Healthcare access is closely tied to healthcare inequality, with lower levels of access being associated with more significant levels of inequality. The report advises governmental initiatives to lessen healthcare disparities in India, such as raising healthcare spending, strengthening healthcare services in underperforming states and enhancing healthcare infrastructure., Practical Implications: For Indian healthcare authorities and practitioners, the study has significant ramifications. In light of the COVID-19 pandemic, there has been a main focus on addressing geographic gaps in healthcare access and inequality. The report suggests upgrading transportation infrastructure, lowering out-of-pocket costs, increasing health insurance coverage and enhancing healthcare infrastructure and services in underperforming states. The HAI and the HII are tools that policymakers can use to identify states needing immediate attention and appropriately spend resources. These doable recommendations provide a framework for lowering healthcare disparities in India and enhancing healthcare outcomes for all communities., Originality/value: The study's originality resides in establishing the HAI and HII indices, using panel data analysis and assessing healthcare inequality regarding geographic disparities. Policy choices targeted at lowering healthcare disparities and enhancing healthcare outcomes for all people in India can be informed by the study's practical consequences., (© Emerald Publishing Limited.)

Increasing evidence suggests that mutations in the nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may enhance viral replication by modulating the assembly process. However, the mechanisms governing the selective packaging of viral genomic RNA by the N protein, along with the assembly and budding processes, remain poorly understood. Utilizing a virus-like particles (VLPs) system, we have identified that the C-terminal domain (CTD) of the N protein is essential for its interaction with the membrane (M) protein during budding, crucial for binding and packaging genomic RNA. Notably, the isolated CTD lacks M protein interaction capacity and budding ability. Yet, upon fusion with the N-terminal domain (NTD) or the linker region (LKR), the resulting NTD/CTD and LKR/CTD acquire RNA-dependent interactions with the M protein and acquire budding capabilities. Furthermore, the presence of the C-tail is vital for efficient genomic RNA encapsidation by the N protein, possibly regulated by interactions with the M protein. Remarkably, the NTD of the N protein appears dispensable for virus particle assembly, offering the virus adaptive advantages. The emergence of N* (NΔN209) in the SARS-CoV-2 B.1.1 lineage corroborates our findings and hints at the potential evolution of a more streamlined N protein by the SARS-CoV-2 virus to facilitate the assembly process. Comparable observations have been noted with the N proteins of SARS-CoV and HCoV-OC43 viruses. In essence, these findings propose that β-coronaviruses may augment their replication by fine-tuning the assembly process.IMPORTANCEAs a highly transmissible zoonotic virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve. Adaptive mutations in the nucleocapsid (N) protein highlight the critical role of N protein-based assembly in the virus's replication and evolutionary dynamics. However, the precise molecular mechanisms of N protein-mediated viral assembly remain inadequately understood. Our study elucidates the intricate interactions between the N protein, membrane (M) protein, and genomic RNA, revealing a C-terminal domain (CTD)-based assembly mechanism common among β-coronaviruses. The appearance of the N* variant within the SARS-CoV-2 B.1.1 lineage supports our conclusion that the N-terminal domain (NTD) of the N protein is not essential for viral assembly. This work not only enhances our understanding of coronavirus assembly mechanisms but also provides new insights for developing antiviral drugs targeting these conserved processes., Competing Interests: The authors declare no conflict of interest.

All coronaviruses (CoVs) encode for a conserved macrodomain (Mac1) located in non-structural protein 3. Mac1 is an ADP-ribosylhydrolase that binds and hydrolyzes mono-ADP-ribose from target proteins. Previous work has shown that Mac1 is important for virus replication and pathogenesis. Within Mac1, there are several regions that are highly conserved across CoVs, including the glycine-isoleucine-phenylalanine motif. While we previously demonstrated the importance of the glycine residue for CoV replication and pathogenesis, the impact of the isoleucine and phenylalanine residues remains unknown. To determine how the biochemical activities of these residues impact CoV replication, the isoleucine and the phenylalanine residues were mutated to alanine (I-A/F-A) in both recombinant Mac1 proteins and recombinant CoVs, including murine hepatitis virus, Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The F-A mutant proteins had ADP-ribose binding and/or hydrolysis defects that correlated with attenuated replication and pathogenesis of F-A mutant MERS-CoV and SARS-CoV-2 viruses in cell culture and mice. In contrast, the I-A mutant proteins had normal enzyme activity and enhanced ADP-ribose binding. Despite only demonstrating increased ADP-ribose binding, I-A mutant MERS-CoV and SARS-CoV-2 viruses were highly attenuated in both cell culture and mice, indicating that this isoleucine residue acts as a gate that controls ADP-ribose binding for efficient virus replication. These results highlight the function of this highly conserved residue and provide unique insight into how macrodomains control ADP-ribose binding and hydrolysis to promote viral replication., Importance: The conserved coronavirus (CoV) macrodomain (Mac1) counters the activity of host ADP-ribosyltransferases and is critical for CoV replication and pathogenesis. As such, Mac1 is a potential therapeutic target for CoV-induced disease. However, we lack a basic knowledge of how several residues in its ADP-ribose binding pocket contribute to its biochemical and virological functions. We engineered mutations into two highly conserved residues in the ADP-ribose binding pocket of Mac1, both as recombinant proteins and viruses for Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Interestingly, a Mac1 isoleucine-to-alanine mutant protein had enhanced ADP-ribose binding which proved to be detrimental for virus replication, indicating that this isoleucine controls ADP-ribose binding and is beneficial for virus replication and pathogenesis. These results provide unique insight into how macrodomains control ADP-ribose binding and will be critical for the development of novel inhibitors targeting Mac1 that could be used to treat CoV-induced disease., Competing Interests: The authors declare no conflict of interest.

The optimization of antibodies to attain the desired levels of affinity and specificity holds great promise for the development of next generation therapeutics. This study delves into the refinement and engineering of complementarity-determining regions (CDRs) through in silico affinity maturation followed by binding validation using isothermal titration calorimetry (ITC) and pseudovirus-based neutralization assays. Specifically, it focuses on engineering CDRs targeting the epitopes of receptor-binding domain (RBD) of the spike protein of SARS-CoV-2. A structure-guided virtual library of 112 single mutations in CDRs was generated and screened against RBD to select the potential affinity-enhancing mutations. Protein-protein docking analysis identified 32 single mutants of which nine mutants were selected for molecular dynamics (MD) simulations. Subsequently, biophysical ITC studies provided insights into binding affinity, and consistent with in silico findings, six mutations that demonstrated better binding affinity than native nanobody were further tested in vitro for neutralization activity against SARS-CoV-2 pseudovirus. Leu106Thr mutant was found to be most effective in virus-neutralization with IC 50 values of ∼0.03 μM, as compared to the native nanobody (IC 50 ∼0.77 μM). Thus, in this study, the developed computational pipeline guided by structure-aided interface profiles and thermodynamic analysis holds promise for the streamlined development of antibody-based therapeutic interventions against emerging variants of SARS-CoV-2 and other infectious pathogens., Competing Interests: Declaration of competing interest We declare that we have no conflicts of interest in the authorship or publication of this contribution., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Limited research suggested that liver cirrhosis is an independent risk factor for severe COVID-19, leading to higher hospitalization and mortality rates. This study aimed to identify the prognostic factors and validate scoring systems for predicting mortality in COVID-19 patients with liver cirrhosis., Methods: This retrospective cohort study extracted electronic health records of patients with COVID-19 who visited the emergency department between April 2021 and September 2022. Adult COVID-19 patients with liver cirrhosis were included, excluding those aged < 18 years and who did not require hospitalization. The primary outcome was in-hospital mortality. The effectiveness of the scoring systems were analyzed for COVID-19 in-house mortality prediction., Results: A total of 1,368 adult COVID-19 patients with liver cirrhosis were included in this study. Compared with the survival group, the non-survival group had lower vital signs such as systolic blood pressure and blood oxygen saturation, higher levels of white blood cells, creatinine, bilirubin, and C-reactive protein, and longer prothrombin time. Higher rates of intubation, oxygen use, and dexamethasone use were observed in the non-survivor group. The WHO ordinal scale, MELD, and MELD-Na scores showed good predictive ability for in-hospital mortality., Conclusions: The WHO ordinal scale showed the best performance in predicting mortality in patients with cirrhosis and COVID-19. MELD and MELD-Na scores were also found good performance for mortality prediction. Coagulation function, intubation, and dexamethasone administration were the most significant prognostic factors., Competing Interests: Declarations Human ethics approval The study was approved by the institutional review board of the Chang-Gung Memorial hospital, Taiwan (IRB no. 202301643B0). This is a retrospective study conducted from de-identified database and informed consent of participation is waived by the Institutional Review Board of CGMH, Taiwan. Consent to participate This is a retrospective study conducted from de-identified database and informed consent of participation is waived by the Institutional Review Board of CGMH, Taiwan (IRB no. 202301643B0). Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: According to the FAIR principles (Findable, Accessible, Interoperable, and Reusable), scientific research data should be findable, accessible, interoperable, and reusable. The COVID-19 pandemic has led to massive research activities and an unprecedented number of topical publications in a short time. However, no evaluation has assessed whether this COVID-19-related research data has complied with FAIR principles (or FAIRness)., Objective: Our objective was to investigate the availability of open data in COVID-19-related research and to assess compliance with FAIRness., Methods: We conducted a comprehensive search and retrieved all open-access articles related to COVID-19 from journals indexed in PubMed, available in the Europe PubMed Central database, published from January 2020 through June 2023, using the metareadr package. Using rtransparent, a validated automated tool, we identified articles with links to their raw data hosted in a public repository. We then screened the link and included those repositories that included data specifically for their pertaining paper. Subsequently, we automatically assessed the adherence of the repositories to the FAIR principles using FAIRsFAIR Research Data Object Assessment Service (F-UJI) and rfuji package. The FAIR scores ranged from 1-22 and had four components. We reported descriptive analysis for each article type, journal category, and repository. We used linear regression models to find the most influential factors on the FAIRness of data., Results: 5,700 URLs were included in the final analysis, sharing their data in a general-purpose repository. The mean (standard deviation, SD) level of compliance with FAIR metrics was 9.4 (4.88). The percentages of moderate or advanced compliance were as follows: Findability: 100.0%, Accessibility: 21.5%, Interoperability: 46.7%, and Reusability: 61.3%. The overall and component-wise monthly trends were consistent over the follow-up. Reviews (9.80, SD = 5.06, n = 160), articles in dental journals (13.67, SD = 3.51, n = 3) and Harvard Dataverse (15.79, SD = 3.65, n = 244) had the highest mean FAIRness scores, whereas letters (7.83, SD = 4.30, n = 55), articles in neuroscience journals (8.16, SD = 3.73, n = 63), and those deposited in GitHub (4.50, SD = 0.13, n = 2,152) showed the lowest scores. Regression models showed that the repository was the most influential factor on FAIRness scores (R2 = 0.809)., Conclusion: This paper underscored the potential for improvement across all facets of FAIR principles, specifically emphasizing Interoperability and Reusability in the data shared within general repositories during the COVID-19 pandemic., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Sofi-Mahmudi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Predicting epidemic trends of coronavirus disease 2019 (COVID-19) remains a key public health concern globally today. However, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection rate in previous studies of the transmission dynamics model was mostly a fixed value. Therefore, we proposed a meta-Susceptible-Exposed-Infectious-Recovered-Susceptible (SEIRS) model by adding a time-varying SARS-CoV-2 reinfection rate to the transmission dynamics model to more accurately characterize the changes in the number of infected persons. The time-varying reinfection rate was estimated using random-effect multivariate meta-regression based on published literature reports of SARS-CoV-2 reinfection rates. The meta-SEIRS model was constructed to predict the epidemic trend of COVID-19 from February to December 2023 in Sichuan province. Finally, according to the online questionnaire survey, the SARS-CoV-2 infection rate at the end of December 2022 in Sichuan province was 82.45%. The time-varying effective reproduction number in Sichuan province had two peaks from July to December 2022, with a maximum peak value of about 15. The prediction results based on the meta-SEIRS model showed that the highest peak of the second wave of COVID-19 in Sichuan province would be in late May 2023. The number of new infections per day at the peak would be up to 2.6 million. We constructed a meta-SEIRS model to predict the epidemic trend of COVID-19 in Sichuan province, which was consistent with the trend of SARS-CoV-2 positivity in China. Therefore, a meta-SEIRS model parameterized based on evidence-based data can be more relevant to the actual situation and thus more accurately predict future trends in the number of infections.

The ongoing global threats posed by COVID-19 pandemic, catalyzed by SARS-CoV-2, underscores the pressing need for effective antiviral strategies. The viral non-structural protein 1 (Nsp1) significantly influences pathogenicity by impeding host protein expression and enhancing viral RNA translation through its interaction with the stem-loop 1 (SL1) in the 5' untranslated region (UTR). We have developed a novel dual-luciferase reporter assay, designed to investigate the critical Nsp1-SL1 interaction, and identified P23E02 as a potential inhibitor. Our investigation, combining molecular docking studies and alanine mutagenesis, has unveiled that P23E02 disrupts Nsp1-40S ribosomal subunit interaction, liberating translational inhibition and empowering host antiviral responses. P23E02 exhibits antiviral efficacy against various sarbecoviruses, making it a promising candidate for combatting COVID-19 and related diseases. This study underscores the therapeutic potential of targeting the Nsp1/SL1 axis and lays the foundation for innovative antiviral interventions, ultimately fortifying global preparedness against future viral threats., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Many aptamers have been generated by systematic evolution of ligands by exponential enrichment (SELEX) to recognize spike proteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2&ek), some of which have been engineered into dimeric and trimeric versions for enhanced affinity for diagnostic applications. However, no studies have been conducted to compare the utilities of monomeric, dimeric and trimeric aptamers in diagnostic assays with real clinical samples to answer the question of what levels of affinity an aptamer must have for accurate clinical diagnostics. Herein, we carried out a comparative study with two monomeric aptamers MSA1 and MSA5, one dimeric aptamer and two homotrimeric aptamers constructed with MSA1 and MSA5, with affinity varying by 1000-fold. Using a colorimetric sandwich assay to analyze 48 human saliva samples, we found that the trimeric aptamer assay (K d ≈10 pM) can identify the SARS-CoV-2 infection much more accurately than the dimeric aptamer assay (K d ≈100 pM) and monomeric aptamer assay (K d ≈10,000 pM). Based on the experimental data, we theoretically predict the levels of affinity an aptamer needs to possess to achieve 80-100 % sensitivity and 100 % specificity. The findings from this study highlight the need for deriving very high affinity aptamers to enable highly accurate detection of viral infection for future pandemics., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Background: While the COVID-19 pandemic disrupted HIV preventative services in sub-Saharan Africa, little is known about the specific impacts the pandemic has had on men who have sex with men (MSM) in Kenya., Methods: Data were from an HIV self-testing intervention implemented in Kisumu, Mombasa and Kiambu counties in Kenya. Baseline data collection took place from May to July 2019, and endline in August-October 2020, coinciding with the lifting of some COVID-19 mitigation measures. Using endline data, this study characterised the impact the pandemic had on participants' risk behaviours, experience of violence and behaviours related to HIV. Logistic regression was used to understand factors related to changes in risk behaviours and experiences of violence; adjusted AORs (AORs) and 95% CIs are reported., Results: Median age was 24 years (IQR: 21-27). Most respondents (93.9%) reported no change or a decrease in the number of sexual partners (median number of male sexual partners: 2, IQR: 2-4). Some participants reported an increase in alcohol (10%) and drug (16%) consumption, while 40% and 28% reported decreases in alcohol and drug consumption, respectively. Approximately 3% and 10% reported an increase in violence from intimate partners and police/authorities, respectively. Compared with those with primary education, those with post-secondary education were 60% less likely to report an increase in the number of male sexual partners per week (AOR: 0.4, 95% CI: 0.2 to 0.9), while those who were HIV positive were at twofold the odds of reporting an increase or sustained levels of violence from intimate partners (AOR: 2.0, 95% CI: 1.1 to 4.0)., Conclusion: The results of this study demonstrate heterogeneity in participants' access to preventative HIV and clinical care services in Kenya after the onset of the COVID-19 epidemic. These results indicate the importance of responding to specific needs of MSM and adapting programmes during times of crisis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Healthcare workers (HCWs) have been of particular relevance for overcoming the SARS-CoV-2 pandemic. At the same time they have been affected by SARS-CoV-2 infections with above average probability. Around 6.5% of the overall infected persons are likely to develop persistent symptoms resulting from the infection, known as long-COVID or post-COVID syndrome (PCS). The aim of this study is (1) to investigate the prevalence, course and characteristics of PCS in German HCWs, (2) to examine its effects on psychosocial variables, (3) to identify rehabilitation and healthcare needs and (4) to analyse treatment experiences., Methods and Analysis: In a cohort study with a randomised selection of participants (N=20 000) from the Employer's Liability Insurance Association for Health and Welfare Care, the health status of HCWs, who had COVID-19 in their professional context will be examined. There will be two measurement points: baseline (T 1 ) and a 12-month follow-up (T2). The outcome measures are the health status with a particular focus on persistent or newly occurring symptoms after a SARS-CoV-2 infection, health-related quality of life, functional capacity, the subjective need for and utilisation of healthcare services. Pre-existing conditions, the course of the acute infection and sociodemographic factors are considered as predictors. An advisory board made up of affected HCWs supports the study by contributing to the surveys' contents., Ethics and Dissemination: The study has been approved by the Local Ethics Committee of the Center for Psychosocial Medicine at the University Hospital Hamburg-Eppendorf (LPEK-0518). For dissemination, the results will be published in peer-reviewed journals, presented at conferences and communicated to relevant stakeholders in general and rehabilitation medicine., Trail Registration Number: https://drks.de/search/de/trial/DRKS00029314., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The COVID-19 epidemic not only impacted China's economy but also induced periodic anxiety among employees, especially during its peak. Even as governmental controls relaxed, enterprises seemed unaffected externally. However, beneath the surface, the lingering effects on employee mental health persisted. Many faced dual stressors concerning their job and personal well-being due to the epidemic, heightening work-related anxieties. This research, a year after China resumed work, delves into the psychological stress influencing this sustained anxiety. A survey of 516 employees helped test the hypothesis using a multiple regression model. Findings indicated heightened continuous work anxiety due to the epidemic, particularly in hard-hit areas. However, individual resilience, organizational, and social support were found to mitigate these effects. The study underscores the sustained psychological aftermath of the epidemic on employees, urging health authorities to address it.

Investigating the causal relationship between circulating immune cells, blood metabolites, and severe COVID-19 and revealing the role of blood metabolite-mediated circulating immune cells in disease onset and progression. Genetic variation data of 731 circulating immune cells, 1400 blood metabolites, and severe COVID-19 from genome-wide association study open-access database (https://gwas.mrcieu.ac.uk) were used as instrumental variables for bidirectional and two-step Mendelian randomization analysis. The study identified 11 circulating immune cells with unidirectional causality to severe COVID-19. Two-step Mendelian randomization analysis showed 10 blood metabolites were causally associated with severe COVID-19, and blood Myristate and Citrulline to phosphate ratio mediated the association of circulating effector memory double negative % DN and CD8dim natural killer T cell % T cells, respectively, with severe COVID-19 (Myristate mediated effect ratio was 10.20%, P = .011; Citrulline to phosphate ratio mediated effect ratio was -9.21%, P = .017). This study provides genetic evidence assessing the causal relationship between circulating immune cells, blood metabolites, and severe COVID-19, elucidates the role of blood metabolite-mediated circulating immune cells in severe COVID-19 development, and offers new insights into severe COVID-19 etiology and related preventive and targeted therapeutic strategies., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Serological diagnostic tests are available that measure antibody levels against SARS-CoV-2 antigens. We utilized the Vaxarray Coronavirus (CoV) seroassay, which measures SARS-CoV-2 IgG antibodies against the full-length spike protein (FLS), receptor binding domain (RBD), and S2 extracellular domain (ECD). Previous serological studies have used reference values that have not been validated and require many samples. Here, we show statistically established reference values determined using the upper tail of the Student t-distribution method. The target population was any personnel age 18 years and older working on a U.S. Navy ship, and vaccinated with Wuhan variant. The relative fluorescence mean (RFM) reference values for the full-length spike protein, RBD, and S2 ECD were 17,731, 13,990 and 9096, respectively. By using generalized non-parametric regression and reference values for the RBD spike protein and S2 ECD of SARS-CoV-2, this study was able to distinguish vaccine-mediated immune responses from natural infections. We provide the method and statistical code as a resource to determine future reference values for other serological assays., Competing Interests: Declarations Ethics approval and consent to participate The study protocol was approved by the Naval Health Research Center Institutional Review Board in compliance with all applicable federal regulations governing the protection of human subjects. Enrollment was voluntary and informed consent to participate was obtained from all participants in the study. Research data were derived from an approved Naval Health Research Center Institutional Review Board protocol, number NHRC.2020.0006. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

With the continuous spread of the SARS-CoV-2 globally, viral mutations have accumulated. As a result, SARS-CoV-2 became more contagious, and has a higher risk of immune escape and reinfection. To identify variants and have an awareness of the prevalence of these variants, this study selected four segments containing mutations on the S gene of the SARS-CoV-2. Then a rapid and convenient variants detection method was established using high-resolution melting(HRM) analysis combined with nested polymerase chain reaction(PCR). The total detection process takes about 5 h. Through comprehensive analysis of the results from the four reaction systems, the identification of seven important Omicron variants(BA.2, BA.2.75, BA.5.2, BF.7, BQ.1, XBB.1 and XBB.2) can be achieved, with significant differentiation in the melting curves of each variant group. The method established in this study was used to genotype positive specimens in COVID-19 nucleic acid testing, the overall concordance rate compared to whole genome sequencing results was 88.9%, and the positive concordance rate of each sublineage was greater than 80% and the negative concordance rate was greater than 94.4%. The detection of clinical specimens has demonstrated that the HRM analysis established in this study is an effective, rapid and convenient variant identification method, which can be used for monitoring SARS-CoV-2 variants and has important value in addressing public health issues caused by the ongoing mutations of the SARS-CoV-2., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The COVID-19 pandemic highlighted the need for the rapid development of antiviral therapies. Viral RNA-dependent RNA polymerases (RdRp) are promising targets, and numerous virtual screenings for potential inhibitors were conducted without validation of the identified hits. Here we have tested a set of presumed RdRp inhibitors in biochemical assays based on fluorometric detection of RdRp activity or on the electrophoretic separation or RdRp products. We find that fluorometric detection of RdRp activity is unreliable as a screening method because many small compounds interfere with fluorophore binding to dsRNA, and this effect is enhanced by the Mg 2+ metal ions used by nucleic acid polymerases. The fact that fluorimetric detection of RdRp activity leads to false-positive hits underscores the requirement for independent validation methods. We also show that suramin, one of the proposed RdRp inhibitors that could be validated biochemically, is a multi-polymerase inhibitor. While this does not hinder its potential as an antiviral agent, it cannot be considered an specific inhibitor of SARS-CoV-2 RdRp., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: Cancer outcome is dependent on multiple predetermining factors including cancer, type of cancer and its related factors. This study aims to investigate the association between COVID-19 & cancer/cancer types, focusing on risk of in-hospital mortality within 30 days of hospitalization of COVID-19 patients with cancer., Materials and Methods: We did a registry (National Clinical Registry for COVID-19) based retrospective observational study including 51,544 patients, of whom 976 were patients with cancer, admitted with COVID-19 between August 2020 and August 2023 across 42 hospitals of India., Results: Out of 51,544 patients, 976 (1.8%) had cancer. Hematological malignancies made up 15.06% (147 cases), while solid cancers accounted for 29.5% (288 cases), with genitourinary (18.4%, 80 cases), gastrointestinal (15.2%, 49 cases), and lung cancers (10.1%, 34 cases) being the most common. Solid cancers had the highest in-hospital mortality rate at 25%. Survival analysis showed that cancer-related hazards were highest at admission but decreased to levels comparable with other morbidities within nine to ten days. For each cancer type, the hazard was significantly elevated compared to that of the cancer-free (Other Comorbidities and No Comorbiditiy) groups during the initial period of hospitalization. The use of Remdesivir, steroids, and anticoagulants reduced mortality risk, and prior COVID-19 vaccination was protective against mortality across all cancer types., Conclusion: This study shows that both cancer in general and specific cancer types significantly increase the risk of severe outcomes among SARS-CoV-2-infected patients, especially immediately after hospitalization. The findings highlight the need for close monitoring and personalized interventions for COVID-19 patients with cancer for at least 10 days post-hospitalization, with a more specific high-risk period ranging from 7 to 18 days depending on the type of cancer., Competing Interests: Declarations Conflict of interest The authors declare no competing interests., (© 2024. The Author(s).)

Background: The COVID-19 pandemic posed many unprecedented challenges to health care systems and public health efforts worldwide. Policy making and science were deeply intertwined, in particular with regard to the justification of health policy measures. In this context, ethical considerations were often at the core of decision-making trade-offs. However, not much is known about the actual ethical challenges encountered by policy makers and scientists involved in policy advice. With this study, we therefore aim to explore the ethical challenges during COVID-19-related political decision-making in Switzerland as perceived by policy makers and scientists involved in policy making. We also explore the role ethics advice had during the pandemic response and what can be learned for future public health crises., Methods: We conducted thirteen qualitative expert interviews with policy makers and scientists involved in decision-making on COVID-19 policy responses in Switzerland on the regional and national level. We used inductive content analysis to analyse the interviews., Results: Among the multitude of ethical challenges highlighted, interviewees perceived making trade-offs between the common good vs. the individual good and between economic welfare vs. health of the population, as well as proportionality of the policy measures, and the capacity of the public to accept uncertainty as central. Interviewees had diverging opinions on whether ethical considerations were sufficiently raised and discussed on the Swiss policy level during the COVID-19 pandemic. Among the reasons why ethics was not sufficiently discussed, they mentioned a lack of time in the fast-paced dynamic of the pandemic, ethics as a complex subject area, the interconnectedness between ethics and law, too much focus on few topics (mostly on vaccination-related ethical questions), and power relationships, such as dominance of medical professionals over ethicists. They evaluated ethics support to have been adequately present in the decision-making process, but wished for ethics training, involvement of the public in the discourse and for accompanying communication to build trust among the population for the future., Conclusions: The study provides empirical insights into the ethical considerations of COVID-19 policy making in practice in Switzerland. It can help to develop ethics assistance for future crises and inform ethical health policy and decision-making not only in Switzerland, but also in other countries., Competing Interests: Declarations Ethics approval and consent to participate The interview study complies with the Declaration of Helsinki and was reviewed and approved by the ETH Zurich Ethics Commission on January 19th 2022 (EK 2022-N-04). The invitation letter informed participants about the aims and procedures of the interview study, as well as their rights: It highlighted that they have the choice whether to participate in the study or not, that they have the right to withdraw at any time without specifying reasons and without any consequences. It emphasized that the interviews will be transcribed in a de-identified manner, stored safely in an encrypted form and reported in an anonymous way. Only the responsible investigators will have access to the original interview transcript under strictly observed rules of confidentiality. De-identified quotations of the interview might be used for scientific publications or conference presentations. Lastly, interviewees were informed that by participating in the interview, they give their informed consent for participation. In the beginning of the interviews, any open questions were addressed, and the interviewees’ verbal consent was obtained for recording the interview. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

To investigate the characteristics of acute visual dysfunction and fundus lesions in patients with COVID-19 pneumonia. A retrospective case series study was conducted. Data from 48 patients (96 eyes) with COVID-19 infection who presented to our ophthalmology department with acute onset visual disturbance between December 5, 2022, and February 28, 2023 were collected. Asymptomatic patients and those who had already recovered were excluded. Data collected included patient demographics, ophthalmic examinations, multicolor imaging (MCI), infrared autofluorescence (IR), spectral-domain optical coherence tomography (OCT), fundus fluorescein angiography (FFA). Of the 48 patients, 15 were male and 33 were female, with a mean age of 32 years. All patients had bilateral involvement. OCT showed hyperreflective signals in the outer plexiform layer and outer nuclear layer of the macular region in all 96 eyes of 48 patients (100%). Additionally, 66 eyes of 33 patients (68.8%) of eyes demonstrated abnormal reflectivity in the ellipsoid and interdigitation zones. MCI revealed petaloid or wedge-shaped hyperreflective areas in the macula in 46 (47.9%) of eyes, corresponding to hyporeflective areas on IR. Cotton-wool spots were observed in the peripapillary or posterior pole area in 54 (56.3%) of eyes. COVID-19 infection can lead to acute, bilateral, symmetric, and widespread retinal damage. Characteristic findings can be observed in ophthalmological examinations such as OCT, MCI, and IR., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethics statement Due to the retrospective nature of the study, the ethics committee of Henan Provincial People’s Hospital waived the need of obtaining informed consent’ in the manuscript.All methods were carried out in accordance with relevant guidelines and regulations.All experimental protocols were approved by Henan Provincial People’s Hospital., (© 2024. The Author(s).)

Background: Although moderate and severe Covid-19 patients have shown obstructive and restrictive disorders in pulmonary function after recovery from the disease, studies evaluating the effectiveness of rehabilitation programs that seek to improve lung function are scarce., Aim: Herein, we evaluate changes in lung function and perceived dyspnea in Covid-19 patients after undergoing 12 weeks of a pulmonary rehabilitation (PR) program., Design: Retrospective observational study., Setting: Cesar, Colombia Neumocesar Pneumological Center., Population: 100 outpatients with a history of Covid-19., Methods: Respiratory function using spirometry parameters, as well as perceived dyspnea, measured by the modified Medical Research Council (mMRC) dyspnea scale, was evaluated in 100 patients with a history of Covid-19. We used univariate and multivariate statistical approaches to assess changes in lung function and perceived dyspnea before and after a PR program to determine whether gender, age, height, weight, comorbidities, and oxygen delivery system affects the recovery of lung function and perceived dyspnea., Results: It was found that PR treatment has positive effects on respiratory pathologies caused by SARS-CoV-2 infection regardless of patient gender (S = 0,029), indicating that rehabilitation provided benefits regardless of the physical characteristics of the patients. Both univariate and multivariate statistical analyses indicated that FVC (P = 0,0001), FEV1(P = 0,0001), and mMRC (P = 0,0001) are robust diagnostic indicators of lung function recovery and perceived dyspnea. Both invasive and non-invasive positive pressure ventilatory support had deleterious effects on lung function prolongating patient recovery (P = 0,0001)., Conclusions: Rehabilitation programs can benefit patients facing respiratory pathologies caused by SARS-CoV-2 infection. Additional research on the long-term effects of the sequelae of Covid-19 is needed., Clinical Rehabilitation Impact: PR programs have positive effects on patients facing respiratory pathologies caused by SARS-CoV-2 infection., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Páez-Mora et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has triggered a protracted global pandemic from 2019 to 2022, and posed a significant threat to human health. One of the non-structural proteins 3CL pro of SARS-CoV-2 is considered as a validated target for the development of inhibitors against the virus. Disulfiram has been reported as a covalent inhibitor of 3CL pro ; however, its structure lacks bonding site with active pockets of 3CL pro and its highly symmetric structure doesn't match well with the irregular cavity of the active center, limiting its therapeutic applications. To enhance their affinity for the 3CL pro target, in this study, two kinds of disulfiram derivatives, designed based on the reevaluation and optimization of disulfiram, have been synthesized through photoredox chemistry, and the novel carbamo(dithioperoxo)thioates 4g-m were found to display 5-17 folds potency against SARS-CoV-2 3CL pro compared to the parent disulfiram, with resulting half-maximal inhibitory concentration (IC 50 ) values ranging from 0.14-0.47 μM. Carbamo(dithioperoxo)thioates 4i containing a 4-hydroxy piperidine and a 4-trifluoromethyl phenyl ring, was identified as the most potent inhibitor to both 3CL pro (IC 50  = 0.14 μM) and PL pro (IC 50  = 0.04 μM). Furthermore, molecular dynamics simulations, binding free energy analysis and mass analysis were performed and provided insights on the stability, conformational behavior, and interactions of 4g with 3CL pro . The green synthetic methodology, the privileged carbamo(dithioperoxo)thioate scaffold, and the molecular mechanisms presented might serve as a useful system for the further discovery of highly potent inhibitors targeting SARS-CoV-2 3CL pro ., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Long COVID is estimated to have affected 6.9 % of US adults, 17.8 million people in the US alone, as of early 2023. While SARS-CoV-2 is primarily considered a respiratory virus, gastrointestinal (GI) symptoms are also frequent in patients with coronavirus disease 2019 (COVID-19) and in patients with Long COVID. The risk of developing GI symptoms is increased with increasing severity of COVID-19, the presence of GI symptoms in the acute infection, and psychological distress both before and after COVID-19. Persistence of the virus in the GI tract, ensuing inflammation, and alteration of the microbiome are all likely mediators of the effects of SARS Co-V-2 virus on the gut. These factors may all increase intestinal permeability and systemic inflammation. GI inflammation and dysbiosis can change the absorption and metabolism of tryptophan, an important neurotransmitter. Long COVID GI symptoms resemble a Disorder of Gut Brain Interaction (DGBI) such as post infection Irritable Bowel Syndrome (IBS). Current standards of treatment for IBS can guide our treatment of Long COVID patients. Dysautonomia, a frequent Long COVID condition affecting the autonomic nervous system, can also affect the GI tract, and must be considered in Long COVID patients with GI symptoms. Long COVID symptoms fall within the broader category of Infection Associated Chronic Conditions (IACCs). Research into the GI symptoms of Long COVID may further our understanding of other post infection chronic GI conditions, and elucidate the roles of therapeutic options including antivirals, probiotics, neuromodulators, and treatments of dysautonomia., Competing Interests: Declaration of competing interest No competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Membrane fusion is the main pathway for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to invade host cells. Harringtonine (HT), derived from cephalotaxus fortunei Hook. f., has been recognized as an effective antagonist of SARS-CoV-2. It can directly block the active binding of spike (S) protein to host angiotensin converting enzyme 2 (ACE2), as well as hinder the enzymolysis of transmembrane serine proteases 2 (TMPRSS2). This study examined the potential of HT metabolites, 5'-de-O-methylharringtonine and cephalotaxine, as the membrane fusion inhibitors for SARS-CoV-2. 5'-De-O-methylharringtonine was synthesized and subsequently characterized by high resolution mass spectrometry and nuclear magnetic resonance to be structurally consistent, with a purity of 92.677% determined by reverse phase high performance liquid chromatography. Both 5'-de-O-methylharringtonine and cephalotaxine can specifically bind to SARS-CoV-2 S protein and TMPRSS2 using cell membrane chromatography. They can form hydrogen bonds with key sites that correlated highly with the enhanced binding affinity of SARS-CoV-2 and its variants to ACE2 or nafamostat to TMPRSS2. Moreover, 5'-de-O-methylharringtonine and cephalotaxine can inhibit pseudotyped virus entry and membrane fusion in a dose-dependent manner, with enhanced effectiveness upon elevated expression of TMPRSS2. Importantly, they displayed low cytotoxic effects on human normal cell lines. Our study suggested that 5'-de-O-methylharringtonine and cephalotaxine were of low toxicity and safety for humans as potential antagonists of SARS-CoV-2 and its variants, which deserve further validation in a biosafety level 3 facility., Competing Interests: Declaration of competing interest All authors declared that no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. The authors declare to comply with scientific research integrity and ethics, and have no plagiarism, duplicate or redundant publication, duplicate submission and other academic misconduct. The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Here, we report the synthesis of a series of oxyacanthine derivatives and evaluation for their anti-SARS-CoV-2 activity in Vero E6 cells. In order to eliminate the potential metabolic activation caused by para-methylene phenol moiety in oxyacanthine, totally 29 derivatives were designed and synthesized, resulting in 23 compounds with antivirus IC 50 below 5.00 μM and 9 compounds with antivirus IC 50 below 1.00 μM. Among them, amides compound 4a and 4d exhibited potent anti-SARS-CoV-2 activity and the most favorable selectivity index (SI) in vitro with the SI values of 115 and 70, respectively. The pharmacokinetic properties of 4a and 4d were also assessed. Much more improved exposure in mice, longer half-life (T 1/2 ), and increased oral bioavailability were observed for both compounds 4a and 4d compared with oxyacanthine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

SARS-CoV-2 causes COVID-19, with symptoms ranging from mild to severe, including pneumonia and death. This beta coronavirus has a 30-kilobase RNA genome and shares about 80 % of its nucleotide sequence with SARS-CoV-1. The replication/transcription complex, essential for viral RNA synthesis, includes RNA-dependent RNA polymerase (RdRp, nsp12) enhanced by nsp7 and nsp8. Antivirals like molnupiravir and remdesivir, which are RdRp inhibitors, treat severe COVID-19 but have limitations, highlighting the need for new therapies. This study assessed (-)-cytisine, methylcytisine, and thermopsine derivatives against SARS-CoV-1 and SARS-CoV-2 in vitro, focusing on their RdRp inhibition. Selected compounds from a previous study were evaluated using a SARS-CoV-2 RNA polymerase assay kit to investigate their structure-activity relationships. Compound 17 (1,3-dimethyluracil conjugate with (-)-cytisine and thermopsine) emerged as a potent inhibitor of SARS-CoV-1 and SARS-CoV-2 RdRp, with an IC50 value of 7.8 μM against SARS-CoV-2 RdRp. It showed a dose-dependent reduction in cytopathic effects in cells infected with SARS-CoV-1 and SARS-CoV-2 replicon-based single-round infectious particles (SRIPs) and significantly inhibited SARS-CoV N protein expression, with EC50 values of 0.12 µM for SARS-CoV-1 and 1.47 µM for SARS-CoV-2 SRIPs. Additionally, compound 17 reduced viral subgenomic RNA levels in a concentration-dependent manner in SRIP-infected cells. The structure-activity relationships of compound 17 with SARS-CoV-1 and SARS-CoV-2 RdRp were also investigated, highlighting it as a promising lead for developing antiviral agents against SARS and COVID-19., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Globally, the continuous spread and evolution of SARS-CoV-2, along with its variants, profoundly impact human well-being, health, security, and the growth of socio-economic. In the field of development of drugs against COVID-19, the main protease (M pro ) is a critical target as it plays a core role in the lifecycle of SARS-CoV-2. Bofutrelvir acts as a potent inhibitor of SARS-CoV-2 M pro , demonstrating high efficacy and broad-spectrum antiviral activity. Compared to therapies that require pharmacokinetic boosters, such as ritonavir, the monotherapy approach of Bofutrelvir reduces the risk of potential drug interactions, making it suitable for a wider patient population. However, further studies on the potency and mechanism of inhibition of Bofutrelvir against the M pro of COVID-19 and its variants, together with other coronaviruses, are needed to prepare for the possibility of a possible re-emerging threat from an analogous virus in the future. Here, we reveal the effective inhibition of Bofutrelvir against the M pro of SARS-CoV-2, SARS-CoV, and HCoV-229E through FRET and crystallographic analysis. Furthermore, the inhibitory mechanisms of Bofutrelvir against two SARS-CoV-2 M pro mutants (G15S and K90R) were also elucidated through FRET and crystallographic studies. Through detailed analysis and comparison of these crystal structures, we identified crucial structural determinants of inhibition and elucidated the binding mode of Bofutrelvir to M pro s from different coronaviruses. These findings are hopeful to accelerate the development of safer and more potent inhibitors against the M pro of coronavirus, and to provide important references for the prevention and treatment of similar viruses that may emerge in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

A large scale of pandemic coronavirus disease (COVID-19) in the past five years motivates a great deal of endeavors donating to the exploration on therapeutic drugs against COVID-19 as well as other diseases caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein is an overview on the organic small molecules that are potentially employed to treat COVID-19 and other SARS-CoV-2-related diseases. These organic small molecules are accessed from both natural resources and synthetic strategies. Notably, typical natural products presented herein consist of polyphenols, lignans, alkaloids, terpenoids, and peptides, which exert an advantage for the further discovery of novel anti-COVID-19 drugs from plant herbs. On the other hand, synthetic prodrugs are composed of a series of inhibitors towards RNA-dependent RNA polymerase (RdRp), main protease (M pro ), 3-chymotrypsin-like cysteine protease (3CL pro ), spike protein, papain-like protease (PL pro ) of the SARS-CoV-2 as well as the angiotensin-converting enzyme 2 (ACE2) in the host cells. Synthetic strategies are worth taken into consideration because they are beneficial for designing novel anti-COVID-19 drugs in the coming investigations. Although examples collected herein are just a drop in the bucket, developments of organic small molecules against coronavirus infections are believed to pave a promising way for the discovery of multi-targeted therapeutic drugs against not only COVID-19 but also other virus-mediated diseases., Competing Interests: Declaration of competing interest The author has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

A 34-year-old man with no medical history presented to our hospital with a sore throat and difficult oral intake for two days before admission. He had various symptoms, including red eyes, ocular discharge, a fever, and intraoral ulcers, and he was admitted immediately. The polymerase chain reaction test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was positive, as was the adenovirus antigen test of the pharyngeal swab fluid, suggesting overlapping adenovirus and SARS-CoV-2 infections. The patient's condition improved with conservative treatment. This case of severe and varied symptoms caused by co-infection with adenovirus and SARS-CoV-2 has been previously reported.

Background: Despite many studies evaluating lung ultrasound (LUS) for coronavirus disease 2019 (COVID-19) prognostication, the generalizability and utility across clinical settings are uncertain., Methods: Adults (≥18 years of age) with COVID-19 were enrolled at 2 military hospitals, an emergency department, home visits, and a homeless shelter in the United States, and in a referral hospital in Uganda. Participants had a 12-zone LUS scan performed at time of enrollment and clips were read off-site. The primary outcome was progression to higher level of care after the ultrasound scan. We calculated the cross-validated area under the curve for the validation cohort for individual LUS features., Results: We enrolled 191 participants with COVID-19 (57.9% female; median age, 45.0 years [interquartile range, 31.5-58.0 years]). Nine participants clinically deteriorated. The top predictors of worsening disease in the validation cohort measured by cross-validated area under the curve were B-lines (0.88 [95% confidence interval {CI}, .87-.90]), discrete B-lines (0.87 [95% CI, .85-.88]), oxygen saturation (0.82 [95%, CI, .81-.84]), and A-lines (0.80 [95% CI, .78-.81])., Conclusions: In an international multisite point-of-care ultrasound cohort, LUS parameters had high discriminative accuracy. Ultrasound can be applied toward triage across a wide breadth of care settings during a pandemic., Competing Interests: Potential conflicts of interest. S. D. P. reports that the USUHS IDCRP, a US DOD institution, and HJF were funded under a cooperative research and development agreement to conduct an unrelated phase 3 COVID-19 monoclonal antibody immunoprophylaxis trial sponsored by AstraZeneca. The HJF, in support of the USUHS IDCRP, was funded by the DOD Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense to augment the conduct of an unrelated phase 3 vaccine trial sponsored by AstraZeneca. Both of these trials were part of the US government COVID-19 response. Neither is related to the work presented here. T.S. receives consulting feeds from Verona Pharmaceuticals, Apogee Therapeutics, and honoraraia from American Thoracic Society and the COPD foundation. T.S. is an advisor to 4D Medical. C.C. receives consulting fees from Johnson & Johnson and Bayer AG regarding unrelated wearable devices. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

During the COVID-19 pandemic, wastewater-based epidemiology has proved to be an important tool for monitoring the spread of a disease in a population. Indeed, wastewater surveillance was successfully used as a complementary approach to support public health monitoring schemes and decision-making policies. An essential feature for the estimation of a disease transmission using wastewater data is the distribution of viral shedding rate of individuals in their personal human wastes as a function of the days of their infection. Several candidate shapes for this function have been proposed in literature for SARS-CoV-2. The purpose of the present work is to explore the proposed function shapes and examine their significance on analyzing wastewater SARS-CoV-2 shedding rate data. For this purpose, a simple model is employed applying to medical surveillance and wastewater data of the city of Thessaloniki during a period of Omicron variant domination in 2022. The distribution shapes are normalized with respect to the total virus shedding and then their basic features are investigated. Detailed analysis reveals that the main parameter determining the results of the model is the difference between the day of maximum shedding rate and the day of infection reporting. Since the latter is not part of the distribution shape, the major feature of the distribution affecting the estimation of the number of infected people is the day of maximum shedding rate with respect to the initial infection day. On the contrary, the duration of shedding (total number of disease days) as well as the exact shape of the distribution are by far less important. The incorporation of such wastewater surveillance models in conventional epidemiological models - based on recorded disease transmission data- may improve predictions for disease spread during outbreaks., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic disrupted respiratory syncytial virus (RSV) seasonality. To optimize the use and evaluation of RSV infant immunization strategies, monitoring changes in RSV epidemiology is essential., Methods: Hospitalizations for acute respiratory infections (ARIs) and RSV-coded ARI in children <2 years were extracted in 4 European hospitals, according to predefined case definitions (International Classification of Diseases, Tenth Revision codes). Prepandemic RSV seasons (2017-2018 to 2019-2020) were compared to 2021-2022 and 2022-2023., Results: In 2021-2022 and 2022-2023, the peak number of RSV hospitalizations was higher than prepandemic peaks after short periods of RSV circulation, and lower than prepandemic peaks after long periods of RSV circulation. A greater proportion of RSV hospitalizations occurred in children 1 to <2 years in 2021-2022 in the Netherlands (18% vs 9%, P = .04). No increase in age was observed elsewhere. High-risk children represented a greater proportion of RSV hospitalizations during the pandemic. The proportion of pediatric intensive care unit admissions did not increase., Conclusions: A decrease in population immunity has been linked to older age at RSV hospitalization. We did not observe an increase in age in 3 of the 4 participating countries. Broad age categories may have prevented detecting an age shift. Monitoring RSV epidemiology is essential as Europe implements RSV immunization., Competing Interests: Potential conflicts of interest. J. G. W. has been an investigator for clinical trials sponsored by pharmaceutical companies, including AstraZeneca, Merck, Pfizer, Sanofi, and Janssen, and participated in the advisory boards of Janssen and Sanofi and was a speaker at a Sanofi sponsored symposium (all fees/honoraria were paid to UMCU). T. H. has received honoraria for lectures or participation in advisory boards or data monitoring committees from Janssen, Sanofi, Enanta, MSD, Pfizer, Moderna, and Shionogi. A. D.-U. participated in clinical trials for vaccines, monoclonals, and antivirals for RSV as a subinvestigator. All honoraria were paid to the institution. F. M.-T. reports honoraria from GSK, Pfizer, Sanofi Pasteur, MSD, Seqirus, Biofabri, and Janssen for taking part in advisory boards and expert meetings and for acting as a speaker in congresses, outside the submitted work; and principal investigator role in randomized controlled trials for GSK, Pfizer, Sanofi Pasteur, MSD, Seqirus, Biofabri, Janssen, Ablynx, Gilead, Regeneron, Roche, Abbott, Novavax, and MedImmune, with honoraria paid to his institution. S. C. has provided consultancy or investigator roles in relation to product development for Ablynx, Janssen, MedImmune, AstraZeneca, Pfizer, GSK, Vertex, AbbVie, and Boehringer Ingelheim, with fees paid to the University of Edinburgh. L. J. B. has regular interaction with pharmaceutical and other industrial partners. He has not received personal fees or other personal benefits. UMCU has received major funding (>€100 000 per industrial partner) for investigator-initiated studies from AbbVie, MedImmune, AstraZeneca, Sanofi, Janssen, Pfizer, MSD, and MeMed Diagnostics. UMCU has received major funding for the RSV GOLD study from the Bill & Melinda Gates Foundation. UMCU has received major funding as part of the public-private partnership IMI-funded RESCEU and PROMISE projects with partners GSK, Novavax, Janssen, AstraZeneca, Pfizer, and Sanofi. UMCU has received major funding by Julius Clinical for participating in clinical studies sponsored by MedImmune and Pfizer. UMCU received minor funding (€1000–€25 000 per industrial partner) for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna, AstraZeneca, MSD, Sanofi, Janssen. L. B. is the founding chairman of the ReSViNET Foundation. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Wastewater-based epidemiological (WBE) surveillance is a viable disease surveillance technique capable of monitoring the spread of infectious disease agents in sewershed communities. In addition to detecting viral genomes in wastewater, WBE surveillance can identify other endogenous biomarkers that are significantly elevated and excreted in the saliva, urine, and/or stool of infected individuals. Human protein biomarkers allow the realization of real-time WBE surveillance using highly sensitive biosensors. In this study, we analyzed endogenous protein biomarkers present in wastewater influent through liquid chromatography-tandem mass spectrophotometry and scaffold data-independent acquisition to identify candidate target protein biomarkers for WBE surveillance of SARS-CoV-2. We found that out of the 1382 proteins observed in the wastewater samples, 44 were human proteins associated with infectious diseases. These included immune response substances such as immunoglobulins, cytokine-chemokines, and complements, as well as proteins belonging to antimicrobial and antiviral groups. A significant correlation was observed between the intensity of human infectious disease-related protein biomarkers in wastewater and COVID-19 case numbers. Real-time WBE surveillance using biosensors targeting immune response proteins, such as antibodies or immunoglobulins, in wastewater holds promise for expediting the implementation of relevant policies for the effective prevention of infectious diseases in the near future., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this study., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The recent coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spurred intense research efforts to develop new materials with antiviral activity. In this study, we genetically engineered amyloid-based nanofibrils for capturing and neutralizing SARS-CoV-2. Building upon the amyloid properties of a short Sup35 yeast prion sequence, we fused it to SARS-CoV-2 receptor-binding domain (RBD) capturing proteins, LCB1 and LCB3. By tuning the reaction conditions, we achieved the spontaneous self-assembly of the Sup35-LCB1 fusion protein into a highly homogeneous and well-dispersed amyloid-like fibrillar material. These nanofibrils exhibited high affinity for the SARS-CoV-2 RBD, effectively inhibiting its interaction with the angiotensin-converting enzyme 2 (ACE2) receptor, the primary entry point for the virus into host cells. We further demonstrate that this functional nanomaterial entraps and neutralizes SARS-CoV-2 virus-like particles (VLPs), with a potency comparable to that of therapeutic antibodies. As a proof of concept, we successfully fabricated patterned surfaces that selectively capture SARS-CoV-2 RBD protein on wet environments. Collectively, these findings suggest that these protein-only nanofibrils hold promise as disinfecting coatings endowed with selective SARS-CoV-2 neutralizing properties to combat viral spread or in the development of sensitive viral sampling and diagnostic tools., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Substantial uncertainties pose challenges to the accuracy of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) quantification in wastewater. We conducted a comprehensive evaluation of two concentration methods, three nucleic acid extraction methods, and the amplification performance of eight primer-probe sets. Our results showed that the two concentration methods exhibited similar recovery rates. Specifically, using a 30 kDa cut-off ultrafilter and a centrifugal force of 2500 g achieved the highest virus recovery rates (27.32 ± 8.06 % and 26.37 ± 7.77 %, respectively), with lower corresponding quantification uncertainties of 29.51 % and 29.47 % in ultrafiltration methods. Similarly, a 15 % PEG concentration with 1.5 M NaCl markedly improved virus recovery (26.76 ± 5.92 % and 28.47 ± 6.74 %, respectively), and reducing variation to 22.16 % and 23.66 % in the PEG precipitation method. Additionally, employing a vigorous bead-beating approach at 6 m/s during viral RNA extraction significantly increased RNA yield, with an efficiency reaching up to 82.18 %. Among the evaluated eight primer-probe sets, the E&#95;Sarbeco primer-probe set provided the most stable and consistent quantitative results across various sample matrices. These findings are crucial for establishing robust viral quantification protocols and enhancing methodological precision for effective wastewater surveillance, enabling sensitive and precise detection of SARS-CoV-2., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest in this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In regions without adequate centralized wastewater treatment plants, sample collection from rivers and sewers can be an alternative sampling strategy for wastewater surveillance. This study aimed to assess the feasibility of alternative sampling strategies by testing samples collected from rivers (n = 246) and sewers (n = 244) in the Kathmandu Valley between March 2021 and February 2022. All samples were concentrated using the skimmed-milk flocculation method and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was quantified using the nucleocapsid (N) and envelope (E) genes qPCR assays. Of the total, 75 % (371/490) of the samples tested positive using at least one qPCR assay, with concentrations ranging from 3.0 to 8.3 log 10 gene copies/L. No significant correlation between concentrations of SARS-CoV-2 from both sewers and river with the number of confirmed coronavirus disease 2019 (COVID-19) cases in the Kathmandu valley was observed (p > 0.05). Despite the high concentration of SARS-CoV-2 in rivers and sewers, we hypothesize this finding to be a result of inaccurate number of clinical cases possibly due to inadequate clinical testing. This longitudinal study further supports the statement to consider sampling strategies from sewers and rivers for WBS in Nepal and other low and middle-income countries., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Therapeutic monoclonal antibodies (mAbs) have been studied in humans, but the impact on immune memory of mAb treatment during an ongoing infection remains unclear. We evaluated the effect of infusion of the anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD) mAb bamlanivimab on memory B cells (MBCs) in SARS-CoV-2-infected individuals. Bamlanivimab treatment skewed the repertoire of MBCs targeting spike toward non-RBD epitopes. Furthermore, the relative affinity of RBD MBCs was weaker in mAb-treated individuals compared to placebo-treated individuals over time. Subsequently, after mRNA coronavirus disease 2019 vaccination, MBC differences persisted and mapped to a specific reduction in recognition of the class II RBD site, the same RBD epitope recognized by bamlanivimab. These findings indicate a substantial role of antibody feedback in regulating MBC responses to infection, and single mAb administration can continue to impact MBC responses to additional antigen exposures months later., Competing Interests: Potential conflicts of interest. S. C. has consulted for GSK, JP Morgan, Citi, Morgan Stanley, Avalia NZ, Nutcracker Therapeutics, University of California, California State Universities, United Airlines, Adagio, Sanofi, and Roche. J. S. C. has consulted for Merck and Company. P. K. is an employee and shareholder of Eli Lilly and Company. K. W. C. has consulted for Pardes Biosciences. D. M. S. has consulted for and has equity stake in Linear Therapies, Model Medicines, and Vx Biosciences and has consulted for Bayer, Kiadis, Signant Health, and Brio Clinical. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Pneumococcal carriage is associated with increased acquisition and duration of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among adults. While pneumococcal conjugate vaccines (PCVs) prevent carriage of vaccine-serotype pneumococci, their potential impact on coronavirus disease 2019 (COVID-19)-related outcomes remains poorly understood in populations with prevalent immunity against SARS-CoV-2., Methods: We undertook a retrospective cohort study of adults aged ≥65 years in the Kaiser Permanente Southern California healthcare system who had received ≥2 COVID-19 vaccine doses, comparing risk of SARS-CoV-2 infection between 1 January 2021 and 31 December 2022 among recipients and nonrecipients of 13-valent PCV (PCV13) employing multiple strategies to mitigate bias from differential test-seeking behavior., Results: The ajusted hazard ratio of confirmed SARS-CoV-2 infection comparing PCV13 recipients to nonrecipients was 0.92 (95% confidence interval [CI], .90-.95), corresponding to prevention of 3.9 (95% CI, 2.6-5.3) infections per 100 person-years. Following receipt of 2, 3, and ≥4 COVID-19 vaccine doses, aHRs (95% CI) were 0.85 (.81-.89), 0.94 (.90-.97), and 0.99 (.93-1.04), respectively. The aHR (95% CI) for persons who had not received COVID-19 vaccination in the preceding 6 months was 0.90 (.86-.93), versus 0.94 (.91-.98) within 6 months after COVID-19 vaccination. Similarly, aHRs (95% CI) were 0.92 (.89-.94) for persons without history of documented SARS-CoV-2 infection, versus 1.00 (.90-1.12) for persons with documented prior infection., Conclusions: Among older adults who had received ≥2 COVID-19 vaccine doses, PCV13 was associated with modest protection against SARS-CoV-2 infection. Protective effects of PCV13 were greater among individuals expected to have weaker immune protection against SARS-CoV-2 infection., Competing Interests: Potential conflicts of interest. J. A. L. discloses receipt of research grants and consulting honoraria from Pfizer and Merck, Sharp & Dohme and consulting honoraria from Seqirus and VaxCyte, all unrelated to this research. S. Y. T. reports receipt of research grants related and unrelated to this research from Pfizer. L. R. G., A. A., A. C., L. J., and B. D. G. are employees of Pfizer and may hold stocks or stock options. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Aims: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the risk of self-harming behaviours warrants further investigation. Here, we hypothesized that people with a history of hospitalization for self-harm may be particularly at risk of readmission in case of SARS-CoV-2 hospitalization., Methods: We conducted a retrospective analysis based on the French national hospitalization database. We identified all patients hospitalized for deliberate self-harm (10th edition of the International Classification of Diseases codes X60-X84) between March 2020 and March 2021. To study the effect of SARS-CoV-2 hospitalization on the risk of readmission for self-harm at 1-year of the inclusion, we performed a multivariable Fine and Gray model considering hospital death as a competing event., Results: A total of 61,782 individuals were hospitalized for self-harm. During the 1-year follow-up, 9,403 (15.22%) were readmitted for self-harm. Between inclusion and self-harm readmission or the end of follow-up, 1,214 (1.96% of the study cohort) were hospitalized with SARS-CoV-2 (mean age 60 years, 52.9% women) while 60,568 were not (mean age 45 years, 57% women). Multivariate models revealed that the factors independently associated with self-harm readmission were: hospitalization with SARS-CoV-2 (adjusted hazard ratio (aHR) = 3.04 [2.73-3.37]), psychiatric disorders (aHR = 1.61 [1.53-1.69]), self-harm history (aHR = 2.00 [1.88-2.04]), intensive care and age above 80., Conclusions: In hospitalized people with a personal history of self-harm, infection with SARS-CoV-2 increased the risk of readmission of self-harm, with an effect that seemed to add to the effect of a history of mental disorders, with an equally significant magnitude. Infection may be a significantly stressful condition that precipitates self-harming acts in vulnerable individuals. Clinicians should pay particular attention to the emergence of suicidal ideation in these patients in the aftermath of SARS-CoV-2 infection.

Background: Early in the COVID-19 pandemic, numerous clinical trials were initiated. Although concerns were raised regarding the quality of the trials, the eventual research output yielded from the trials remains unknown. The objective of this study was to include all clinical trials registered on ClinicalTrials.gov during the first 6 months of the pandemic and assess if and where their results had been reported, their completion and discontinuation rates, achieved enrolment and changes made to the primary outcome after trial registration., Methods: We included all interventional studies related to COVID-19 first registered on ClinicalTrials.gov between 1 January 2020 and 1 July 2020. We systematically searched for trial results, reported through 15 May 2023, in scientific publications, preprints and ClinicalTrials.gov. We assessed the achieved trial enrolment, trial discontinuation (reaching <90% of target enrolment), and whether the primary outcome had been changed as compared with the initial protocol registration., Results: The 775 clinical trials included in the analysis planned to enrol 238 933 (median (IQR) 120 (60, 304) patients; 355 (46%) of the trials had reported results, and 283 (36%) were published in a scientific journal. In the reported trials, the total enrolment was 95 332 (median (IQR) 105 (45, 222) patients. 186 (24%) trials were completed, and 169 (22%) trials were discontinued, with slow recruitment being the most stated reason for discontinuation (9% of all trials, although 30% of the discontinued trials did not report a reason). 117 (33%) of the reported trials had changed their primary outcome. In total, 157 (20%) trials were completed and published in a scientific journal, of which 105 enrolled ≥100 patients and 103 had not changed the primary outcome. 63 completed and published trials enrolled ≥100 patients and had not changed the primary outcome., Conclusions: Most clinical trials of COVID-19 registered at ClinicalTrials.gov during the first 6 months of the pandemic remained unreported or had been discontinued. Many of the trials whose results had been reported enrolled few patients and changed the primary outcome after trial registration., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Long-COVID symptoms remain incompletely defined due to a large heterogeneity in the populations studied, case definitions, and settings of care. The aim of this study was to assess, in patients accessing care for Long-COVID, the profile of symptoms reported, the possible clustering of symptoms and cases, the functional status compared to pre-infection, and the impact on working activity., Methods: Multicentre cohort study with a collection of both retrospective and prospective data. Demographics, comorbidities, severity and timing of acute COVID, subjective functional status, working activity and presence of 30 different symptoms were collected using a shortened version of the WHO Post COVID-19 Case Report Form. The impact on working activity was assessed in multivariable logistic regression models. Clustering of symptoms was analysed by hierarchical clustering and the clustering of cases by two-step automatic clustering., Results: The study evaluated 1297 individuals (51.5% women) from 30 clinical centres. Men and women had different profiles in terms of comorbidities, vaccination status, severity and timing of acute SARS-CoV-2 infection. Fatigue (55.9%) and dyspnea (47.2%) were the most frequent symptoms. Women reported more symptoms (3.6 vs. 3.1, p < 0.001), with a significantly higher prevalence of memory loss, difficult concentration, cough, palpitation or tachycardia, dermatological abnormalities, brain fog, headache and visual disturbances. Dyspnea was more common in men. In the cluster analysis of the 19 more common symptoms, five aggregations were found: four two-symptom clusters (smell and taste reduction; anxiety and depressed mood; joint pain or swelling and muscle pain; difficult concentration and memory loss) and one six-symptom cluster (brain fog, equilibrium/gait disturbances, headache, paresthesia, thoracic pain, and palpitations/tachycardia). In a multivariable analysis, headache, dyspnea, difficult concentration, disturbances of equilibrium or gait, visual disturbances and muscular pain were associated with reduced or interrupted working activity. Clustering of cases defined two clusters, with distinct characteristics in terms of phase and severity of acute infection, age, sex, number of comorbidities and symptom profile., Conclusions: The findings provide further evidence that Long-COVID is a heterogeneous disease with manifestations that differ by sex, phase of the pandemic and severity of acute disease, and support the possibility that multiple pathways lead to different clinical manifestations., Competing Interests: Declarations Ethics approval and consent to participate The Italian National Ethics Committee approved the project (AOO-ISS—19/04/2022–0015066 Class: PRE BIO CE 01.00). Written informed consent was required for patient inclusion, using a patient information and consent form also approved by the Italian National Ethics Committee. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The COVID-19 pandemic has highlighted the importance of point-of-care (POC) pathogen detection. Accurate and accessible diagnostic techniques for virus identification are crucial for controlling the spread of diseases and have profound implications for our communities and global health. Reagentless surface-enhanced Raman scattering (SERS) sensors offer a promising solution for POC testing due to their capability to function without complex processing steps. However, their application in this space is limited by the fact that these solution-based assays are challenging to administer, transport and store. To overcome these limitations, we employed a freeze-drying (lyophilization) process on reagentless SERS sensors and investigated their improved stability and shelf-life. We explored this mechanism using different concentrations of cryoprotectants. Lyophilized sensors were then tested in a mix-and-detect fashion by adding to the dry sensors a drop of the sample, consisting of saliva spiked with target DNA oligonucleotides relative to different SARS-CoV-2 variants. In addition, we further uncovered how lyophilization benefits sensors with a DNA-catalysis mechanism. In summary, our findings indicate that lyophilization substantially enhances the practicality and usability of reagentless SERS sensors, contributing to the translation of this powerful diagnostic tool to POC testing in remote areas with limited resources.

Anti-SARS-CoV-2 vaccination has saved millions of lives in the past few years. To maintain a high level of protection, particularly in at-risk populations, booster doses are recommended to counter the waning of circulating antibody levels over time and the continuous emergence of immune escape variants of concern (VOCs). As anti-spike serology is now widely available, it may be considered a useful tool to identify individuals needing an additional vaccine dose, i.e., to screen certain populations to identify those whose plasma antibody levels are too low to provide protection. However, no recommendations are currently available on this topic. We reviewed the relevant supporting and opposing arguments, including areas of uncertainty, and concluded that in most populations, spike serology should not be used to decide about the administration of a booster dose. The main counterarguments are as follows: correlates of protection are imperfectly characterised, essentially owing to the emergence of VOCs; spike serology has an intrinsic inability to comprehensively reflect the whole immune memory; and booster vaccines are now VOC-adapted, while the commonly available commercial serological assays explore antibodies against the original virus., Competing Interests: Declaration of competing interest Anna L. Goodman reports grants from Novavax to run vaccine trials and non-commercial funding from the INSIGHT network (NIH-TICO trial) to her institution outside of the submitted work; moreover, ALG is named on a patent AstraZeneca vaccine issued to the University of Oxford and has received personal financial contributions for this. Manuel Krone received honoraria from Abbott, GSK and Pfizer outside this work. All other authors have not conflict of interest to declare., (Copyright © 2024. Published by Elsevier Ltd.)

Background: To overcome supply issues of COVID-19 vaccines, this partially single blind, multi-centric, vaccine trial aimed to evaluate humoral immunogenicity using lower vaccine doses, intradermal vaccination, and heterologous vaccine schedules. Also, the immunity after a booster vaccination was assessed., Methodology: 566 COVID-19-naïve healthy adults were randomized to 1 of 8 treatment arms consisting of combinations of BNT162b2, mRNA-1273, and ChAdOx1-S. Anti-Receptor-Binding Domain immunoglobulin G (RBD IgG) titers, neutralizing antibody titres, and avidity of the anti-RBD IgGs was assessed up to 1 year after study start., Results: Prolonging the interval between vaccinations from 28 to 84 days and the use of a heterologous BNT162b2 + mRNA-1273 vaccination schedule led to a non-inferior immune response, compared to the reference schedule. A low dose of mRNA-1273 was sufficient to induce non-inferior immunity. Non-inferiority could not be demonstrated for intradermal vaccination. For all adapted vaccination schedules, anti-RBD IgG titres measured after a first booster vaccination were non-inferior to their reference schedule., Conclusion: This study suggests that reference vaccine schedules can be adapted without jeopardizing the development of an adequate immune response. Immunity after a booster vaccination did not depend on the dose or brand of the booster vaccine, which is relevant for future booster campaigns. The trial is registered in the European Union Clinical Trials Register (number 2021-001993-52) and on clinicaltrials.gov (NCT06189040)., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Pierre Van Damme reports financial support was provided by Belgian Health Care Knowledge Centre. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper]., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Suspected allergic reactions after mRNA COVID-19 vaccination withheld multiple individuals from getting fully vaccinated during the pandemic. We vaccinated adults who had experienced possible allergic symptoms after their first intramuscular dose of a COVID-19 mRNA vaccine with a 1/5th fractional intradermal test dose of the mRNA-1273 (Moderna) COVID-19 vaccine. No anaphylactic reactions were observed after intradermal vaccination (n = 56). Serum anti-S1 IgG concentrations were measured using a bead-based multiplex assay four weeks after vaccinations. Antibody concentrations were compared with a previously collected nationwide cohort that had received two intramuscular doses of mRNA-1273. Antibody responses in all subjects tested (n = 47) were comparable to standard of care intramuscular dosing. Fractional intradermal dosing of mRNA COVID-19 vaccines may provide a pragmatic solution that is safe, time efficient compared to skin prick testing, dose sparing and immunogenic in individuals with suspected vaccine allergy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To measure and evaluate the impact of receiving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in pregnancy on immunoglobulin G (IgG) and immunoglobulin A (IgA) titres in maternal and infant samples., Design: Prospective cohort study., Setting: Tertiary obstetric centre., Population or Sample: 52 pregnant women who received one or more SARS-CoV-2 vaccine doses during pregnancy and their neonates., Methods: IgG and IgA concentrations against SARS-CoV-2 antigens were measured from samples collected at delivery and 4-6 weeks postpartum and compared using Spearman correlations., Main Outcome Measures: Maternal and infant IgG and IgA titres in response to vaccination and infection in pregnancy., Results: In maternal serum collected at delivery, participants without evidence of prior infection who received 3 + doses of a SARS-CoV-2 vaccine had higher Anti-Spike (S) IgG geometric mean concentrations (log 10 AU/mL)(GMC) than those who received 2 doses (3 + Doses = 5.00, 2 Doses = 4.60, p = 0.08). The differences in IgG Anti-S GMC were statistically significant in cord serum, and in postpartum samples of maternal serum, infant serum and breast milk (Cord GMCs: 3 + Doses = 5.32, 2 Doses = 4.98, p < 0.05; Postpartum maternal serum GMCs: 3 + Doses = 5.25, 2 Doses = 4.57, p < 0.001; Postpartum infant serum GMCs: 3 + Doses = 5.10, 2 Doses = 4.72, p = 0.03; Postpartum breast milk GMCs: 3 + Doses = 2.61, 2 Doses = 1.94, p < 0.0001). Among participants with 3 + Doses, those with evidence of SARS-CoV-2 infection had statistically significant higher anti-S IgG GMCs than those without prior infection (Maternal serum at delivery: SARS-CoV-2+=5.65, SARS-CoV-2-=5.00, p = 0.004; Cord: SARS-CoV-2+=5.68, SARS-CoV-2-=5.32, p = 0.02; Postpartum maternal serum: SARS-CoV-2+=5.66, SARS-CoV-2-=5.25, p < 0.001; postpartum infant serum: SARS-CoV-2+=5.50, SARS-CoV-2-=5.10, p = 0.003; Postpartum breast milk: SARS-COV-2+=3.25, SARS-COV-2-=2.61, p = 0.009). Significant positive correlations were found for anti-S IgG titres between paired maternal and infant samples at delivery and postpartum (Delivery: R = 0.91, p < 0.001; postpartum: R = 0.86, p < 0.001)., Conclusions: Receipt of a SARS-CoV-2 vaccine and SARS-CoV-2 infection elicit strong IgG and IgA antibody responses in pregnant women with evidence of transplacental transfer to the fetus., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: IK, CM, EM, GA, JA, CE, AJ, MK, MM, GT, IS and DM have no conflicts to disclose. MS has been an investigator on projects funded by GlaxoSmithKline, Merck, Moderna, Pfizer, Sanofi-Pasteur, Seqirus, Symvivo and VBI Vaccines, with funds paid to his institute. MS is supported via salary awards from the BC Children’s Hospital Foundation and Michael Smith Health Research BC., (Copyright © 2024. Published by Elsevier Ltd.)

Though widely applied in other epidemiological fields, the case-cohort study design has seen little application in the field of vaccinology. Case-cohort studies use probabilistic sampling and reweighting to draw inferences about effects (in this case vaccine efficacy) at the population level in an efficient manner. The SARS-CoV-2 pandemic was met with high vaccine uptake, and high rates of population testing prior to the emergence of Omicron variants of concern, in Ontario, Canada, providing an ideal environment for application of case-cohort methodology. We combined a population-based case line list and vaccination database for the province of Ontario between December 2020 and October 2021. Risk of infection after vaccination was evaluated in all laboratory-confirmed vaccinated SARS-CoV-2 cases, and a 2 % sample of vaccinated controls, evaluated using survival analytic methods, including construction of Cox proportional hazards models. Vaccination status was treated as a time-varying covariate. First and second doses of SARS-CoV-2 vaccine markedly reduced risk of infection (first dose efficacy 68 %, 95 % CI 67 %-69 %; second dose efficacy 88 %, 95 % CI 87-88 %). In multivariable models, extended dosing intervals were associated with lowest risk of breakthrough infection (HR for redosing 0.64 (95 % CI 0.61-0.67) at 6-8 weeks). Heterologous vaccine schedules that mixed viral vector vaccine first doses with mRNA second doses were significantly more effective than mRNA only vaccines. Risk of infection largely vanished during the time period 4-6 months after the second vaccine dose, but rose markedly thereafter. We conclude that a case-cohort design provided an efficient means to identify strong protective effects associated with SARS-CoV-2 vaccination in real time, and also served to quantify the timing and magnitude of infection breakthrough risk in the same cohort. Heterologous vaccination and extended dosing intervals improved the durability of immune response., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: David Fisman reports financial support was provided by Canadian Institutes of Health Research. David Fisman reports a relationship with Pfizer Inc that includes: consulting or advisory. David Fisman reports a relationship with Seqirus Inc that includes: consulting or advisory. David Fisman reports a relationship with AstraZeneca Canada Inc that includes: consulting or advisory. David Fisman reports a relationship with Merck & Co Inc that includes: consulting or advisory. David Fisman reports a relationship with Sanofi Pasteur Inc that includes: consulting or advisory. David Fisman reports a relationship with Elementary Teachers’ Federation of Ontario that includes: paid expert testimony. David Fisman reports a relationship with Ontario Nurses’ Association that includes: paid expert testimony. Ashleigh Tuite reports a relationship with Public Health Agency of Canada that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)