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<title>05 May, 2023</title>
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<title>Covid-19 Sentry</title><meta content="width=device-width, initial-scale=1.0" name="viewport"/><link href="styles/simple.css" rel="stylesheet"/><link href="../styles/simple.css" rel="stylesheet"/><link href="https://unpkg.com/aos@2.3.1/dist/aos.css" rel="stylesheet"/><script src="https://unpkg.com/aos@2.3.1/dist/aos.js"></script></head>
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<h1 data-aos="fade-down" id="covid-19-sentry">Covid-19 Sentry</h1>
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<h1 data-aos="fade-right" data-aos-anchor-placement="top-bottom" id="contents">Contents</h1>
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<li><a href="#from-preprints">From Preprints</a></li>
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<li><a href="#from-clinical-trials">From Clinical Trials</a></li>
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<li><a href="#from-pubmed">From PubMed</a></li>
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<li><a href="#from-patent-search">From Patent Search</a></li>
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<h1 data-aos="fade-right" id="from-preprints">From Preprints</h1>
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<li><strong>A bivalent ChAd nasal vaccine protects against SARS-CoV-2 BQ.1.1 and XBB.1.5 infection and disease in mice and hamsters</strong> -
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We previously described a nasally delivered monovalent adenoviral-vectored SARS-CoV-2 vaccine (ChAd-SARS-CoV-2-S, targeting Wuhan-1 spike [S]; iNCOVACC) that is currently used in India as a primary or booster immunization. Here, we updated the mucosal vaccine for Omicron variants by creating ChAd-SARS-CoV-2-BA.5-S, which encodes for a pre-fusion and surface-stabilized S protein of the BA.5 strain, and then tested monovalent and bivalent vaccines for efficacy against circulating variants including BQ.1.1 and XBB.1.5. Whereas monovalent ChAd-vectored vaccines effectively induced systemic and mucosal antibody responses against matched strains, the bivalent ChAd-vectored vaccine elicited greater breadth. However, serum neutralizing antibody responses induced by both monovalent and bivalent vaccines were poor against the antigenically distant XBB.1.5 Omicron strain and did not protect in passive transfer experiments. Nonetheless, nasally delivered bivalent ChAd-vectored vaccines induced robust antibody and spike-specific memory T cell responses in the respiratory mucosa, and conferred protection against WA1/2020 D614G and Omicron variants BQ.1.1 and XBB.1.5 in the upper and lower respiratory tracts of both mice and hamsters. Our data suggest that a nasally delivered bivalent adenoviral-vectored vaccine induces protective mucosal and systemic immunity against historical and emerging SARS-CoV-2 strains without requiring high levels of serum neutralizing antibody.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.05.04.539332v1" target="_blank">A bivalent ChAd nasal vaccine protects against SARS-CoV-2 BQ.1.1 and XBB.1.5 infection and disease in mice and hamsters</a>
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</div></li>
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<li><strong>Integrated NMR and MS analysis of plasma metabolome reveals major changes in inflammatory markers, one-carbon, lipid, and amino acid metabolism in severe and fatal COVID-19 subjects</strong> -
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Brazil has the second highest COVID-19 death rate while Rio de Janeiro is among the states with the highest rate in the country. Although effective vaccines have been developed, it is anticipated that the ongoing COVID-19 pandemic will transition into an endemic state. Under this scenario, it is worrisome that the underlying molecular mechanisms associated with the disease clinical evolution from mild to severe, as well as the mechanisms leading to long COVID are not yet fully understood. In this study, 1H Nuclear Magnetic Resonance spectroscopy and Liquid Chromatography-Mass spectrometry-based metabolomics were used to identify potential pathways and metabolites involved in COVID-19 pathophysiology and disease outcome. Between April and July 2020, 35 plasma samples from patients with confirmed severe COVID-19 from two reference centers in Rio de Janeiro, and 12 samples from non-infected control subjects, were collected and included in this study. Of the 35 samples from COVID-19 patients, 18 were from survivors and 17 from non-survivors. We observed that patients with severe COVID-19 had their plasma metabolome significantly changed if compared to control subjects. We observed lower levels of glycerophosphocholine and other choline-related metabolites, serine, glycine, and betaine, indicating a dysregulation in methyl donors and one-carbon metabolism. Importantly, non-survivors had higher levels of creatine/creatinine, 4-hydroxyproline, gluconic acid and N-acetylserine compared to survivors and controls, reflecting uncontrolled inflammation, liver and kidney dysfunction, and insulin resistance in these patients. Lipoprotein dynamics and amino acid metabolism were also altered in severe COVID-19 subjects. Several changes were greater in women, thus patient9s sex should be considered in pandemic surveillance to achieve better disease stratification and improve outcomes. The incidence of severe outcome after hospital discharge is very high in Brazil, thus these metabolic alterations may be used to monitor patients9 organs and tissues and to understand the pathophysiology of long-post COVID-19.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.19.23288802v1" target="_blank">Integrated NMR and MS analysis of plasma metabolome reveals major changes in inflammatory markers, one-carbon, lipid, and amino acid metabolism in severe and fatal COVID-19 subjects</a>
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<li><strong>Enhancing drug repurposing on graphs by integrating drug molecular structure as feature</strong> -
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Drug repurposing has become increasingly important, particularly in light of the COVID-19 pandemic. This process involves identifying new therapeutic uses for existing drugs, which can significantly reduce the cost, risk, and time associated with developing new drugs, de novo development. A previous conducted study proved that Deep Learning can be used to streamline this process by identifying drug repurposing hypotheses. The study presented a model called REDIRECTION, which utilized the rich biomedical information available in graph form and combined it with Geometric Deep Learning to find new indications for existing drugs. The reported metrics for this model were 0.87 for AUROC and 0.83 for AUPRC. In this current study, the importance of node features in GNNs is explored. Specifically, the study used GNNs to embed two-dimensional drug molecular structures and obtain corresponding features. These features were incorporated into the drug repurposing graph, along with some other enhancements, resulting in an improved model called DMSR. Performance score for the reported metrics values raised by 0.0448 in AUROC and 0.0919 in AUPRC. Based on these findings, we believe that the method used for embedding drug molecular structures is interesting and captures valuable information about drugs. Its incorporation in the graph for drug repurposing can significantly benefit the process, leading to improved performance evaluation metrics.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.05.03.539227v1" target="_blank">Enhancing drug repurposing on graphs by integrating drug molecular structure as feature</a>
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<li><strong>Researching COVID to enhance recovery (RECOVER) autopsy study protocol: Rationale, objectives, and design</strong> -
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Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or organ dysfunction after the acute phase of infection, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are poorly understood. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Tissue Pathology Study (RECOVER-Pathology) are to: (1) characterize prevalence and types of organ injury/disease and pathology occurring with PASC; (2) characterize the association of pathologic findings with clinical and other characteristics; (3) define the pathophysiology and mechanisms of PASC, and possible mediation via viral persistence; and (4) establish a post-mortem tissue biobank and post-mortem brain imaging biorepository. Methods: RECOVER-Pathology is a cross-sectional study of decedents dying at least 15 days following initial SARS-CoV-2 infection. Eligible decedents must meet WHO criteria for suspected, probable, or confirmed infection and must be aged 18 years or more at the time of death. Enrollment occurs at 7 sites in four U.S. states and Washington, DC. Comprehensive autopsies are conducted according to a standardized protocol within 24 hours of death; tissue samples are sent to the PASC Biorepository for later analyses. Data on clinical history are collected from the medical records and/or next of kin. The primary study outcomes include an array of pathologic features organized by organ system. Casual inference methods will be employed to investigate associations between risk factors and pathologic outcomes. Discussion: RECOVER-Pathology is the largest autopsy study addressing PASC among US adults. Results of this study are intended to elucidate mechanisms of organ injury and disease and enhance our understanding of the pathophysiology of PASC.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.27.23289234v1" target="_blank">Researching COVID to enhance recovery (RECOVER) autopsy study protocol: Rationale, objectives, and design</a>
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<li><strong>Antibody escape, the risk of serotype formation, and rapid immune waning: modeling the implications of SARS-CoV-2 immune evasion</strong> -
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As the COVID-19 pandemic progresses, widespread community transmission of SARS-CoV-2 has ushered in a volatile era of viral immune evasion rather than the much-heralded stability of “endemicity” or “herd immunity.” At this point, an array of viral variants has rendered essentially all monoclonal antibody therapeutics obsolete and strongly undermined the impact of vaccinal immunity on SARS-CoV-2 transmission. In this work, we demonstrate that antigenic drift resulting in evasion of pre-existing immunity is highly evolutionarily favored and likely to cause waves of short-term transmission. In the long-term, invading variants that induce weak cross-immunity against pre-existing strains may co-circulate with those pre-existing strains. This would result in the formation of serotypes that increase disease burden, complicate SARS-CoV-2 control and raise the potential for increases in viral virulence. Less durable immunity does not drive positive selection as a trait, but such strains may transmit at high levels if they establish. Overall, our results draw attention to the importance of inter-strain cross-immunity as a driver of transmission trends and the importance of early immune evasion data to predict the trajectory of the pandemic.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.01.25.23285031v2" target="_blank">Antibody escape, the risk of serotype formation, and rapid immune waning: modeling the implications of SARS-CoV-2 immune evasion</a>
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<li><strong>Composition of nasopharyngeal microbiota in individuals with SARS-CoV-2 infection across three COVID-19 waves in India</strong> -
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Multiple variants of the SARS-CoV-2 virus have been plaguing the world through successive waves of infection over the past three years. Studies by independent research groups across geographies have shown that the microbiome composition in COVID-19 patients (CP) differ from that of healthy individuals (CN). However, such observations were based on limited-sized sample-sets collected primarily from the early days of the pandemic. Here, we study the nasopharyngeal microbiota in COVID-19 patients, wherein the samples have been collected across the three COVID-19 waves witnessed in India, which were driven by different variants of concern. We also present the variations in microbiota of symptomatic vs asymptomatic COVID-19 patients. The nasopharyngeal swabs were collected from 589 subjects providing samples for diagnostics purposes at Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India. CP showed a marked shift in the microbial diversity and composition compared to CN, in a wave-dependent manner. Rickettsiaceae was the only family that was noted to be consistently depleted in CP samples across the waves. The genera Staphylococcus, Anhydrobacter, Thermus, and Aerococcus were observed to be highly abundant in the symptomatic CP patients when compared to the asymptomatic group. In general, we observed a decrease in the burden of opportunistic pathogens in the host microbiota during the later waves of infection. To our knowledge, this is the first longitudinal study which was designed to understand the relation between the evolving nature of the virus and the changes in the human nasopharyngeal microbiota. Such studies not only pave way for better understanding of the disease pathophysiology but also help gather preliminary evidence on whether interventions to the host microbiota can help in better protection or faster recovery.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.01.02.522449v4" target="_blank">Composition of nasopharyngeal microbiota in individuals with SARS-CoV-2 infection across three COVID-19 waves in India</a>
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<li><strong>Design of mobile medical testing laboratories with the focus on COVID-19 testing procedures</strong> -
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The COVID-19 pandemic caused by corona virus in 2019 has forced all the health and public organi-zations, across the globe, to take different measures for identification, prevention, and control of the disease. Early and accurate detection of the corona virus in human body being one of the im-portant measures to prevent the disease spread in population and successful eradication. However, available and known methods and technologies and project management systems in this context have not been used to the extent necessary to adequately control infection events (Lehrach, 2020; Glitscher, 2021). Today different testing methods are being used to check the COVID-19 infection for isolation of in-fected from uninfected population. The accuracy, time between sample collection to results declara-tion, testing cost, etc. depend on the type of testing method. In addition to the use of accurate testing method, it becomes necessary to ensure that the test centers are mobile and accessible to a maximum extent, so that the testing intensity can be regulated depending on the rate of spread, potential sudden outbreaks, areas of concern, etc. In this context, a new high throughput genome -based testing pipeline for SARS-CoV-2 is proposed (Lehrach, 2022) which uses the combination of state-of-the art biotechnology and in-formatics. This proposed new method is claimed to deliver faster and cheaper test results at the population scale, without compromising the testing quality. This study is aimed to develop a project plan to design such a container-based COVID- 19 testing facility. Literature study shows a lack of frameworks to develop a design for mobile medical facility (Carl Heneghan et al. 2020; Bridges et al. 2014). On the other hand, at least in Germany, companies like centogene have deployed container-based mobile test stations. However, based on available experience, these are limited in terms of use and throughput of tests (Centogene 2020; Kyoug Ho Roh 2022). Thus, this study proposes a framework to design a mobile medical test facility, in addition to propos-ing a project plan to design a mobile container-based facility to implement the new COVID-19 test-ing method. The framework proposed is based on the combined adaptation of facility design meth-ods, namely - Systematic Layout Planning and project-based approach as per VDI 5200. The resulting outputs in the form of a project plan include - capacity plan, material flow plan and financial plan. It is clear from these plans that the industrialization of the new testing facility is feasi-ble in terms of testing throughput - approximately 450,000 tests per day (when the line is operated in all three shifts) - and cost per test being 3 Euros, spatial requirements as proposed in the draft layout, based on the inputs as published (Lehrach, 2022). The identified risks do not pose alarming threats to continue with the implementation, however contingency plans should be considered for every worst-case scenario.
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🖺 Full Text HTML: <a href="https://osf.io/mhxez/" target="_blank">Design of mobile medical testing laboratories with the focus on COVID-19 testing procedures</a>
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<li><strong>Effect of Nirmatrelvir/Ritonavir (Paxlovid) on Hospitalization among Adults with COVID-19: an EHR-based Target Trial Emulation from N3C</strong> -
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This study leverages electronic health record data in the National COVID Cohort Collaborative9s (N3C) repository to investigate disparities in Paxlovid treatment and to emulate a target trial assessing its effectiveness in reducing COVID-19 hospitalization rates. From an eligible population of 632,822 COVID-19 patients seen at 33 clinical sites across the United States between December 23, 2021 and December 31, 2022, patients were matched across observed treatment groups, yielding an analytical sample of 410,642 patients patients. We estimate a 65% reduced odds of hospitalization among Paxlovid-treated patients within a 28-day follow-up period, and this effect did not vary by patient vaccination status. Notably, we observe disparities in Paxlovid treatment, with lower rates among Black and Hispanic or Latino patients, and within socially vulnerable communities. Ours is the largest study of Paxlovid9s real-world effectiveness to date, and our primary findings are consistent with previous randomized control trials and real-world studies.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.05.03.23289084v1" target="_blank">Effect of Nirmatrelvir/Ritonavir (Paxlovid) on Hospitalization among Adults with COVID-19: an EHR-based Target Trial Emulation from N3C</a>
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<li><strong>Spatial Variation in Excess Mortality Across Europe: A Cross-sectional Study of 561 Regions in 21 Countries</strong> -
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Objective: To measure the burden of the COVID-19 pandemic in 2020 at the subnational level by estimating excess mortality, defined as the increase in all-cause mortality relative to an expected baseline mortality level. Design: Statistical and demographic analyses of regional all-cause mortality data. Setting: The vital statistics systems of 21 European countries. Participants: The entire population of 561 spatial units in 21 European countries. Main Outcome Measures: Losses of life expectancy at ages 0 and 60 for males and females. Results: Evidence was found of a loss in life expectancy in 391 regions, while only three regions exhibit notable gains in life expectancy in 2020. For 12 regions, losses of life expectancy amounted to more than 2 years, and three regions showed losses greater than 3 years. Geographic clusters of high mortality were found in Northern Italia, Spain and Poland, while clusters of low mortality were found in Western France, Germany/Denmark and Norway/Sweden. Conclusions: Regional differences of loss of life expectancy are impressive, ranging from a loss of more than 4 years to a gain of 8 months. These findings provide a strong rationale for regional analysis, as national estimates hide significant regional disparities.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.04.23284990v2" target="_blank">Spatial Variation in Excess Mortality Across Europe: A Cross-sectional Study of 561 Regions in 21 Countries</a>
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<li><strong>Diagnosing and remediating harmful data shifts for the responsible deployment of clinical AI models</strong> -
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Harmful data shifts occur when the distribution of data used to train a clinical AI system differs significantly from the distribution of data encountered during deployment, leading to erroneous predictions and potential harm to patients. We evaluated the impact of data shifts on an early warning system for in-hospital mortality that uses electronic health record data from patients admitted to a general internal medicine service, across 7 large hospitals in Toronto, Canada. We found model performance to differ across subgroups of clinical diagnoses, sex and age. To explore the robustness of the model, we evaluated potentially harmful data shifts across demographics, hospital types, seasons, time of hospital admission, and whether the patient was admitted from an acute care institution or nursing home, without relying on model performance. Interestingly, many of these harmful data shifts were unidirectional. We found models trained on community hospitals experience harmful data shifts when evaluated on academic hospitals, whereas models trained on academic hospitals transfer well to the community hospitals. To improve model performance across hospital sites we employed transfer learning, a strategy that stores knowledge gained from learning one domain and applies it to a different but related domain. We found hospital type-specific models that leverage transfer learning, perform better than models that use all available hospitals. Furthermore, we monitored data shifts over time and identified model deterioration during the COVID-19 pandemic. Typically, machine learning models remain locked after deployment, however, this can lead to model deterioration due to harmful data shifts that occur over time. We used continual learning, the process of learning from a continual stream of data in a sequential manner, to mitigate data shifts over time and improve model performance. Overall, our study is a crucial step towards the deployment of clinical AI models, by providing strategies and workflows to ensure the safety and efficacy of these models in real-world settings.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.03.26.23286718v2" target="_blank">Diagnosing and remediating harmful data shifts for the responsible deployment of clinical AI models</a>
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<li><strong>Characterising Long Covid: a living systematic review update with controlled studies</strong> -
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The authors have withdrawn their manuscript owing to a reporting error that we have identified in the conduct of this updated systematic review. On 7th March 2022 we made changes to the original protocol published in F1000, to highlight the need to keep up with the evolving landscape of Covid-19 and Covid-19 research and focus on comparative, controlled studies. The revisions included also changes in data extraction and analysis that would be needed to do so. These changes were done in consultation with members of the Long COVID Support Group. However, we omitted to publicize these changes in an accessible, modified version of our protocol, and/or by updating our preregistered PROSPERO record (CRD42020211131) and F1000 publication, prior to commencing and completing these stages of the process. In this manuscript, which reports the revised analyses, we have consequently also omitted to explicitly describe these changes as important deviations from the published protocol. Additionally, following rapid, sustained, and continuous growth in the conduct and reporting of eligible primary studies, it has become clear that, with or without the changes described above, we do not have sufficient capacity or resources to transition our baseline systematic review to being regularly updated using a living systematic review approach. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.08.29.22279338v2" target="_blank">Characterising Long Covid: a living systematic review update with controlled studies</a>
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<li><strong>What happened to health labour markets during COVID-19? Insights from a survey of medical doctors in Brazil</strong> -
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Background. Limited evidence exists on impacts and adaptations of global health markets during COVID-19. We examined physicians perceptions of changing employment opportunities in Brazil, to gain an insight into labour markets in low- and middle-income countries (LMICs) during the pandemic. Methods. We conducted secondary analysis of a dataset from a representative cross-sectional survey of 1,183 physicians in Sao Paulo and Maranhao states in Brazil. We estimated prevalence and 95% Confidence Intervals (CI) for proxy variables of demand and supply of doctors, and prices of medical services for facilities of practice in the two States, stratified by public, private, and dual practice physicians. Results. Most doctors reported increased job opportunities in the public sector (59.0%, 95% CI 56.1-61.9), particularly in Maranhao state (66.4%, 95% CI 62.3-70.3). For the private sector, increased opportunities were reported only in large private hospitals (51.4%, 95% CI 48.4-54.4), but not in smaller clinics. We recorded perceptions of slight increases in availability of doctors in Maranhao, particularly in the public sector (54.1%, 95 CI 45.7-62.3). Younger doctors recounted increased vacancies in the public sector (64%, 95 CI 58.1-68.1); older doctors only in walk-in clinics in Maranhao (47.5%, 95 CI 39.9-55.1). Those working directly with COVID-19 saw opportunities in public hospitals (65%, 95 CI 62.3-68.4), and in large private ones (55%, 95 CI 51.8-59.1) Conclusions. Our findings suggest that health labour markets in (LMICs) may not necessarily shrink during epidemics, and that impacts will depend on the balance of public and private services in national health systems.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.05.03.23289458v1" target="_blank">What happened to health labour markets during COVID-19? Insights from a survey of medical doctors in Brazil</a>
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<li><strong>UDCA May Promote COVID-19 Recovery: A Cohort Study with AI-Aided Analysis</strong> -
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To investigate the impact of ursodeoxycholic acid (UDCA) treatment on the clinical outcome of mild and moderate COVID-19 cases, a retrospective analysis was conducted to evaluate the efficacy of UDCA on patients diagnosed with COVID-19 during the peak of the Omicron outbreak in China. This study presents promising results, demonstrating that UDCA significantly reduced the time to Body Temperature Recovery after admission and a higher daily dose seems to be associated with a better outcome without observed safety concerns. We also introduced VirtualBody, a physiologically plausible artificial neural network model, to generate an accurate depiction of the drug concentration-time curve individually, which represented the absorption, distribution, metabolism, and excretion of UDCA in each patient. It exhibits exceptional performance in modeling the complex PK-PD profile of UDCA, characterized by its endogenous and enterohepatic cycling properties, and further validates the effectiveness of UDCA as a treatment option from the drug exposure-response perspective. Our work highlights the potential of UDCA as a novel treatment option for periodic outbreaks of COVID-19 and introduces a new paradigm for PK-PD analysis in retrospective studies to provide evidence for optimal dosing strategies.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.05.02.23289410v1" target="_blank">UDCA May Promote COVID-19 Recovery: A Cohort Study with AI-Aided Analysis</a>
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<li><strong>Genomic screening of 16 UK native bat species through conservationist networks uncovers coronaviruses with zoonotic potential</strong> -
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There has been limited characterisation of bat-borne coronaviruses in Europe. Here, we screened for coronaviruses in 48 faecal samples from 16 of the 17 bat species breeding in the UK, collected through a bat rehabilitation and conservationist network. We recovered nine (two novel) complete genomes across six bat species: four alphacoronaviruses, a MERS-related betacoronavirus, and four closely related sarbecoviruses. We demonstrate that at least one of these sarbecoviruses can bind and use the human ACE2 receptor for infecting human cells, albeit suboptimally. Additionally, the spike proteins of these sarbecoviruses possess an R-A-K-Q motif, which lies only one nucleotide mutation away from a furin cleavage site (FCS) that enhances infectivity in other coronaviruses, including SARS-CoV-2. However, mutating this motif to an FCS does not enable spike cleavage. Overall, while UK sarbecoviruses would require further molecular adaptations to infect humans, their zoonotic risk is unknown and warrants closer surveillance.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.01.17.524183v5" target="_blank">Genomic screening of 16 UK native bat species through conservationist networks uncovers coronaviruses with zoonotic potential</a>
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<li><strong>Role of SARS-CoV-2 mutations in the evolution of the COVID-19 pandemic</strong> -
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RNA viruses, including SARS-CoV-2, evolve by mutation acquisition, or by hybridization between viral genomes. The SARS-CoV-2 pandemic provided an exceptional opportunity to analyze the mutations that appeared over a three-year period. In this study, we analysed the type of mutations and their epidemic consequences on the thousands of genomes produced in our laboratory. These were obtained by next-generation sequencing from respiratory samples performed for genomic surveillance. The frequencies of mutations were calculated using Nextclade, Microsoft Excel, and an in-house Python script. In total, 61,397 genomes matching 483 Pangolin lineages were analyzed; 22,225 nucleotide mutations were identified, and of them 220 (1.0%) were each at the root of at least 836 genomes, a frequency threshold classifying mutations as hyperfertile. Two of these seeded the pandemic in Europe, namely a mutation in the RNA-dependent RNA polymerase associated with an increased mutation rate (P323L) and one in the spike protein (D614G), which plays a particular role in virus fitness. Most of these 220 hyperfertile mutations occurred in areas not predicted to be associated with increased virulence. Their number was 8+/-6 (0-22) per 1,000 nucleotides on average per gene. They were 3.7 times more frequent in accessory than informational genes (14 versus 4; p= 0.0037). Particularly, they were 4.1 times more frequent in ORF8 than in the gene encoding RNA polymerase. Interestingly, stop codons were present in 97 positions, almost only in six accessory genes including ORF7a (25 per 100 codons) and ORF8 (21). Furthermore, 1,661 mutations (16.3%) were associated with a lower number of offspring (50-835) and classified as fertile. In conclusion, except for two initial mutations that could predict a change in the dynamics of the epidemic (mutation rate and change in the virus attachment site), most of the hyperfertile mutations did not predict the emergence of a new epidemic form. Significantly, some mutations were in non-coding areas and some consisted of stop codons, indicating that some genes (particularly ORF7a and ORF8) were rather non-virulence genes at a given stage of the epidemic, which is an unusual concept for viruses.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.05.01.538506v1" target="_blank">Role of SARS-CoV-2 mutations in the evolution of the COVID-19 pandemic</a>
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<h1 data-aos="fade-right" id="from-clinical-trials">From Clinical Trials</h1>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Long COVID-19 Syndrome Lifestyle Intervention Study</strong> - <b>Condition</b>: Long COVID-19 Syndrome<br/><b>Intervention</b>: Dietary Supplement: Low carbohydrate diet intervention<br/><b>Sponsor</b>: University of Southern California<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Working Towards Empowered Community-driven Approaches to Increase Vaccination and Preventive Care Engagement</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Other: mHealth Outreach; Other: Care Coordination<br/><b>Sponsors</b>: University of California, San Diego; San Ysidro Health Center<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Coping and Resilience Intervention for Adolescents</strong> - <b>Condition</b>: COVID-19 Pandemic<br/><b>Interventions</b>: Behavioral: Coping and Resilience Intervention for Adolescents; Other: Printing materials of Coping and Resilience Intervention for Adolescents<br/><b>Sponsor</b>: Taipei Medical University<br/><b>Enrolling by invitation</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Effectiveness of Modified Diaphragmatic Training for Gastroesophageal Reflux Disease Post Covid-19</strong> - <b>Conditions</b>: GERD; Post COVID-19 Condition; Diaphragm Issues<br/><b>Interventions</b>: Other: modified diaphragmatic training; Other: standard diaphragmatic training<br/><b>Sponsor</b>: Indonesia University<br/><b>Completed</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>The Safety, Tolerability and Pharmacokinetics Study of RAY1216 in Healthy Adult Participants</strong> - <b>Condition</b>: COVID-19 (Coronavirus Disease 2019)<br/><b>Interventions</b>: Drug: RAY1216 dose 1; Drug: RAY1216 dose 2; Drug: RAY1216 dose 3; Drug: RAY1216 dose 4 &ritonavir Drug: RAY1216 dose 5; Drug: RAY1216 dose 6; Drug: RAY1216 dose 7; Drug: RAY1216 dose 8; Drug: RAY1216 dose 9; Drug: RAY1216 dose 10<br/><b>Sponsor</b>: Guangdong Raynovent Biotech Co., Ltd<br/><b>Completed</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>COVID-19 Vaccination Detoxification</strong> - <b>Conditions</b>: COVID-19 Stress Syndrome; COVID-19 Vaccine Adverse Reaction; COVID-19-Associated Thromboembolism; COVID-19 Post-Intensive Care Syndrome; COVID-19-Associated Stroke; COVID-19 Respiratory Infection<br/><b>Intervention</b>: Combination Product: Atorvastatin Calcium Tablets<br/><b>Sponsor</b>: Yang I. Pachankis<br/><b>Active, not recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Study in Healthy Volunteers to Evaluate the Safety, Tolerability, Pharmacokinetics, and Drug-Drug Interaction Potential of Single and Multiple Doses of ALG-097558</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: ALG-097558; Drug: Placebo; Drug: Midazolam; Drug: Itraconazole; Drug: Carbamazepine; Drug: ALG-097558 in solution formulation; Drug: ALG-097558 in tablet formulation<br/><b>Sponsor</b>: Aligos Therapeutics<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Strategies and Treatments for Respiratory Infections &Amp; Viral Emergencies (STRIVE): Immune Modulation Strategy Trial</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: abatacept infusion; Drug: Placebo group<br/><b>Sponsor</b>: University of Minnesota<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Immunoadsorption Study Mainz in Adults With Post-COVID Syndrome</strong> - <b>Conditions</b>: Post-COVID-19 Syndrome; Post-COVID Syndrome; Post COVID-19 Condition<br/><b>Interventions</b>: Device: Immunoadsorption; Device: Sham-apheresis<br/><b>Sponsor</b>: University Medical Center Mainz<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Computerized Training of Attention and Working Memory in Post COVID-19 Patients With Cognitive Complaints</strong> - <b>Conditions</b>: COVID-19; Cognitive Impairment; Cognition Disorder; Memory Disorders; Attention Deficit; Memory Impairment; Memory Loss; Attention Impaired<br/><b>Intervention</b>: Device: RehaCom<br/><b>Sponsor</b>: Erasmus Medical Center<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Digital Mental Health Care for COVID-19 High-Risk Populations - Phase 2</strong> - <b>Conditions</b>: Stigma, Social; Help-Seeking Behavior<br/><b>Interventions</b>: Other: Adjusted Content Intervention; Other: Non-Adjusted Intervention Video<br/><b>Sponsors</b>: Research Foundation for Mental Hygiene, Inc.; Columbia University<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>imPROving Quality of LIFe In the Long COVID Patient</strong> - <b>Conditions</b>: Post-COVID-19 Syndrome; Long COVID; Long Covid19; COVID-19; POTS - Postural Orthostatic Tachycardia Syndrome; Post COVID-19 Condition; Post-COVID Syndrome; Post COVID-19 Condition, Unspecified; Postinfectious Inflammation; Postinfectious Disorder<br/><b>Interventions</b>: Drug: Nirmatrelvir/ritonavir; Drug: Placebo/ritonavir<br/><b>Sponsors</b>: Karolinska Institutet; Karolinska University Hospital; Pfizer<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Study of mRNA-based Influenza and SARS-CoV-2 (COVID-19) Multi-component Vaccines in Healthy Adults</strong> - <b>Conditions</b>: SARS-CoV-2; Influenza<br/><b>Interventions</b>: Biological: Fluarix; Biological: mRNA-1083.1; Biological: mRNA-1083.2; Biological: mRNA-1083.3; Biological: mRNA-1010.4; Biological: mRNA-1283.222; Biological: mRNA-1273.222; Biological: mRNA-1010; Biological: Fluzone HD<br/><b>Sponsor</b>: ModernaTX, Inc.<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Efficacy of an Smartphone App Intervention Based on Self-compassion for Mental Health Among University Students</strong> - <b>Condition</b>: Mental Health Issue<br/><b>Interventions</b>: Behavioral: mHealth Intervention Based on Self-Compassion; Behavioral: Psychoeducation Intervention<br/><b>Sponsors</b>: Federal University of Health Science of Porto Alegre; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior.<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Obesity, Insulin Resistance, and PASC: Persistent SARS-CoV-2</strong> - <b>Conditions</b>: Long COVID; Insulin Resistance; Insulin Sensitivity<br/><b>Interventions</b>: Procedure: Adipose Tissue Biopsy; Diagnostic Test: Steady State Plasma Glucose (SSPG) Test<br/><b>Sponsor</b>: Stanford University<br/><b>Not yet recruiting</b></p></li>
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<h1 data-aos="fade-right" id="from-pubmed">From PubMed</h1>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Orthogonal dual reporter-based gain-of-signal assay for probing SARS-CoV-2 3CL protease activity in living cells: inhibitor identification and mutation investigation</strong> - The main protease (3-chymotrypsin-like protease, 3CLpro) of SARS-CoV-2 has become a focus of anti-coronavirus research. Despite efforts, drug development targeting 3CLpro has been hampered by limitations in the currently available activity assays. Additionally, the emergence of 3CLpro mutations in circulating SARS-CoV-2 variants has raised concerns about potential resistance. Both emphasize the need for a more reliable, sensitive, and facile 3CLpro assay. Here, we report an orthogonal dual…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>SARS-CoV-2 N Protein Triggers Acute Lung Injury via Modulating Macrophage Activation and Infiltration in in vitro and in vivo</strong> - CONCLUSION: SARS-CoV-2 and its N protein but not S protein induced acute lung injury and systemic inflammation, which was closely related to macrophage activation, infiltration and release cytokines.</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Biogenic silver nanoparticles eradicate of <em>Pseudomonas aeruginosa</em> and Methicillin-resistant <em>Staphylococcus aureus</em> (MRSA) isolated from the sputum of COVID-19 patients</strong> - In recent investigations, secondary bacterial infections were found to be strongly related to mortality in COVID-19 patients. In addition, Pseudomonas aeruginosa and Methicillin-resistant Staphylococcus aureus (MRSA) bacteria played an important role in the series of bacterial infections that accompany infection in COVID-19. The objective of the present study was to investigate the ability of biosynthesized silver nanoparticles from strawberries (Fragaria ananassa L.) leaf extract without a…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Immunogenicity and reactogenicity of heterologous prime-boost vaccination with inactivated COVID-19 and ChAdOx1 nCoV-19 (AZD1222) vaccines, a quasi-experimental study</strong> - The global supply of COVID-19 vaccines has been limited, and concerns have arisen about vaccine supply chain disruptions in developing countries. Heterologous prime-boost vaccination, which involves using different vaccines for the first and second doses, has been proposed to enhance the immune response. We aimed to compare the immunogenicity and safety of a heterologous prime-boost vaccination using an inactivated COVID-19 vaccine and AZD1222 vaccine with that of a homologous vaccination using…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Proton Pump Inhibitors, Kidney Damage, and Mortality: An Updated Narrative Review</strong> - Since their approval by the Food and Drug Administration (FDA) in 1989, proton pump inhibitors (PPIs) have become one of the most highly utilized drugs in the United States, assuming a position as one of the top 10 most prescribed medications in the country. The purpose of PPIs is to limit the amount of gastric acid secreted by the parietal cells via irreversible inhibition of the H+/K+-ATPase pump, therefore maintaining an elevated gastric acid pH of greater than 4 for 15-21 h. Even though PPIs…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>New Ways to Protect the Host from SARS-CoV-2? Lung Microbiome Metabolites Inhibit STAT3 and Modulate the Immunological Network</strong> - COVID-19 caused by the SARS-CoV-2 infection is a systemic disease that affects multiple organs, biological pathways, and cell types. A systems biology approach would benefit the study of COVID-19 in the pandemic as well as the endemic state. Notably, patients with COVID-19 have dysbiosis of lung microbiota whose functional relevance to the host is largely unknown. We carried out a systems biology investigation of the impact of lung microbiome-derived metabolites on host immune system during…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Multicenter Randomized Controlled Trial To Evaluate the Efficacy and Safety of Nelfinavir in Patients with Mild COVID-19</strong> - Nelfinavir, an orally administered inhibitor of human immunodeficiency virus protease, inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. We conducted a randomized controlled trial to evaluate the clinical efficacy and safety of nelfinavir in patients with SARS-CoV-2 infection. We included unvaccinated asymptomatic or mildly symptomatic adult patients who tested positive for SARS-CoV-2 infection within 3 days before enrollment. The patients were…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong><em>In silico</em> evaluation of some commercially available terpenoids as spike glycoprotein of SARS-CoV-2 - inhibitors using molecular dynamic approach</strong> - Coronavirus, an extremely contagious infections disease had a harmful effect on the world’s population. It is a family of enveloped, single-stranded, positive-strand RNA viruses of Nidovirales order belongs to coroviridae family. At present, worldwide several lakhs of deaths and several billions of infections have been reported. Hence, the focus of the present study was to assess the SARS-CoV-2 enzyme inhibitory potential of certain commercially available terpenoids using Lamarckian genetic…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Infection routes, invasion mechanisms, and drug inhibition pathways of human coronaviruses on the nervous system</strong> - So far, numerous studies have reported on how coronaviruses affect the human nervous system. However, these studies mainly focused on the impact of a single coronavirus on the nervous system, and failed to fully report the invasion mechanisms and the rules of symptoms of the seven human coronaviruses. This research can assist medical professionals in identifying the regularity of coronavirus invasion into the nervous system by examining the impacts of human coronaviruses on the nervous system….</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>High-breathable, antimicrobial and water-repellent face mask for breath monitoring</strong> - Face masks with multiple functionalities and exceptional durability have attracted increasing interests during the COVID-19 pandemic. How to integrate the antibacterial property, comfortability during long-time wearing, and breath monitoring capability together on a face mask is still challenging. Here we developed a kind of face mask that assembles the particles-free water-repellent fabric, antibacterial fabric, and hidden breath monitoring device together, resulting in the highly breathable,…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Non-neutralizing antibodies to SARS-Cov-2-related linear epitopes induce psychotic-like behavior in mice</strong> - OBJECTIVE: An increasing number of studies have reported that numerous patients with coronavirus disease 2019 (COVID-19) and vaccinated individuals have developed central nervous system (CNS) symptoms, and that most of the antibodies in their sera have no virus-neutralizing ability. We tested the hypothesis that non-neutralizing anti-S1-111 IgG induced by the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could negatively affect the CNS.</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Furin as a therapeutic target in cystic fibrosis airways disease</strong> - Clinical management of cystic fibrosis (CF) has been greatly improved by the development of small molecule modulators of the CF transmembrane conductance regulator (CFTR). These drugs help to address some of the basic genetic defects of CFTR; however, no suitable CFTR modulators exist for 10% of people with CF (PWCF). An alternative, mutation-agnostic therapeutic approach is therefore still required. In CF airways, elevated levels of the proprotein convertase furin contribute to the…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Clomipramine inhibits dynamin GTPase activity by L-α-phosphatidyl-L-serine stimulation</strong> - Three dynamin isoforms play critical roles in clathrin-dependent endocytosis. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells via clathrin-dependent endocytosis. We previously reported that 3-(3-chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine (clomipramine) inhibits the GTPase activity of dynamin 1, which is in mainly neuron. Therefore, we investigated whether clomipramine inhibits the activity of other dynamin isoforms in this study. We…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>An ACAT inhibitor suppresses SARS-CoV-2 replication and boosts antiviral T cell activity</strong> - The severity of disease following infection with SARS-CoV-2 is determined by viral replication kinetics and host immunity, with early T cell responses and/or suppression of viraemia driving a favourable outcome. Recent studies uncovered a role for cholesterol metabolism in the SARS-CoV-2 life cycle and in T cell function. Here we show that blockade of the enzyme Acyl-CoA:cholesterol acyltransferase (ACAT) with Avasimibe inhibits SARS-CoV-2 pseudoparticle infection and disrupts the association of…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Improved recovery of SARS-CoV-2 from wastewater through application of RNA and DNA stabilising agents</strong> - Wastewater Based Epidemiology (WBE) has become an integral part of the public health effort to track the levels of SARS-CoV-2 within communities. Detection of SARS-CoV-2 in wastewater can be challenging due to relatively low levels of virus within the sample. The wastewater matrix is also comprised of commercial and domestically derived contaminants, as well as RNases, all of which can adversely affect RT-qPCR analysis. To improve SARS-CoV-2 detection within wastewater samples we investigated…</p></li>
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<h1 data-aos="fade-right" id="from-patent-search">From Patent Search</h1>
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