Covid-19 Sentry

Contents

• From Preprints
• From Clinical Trials
• From PubMed
• From Patent Search

From Preprints

• Pooled PPIseq: screening the SARS-CoV-2 and human interface with a scalable multiplexed protein-protein interaction assay platform -
  Protein-Protein Interactions (PPIs) are a key interface between virus and host, and these interactions are important to both viral reprogramming of the host and to host restriction of viral infection. In particular, viral-host PPI networks can be used to further our understanding of the molecular mechanisms of tissue specificity, host range, and virulence. At higher scales, viral-host PPI screening could also be used to screen for small-molecule antivirals that interfere with essential viral-host interactions, or to explore how the PPI networks between interacting viral and host genomes co-evolve. Current high-throughput PPI assays have screened entire viral-host PPI networks. However, these studies are time consuming, often require specialized equipment, and are difficult to further scale. Here, we develop methods that make larger-scale viral-host PPI screening more accessible. This approach combines the mDHFR split-tag reporter with the iSeq2 interaction-barcoding system to permit massively-multiplexed PPI quantification by simple pooled engineering of barcoded constructs, integration of these constructs into budding yeast, and fitness measurements by pooled cell competitions and barcode-sequencing. We applied this method to screen for PPIs between SARS-CoV-2 proteins and human proteins, screening in triplicate >180,000 ORF-ORF combinations represented by >1,000,000 barcoded lineages. Our results complement previous screens by identifying 74 putative PPIs, including interactions between ORF7A with the taste receptors TAS2R41 and TAS2R7, and between NSP4 with the transmembrane KDELR2 and KDELR3. We show that this PPI screening method is highly scalable, enabling larger studies aimed at generating a broad understanding of how viral effector proteins converge on cellular targets to effect replication.
  🖺 Full Text HTML: Pooled PPIseq: screening the SARS-CoV-2 and human interface with a scalable multiplexed protein-protein interaction assay platform
• Single-cell Masked Autoencoder: An Accurate and Interpretable Automated Immunophenotyper -
  High-throughput single-cell cytometry data are crucial for understanding immune system's involvement in diseases and responses to treatment. Traditional methods for annotating cytometry data, specifically manual gating and clustering, face challenges in scalability, robustness, and accuracy. In this study, we propose a single-cell masked autoencoder (scMAE), which offers an automated solution for immunophenotyping tasks including cell type annotation. The scMAE model is designed to uphold user-defined cell type definitions, thereby facilitating easier interpretation and cross-study comparisons. The scMAE model operates on a pre-train and fine-tune approach. In the pre-training phase, scMAE employs Masked Single-cell Modelling (MScM) to learn relationships between protein markers in immune cells solely based on protein expression, without relying on prior information such as cell identity and cell type-specific marker proteins. Subsequently, the pre-trained scMAE is fine-tuned on multiple specialized tasks via task-specific supervised learning. The pre-trained scMAE addresses the shortcomings of manual gating and clustering methods by providing accurate and interpretable predictions. Through validation across multiple cohorts, we demonstrate that scMAE effectively identifies co-occurrence patterns of bound labeled antibodies, delivers accurate and interpretable cellular immunophenotyping, and improves the prediction of subject metadata status. Specifically, we evaluated scMAE for cell type annotation and imputation at the cellular-level and SARS-CoV-2 infection prediction, secondary immune response prediction against COVID-19, and prediction the infection stage in the COVID-19 progression at the subject-level. The introduction of scMAE marks a significant step forward in immunology research, particularly in large-scale and high-throughput human immune profiling. It offers new possibilities for predicting and interpretating cellular-level and subject-level phenotypes in both health and disease.
  🖺 Full Text HTML: Single-cell Masked Autoencoder: An Accurate and Interpretable Automated Immunophenotyper
• A spring-loaded and leakage-tolerant synthetic gene switch for in-vitro detection of DNA and RNA -
  Nucleic acid tests (NATs) are essential for biomedical diagnostics. Traditional NATs, often complex and expensive, have prompted the exploration of Toehold-Mediated Strand Displacement (TMSD) circuits as an economical alternative. However, the wide application of TMSD-based reactions is limited by leakage-the spurious activation of the reaction leading to high background signals and false positives. Here we introduce a new TMSD cascade that recognizes a custom nucleic acid input and generates an amplified output. The system is based on a pair of thermodynamically spring-loaded DNA modules. The binding of a predefined nucleic acid target triggers an intermolecular reaction that activates a T7 promoter, leading to the perpetual transcription of a fluorescent aptamer that can be detected by a smartphone camera. The system is designed to permit the selective depletion of leakage byproducts to achieve high sensitivity and zero-background signal in the absence of the correct trigger. Using Zika virus (ZIKV)- and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived nucleic acid sequences, we show that the assay generates a reliable target-specific readout. Native RNA can be directly detected under isothermal conditions, without requiring reverse transcription, with a sensitivity as low as 200 attomole. The modularity of the assay allows easy re-programming for the detection of other targets by exchanging a single sequence domain. This work provides a low-complexity and high-fidelity synthetic biology tool for point-of-care diagnostics and for the construction of more complex biomolecular computations.
  🖺 Full Text HTML: A spring-loaded and leakage-tolerant synthetic gene switch for in-vitro detection of DNA and RNA
• Data mining antibody sequences for database searching in bottom-up proteomics -
  Mass spectrometry (MS)-based proteomics allows identifying and quantifying thousands of proteins but suffers from challenges when measuring human antibodies due to their vast variety. The mainly used bottom-up proteomics approaches rely on database searches that compare experimental values of peptides and their fragments to theoretical values derived from protein sequences in a database. While the human body can produce millions of distinct antibodies, the current databases for human antibodies such as UniProtKB/Swiss-Prot are limited to only 1095 sequences (as of 2024 Jan). This limitation may hinder the identification of new antibodies using mass spectrometry. Therefore, extending the database for mass spectrometry is an important task for discovering new antibodies. Recent genomic studies have compiled millions of human antibody sequences publicly accessible through the Observed Antibody Space (OAS) database. However, this data has yet to be exploited to confirm the presence of these antibodies. In this study, we adopted this extensive collection of antibody sequences for conducting efficient database searches in publicly available proteomics data with a focus on the SARS-CoV-2 disease. Thirty million heavy antibody sequences from 146 SARS-CoV-2 patients in the OAS database were digested in silico to obtain 18 million unique peptides. These peptides were then used to create new databases for bottom-up proteomics. We used those databases for searching new antibody peptides in publicly available SARS-CoV-2 human plasma samples in the Proteomics Identification Database (PRIDE). This approach avoids false positives in antibody peptide identification as confirmed by searching against negative controls (brain samples) and employing different database sizes. We show that the found sequences provide valuable information to distinguish diseased from healthy and expect that the newly discovered antibody peptides can be further employed to develop therapeutic antibodies. The method will be broadly applicable to find characteristic antibodies for other diseases.
  🖺 Full Text HTML: Data mining antibody sequences for database searching in bottom-up proteomics
• Emergence and spread of SARS-CoV-2 variants from farmed mink to humans and back during the epidemic in Denmark, June-November 2020. -
  The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has not only caused the COVID-19 pandemic but also had a major impact on farmed mink production in several European countries. In Denmark, the entire population of farmed mink (over 15 million animals) was culled in late 2020. During the period of June to November 2020, mink on 290 farms (out of about 1100 in the country) were shown to be infected with SARS-CoV-2. Genome sequencing identified changes in the virus within the mink and it is estimated that about 4000 people in Denmark became infected with these mink virus variants. Phylogenetic analysis revealed the generation of multiple clusters of the virus within the mink. A detailed analysis of the changes in the virus during replication in mink and, in parallel, in the human population in Denmark, during the same time period, has been performed here. The majority of cases in mink involved variants that had the Y435F substitution and the H69/V70 deletion within the Spike (S) protein; these changes emerged early on during the outbreak. However, further introductions of the virus, with variants lacking these changes, from the human population into mink also occurred. Based on phylogenetic analysis of the available viral genome data, we estimate that there were a minimum of about 17 separate examples of mink to human transmission of the virus in Denmark, using a conservative approach, but up to 60 such events (95% credible interval: (35-77)) were identified using parsimony to count cross-species jumps on transmission trees inferred using a Bayesian method. Using the latter approach, it was estimated that there were 136 jumps (95% credible interval: (112-164)) from humans to mink. Thus, transmission of these viruses from humans to mink, mink to mink, from mink to humans and between humans were all observed.
  🖺 Full Text HTML: Emergence and spread of SARS-CoV-2 variants from farmed mink to humans and back during the epidemic in Denmark, June-November 2020.
• Evolving Trends in Neuropsychological Profiles of Post COVID-19 Condition: A 1-Year Follow-up in Individuals with Cognitive Complaints -
  Background: Cognitive difficulties are reported as lasting sequelae within post COVID-19 condition. However, the chronicity of these difficulties and related factors of fatigue, mood, and perceived health have yet to be fully determined. More longitudinal studies are needed to clarify the trends of cognitive test performance and cognitive domain impairment following COVID-19 onset, and whether hospitalization influences outcomes. Methods: 57 participants who reported subjective cognitive difficulties after confirmed COVID-19 infection were assessed at baseline (~6 months post COVID-19) and follow-up (~15 months later) visits. Assessments included measures across multiple cognitive domains and self-report questionnaires of fatigue, mood, and overall health. Analyses were conducted in three stages: at the test score level (raw and adjusted scores), at the cognitive domain level, and stratified by hospitalization status during infection. Results: Impacts on cognitive test scores remain stable across assessments. Cognitive domain analyses indicate significant reductions in attention and executive functioning impairment, while memory impairment is slower resolve. On self-report measures, there was a significant improvement in overall health ratings at follow-up. Finally, those hospitalized during infection performed worse on timed cognitive measures across visits and accounted for a larger proportion of cases with short-term and working memory impairment at follow-up. Conclusions: Cognitive difficulties persist both at test score and cognitive domain levels in many cases of post COVID-19 condition, but evidence suggests some improvement in global measures of attention, executive functioning and overall self-rated health. An effect of hospitalization on cognitive symptoms post COVID-19 may be more discernible over time.
  🖺 Full Text HTML: Evolving Trends in Neuropsychological Profiles of Post COVID-19 Condition: A 1-Year Follow-up in Individuals with Cognitive Complaints
• The Your COVID-19 Risk Assessment Tool and the Accompanying Open Access Data and Materials Repositories -
  In March 2020, the Your COVID-19 Risk tool was developed in response to the global spread of SARS-CoV-2. The tool is an online resource based on key behavioural evidence-based risk factors related to contracting and spreading SARS-CoV-2. This article describes the development of the tool, the produced resources, the associated open repository, and initial results. This tool was developed by a multidisciplinary research team consisting of more than 150 international experts. This project leverages knowledge obtained in behavioural science, aiming to promote behaviour change by assessing risk and supporting individuals completing the assessment tool to protect themselves and others from infection. To enable iterative improvements of the tool, tool users can optionally answer questions about behavioural determinants. The data and results are openly shared to support governments and health agencies developing behaviour change interventions. Over 60 000 users in more than 150 countries have assessed their risk and provided data.
  🖺 Full Text HTML: The Your COVID-19 Risk Assessment Tool and the Accompanying Open Access Data and Materials Repositories
• Long-term cardiovascular safety of COVID-19 vaccination according to brand, dose and combinations: Cohort study of 46 million adults in England -

  Using longitudinal health records from 45.7 million adults in England followed for a year, our study compared the incidence of thrombotic and cardiovascular complications after first, second and booster doses of brands and combinations of COVID-19 vaccines used during the first two years of the UK vaccination program with the incidence before or without the corresponding vaccination. The incidence of common arterial thrombotic events (mainly acute myocardial infarction and ischaemic stroke) was generally lower after each vaccine dose, brand and combination. Similarly, the incidence of common venous thrombotic events, (mainly pulmonary embolism and lower limb deep venous thrombosis) was lower after vaccination. There was a higher incidence of previously reported rare harms after vaccination: vaccine-induced thrombotic thrombocytopenia after first ChAdOx1 vaccination, and myocarditis and pericarditis after first, second and transiently after booster mRNA vaccination (BNT-162b2 and mRNA-1273) These findings support the wide uptake of future COVID-19 vaccination programs.

  🖺 Full Text HTML: Long-term cardiovascular safety of COVID-19 vaccination according to brand, dose and combinations: Cohort study of 46 million adults in England
• Knowledge, Attitude, and Practices towards COVID-19 Infection and Prevention Measures among Medical Students -

  The COVID-19 pandemic has rapidly led to an unprecedented health threat worldwide. During this time, disease prevention is considered to be the best way for general health protection. This is achieved through public health education by extending proper knowledge, promoting an optimistic attitude, and keeping the public compliant with preventive measures. As components of the healthcare system, medical students should also play a role in disease prevention more so in the Philippines where the Department of Health has called upon medical graduates to render services in response to the national emergency. In this study, the knowledge, attitude, and practices (KAP) of medical students from Cebu Institute of Medicine (CIM) towards COVID-19 infection and preventive measures were assessed. Demographic factors, their respective effect size on KAP, as well as the relationship between KAP variables were determined. The revised questionnaire, drafted based on qualitative and quantitative validity tests, was then used for the pilot study to generate the final questionnaire. Responses from participants underwent descriptive and correlational analysis. The results showed that the majority of the medical students of CIM have adequate knowledge (78.24%), positive attitude (80.68%), and good practices (94.38%) towards COVID-19 infection and prevention measures. Females have a significant association (p-value = 0.03) with better practices than male counterparts. Knowledge (p-value = 0.004) and attitude (p-value = 0.003) also showed significant correlation with practices, implying that knowledge and attitude play a role in shaping compliance to health practices. Therefore, health interventions should aim to disseminate accurate, evidence-based information and improve attitude towards the implemented precautionary measures in order to increase effectiveness of policies.

  🖺 Full Text HTML: Knowledge, Attitude, and Practices towards COVID-19 Infection and Prevention Measures among Medical Students
• SARS-CoV-2 virus in Raw Wastewater from Student Residence Halls with concomitant 16S rRNA Bacterial Community Structure changes -

  The detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in sewage is well-established, but the concomitant changes in microbial compositions during the pandemic remain insufficiently explored. This study investigates the impact of the SARS-CoV-2 virus on microbial compositions in raw sewage, utilizing 16S rRNA sequencing to analyze wastewater samples collected from six dormitories over a one-year field trial at the University of Tennessee, Knoxville. The concentration of SARS-CoV-2 RNA was assessed using a reverse transcription-quantitative polymerase chain reaction. Significant variations in bacterial composition were evident across the six dormitories, highlighting the importance of independently considering spatial differences when evaluating the raw wastewater microbiome. Positive samples for SARS-CoV-2 exhibited a prominent representation of exclusive species across all dormitories, coupled with significantly reduced bacterial diversity compared to negative samples. The correlation observed between the relative abundance of enteric pathogens and potential pathogens at sampling sites introduces a significant dimension to our understanding of COVID-19, especially the notable correlation observed in positive SARS-CoV-2 samples. Furthermore, the significant correlation in the relative abundance of potential pathogens between positive and negative SARS-CoV-2 raw sewage samples may be linked to the enduring effects of microbial dysbiosis observed during COVID-19 recovery. These findings provide valuable insights into the microbial dynamics in raw sewage during the COVID-19 pandemic.

  🖺 Full Text HTML: SARS-CoV-2 virus in Raw Wastewater from Student Residence Halls with concomitant 16S rRNA Bacterial Community Structure changes
• Body mass index changes and their association with SARS-CoV-2 infection: a real-world analysis -

  Objective: To study body mass index (BMI) changes among individuals aged 18-99 years with and without SARS-CoV-2 infection. Subjects/Methods: Using real-world data from the OneFlorida+ Clinical Research Network of the National Patient-Centered Clinical Research Network, we compared changes over time in BMI in an Exposed cohort (positive SARS-CoV-2 test between March 2020 - January 2022), to a contemporary Unexposed cohort (negative SARS-CoV-2 tests), and an age/sex-matched Historical control cohort (March 2018 - January 2020). Body mass index (kg/m2) was retrieved from objective measures of height and weight in electronic health records. We used target trial approaches to estimate BMI at baseline and change per 100 days of follow-up for Unexposed and Historical cohorts relative to the Exposed cohort by categories of sex, race-ethnicity, age, and hospitalization status. Results: The study sample consisted of 44,436 (Exposed cohort), 164,118 (Unexposed cohort), and 41,189 (Historical cohort). Cumulatively, 62% were women, 21.5% Non-Hispanic Black, 21.4% Hispanic and 5.6% Non-Hispanic Other. Patients had an average age of 51.9 years (SD: 18.9). At baseline, relative to the Exposed cohort (mean BMI: 29.3 kg/m2 [95%CI: 29.0, 29.7]), the Unexposed (-0.07 kg/m2 [95%CI; -0.12, -0.01]) and Historical controls (-0.27 kg/m2 [95%CI; -0.34, -0.20]) had lower BMI. Relative to no change in the Exposed over 100 days (0.00 kg/m2 [95%CI; -0.03,0.03]), the BMI of those Unexposed decreased (-0.04 kg/m2 [95%CI; -0.06, -0.01]) while the Historical cohort9s BMI increased (+0.03 kg/m2 [95%CI;0.00,0.06]). BMI changes were consistent between Exposed and Unexposed cohorts for most population groups, except at start of follow-up period among Males and those 65 years or older, and in changes over 100 days among Males and Hispanics. Conclusions: In a diverse real-world cohort of adults, mean BMI of those with and without SARS-CoV2 infection varied in their trajectories. The mechanisms and implications of weight retention following SARS-CoV-2 infection remain unclear.

  🖺 Full Text HTML: Body mass index changes and their association with SARS-CoV-2 infection: a real-world analysis
• Association between altitude and death from COVID-19 in subjects with diabetes mellitus during the first wave: cross sectional study of the National Death Index -

  Background. In high Andean areas, there is greater insulin sensitivity which may be a protective factor against complications in subjects with diabetes mellitus.  Objective: Determine the association between altitude of residence and death from COVID-19 in deaths with diabetes mellitus in Peru during the first wave.. Methods: We carried out a cross-sectional analysis of deaths registered in the National Death System of Peru (SINADEF in Spanish). We selected Peruvians with diabetes mellitus identified by presenting the diagnosis in any of the six boxes on the certificate. The dependent variable was death from COVID-19 as the basic cause of death, located in last place among causes A, B, C and D according to the Pan American Health Organization. The independent variable was the altitude of residence, categorized as less than 1 500 m a.s.l, 1 500 to 2 499 m  a.s.l. and greater than 2 500 m a.sl. Through a multilevel analysis by geographic region and using a Poisson regression, we obtained the risk ratios of death from COVID-19 according to the altitude of residence. We adjusted by individual and contextual variables. Results: We included 16 406 deaths with diabetes mellitus between March-December 2020. 34.3% died from Covid19 and 9.7% came from areas above 2 500 m. The proportion of deaths from COVID-19 of those with residence altitude above 2 500 m  was 20% lower compared to residents below 1 500 m (RR: 0.80; 95% CI: 0.70 – 0.91; p<0.001), adjusted for individual and socioeconomic factors. Its influence is also shown as the altitude changes every 100, 250, 500 and 1000 m a.s.l., through multilevel analysis. Conclusion: A higher altitude of residence is associated with a lower proportion of deaths from COVID-19 in people with diabetes mellitus during the first wave in Peru. The study contribute to expanding knowledge of the effects of altitude with respect to mortality in people with diabetes mellitus in a context of a highly contagious and virulent infectious disease.

  🖺 Full Text HTML: Association between altitude and death from COVID-19 in subjects with diabetes mellitus during the first wave: cross sectional study of the National Death Index
• Mathematical assessment of the role of human behavior changes on SARS-CoV-2 transmission dynamics -

  The COVID-19 pandemic has not only presented a major global public health and socio-economic crisis, but has also significantly impacted human behavior towards adherence (or lack thereof) to public health intervention and mitigation measures implemented in communities worldwide. The dynamic nature of the pandemic has prompted extensive changes in individual and collective behaviors towards the pandemic. This study is based on the use of mathematical modeling approaches to assess the extent to which SARS-CoV-2 transmission dynamics is impacted by population-level changes of human behavior due to factors such as (a) the severity of transmission (such as disease-induced mortality and level of symptomatic transmission), (b) fatigue due to the implementation of mitigation interventions measures (e.g., lockdowns) over a long (extended) period of time, (c) social peer-pressure, among others. A novel behavior-epidemiology model, which takes the form of a deterministic system of nonlinear differential equations, is developed and fitted using observed cumulative SARS-CoV-2 mortality data during the first wave in the United States. Rigorous analysis of the model shows that its disease-free equilibrium is locally-asymptotically stable whenever a certain epidemiological threshold, known as the control reproduction number (denoted by R_C) is less than one, and the disease persists (i.e., causes significant outbreak or outbreaks) if the threshold exceeds one. The model fits the observed data, as well as makes a more accurate prediction of the observed daily SARS-CoV-2 mortality during the first wave (March 2020 -June 2020), in comparison to the equivalent model which does not explicitly account for changes in human behavior. Of the various metrics for human behavior changes during the pandemic considered in this study, it is shown that behavior changes due to the level of SARS-CoV-2 mortality and symptomatic transmission were more influential (while behavioral changes due to the level of fatigue to interventions in the community was of marginal impact). It is shown that an increase in the proportion of exposed individuals who become asymptomatically-infectious at the end of the exposed period (represented by a parameter r) can lead to an increase (decrease) in the control reproduction number (R_C) if the effective contact rate of asymptomatic individuals is higher (lower) than that of symptomatic individuals. The study identifies two threshold values of the parameter r that maximize the cumulative and daily SARS-CoV-2 mortality, respectively, during the first wave. Furthermore, it is shown that, as the value of the proportion r increases from 0 to 1, the rate at which susceptible non-adherent individuals change their behavior to strictly adhere to public health interventions decreases. Hence, this study suggests that, as more newly-infected individuals become asymptomatically-infectious, the level of positive behavior change, as well as disease severity, hospitalizations and disease-induced mortality in the community can be expected to significantly decrease (while new cases may rise, particularly if asymptomatic individuals have higher contact rate, in comparison to symptomatic individuals).

  🖺 Full Text HTML: Mathematical assessment of the role of human behavior changes on SARS-CoV-2 transmission dynamics
• Temporal variations in international air travel: implications for modelling the spread of infectious diseases -

  Background The international flight network creates multiple routes by which pathogens can quickly spread across the globe. In the early stages of infectious disease outbreaks, analyses using flight passenger data to identify countries at risk of importing the pathogen are common and can help inform disease control efforts. A challenge faced in this modelling is that the latest aviation statistics (referred to as contemporary data) are typically not immediately available. Therefore, flight patterns from a previous year are often used (referred to as historical data). We explored the suitability of historical data for predicting the spatial spread of emerging epidemics. Methods We analysed monthly flight passenger data from the International Air Transport Association to assess how baseline air travel patterns were affected in outbreaks of MERS, Zika, and SARS-CoV-2 over the past decade. We then used a stochastic discrete time SEIR metapopulation model to simulate global spread of different pathogens, comparing how epidemic dynamics differed in simulations based on historical and contemporary data. Results We observed local, short-term disruptions to air travel from South Korea and Brazil for the MERS and Zika outbreaks we studied, whereas global and longer-term flight disruption occurred during the SARS-CoV-2 pandemic. For outbreak events that were accompanied by local, small, and short-term changes in air travel, epidemic models using historical flight data gave similar projections of timing and locations of disease spread as when using contemporary flight data. However, historical data were less reliable to model the spread of an atypical outbreak such as SARS-CoV-2 in which there were durable and extensive levels of global travel disruption. Conclusions The use of historical flight data as a proxy in epidemic models is an acceptable practice except in rare, large epidemics that lead to substantial disruptions to international travel.

  🖺 Full Text HTML: Temporal variations in international air travel: implications for modelling the spread of infectious diseases
• Host-Microbe Multiomic Profiling Reveals Age-Dependent COVID-19 Immunopathology -

  Age is a major risk factor for severe coronavirus disease-2019 (COVID-19), yet the mechanisms responsible for this relationship have remained incompletely understood. To address this, we evaluated the impact of aging on host and viral dynamics in a prospective, multicenter cohort of 1,031 patients hospitalized for COVID-19, ranging from 18 to 96 years of age. We performed blood transcriptomics and nasal metatranscriptomics, and measured peripheral blood immune cell populations, inflammatory protein expression, anti-SARS-CoV-2 antibodies, and anti- interferon (IFN) autoantibodies. We found that older age correlated with an increased SARS-CoV- 2 viral load at the time of admission, and with delayed viral clearance over 28 days. This contributed to an age-dependent increase in type I IFN gene expression in both the respiratory tract and blood. We also observed age-dependent transcriptional increases in peripheral blood IFN-gamma, neutrophil degranulation, and Toll like receptor (TLR) signaling pathways, and decreases in T cell receptor (TCR) and B cell receptor signaling pathways. Over time, older adults exhibited a remarkably sustained induction of proinflammatory genes (e.g., CXCL6) and serum chemokines (e.g., CXCL9) compared to younger individuals, highlighting a striking age-dependent impairment in inflammation resolution. Augmented inflammatory signaling also involved the upper airway, where aging was associated with upregulation of TLR, IL17, type I IFN and IL1 pathways, and downregulation TCR and PD-1 signaling pathways. Metatranscriptomics revealed that the oldest adults exhibited disproportionate reactivation of herpes simplex virus and cytomegalovirus in the upper airway following hospitalization. Mass cytometry demonstrated that aging correlated with reduced naïve T and B cell populations, and increased monocytes and exhausted natural killer cells. Transcriptional and protein biomarkers of disease severity markedly differed with age, with the oldest adults exhibiting greater expression of TLR and inflammasome signaling genes, as well as proinflammatory proteins (e.g., IL6, CXCL8), in severe COVID-19 compared to mild/moderate disease. Anti-IFN autoantibody prevalence correlated with both age and disease severity. Taken together, this work profiles both host and microbe in the blood and airway to provide fresh insights into aging-related immune changes in a large cohort of vaccine-naïve COVID-19 patients. We observed age-dependent immune dysregulation at the transcriptional, protein and cellular levels, manifesting in an imbalance of inflammatory responses over the course of hospitalization, and suggesting potential new therapeutic targets.

  🖺 Full Text HTML: Host-Microbe Multiomic Profiling Reveals Age-Dependent COVID-19 Immunopathology

From Clinical Trials

• Correlation of Antibody Response to COVID-19 Vaccination in Pregnant Woman and Transplacental Passage Into Cord Blood. - Conditions: Covid-19
  Interventions: Diagnostic Test: COVID-19 Spike Protein IgG Quantitative Antibody (CMIA)
  Sponsors: Vachira Phuket Hospital
  Recruiting

• UNAIR Inactivated COVID-19 Vaccine as Homologue Booster (Immunobridging Study) - Conditions: COVID-19 Pandemic; COVID-19 Vaccines; COVID-19 Virus Disease
  Interventions: Biological: INAVAC (Vaksin Merah Putih - UA- SARS CoV-2 (Vero Cell Inactivated) 5 μg
  Sponsors: Dr. Soetomo General Hospital; Universitas Airlangga; Biotis Pharmaceuticals, Indonesia; Indonesia-MoH
  Recruiting

• Safety and Immunogenicity of a Sub-unit Protein CD40.RBDv Bivalent COVID-19 Vaccine, Adjuvanted or Not, as a Booster in Volunteers. - Conditions: COVID-19
  Interventions: Drug: CD40.RBDv vaccin (SARS-Cov2 Vaccin)
  Sponsors: ANRS, Emerging Infectious Diseases; LinKinVax; Vaccine Research Institute (VRI), France
  Not yet recruiting

• ADJUVANT TREATMENT TO REDUCE CARDIOVASCULAR RISK IN PATIENTS WITH LONG COVID: HIGH-DEFINITION TRANSCRANIAL DIRECT CURRENT STIMULATION (HD-TDCS) AND CHLORELLA PYREINOIDOSA - Conditions: Cardiovascular Diseases; Long Covid19
  Interventions: Other: High Definition-transcranial Direct Current Stimulation; Dietary Supplement: Chlorella Pyreinodosa
  Sponsors: Federal University of Paraíba; City University of New York
  Recruiting

• SGB for COVID-induced Parosmia - Conditions: COVID-19-Induced Parosmia
  Interventions: Drug: Stellate Ganglion Block; Drug: Placebo Sham Injection
  Sponsors: Washington University School of Medicine
  Recruiting

• Investigating the Effectiveness of Vimida - Conditions: Long COVID; Post COVID-19 Condition
  Interventions: Behavioral: vimida
  Sponsors: Gaia AG; Medical School Hamburg; Institut Long-Covid Rostock
  Not yet recruiting

• Effects of Physiotherapy Via Video Calls in Patients With COVID-19 - Conditions: COVID-19; Long COVID-19; Cardiopulmonary Function; Physical Function
  Interventions: Behavioral: Exercise training
  Sponsors: Chulabhorn Hospital
  Active, not recruiting

• Acute Cardiovascular Responses to a Single Exercise Session in Patients With Post-COVID-19 Syndrome - Conditions: Post-Acute COVID-19 Syndrome
  Interventions: Behavioral: Exercise session; Behavioral: Control session
  Sponsors: University of Nove de Julho
  Not yet recruiting

• Reducing Respiratory Virus Transmission in Bangladeshi Classrooms - Conditions: SARS-CoV2 Infection; Influenza Viral Infections; Respiratory Viral Infection
  Interventions: Device: Box Fan; Device: UV Germicidal Irradiation Lamp Unit; Device: Combined: Box Fan and UV Germicidal Irradiation Lamp Units
  Sponsors: Stanford University; Centers for Disease Control and Prevention; International Centre for Diarrhoeal Disease Research, Bangladesh
  Not yet recruiting

• SMILE: Clinical Trial to Evaluate Mindfulness as Intervention for Racial and Ethnic Populations During COVID-19 - Conditions: Anxiety; COVID-19 Pandemic
  Interventions: Behavioral: Mindfulness
  Sponsors: University of North Carolina, Chapel Hill; National Institute on Minority Health and Health Disparities (NIMHD); RTI International
  Not yet recruiting

• The Effects of Nutritional Intervention on Health Parameters in Participants With Type 2 Diabetes Mellitus - Conditions: Diabetes Mellitus Type 2; Diabetes Mellitus Type 2 in Obese; Diabetes; Diabetes Mellitus Non-insulin-dependent; Hypertension; Type 2 Diabetes Mellitus
  Interventions: Behavioral: Nutritional Intervention
  Sponsors: Sao Jose do Rio Preto Medical School; Fundação de Amparo à Pesquisa do Estado de São Paulo
  Completed

• A Study to Learn About a Combined COVID-19 and Influenza Shot in Healthy Adults - Conditions: Influenza, Human; SARS-CoV-2 Infection; COVID-19
  Interventions: Biological: BNT162b2 (Omi XBB.1.5)/RIV; Biological: BNT162b2 (Omi XBB.1.5); Biological: RIV; Other: Normal saline placebo
  Sponsors: Pfizer
  Recruiting

• The Impact of the Covid-19 Pandemic on Orthopedic Trauma Management - Conditions: Trauma; COVID-19 Pandemic
  Interventions: Other: epidemyolojical
  Sponsors: Bakirkoy Dr. Sadi Konuk Research and Training Hospital
  Completed

From PubMed

• Targeting mevalonate pathway by zoledronate ameliorated pulmonary fibrosis in a rat model: Promising therapy against post-COVID-19 pulmonary fibrosis - CONCLUSION: ZA in a dose-dependent manner prevented the pathological effect of CCl4 in the lung by targeting mevalonate pathway. It could be promising therapy against PCPF.

• Methotrexate Inhibits the Binding of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Receptor Binding Domain to the Host-Cell Angiotensin-Converting Enzyme-2 (ACE-2) Receptor - As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus mutates, finding effective drugs becomes more challenging. In this study, we use ultrasensitive frequency locked microtoroid optical resonators in combination with in silico screening to search for COVID-19 drugs that can stop the virus from attaching to the human angiotensin-converting enzyme 2 (hACE2) receptor in the lungs. We found 29 promising candidates that could block the binding site and selected four of them that…

• Evaluating NSAIDs in SARS-CoV-2: Immunomodulatory mechanisms and future therapeutic strategies - Non-steroidal anti-inflammatory drugs (NSAIDs) are widely recognized for their analgesic and anti-inflammatory properties. Amidst the SARS-CoV-2 pandemic, the role of NSAIDs in modulating viral and bacterial infections has become a critical area of research, sparking debates and necessitating a thorough review. This review examines the multifaceted interactions between NSAIDs, immune responses, and infections. Focusing on the immunomodulatory mechanisms of NSAIDs in SARS-CoV-2 and their…

• Molecular docking of bioactive compounds extracted and purified from selected medicinal plant species against covid-19 proteins and in vitro evaluation - Bioactive compounds are secondary metabolites of plants. They offer diverse pharmacological properties. Peganum harmala is reported to have pharmaceutical effects like insecticidal, antitumor, curing malaria, anti-spasmodic, vasorelaxant, antihistaminic effect. Rosa brunonii has medicinal importance in its flower and fruits effective against different diseases and juice of leaf is reported to be applied externally to cure wounds and cuts. Dryopteris ramosa aqueous leaf extract is used to treat…

• Asialoglycoprotein receptor 1 promotes SARS-CoV-2 infection of human normal hepatocytes - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes multi-organ damage, which includes hepatic dysfunction, as observed in over 50% of COVID-19 patients. Angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 (ACE2) is the primary receptor for SARS-CoV-2 entry into host cells, and studies have shown the presence of intracellular virus particles in human hepatocytes that express ACE2, but at extremely low levels. Consequently, we asked if hepatocytes might express receptors…

• SARS-CoV-2 spike protein-ACE2 interaction increases carbohydrate sulfotransferases and reduces N-acetylgalactosamine-4-sulfatase by p38 MAPK - Immunostaining in lungs of patients who died with COVID-19 infection showed increased intensity and distribution of chondroitin sulfate and decline in N-acetylgalactostamine-4-sulfatase (Arylsulfatase B; ARSB). To explain these findings, human small airway epithelial cells were exposed to the SARS-CoV-2 spike protein receptor binding domain (SPRBD) and transcriptional mechanisms were investigated. Phospho-p38 MAPK and phospho-SMAD3 increased following exposure to the SPRBD, and their inhibition…

• Investigating vulnerability of the conserved SARS-CoV-2 spike’s heptad repeat 2 as target for fusion inhibitors using chimeric miniproteins - Inhibition of SARS-CoV-2 membrane fusion is a highly desired target to combat COVID-19. The interaction between the spike’s heptad repeat (HR) regions 1 (HR1) and 2 (HR2) is a crucial step during the fusion process and these highly conserved HR regions constitute attractive targets for fusion inhibitors. However, the relative importance of each subregion of the long HR1-HR2 interface for viral inhibition remains unclear. Here, we designed, produced, and characterized a series of chimeric…

• TYPE I INTERFERON PATHWAY GENETIC VARIANTS IN SEVERE COVID-19 - Coronavirus Disease 2019 (COVID-19) is an infectious disease caused by SARS-CoV-2. According to the World Health Organization (WHO), there have been over 760 million reported cases and over 6 million deaths caused by this disease worldwide. The severity of COVID-19 is based on symptoms presented by the patient and is divided as asymptomatic, mild, moderate, severe, and critical. The manifestations are interconnected with genetic variations. The innate immunity is the quickest response mechanism…

• Inhibition of CD40L with Frexalimab in Multiple Sclerosis - CONCLUSIONS: In a phase 2 trial involving participants with multiple sclerosis, inhibition of CD40L with frexalimab had an effect that generally favored a greater reduction in the number of new gadolinium-enhancing T1-weighted lesions at week 12 as compared with placebo. Larger and longer trials are needed to determine the long-term efficacy and safety of frexalimab in persons with multiple sclerosis. (Funded by Sanofi; ClinicalTrials.gov number, NCT04879628.).

• Hyperacetylated microtubules assist porcine deltacoronavirus nsp8 to degrade MDA5 via SQSTM1/p62-dependent selective autophagy - The microtubule (MT) is a highly dynamic polymer that functions in various cellular processes through MT hyperacetylation. Thus, many viruses have evolved mechanisms to hijack the MT network of the cytoskeleton to allow intracellular replication of viral genomic material. Coronavirus non-structural protein 8 (nsp8), a component of the viral replication transcriptional complex, is essential for viral survival. Here, we found that nsp8 of porcine deltacoronavirus (PDCoV), an emerging…

• An isothermal calorimetry assay for determining steady state kinetic and enzyme inhibition parameters for SARS-CoV-2 3CL-protease - This manuscript describes the application of Isothermal Titration Calorimetry (ITC) to characterize the kinetics of 3CL ^(pro) from the Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) and its inhibition by Ensitrelvir, a known non-covalent inhibitor. 3CL ^(pro) is the main protease that plays a crucial role of producing the whole array of proteins necessary for the viral infection that caused the spread of COVID-19, responsible for millions of deaths worldwide as well as global…

• Identification of new pharmacophore against SARS-CoV-2 spike protein by multi-fold computational and biochemical techniques - COVID-19 appeared as a highly contagious disease after its outbreak in December 2019 by the virus, named SARS-CoV-2. The threat, which originated in Wuhan, China, swiftly became an international emergency. Among different genomic products, spike protein of virus plays a crucial role in the initiation of the infection by binding to the human lung cells, therefore, SARS-CoV-2’s spike protein is a promising therapeutic target. Using a combination of a structure-based virtual screening and…

• Calpain-2 mediates SARS-CoV-2 entry via regulating ACE2 levels - Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, much effort has been dedicated to identifying effective antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A number of calpain inhibitors show excellent antiviral activities against SARS-CoV-2 by targeting the viral main protease (M^(pro)), which plays an essential role in processing viral polyproteins. In this study, we found that calpain inhibitors potently inhibited the infection of a…

• Combination of Polygonatum Rhizoma and Scutellaria baicalensis triggers apoptosis through downregulation of PON₃ -induced mitochondrial damage and endoplasmic reticulum stress in A549 cells - CONCLUSION: SP inhibits proliferation of lung cancer A549 cells by downregulating PON(3) -induced apoptosis in the mitochondrial and ER pathways.

• Omicron BA.4/5 neutralization and cell-mediated immune responses in relation to baseline immune status and breakthrough infection among PLWH: A follow-up cohort study - There is a paucity of data on hybrid immunity (vaccination plus breakthrough infection [BI]), especially cell-mediated responses to Omicron among immunosuppressed patients. We aim to investigate humoral and cellular responses to Omicron BA.4/5 among people living with HIV (PLWH) with/without BIs, the most prevalent variant of concern after the reopening of China. Based on our previous study, we enrolled 77 PLWH with baseline immune status of severe acute respiratory syndrome coronavirus 2…

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