Covid-19 Sentry

Contents

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

From Preprints

• Antiporphyrics, antithrombotics and erythropoiesis stimulating agents to treat Covid-19: A living systematic review and meta-analysis -
  Abstract Aims: Covid-19 hematology is hallmarked by porphyrin dysmetabolism, altered hemostasis and erythropoietic distress. We hypothesize that antiporphyrics, antithrombotics and erythropoiesis stimulating agents (ESAs) may prove beneficial in the treatment of severe Covid-19. The objective of the current study was to systematically review and meta-analyse the mortality risk profile of hospitalized Covid-19 patients, when treated with each of the three interventions of interest - versus placebo, standard of care or non-intervention. Methods: Eligible studies were identified from: biorxiv and medrxiv, clinical trials govR4, covid19 trials tracker netR5, DISCOVERR2 (Ebsco), ICTRPR7, PubMedR1 and Google ScholarR3 during search period 27 May-07 June 2022. Risk of bias was assessed with SIGN, NIH and JBI checklists and results quantitatively synthesised for antiporphyrics plus antithrombotics studies. Quantitative synthesis was performed in RevMan 5.4R9 with random effects model meta-analysis. Publication bias was assessed in R by funnel plot, Egger’s regression and trimfill analysis (metafor). Results: Number and type of studies included was 6 RCTs for antiporphyrics, 16 cohort for antithrombotics, and 3 case report/series for ESAs. Both unadjusted and adjusted analyses suggested that hydroxychloroquine treatment was not significantly associated with mortality risk in hospitalised Covid-19 patients (RR 0.95 [0.71, 1.29], P=0.76; aHR 0.78 [0.51, 1.22], P=0.28). Interestingly, the direction of effect shifted further towards favoring intervention when only high quality studies were included in the analysis (unadjusted RR 0.80 [0.42, 1.55]) compared with low quality studies (unadjusted RR 1.59 [0.71, 3.53]) although neither were statistically significant (P=0.51 and P=0.26, respectively). Exposure to antithrombotics was associated with reduced in-hospital mortality risk in adjusted analysis (aOR 0.54 [0.33, 0.86], P=0.01; aHR 0.65 [0.52, 0.82], P=0.0003). Subgroup analysis of adjusted estimates showed that exposure to aspirin (aHR 0.62 [0.50, 0.77], P<0.00001) and heparin (aOR 0.35 [0.14, 0.90], P=0.03) individually were associated with reduced mortality risk. The finding was robust to type of regimen, with pre-admission exposure to antithrombotics (aHR 0.79 [0.67, 0.93], P=0.005) and aspirin (aHR 0.66 [0.52, 0.84], P=0.0009] both showing reduced mortality risk. Additionally, prophylactic dose antithrombotics were associated with reduced mortality (aHR 0.44 [0.32, 0.60], P<0.00001). Publication bias was negative by Egger’s regression test (P=0.95). The direction of effect remained significantly in favor of intervention after trim-and-fill analysis (P=0.0034). Discussion: We make an interim recommendation in favor of antithrombotics, with very low certainty of evidence. We make an interim recommendation in favor of either intervention or non-intervention for both antiporphyrics and ESAs, with low and very low certainty of evidence.
  🖺 Full Text HTML: Antiporphyrics, antithrombotics and erythropoiesis stimulating agents to treat Covid-19: A living systematic review and meta-analysis
• Resistance of SARS-CoV-2 Omicron Subvariant BA.4.6 to Antibody Neutralization -
  SARS-CoV-2 Omicron subvariants BA.4.6, BA.4.7, and BA.5.9 have recently emerged, and BA.4.6 appears to be expanding even in the presence of BA.5 that is globally dominant. Compared to BA.5, these new subvariants harbor a mutation at R346 residue in the spike glycoprotein, raising concerns for further antibody evasion. We compared the viral receptor binding affinity of the new Omicron subvariants with BA.5 by surface plasmon resonance. We also performed VSV-based pseudovirus neutralization assays to evaluate their antigenic properties using sera from individuals who received three doses of a COVID-19 mRNA vaccine (boosted) and patients with BA.1 or BA.2 breakthrough infection, as well as using a panel of 23 monoclonal antibodies (mAbs). Compared to the BA.5 subvariant, BA.4.6, BA.4.7, and BA.5.9 showed similar binding affinities to hACE2 and exhibited similar resistance profiles to boosted and BA.1 breakthrough sera, but BA.4.6 was slightly but significantly more resistant than BA.5 to BA.2 breakthrough sera. Moreover, BA.4.6, BA.4.7, and BA.5.9 showed heightened resistance over to a class of mAbs due to R346T/S/I mutation. Notably, the authorized combination of tixagevimab and cilgavimab completely lost neutralizing activity against these three subvariants. The loss of activity of tixagevimab and cilgavimab against BA.4.6 leaves us with bebtelovimab as the only therapeutic mAb that has retained potent activity against all circulating forms of SARS-CoV-2. As the virus continues to evolve, our arsenal of authorized mAbs may soon be depleted, thereby jeopardizing the wellbeing of millions of immunocompromised persons who cannot robustly respond to COVID-19 vaccines.
  🖺 Full Text HTML: Resistance of SARS-CoV-2 Omicron Subvariant BA.4.6 to Antibody Neutralization
• Omicron-induced interferon signalling prevents influenza A virus infection -
  Recent findings in permanent cell lines suggested that SARS-CoV-2 Omicron BA.1 induces a stronger interferon response than Delta. Here, we show that BA.1 and BA.5 but not Delta induce an antiviral state in air-liquid interface (ALI) cultures of primary human bronchial epithelial (HBE) cells and primary human monocytes. Both Omicron subvariants caused the production of biologically active type I (alpha/beta) and III (lambda) interferons and protected cells from super-infection with influenza A viruses. Notably, abortive Omicron infection of monocytes was sufficient to protect monocytes from influenza A virus infection. Interestingly, while influenza-like illnesses surged during the Delta wave in England, their spread rapidly declined upon the emergence of Omicron. Mechanistically, Omicron-induced interferon signalling was mediated via double-stranded RNA recognition by MDA5, as MDA5 knock-out prevented it. The JAK/ STAT inhibitor baricitinib inhibited the Omicron-mediated antiviral response, suggesting it is caused by MDA5-mediated interferon production, which activates interferon receptors that then trigger JAK/ STAT signalling. In conclusion, our study 1) demonstrates that only Omicron but not Delta induces a substantial interferon response in physiologically relevant models, 2) shows that Omicron infection protects cells from influenza A virus super-infection, and 3) indicates that BA.1 and BA.5 induce comparable antiviral states.
  🖺 Full Text HTML: Omicron-induced interferon signalling prevents influenza A virus infection
• Controllable self-replicating RNA vaccine delivered intradermally elicits predominantly cellular immunity -
  Intradermal delivery of self-replicating RNA (srRNA) is a promising vaccine platform. Considering that human skin temperature is around 33{degrees}C, lower than core body temperature of 37{degrees}C, we have developed an srRNA that functions optimally at skin temperature and is inactivated at or above 37{degrees}C as a safety switch. This temperature-controllable srRNA (c-srRNA), when tested as an intradermal vaccine against SARS-CoV-2, functions when injected naked without lipid nanoparticles. Unlike most currently available vaccines, c-srRNA vaccines predominantly elicit cellular immunity with little or no antibody production. Interestingly, c-srRNA-vaccinated mice produced antigen-specific antibodies upon subsequent stimulation with antigen protein. Antigen-specific antibodies were also produced when B-cell stimulation using antigen protein was followed by c-srRNA booster vaccination. Using c-srRNA, we have designed a pan-coronavirus booster vaccine that incorporates both spike receptor binding domains as viral surface proteins and evolutionarily conserved nucleoproteins as viral non-surface proteins, from both SARS-CoV-2 and MERS-CoV. It can thereby potentially immunize against SARS-CoV-2, SARS-CoV, MERS-CoV, and their variants. c-srRNA may provide a route to activate cellular immunity against a wide variety of pathogens.
  🖺 Full Text HTML: Controllable self-replicating RNA vaccine delivered intradermally elicits predominantly cellular immunity
• A multi-population-based genomic analysis uncovers unique haplotype variants and crucial mutant genes in SARS-CoV-2 -

  Background: COVID-19 is a disease caused by severe acute respiratory syndrome coronavirus 2, SARS-CoV-2. Rigorous detection and treatment strategies against SARS-CoV-2 have become very challenging due to continuous evolutions to the viral genome. Therefore, careful genomic analysis is sorely needed to understand transmission, the cellular mechanism of pathogenicity, and the development of vaccines or drugs. Objective: In this study, we intended to identify SARS-CoV-2 genome variants that may help understand the cellular and molecular foundation of coronavirus infections required to develop effective intervention strategies. Methods: SARS-CoV-2 genome sequences were downloaded from an open-source public database, processed, and analyzed for variants in target detection sites and genes. Results: We have identified six unique variants, G….AAC, T….AAC….T; AAC….T; C……C; C……..C; and C……..T at the nucleocapsid region and eleven major hotspot mutant genes: nsp3, surface glycoprotein, nucleocapsid phosphoprotein, ORF8, nsp6, nsp2, nsp4, helicase, membrane glycoprotein, 39-59 exonuclease, and 2-O-ribose methyltransferases. In addition, we have identified eleven major mutant genes that may have a crucial role in SARS-CoV-2 pathogenesis. Conclusion: Studying haplotype variants and 11 major mutant genes to understand the mechanism of action of fatal pathogenicity and inter-individual variations in immune responses is inevitable for managing target patient groups with identified variants and developing effective anti-viral drugs and vaccines.

  🖺 Full Text HTML: A multi-population-based genomic analysis uncovers unique haplotype variants and crucial mutant genes in SARS-CoV-2
• Scaling rules for pandemics: Estimating infected fraction from identified cases for the SARS-CoV-2 Pandemic -

  Using a modified form of the SIR model, we show that, under general conditions, all pandemics exhibit certain scaling rules. Using only daily data for symptomatic, confirmed cases, these scaling rules can be used to estimate: (i) r_eff, the effective pandemic R-parameter; (ii) f_tot, the fraction of exposed individuals that were infected (symptomatic and asymptomatic); (iii) L_eff, the effective latency, the average number of days an infected individual is able to infect others in the pool of susceptible individuals; and (iv) alpha, the probability of infection per contact between infected and susceptible individuals. We validate the scaling rules using an example and then apply our method to estimate r_eff, f_tot, L_eff and alpha for the first phase of the SARS-Cov-2, Covid-19 pandemic for thirty-four countries where there was a well separated first peak in identified infected daily cases after the outbreak of this pandemic in early 2020. Our results are general and can be applied to any pandemic.

  🖺 Full Text HTML: Scaling rules for pandemics: Estimating infected fraction from identified cases for the SARS-CoV-2 Pandemic
• Persistent somatic symptoms are key to individual illness perception at one year after COVID-19 -

  Background: Sequelae of Coronavirus disease 2019 (COVID-19) were investigated by both patient-initiated and academic initiatives. Patient9s subjective illness perceptions might differ from physician9s clinical assessment results. Herein, we explored factors influencing patient9s perception during COVID-19 recovery. Methods: Participants of the prospective observation CovILD study with persistent somatic symptoms or cardiopulmonary findings at the clinical follow-up one year after COVID-19 were analyzed (n = 74). Explanatory variables included baseline demographic and comorbidity data, COVID-19 course and one-year follow-up data of persistent somatic symptoms, physical performance, lung function testing (LFT), chest computed tomography (CT) and trans-thoracic echocardiography (TTE). Factors affecting illness perception (Brief Illness Perception Questionnaire, BIPQ) were identified by penalized multi-parameter regression and unsupervised clustering. Results: In modeling, 47% of overall illness perception variance at one year after COVID-19 was attributed to fatigue intensity, reduced physical performance, hair loss and baseline respiratory comorbidity. Overall illness perception was independent of LFT results, pulmonary lesions in CT or heart abnormality in TTE. As identified by clustering, persistent somatic symptom count, fatigue, diminished physical performance, dyspnea, hair loss and sleep problems at the one-year follow-up and severe acute COVID-19 were associated with the BIPQ domains of concern, emotional representation, complaints, disease timeline and consequences. Conclusion: Persistent somatic symptoms rather than clinical assessment results, revealing lung and heart abnormalities, impact on severity and quality of illness perception at one year after COVID-19 and may foster unhelpful coping mechanisms. Besides COVID-19 severity, individual illness perception should be taken into account when allocating rehabilitation and psychological therapy resources. Study registration: ClinicalTrials.gov: NCT04416100.

  🖺 Full Text HTML: Persistent somatic symptoms are key to individual illness perception at one year after COVID-19
• The prevalence of SARS-CoV-2 infection and long COVID in US adults during the BA.5 surge, June-July 2022 -

  Due to changes in SARS-CoV-2 testing practices, passive case-based surveillance may be an increasingly unreliable indicator for monitoring the burden of SARS-CoV-2, especially during surges. We conducted a cross-sectional survey of a population-representative sample of 3,042 U.S. adults between June 30 and July 2, 2022, during the Omicron BA.5 surge. Respondents were asked about SARS-CoV-2 testing and outcomes, COVID-like symptoms, contact with cases, and experience with prolonged COVID-19 symptoms following prior infection. We estimated the weighted age and sex-standardized SARS-CoV-2 prevalence, during the 14-day period preceding the interview. We estimated age and gender adjusted prevalence ratios (aPR) for current SARS-CoV-2 infection using a log-binomial regression model. An estimated 17.3% (95% CI 14.9, 19.8) of respondents had SARS-CoV-2 infection during the two-week study period, equating to 44 million cases as compared to 1.8 million per the CDC during the same time period. SARS-CoV-2 prevalence was higher among those 18-24 years old (aPR 2.2, 95% CI 1.8, 2.7) and among non-Hispanic Black (aPR 1.7, 95% CI 1.4 ,2.2) and Hispanic (aPR 2.4, 95% CI 2.0 , 2.9). SARS-CoV-2 prevalence was also higher among those with lower income (aPR 1.9, 95% CI 1.5, 2.3), lower education (aPR 3.7 95% CI 3.0,4.7), and those with comorbidities (aPR 1.6, 95% CI 1.4, 2.0). An estimated 21.5% (95% CI 18.2, 24.7) of respondents with a SARS-CoV-2 infection more than 4 weeks prior reported long COVID symptoms. The inequitable distribution of SARS-CoV-2 prevalence during the BA.5 surge will likely drive inequities in the future burden of long COVID.

  🖺 Full Text HTML: The prevalence of SARS-CoV-2 infection and long COVID in US adults during the BA.5 surge, June-July 2022
• The COVID-19 Pandemic as an Opportunity for Unravelling the Causative Association between Respiratory Viruses and Pneumococcus-Associated Disease in Young Children: A Prospective Cohort Study -

  BACKGROUND: In young children, rates of community-acquired alveolar pneumonia (CAAP) or invasive pneumococcal disease (IPD) have been associated with respiratory syncytial virus (RSV), human metapneumovirus (hMPV), influenza (flu), and parainfluenza (PIV) (collectively termed here as pneumococcal disease-associated viruses [PDA-viruses]). However, their contribution to the pathogenesis of pneumococcal-associated disease has not yet been elucidated. The COVID-19 pandemic provided a unique opportunity to examine the question. METHODS: This prospective study comprised all children <5 years, living in southern Israel, during 2016 through 2021. The data were derived from multiple ongoing prospective cohort surveillance programs and include: hospital visits for CAAP, non-CAAP lower respiratory infections (LRI); nasopharyngeal pneumococcal carriage (<3 years of age); respiratory virus activity; all-ages COVID-19 episodes; and IPD in children <5 years (nationwide) A hierarchical negative binominal regression model was developed to estimate the proportion of the disease outcomes attributable to each of the viruses from monthly time series data, stratified by age and ethnicity. A separate model was fit for each outcome, with covariates that included a linear time trend, 12-month harmonic variables to capture unexplained seasonal variations, and the proportion of tests positive for each virus in that month. FINDINGS: During 2016 through 2021, 3,204, 26,695, 257, and 619 episodes of CAAP, non-CAAP LRI, pneumococcal bacteremic pneumonia and non-pneumonia IPD, respectively, were reported. Compared to 2016-2019, broad declines in the disease outcomes were observed shortly after the pandemic surge, coincident with a complete disappearance of all PDA-viruses and continued circulation of rhinovirus (RhV) and adenovirus (AdV). From April 2021, off-season and abrupt surges of all disease outcomes occurred, associated with similar dynamics among the PDA-viruses, which re-emerged sequentially. Using our model fit to the entire 2016-2021 period, 82% (95% CI, 75-88%) of CAAP episodes in 2021 were attributable to the common respiratory viruses, as were 22%-31% of the other disease outcomes. Virus-specific contributions to CAAP were: RSV, 49% (95% CI, 43-55%); hMPV, 13% (10-17%); PIV, 11% (7-15%); flu, 7% (1-13%). RhV and AdV did not contribute. RSV was the main contributor in all outcomes, especially in infants. Pneumococcal carriage prevalence remained largely stable throughout the study. INTERPRETATION: RSV and hMPV play a critical role in the burden of CAAP and pneumococcal disease in children. Interventions targeting these viruses could have a secondary effect on the disease burden typically attributed to bacteria.

  🖺 Full Text HTML: The COVID-19 Pandemic as an Opportunity for Unravelling the Causative Association between Respiratory Viruses and Pneumococcus-Associated Disease in Young Children: A Prospective Cohort Study
• Community engagement to increase vaccine uptake: Quasi-experimental evidence from Islamabad and Rawalpindi, Pakistan -

  Developing countries have been facing difficulties in reaching out to low-income and underserved communities for COVID-19 vaccination coverage. The rapidity of vaccine development caused a mistrust among certain subgroups of the population, and hence innovative approaches were taken to reach out to such populations. Using a sample of 1760 respondents in five low-income, informal localities of Islamabad and Rawalpindi, Pakistan, we evaluated a set of interventions involving community engagement by addressing demand and access barriers. We used multi-level mixed effects models to estimate average treatment effects across treatment areas. We found that our interventions increased COVID-19 vaccine willingness in two treatment areas that are furthest from city centers by 7.6% and 6.6% respectively, while vaccine uptake increased in one of the treatment areas by 17.1%, compared to the control area. Our results suggest that personalized information campaigns such as community mobilization help to increase COVID-19 vaccine willingness. Increasing uptake however, requires improving access to the vaccination services. Both information and access may be different for various communities and therefore a “one-size-fits-all” approach may need to be better localized. Such underserved and marginalized communities are better served if vaccination efforts are contextualized.

  🖺 Full Text HTML: Community engagement to increase vaccine uptake: Quasi-experimental evidence from Islamabad and Rawalpindi, Pakistan
• Impact of COVID-19 and Effects of Vaccination with BNT162b2 on Patient-Reported Health-Related Quality of Life, Symptoms, and Work Productivity Among US Adult Outpatients with SARS-CoV-2 -

  Background: Although there is extensive literature on the clinical benefits of COVID-19 vaccination, data on humanistic effects are limited. This study evaluated the impact of SARS-CoV-2 infection on symptoms, Health Related Quality of Life (HRQoL) and Work Productivity and Impairment (WPAI) prior to and one month following infection, and compared results between individuals vaccinated with BNT162b2 and those unvaccinated. Methods: Subjects with ≥1 self-reported symptom and positive RT-PCR for SARS-CoV-2 at CVS Health US test sites were recruited between 01/31/2022-04/30/2022. Socio-demographics, clinical characteristics and vaccination status were evaluated. Self-reported symptoms, HRQoL, and WPAI outcomes were assessed using questionnaires and validated instruments (EQ-5D-5L, WPAI-GH) across acute COVID time points from pre-COVID to Week 4, and between vaccination groups. Mixed models for repeated measures were conducted for multivariable analyses, adjusting for several covariates. Effect size (ES) of Cohen9s d was calculated to quantify the magnitude of outcome changes within and between vaccination groups. Results: The study population included 430 subjects: 197 unvaccinated and 233 vaccinated with BNT162b2. Mean (SD) age was 42.4 years (14.3), 76.0% were female, 38.8% reported prior infection and 24.2% at least one comorbidity. Statistically significant differences in outcomes were observed compared with baseline and between groups. The EQ-Visual analogue scale scores and Utility Index dropped in both cohorts at Day 3 and increased by Week 4, but did not return to pre-COVID levels. The mean changes were statistically lower in the BNT162b2 cohort at Day 3 and Week 4. The BNT162b2 cohort reported lower prevalence and fewer symptoms at index date and Week 4. At Week 1, COVID-19 had a large impact on all WPAI-GH domains: the work productivity time loss among unvaccinated and vaccinated was 65.0% and 53.8%, and the mean activity impairment was 50.2% and 43.9%, respectively. With the exception of absenteeism at Week 4, the BNT162b2 cohort was associated with statistically significant less worsening in all WPAI-GH scores at both Week 1 and 4. Conclusions: COVID-19 negatively impacted HRQoL and work productivity among mildly symptomatic outpatients. Compared with unvaccinated, those vaccinated with BNT162b2 were less impacted by COVID-19 infection and recovered faster.

  🖺 Full Text HTML: Impact of COVID-19 and Effects of Vaccination with BNT162b2 on Patient-Reported Health-Related Quality of Life, Symptoms, and Work Productivity Among US Adult Outpatients with SARS-CoV-2
• Exploration of million-sequence phylogenies with Taxonium -
  The COVID-19 pandemic has resulted in a step change in the scale of sequencing data, with more genomes of SARS-CoV-2 having been sequenced than any other organism on earth. These sequences reveal key insights when represented as a phylogenetic tree, which captures the evolutionary history of the virus, and allows the identification of transmission events and the emergence of new variants. However, existing web-based tools for analysing and exploring phylogenies do not scale to the size of datasets now available for SARS-CoV-2. We have developed Taxonium, a new tool that uses WebGL to allow the exploration of trees with tens of millions of nodes in the browser for the first time. Taxonium links each node to associated metadata and supports mutation-annotated trees, which are able to capture all known genetic variation in a dataset. We describe insights that analysing a tree of five million sequences can provide into SARS-CoV-2 evolution, and provide an application at http://cov2tree.org for exploring a public tree of more than five million SARS-CoV-2 sequences. Taxonium can be applied to any tree, and is available at http://taxonium.org, with source code at https://github.com/theosanderson/taxonium.
  🖺 Full Text HTML: Exploration of million-sequence phylogenies with Taxonium
• Naturally occurring mutations of SARS-CoV-2 main protease confer drug resistance to nirmatrelvir -
  The SARS-CoV-2 main protease (Mpro) is the drug target of Pfizer oral drug Paxlovid. The emergence of SARS-CoV-2 variants with mutations in Mpro raised the alarm of potential drug resistance. In this study, we identified 100 naturally occurring Mpro mutations located at the nirmatrelvir binding site, among which 20 mutants, including S144M/F/A/G/Y, M165T, E166G, H172Q/F, and Q192T/S/L/A/I/P/H/V/W/C/F, showed comparable enzymatic activity to the wild-type (kcat/Km < 10-fold change) and resistance to nirmatrelvir (Ki > 10-fold increase). X-ray crystal structures were determined for seven representative mutants with and/or without GC-376/nirmatrelvir. Viral growth assay showed that Mpro mutants with reduced enzymatic activity led to attenuated viral replication. Overall, our study identified several drug resistant hot spots that warrant close monitoring for possible clinical evidence of Paxlovid resistance.
  🖺 Full Text HTML: Naturally occurring mutations of SARS-CoV-2 main protease confer drug resistance to nirmatrelvir
• SARS-CoV-2 invades cognitive centers of the brain and induces Alzheimer’s-like neuropathology -
  The neurotropism of SARS-CoV-2 and the phenotypes of infected neurons are still in debate. Long COVID manifests with “brain diseases” and the cause of these brain dysfunction is mysterious. Here, we analyze 34 age- and underlying disease-matched COVID-19 or non-COVID-19 human brains. SARS-CoV-2 RNA, nucleocapsid, and spike proteins are present in neurons of the cognitive centers of all COVID-19 patients, with its non-structural protein NSF2 detected in adult cases but not in the infant case, indicating viral replications in mature neurons. In adult COVID-19 patients without underlying neurodegeneration, SARS-CoV-2 infection triggers A{beta} and p-tau deposition, degenerating neurons, microglia activation, and increased cytokine, in some cases with A{beta} plaques and p-tau pretangles. The number of SARS-CoV-2+ cells is higher in patients with neurodegenerative diseases than in those without such conditions. SARS-CoV-2 further activates microglia and induces A{beta} and p-tau deposits in non-Alzheimer’s neurodegenerative disease patients. SARS-CoV-2 infects mature neurons derived from inducible pluripotent stem cells from healthy and Alzheimer’s disease (AD) individuals through its receptor ACE2 and facilitator neuropilin-1. SARS-CoV-2 triggers AD-like gene programs in healthy neurons and exacerbates AD neuropathology. An AD infectious etiology gene signature is identified through SARS-CoV-2 infection and silencing the top three downregulated genes in human primary neurons recapitulates the neurodegenerative phenotypes of SARS-CoV-2. Thus, our data suggest that SARS-CoV-2 invades the brain and activates an AD-like program.
  🖺 Full Text HTML: SARS-CoV-2 invades cognitive centers of the brain and induces Alzheimer’s-like neuropathology
• How Have Global Scientists Responded to Tackling COVID-19? -

  Since the outbreak of COVID-19, the global scientific communities across almost all countries have made urgent, intensive, and continuous effort on understanding, fighting and modeling the COVID-19 pandemic. COVID-19 research turns out to be the first overwhelming global scientific reaction to significant global crises and threats. This literature analysis report collects and summarizes the profiles, trends, quality and impact of this global scientific response. It collects and analyzes 346,267 scientific references in English, involving researchers from 189 countries and regions in 27 subject areas. The report generates a picture of how global scientists have responded to COVID-19 between Jan 2020 and Mar 2022 in terms of their publication quantity, impact, focused major problems, and research areas and methods over country/region, discipline and time and collaboratively. The report also captures broad-reaching distributions and trends of modeling COVID-19 by AI, data science, analytics, shallow and deep machine learning, epidemic modeling, applied mathematics, and social science methods, etc. We further show the correlations between publication quality and quantity and economic status and COVID-19 infections globally and in major countries and regions. The literature analysis results of this global scientific response to COVID-19 present a comprehensive global, regional and subject-specific picture of the significant cross-disciplinary, cross-country, cross-problem, and cross-technique profiles and differences of the COVID-19 publication quantity and quality. The report also discloses significant imbalances in the COVID-19 research across countries/regions, subject areas, problems, topics, methods, research collaborations, and economic statuses. We share the source and analytical data of this global literature analysis for further research on this unprecedented and future crises.

  🖺 Full Text HTML: How Have Global Scientists Responded to Tackling COVID-19?

From Clinical Trials

• Booster Study of COVID-19 Protein Subunit Recombinant Vaccine - Condition:   COVID-19
  Interventions:   Biological: SARS-CoV-2 subunit protein recombinant vaccine;   Biological: Active Comparator
  Sponsors:   PT Bio Farma;   Faculty of Medicine Universitas Padjadjaran;   Faculty of Medicine Universitas Udayana
  Recruiting

• A Study to Evaluate the Immunogenicity and Safety of a Recombinant Protein COVID-19 Vaccine SCTV01E-1 in Population Aged Above 18 Years - Conditions:   COVID-19;   SARS-CoV-2 Infection
  Interventions:   Biological: SCTV01E-1 on D0;   Biological: SCTV01E-1 on D28;   Biological: SCTV01E-1 on D150;   Biological: SCTV01E on D0;   Biological: SCTV01E on D28;   Biological: SCTV01E on D150;   Biological: SCTV01E-1 on D120;   Biological: SCTV01E on D120
  Sponsor:   Sinocelltech Ltd.
  Not yet recruiting

• A Novel Parameter LIT/N That Predicts Survival in COVID-19 ICU Patients - Condition:   COVID-19 Pneumonia
  Intervention:   Diagnostic Test: the LIT test
  Sponsors:   Gazi University;   Oxford MediStress
  Completed

• Efficacy and Safety of ES16001 in Patients With COVID-19 - Condition:   COVID-19
  Interventions:   Drug: ES16001 40 mg;   Drug: ES16001 80 mg;   Drug: ES16001 160 mg;   Drug: Placebo
  Sponsor:   Genencell Co. Ltd.
  Recruiting

• Phase 2a Trial to Evaluate Safety and Immunogenicity of COVID-19 Vaccine Strategies in HIV-infected/Uninfected Adults. - Condition:   COVID-19
  Intervention:   Drug: Ad26.COV2.S (VAC31518, JNJ-78436735) Vaccine, SARS-CoV-2 rS (CovovaxTM), BNT162b2 (Pfizer)
  Sponsors:   The Aurum Institute NPC;   Coalition for Epidemic Preparedness Innovations
  Recruiting

• COVID Protection After Transplant - Sanofi GSK (CPAT-SG) Study - Conditions:   COVID-19;   Kidney Transplant
  Intervention:   Biological: Sanofi-GSK monovalent (B.1.351) CoV2 preS dTM-AS03 COVID-19 vaccine
  Sponsors:   National Institute of Allergy and Infectious Diseases (NIAID);   PPD;   Johns Hopkins University;   Sanofi Pasteur, a Sanofi Company
  Not yet recruiting

• Safety and Immunogenicity of COVID-19 Vaccine, AdCLD-CoV19-1 - Conditions:   COVID-19;   Vaccines
  Intervention:   Biological: AdCLD-CoV19-1
  Sponsors:   International Vaccine Institute;   Cellid Co., Ltd.
  Not yet recruiting

• Smartphone Intervention for Overdose and COVID-19 - Conditions:   Substance Use Disorders;   Overdose;   COVID-19
  Intervention:   Device: iThrive WI Intervention
  Sponsors:   University of Wisconsin, Madison;   National Institute on Drug Abuse (NIDA)
  Not yet recruiting

• A Study to Evaluate the Safety and Immunogenicity of COVID-19 and Influenza Combination Vaccine - Conditions:   COVID-19;   Influenza
  Interventions:   Drug: CIC Vaccine;   Drug: qNIV Vaccine;   Drug: SARS-CoV-2 rS Vaccine;   Drug: Influenza Vaccine
  Sponsor:   Novavax
  Not yet recruiting

• Study to Assess Efficacy and Safety of Treamid for Patients With Reduced Exercise Tolerance After COVID-19 - Conditions:   SARS-CoV-2 Infection;   Lung Fibrosis
  Interventions:   Drug: Treamid;   Drug: Treamid twice a day;   Drug: Treamid once a day;   Drug: Placebo
  Sponsor:   PHARMENTERPRISES LLC
  Not yet recruiting

• Self-proning and Repositioning in COVID-19 Outpatients at Risk of Complicated Illness - Conditions:   COVID-19;   COVID-19 Pneumonia;   Proning;   Hospitalization;   Death;   Outpatient;   Complication
  Intervention:   Other: Self-proning
  Sponsors:   Unity Health Toronto;   Applied Health Research Centre
  Recruiting

• Effects of Immulina TM Supplements With PASC Patients - Condition:   Post Acute COVID-19 Syndrome
  Interventions:   Dietary Supplement: Immulina TM;   Dietary Supplement: Placebo
  Sponsors:   University of Mississippi Medical Center;   National Institute of General Medical Sciences (NIGMS)
  Not yet recruiting

• Evaluation of Clinical Performance and Usability of iStatis COVID-19 Ag Rapid Test at POC - Conditions:   COVID-19 Virus Infection;   COVID-19;   Coronavirus Disease-19;   COVID-19 Pandemic;   SARS-CoV-2 Infection
  Interventions:   Diagnostic Test: iStatis COVID-19 Ag Rapid Test;   Diagnostic Test: “COVID-19 RT-PCR Test EUA Number: EUA200011, Company: Laboratory Corporation of America (”Labcorp")
  Sponsor:   bioLytical Laboratories
  Completed

• Resilience Intervention for Health Professionals COVID-19 - Condition:   Mental Health Wellness 1
  Intervention:   Other: Mindfulness-based Intervention
  Sponsor:   Universidad de Monterrey
  Completed

• Addressing Post-COVID-19 Musculoskeletal Symptoms - Conditions:   Telemedicine;   Musculoskeletal Disease;   SARS-CoV-2;   Pain;   COVID-19;   Exercise
  Interventions:   Other: Multicomponent exercise program;   Other: Tele-health primary care rehabilitation program
  Sponsor:   Universidad Europea de Madrid
  Not yet recruiting

From PubMed

• Restoration of vascular endothelial integrity by mesenchymal stromal/stem cells in debilitating virus diseases - Endothelial dysfunction is one of the key cornerstone complications of emerging and re-emerging viruses which lead to vascular leakage and a high mortality rate. The mechanism that regulates the origin of endothelial dysregulation is not completely elucidated. Currently, there are no potential pharmacological treatments and curable management for such diseases. In this sense, mesenchymal stromal/stem cells (MSCs) has been emerging to be a promising therapeutic strategy in restoring endothelial…

• RNA G-quadruplex formed in SARS-CoV-2 used for COVID-19 treatment in animal models - The ongoing COVID-19 pandemic has continued to affect millions of lives worldwide, leading to the urgent need for novel therapeutic strategies. G-quadruplexes (G4s) have been demonstrated to regulate life cycle of multiple viruses. Here, we identify several highly conservative and stable G4s in SARS-CoV-2 and clarify their dual-function of inhibition of the viral replication and translation processes. Furthermore, the cationic porphyrin compound 5,10,15,20-tetrakis-(N-methyl-4-pyridyl)porphine…

• Hypoxia inducible factors regulate infectious SARS-CoV-2, epithelial damage and respiratory symptoms in a hamster COVID-19 model - Understanding the host pathways that define susceptibility to Severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) infection and disease are essential for the design of new therapies. Oxygen levels in the microenvironment define the transcriptional landscape, however the influence of hypoxia on virus replication and disease in animal models is not well understood. In this study, we identify a role for the hypoxic inducible factor (HIF) signalling axis to inhibit SARS-CoV-2 infection,…

• Diminished cell proliferation promotes natural killer cell adaptive-like phenotype by limiting FcεRIγ expression - Human adaptive-like natural killer (NK) cells express low levels of FcεRIγ (FcRγ-/low) and are reported to accumulate during COVID-19 infection; however, the mechanism underlying and regulating FcRγ expression in NK cells has yet to be fully defined. We observed lower FcRγ protein expression in NK cell subsets from lung transplant patients during rapamycin treatment, suggesting a link with reduced mTOR activity. Further, FcRγ-/low NK cell subsets from healthy donors displayed reduced mTOR…

• Recent advances in molecular biology of metabolic syndrome pathophysiology: endothelial dysfunction as a potential therapeutic target - Current advances in molecular pathobiology of endotheliocytes dysfunctions are promising in finding the pathogenetic links to the emergence of insulin resistance syndrome. Physiologically, human organism homeostasis is strictly controlled to maintain metabolic processes at the acquainted level. Many factors are involved in maintaining these physiological processes in the organism and any deviation is undoubtedly accompanied by specific pathologies related to the affected process. Fortunately,…

• NETosis and thrombosis in vaccine-induced immune thrombotic thrombocytopenia - Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare yet serious adverse effect of the adenoviral vector vaccines ChAdOx1 nCoV-19 (AstraZeneca) and Ad26.COV2.S (Janssen) against COVID-19. The mechanisms involved in clot formation and thrombocytopenia in VITT are yet to be fully determined. Here we show neutrophils undergoing NETosis and confirm expression markers of NETs in VITT patients. VITT antibodies directly stimulate neutrophils to release NETs and induce thrombus formation…

• Beyond the vaccines: a glance at the small molecule and peptide-based anti-COVID19 arsenal - Unprecedented efforts of the researchers have been witnessed in the recent past towards the development of vaccine platforms for the control of the COVID-19 pandemic. Albeit, vaccination stands as a practical strategy to prevent SARS-CoV-2 infection, supplementing the anti-COVID19 arsenal with therapeutic options such as small molecules/peptides and antibodies is being conceived as a prudent strategy to tackle the emerging SARS-CoV-2 variants. Noteworthy to mention that collective efforts from…

• Targeting spike protein-induced TLR/NET axis by COVID-19 therapeutic NRICM102 ameliorates pulmonary embolism and fibrosis - The global COVID-19 pandemic remains a critical public health threat, as existing vaccines and drugs appear insufficient to halt the rapid transmission. During an outbreak from May to August 2021 in Taiwan, patients with severe COVID-19 were administered NRICM102, which was a traditional Chinese medicine (TCM) formula developed based on its predecessor NRICM101 approved for treating mild cases. This study aimed to explore the mechanism of NRICM102 in ameliorating severe COVID-19-related embolic…

• Computational investigation of potent inhibitors against SARS-CoV-2 2’-O-methyltransferase (nsp16): Structure-based pharmacophore modeling, molecular docking, molecular dynamics simulations and binding free energy calculations - The Coronavirus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has created unprecedented public health and economic crises around the world. SARS-CoV-2 2’-O-methyltransferase (nsp16) adds a “cap” to viral RNA to maintain the stability of viral RNA, and inhibition of nsp16 activity may reduce viral proliferation, making this protein an attractive drug target. Here, we report the identification of several small molecule inhibitors of…

• A Review of Safety Outcomes from Clinical Trials of Baricitinib in Rheumatology, Dermatology and COVID-19 - Baricitinib is an oral, selective inhibitor of Janus kinase (JAK)1/JAK2 that transiently and reversibly inhibits many proinflammatory cytokines. This mechanism is a key mediator in a number of chronic inflammatory diseases; accordingly, baricitinib has been studied and approved for the treatment of several rheumatological and dermatological disorders, as well as COVID-19. This narrative review summarises and discusses the safety profile of baricitinib across these diseases, with special focus on…

• Screening, molecular simulation and in silico kinetics of virtually designed Covid main protease inhibitors - Coronavirus (covid-19) infection is considered to deadliest ever pandemic experienced by the human being. It has very badly affected the socio-economic health of human and stuck the scientific community to think and rethink about its complete eradication. But due to no effective treatment or unavailability of vaccine the health professional could not show any significant improvement to control the pandemic. The situation needs newer molecule, vaccine or effective treatment to control covid-19…

• ZnO-chlorogenic acid nanostructured complex inhibits Covid-19 pathogenesis and increases hydroxychloroquine efficacy - The study purpose was to compare the anti- the novel coronavirus disease 2019 (COVID-19) property of chlorogenic acid (CGA) and Zinc oxide nanoparticles (ZnO-NP) with the new valid synthesized complex of ZnO /CGA-NPs. Methods The facile mixing method was utilized to prepare ZnO/CGA-NPs. The in vitro effect of different ZnO/CGA-NPs concentrations on papain-like protease (PL^(pro)) and spike protein- receptor-binding domain (RBD) was measured by ELISA technique. The compounds effects on SARS-CoV2…

• Emodin from Aloe inhibits Swine acute diarrhea syndrome coronavirus in cell culture - Swine acute diarrhea syndrome coronavirus (SADS-CoV) is an emerging swine enteropathogenic coronavirus that causes severe diarrhea in neonatal piglets, leading to serious economic losses to the pig industries. At present, there are no effective control measures for SADS, making an urgent need to exploit effective antiviral therapies. Here, we confirmed that Aloe extract (Ae) can strongly inhibit SADS-CoV in Vero and IPI-FX cells in vitro. Furthermore, we detected that Emodin from Ae had…

• Folic acid restricts SARS-CoV-2 invasion by methylating ACE2 - The current COVID-19 pandemic is motivating us to elucidate the molecular mechanism of SARS-CoV-2 invasion and find methods for decreasing its transmissibility. We found that SARS-CoV-2 could increase the protein level of ACE2 in mice. Folic acid and 5-10-methylenetetrahydrofolate reductase (MTHFR) could promote the methylation of the ACE2 promoter and inhibit ACE2 expression. Folic acid treatment decreased the binding ability of Spike protein, pseudovirus and inactivated authentic SARS-CoV-2 to…

• SARS-CoV-2 Infection-Associated Aortic Thrombosis Treated with Oral Factor Xa Inhibition - Coronavirus disease 2019 (COVID-19) is an acute complex systemic disorder caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).While SARS-CoV-2 is known to cause significant pulmonary disease, various extrapulmonary manifestations of COVID-19 have also been reported. Growing evidence suggests that COVID-19 is associated with coagulopathy leading to micro and macrovascular complications. Although in patients with COVID-19, venous thromboembolic events are more frequent,…

From Patent Search