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Mild SARS-CoV-2 infection results in long-lasting microbiota instability
Mild SARS-CoV-2 infection results in long-lasting microbiota instability
Viruses targeting mammalian cells can indirectly alter the gut microbiota, potentially compounding their phenotypic effects. Multiple studies have observed a disrupted gut microbiota in severe cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that require hospitalization. Yet, despite demographic shifts in disease severity resulting in a large and continuing burden of non-hospitalized infections, we still know very little about the impact of mild SARS-CoV-2 infection on the gut microbiota in the outpatient setting. To address this knowledge gap, we longitudinally sampled 14 SARS-CoV-2-positive subjects who remained outpatient and 4 household controls. SARS-CoV-2 cases exhibited a significantly less stable gut microbiota relative to controls. These results were confirmed and extended in the K18-humanized angiotensin-converting enzyme 2 mouse model, which is susceptible to SARS-CoV-2 infection. All of the tested SARS-CoV-2 variants significantly disrupted the mouse gut microbiota, including USA-WA1/2020 (the original variant detected in the USA), Delta, and Omicron. Surprisingly, despite the fact that the Omicron variant caused the least severe symptoms in mice, it destabilized the gut microbiota and led to a significant depletion in Akkermansia muciniphila. Furthermore, exposure of wild-type C57BL/6J mice to SARS-CoV-2 disrupted the gut microbiota in the absence of severe lung pathology.
·journals.asm.org·
Mild SARS-CoV-2 infection results in long-lasting microbiota instability
FACT SHEET FOR HEALTHCARE PROVIDERS: EMERGENCY USE AUTHORIZATION FOR PAXLOVIDTM
FACT SHEET FOR HEALTHCARE PROVIDERS: EMERGENCY USE AUTHORIZATION FOR PAXLOVIDTM
The U.S. Food and Drug Administration has issued an EUA for the emergency use of PAXLOVID which includes nirmatrelvir, a SARS-CoV-2 main protease (M pro : also referred to as 3CLpro or nsp5 protease) inhibitor, and ritonavir, an HIV-1 protease inhibitor and CYP3A inhibitor, for the treatment of adults and pediatric patients (12 years of age and older weighing at least 40 kg) with mild-to-moderate coronavirus disease 2019 (COVID-19) and who are at high risk for progression to severe COVID-19, including hospitalization or death.
·fda.gov·
FACT SHEET FOR HEALTHCARE PROVIDERS: EMERGENCY USE AUTHORIZATION FOR PAXLOVIDTM
Plasma proteome of Long-COVID patients indicates HIF-mediated vasculo-proliferative disease with impact on brain and heart function - Journal of Translational Medicine
Plasma proteome of Long-COVID patients indicates HIF-mediated vasculo-proliferative disease with impact on brain and heart function - Journal of Translational Medicine
Aims Long-COVID occurs after SARS-CoV-2 infection and results in diverse, prolonged symptoms. The present study aimed to unveil potential mechanisms, and to inform prognosis and treatment. Methods Plasma proteome from Long-COVID outpatients was analyzed in comparison to matched acutely ill COVID-19 (mild and severe) inpatients and healthy control subjects. The expression of 3072 protein biomarkers was determined with proximity extension assays and then deconvoluted with multiple bioinformatics tools into both cell types and signaling mechanisms, as well as organ specificity. Results Compared to age- and sex-matched acutely ill COVID-19 inpatients and healthy control subjects, Long-COVID outpatients showed natural killer cell redistribution with a dominant resting phenotype, as opposed to active, and neutrophils that formed extracellular traps. This potential resetting of cell phenotypes was reflected in prospective vascular events mediated by both angiopoietin-1 (ANGPT1) and vascular-endothelial growth factor-A (VEGFA). Several markers (ANGPT1, VEGFA, CCR7, CD56, citrullinated histone 3, elastase) were validated by serological methods in additional patient cohorts. Signaling of transforming growth factor-β1 with probable connections to elevated EP/p300 suggested vascular inflammation and tumor necrosis factor-α driven pathways. In addition, a vascular proliferative state associated with hypoxia inducible factor 1 pathway suggested progression from acute COVID-19 to Long-COVID. The vasculo-proliferative process predicted in Long-COVID might contribute to changes in the organ-specific proteome reflective of neurologic and cardiometabolic dysfunction. Conclusions Taken together, our findings point to a vasculo-proliferative process in Long-COVID that is likely initiated either prior hypoxia (localized or systemic) and/or stimulatory factors (i.e., cytokines, chemokines, growth factors, angiotensin, etc). Analyses of the plasma proteome, used as a surrogate for cellular signaling, unveiled potential organ-specific prognostic biomarkers and therapeutic targets.
·translational-medicine.biomedcentral.com·
Plasma proteome of Long-COVID patients indicates HIF-mediated vasculo-proliferative disease with impact on brain and heart function - Journal of Translational Medicine
Diabetes mellitus: Höhere Dosis für Metformin empfohlen
Diabetes mellitus: Höhere Dosis für Metformin empfohlen
Bei der Behandlung des Diabetes mellitus Typ 2 mit Metformin wurde bisher zu niedrig dosiert, um das volle Wirkpotenzial des Biguanids auszunutzen. Neueste Studien belegen bessere Therapieerfolge bei höheren Dosierungen bis maximal 3000 mg täglich. In der UKPD-Studie (United Kingdom Prospective Diabetes Study) verbesserte Metformin in der Monotherapie die Prognose adipöser Diabetiker signifikant.
·deutsche-apotheker-zeitung.de·
Diabetes mellitus: Höhere Dosis für Metformin empfohlen
Metformin reduces SARS-CoV-2 in a Phase 3 Randomized Placebo Controlled Clinical Trial
Metformin reduces SARS-CoV-2 in a Phase 3 Randomized Placebo Controlled Clinical Trial
Current antiviral treatment options for SARS-CoV-2 infections are not available globally, cannot be used with many medications, and are limited to virus-specific targets.1-3 Biophysical modeling of SARS-CoV-2 replication predicted that protein translation is an especially attractive target for antiviral therapy.4 Literature review identified metformin, widely known as a treatment for diabetes, as a potential suppressor of protein translation via targeting of the host mTor pathway.5 In vitro, metformin has antiviral activity against RNA viruses including SARS-CoV-2.6,7 In the COVID-OUT phase 3, randomized, placebo-controlled trial of outpatient treatment of COVID-19, metformin had a 42% reduction in ER visits/hospitalizations/death through 14 days; a 58% reduction in hospitalizations/death through 28 days, and a 42% reduction in Long COVID through 10 months.8,9 Here we show viral load analysis of specimens collected in the COVID-OUT trial that the mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95%CI, -1.05 to -0.06, p=0.027) while there was no virologic effect for ivermectin or fluvoxamine vs placebo. The metformin effect was consistent across subgroups and with emerging data.10,11 Our results demonstrate, consistent with model predictions, that a safe, widely available,12 well-tolerated, and inexpensive oral medication, metformin, can be repurposed to significantly reduce SARS-CoV-2 viral load. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial ClinicalTrials.gov: [NCT04510194][1] ### Funding Statement The fluvoxamine placebo tablets were donated by the Apotex pharmacy. The ivermectin placebo and active tablets were donated by the Edenbridge pharmacy. The trial was funded by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and the United Health Foundation. The funders had no influence on the design or conduct of the trial and were not involved in data collection or analysis, writing of the manuscript, or decision to submit for publication. The authors assume responsibility for trial fidelity and the accuracy and completeness of the data and analyses. Dr. Bramante was supported by grants (KL2TR002492 and UL1TR002494) from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) and by a grant (K23 DK124654) from the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH. Dr. Buse was supported by a grant (UL1TR002489) from NCATS. Dr. Nicklas was supported by a grant (K23HL133604) from the National Heart, Lung, and Blood Institute of the NIH. Dr. Odde was supported by the Institute for Engineering in Medicine, UMN Office of Academic and Clinical Affairs COVID-19 Rapid Response Grant, the Earl E. Bakken Professorship for Engineering in Medicine, and by grants (U54 CA210190 and P01 CA254849) from the National Cancer Institute of the NIH. Dr. Murray was supported in part by the Medtronic Faculty Fellowship. Dr. Liebovitz receives funding from NIH RECOVER (OT2HL161847). Dr. Siegel was supported by NIH grants (18X107CF6 and 18X107CF5) through a contract with Leidos Biomedical and by grants from National Heart, Lung, and Blood Institute of the NIH (T32HL129956), and the NIH (R01LM012982 and R21LM012744). Dr. Puskarich receives grants from Bill and Melinda Gates Foundation (INV-017069), Minnesota Partnership for Biotechnology and Medical Genomics (00086722), National Heart, Lung, and Blood Institute of the NIH (OT2HL156812). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Board of Advarra gave ethical approval for this work (MET29324). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data availability The data for this manuscript, as well as the code used to generate the results, will be made freely available for individuals with a defined research question within approximately 1 month of it being published. https://covidout.umn.edu [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04510194&atom=%2Fmedrxiv%2Fearly%2F2023%2F06%2F07%2F2023.06.06.23290989.atom
·medrxiv.org·
Metformin reduces SARS-CoV-2 in a Phase 3 Randomized Placebo Controlled Clinical Trial
Safety of COVID-19 mRNA Vaccination Among Young Children in the Vaccine Safety Datalink
Safety of COVID-19 mRNA Vaccination Among Young Children in the Vaccine Safety Datalink
We previously assessed safety of monovalent messenger RNA (mRNA) coronavirus disease 2019 (COVID-19) vaccines using weekly surveillance monitoring known as rapid cycle analysis (RCA) among individuals aged 5 years and older, identifying an increased risk for myocarditis and pericarditis in younger males, particularly following dose 2 of the primary series.1–3...
·publications.aap.org·
Safety of COVID-19 mRNA Vaccination Among Young Children in the Vaccine Safety Datalink
Dr Graham Lloyd-Jones on Twitter
Dr Graham Lloyd-Jones on Twitter
There is now even more evidence for the connections between gum disease and development of severe COVID.For example, in acute COVID this paper reports an odds ratio for death of 14 in those with active gum disease.https://t.co/Z7w7DicIpb— Dr Graham Lloyd-Jones (@DrGrahamLJ) April 22, 2023
·twitter.com·
Dr Graham Lloyd-Jones on Twitter
Spike in severe illness caused by strep A bacteria is 'global phenomenon' — including in Canada | CBC News
Spike in severe illness caused by strep A bacteria is 'global phenomenon' — including in Canada | CBC News
As various countries continue to report high levels of invasive group A streptococcal (iGAS) infections — which cause severe illness, and in rare cases death within days — Canadian physicians are also raising alarms over a rise in serious cases this season.
·cbc.ca·
Spike in severe illness caused by strep A bacteria is 'global phenomenon' — including in Canada | CBC News
SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity
SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity
Numerous viruses use specialized surface molecules called fusogens to enter host cells. Many of these viruses, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can infect the brain and are associated with severe neurological symptoms through poorly understood mechanisms. We show that SARS-CoV-2 infection induces fusion between neurons and between neurons and glia in mouse and human brain organoids. We reveal that this is caused by the viral fusogen, as it is fully mimicked by the expression of the SARS-CoV-2 spike (S) protein or the unrelated fusogen p15 from the baboon orthoreovirus. We demonstrate that neuronal fusion is a progressive event, leads to the formation of multicellular syncytia, and causes the spread of large molecules and organelles. Last, using Ca2+ imaging, we show that fusion severely compromises neuronal activity. These results provide mechanistic insights into how SARS-CoV-2 and other viruses affect the nervous system, alter its function, and cause neuropathology.
·science.org·
SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity
🌍Derfel The Crackpot 🌍 on Twitter
🌍Derfel The Crackpot 🌍 on Twitter
In diesem Thread sammle ich Studien/ Daten, die einen Zusammenhang von Covid19 und Diabetes untersuchen. Ich trage nur Literatur zusammen und versuche soweit es mir möglich ist werteneutral die Ergebnisse zu beschreiben. Der Thread ist erstmal unsortiert und ordnet nicht ein.— 🌍Derfel The Crackpot 🌍 (@DerfelTheMighty) January 31, 2022
·twitter.com·
🌍Derfel The Crackpot 🌍 on Twitter
Neutralising immunity to omicron sublineages BQ.1.1, XBB, and XBB.1.5 in healthy adults is boosted by bivalent BA.1-containing mRNA vaccination and previous Omicron infection
Neutralising immunity to omicron sublineages BQ.1.1, XBB, and XBB.1.5 in healthy adults is boosted by bivalent BA.1-containing mRNA vaccination and previous Omicron infection
The global COVID-19 landscape is increasingly complex; emerging new variants rapidly cause waves of infection in people with variably induced immunity. Most individuals now have so-called hybrid immunity from both infection and vaccination. However, sequential infecting variants, induction of immunity, and subsequent waning are interlinked, and immune protection against new variants is unclear.
·thelancet.com·
Neutralising immunity to omicron sublineages BQ.1.1, XBB, and XBB.1.5 in healthy adults is boosted by bivalent BA.1-containing mRNA vaccination and previous Omicron infection
Protective immunity of SARS-CoV-2 infection and vaccines against medically attended symptomatic omicron BA.4, BA.5, and XBB reinfections in Singapore: a national cohort study
Protective immunity of SARS-CoV-2 infection and vaccines against medically attended symptomatic omicron BA.4, BA.5, and XBB reinfections in Singapore: a national cohort study
Despite a large proportion of the population having been vaccinated and infected, Singapore had SARS-CoV-2 waves driven by the BA.5 and XBB sublineages of the omicron (B.1.1.529) variant. Data on the protective immunity against medically attended, symptomatic reinfections with omicron BA.4, BA.5, and XBB conferred by previous SARS-CoV-2 infections and vaccinations are scarce. We therefore aimed to derive information from Singapore's experience as one of the first countries with an XBB-driven wave.
·thelancet.com·
Protective immunity of SARS-CoV-2 infection and vaccines against medically attended symptomatic omicron BA.4, BA.5, and XBB reinfections in Singapore: a national cohort study
Emma Wall on Twitter
Emma Wall on Twitter
❓Why didn’t the UK🇬🇧 experience a severe COVID wave from Omicron “escape variants” XBB & BQ.1.1 in Winter 2022, unlike others (e.g. 🇸🇬🇺🇸)?🚨New data from @UCHLResearch @TheCrick Legacy study, out today @TheLancetInfDis⏩ https://t.co/Pk9pkidExwRead on: a 🧵... 1/n pic.twitter.com/Z9GEl7IH4v— Emma Wall (@dremmacbw) June 6, 2023
·twitter.com·
Emma Wall on Twitter
Single-cycle SARS-CoV-2 vaccine elicits high protection and sterilizing immunity in hamsters
Single-cycle SARS-CoV-2 vaccine elicits high protection and sterilizing immunity in hamsters
Vaccines have been central in ending the COVID-19 pandemic, but newly emerging SARS-CoV-2 variants increasingly escape first-generation vaccine protection. To fill this gap, live particle-based vaccines mimicking natural infection aim at protecting against a broader spectrum of virus variants. We designed “single-cycle SARS-CoV-2 viruses” (SCVs) that lack essential viral genes, possess superior immune-modulatory features and provide an excellent safety profile in the Syrian hamster model. Full protection of all intranasally vaccinated animals was achieved against an autologous challenge with SARS-CoV-2 virus using an Envelope-gene-deleted vaccine candidate. By deleting key immune-downregulating genes, sterilizing immunity was achieved with an advanced candidate without virus spread to contact animals. Hence, SCVs have the potential to induce a broad and durable protection against COVID-19 superior to a natural infection. ### Competing Interest Statement VC owns shares of RocketVax AG, Basel, CH. The other authors declare no competing interests. A patent application (no. WO 203/036947 A1) has been filed on the topic of this vaccine.
·biorxiv.org·
Single-cycle SARS-CoV-2 vaccine elicits high protection and sterilizing immunity in hamsters
Vipin M. Vashishtha on Twitter
Vipin M. Vashishtha on Twitter
A new, intranasal, single-cycle vaccine concept consolidates the high safety of an intranasally applied vaccine that induces sterilizing immunity, which will be key to overcoming the ongoing SARS-CoV-2 outbreaks. 1/ pic.twitter.com/lhqd8pUia3— Vipin M. Vashishtha (@vipintukur) May 18, 2023
·twitter.com·
Vipin M. Vashishtha on Twitter
Nathan Cole ⚕️ @mastodontech.de on Twitter
Nathan Cole ⚕️ @mastodontech.de on Twitter
Lustig ist ja, dass die Querdullies diese Studie jetzt für die Einzige halten, die jemals zu diesem Thema gemacht wurde und sich jetzt auf das Sponsoring stürzen. 🤡https://t.co/JHAtW4HaIthttps://t.co/EXLk3xLENMhttps://t.co/EXLk3xLENMhttps://t.co/tWw4BKmP7A— Nathan Cole ⚕️ @mastodontech.de (@DrNathanCole) May 21, 2023
·twitter.com·
Nathan Cole ⚕️ @mastodontech.de on Twitter
Myocarditis in SARS-CoV-2 infection vs. COVID-19 vaccination: A systematic review and meta-analysis
Myocarditis in SARS-CoV-2 infection vs. COVID-19 vaccination: A systematic review and meta-analysis
BackgroundThis study aimed to compare the incidence of myocarditis in COVID-19 vaccines and in severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection groups.MethodsElectronic databases (MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and the WHO Global Literature on Coronavirus Disease) and trial registries were searched up to May 2022, for randomized controlled trials and observational cohort studies reporting the risk of myocarditis associated with the COVID-19 vaccines and the risk associated with SARS-CoV-2 infection. We estimated the effect of COVID-19 infection and vaccines on rates of myocarditis by random-effects meta-analyses using the generic inverse variance method. Meta-regression analyses were conducted to assess the effect of sex and age on the incidence of myocarditis.ResultsWe identified 22 eligible studies consisting of 55.5 million vaccinated cohorts and 2.5 million in the infection cohort. The median age was 49 years (interquartile range (IQR): 38–56), and 49% (IQR: 43 to 52%) were men. Of patients diagnosed with myocarditis (in both vaccination and COVID-19 cohort) 1.07% were hospitalized and 0.015% died. The relative risk (RR) for myocarditis was more than seven times higher in the infection group than in the vaccination group [RR: 15 (95% CI: 11.09–19.81, infection group] and RR: 2 (95% CI: 1.44-2.65, vaccine group). Of patients who developed myocarditis after receiving the vacc...
Conclusion: In this systematic review and meta-analysis, we found that the risk of myocarditis is more than seven fold higher in persons who were infected with the SARS-CoV-2 than in those who received the vaccine. These findings support the continued use of mRNA COVID-19 vaccines among all eligible persons per CDC and WHO recommendations.
·frontiersin.org·
Myocarditis in SARS-CoV-2 infection vs. COVID-19 vaccination: A systematic review and meta-analysis