30:I[703058,["/_next/static/immutable/chunks/3bhq_5eh1d760.js","/_next/static/immutable/chunks/1855-ogyi8eh4.js","/_next/static/immutable/chunks/2pfsjpn6k6zlg.js","/_next/static/immutable/chunks/26c7v3_3uwnwu.js","/_next/static/immutable/chunks/25a3ozcrvi1ff.js","/_next/static/immutable/chunks/2r4wx50nvjh_4.js","/_next/static/immutable/chunks/23fsw06hsi5b1.js","/_next/static/immutable/chunks/06_yt270h41rg.js","/_next/static/immutable/chunks/3ezsiz-7shkna.js","/_next/static/immutable/chunks/20x2y96ldu5wx.js","/_next/static/immutable/chunks/2lxntcm3pd1_h.js","/_next/static/immutable/chunks/00dgco8irq3jw.js","/_next/static/immutable/chunks/00nwe-kq0rboc.js","/_next/static/immutable/chunks/2051ffx3xzio9.js"],"PaperListPageClient"] 2f:T45b,{"@context":"https://schema.org","@type":"CollectionPage","name":"Prospective Cohort Study (nested within Randomized Controlled Trial): study design Research & Clinical Takeaways","description":"Explore peer-reviewed papers on Prospective Cohort Study (nested within Randomized Controlled Trial) (study design). Clinician-written summaries and actionable practice insights. Updated daily.","url":"https://www.reachrx.ai/hub/tag/study_design/Prospective%20Cohort%20Study%20(nested%20within%20Randomized%20Controlled%20Trial)","breadcrumb":{"@type":"BreadcrumbList","itemListElement":[{"@type":"ListItem","position":1,"name":"Home","item":"https://www.reachrx.ai"},{"@type":"ListItem","position":2,"name":"Research Hub","item":"https://www.reachrx.ai/hub"},{"@type":"ListItem","position":3,"name":"Study Designs","item":"https://www.reachrx.ai/hub/tag/study_design"},{"@type":"ListItem","position":4,"name":"Prospective Cohort Study (nested within Randomized Controlled Trial)","item":"https://www.reachrx.ai/hub/tag/study_design/Prospective%20Cohort%20Study%20(nested%20within%20Randomized%20Controlled%20Trial)"}]}}31:T6dc,COVID-19 and other respiratory viral infections can cause cardiovascular complications. SARS-CoV-2 virions are found in the blood, and circulating viral RNA levels are associated with death. We hypothesized that viremia can induce thrombotic endotheliopathy that contributes to death and studied this relationship in patients hospitalized for COVID-19 and enrolled in the ACTIV-4a (Accelerating COVID-19 Therapeutic Interventions and Vaccines) randomized trial of antithrombotic therapy. We quantified SARS-CoV-2 nucleocapsid RNA and protein in plasma and measured their associations with clinical outcomes and biomarkers of thromboinflammation and endotheliopathy. We used Cox regression and Fine-Gray competing risk models to analyze survival and thrombosis. We conducted causal mediation analysis to explore whether thrombotic endotheliopathy mediates the relationship between viral RNA and death. In 93 patients, SARS-CoV-2 RNA and N-antigen were higher in nonsurvivors. Baseline viral RNA levels were associated with increased 90-day death (hazard ratio [HR], 1.31 [95% CI, 1.17-1.46]) and thrombosis (HR, 1.35 [95% CI, 1.24-1.47]). Viral RNA more effectively predicted survivorship than N-antigen levels. Soluble thrombomodulin, a biomarker of thrombotic endotheliopathy, positively correlated with viral RNA levels. Mediation analysis revealed that soluble thrombomodulin accounts for 12.2% (95% CI, 0.1%-32.3%; Elevated plasma SARS-CoV-2 RNA levels are associated with death in ACTIV-4a, which is causally mediated in part by soluble thrombomodulin. We propose that lung-blood viral dissemination is a potential mechanism for cardiovascular complications of respiratory viruses. URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04505774.32:Tc48, Background COVID‐19 and other respiratory viral infections can cause cardiovascular complications. SARS‐CoV‐2 virions are found in the blood, and circulating viral RNA levels are associated with death. We hypothesized that viremia can induce thrombotic endotheliopathy that contributes to death and studied this relationship in patients hospitalized for COVID‐19 and enrolled in the ACTIV‐4a (Accelerating COVID‐19 Therapeutic Interventions and Vaccines) randomized trial of antithrombotic therapy. Methods We quantified SARS‐CoV‐2 nucleocapsid RNA and protein in plasma and measured their associations with clinical outcomes and biomarkers of thromboinflammation and endotheliopathy. We used Cox regression and Fine–Gray competing risk models to analyze survival and thrombosis. We conducted causal mediation analysis to explore whether thrombotic endotheliopathy mediates the relationship between viral RNA and death. Results In 93 patients, SARS‐CoV‐2 RNA and N‐antigen were higher in nonsurvivors. Baseline viral RNA levels were associated with increased 90‐day death (hazard ratio [HR], 1.31 [95% CI, 1.17–1.46]) and thrombosis (HR, 1.35 [95% CI, 1.24–1.47]). Viral RNA more effectively predicted survivorship than N‐antigen levels. Soluble thrombomodulin, a biomarker of thrombotic endotheliopathy, positively correlated with viral RNA levels. Mediation analysis revealed that soluble thrombomodulin accounts for 12.2% (95% CI, 0.1%–32.3%; P =0.048) after adjustment for age and sex of the relationship between viral RNA and the 90‐day mortality rate. Conclusions Elevated plasma SARS‐CoV‐2 RNA levels are associated with death in ACTIV‐4a, which is causally mediated in part by soluble thrombomodulin. We propose that lung–blood viral dissemination is a potential mechanism for cardiovascular complications of respiratory viruses. Registration URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT04505774. 25:[[["$","script","0",{"type":"application/ld+json","dangerouslySetInnerHTML":{"__html":"$2f"}}]],["$","$L30",null,{"title":"Prospective Cohort Study (nested within Randomized Controlled Trial): Research & Clinical Takeaways","description":"Browse Prospective Cohort Study (nested within Randomized Controlled Trial) research papers with clear, practical takeaways for your clinical practice.","papers":[{"doi":"10.1161/jaha.125.047693","pmid":"42089155","title":"Soluble Thrombomodulin Links Viremia and Mortality During COVID‐19: Results From the ACTIV‐4a Trial","journal_title":"Journal of the American Heart Association","journal_issn":"2047-9980","published_at":"2026-05-06T00:00:00.000Z","url":"https://doi.org/10.1161/jaha.125.047693","source_score":33,"is_retracted":false,"is_open_access":true,"raw_metadata":{"ooir":{"day":"2026-05-11","doi":"10.1161/jaha.125.047693","days":"7","issn":"2047-9980","rank":"9","field":"Clinical Medicine","score":"33","category":"Cardiac & Cardiovascular Systems","categories":["Cardiac & Cardiovascular Systems"],"_categories":["Cardiac & Cardiovascular Systems"]},"pubmed":{"doi":"10.1161/JAHA.125.047693","title":"Soluble Thrombomodulin Links Viremia and Mortality During COVID-19: Results From the ACTIV-4a Trial.","journal":"Journal of the American Heart Association","methods":"","results":"In 93 patients, SARS-CoV-2 RNA and N-antigen were higher in nonsurvivors. Baseline viral RNA levels were associated with increased 90-day death (hazard ratio [HR], 1.31 [95% CI, 1.17-1.46]) and thrombosis (HR, 1.35 [95% CI, 1.24-1.47]). Viral RNA more effectively predicted survivorship than N-antigen levels. Soluble thrombomodulin, a biomarker of thrombotic endotheliopathy, positively correlated with viral RNA levels. Mediation analysis revealed that soluble thrombomodulin accounts for 12.2% (95% CI, 0.1%-32.3%; ","abstract":"$31","keywords":["SARS‐CoV‐2","endotheliopathy","mediation analysis","thrombosis","viremia"],"pubmed_id":"42089155","conclusions":"","publication_date":"2026-05-06T00:00:00"},"crossref":{"DOI":"10.1161/jaha.125.047693","URL":"https://doi.org/10.1161/jaha.125.047693","ISSN":["2047-9980"],"link":[{"URL":"https://www.ahajournals.org/doi/full/10.1161/JAHA.125.047693","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"page":null,"type":"journal-article","issue":null,"score":1,"title":["Soluble Thrombomodulin Links Viremia and Mortality During COVID‐19: Results From the ACTIV‐4a Trial"],"author":[{"given":"Benjamin E.","family":"Zuchelkowski","sequence":"first","affiliation":[{"name":"University of Pittsburgh School of Medicine"}]},{"given":"Kyle W.","family":"Inman","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine"}]},{"given":"S. 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magnitude.","value_numeric":null},{"paper_doi":"10.1161/jaha.125.047693","tag_type":"warning","value":"This is a small substudy (n=93) nested within the larger ACTIV-4a RCT; findings may not reflect the full trial population and should be interpreted cautiously.","value_numeric":null}],"summaries":{"what_studied":"In 93 hospitalized COVID-19 patients enrolled in the ACTIV-4a randomized antithrombotic trial, this study examined whether plasma SARS-CoV-2 RNA and nucleocapsid antigen levels predict 90-day death and thrombosis, and whether soluble thrombomodulin (a marker of thrombotic endotheliopathy) mediates the link between viremia and mortality.","key_result":"Higher baseline viral RNA was associated with increased 90-day death (HR 1.31, 95% CI 1.17–1.46) and thrombosis (HR 1.35, 95% CI 1.24–1.47). Soluble thrombomodulin mediated 12.2% (95% CI 0.1%–32.3%; P=0.048) of the relationship between viral RNA and 90-day mortality, and viral RNA outperformed N-antigen in predicting survival.","limitations":"- Small substudy sample (n=93) limits statistical power and generalizability.\n- Wide confidence interval on the mediation estimate (0.1%–32.3%) indicates considerable uncertainty about the size of the thrombomodulin-mediated effect.\n- Causal mediation analysis is observational and cannot fully exclude unmeasured confounders.","practice_takeaway":"Plasma SARS-CoV-2 RNA levels at admission may help identify hospitalized COVID-19 patients at highest risk for death and thrombosis. Thrombotic endotheliopathy, reflected by soluble thrombomodulin, appears to be a partial — but not complete — mechanistic link, suggesting that antithrombotic strategies alone may not fully address viremia-driven mortality."}}],"initialOffset":1,"fetchConfig":{"kind":"tags","tags":[{"tag_type":"study_design","value":"Prospective Cohort Study (nested within Randomized Controlled Trial)"}]},"breadcrumbItems":[{"name":"Home","href":"/"},{"name":"Research Hub","href":"/hub"},{"name":"Study Designs","href":"/hub/tag/study_design"},{"name":"Prospective Cohort Study (nested within Randomized Controlled Trial)"}],"hrefConfig":{"basePath":"/hub/papers","webViewQueryParams":{"hub_ctx":"tag","hub_tag_type":"study_design","hub_tag_value":"Prospective Cohort Study (nested within Randomized Controlled Trial)"}}}]]

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