Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Utilization of cellulose microcapillary tubes as a model system for culturing and viral infection of mammalian cells

Cryofixation by high-pressure freezing (HPF) and freeze substitution (FS) gives excellent preservation of intracellular membranous structures, ideal for ultrastructural investigations of virus infected cells. Conventional sample preparation methods of tissue cultured cells can however disrupt the association between neighbouring cells or of viruses with the plasma membrane, which impacts upon the effectiveness whereby virus release from cells can be studied. We established a system for virus infection and transmission electron microscopy preparation of mammalian cells that allowed optimal visualisation of membrane release events. African horse sickness virus (AHSV) is a non-enveloped virus that employs two different release mechanisms from mammalian cells, i.e. lytic release through a disrupted plasma membrane and a non-lytic buddingtype release. Cellulose microcapillary tubes were used as support layer for culturing Vero cells. The cells grew to a confluent monolayer along the inside of the tubes and could readily be infected with AHSV. Sections of the microcapillary tubes proved easy to manipulate during the HPF procedure, showed no distortion or compression, and yielded well preserved cells in their native state. There was ample cell surface area available for visualisation, which allowed detection of both types of virus release at the plasma membrane at a significantly higher frequency than when utilising other methods. The consecutive culturing, virus infection and processing of cells within microcapillary tubes therefore represent a novel model system for monitoring intracellular virus life cycle and membrane release events, specifically suited to viruses that do not grow to high titres in tissue culture.http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1097-002

Impact of Evidence-Based Stroke Care on Patient Outcomes: A Multilevel Analysis of an International Study

Background-The uptake of proven stroke treatments varies widely. We aimed to determine the association of evidence-based processes of care for acute ischemic stroke (AIS) and clinical outcome of patients who participated in the HEADPOST (Head Positioning in Acute Stroke Trial), a multicenter cluster crossover trial of lying flat versus sitting up, head positioning in acute stroke. Methods and Results-Use of 8 AIS processes of care were considered: reperfusion therapy in eligible patients; acute stroke unit care; antihypertensive, antiplatelet, statin, and anticoagulation for atrial fibrillation; dysphagia assessment; and physiotherapist review. Hierarchical, mixed, logistic regression models were performed to determine associations with good outcome (modified Rankin Scale scores 0-2) at 90 days, adjusted for patient and hospital variables. Among 9485 patients with AIS, implementation of all processes of care in eligible patients, or defect-free care, was associated with improved outcome (odds ratio, 1.40; 95% CI, 1.18-1.65) and better survival (odds ratio, 2.23; 95% CI, 1.62-3.09). Defect-free stroke care was also significantly associated with excellent outcome (modified Rankin Scale score 0-1) (odds ratio, 1.22; 95% CI, 1.04-1.43). No hospital characteristic was independently predictive of outcome. Only 1445 (15%) of eligible patients with AIS received all processes of care, with significant regional variations in overall and individual rates. Conclusions-Use of evidence-based care is associated with improved clinical outcome in AIS. Strategies are required to address regional variation in the use of proven AIS treatments.National Health and Medical Research Council of AustraliaUniv New South Wales, Fac Med, George Inst Global Hlth, Sydney, NSW, AustraliaCtr Estudios Clin, Inst Ciencias & Innovac Med, Santiago, ChileClin Alemana Univ Desarrollo, Fac Med, Serv Neurol, Dept Neurol & Psiquiatria, Santiago, ChilePeking Univ, Hlth Sci Ctr, George Inst Global Hlth, Beijing, Peoples R ChinaAustralian Catholic Univ, Nursing Res Inst, St Vincents Hlth Australia Sydney, Sydney, NSW, AustraliaUniv Cent Lancashire, Fac Hlth & Wellbeing, Preston, Lancs, EnglandUniv Chile, Fac Med, Dept Ciencias Neurol, Santiago, ChileUniv Sao Paulo, Ribeirao Preto Med Sch, Stroke Serv Neurol Div, Ribeirao Preto, BrazilFukuoka Univ, Fac Med, Dept Prevent Med & Publ Hlth, Fukuoka, Fukuoka, JapanUniv Leicester, Dept Cardiovasc Sci, Leicester Biomed Res Ctr, Leicester, Leics, EnglandUniv Leicester, Natl Inst Hlth Res, Leicester Biomed Res Ctr, Leicester, Leics, EnglandUniv Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, ScotlandGeorge Inst Global Hlth, Sydney, NSW, AustraliaUniv Desarrollo, Serv Neurol, Dept Neurol & Psiquiatria Clin Alemana Santiago, Santiago, ChileSt Vincents Hlth Australia Sydney, Sydney, NSW, AustraliaAustralian Catholic Univ, Sydney, NSW, AustraliaUniv Cent Lancashire, Stroke Practice Res Unit, Sch Hlth, Lancashire Clin Trials Unit, Preston, Lancs, EnglandUniv Leicester, Dept Cardiovasc Sci, Cardiovasc Res Ctr, British Heart Fdn, Leicester, Leics, EnglandUniv Kelaniya, Dept Pharmacol, Fac Med, Colombo, Sri LankaChristian Med Coll & Hosp, Dept Neurol, Ludhiana, IndiaKaohsiung Med Univ & Hosp, Dept Neurol, Kaohsiung, TaiwanLinkou Chang Gung Mem Hosp, Dept Neurol, Taipei, TaiwanPeking Union Med Coll Hosp, Beijing, Peoples R ChinaUniv Sao Paulo, Ribeirao Preto Sch Med, Ribeirao Preto, BrazilMonash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic, AustraliaUniv Cent Lancashire, Sch Hlth Sci, Coll Hlth & Wellbeing, Preston, Lancs, EnglandUniv Desarrollo, Santiago, ChileUniv New South Wales, Neurosci Res Australia, Sydney, NSW, AustraliaNatl Univ Singapore, Dept Pharmacol, Singapore, SingaporeBradford Royal Infirm, Bradford Inst Hlth Res, Leeds, W Yorkshire, EnglandChristian Med College, Ludhiana, Punjab, IndiaRemediumOne Pvt Ltd, Kandy, Sri LankaKaohsiung Med Univ, Chung Ho Mem Hosp, Kaohsiung, TaiwanCalvary Publ Hosp Bruce, Bruce, AustraliaRoyal North Shore Hosp, St Leonards, NSW, AustraliaRoyal Prince Alfred Hosp, Camperdown, NSW, AustraliaConcord Repatriat Gen Hosp, Camperdown, NSW, AustraliaFiona Stanley Hosp, Camperdown, NSW, AustraliaMacquarie Base Hosp, Melbourne, Vic, AustraliaUniv Sao Paulo, Fac Med Ribeirao Preto, Hosp Clin, Sao Paulo, BrazilHosp Governador Celso Ramos, Florianopolis, SC, BrazilSao Paulo State Univ, Hosp Fac Med Botucatu, UNESP, Sao Paulo, BrazilYangquan Coalmine Grp Gen Hosp, Yangquan, Peoples R ChinaNanjing Med Univ, Nanjing Hosp 1, Nanjing, Jiangsu, Peoples R China85 Hosp Peoples Liberat Army, Beijing, Peoples R ChinaChifeng Univ, Affiliated Hosp, Chifeng, Peoples R ChinaBeijing Pinggu Hosp, Beijing, Peoples R ChinaWenzhou Med Univ, Affiliated Hosp 1, Wenzhou, Peoples R ChinaSoochow Univ, Affiliated Hosp 2, Suzhou, Peoples R ChinaHebei Med Univ, Hosp 3, Shijiazhuang, Hebei, Peoples R ChinaCapital Med Univ, Xuanwu Hosp, Beijing, Peoples R ChinaJining Med Univ, Affiliated Hosp, Jining, Peoples R ChinaThird Peoples Hosp Huizhou, Huizhou, Peoples R ChinaSecond Cangzhou Cent Hosp, Cangzhou, Peoples R ChinaShanghai Jiao Tong Univ, Hosp Affiliated, Sch Med, Shanghai, Peoples R ChinaBaogang Hosp, Baotou, Peoples R ChinaHarbin Med Univ, Affiliated Hosp 1, Harbin, Heilongjiang, Peoples R ChinaShanghai Jiao Tong Univ Sch, Tong Ren Hosp, Peoples Hosp Hejian City, Shanghai, Peoples R ChinaPeking Univ, Shougang Hosp, Beijing, Peoples R ChinaGuangzhou Med Univ, Affiliated Hosp 3, Guangzhou, Guangdong, Peoples R ChinaSecond Hosp Nanchang, Nanchang, Jiangxi, Peoples R ChinaBethune Int Peace Hosp, Beijing, Peoples R ChinaHua Henan Prov Peoples Hosp, Beijing, Peoples R ChinaHua Henan Prov Peoples Hosp, Zhengzhou, Henan, Peoples R ChinaShanghai Jiao Tong Univ, Sch Med, Shanghai Ninth Peoples Hosp, Shanghai, Peoples R ChinaShijiazhuang Cent Hosp, Shijiazhuang, Hebei, Peoples R ChinaHosp Base San Jos de Osorno, Osorno, ChileChristian Med Coll & Hosp, Ludhiana, Punjab, IndiaUnit Narayana Hrudayalaya Ltd, Mazumdar Shaw Med Ctr, Bangalore, Karnataka, IndiaDr Ramesh Cardiac & Multispecial Hosp Pvt Ltd, Guntur, IndiaPost Grad Inst Med Educ & Res, Chandigarh, IndiaBaby Mem Hosp Ltd, Calicut, Kerala, IndiaSree Chitra Tirunal Inst Med Sci & Technol, Thiruvananthapuram, Kerala, IndiaSri Jayawardenepura Gen Hosp, Sri Jayawardenepura Kott, Sri LankaColombo North Teaching Hosp, Colombo, Sri LankaColombo South Coching Hosp, Colombo, Sri LankaLinkou Chang Gung Mem Hosp, Taoyuan, TaiwanTaipei Med Univ, Shuang Ho Hosp, Taipei, TaiwanEn Chu Kong Hosp, New Taipei, TaiwanNatl Cheng Kung Univ Hosp, Tainan, TaiwanQueen Alexandra Hosp, Portsmouth, Hants, EnglandPortsmouth Hosp NHS Natl Hlth Serv iTrust, Portsmouth, Hants, EnglandUniv Coll London Hosp NHS Fdn Trust, London, EnglandUniv Hosp Birmingham NHS Fdn Trust, Queen Elizabeth Hosp Birmingham, Birmingham, W Midlands, EnglandSouthend Univ Hosp NHS Fdn Trust, Southend On Sea, EnglandKings Coll Hosp London, London, EnglandYork Teaching Hosp NHS Fdn Trust, York, N Yorkshire, EnglandNottingham Univ Hosp NHS Trust, Nottingham, EnglandBlackpool Teaching Hosp NHS Fdn Trust, Blackpool, EnglandGloucestershire Hosp NHS Fdn Trust, Gloucestershire Royal Hosp, Gloucester, EnglandTeaching Hospi NHS Fdn Trust, London, EnglandRoyal Cornwall Hosp NHS Trust, Truro, EnglandRoyal London Hosp, Barts Hlth NHS Trust, London, EnglandSheffield Teaching Hosp NHS Fdn Trust, Sheffield, S Yorkshire, EnglandCambridge Univ Hosp NHS Fdn Trust, Addenbrookes Hosp, Cambridge, EnglandRoyal Victoria Hosp, Belfast Hlth & Social Care Trust, London, EnglandPinderfields Gen Hosp, Mid Yorkshire Hosp NHS Trust, Wakefield, EnglandRoyal Devon & Exeter NHS Fdn Trust, London, EnglandBradford Teaching Hosp NHS Fdn Trust, Bradford, W Yorkshire, EnglandGreat Western Hosp NHS Fdn Trust, Swindon, Wilts, EnglandWatford Dist Gen Hosp, Watford, EnglandImperial Coll Healthcare NHS Trust, London, EnglandMedway NHS Fdn Trust, Gillingham, EnglandRoyal Liverpool & Broadgreen Univ NHS Trust, Liverpool, Merseyside, EnglandCalderdale & Huddersfield NHS Fdn Trust, Huddersfield, W Yorkshire, EnglandHywel Dda Univ Hlth Board, Haverfordwest, WalesChesterfield Royal Hosp NHS Fdn Trust, Calow, EnglandLuton & Dunstable Univ Hosp NHS Fdn Trust, Luton, Beds, EnglandCountess Chester Hosp NHS Fdn Trust, Chester, Cheshire, EnglandPeterborough City Hosp, Peterborough, Cambs, EnglandUniv Hosp Leicester NHS Trust, Leicester Royal Infirm, Leicester, Leics, EnglandDist Hosp NHS Fdn Trust, London, EnglandBarnsley Hosp NHS Fdn Trust, Barnsley, EnglandDorset Cty Hosp NHS Fdn Trust, Dorchester, EnglandRoyal Bournemouth & Christchurch Hosp NHS Fdn Tru, Royal Bournemouth Hosp, Bournemouth, Dorset, EnglandSouthern Hlth & Social Care Trust, Craigavon Area Hosp, Portadown, EnglandUnited Lincolnshire Hosp NHS Trust, Pilgrim Hosp, Lincoln, EnglandBedford Hosp NHS Trust, Bedford, EnglandSao Paulo State Univ, Hosp Fac Med Botucatu, UNESP, Sao Paulo, BrazilNational Health and Medical Research Council of Australia: 106696

Impact of Evidence‐Based Stroke Care on Patient Outcomes: A Multilevel Analysis of an International Study

Background The uptake of proven stroke treatments varies widely. We aimed to determine the association of evidence‐based processes of care for acute ischemic stroke ( AIS ) and clinical outcome of patients who participated in the HEADPOST (Head Positioning in Acute Stroke Trial), a multicenter cluster crossover trial of lying flat versus sitting up, head positioning in acute stroke. Methods and Results Use of 8 AIS processes of care were considered: reperfusion therapy in eligible patients; acute stroke unit care; antihypertensive, antiplatelet, statin, and anticoagulation for atrial fibrillation; dysphagia assessment; and physiotherapist review. Hierarchical, mixed, logistic regression models were performed to determine associations with good outcome (modified Rankin Scale scores 0–2) at 90 days, adjusted for patient and hospital variables. Among 9485 patients with AIS, implementation of all processes of care in eligible patients, or “defect‐free” care, was associated with improved outcome (odds ratio, 1.40; 95% CI, 1.18–1.65) and better survival (odds ratio, 2.23; 95% CI , 1.62–3.09). Defect‐free stroke care was also significantly associated with excellent outcome (modified Rankin Scale score 0–1) (odds ratio, 1.22; 95% CI , 1.04–1.43). No hospital characteristic was independently predictive of outcome. Only 1445 (15%) of eligible patients with AIS received all processes of care, with significant regional variations in overall and individual rates. Conclusions Use of evidence‐based care is associated with improved clinical outcome in AIS . Strategies are required to address regional variation in the use of proven AIS treatments. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique Identifier: NCT 02162017. </jats:sec

Long-term (180-Day) outcomes in critically Ill patients with COVID-19 in the REMAP-CAP randomized clinical trial

Importance The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. Objective To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. Design, Setting, and Participants Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. Interventions Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). Main Outcomes and Measures The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. Results Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. Conclusions and Relevance Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months