Objective To determine whether disrupting the renin angiotensin system with angiotensin receptor blockers will improve clinical outcomes in people with covid-19. Design CLARITY was a pragmatic, adaptive, multicentre, phase 3, randomised controlled trial. Setting 17 hospital sites in India and Australia. Participants Participants were at least 18 years old, previously untreated with angiotensin receptor blockers, with a laboratory confirmed diagnosis of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection who had been admitted to hospital for management of covid-19. Intervention Oral angiotensin receptor blockers (telmisartan in India) or placebo (1:1) for 28 days. Main outcome measures The primary endpoint was covid-19 disease severity using a modified World Health Organization Clinical Progression Scale (WHO scale) at day 14. Secondary outcomes were WHO scale scores at day 28, mortality, intensive care unit admission, and respiratory failure. Analyses were evaluated on an ordinal scale in the intention-to-treat population. Results Between 3 May 2020 and 13 November 2021, 2930 people were screened for eligibility, with 393 randomly assigned to angiotensin receptor blockers (of which 388 (98.7%) to telmisartan 40 mg/day) and 394 to the control group. 787 participants were randomised: 778 (98.9%) from India and nine (1.1%) from Australia. The median WHO scale score at day 14 was 1 (interquartile range 1-1) in 384 participants assigned angiotensin receptor blockers and 1 (1-1) in 382 participants assigned placebo (adjusted odds ratio 1.51 (95% credible interval 1.02 to 2.23), probability of an odds ratio of >1 (Pr(OR>1)=0.98). WHO scale scores at day 28 showed little evidence of difference between groups (1.02 (0.55 to 1.87), Pr(OR>1)=0.53). The trial was stopped when a prespecified futility rule was met. Conclusions In patients admitted to hospital for covid-19, mostly with mild disease, not requiring oxygen, no evidence of benefit, based on disease severity score, was found for treatment with angiotensin receptor blockers, using predominantly 40 mg/day of telmisartan. Trial registration ClinicalTrials.gov NCT04394117 .
Background: A widespread G2P[4] rotavirus epidemic in rural and remote Australia provided an opportunity to evaluate the performance of Rotarix and RotaTeq rotavirus vaccines, ten years after their incorporation into Australia’s National Immunisation Program. Methods: We conducted a retrospective case-control analysis. Vaccine-eligible children with laboratory-confirmed rotavirus infection were identified from jurisdictional notifiable infectious disease databases and individually matched to controls from the national immunisation register, based on date of birth, Aboriginal status and location of residence. Results: 171 cases met the inclusion criteria; most were Aboriginal and/or Torres Strait Islander (80%) and the median age was 19 months. Of these cases, 65% and 25% were fully or partially vaccinated, compared to 71% and 21% of controls. Evidence that cases were less likely than controls to have received a rotavirus vaccine dose was weak, OR 0.79 (95% CI, 0.46–1.34). On pre-specified subgroup analysis, there was some evidence of protection among children <12 months (OR 0.48 [95% CI, 0.22–1.02]), and among fully vs. partially vaccinated children (OR 0.65 [95% CI, 0.42–1.01]). Conclusion: Despite the known effectiveness of rotavirus vaccination, a protective effect of either rotavirus vaccine during a G2P[4] outbreak in these settings among predominantly Aboriginal children was weak, highlighting the ongoing need for a more effective rotavirus vaccine and public health strategies to better protect Aboriginal children.
Background Recently, retrospective registry-based studies have reported the decreasing incidence and increasing mortality of postinjury multiple organ failure (MOF). We aimed to describe the current epidemiology of MOF following the introduction of haemostatic resuscitation. Methods A 10-year prospective cohort study was undertaken at a Level-1 Trauma Centre-based ending in December 2015. Inclusion criteria age ≥ 16 years, Injury Severity Score (ISS) > 15, Abbreviated Injury Scale (AIS) Head < 3 and survived > 48 h. Demographics, physiological and shock resuscitation parameters were collected. The primary outcome was MOF defined by a Denver Score > 3. Secondary outcomes: intensive care unit length of stay (ICU LOS), ventilation days and mortality. Results Three hundred and forty-seven patients met inclusion criteria (age 48 ± 20; ISS 30 ± 11, 248 (71%) were males and 23 (6.6%) patients died. The 74 (21%) MOF patients (maximum Denver Score: 5.5 ± 1.8; Duration; 5.6 ± 5.8 days) had higher ISS (32 ± 11 versus 29 ± 11) and were older (54 ± 19 versus 46 ± 20 years) than non-MOF patients. Mean daily Denver scores adjusted for age, sex, MOF and ISS did not change over time. Crystalloid usage decreased over the 10-year period (p value < 0.01) and PRBC increased (p value < 0.01). Baseline cumulative incidence of MOF at 28 days was 9% and competing risk analyses showed that incidence of MOF increased over time (subdistribution hazard ratio 1.14, 95% CI 1.04 to 1.23, p value < 0.01). Mortality risk showed no temporal change. ICU LOS increased over time (subdistribution hazard ratio 0.95, 95% CI 0.92 to 0.98, p value < 0.01). Ventilator days increased over time (subdistribution hazard ratio 0.94, 95% CI 0.9 to 0.97, p value < 0.01). Conclusion The epidemiology of MOF continues to evolve. Our prospective cohort suggests an ageing population with increasing incidence of MOF, particularly in males, with little changes in injury or shock parameters, who are being resuscitated with less crystalloids, stay longer on ICU without improvement in survival.
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