Background In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov ( NCT04381936 ). Findings Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

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Objective: To identify risk factors for intracranial hemorrhage in the natural history course of brain arteriovenous malformations (AVMs) using individual patient data meta-analysis of 4 existing cohorts.Methods: We harmonized data from Kaiser Permanente of Northern California (n 5 856), University of California San Francisco (n 5 787), Columbia University (n 5 672), and the Scottish Intracranial Vascular Malformation Study (n 5 210). We censored patients at first treatment, death, last visit, or 10-year follow-up, and performed stratified Cox regression analysis of timeto-hemorrhage after evaluating hemorrhagic presentation, sex, age at diagnosis, deep venous drainage, and AVM size as predictors. Multiple imputation was performed to assess impact of missing data.Results: A total of 141 hemorrhage events occurred during 6,074 patient-years of follow-up (annual rate of 2.3%, 95% confidence interval [CI] 2.0%-2.7%), higher for ruptured (4.8%, 3.9%-5.9%) than unruptured (1.3%, 1.0%-1.7%) AVMs at presentation. Hemorrhagic presentation (hazard ratio 3.86, 95% CI 2.42-6.14) and increasing age (1.34 per decade, 1.17-1.53) independently predicted hemorrhage and remained significant predictors in the imputed dataset. Female sex (1.49, 95% CI 0.96-2.30) and exclusively deep venous drainage (1.60, 0.95-2.68, p 5 0.02 in imputed dataset) may be additional predictors. AVM size was not associated with intracerebral hemorrhage in multivariable models (p . 0.5). Conclusion:This large, individual patient data meta-analysis identified hemorrhagic presentation and increasing age as independent predictors of hemorrhage during follow-up. Additional AVM cohort data may further improve precision of estimates, identify new risk factors, and allow validation of prediction models. Brain arteriovenous malformations (BAVMs) are the most common cause of intracranial hemorrhage in younger people, who are at risk of long-term morbidity and mortality. The most common presentation is hemorrhage (approximately 50%), followed by seizures and neurologic deficits.Understanding hemorrhage risk in the natural history course of BAVM is crucial when making treatment decisions. However, obtaining accurate estimates is challenging because of short follow-up times from censoring by treatment, low event rates, and low prevalence of disease, which are major limitations of all BAVM longitudinal studies. Current BAVM annual hemorrhage rates range from 2%-4% overall 1-9 to 1%-3% among unruptured patients, 1,4,6,9 but vary †Deceased.