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.

Long-term caloric restriction (CR) has been repeatedly shown to increase life span and delay the onset of age-associated pathologies in laboratory mice and rats. The purpose of the current study was to determine whether the CR-associated increase in life span occurs in all strains of mice or only in some genotypes and whether the effects of CR and ad libitum (AL) feeding on mortality accrue gradually or are rapidly inducible and reversible. In one experiment, groups of male C57BL/6, DBA/ 2, and B6D2F 1 mice were fed AL or CR (60% of AL) diets beginning at 4 months of age until death. In the companion study, separate groups of mice were maintained chronically on AL or CR regimens until 7, 17, or 22-24 months of age, after which, half of each AL and CR group was switched to the opposite regimen for 11 wk. This procedure yielded four experimental groups for each genotype, namely AL→AL, AL→CR, CR→CR, and CR→AL, designated according to long-term and shortterm caloric regimen, respectively. Long-term CR resulted in increased median and maximum life span in C57BL/6 and B6D2F 1 mice but failed to affect either parameter in the DBA/2 mice. The shift from AL→CR increased mortality in 17-and 24-month-old mice, whereas the shift from CR→AL did not significantly affect mortality of any age group. Such increased risk of mortality following implementation of CR at older ages was evident in all three strains but was most dramatic in DBA/ 2 mice. Results of this study indicate that CR does not have beneficial effects in all strains of mice, and it increases rather than decreases mortality if initiated in advanced age.Keywords caloric restriction; aging; C57BL/6; DBA/2; B6D2F 1 Caloric restriction (CR), compared with ad libitum (AL) feeding, has been shown to increase the life span of laboratory mice and rats (e.g., 1,2-4). For instance, a 40% decrease in total caloric intake, implemented after 3 months of age, has been found to increase the life span of C57BL/6 mice by more than 35% (5), and comparable findings have been made in Fischer 344 rats (4). Because CR produces such robust extensions in both the average and maximum life span, this regimen is widely assumed to provide a model for understanding the fundamental causes of the aging process. Notwithstanding, understanding of the mechanism by which CR retards the progression of age-related alterations has remained elusive even though several hypotheses have been proffered. A fundamental, but as yet, unresolved issue pertaining to the elucidation of the putative mechanism is whether the effects of CR accrue gradually or are they rapidly inducible and reversible upon shifting from AL feeding to the CR regimen and vice versa.Another issue critical to understanding the mechanistic basis of CR effects on aging is whether CR causes life span extension in virtually all animal species or only in some genotypes. The majority of previous studies on the effects of CR have been conducted on relatively few strains of rats and mice in which CR has been well established to result in...

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