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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Pediatr. Res. 14: 956-962 (1980) SummaryA total of 40 skin fibroblast cultures from pediatric cases of lactic acidosis were subjected to a series of tests designed to elucidate the nature of an underlying defect in metabolism. Of these 40 cases, in 14 we were able to define the following problems.Pyruvate carboxylase deficiency was evident in five cases showing <10% normal activity. Phosphoenolpyruvate carboxykinase deficiency was evident in one case where the whole cells showed 17% of normal activity whereas the mitochondria1 activity of this enzyme was 6% of normal. Pyruvate dehydrogenase deficiency was present in six cases showing 8 to 39% of normal activity, five of them being due to deficient pyruvate decarboxylase activity and one of them being due to deficient dihydrolipoyl dehydrogenase activity. Two cases were found with normal enzymes of pyruvate metabolism in which the production of '4COz from was deficient at 13 and 28% of normal activity, respectively, which we consider to be indicative of reduced activity of the Krebs' cycle. The grounds for the diagnosis of these 14 affected cases are documented, and the clinical presentation of these enzyme deficiencies is assessed in the light of present knowledge about lactic acidosis. Speculation years, the diagnosis being made most commonly on measurement of enzyme activity on a liver biopsy specimen. Where phosphoenolpyruvate carboxykinase (PEPCK) and pymvate carboxylase deficiencies are concerned, the number of cases are few, and the associated symptoms not always similar. Two diagnoses have been made based on the measurement of pyruvate carboxylase activity in fibroblasts (1, 10); in other cases, the diagnosis has been made on liver biopsy (29,31,33,35). Three cases of PEPCK deficiency have been documented, in two of which the localization of the defect is not specified (13,15). and in one of which the cytosolic PEPCK is identified as the missing component (36).Fatal lactic acidosis has been described in which postmortem examination of muscle tissue showed in one case deficient cytochrome aa3 and cytochrome b (34), and in another case, deficient cytochrome aas (38). In both cases, the defect seemed to be confined to skeletal muscle.We present here the results of our studies on the skin fibroblasts from 40 new patients with lactic acidosis and attempt to correlate identifiable metabolic deficiencies with clinical presentation. fetal calf semm added. Confluent cells were harvested with 0.025% tetramer, dihydrolipoyl transacet~lase, and d i h~d r o l i~o~l dehy-trypsin. Cells used for studies were washed free of trypsin by drogenase (Ed. although there is a specific kinase and a ~h o s~h a -repeated ( X 3) centrifugation and resuspension of the packed cells tase modulating the activity of El (9. 26, 37). At least nine in phosphate-buffered saline. confirmed cases of El deficiency have been described (3, 5, 6, 11, 12. 30). A presumptive, but unproven, diagnosis of dihydrolipoyl WHOLE-CELL ASSAYS transacetylase deficiency has been made (8), and two cases...