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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Single-pair fluorescence resonance energy transfer was used to track RNA exiting from RNA polymerase II (Pol II) in elongation complexes. Measuring the distance between the RNA 5 end and three known locations within the elongation complex allows us determine its position by means of triangulation. RNA leaves the polymerase active center cleft via the previously proposed exit tunnel and then disengages from the enzyme surface. When the RNA reaches lengths of 26 and 29 nt, its 5 end associates with Pol II at the base of the dock domain. Because the initiation factor TFIIB binds to the dock domain and exit tunnel, exiting RNA may prevent TFIIB reassociation during elongation. RNA further extends toward the linker connecting to the polymerase C-terminal repeat domain (CTD), which binds the 5-capping enzyme and other RNA processing factors.Pol II ͉ transcription ͉ FRET ͉ triangulation ͉ fluorescence P ol II synthesizes all eukaryotic mRNA and comprises 12 subunits, Rpb1 to Rpb12. An atomic model of Pol II has been obtained by x-ray crystallography (1, 2). Additional studies of Pol II-nucleic acid complexes have given insights into the elongation complex structure and molecular aspects of the transcription mechanism (3-7). Crystallographic analysis detected the position of the nascent RNA within the DNA-RNA hybrid above the active site (positions ϩ1 to Ϫ8, with ϩ1 denoting the nucleotide addition site) and for 2 nt upstream of the hybrid after the point of DNA-RNA strand separation (positions Ϫ9 and Ϫ10) (3, 7). The last-ordered RNA nucleotide is located at the entrance to a tunnel [called the RNA exit channel for the bacterial RNA polymerase (8)], which is formed among the polymerase wall, clamp, and lid. This tunnel leads from the active center cleft to the exterior and was proposed to accommodate exiting RNA (1,3,6,7). Beyond the putative exit tunnel, two prominent surface grooves on either side of the dock domain in principle could further accommodate exiting RNA (1, 9). Groove 1 winds along the base of the clamp toward the Rpb4/7 subcomplex, whereas groove 2 leads along Rpb11 toward Rpb8. Recently, nascent RNA could be crosslinked to Rpb7, providing apparent support for groove 1 (10). RNA beyond position Ϫ10 was present in one of the crystallographic studies of the elongation complex (3) but could not be observed in the tunnel or in the subsequent grooves, suggesting that its interactions, if they exist, are transient and cannot be detected in medium-resolution electron density maps.To study if the nascent RNA indeed exits through the proposed tunnel, and whether it follows a defined surface path beyond the tunnel, we used single-molecule fluorescence experiments. Singleparticle methods prevent the loss of information because of averaging that is inherent to bulk experiments and crystallography (11)(12)(13)(14). Fluorescence resonance energy transfer between two fluorophores [single-pair (sp)-FRET] provides a very sensitive tool for studying distances and conformational changes within biological complexes in the ...