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.

No abstract

No abstract

Ileal loops including Peyer's patch were prepared in five 28-day-old calves and infused Salmonella typhimurium strain ST4/74. Loops were fixed 5 minutes to 2 hours after inoculation, and the mucosa was examined by light and electron microscopy. Within 5 minutes, the bacteria were interacting with the follicle-associated epithelium (FAE); the surface of M cells changed to lamellipodia, engulfing many bacteria. This process proceeded rapidly to 30 minutes, involving most M cells above crypt level. Most cells were exfoliated, and many were packed with bacteria, and the domed villi became stunted. There was a rapid migration of neutrophils through the FAE into the lumen by 15 minutes. By 60 minutes, there was no further interaction between the bacteria and the FAE; at this time bacteria were present in macrophages in the lamina propria. Restitution of the FAE was complete by 2 hours in spite of the many bacteria in the cell debris overlying the epithelium. Interaction of bacteria with the absorptive villi was delayed compared with interaction with the FAE. After 15 minutes, bacteria were seen adhering to some enterocytes of the upper third of the villi; many bacteria were adhering to the surface of the enterocytes at 20 and 30 minutes, but few were seen thereafter. Adherence was patchy and largely confined to cells whose surfaces were depressed relative to others. The microvillous surface of these enterocytes was extensively remodelled. Tissue response, with uptake of bacteria into vacuoles, exfoliation of enterocytes containing bacteria, and subsequent stunting of the villi, began at 30 minutes and was severe and progressive to 2 hours. Following the initial attachment and uptake of the bacteria loss of enterocytes progressed from these initial sites; bacteria were associated with the lateral cell membrane of cells adjacent to cells being extruded and not with the microvilli of cells at new sites. In a calf 4 hours after dosing orally with the same strain, M cells were engulfing bacteria and their cell surface was changed as seen in the inoculated loops; absorptive enterocytes were also taking up bacteria as seen in the ileal loops, indicating the process seen in the loops and after oral dosage was similar. For this strain of S typhimurium, there was an initial concentration of bacilli around the domed villus epithelium. This distribution was not random but may have resulted from a specific attraction to the FAE.

Heat (85 degrees C for 20 min) and pressure (600 MPa for 15 min) treatments were applied to skim milk fortified by addition of whey protein concentrate. Both treatments caused > 90 % denaturation of beta-lactoglobulin. During heat treatment this denaturation took place in the presence of intact casein micelles; during pressure treatment it occurred while the micelles were in a highly dissociated state. As a result micelle structure and the distribution of beta-lactoglobulin were different in the two milks. Electron microscopy and immunolabelling techniques were used to examine the milks after processing and during their transition to yogurt gels. The disruption of micelles by high pressure caused a significant change in the appearance of the milk which was quantified by measurement of the colour values L*, a* and b*. Heat treatment also affected these characteristics. Casein micelles are dynamic structures, influenced by changes to their environment. This was clearly demonstrated by the transition from the clusters of small irregularly shaped micelle fragments present in cold pressure-treated milk to round, separate and compact micelles formed on warming the milk to 43 degrees C. The effect of this transition was observed as significant changes in the colour indicators. During yogurt gel formation, further changes in micelle structure, occurring in both pressure and heat-treated samples, resulted in a convergence of colour values. However, the microstructure of the gels and their rheological properties were very different. Pressure-treated milk yogurt had a much higher storage modulus but yielded more readily to large deformation than the heated milk yogurt. These changes in micelle structure during processing and yogurt preparation are discussed in terms of a recently published micelle model.