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.

Rationale: The immunological and protective role of pneumococcal carriage in healthy adults is not known, but high rates of disease and death in the elderly are associated with low carriage prevalence. Objectives: We employed an experimental human pneumococcal carriage model to investigate the immunizing effect of a single carriage episode. Methods: Seventy healthy adults were challenged, and of those with carriage, 10 were rechallenged intranasally with live 6B Streptococcus pneumoniae up to 11 months after clearance of the first carriage episode. Serum and nasal wash antibody responses were measured before and after each challenge. Measurements and Main Results: A total of 29 subjects were experimentally colonized. No subjects were colonized by experimental rechallenge, demonstrating the protective effect of initial carriage against subsequent infection. Carriage increased both mucosal and serum IgG levels to pneumococcal proteins and polysaccharide, resulting in a fourfold increase in opsonophagocytic activity. Importantly, passive transfer of postcarriage sera from colonized subjects conferred 70% protection against lethal challenge by a heterologous strain in a murine model of invasive pneumococcal pneumonia. These levels were significantly higher than the protection conferred by either precarriage sera (30%) or saline (10%). Conclusions: Experimental human carriage resulted in mucosal and systemic immunological responses that conferred protection against recolonization and invasive pneumococcal disease. These data suggest that mucosal pneumococcal vaccination strategies may be important for vulnerable patient groups, particularly the elderly, who do not sustain carriage.

The current explosion in mobile computing and telecommunications technologies holds the potential to transform "everyday" time and space, as well as changes to the rhythms of social institutions. Sociologists are only just beginning to explore what the notion of "mobility" might mean when mediated through computing and communications technologies, and so far, the sociological treatment has been largely theoretical. This article seeks instead to explore how a number of dimensions of time and space are being newly reconstructed through the use of mobile communications technologies in everyday life. The article draws on long-term ethnographic research entitled "The Socio-Technical Shaping of Mobile Multimedia Personal Communications," conducted at the University of Surrey. This research has involved ethnographic eldwork conducted in a variety of locales and with a number of groups. This research is used here as a resource to explore how mobile communications technologies mediate time in relation to mobile spaces. First the paper offers a review and critique of some of the major sociological approaches to understanding time and space. This review entails a discussion of how social practices and institutions are maintained and/or transformed via mobile technologies. Ethnographic data is used to explore emerging mobile temporalities. Three interconnected domains in mobile time are proposed: rhythms of mobile use, rhythms of mobile use in everyday life, and rhythms of mobility and institutional change. The article argues that while these mobile temporalities are emerging, and offer new ways of acting in and perceiving time and space, the practical construction of mobile time in everyday life remains rmly connected to well-established time-based social practices, whether these be Address correspondence to Nicola Green, Department of Sociology, University of Surrey, Guildford, Surrey GU2 7XH, UK. E-mail: n.green@soc.surrey.ac.uk; web site: http://www.soc.surrey.ac.uk institutional (such as clock time, "work time") or subjective (such as "family time").Keywords mobility, modernity, social change, telecommunications, timeThe current explosion in mobile telecommunication s and computing technologies provides the potential to transform "everyday" time and space. Indeed, this transformative theme can be found not only in social research, but also in marketing imagery (the "anywhere, anytime" connectivity promised by mobile technologies and services), and in the everyday stories of those who currently use the technologies for a variety of purposes. Current research on the construction of everyday space, place, and movement through it demonstrates that changing geographical/spatial practices affect the social regulation and subjective experience of time. It is now commonplace in social and cultural geography to argue that time and space are always interlinked-changes in space provoke changes in time, and vice versa (Adam, 1990;Giddens, 1990).Historical and contemporary work in cultural geography, sociology, and anthropolog y ha...

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Antigen-specific human T cell clones specific for defined peptides of influenza A hemagglutinin were found to be rendered unresponsive by incubation with moderately high concentrations of antigen. This was the case whether the synthetic peptide antigen was present for the duration of the culture or the cloned T cells were preincubated with antigen for 3-18 h at 37 degrees C, before stimulation with T-depleted irradiated sheep erythrocyte non-rosette-forming lymphocytes (E-) pulsed with the optimal dose of peptide. Tolerance could not be overcome by culture with various numbers of E- cells and antigen. The induction of unresponsiveness was antigen specific, since it depended upon incubation with the appropriate peptide recognized by that clone. In addition, the tolerant T cells remained unresponsive to stimulation with the specific peptide for at least 7 d after induction even though maintained in culture in the presence of T cell growth factor. This state of antigen-specific unresponsiveness is akin to immunological tolerance. Furthermore, the experiments reported here demonstrate that the helper T cell clone can be inhibited by the relevant peptide in the absence of any suppressor cells or their precursors. This suggests that antigen-induced unresponsiveness need not always depend on the presence of suppressor T cells. The induction of tolerance in T cell clones does not result in early T cell death, since cells that no longer proliferate in response to the specific antigen and accessory cells still proliferate in response to T cell growth factor.