Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. 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. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

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

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease

Rural regeneration

Architectural regeneration tends to be an urban affair. Regeneration projects that focus on the adaptation, reuse or repurposing of buildings or places are commonly focused on needs, challenges and opportunities in urban settings. Regardless of the nature or scale of a regeneration project (i.e. whether it is government- or community-led, permanent or temporary, or on a neighbourhood or building scale), it is almost inevitably city based. The literature on architectural regeneration equally focuses almost exclusively on urban regeneration. Studies that look at the history, economics, planning or design of architectural regeneration projects nearly all deal with the situation in towns and cities, most often in a Western (i.e. European or North American) context (Roberts and Sykes 2000; Pierson and Smith 2001; Leary and McCarthy 2013). This urban and Western focus is understandable seeing that the origins of the practice may be found in early attempts by late nineteenth century social reformers to alleviate the poor, crowded and unhygienic living conditions in the rapidly growing industrial cities of Europe and North America (Roberts and Sykes 2000; Hall 2014). It is even more understandable in view of the unprecedented level of urbanisation today, not just in the West but all around the world, and the inevitable interest in urban issues that this has generated (Nel-lo and Mele 2016). Nonetheless, it does mean that the extent to which architectural regeneration projects are carried out in non-urban, rural settings, is much less known and understood. The aim of this chapter is to address this gap in knowledge.  The interest in rural architecture has commonly lagged behind that in urban architecture. Apart from its sustained interest in country estates and village churches, architectural history has been predominantly a history of urban buildings (Fleming, Honour and Pevsner 1999; Sennott 2001; Curl 2006). Other disciplines like anthropology, ethnology or geography have similarly shown relatively little interest in rural architecture. The study of rural architecture has commonly been subsumed under the study of vernacular architecture, a field that itself has been consistently marginalised in architectural discourse (Oliver 1997; Asquith and Vellinga 2006; Brown and Maudlin 2012). The architectural design profession has similarly tended to prioritise work done in urban contexts. Nonetheless, the turn of the twenty-first century has seen a slowly increasing interest in rural architectural design. A large number of successful practices that expressly specialise in design in rural contexts have been established around the world. At the same time, various publications that deal with the specificities, challenges and opportunities of architectural design in rural contexts have begun to appear (Thorbeck 2012; Arendt 2017). However, much of this new interest is focused on new design in rural contexts and is thus not concerned with the regeneration of existing rural architecture, or rural regions; even if the new designs often draw on vernacular rural precedents. In some instances professional and academic interest has focused on the conversion of existing agricultural buildings, particularly barns, or the adaptation of rural housing for tourism purposes (e.g. Corbett-Winder and Parmiter 1990). Architectural regeneration projects that focus on the reuse and repurposing of rural architecture with the specific aim of revitalising not just the buildings, but the local communities, economies and places of which they form a part have received much less attention - other than as the focus of educational projects (see Orbasli, Vellinga, Wedel and Randell, this volume).   This academic and professional lack of interest in rural architectural regeneration is remarkable for two reasons. First of all, despite consistent popular conceptualisations of the rural countryside as an idyllic counterpart to the city, rural areas all around the world face serious social, economic and environmental challenges that are not dissimilar to those faced by urban communities. Problems like economic decline, environmental pollution, social division, substandard housing or poor healthcare facilities are not the prerogative of cities and urban conglomerations, but are equally prominent in rural towns and villages across the globe (Cloke, Marsden and Mooney 2006). Indeed, in some instances, especially in the developing world, they may be seen to be more acute than they are in urban areas. Of course the underlying causes of such issues and the specific ways in which they manifest themselves will be different in rural areas. One key distinction in this regard is that, whereas in urban areas problems are often caused by rapid and sometimes uncontrolled population growth, in rural places it is often the decline of population that creates and exacerbates difficulties. Although the literature on the social, demographic, economic and environmental challenges faced by rural areas and the ways in which they may be overcome by means of rural development programmes is extensive (Shepherd 1998; Moseley 2003), it hardly ever takes into account the role that architectural regeneration can play in such projects.  The second reason why the lack of interest in rural regeneration is remarkable is that in many parts of the world, rural architectural heritage is in a state of dilapidation and decline. In many countries, rural houses have often been abandoned by their owners or are now only inhabited by (often elderly) family members who do not have the resources to leave the area or maintain the buildings. In many cases, especially in the developing world, the inhabitants may have simply left the region and moved to the city, leaving behind buildings that they no longer need. In other instances, old buildings have been replaced by new houses that have been built alongside them and that incorporate more up-to-date facilities and conveniences, and better meet contemporary expectations of what a ‘modern’ house should look like. In yet other instances, rural housing remains inhabited, but the owners lack the means to properly maintain it or to adapt it to current requirements and standards. This may also be the fate of rural community buildings, such as parish churches, schools or village halls. In rural areas in the developed world that still maintain their agricultural function, it is not uncommon to come across abandoned farm buildings (barns, stables, sheds) that are no longer needed because they have been replaced by more modern facilities that better suit more intensive and industrialised contemporary farming practices. In those rural areas characterised by the presence of industrial buildings (for example in Eastern Europe), abandoned factories and high-rise housing blocks may dominate the rural landscape.  This chapter aims to provide an introduction to the topic of rural regeneration. It will argue that rural areas all around the world are environmentally, socially, economically and architecturally varied, dynamic and complex, and constitute what, in a European context, has been called a ‘differentiated countryside’ (Marsden et al. 1993). Rather than the bucolic backwaters of popular imagination, defined as ‘timeless’, ‘slow’ and ‘unchanging’ in direct and exclusive opposition to the ‘fast’ and dynamic city, rural areas are integral, productive and ever-changing parts of the modern world that face a complex myriad of demographic, environmental, social and economic challenges. Although unique in their specific manifestations, those challenges are not unlike those faced by urban areas. The chapter will show that, despite a common recognition of the challenges faced by rural areas all around the world, work in the field of rural regeneration has lagged behind that in urban contexts. It will argue that architectural regeneration projects that build on existing local opportunities, take into account place-specific cultural characteristics and use the transformative potential of architecture may nonetheless help to enhance and develop rural economies, places and communities in the same way that their urban counterparts do so in cities.  The chapter is based on a literature review that covers several topics of importance to our understanding of rural areas, including the definition and perception of rurality, rural-urban relationships, the transformation of rural space and architecture, and current economic and social trends. It further includes several case studies from a number of European countries (Croatia, Slovenia, Italy and Poland) that present examples of the different contexts in which architectural regeneration can appear

Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory actions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19. Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospital with COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once per day by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatment groups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment and were twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants and local study staff were not masked to the allocated treatment, but all others involved in the trial were masked to the outcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) were eligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was 65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomly allocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall, 561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days (rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median 10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days (rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, no significant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24). Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or other prespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restricted to patients in whom there is a clear antimicrobial indication. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research