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

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

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

'State of the Art': Negotiating a Standards-approved Digital Humanities Curriculum

The University of Canterbury has recently completed development of New Zealand (and Australasia’s) first digital humanities degree program that is also standards-approved on a national level. The process required the development of document sets that were submitted for review by the University of Canterbury Faculty, Academic Advisory Committee, Academic Board, the New Zealand Vice-Chancellor’s Committee on University Academic Programs (CUAP), the New Zealand Vice-Chancellor’s Committee, and the Tertiary Education Commission. Fourteen national and international reviewers, drawn from technology education, information science, computer science, high performance computing and the digital humanities also provided their opinions. The program represents a significant baseline for future digital humanities programs, and the lessons learned during its development are of importance to the broader digital humanities community. Although New Zealand universities operate with basically the same degree of independence in course and program development as universities elsewhere in the world, the requirement to submit all new programs to a national standards body is unusual, if not unique. It may be that the University of Canterbury digital humanities program is the most closely scrutinised example the digital humanities community have seen. This has resulted in a program that is embedded within both the culture of Canterbury, and the national educational policies of NZ. It therefore comes with a higher degree of legitimacy, but also a complex set of stake holders. Moreover, because of the close policy ties between New Zealand and Australia (in education as well as other areas) the program has implications for the Australasian region as a whole. The implications of national accreditation Programs and curriculums have pedagogical, methodological, administrative and indeed philosophical issues embedded in them. Their final form reflects not only the ‘state of the art’ in the discipline in question, but the ‘state of the art’ as parsed through academic staff, informed (and uninformed) reviewers, institutional context (and necessity), national educational politics, and the shifting sands of methodological and critical best practice. The forces are such that it is quite possible for the final program of study to be quite different from that originally intended, although for obvious reasons the applicants tend to press on regardless, making modifications where necessary but attempting to safeguard the core pedagogical principles wherever possible. This is a process that many digital humanities teams should be expected to go through in the coming years as more institutions attempt to establish programs; it is a period in time when the digital humanities are going to begin to be influenced not only by internal pressure, but external ones such as the need to conform to national educational standards. Teaching applied and critical DH in the context of standards-approved accreditation The program will be delivered to fourth year students undertaking their ‘Honours’ year, a first year of post-graduate study often taken before embarking on more advanced Masters or Ph.D. study. The program was informed by existing programs at Kings College London, University College London, the Open University (Wilks 2011) and the University of California, but the author drew most heavily on theoretical and pedagogical perspectives raised through DH social media and publishing channels over the past five years. A balance has been struck between the ‘hack’ and ‘yak’ positions (Cecire 2011; Ramsay 2011; Koh 2012 and others), in the light of what Alexander Reid has suggested is a need for the field to equip students with a broad “yet undefined digital literacy” (Reid 2012, 354) encompassing both technical and critical skills. The position taken is similar to that espoused by Alan Liu and Andrew Prescott, who argue that tomorrows students and scholars will need to function in a world in which computers are not only ubiquitous, but knowledge itself is a commodity (Liu, 2004; Prescott, 2012). In this sense, the program assumes an ethical imperative to prepare students for work in the post-industrial society that was envisaged by Daniel Bell in 1973, and now forms the basis of both graduate employment structures (Castells and Aoyama, 1994; Aneesh, 2001; Cohen 2010) and tertiary education systems (Donoghue 2008; Brier 2012). In keeping with the core values of the digital humanities community, emphasis has been placed on the development of technical skills that can enhance and extend humanities research activities, and promote awareness of the engineered nature of the digital world. The program is structured around two core assessment papers: DIGI 401: Introduction to Digital Humanities and DIGI 402: Humanities and New Media. DIGI 480: Research Essay will also be available, to students interested in exploring a topic in detail via a 10,000 word essay. A variety of other (assessment) papers will be rolled out in future years, including Applied Digital Humanities, Digital Literary Studies, and Digital History. Masters and Ph.D. offerings are expected to follow. DIGI 401: Introduction to Digital Humanities is modelled on courses in historical method that are well known to History students. The course provides a broad and challenging overview of the digital humanities, organised into History, Theory and Applied modules. Topics include technological determinism, systems theory, materiality and digital forensics, the nature of digital texts, and data visualization. Introductory lectures on TEI and GIS will prepare students for further study in Digital Literary Studies and Digital History. In order to provide students with generically useful programming knowledge an applied module will concentrate on teaching TEI, GIS, Python and use of APIs. Lecturers will be drawn from University of Canterbury’s Digital Humanities program, Human Interface Technology Laboratory, Computer Science, Information Systems, and Geography. The aim is to offer the students an overview of tools and methods in the digital humanities, and encourage them to think about how the digital world is engineered. DIGI 402: Humanities and New Media is an overt attempt to blend the ‘hack’ and ‘yak’ sides to DH as a practice. Students will be strongly encouraged to take DIGI 401 before taking 402 so they have a solid understanding of the technical side to new media culture and politics. Topics in this course include digital modernity, technocracy, cybernetics, knowledge economies, the Internet, open and closed data, open and closed ecosystems. Focus will be placed on both the engineered nature of the digital world, and the concepts required to critique it. Assessment will include traditional essay-based assessment, blog posts, forum posts, and quizzes designed to ensure students are capable of analysing the digital world as an engineered phenomenon. Pedagogical focus will be placed on graduate outcomes across the program as a whole, and students will be offered opportunities for student exchanges, internship and work experience opportunities. The aim is for graduates to have a blend of traditional humanities-related skills and applied computing skills. They should have an understanding of the moral and ethical issues surrounding digital technologies, the ability to write clear, concise prose, and an understanding of the technical constraints and opportunities provided by digital technologies. Students should be well suited to work in all new media and digital industries, but especially ones requiring a blend of analytical and technical skills. Graduates would be suitable for work in research, relationship management, business analysis, digital archiving, project management, and the creative and cultural heritage sectors. They should be particularly suited to policy analysis positions related to technology and culture, and any position that requires communication across technical and non-technical audiences. The aim is to create a ‘porous’ educational environment that encourages interaction both inside and outside the university, equipping students with experiences and relationships that can translate into enhanced employment prospects. Inter-disciplinarily will be encouraged, and it is hoped that a DH Commons can be developed to integrate university service support teams in the library and digital media group into the learning experience. The accreditation process means that, while reflecting the core aims and values of the digital humanities community, the program is also relevant to the pedagogical and strategic aims of the University of Canterbury and the wider New Zealand tertiary education sector. Although challenging, once successfully negotiated the accreditation process effectively embeds the digital humanities into the New Zealand government’s long-term education strategy, providing significant pedagogical sanction, integration with the secondary education sector, and a strong platform for future growth. All New Zealand, and undoubtedly Australian, universities aiming to develop digital humanities programs will need to reference the University of Canterbury as a baseline. The implications of this for the development of the digital humanities across Australasia are significant, and (as long as the Canterbury program enshrines core DH aims and values) largely positive. This paper will provide an overview of the program from intellectual, pedagogical and strategic perspectives in an attempt to share lessons learned with the international DH community, and redress some of the “emphasis on research over teaching” prevalent in the field (Brier 2012, 391). Specific focus will be placed on the implications of the program for Australia and the development of the digital humanities across Australasia as a whole. All program documentation will be made available online so that conference participants have full-text access to the issues being discussed