English - the torch of life: reflections on the Newbolt Report from an ITE perspective

This article reflects on how English as a school subject was positioned in the seminal paper “The Teaching of English in England”, otherwise known as The Newbolt Report, and its relationship with current government policy in England. Nearly a century after the Report’s publication, questions regarding the content and purpose of English as a subject that arise from Newbolt are used as a lens to consider the challenges presented in the initial training year to Secondary English teachers

Genome-Wide Identification of Ampicillin Resistance Determinants in Enterococcus faecium

Enterococcus faecium has become a nosocomial pathogen of major importance, causing infections that are difficult to treat owing to its multi-drug resistance. In particular, resistance to the β-lactam antibiotic ampicillin has become ubiquitous among clinical isolates. Mutations in the low-affinity penicillin binding protein PBP5 have previously been shown to be important for ampicillin resistance in E. faecium, but the existence of additional resistance determinants has been suggested. Here, we constructed a high-density transposon mutant library in E. faecium and developed a transposon mutant tracking approach termed Microarray-based Transposon Mapping (M-TraM), leading to the identification of a compendium of E. faecium genes that contribute to ampicillin resistance. These genes are part of the core genome of E. faecium, indicating a high potential for E. faecium to evolve towards β-lactam resistance. To validate the M-TraM results, we adapted a Cre-lox recombination system to construct targeted, markerless mutants in E. faecium. We confirmed the role of four genes in ampicillin resistance by the generation of targeted mutants and further characterized these mutants regarding their resistance to lysozyme. The results revealed that ddcP, a gene predicted to encode a low-molecular-weight penicillin binding protein with D-alanyl-D-alanine carboxypeptidase activity, was essential for high-level ampicillin resistance. Furthermore, deletion of ddcP sensitized E. faecium to lysozyme and abolished membrane-associated D,D-carboxypeptidase activity. This study has led to the development of a broadly applicable platform for functional genomic-based studies in E. faecium, and it provides a new perspective on the genetic basis of ampicillin resistance in this organism

Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19.

BACKGROUND: The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both. RESULTS: Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists. CONCLUSIONS: In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.)

Journalism, public imagination and cultural policy

Although the phrase 'cultural policy' would rarely form on journalists' lips, the cultural results of journalism permeate national imaginations in the totality of their impressions, through processes of persuasion set-up within an apparent framework of choice. Problematic cultural effects are produced through the mechanisms of gigantic markets whose very randomness seduces observers into believing that they are protected from conspiracy and manipulation. The paper explores certain mystifications within the ethos of mass market journalism, whose professional techniques beguile both producers and public in the way they suppress criticism or sympathy, and eradicate all but populist positions. The paper contends that many journalists are fuelled by an ethos of puritanical anti-intellectualism. These themes are pursued by deconstructing some of the 'professional' codes in journalism and its didactic literature, in order to expose a mechanism for channelling public mentality that is condoned through the anti-intellectualism of its techniques. The paper analyses media texts and processes of journalistic enculturation, engaging broadly with discourses inspired by the Frankfurt School and ideas of hegemony refined by Gramsci

Directing Modernist Spirituality: Evelyn Underhill, the Subliminal Consciousness and Spiritual Direction

Outlining an alternative trajectory for modernist spirituality to that traced in Pericles Lewis’s 'Religious Experience and the Modernist Novel' (2010), I argue that modernist religious thought, far from playing heir to the long march of secularization, was in fact conditioned by a late-nineteenth-century cultural crisis that issued in a range of religious experiments and renewals, one of which was Evelyn Underhill’s 'Mysticism: A Study in the Nature and Development of Man’s Spiritual Consciousness' (1911), a text that not only brought together mystical traditions and scientific discoveries, but also used this interdisciplinary remit to counter existing secularizing perspectives. An important dimension of Underhill’s work was its collaborative nature; it offers, I argue, not access to rarefied enlightenment, but rather a bold attempt to navigate a treacherous religious landscape

Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal alpha-toxin

The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor-mediated nuclear factor kappa B signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor alpha-toxin. Naturally elicited antibodies against alpha-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to alpha-toxin in nonleukocytic cells.Peer reviewe

Economic imaginaries of the Anti-biosis : between ‘economies of resistance’ and the ‘resistance of economies’

This paper seeks reports on the way economic principles, formulae and discourse inform biological research on antimicrobial resistance (AMR) in the life sciences. AMR, it can be argued, has become the basis for performing certain forms of ‘economic imaginary’. Economic imaginaries are ways of projecting and materially restructuring economic and political orders through motifs, metaphors, images and practices. The paper contributes to critical social science and humanities research on the socio-economic underpinning of biological discourse. The performance of economy in this context can be seen to follow two key trajectories. The first trajectory, discussed at length in this paper, might be described as ‘economies of resistance’. Here the language of market economics structures and frames microbiological explanations of bacterial resistance. This can be illustrated through, for example, biological theories of ‘genetic capitalism’ where capitalism itself is seen to furnish microbial life with modes of economic behaviour and conduct. ‘Economies of resistance’ are evidence of the naturalisation of socio-economic structures in expert understandings of AMR. The methodological basis of this paper lies in a historical genealogical investigation into the use of economic and market principles in contemporary microbiology. The paper reports on a corpus of published academic sources identified through the use of keywords, terms, expressions and metaphors linked to market economics. Search terms included, but were not limited to: ‘trade-off’, ‘investment’, ‘market/s’, ‘investment’, ‘competition’, ‘cooperation’, ‘economy’, ‘capital/ism’, ‘socialist/ism’, etc. ‘Economies of resistance’ complements a second distinct trajectory that can be seen to flow in the opposite direction from biology to economic politics (the ‘resistance of economies’). Here, economic imaginaries of microbial life are redeployed in large-scale debates about the nature of economic life, about the future of the welfare state, industrial strategy, and about the politics of migration and race, etc. ‘Economies of resistance’ and the ‘resistance of economies’ are not unrelated but, instead, they are mutually constituting dynamics in the co-production of AMR. In attempting to better understand this co-production, the paper draws upon literatures on the biopolitics of immunity in political philosophy and Science and Technology Studies (STS)

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570