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Trials of anti-GM-CSF therapies in COVID-19 show divergent results; this may be explained by underlying biology and the fragility of the study findings. Further investigation of the pathophysiology of COVID-19 is required to better target therapies. http://bit.ly/3O1AuIo KK is supported by grants from the Academy of Medical Sciences (SG023\1048) and NIHR Development and Skills Enhancement award (NIHR 302841). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. ACM is supported by a Clinician Scientist Fellowship from the Medical Research Council (MR/V006118/1).

As COVID-19 swept the world it also became the subject of a quickly growing body of theoretical scholarship aimed at understanding the social, political and economic implications of the ‘pandemic event’. Taking a step back, this paper draws on Deleuze and Foucault to interrogate whether, and in what way, the COVID-19 pandemic can and should in fact be understood as an event. We first offer a structured overview of existing ‘pandemic theory’ where we highlight that the productivity unfolded by the pandemic event is here either politically or ontologically fixed. Against this background, we show that, in distinct ways, Deleuze’s and Foucault’s concepts of the event caution against reifying a pandemic event. Any political force the pandemic can unfold is always made after the fact, and is contingent on what is (counter-)effectuated from the pandemic, or which discursive dispersions intersect with and unfold from it. The pandemic is evental rather than event – it is made up of events, and holds the potential to produce events. For critical theory, the significance of the pandemic event is thus in the first place methodological: it gives insight to how (post-)pandemic societies are produced, and where openings for the actualisation of alternatives might lie. © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/). Peer reviewed

Rural and Agricultural Shows are rich in tradition but their function in the rural economy is evolving. The cancellation of Shows during the Covid-19 pandemic led us to examine how rural Shows would re-emerge and what opportunities and challenges they now face. The research draws on interviews with organisers and exhibitors, attendance at live events and evaluations of online events that were staged during the pandemic. This has revealed that Shows have accelerated their digitalisation but also that the physical meeting space is critical to their social function. The research identified new expectations from exhibitors which have discovered alternative routes to market, including online. There is an imperative for Show organisers to identify methods to tap into online markets and offer value to their exhibitors. Shows re-opening in 2022 are having to adapt quickly to the post-pandemic economy including the cost-of-living crisis, a loss of volunteers and a more competitive event environment.

The Covid-19 pandemic encouraged remote healthcare and led to dependency on virtual fracture clinics (VFC). VFC are orthopaedic consultant-led clinics where cases are reviewed virtually following referral by emergency department clinicians. Success is contingent on a comprehensive initial history and examination. This pathway has high patient satisfaction rates and cost-saving benefits. However, clinicians must be vigilant for high-energy mechanisms or examination findings suggestive of greater underlying injury. In this case, VFC missed a rare ipsilateral annular ligament injury in a 15-year old with an undisplaced radial neck fracture, following a fall from a horse. This led to radial head dislocation and delayed surgical repair. Untreated, radial head dislocations lead to pain and reduced range of movement. Despite the rarity of this injury pattern, face-to-face orthopaedic examination would have raised concern for significant ligamentous injury. A high-energy mechanism of injury mandates face-to-face senior orthopaedic review to avoid missing serious concomitant injury.

Membranoproliferative glomerulonephritis (MPGN) comprises a histologic pattern of glomerular injury with different underlying diseases. Here we report on a 47-year-old female with rapidly progressive glomerulonephritis (RPGN) on top of a previously diagnosed idiopathic MPGN after receiving the first dose of the Pfizer-BioNTech coronavirus disease 2019 (COVID-19) mRNA vaccine. After aggressive immunosuppression her serum creatinine returned to normal values, along with reduction of proteinuria. Recently, numerous publications have reported an association of glomerular diseases with COVID-19 vaccination. Our case presents to the best of our knowledge the first occurrence of possible association of COVID-19 mRNA vaccination with a crescentic form of MPGN.

Purpose Patients hospitalized with COVID-19 may develop a hyperinflammatory, dysregulated cytokine “storm” that rapidly progresses to acute respiratory distress syndrome, multiple organ dysfunction, and even death. Remote ischaemic conditioning (RIC) has elicited anti-inflammatory and cytoprotective benefits by reducing cytokines following sepsis in animal studies. Therefore, we investigated whether RIC would mitigate the inflammatory cytokine cascade induced by COVID-19. Methods We conducted a prospective, multicentre, randomized, sham-controlled, single-blind trial in Brazil and South Africa. Non-critically ill adult patients with COVID-19 pneumonia were randomly allocated (1:1) to receive either RIC (intermittent ischaemia/reperfusion applied through four 5-min cycles of inflation (20 mmHg above systolic blood pressure) and deflation of an automated blood-pressure cuff) or sham for approximately 15 days. Serum was collected following RIC/sham administration and analyzed for inflammatory cytokines using flow cytometry. The endpoint was the change in serum cytokine concentrations. Participants were followed for 30 days. Results Eighty randomized participants (40 RIC and 40 sham) completed the trial. Baseline characteristics according to trial intervention were overall balanced. Despite downward trajectories of all cytokines across hospitalization, we observed no substantial changes in cytokine concentrations after successive days of RIC. Time to clinical improvement was similar in both groups (HR 1.66; 95% CI, 0.938–2.948, p 0.08). Overall RIC did not demonstrate a significant impact on the composite outcome of all-cause death or clinical deterioration (HR 1.19; 95% CI, 0.616–2.295, p = 0.61). Conclusion RIC did not reduce the hypercytokinaemia induced by COVID-19 or prevent clinical deterioration to critical care. © The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Peer reviewed

The process of finding molecules that bind to a target protein is a challenging first step in drug discovery. Crystallographic fragment screening is a strategy based on elucidating binding modes of small polar compounds and then building potency by expanding or merging them. Recent advances in high-throughput crystallography enable screening of large fragment libraries, reading out dense ensembles of fragments spanning the binding site. However, fragments typically have low affinity thus the road to potency is often long and fraught with false starts. Here, we take advantage of high-throughput crystallography to reframe fragment-based hit discovery as a denoising problem – identifying significant pharmacophore distributions from a fragment ensemble amid noise due to weak binders – and employ an unsupervised machine learning method to tackle this problem. Our method screens potential molecules by evaluating whether they recapitulate those fragment-derived pharmacophore distributions. We retrospectively validated our approach on an open science campaign against SARS-CoV-2 main protease (Mpro), showing that our method can distinguish active compounds from inactive ones using only structural data of fragment-protein complexes, without any activity data. Further, we prospectively found novel hits for Mpro and the Mac1 domain of SARS-CoV-2 non-structural protein 3. More broadly, our results demonstrate how unsupervised machine learning helps interpret high throughput crystallography data to rapidly discover of potent chemical modulators of protein function.

SUMMARY The SARS-CoV-2 genome encodes a multitude of accessory proteins. Using comparative genomic approaches, an additional accessory protein, ORF3c, has been predicted to be encoded within the ORF3a sgmRNA. Expression of ORF3c during infection has been confirmed independently by ribosome profiling. Despite ORF3c also being present in the 2002-2003 SARS-CoV, its function has remained unexplored. Here we show that ORF3c localises to mitochondria during infection, where it inhibits innate immunity by restricting IFN-β production, but not NF-κB activation or JAK-STAT signalling downstream of type I IFN stimulation. We find that ORF3c acts after stimulation with cytoplasmic RNA helicases RIG-I or MDA5 or adaptor protein MAVS, but not after TRIF, TBK1 or phospho-IRF3 stimulation. ORF3c co-immunoprecipitates with the antiviral proteins MAVS and PGAM5 and induces MAVS cleavage by caspase-3. Together, these data provide insight into an uncharacterised mechanism of innate immune evasion by this important human pathogen.

Peer reviewed: True Here researchers have the disposition to engage in the scholarly discourse on how the pandemic adversely influenced individuals' mental health and what remedies should be exercised in response to the mental health challenges. There is a shortage of scholarly discussion about who benefitted from the occurrence of the pandemic. Mancini et al. argued that the pandemic benefitted the social and mental health functioning of a subset of the population, despite the pandemic causing considerable risks of harm to mental health. In this perspective, the author summarizes relevant findings and arguments to present which subsets of the population benefitted at school, at home, and in the workplace during the pandemic. Although COVID-19 is no longer deemed a pandemic, many by-products of the public health crisis, including the encouragement of remote work and studies, remain. In this perspective, by understanding who benefitted from the pandemic and why, the author can evaluate if any public policies formed in response to the pandemic should be kept in the long run in order to maximize individuals' mental health.