Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

The public and the relational: The collaborative practices of the Inclusive Archive of Learning Disability History

This chapter discusses the Inclusive Archive of Learning Disability History. It points to a collaborative relationship between the political ideas derived from public political logics — public service, public sphere, ‘on behalf of the public’ and for posterity — and those that derive from relational and personal-centred politics. Rather than favouring one or the other, the chapter argues that for an archive to be an archive, and for it to be an inclusive one, an approach to archival practice that held both the public and the relational political traditions in dialogue needed to be developed. Both political traditions have a history of being very effectively expressed in the learning disability self-advocacy movement as speaking up and being heard, and of arguing for services to start with the individual by being more ‘person-centered’. As such, the chapter reveals that the task of this archive is to explore fruitful combinations and collaborations between the two political traditions

Field Techniques in Sea-Ice Research

This contribution provides a brief overview of current approaches and anticipated advances in obtaining a range of field measurements for sea ice in (sub)polar regions. The multiple uses of the ice cover and its important role in social-environmental systems at high north- ern and southern latitudes require a broad range of approaches and measurements to be considered. Building on a recently published monograph with detailed information about the state of the art, the present contributions provides concise summaries and updates for the following topical areas: Field research study and sampling de- sign, snow on sea ice, ice thickness and morphology, ice coring and measurement of key physical properties, ice optics and surface en- ergy budget, transport properties, sea ice biota and biogeochemical properties, autonomous sensors, UASs and UAVs, and ship-based observations. For each of these topics, relevant background infor- mation is provided before discussing key methodological approaches and techniques in more detail. Most of the topical sections then include an example to illustrate how the approaches are applied in specific cases. Each section then concludes with a outlook on fu- ture developments and research needs. Common to all types of field measurements is the conclusion that due to a substantial in- crease in human activities in ice-covered maritime regions and the impacts of rapid environmental change a great need for accurate, consistent and intercomparable sea-ice datasets has arisen. Method- ological advances and scientific progress over the past few decades now puts the research and operations community in a position to develop best practices with respect to field measurements that can lead to standardized, interoperable approaches, greatly minimizing risks associated with lack of suitable, consistent datasets

CPG-based locomotion control of a quadruped robot with an active spine

Central pattern generators (CPGs) are neural networks re- sponsible for producing rhythmic behaviours and are commonly found in both vertebrate and invertebrate animals. This paper proposes a novel internal feedback mechanism for a CPG model designed to generate leg- spine coordinated locomotion in a quadruped robot with an active spine. This mechanism enables the CPG to independently control the frequency and amplitude of the stance and swing durations while also modifying the definition of stance and swing phases to generate more gaits. The CPG model’s results are demonstrated on a simulated ”tensegrity quadruped robot” called TQbot, which features a flexible spine with 3 degrees of freedom (DOF). By adjusting the parameters, the CPG model can gen- erate gaits with leg-spine coordination and uses the spine for turning

Between speaking out in public and being person-centred: collaboratively designing an inclusive archive of learning disability history

The Living Archive of Learning Disability History is being developed by an inclusive team of researchers both with and without learning disabilities. We argue the archive is important in making publicly visible the lives of people with learning disabilities. Yet – drawing on thinking that came out of our collaborative workshops – we also identify alternative imperatives, that you might want to have control over how you share your personal memories and stories, with whom, when you share them and for how long. We show how we are responding to these different ideas in the design of the Living Archive in order to create pathways between two traditions that have emerged through self-advocacy: ‘speaking out in public’ and ‘being person-centred’. We outline our research on consent processes to ensure that our archive builds capacity for as many people as possible to consent while also offering a legally compliant ‘Best Interests’ process in line with the requirements of the Mental Capacity Act, England and Wales (2005). We argue that deploying and actively navigating between the different political logics of ‘speaking out in public’ and ‘being person-centred’ offers a way forward for ongoing debates concerning community engagement in archives, museums and heritage