Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group

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

Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking.

Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function

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

Individual Dynamic Risk Analysis (iDRA): A systematic review and network model development

Dynamic Risk Analysis (DRA) is a continuous, adaptive process of risk evaluation that can play a fundamental role in the prevention, control and mitigation of new or changing risks in real time. In order to better understand DRA, a systematic review was conducted, followed by thematic analysis and the development of a network model. This model depicts weighted and directional connections to reveal the significance of information and decision making in managing dynamic risk. The research also reveals that people follow rules to a point but will then adapt to meet the challenge of unexpected circumstances. The influence of the environment is also evident, as it cannot only create unique risks but exacerbate existing ones. Throughout the literature there is some debate regarding the use of qualitative and quantitative risk assessment methods in managing dynamic risks. However, when allied with DRA, greater resilience may be added to safety management systems. Considering the factors identified in this research offers a new approach to the problem of managing new or changing risks. What this now means in practical terms is that there is potential to develop a syllabus for DRA training

Depression anxiety stress scale: is it valid for children and adolescents?

The Depression Anxiety Stress Scale (Lovibond & Lovibond, 1995) is used to assess the severity of symptoms in child and adolescent samples although its validity in these populations has not been demonstrated. The authors assessed the latent structure of the 21-item version of the scale in samples of 425 and 285 children and adolescents on two occasions, one year apart. On each occasion, parallel analyses suggested that only one component should be extracted, indicating that the test does not differentiate depression, anxiety, and stress in children and adolescents. The results provide additional evidence that adult models of depression do not describe the experience of depression in children and adolescents

A sub-centennial-scale optically stimulated luminescence chronostratigraphy and late Holocene flood history from a temperate river confluence

River confluences can be metastable and contain valuable geological records of catchment response to decadal- to millennial-scale environmental change. However, in alluvial reaches, flood stratigraphies are particularly hard to date using 14C. In this paper, we use a novel combination of optically stimulated luminescence and multiproxy sedimentological analyses to provide a flood record for the confluence of the Rivers Severn and Teme (United Kingdom) over the past two millennia, which we compare with independent European climate records. The results show that by ca. 2000 yr B.P., the Severn-Teme confluence had stabilized and overbank alluviation had commenced. Initially, this occurred from moderately high flood magnitudes between ca. 2000 and 1800 yr B.P. (50 BCE–150 CE), but was followed from 1800 to 1600 yr B.P. (150–350 CE) by fine alluvial deposition and decreased flood intensity. From 1600 to 1400 yr B.P. (350–550 CE), the accumulation rate increased, with evidence of large flood events associated with the climatic deterioration of the Dark Age Cold Period. Following a period of reduced flood activity after ca. 1400 yr B.P. (ca. 550 CE), larger flood events and increase in accumulation rate once again became more prevalent from ca. 850 yr B.P. (ca. 1100 CE), coincident with the start of the Medieval Climate Anomaly, a period associated with warmer, wetter conditions and increased land-use intensity. This state persisted until ca. 450 yr B.P. (ca. 1500 CE), after which increased flood magnitudes can be associated with climatic variations during the Little Ice Age. We demonstrate that from the combination of high-resolution dating techniques and multiple analytical parameters, distinctive phases of relative flood magnitude versus flood duration can be determined to a detailed chronological precision beyond that possible from 14C dating. This permits the identification of the regional factors behind floodplain sedimentation, which we correlate with the intensification of land-use and climatic drivers over the last two millennia

Building with uncertain ethics

A reflective focus on ethics can help built environment practitioners to clarify objectives and priorities, guide decision-making, and help to evaluate outcomes during confusion of personal opinion, and hidden agendas. Virtue ethics, associated particularly with Aristotle, focuses on the character of the agent rather than on the nature or consequences of a particular action. The teleological ethics is an approach that judges the morality of an action based on its outcomes or consequences. Several professional literatures on ethics in architecture address interpersonal ethics, architects' responsibilities to each other, their clients, building users, and the wider community. It covers issues as employment, contracts, a duty of care to safeguard and promote physical and psychological well-being, and to support cultures by appropriate designs, and points variously to deontological ethics and virtue ethics. Pragmatism and responsive cohesion both emphasize specific circumstances and contingencies.Graham Farmer and Antony Radfor