Lymphoma driver mutations at the root of somatic evolution of nerve-damaging autoantibodies in myelin associated glycoprotein neuropathy.

Background: In autoimmune disease it is not understood how self-reactive B cells escape immune tolerance checkpoints to produce pathogenic autoantibodies.

Objective: In patients with demyelinating polyneuropathy caused by IgM autoantibodies against myelin associated glycoprotein (MAG) and the sulphated trisaccharide CD57, we aimed to test the hypothesis that B cells making the autoantibody escaped tolerance by acquiring lymphoma driver somatic mutations.

Methods: Deep single-cell RNA, DNA, flow cytometric and antibody specificity analysis of blood from three patients with MAG neuropathy.

Increasing pathogenic germline variant diagnosis rates in precision medicine: current best practices and future opportunities.

The accurate diagnosis of pathogenic variants is essential for effective clinical decision making within precision medicine programs. Despite significant advances in both the quality and quantity of molecular patient data, diagnostic rates remain suboptimal for many inherited diseases. As such, prioritisation and identification of pathogenic disease-causing variants remains a complex and rapidly evolving field.

Essential cell-intrinsic requirement for GMDS in T cell development.

Fucosylation, a type of glycosylation, is the attachment of a fucose to -glycans, -glycans and glycolipids, and is critical for the post-translational regulation of many essential pathways. Here we describe a mouse strain with an -ethyl--nitrosourea-induced point mutation in the gene encoding guanosine diphosphate (GDP)-mannose 4,6-dehydratase (GMDS), an enzyme involved in the generation of GDP-fucose, a substrate for fucosylation. mice displayed growth retardation and increased postnatal mortality.

Evaluating the effectiveness of the Drink Less smartphone app for reducing alcohol consumption compared with usual digital care: a comprehensive synopsis from a 6-month follow-up RCT.

Background: Digital interventions can be effective for reducing alcohol consumption. However, most digital interventions that have been evaluated are websites and there is little evidence on the effectiveness of smartphone apps, especially in a United Kingdom context. We developed an evidence- and theory-informed app, Drink Less, to help increasing-and-higher-risk drinkers (Alcohol Use Disorders Identification Test score ≥ 8) reduce their alcohol consumption.

TARGET-SL: precision essential gene prediction using driver prioritisation and synthetic lethality.

The ability to identify patient-specific vulnerabilities to guide cancer treatments is a vital area of research. However, predictive bioinformatics tools are difficult to translate into clinical applications due to a lack of in vitro and in vivo validation. While the increasing number of personalised driver prioritisation algorithms (PDPAs) report powerful patient-specific information, the results do not easily translate into treatment strategies.

Value-based decision-making in daily tobacco smokers following experimental manipulation of mood.

Induction of negative mood increases tobacco choice in dependent smokers; however, less is known about the mechanisms behind this. This study addressed this gap by applying a computational model of value-based decision making to tobacco and tobacco-unrelated choices following mood manipulation. Using a preregistered, within-subject design, 49 daily tobacco smokers (>10 daily cigarettes) watched two different videos which primed them to experience negative and positive mood (tobacco valuation and devaluation, respectively).

Putting Structural Variants Into Practice: The Role of Chromosomal Inversions in the Management of Marine Environments.

Major threats to marine species and ecosystems include overfishing, invasive species, pollution and climate change. The changing climate not only imposes direct threats through the impacts of severe marine heatwaves, cyclones and ocean acidification but also complicates fisheries and invasive species management by driving species range shifts. The dynamic nature of these threats means that the future of our oceans will depend on the ability of species to adapt.

Reevaluating the brain disease model of addiction.

The brain disease model of addiction has dominated public and scientific discourse on addiction (termed substance use disorder [SUD] in the DSM-5) over the past 3 decades. The model framed addiction as a chronic and relapsing brain disease caused by structural and functional brain alterations. The purpose of this model was purportedly dual, as both an aetiological theory and a tool to reduce stigma.

How did the 'whistle-to-whistle' ban affect gambling advertising on TV? A live football matching study.

Background: In 2019, the gambling industry introduced a voluntary partial advertising ban during live sports broadcasts in the United Kingdom known as the 'whistle-to-whistle' ban. This study explores the change in television advertising around live football games following the introduction of this ban.

Methods: Inverse Probability Weighted (IPW) matching models identified the change in the frequency of advertising associated with the implementation of restrictions in each section, and across the entire duration, of a live football game.

CD8 T cells mediate vaccination-induced lymphatic containment of latent infection following immunosuppression, while B cells are dispensable.

It is estimated that two billion people are latently infected with ( ), the causative agent of tuberculosis (TB). Latent infection (LTBI) can occur in multiple organs, including the lymphatics. The risk of LTBI reactivation increases in immunocompromised conditions, such as coinfection with human immunodeficiency virus (HIV), and during treatment of autoimmune diseases and organ transplantation.

A triad of somatic mutagenesis converges in self-reactive B cells to cause a virus-induced autoimmune disease.

The unexplained association between infection and autoimmune disease is strongest for hepatitis C virus-induced cryoglobulinemic vasculitis (HCV-cryovas). To analyze its origins, we traced the evolution of pathogenic rheumatoid factor (RF) autoantibodies in four HCV-cryovas patients by deep single-cell multi-omic analysis, revealing three sources of B cell somatic mutation converged to drive the accumulation of a large disease-causing clone. A method for quantifying low-affinity binding revealed recurring antibody variable domain combinations created by V(D)J recombination that bound self-immunoglobulin G (IgG) but not viral E2 antigen.

What is the impact of sports-related gambling advertising on gambling behaviour? A systematic review.

Background And Aims: Gambling is a public health issue and widespread advertising of gambling products may contribute to gambling harms. Sports-related gambling advertising includes advertising around sports games or for sports betting products. This review aimed to provide the most systematic and up-to-date review of the literature on the association between sports-related gambling advertising and gambling behaviour.

Modeling the Potential Health, Health Economic, and Health Inequality Impact of a Large-Scale Rollout of the Drink Less App in England.

Objectives: Alcohol places a significant burden on the National Health Service (NHS); yet, uptake of cost-effective approaches remains low. Digital interventions may overcome some barriers to delivery. The Drink Less app has evidence of being effective at supporting heavier drinkers to reduce their alcohol intake.

The effect of proportional pricing on alcohol purchasing in two online experiments.

Background And Aims: Buying smaller-sized alcohol products can reduce alcohol consumption, but larger products have better value for money, which presents a barrier to switching. We tested whether proportional pricing prompts drinkers to buy smaller alcohol products and reduce alcohol purchasing.

Design, Setting And Participants: This study was an online experiment set in the United Kingdom, using hypothetical shopping tasks in which participants purchased different-sized products presented under proportional pricing (i.

Harnessing genomic technologies for one health solutions in the tropics.

Background: The targeted application of cutting-edge high-throughput molecular data technologies provides an enormous opportunity to address key health, economic and environmental issues in the tropics within the One Health framework. The Earth's tropical regions are projected to contain > 50% of the world's population by 2050 coupled with 80% of its biodiversity however these regions are relatively less developed economically, with agricultural productivity substantially lower than temperate zones, a large percentage of its population having limited health care options and much of its biodiversity understudied and undescribed. The generation of high-throughput molecular data and bespoke bioinformatics capability to address these unique challenges offers an enormous opportunity for people living in the tropics.

Reversing the decline of threatened koala () populations in New South Wales: Using genomics to enhance conservation outcomes.

Genetic management is a critical component of threatened species conservation. Understanding spatial patterns of genetic diversity is essential for evaluating the resilience of fragmented populations to accelerating anthropogenic threats. Nowhere is this more relevant than on the Australian continent, which is experiencing an ongoing loss of biodiversity that exceeds any other developed nation.

A TNIP1-driven systemic autoimmune disorder with elevated IgG4.

Whole-exome sequencing of two unrelated kindreds with systemic autoimmune disease featuring antinuclear antibodies with IgG4 elevation uncovered an identical ultrarare heterozygous TNIP1 variant segregating with disease. Mice with the orthologous Q346P variant developed antinuclear autoantibodies, salivary gland inflammation, elevated IgG2c, spontaneous germinal centers and expansion of age-associated B cells, plasma cells and follicular and extrafollicular helper T cells. B cell phenotypes were cell-autonomous and rescued by ablation of Toll-like receptor 7 (TLR7) or MyD88.

Chromosomal inversions harbour excess mutational load in the coral, Acropora kenti, on the Great Barrier Reef.

The future survival of coral reefs in the Anthropocene depends on the capacity of corals to adapt as oceans warm and extreme weather events become more frequent. Targeted interventions designed to assist evolutionary processes in corals require a comprehensive understanding of the distribution and structure of standing variation, however, efforts to map genomic variation in corals have so far focussed almost exclusively on SNPs, overlooking structural variants that have been shown to drive adaptive processes in other taxa. Here, we show that the reef-building coral, Acropora kenti, harbours at least five large, highly polymorphic structural variants, all of which exhibit signatures of strongly suppressed recombination in heterokaryotypes, a feature commonly associated with chromosomal inversions.

Evaluating the Acceptability of the Drink Less App and the National Health Service Alcohol Advice Web Page: Qualitative Interview Process Evaluation.

Background: The extent to which interventions are perceived as acceptable to users impacts engagement and efficacy.

Objective: In this study, we evaluated the acceptability of (1) the smartphone app Drink Less (intervention) and (2) the National Health Service (NHS) alcohol advice web page (usual digital care and comparator) among adult drinkers in the United Kingdom participating in a randomized controlled trial evaluating the effectiveness of the Drink Less app.

Methods: A subsample of 26 increasing- and higher-risk drinkers (Alcohol Use Disorders Identification Test score≥8) assigned to the intervention group (Drink Less; n=14, 54%; female: n=10, 71%; age: 22-72 years; White: n=9, 64%) or usual digital care group (NHS alcohol advice web page; n=12, 46%; female: n=5, 42%; age: 23-68 years: White: n=9, 75%) took part in semistructured interviews.

Heterogeneity in choice models of addiction: the role of context.

Rationale: Theories of addiction guide scientific progress, funding priorities, and policy development and ultimately shape how people experiencing or recovering from addiction are perceived and treated. Choice theories of addiction are heterogenous, and different models have divergent implications. This breeds confusion among laypeople, scientists, practitioners, and policymakers and reduces the utility of robust findings that have the potential to reduce the global burden of addiction-associated harms.

Do engagement and behavioural mechanisms underpin the effectiveness of the Drink Less app?

This is a process evaluation of a large UK-based randomised controlled trial (RCT) (n = 5602) evaluating the effectiveness of recommending an alcohol reduction app, Drink Less, compared with usual digital care in reducing alcohol consumption in increasing and higher risk drinkers. The aim was to understand whether participants' engagement ('self-reported adherence') and behavioural characteristics were mechanisms of action underpinning the effectiveness of Drink Less. Self-reported adherence with both digital tools was over 70% (Drink Less: 78.

Value-based decision-making in regular alcohol consumers following experimental manipulation of alcohol value.

Background: Devaluation of alcohol leads to reductions in alcohol choice and consumption; however, the cognitive mechanisms that underpin this relationship are not well-understood. In this study we applied a computational model of value-based decision-making (VBDM) to decisions made about alcohol and alcohol-unrelated cues following experimental manipulation of alcohol value.

Method: Using a pre-registered within-subject design, thirty-six regular alcohol consumers (≥14 UK units per week) completed a two-alternative forced choice task where they chose between two alcohol images (in one block) or two soft drink images (in a different block) after watching videos that emphasised the positive (alcohol value), and separately, the negative (alcohol devalue) consequences of alcohol.

Effectiveness of a smartphone app (Drink Less) versus usual digital care for reducing alcohol consumption among increasing-and-higher-risk adult drinkers in the UK: a two-arm, parallel-group, double-blind, randomised controlled trial.

Background: Digital interventions, including apps and websites, can be effective for reducing alcohol consumption. However, many are not evidence- or theory-informed and have not been evaluated. We tested the effectiveness of the Drink Less app for reducing alcohol consumption compared with usual digital care in the UK.