CD4\u3csup\u3e+\u3c/sup\u3e T cells in the lungs of acute sarcoidosis patients recognize an Aspergillus nidulans epitope

Löfgren’s syndrome (LS) is an acute form of sarcoidosis characterized by a genetic association with HLA-DRB1*03 (HLA-DR3) and an accumulation of CD4+ T cells of unknown specificity in the bronchoalveolar lavage (BAL). Here, we screened related LS-specific TCRs for antigen specificity and identified a peptide derived from NAD-dependent histone deacetylase hst4 (NDPD) of Aspergillus nidulans that stimulated these CD4+ T cells in an HLA-DR3–restricted manner. Using ELISPOT analysis, a greater number of IFN-γ– and IL-2–secreting T cells in the BAL of DR3+ LS subjects compared with DR3+ control subjects was observed in response to the NDPD peptide. Finally, increased IgG antibody responses to A. nidulans NDPD were detected in the serum of DR3+ LS subjects. Thus, our findings identify a ligand for CD4+ T cells derived from the lungs of LS patients and suggest a role of A. nidulans in the etiology of LS

Identifying change processes in group-based health behaviour-change interventions: development of the mechanisms of action in group-based interventions (MAGI) framework

Group-based interventions are widely used to promote health-related behaviour change. While processes operating in groups have been extensively described, it remains unclear how behaviour change is generated in group-based health-related behaviour-change interventions. Understanding how such interventions facilitate change is important to guide intervention design and process evaluations. We employed a mixed-methods approach to identify, map and define change processes operating in group-based behaviour-change interventions. We reviewed multidisciplinary literature on group dynamics, taxonomies of change technique categories, and measures of group processes. Using weight-loss groups as an exemplar, we also reviewed qualitative studies of participants' experiences and coded transcripts of 38 group sessions from three weight-loss interventions. Finally, we consulted group participants, facilitators and researchers about our developing synthesis of findings. The resulting 'Mechanisms of Action in Group-based Interventions' (MAGI) framework comprises six overarching categories: (1) group intervention design features, (2) facilitation techniques, (3) group dynamic and development processes, (4) inter-personal change processes, (5) selective intra-personal change processes operating in groups, and (6) contextual influences. The framework provides theoretical explanations of how change occurs in group-based behaviour-change interventions and can be applied to optimise their design and delivery, and to guide evaluation, facilitator training and further research

Macrophages directly contribute collagen to scar formation during zebrafish heart regeneration and mouse heart repair

Canonical roles for macrophages in mediating the fibrotic response after a heart attack include extracellular matrix turnover and activation of cardiac fibroblasts to initiate collagen deposition. Here we reveal that macrophages directly contribute collagen to the forming post-injury scar. Unbiased transcriptomics shows an upregulation of collagens in both zebrafish and mouse macrophages following heart injury. Adoptive transfer of macrophages, from either collagen-tagged zebrafish or adult mouse GFPtpz-collagen donors, enhances scar formation via cell autonomous production of collagen. In zebrafish, the majority of tagged collagen localises proximal to the injury, within the overlying epicardial region, suggesting a possible distinction between macrophage-deposited collagen and that predominantly laid-down by myofibroblasts. Macrophage-specific targeting of col4a3bpa and cognate col4a1 in zebrafish significantly reduces scarring in cryoinjured hosts. Our findings contrast with the current model of scarring, whereby collagen deposition is exclusively attributed to myofibroblasts, and implicate macrophages as direct contributors to fibrosis during heart repair

A community-based physical activity intervention to prevent mobility-related disability for retired older people (REtirement in ACTion (REACT)): Study protocol for a randomised controlled trial

© 2018 The Author(s). Background: The REtirement in ACTion (REACT) study is a multi-centre, pragmatic, two-arm, parallel-group randomised controlled trial (RCT) with an internal pilot phase. It aims to test the effectiveness and cost-effectiveness of a community, group-based physical activity intervention for reducing, or reversing, the progression of functional limitations in older people who are at high risk of mobility-related disability. Methods/design: A sample of 768 sedentary, community-dwelling, older people aged 65 years and over with functional limitations, but who are still ambulatory (scores between 4 and 9 out of 12 in the Short Physical Performance Battery test (SPPB)) will be randomised to receive either the REACT intervention, delivered over a period of 12 months by trained facilitators, or a minimal control intervention. The REACT study incorporates comprehensive process and economic evaluation and a nested sub-study which will test the hypothesis that the REACT intervention will slow the rate of brain atrophy and of decline in cognitive function assessed using magnetic resonance imaging (MRI). Outcome data will be collected at baseline, 6, 12 and 24 months for the main study, with MRI sub-study data collected at baseline, 6 and 12 months. The primary outcome analysis (SPPB score at 24 months) will be undertaken blinded to group allocation. Primary comparative analyses will be on an intention-to-treat (ITT) basis with due emphasis placed on confidence intervals. Discussion: REACT represents the first large-scale, pragmatic, community-based trial in the UK to target the non-disabled but high-risk segment of the older population with an intervention to reduce mobility-related disability. A programme that can successfully engage this population in sufficient activity to improve strength, aerobic capacity, coordination and balance would have a major impact on sustaining health and independence. REACT is also the first study of its kind to conduct a full economic and comprehensive process evaluation alongside the RCT. If effective and cost-effective, the REACT intervention has strong potential to be implemented widely in the UK and elsewhere

The community-based prevention of diabetes (ComPoD) study: A randomised, waiting list controlled trial of a voluntary sector-led diabetes prevention programme

© 2019 The Author(s). Objective: This two-site randomised trial compared the effectiveness of a voluntary sector-led, community-based diabetes prevention programme to a waiting-list control group at 6 months, and included an observational follow-up of the intervention arm to 12 months. Methods: Adults aged 18-75 years at increased risk of developing type 2 diabetes due to elevated blood glucose and being overweight were recruited from primary care practices at two UK sites, with data collected in participants' homes or community venues. Participants were randomised using an online central allocation service. The intervention, comprising the prototype "Living Well, Taking Control" (LWTC) programme, involved four weekly two-hour group sessions held in local community venues to promote changes in diet and physical activity, plus planned follow-up contacts at two, three, six, nine and 12 months alongside 5 hours of additional activities/classes. Waiting list controls received usual care for 6 months before accessing the programme. The primary outcome was weight loss at 6 months. Secondary outcomes included glycated haemoglobin (HbA1c), blood pressure, physical activity, diet, health status and well-being. Only researchers conducting analyses were blinded. Results: The target sample of 314 participants (157 each arm) was largely representative of local populations, including 44% men, 26% from ethnic minorities and 33% living in deprived areas. Primary outcome data were available for 285 (91%) participants (141 intervention, 144 control). Between baseline and 6 months, intervention participants on average lost more weight than controls (- 1.7 kg, 95% CI - 2.59 to - 0.85). Higher attendance was associated with greater weight loss (- 3.0 kg, 95% CI - 4.5 to - 1.5). The prototype LWTC programme more than doubled the proportion of participants losing > 5% of their body weight (21% intervention vs. 8% control, OR 2.83, 95% CI 1.36 to 5.90) and improved self-reported dietary behaviour and health status. There were no impacts on HbA1c, blood pressure, physical activity and well-being at 6 months and, amongst intervention participants, few further changes from six to 12-months (e.g. average weight re-gain 0.36 kg, 95% CI - 0.20 to 0.91). There were no serious adverse events but four exercise-related injuries were reported in the intervention arm. Conclusions: This voluntary sector-led diabetes prevention programme reached a broad spectrum of the population and had modest effects on weight-related outcomes, but limited impacts on other diabetes risk factors. Trial registration: Trial registration number: ISRCTN70221670, 5 September 2014 Funder (National Institute for Health Research School for Public Health Research) project reference number: SPHR-EXE-PES-COM

Cross-National Differences in Victimization : Disentangling the Impact of Composition and Context

Varying rates of criminal victimization across countries are assumed to be the outcome of countrylevel structural constraints that determine the supply ofmotivated o¡enders, as well as the differential composition within countries of suitable targets and capable guardianship. However, previous empirical tests of these ‘compositional’ and ‘contextual’ explanations of cross-national di¡erences have been performed upon macro-level crime data due to the unavailability of comparable individual-level data across countries. This limitation has had two important consequences for cross-national crime research. First, micro-/meso-level mechanisms underlying cross-national differences cannot be truly inferred from macro-level data. Secondly, the e¡ects of contextual measures (e.g. income inequality) on crime are uncontrolled for compositional heterogeneity. In this paper, these limitations are overcome by analysing individual-level victimization data across 18 countries from the International CrimeVictims Survey. Results from multi-level analyses on theft and violent victimization indicate that the national level of income inequality is positively related to risk, independent of compositional (i.e. micro- and meso-level) di¡erences. Furthermore, crossnational variation in victimization rates is not only shaped by di¡erences in national context, but also by varying composition. More speci¢cally, countries had higher crime rates the more they consisted of urban residents and regions with lowaverage social cohesion.

Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomised trial of 45 000 donors

Background: Limits on the frequency of whole blood donation exist primarily to safeguard donor health. However, there is substantial variation across blood services in the maximum frequency of donations allowed. We compared standard practice in the UK with shorter inter-donation intervals used in other countries. Methods: In this parallel group, pragmatic, randomised trial, we recruited whole blood donors aged 18 years or older from 25 centres across England, UK. By use of a computer-based algorithm, men were randomly assigned (1:1:1) to 12-week (standard) versus 10-week versus 8-week inter-donation intervals, and women were randomly assigned (1:1:1) to 16-week (standard) versus 14-week versus 12-week intervals. Participants were not masked to their allocated intervention group. The primary outcome was the number of donations over 2 years. Secondary outcomes related to safety were quality of life, symptoms potentially related to donation, physical activity, cognitive function, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin. This trial is registered with ISRCTN, number ISRCTN24760606, and is ongoing but no longer recruiting participants. Findings: 45 263 whole blood donors (22 466 men, 22 797 women) were recruited between June 11, 2012, and June 15, 2014. Data were analysed for 45 042 (99·5%) participants. Men were randomly assigned to the 12-week (n=7452) versus 10-week (n=7449) versus 8-week (n=7456) groups; and women to the 16-week (n=7550) versus 14-week (n=7567) versus 12-week (n=7568) groups. In men, compared with the 12-week group, the mean amount of blood collected per donor over 2 years increased by 1·69 units (95% CI 1·59–1·80; approximately 795 mL) in the 8-week group and by 0·79 units (0·69–0·88; approximately 370 mL) in the 10-week group (p<0·0001 for both). In women, compared with the 16-week group, it increased by 0·84 units (95% CI 0·76–0·91; approximately 395 mL) in the 12-week group and by 0·46 units (0·39–0·53; approximately 215 mL) in the 14-week group (p<0·0001 for both). No significant differences were observed in quality of life, physical activity, or cognitive function across randomised groups. However, more frequent donation resulted in more donation-related symptoms (eg, tiredness, breathlessness, feeling faint, dizziness, and restless legs, especially among men [for all listed symptoms]), lower mean haemoglobin and ferritin concentrations, and more deferrals for low haemoglobin (p<0·0001 for each) than those observed in the standard frequency groups. Interpretation: Over 2 years, more frequent donation than is standard practice in the UK collected substantially more blood without having a major effect on donors' quality of life, physical activity, or cognitive function, but resulted in more donation-related symptoms, deferrals, and iron deficiency. Funding: NHS Blood and Transplant, National Institute for Health Research, UK Medical Research Council, and British Heart Foundation

Development of a peer support intervention to encourage dietary behaviour change towards a Mediterranean diet in adults at high cardiovascular risk.

BACKGROUND: Mediterranean diet (MD) interventions are demonstrated to significantly reduce cardiovascular disease (CVD) risk but are typically resource intensive and delivered by health professionals. There is considerable interest to develop interventions that target sustained dietary behaviour change and that are feasible to scale-up for wider public health benefit. The aim of this paper is to describe the process used to develop a peer support intervention to encourage dietary behaviour change towards a MD in non-Mediterranean adults at high CVD risk. METHODS: The Medical Research Council (MRC) and Behaviour Change Wheel (BCW) frameworks and the COM-B (Capability, Opportunity, Motivation, Behaviour) theoretical model were used to guide the intervention development process. We used a combination of evidence synthesis and qualitative research with the target population, health professionals, and community health personnel to develop the intervention over three main stages: (1) we identified the evidence base and selected dietary behaviours that needed to change, (2) we developed a theoretical basis for how the intervention might encourage behaviour change towards a MD and selected intervention functions that could drive the desired MD behaviour change, and (3) we defined the intervention content and modelled outcomes. RESULTS: A theory-based, culturally tailored, peer support intervention was developed to specifically target behaviour change towards a MD in the target population. The intervention was a group-based program delivered by trained peer volunteers over 12-months, and incorporated strategies to enhance social support, self-efficacy, problem-solving, knowledge, and attitudes to address identified barriers to adopting a MD from the COM-B analysis. CONCLUSIONS: The MRC and BCW frameworks provided a systematic and complementary process for development of a theory-based peer support intervention to encourage dietary behaviour change towards a MD in non-Mediterranean adults at high CVD risk. The next step is to evaluate feasibility, acceptability, and diet behaviour change outcomes in response to the peer support intervention (change towards a MD and nutrient biomarkers) using a randomized controlled trial design

Personalised Exercise-Rehabilitation FOR people with Multiple long-term conditions (PERFORM): protocol for a randomised feasibility trial

Introduction: Personalised Exercise-Rehabilitation FOR people with Multiple long-term conditions (PERFORM) is a research programme that seeks to develop and evaluate a comprehensive exercise-based rehabilitation intervention designed for people with multimorbidity, the presence of multiple long-term conditions (MLTCs). This paper describes the protocol for a randomised trial to assess the feasibility and acceptability of the PERFORM intervention, study design and processes. Methods and analysis: A multicentre, parallel two-group randomised trial with individual 2:1 allocation to the PERFORM exercise-based intervention plus usual care (intervention) or usual care alone (control). The primary outcome of this feasibility trial will be to assess whether prespecified progression criteria (recruitment, retention, intervention adherence) are met to progress to the full randomised trial. The trial will be conducted across three UK sites and 60 people with MLTCs, defined as two or more LTCs, with at least one having evidence of the beneficial effect of exercise. The PERFORM intervention comprises an 8-week (twice a week for 6 weeks and once a week for 2 weeks) supervised rehabilitation programme of personalised exercise training and self-management education delivered by trained healthcare professionals followed by two maintenance sessions. Trial participants will be recruited over a 4.5-month period, and outcomes assessed at baseline (prerandomisation) and 3 months postrandomisation and include health-related quality of life, psychological well-being, symptom burden, frailty, exercise capacity, physical activity, sleep, cognition and serious adverse events. A mixed-methods process evaluation will assess acceptability, feasibility and fidelity of intervention delivery and feasibility of trial processes. An economic evaluation will assess the feasibility of data collection and estimate the costs of the PERFORM intervention. Ethics and dissemination: The trial has been given favourable opinion by the West Midlands, Edgbaston Research Ethics Service (Ref: 23/WM/0057). Participants will be asked to give full, written consent to take part by trained researchers. Findings will be disseminated via journals, presentations and targeted communications to clinicians, commissioners, service users and patients and the public. Trial registration number: ISRCTN68786622. Protocol version 2.0 (16 May 2023)

Processed pseudogenes acquired somatically during cancer development.

Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5' truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context