Genetic determinants of risk in pulmonary arterial hypertension:international genome-wide association studies and meta-analysis

Background: Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods: We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. Findings: A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13 × 10 –15 ) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65 × 10 –20 ) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69 × 10 –12 ; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to &gt;13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity. Interpretation: This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. Funding: UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR. </p

The individual and situational factors predicting unethical behaviour in the workplace : a direct and conceptual replication of Jones & Kavanagh (1996)

Intentions to act unethically in the workplace are purported to be driven by a number of situational and individual factors. Across two seminal vignette experiments, Jones and Kavanagh reported inconsistent effect sizes for manager and peer influence and locus of control, consistent significant effects for work quality and Machiavellianism, and consistent non-significant effects for gender. Using an innovative multi-site collaboration, the current Registered Report represents a direct replication of these experiments (N = 2218), and adds a longitudinal conceptual replication capturing self-reported unethical work behaviour (N = 1747). Both replications found a consistent small effect of having a more external locus of control and male identity, and a consistent moderate effect of machiavellianism, for increasing unethical intentions and behaviour. The situational factors, whilst consistent in direction with that of the original study, varied more substantively in effect size. Our results highlight the value of multi-site collaborations and different replication types in developing conceptual, methodological, measurement and theoretical clarity to ensure future works can progress more rapidly to minimize the negative impacts of unethical workplace behaviour and improve individual’s working lives. All materials, code and data for this project can be found here: osf.io/d3arx

Supporting after stroke : significant others’ understanding of and perceived role in self-management

Background and aims Self-management support is important in persons adaptation to a new life after stroke. Significant others often provide a meaningful part of that support. The impact on family members caring for a person after stroke has been extensively studied, however there is a lack of research into significant others’ understanding and experiences of self-management after stroke. Therefore, this study aimed to explore how significant others understand self-management and how they perceive their role in supporting self-management in post-stroke rehabilitation at home. Method Qualitative, semi-structured interviews were conducted with 28 significant others of persons in rehabilitation after stroke. Data were analysed using inductive content analysis. Results The preliminary results showed that significant others commonly relate self- management to activities of daily living (ADL) and rehabilitation training. Participants saw their role as important not only to assist the stroke survivor practically, but also to provide emotional support and companionship. Conclusion There is an emerging discrepancy between descriptions in the literature and significant others’ perceptions of and actions to support self-management. If significant others obtained a clearer understanding of the concept of self- management, their support could be more efficient in strengthening self-efficacy and self-management abilities in stroke survivors. How will this research improve life after stroke for stroke survivors? By highlighting the characteristics of significant others’ self-management support and their understanding of the concept, interventions to enhance self-managementsupport for stroke survivors can be improved in the future

Supporting after stroke : significant others’ understanding of and perceived role in self-management

Background and aims Self-management support is important in persons adaptation to a new life after stroke. Significant others often provide a meaningful part of that support. The impact on family members caring for a person after stroke has been extensively studied, however there is a lack of research into significant others’ understanding and experiences of self-management after stroke. Therefore, this study aimed to explore how significant others understand self-management and how they perceive their role in supporting self-management in post-stroke rehabilitation at home. Method Qualitative, semi-structured interviews were conducted with 28 significant others of persons in rehabilitation after stroke. Data were analysed using inductive content analysis. Results The preliminary results showed that significant others commonly relate self- management to activities of daily living (ADL) and rehabilitation training. Participants saw their role as important not only to assist the stroke survivor practically, but also to provide emotional support and companionship. Conclusion There is an emerging discrepancy between descriptions in the literature and significant others’ perceptions of and actions to support self-management. If significant others obtained a clearer understanding of the concept of self- management, their support could be more efficient in strengthening self-efficacy and self-management abilities in stroke survivors. How will this research improve life after stroke for stroke survivors? By highlighting the characteristics of significant others’ self-management support and their understanding of the concept, interventions to enhance self-managementsupport for stroke survivors can be improved in the future

Supporting after stroke [Elektronisk resurs] : significant others’ understanding of and perceived role in self-management

Background and aims Self-management support is important in persons adaptation to a new life after stroke. Significant others often provide a meaningful part of that support. The impact on family members caring for a person after stroke has been extensively studied, however there is a lack of research into significant others’ understanding and experiences of self-management after stroke. Therefore, this study aimed to explore how significant others understand self-management and how they perceive their role in supporting self-management in post-stroke rehabilitation at home.Method Qualitative, semi-structured interviews were conducted with 28 significant others of persons in rehabilitation after stroke. Data were analysed using inductive content analysis.Results The preliminary results showed that significant others commonly relate self- management to activities of daily living (ADL) and rehabilitation training. Participants saw their role as important not only to assist the stroke survivor practically, but also to provide emotional support and companionship.Conclusion There is an emerging discrepancy between descriptions in the literature and significant others’ perceptions of and actions to support self-management. If significant others obtained a clearer understanding of the concept of self- management, their support could be more efficient in strengthening self-efficacy and self-management abilities in stroke survivors.How will this research improve life after stroke for stroke survivors? By highlighting the characteristics of significant others’ self-management support and their understanding of the concept, interventions to enhance self-managementsupport for stroke survivors can be improved in the future.</p

Instruments for assessing social support in social networks and in the self-management and rehabilitation process of persons poststroke : a scoping review protocol

INTRODUCTION: As care and rehabilitation poststroke are increasingly moving into persons' home environment, the importance of support from social networks in self-management and rehabilitation has emerged as an important topic for research and practice. While there are instruments used to assess social support and collective efficacy, a clearer scope of the availability and quality of these instruments is needed. This clarification will enable the development of interventions integrating social network perspectives in poststroke rehabilitation. METHODS AND ANALYSIS: To assess the availability and quality of instruments assessing social support and collective efficacy, a scoping review will be conducted and reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses Extension for Scoping Reviews guidelines (PRISMA-ScR). Literature searches conducted between 14 November 2024 and 15 November 2024 in the CINAHL and PubMed/Medline databases resulted in 4631 articles potentially eligible. After removing duplicates, 4121 articles' titles and abstracts were initially screened. Full-text screening, searches of reference lists and data extraction started in June 2025. Starting August 2025, two reviewers will assess the full texts against the inclusion criteria in Covidence using a coding template. Identified instruments will be appraised following the COSMIN (Consensus-based Standards for the selection of health Measurement INstruments guidelines) and analysed using a narrative descriptive method. Results will be reported in February 2026 according to PRISMA-ScR guidelines. ETHICS AND DISSEMINATION: Ethical approval is not required for this scoping review, as it does not involve primary data. However, this review follows established ethical guidelines and best practices, and included studies will be reviewed to ensure that they received ethical approval and included informed consent. Results from the review will be disseminated through an article in a scientific journal, at relevant conferences and surmised to stroke organisations. A policy brief will be developed for health and social care professionals and policy makers

Neural substrates of similarity and rule-based strategies in judgment

Making accurate judgments is a core human competence and a prerequisite for success in many areas of life. Plenty of evidence exists that people can employ different judgment strategies to solve identical judgment problems. In categorization, it has been demonstrated that similarity-based and rule-based strategies are associated with activity in different brain regions. Building on this research, the present work tests whether solving two identical judgment problems recruits different neural substrates depending on people's judgment strategies. Combining cognitive modeling of judgment strategies at the behavioral level with functional magnetic resonance imaging (fMRI), we compare brain activity when using two archetypal judgment strategies: a similarity-based exemplar strategy and a rule-based heuristic strategy. Using an exemplar-based strategy should recruit areas involved in long-term memory processes to a larger extent than a heuristic strategy. In contrast, using a heuristic strategy should recruit areas involved in the application of rules to a larger extent than an exemplar-based strategy. Largely consistent with our hypotheses, we found that using an exemplar-based strategy led to relatively higher BOLD activity in the anterior prefrontal and inferior parietal cortex, presumably related to retrieval and selective attention processes. In contrast, using a heuristic strategy led to relatively higher activity in areas in the dorsolateral prefrontal and the temporal-parietal cortex associated with cognitive control and information integration. Thus, even when people solve identical judgment problems, different neural substrates can be recruited depending on the judgment strategy involved