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Haplotype-resolved genomes provide insights into the origins and functional significance of genome diversity in bivalves
Get PDFBivalves are famed for exhibiting vast genetic diversity of poorly understood origins and functional significance. Through comparative genomics, we demonstrate that high genetic diversity in these invertebrates is not directly linked to genome size. Using oysters as a representative clade, we show that despite genome size reduction during evolution, these bivalves maintain remarkable genetic variability. By constructing a haplotype-resolved genome for Crassostrea sikamea, we identify widespread haplotype divergent sequences (HDSs), representing genomic regions unique to each haplotype. We show that HDSs are driven by transposable elements, playing a key role in creating and maintaining genetic diversity during oyster evolution. Comparisons of haplotype-resolved genomes across four bivalve orders uncover diverse HDS origins, highlighting a role in genetic innovation and expression regulation across broad timescales. Further analyses show that, in oysters, haplotype polymorphisms drive gene expression variation, which is likely to promote phenotypic plasticity and adaptation. These findings advance our understanding of the relationships among genome structure, diversity, and adaptability in a highly successful invertebrate group.</p
Investigating the cultural sensitivity of athletic talent:Comparisons between the U.S.A. and European sporting environments
Get PDFIt has been suggested that models of athletic talent are not universally applicable and that attempts to uncritically replicate successful ideas from one country to another may be problematic. From a holistic ecological perspective, this may be a result of differences in macro-level variables. In short, athletic talent, or at least some aspects of its expression, may be culturally sensitive. This study explored whether models of athletic talent should be more critically interpreted and reviewed before they are uncritically imported across cultural contexts. In a synthesis of contemporary sport-related comparisons between the U.S.A. and Europe, this study identified seven distinctive macro-level themes which appeared to exhibit an interactive relationship, clearly indicating that sporting cultures between countries may not be equal. These findings suggest that athletes and coaches of different countries (and associated cultural backgrounds) are exposed to their own specific variety of multidimensional cultural influences. Logically, therefore, when operating within talented populations, considerations should be given to cultural context, similar to what already occurs within sport-specific, gender-specific and age-specific approaches. Reinvestigating existing knowledge through culturally specific studies is essential to ensure the most accurate guidance for coaches, athletes and systems.</p
Cost-Effectiveness of a2Agonists for Intravenous Sedation in Patients With Critical Illness
Get PDFIMPORTANCE Propofol and the α2 agonists dexmedetomidine and clonidine are used for sedationin patients with critical illness receiving mechanical ventilation. Evidence about the costeffectiveness of intravenous (IV) sedation with these medications is lacking.OBJECTIVE To investigate the cost-effectiveness of dexmedetomidine-, clonidine-, and propofolbased IV sedation in patients with critical illness receiving mechanical ventilation.DESIGN, SETTING, AND PARTICIPANTS This economic evaluation used within-trial cost-utilityanalysis with a 6-month time horizon comparing dexmedetomidine-, clonidine-, and propofol-basedIV sedation from a UK National Health Service and Personal Social Services perspective, withindividual-level data collected from the Alpha 2 Agonists for Sedation to Produce Better OutcomesFrom Critical Illness (A2B) trial. Adults with critical illness receiving mechanical ventilation, with ananticipated total requirement for mechanical ventilation of at least 2 days, from 41 intensive careunits in the UK were included. Recruitment ran from December 2018 through October 2023; the lastdate of follow-up was December 10, 2023.INTERVENTIONS Dexmedetomidine, clonidine, or propofol IV sedation. Patients receiving α2agonists were permitted to receive supplemental propofol to achieve the target sedation score ifrequired.MAIN OUTCOMES AND MEASURES Incremental costs and quality-adjusted life years (QALYs)gained between dexmedetomidine-based vs propofol-based and clonidine-based vs propofol-basedIV sedation were assessed. Mean net monetary benefits with each medication were assessed.RESULTS Among 1404 adults with critical illness receiving mechanical ventilation (mean [SD] age,59.2 [14.9] years; 901 male [64.2%]), the mean (SD) Acute Physiology and Chronic Health Evaluation(APACHE) II score was 20.3 (8.2). The incremental cost for dexmedetomidine vs propofol was 5000 to 1328 (−4459). Fordexmedetomidine vs propofol, there were 0.0008 QALYs (95% CI, −0.0198 to 0.0214 QALYs)gained, and for clonidine vs propofol, there were −0.0019 QALYs (95% CI, −0.0221 to 0.0181 QALYs)gained. Mean net monetary benefits for dexmedetomidine, clonidine, and propofol were −58 063 to −50 882 (95% CI, −46 762), and −56 230 to −16 250.CONCLUSIONS AND RELEVANCE In this study, dexmedetomidine-, clonidine-, and propofol-basedIV sedation in patients with critical illness receiving mechanical ventilation had similar costs andQALYs. These findings suggest that economic considerations should not affect which sedative thesepatients receiv
Improving outcomes for people who are homeless and have severe mental illness in Ethiopia, Ghana and Kenya:overview of the HOPE programme
Get PDFAIM: HOPE (National Institute for Health and Care Research Global Health Research Group on Homelessness and Mental Health in Africa) aims to develop and evaluate interventions that address the unmet needs of people who are homeless and have severe mental illness (SMI) living in three African countries in ways that are rights-based, contextually grounded, scalable and sustainable.METHODS: We will work in the capital city (Addis Ababa) in Ethiopia, a regional city (Tamale) in Ghana, and the capital city (Nairobi) and a rural county (Makueni) in Kenya to understand different approaches to intervention needed across varied settings.We will be guided by the MRC/NIHR framework on complex interventions and implementation frameworks and emphasise co-production. Formative work will include synthesis of global evidence (systematic review, including grey literature, and a Delphi consensus exercise) on interventions and approaches to homelessness and SMI. We will map contexts; conduct focused ethnography to understand lived experiences of homelessness and SMI; carry out a cross-sectional survey of people who are homeless (n = 750 Ghana/Ethiopia; n = 350 Kenya) to estimate prevalence of SMI and identify prioritised needs; and conduct in-depth interviews and focus group discussions with key stakeholders to understand experiences, challenges and opportunities for intervention. This global and local evidence will feed into Theory of Change (ToC) workshops with stakeholders to establish agreement about valued primary outcomes, map pathways to impact and inform selection and implementation of interventions. Intervention packages to address prioritised needs will be co-produced, piloted and optimised for feasibility and acceptability using participatory action research. We will use rights-based approaches and focus on community-based care to ensure sustainability. Realist approaches will be employed to analyse how contextual variation affects mechanisms and outcomes to inform methods for a subsequent evaluation of larger scale implementation. Extensive capacity-strengthening activities will focus on equipping early career researchers and peer researchers. People with lived experience of SMI and policymakers are an integral part of the research team. Community engagement is supported by working closely with multisectoral Community Advisory Groups.CONCLUSIONS: HOPE will develop evidence to support action to respond to the needs and preferences of people experiencing homelessness and SMI in diverse settings in Africa. We are creating a new partnership of researchers, policymakers, community members and people with lived experience of SMI and homelessness to enable African-led solutions. Key outputs will include contextually relevant practice and policy guidance that supports achievement of inclusive development.</p
Zero-Shot Speech-Based Depression and Anxiety Assessment with LLMs
Get PDFThe use of Large Language Models (LLMs) for psychological state assessment from speech has gained significant interest, particularly in analysing and predicting mental health. In this paper, we explore the potential of eight instruct-tuned LLMs (Llama-3.1-8B, Ministral, Gemma-2-9B, Phi-4, Mistral, DeepSeek-Qwen, QwQ-Preview and Llama-3.3-70B) in a zero-shot setting to predict Hospital Anxiety and Depression Scale (HADS) depression and anxiety scores from one-to-two minute spontaneous speech recordings from the PsyVoiD database. We evaluate how transcript quality affects LLM responses by comparing performance using ground-truth transcriptions versus transcripts generated by Whisper models of different sizes. Spearman correlation coefficients and statistical analysis demonstrate significant and notable potential of the LLMs to predict psychological states in a zero-shot setting
Machine learning to optimize use of natriuretic peptides in the diagnosis of acute heart failure
Get PDFAIMS: B-type natriuretic peptide (BNP) and mid-regional pro-atrial natriuretic peptide (MR-proANP) testing are guideline-recommended to aid in the diagnosis of acute heart failure. Nevertheless, the diagnostic performance of these biomarkers is uncertain.METHODS: We performed a systematic review and individual patient-level data meta-analysis to evaluate the diagnostic performance of BNP and MR-proANP. We subsequently developed and externally validated a decision-support tool called CoDE-HF that combines natriuretic peptide concentrations with clinical variables using machine learning to report the probability of acute heart failure.RESULTS: Fourteen studies from 12 countries provided individual patient-level data in 8,493 patients for BNP and 3,899 patients for MR-proANP, in whom, 48.3% (4,105/8,493) and 41.3% (1,611/3,899) had an adjudicated diagnosis of acute heart failure, respectively. The negative predictive value (NPV) of guideline-recommended thresholds for BNP (100 pg/mL) and MR-proANP (120 pmol/L) was 93.6% (95% confidence interval 88.4-96.6%) and 95.6% (92.2-97.6%), respectively, whilst the positive predictive value (PPV) was 68.8% (62.9-74.2%) and 64.8% (56.3-72.5%). Significant heterogeneity in the performance of these thresholds was observed across important subgroups. CoDE-HF was well calibrated with excellent discrimination in those without prior acute heart failure for both BNP and MR-proANP (area under the curve of 0.914 [0.906-0.921] and 0.929 [0.919-0.939], and Brier scores of 0.110 and 0.094, respectively). CoDE-HF with BNP and MR-proANP identified 30% and 48% as low-probability (NPV of 98.5% [97.1-99.3%] and 98.5% [97.7-99.0%]), and 30% and 28% as high-probability (PPV of 78.6% [70.4-85.0%] and 75.1% [70.9-78.9%]), respectively, and performed consistently across subgroups.CONCLUSION: The diagnostic performance of guideline-recommended BNP and MR-proANP thresholds for acute heart failure varied significantly across patient subgroups. A decision-support tool that combines natriuretic peptides and clinical variables was more accurate and supports more individualised diagnosis.STUDY REGISTRATION: PROSPERO number, CRD42019159407.</p
A qualitative evaluation of ETHICA-4P, a toolkit for ethical clinical decision-making and overcoming cultural barriers in psychotherapy in the United Kingdom
Get PDFEthnic minority service users in the UK face persistent disparities in access to and outcomes of mental health care. While the need for culturally adapted treatment is increasingly acknowledged, implementation remains limited. This study qualitatively evaluates ETHICA-4P—an Ethics Toolkit for Harnessing Integrity in Complex Arenas through Place, People, Principles, and Precedents—which aims to support ethical decision-making and address cultural barriers in psychotherapy. Findings suggest that ETHICA-4P is a useful tool for reflecting on ethical challenges in individual clinical work. Its impact could be enhanced by clarifying how it can be applied across multiple levels, including clinical supervision, training, team collaboration, and service design. The toolkit offers timely potential for helping practitioners and service managers deliver more culturally responsive care and aligns with efforts to reduce racialized health inequalities in the UK
People with long Covid and ME/CFS exhibit similarly impaired dexterity and bimanual coordination:A case-case-control study
Get PDFPurposeDexterity and bimanual coordination had not previously been compared between people with long COVID and people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Therefore, this study determined dexterity and bimanual coordination in people with long COVID (∼16-month illness duration; n = 21) and ME/CFS (∼16-year illness duration; n = 20), vs age-matched healthy controls (n = 20).MethodsDexterity and bimanual coordination was determined using the Purdue pegboard test.ResultsThe main findings of the present investigation were that people with ME/CFS and people with long COVID were generally comparable for Purdue pegboard tests (P > .556 and d < 0.36 for pairwise comparisons). It is worth noting however, that both these patient groups performed poorer in the Perdue pegboard test than healthy controls (P < .169 and d > 0.40 for pairwise comparisons).ConclusionsThese data suggest that both people with long COVID and people with ME/CFS have similarly impaired dexterity and bimanual coordination. Therefore, there is an urgent need for interventions to target dexterity and bimanual coordination in people with ME/CFS, and given the current pandemic, people with long COVID
Is emotion dysregulation in childhood a precursor to internalising problems in adolescence?
Get PDFInternalising problems such as anxiety and depression affect a sizeable proportion of adolescents and show a peak age of onset around the transition to adolescence. Emotion regulation issues have been associated with internalising problems; however, it is less clear whether emotion regulation issues in childhood are a causal precursor to internalising problems in adolescence. The present study uses a counterfactual analysis approach in a large-scale UK representative study to assess whether emotion regulation issues at age 7 appear to have a causal impact on internalising problems at age 11,14, and 17, when accounting for confounding factors, including pre-existing internalising problems. Results suggested a modest but significant effect of emotion dysregulation in childhood on adolescent mental health. These results suggest that childhood emotion regulation problems impact mental health later in development and potentially point to childhood emotion dysregulation as a promising intervention target for reducing adolescent mental health issues
Antibody drug conjugate targets are highly differentially expressed across the major types of ovarian cancer
Get PDFBackgroundAntibody-drug conjugates (ADCs) are emerging anti-cancer agents. The folate receptor alpha (FOLRα)-directed ADC mirvetuximab soravtansine recently demonstrated clinical activity in platinum-resistant ovarian cancer, with other ADCs currently in development. The relative expression of FOLRα and other ADC targets is largely unknown across ovarian cancer histotypes.MethodsExpression levels of the ADC targets FOLRα, TROP2 and B7-H4 were assessed by immunohistochemistry in patient cohorts using tumour tissue microarrays of the major ovarian cancer histotypes: high grade serous (HGSOC, n=331); endometrioid (EnOC, n=101) and clear cell ovarian carcinoma (CCOC, n=60). Degree of expression was quantified by membrane histoscore.ResultsWe observed differences in ADC target expression patterns across ovarian cancer histotypes. FOLRα expression was highest in HGSOC, with few EnOC or CCOC demonstrating positivity (HGSOC: 70.9% FOLRα histoscore ≥50 vs 21.1% and 29.3% in EnOC and CCOC). B7-H4 was expressed in HGSOC, EnOC and CCOC (99.7%, 89.8% and 80.7% with histoscore ≥50). CCOC were mostly TROP2 negative (89.3% with histoscore <50); a subset of HGSOC and EnOC expressed TROP2 (54.8% and 57.7% with histoscore ≥50, respectively). There was no significant association between ADC target expression and molecular subtypes of HGSOC (BRCA1/2-mutant, CCNE1-gained, other) or EnOC (TP53-mutant, CTNNB1-mutant, POLE-mutant, MMR deficient, no specific molecular profile). In CCOC, ARID1A/B mutation was associated with lower B7-H4 expression (P-adj=0.024).ConclusionEnOC and CCOC are usually FOLRα negative, while HGSOC, EnOC and CCOC frequently express B7-H4. TROP2 positivity is limited to HGSOC and EnOC. Careful consideration of histotype and ADC target expression levels is warranted when designing and analysing clinical studies of ADCs
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