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PubMed2026

Pilot Distractions and Interruptions in Airlines: Ranking of Sources by Analytic Hierarchy Process.

ObjectiveThis work establishes a methodological framework for sources of pilot distraction and interruptions in a structured model that can be used as a tool for cockpit design/procedure assessment.BackgroundPilots must complete complex tasks, and distractions can impair performance and lead to errors that can cause aircraft accidents. Although various cockpit distractors are examined individually, there is no integrated approach.MethodDistraction and interruption sources were identified through a literature review and confirmed/extended by interviews with airline pilots. Associated weights were determined through pairwise comparisons, yielding a hierarchical model using the Analytic Hierarchy Process.Results26 sources of pilot distraction and interruptions were quantified and categorized into four categories: communication, head-down time, responding to abnormal conditions & unexpected situations, and searching for traffic.ConclusionA taxonomic structure for assessment is achieved with the top 5 sources identified as communications, technical interruptions, experience in type, environmental factors, operational irregularities, and airspace high terrain, accounting for 63.07%.ApplicationThe structured system is a flexible assessment scale that provides a taxonomic framework for airline risk management, supports future research, and cockpit design efforts.

Humans↗

PubMed2026

AI-enabled viral genomics: from virus discovery to host prediction and emerging variant forecasting.

The rapid expansion of metagenomic sequencing has generated vast repositories of viral sequence data that far outpace our capacity to interpret them using conventional approaches. Highly divergent sequences, sparse functional annotation, and taxonomically uneven sampling present fundamental challenges for reference-dependent methods, which lose sensitivity precisely for novel and understudied viruses with high public health relevance. Artificial intelligence (AI) provides a new avenue to address these challenges by enabling predictive inference from viral genomes and proteins while reducing dependence on sequence similarity. In this Review, we discuss representative advances in AI for virus discovery, taxonomic classification and functional annotation, prediction of host range and zoonotic potential, and efforts toward forecasting emerging variants. These advances are transforming viral genomics from a largely descriptive discipline into one with increasing predictive capability. We also critically assess the major challenges that constrain current approaches, including the availability of high-quality and representative datasets, rigorous model evaluation, biological interpretability and responsible governance for increasingly capable AI models.

Artificial Intelligence↗

PubMed2026

Unravelling Ovarian Cancer: an analysis of the Influence of LRP1 and PAI1 Genetic Variations.

To assess the potential association between LRP1 (rs715948) and PAI1 (rs2227631, rs1799889) gene variation and ovarian cancer (OC) susceptibility. This study evaluated the genotypic and allelic distributions of LRP1 gene and PAI1 gene variants using Restriction Fragment Length Polymorphism (RFLP) analysis in 134 °C patients and 134 healthy controls. LRP1 (rs715948) showed a significant association with OC risk. The TC genotype was (OR = 3.7823, 95% CI: 2.1732-6.5825, p < 0.0001), and the CC genotype has (OR = 2.1613, 95% CI: 1.0054-4.6459, p = 0.0484). The C allele was significantly more frequent in cases (46%) than controls (32%) (OR = 1.7684, 95% CI: 1.2443-2.5133, p = 0.0015). For PAI1 (rs2227631), AG and GG genotypes showed no significant association (p = 0.3519 and p = 0.1165, respectively). PAI1 (rs1799889) AG genotype was (OR = 5.855, 95% CI: 2.4663-13.9027, p < 0.0001), while GG genotype showed no significance (p = 0.1025). The dominant model of LRP1, (TC + CC) and C alleles, were significantly more frequent in OC cases, indicating a potential risk factor. In contrast, the dominant models (AG + GG) and G alleles of PAI1 (rs2227631, rs1799889) showed no significance with OC susceptibility. Genetic variation in LRP1 (rs715948) significantly associated with increased OC risk, particularly the TC and CC genotypes and C allele. The C allele of this gene is key markers linked to higher OC susceptibility. Whereas in PAI1 (rs2227631, rs1799889), dominant models (AG + GG) show no significance, association suggesting a less prominent role in OC susceptibility. These findings highlight LRP1 as a potential genetic biomarker for OC risk assessment, while the role of PAI1 variants warrants further investigation in larger sample size.

Humans↗

PubMed2026

A systematic review and meta-analysis of OCT-based ophthalmic changes in amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by motor decline and respiratory failure. Optical coherence tomography (OCT), a non-invasive imaging technique, has been explored for detecting retinal structural changes that may reflect neurodegeneration in ALS. While some studies report thinning of retinal layers, findings remain inconsistent. Therefore, a meta-analysis is needed to clarify the extent of retinal involvement and the potential of OCT as a biomarker in ALS. METHODS: A systematic literature search was conducted across PubMed, EMBASE, and Cochrane databases for studies published between 2010 and May 2025. Study quality was assessed using the Newcastle-Ottawa Scale (NOS), and publication bias was evaluated through funnel plot asymmetry and Egger's test. Pooled effect sizes were calculated using random-effects models to account for between-study heterogeneity, and differences in OCT parameters between ALS patients and healthy controls were expressed as standardized mean differences (SMD) with 95% confidence intervals (CI). Statistical heterogeneity was quantified using the I2 statistic. RESULTS: A total of 17 studies were included in the present meta-analysis. The primary unadjusted global model demonstrated significant reduction of retinal nerve fibre layer (RNFL) thickness in ALS patients compared to controls (unadjusted SMD = -0.295, 95% CI: -0.522, -0.068). Upon applying a Design Effect variance inflation model to address fellow-eye non-independence, the pooled estimate remained robustly significant across a conservative range of intraclass correlations (SMD ranged from -0.256 to -0.249). Subgroup analyses revealed that RNFL thinning was particularly pronounced in spinal-onset ALS (SMD = -0.54, 95% CI: (-0.98, -0.10). When studies were stratified by the region of conduct, RNFL and macular thinning reached statistical significance only within the non-Asian subgroup, though the formal test for subgroup differences was not significant. CONCLUSION: This meta-analysis demonstrates significant bilateral RNFL thinning in ALS, with relative preservation of the Inner Nuclear Layer and Ganglion Cell Layer - Inner Plexiform Layer, supporting retinal neurodegeneration as a feature of this multisystem disorder. SYSTEMATIC REVIEW REGISTRATION: PROSPERO identifier CRD420251076035.

Humans↗

PubMed2026

Precision targeting of teacher burnout using network-informed ecological momentary interventions.

Teacher well-being affects classroom functioning and workforce stability, yet generic digital programs rarely use person-specific affect dynamics to select support. This cluster-randomised trial evaluated whether micro-interventions selected from high expected influence (EI) nodes in teachers' contemporaneous affect networks produced larger changes in burnout-related EI and everyday happiness than content-matched random allocation. The objectives were to estimate allocation effects on changes in estimated network summaries and happiness, evaluate network change as a statistical mediator, examine personality moderation, and benchmark simpler allocation rules. A two-arm cluster randomised platform trial was conducted in 84 public schools across four urban districts in H Province. After a 14 day baseline of ecological momentary assessment (EMA), person specific partial correlation networks were estimated for happiness, exhaustion, detachment, efficacy and rumination. An optimisation engine prioritised three brief micro-intervention types per teacher according to baseline EI, while the active control received the same library without network information. EMA continued for 8 weeks; Bayesian multilevel models, permutation-based mediation, and benchmarking analyses were applied. EI-based targeting produced larger reductions in the composite EI-change index than active control (mean difference 0.11, 95% credible interval 0.08 to 0.14) and higher week 7 EMA happiness (4.4 points on a 0 to 100 scale, 95% credible interval 2.7 to 6.0), with a positive arm by week slope difference of 0.62 points per week (95% credible interval 0.39 to 0.85). Model-based mediation estimates were consistent with approximately one half of the happiness difference being statistically associated with change in the composite EI-change index (average conditional mediation estimate 3.5 points, 95% credible interval 2.0 to 5.2). Benchmarking showed smaller gains under severity, threshold, or group-level centrality rules. Effects were stronger among teachers higher in conscientiousness. The findings indicate that integrating EMA, network modelling, and EI-driven optimisation yields measurable gains beyond content-matched exposure, providing a proof of concept for district-scale precision mental health that requires prospective implementation testing. Replication in additional regions, expanded node sets, and longer follow up are warranted to assess durability and generalisability.

Female↗

PubMed2026

Physical Appearance Anxiety and Eating Disorders Symptomatology: A Systematic Review and Meta-Analysis.

The present study aimed to assess the link between physical appearance anxiety (PAA) and eating disorder (ED) symptomatology by a meta-analysis of existing literature. Eligible studies were searched across six electronic databases up until November 20, 2025. Pooled effect sizes (r) were calculated using random-effects models. Potential variables that influence effect heterogeneity were analyzed by univariable and multivariable meta-regressions. Influence analyses and a three-parameter selection model (3PSM) were used to assess robustness of the results and publication bias. Twenty-seven effect sizes from 21 studies (N = 5261) were obtained. The results indicated a strong association (i.e., r = 0.559) between the two variables under consideration, which was notably stronger (i) among females compared to males; and (ii) for overall eating disorder symptoms rather than bulimic symptoms. The results of this study advocate for further investigation into the effectiveness of addressing anxiety responses related to personal body traits, particularly among females, within the context of preventing and treating eating disorders.

Humans↗

PubMed2026

Substance use and co-occurring mental health conditions among adolescents and young adults in North America: a systematic review.

BACKGROUND: Substance use and co-occurring mental health conditions are common among adolescents and young adults and represent an important clinical and public health concern in North America. Trauma exposure, psychiatric symptoms, and social adversity frequently co-occur with substance-related problems in this population. This systematic review aimed to synthesize evidence on prevalence patterns, associated clinical and psychosocial factors, and care-related implications described in the literature on adolescents and young adults with substance use and co-occurring mental health conditions. METHODS: This systematic review followed PRISMA guidelines and was preregistered in PROSPERO (CRD42024581685). A systematic search was conducted in MEDLINE (Ovid), Embase, PsycINFO, and Google Scholar. Eligible studies examined adolescents and young adults (≤ 25 years) in North America. A combination of subject headings, keywords, and synonyms for the concepts "adolescents," "young adults," "substance use disorders," and "co-occurring mental health conditions" was used. Of 1,882 records identified, 29 studies met the inclusion criteria. Given the heterogeneity of the literature, findings were synthesized narratively. RESULTS: The included studies showed heterogeneity in population, setting, denominator, and ascertainment method. Across the literature, depressive, anxiety-related, trauma-related, and externalizing mental health presentations were frequently reported alongside substance-related problems in adolescents and young adults. Trauma exposure, adverse childhood experiences, and broader social adversity were also commonly reported in association with substance-related problems across studies. Care-related implications were more limited and were largely derived as future directions mentioned across studies rather than direct evaluations of youth-specific service models. CONCLUSION: Co-occurring mental health and substance-related problems were frequently reported among adolescents and young adults in high-risk and service-engaged populations in North America. Trauma and social adversity were prominent across the reviewed literature, while direct evidence for evaluated, integrated, youth-specific care models remains limited. These findings support the relevance of developmentally appropriate, integrated, and trauma-informed approaches to care and highlight the need for further research directly evaluating improved service delivery models for this population. CLINICAL TRIAL NUMBER: Not applicable.

Humans↗

PubMed2026

Machine learning-ready genomic biomarkers: ATF3 polymorphisms predict postoperative analgesic demand through AI-compatible phenotyping.

PURPOSE: To determine whether ATF3 polymorphisms can serve as genetic biomarkers for machine learning-based precision analgesia by establishing a genotype-phenotype association suitable for predictive modeling of postoperative opioid requirements. METHODS: In a prospective cohort of 167 adults undergoing abdominal surgery, ATF3 SNPs rs3122721 and rs3125293 were genotyped. A structured dataset architecture was developed to represent genetic profiles as input features for supervised learning models, enabling translational analysis of genotype‑dependent opioid consumption over 72 h. RESULTS: Patients with homozygous genotypes of the ATF3 SNPs had significantly higher opioid requirements than non‑carriers, despite reporting similar subjective pain scores. This consistent genotype‑dependent pattern provided a clinically relevant phenotype suitable for integration into predictive algorithms. CONCLUSION: ATF3 genotyping offers a promising biomarker for computationally informed precision analgesia. By linking genomic variability to clinically meaningful outcomes within a structured clinical and genomic framework, this approach supports the future development of risk-stratified clinical decision-support systems to optimize postoperative pain management.Trial registration ChiCTR1900021991, registered 30 April 2019. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s13755-026-00480-9.

ATF3↗

PubMed2026

Association between hepatic steatosis index and female infertility: a cross-sectional study using NHANES 2013-2018.

Female infertility is a major reproductive health concern. Hepatic steatosis index (HSI), a non-invasive marker of liver-related metabolic burden, has not been well studied in relation to infertility across its distribution. We analyzed women aged 20-49 years from three NHANES cycles (2013-2018). HSI was examined as both a continuous variable and in quartiles, and restricted cubic spline models were used to assess potential nonlinearity. Sensitivity analyses using alternative infertility definitions and exploratory interaction analyses were also performed. Among 3,007 women, 416 (13.8%) were classified as having infertility. In the fully adjusted model, women in the highest HSI quartile had higher odds of infertility than those in the lowest quartile (OR 1.66, 95% CI 1.08-2.57; P = 0.031), with a significant trend across quartiles (P for trend = 0.010). Restricted cubic spline analysis showed a nonlinear association between HSI and infertility (P for overall association = 0.005), which was more evident at higher HSI levels. Higher HSI was associated with greater odds of infertility among reproductive-aged women.

Humans↗

PubMed2026

Proteomic profiling reveals that DPP4 overexpression increases cell adhesion, inhibits cell migration, and restores androgen sensitivity in prostate cancer.

Dipeptidyl peptidase-4 (DPP4), a serine protease with both enzymatic and non-enzymatic roles, has emerged as a context-dependent modulator of tumor progression. In the present study, we investigated the expression and function of DPP4 in androgen-sensitive and castration-resistant prostate cancer (CRPC) models. Proteomic analysis of androgen-resistant prostate cells overexpressing DPP4 identified the involvement of the cellular adhesion molecules pathway. In prostate cells, lentiviral-mediated DPP4 overexpression restored androgen receptor signaling, inhibited epithelial-to-mesenchymal transition, and reduced cell migration, whereas DPP4 silencing produced the opposite effects. We demonstrate that DPP4 expression is down-regulated in CRPC cells and that treatment with capsaicin (CAP), a bioactive compound derived from red peppers, restores DPP4 expression. Moreover, DPP4 restoration by CAP suppresses prostate tumorigenesis in the TRAMP mice in vivo model of prostate cancer. Our results suggest that DPP4 could be a new target for CRPC.

Male↗

PubMed2026

The effect of tDCS on emotion-related risk-taking behavior and delay discounting in adults with ADHD.

INTRODUCTION: Adults with Attention Deficit Hyperactivity Disorder (ADHD) often engage in risky behaviors due to impaired decision-making processes. This study aims to investigate the effects of transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (dlPFC) and ventromedial prefrontal cortex (vmPFC) on emotion-related risk-taking behavior and delay discounting in adults with ADHD. METHODS: Thirty adults with ADHD underwent three tDCS conditions, administered in a randomized order with at least one week between sessions: (1) left dlPFC anode/right vmPFC cathode, (2) left dlPFC cathode/right vmPFC anode, and (3) sham stimulation. In each session, participants completed the Delay Discounting Task (DDT) and the Modified Balloon Analogue Risk Task (mBART) under three emotional conditions (neutral, positive, and negative) which were induced using emotionally congruent photographs and sounds. Galvanic skin responses (GSR) were also recorded. In the DDT, both area under the curve (AUC) values and log-transformed discounting rates (log k) were calculated for small, medium, and large reward magnitudes (RM). Exploratory electric field modeling was also performed to characterize current distribution. RESULTS: The findings demonstrated task-specific effects of tDCS on decision-making. Although no overall tDCS effect was observed on DDT performance, significant tDCS × RM interactions emerged, particularly for smaller rewards. In contrast, exploratory analyses suggested that tDCS affected all mBART scores. Emotional condition did not influence consistently behavioral performance in either task, whereas both emotional stimulation and tDCS significantly affected GSR responses. However, exploratory electric field modeling indicated a broad prefrontal current distribution extending beyond the intended cortical targets. CONCLUSIONS: These findings suggest preliminary evidence that prefrontal tDCS can influence risk-related decision-making and autonomic responses in adults with ADHD. However, its effects on delay discounting appear to be context-dependent and limited to specific RMs. Future studies combining neuroimaging with individualized electric field modeling are needed to clarify the neural mechanisms underlying the observed effects of tDCS and to optimize stimulation protocols in adults with ADHD.

Humans↗

PubMed2026

Predictive evolutionary genomics: principles, validation, and practice.

Climate change and habitat loss are driving rapid evolutionary responses in populations world-wide, which creates an urgent need for evolutionary forecasting in conservation and agriculture. Such forecasting can be categorized into three time scales: trait-based models that use multivariate quantitative genetic equations to project correlated phenotypic responses up to c. 20 generations, allele-based analyses that model allele frequency dynamics up to 100 generations, and composite adaptation scores that aggregate many small effects to yield predictions across longer horizons. However, these approaches have remained largely disconnected. Here, we present a Bayesian framework that integrates these three complementary approaches for evolutionary prediction. Our framework combines genomic, phenotypic, and environmental data to yield probabilistic predictions with explicit uncertainty. We show how predictive evolutionary forecasts can be validated with experimental evolution, field experimentation, historical specimens, and reciprocal transplants. These validated forecasts can help advance conservation and agricultural programmes by helping predict which populations are at risk of future extinction, optimizing breeding programmes for future climates, and planning ecosystem management under environmental change. By supporting a shift towards more predictive approaches in evolutionary biology, this framework may help improve our ability to manage biodiversity and food security in a changing world.

Genomics↗

PubMed2026

Nephropathies Associated with Sickle Cell Trait and How to Study Them.

Sickle cell trait (SCT), which carries a single point mutation in the hemoglobin-β (HBB) gene, has long been considered a benign condition. However, epidemiological evidence challenges this assumption, revealing that individuals with SCT face an elevated risk of renal dysfunction. However, this field of study remains ill-defined as it has focused on sickle cell disease (SCD), where renal complications are severe. As SCT is more prevalent than SCD, consequences of nephropathies in this group translate into a substantial and largely unaddressed public health burden. Clinical data, primarily observational, implicate age and sex in the development of SCT-associated nephropathies. These manifestations span glomerular hyperfiltration, tubular damage, hematuria, renal papillary necrosis, renal medullary carcinoma, and progression to chronic kidney disease, all complications that cluster disproportionately in older male individuals. Despite this, the mechanistic basis of SCT nephropathy, the thresholds at which renal injury becomes clinically significant, and the optimal strategies for early identification and prevention remain inadequately defined. In vitro studies have primarily focused on SCD blood cell biology, with SCT receiving comparatively little attention. Humanized murine models (i.e., Berkeley and Townes) have recapitulated some SCT-associated renal phenotypes but need to be more fully characterized. This review aims to provide an overview of the biology of sickle cell trait nephropathies, the gaps in our knowledge, and the model systems we can use to fill those gaps.

Journal Article↗

PubMed2026

To longevity and beyond: A systems view of aging and stress resilience.

Aging is a dynamic and time-dependent process characterized by progressive functional decline across biological systems. Key hallmarks, including genomic instability, telomere attrition, loss of proteostasis, mitochondrial dysfunction, and immunosenescence, have been widely described, each reflecting distinct yet interconnected mechanistic frameworks. Rather than acting in isolation, these processes arise from complex interactions among cellular stressors, impaired repair mechanisms, and the cumulative burden of maladaptive responses. This system-level perspective explains the inter-individual variability in aging trajectories. Centenarians represent an extreme and informative model of successful aging, in which the balance between damage accumulation and repair is shifted toward the maintenance of physiological function. Their exceptional longevity is supported by coordinated genetic, epigenetic, metabolic, and immunological adaptations that enhance resilience to age-related stressors. Here, we summarize the biological drivers and theoretical frameworks of aging within an integrative context, focusing on mechanisms associated with extended healthspan in centenarians. We also examine the contribution of major animal models, highlighting their complementary roles in elucidating conserved and species-specific aging pathways. Overall, aging outcomes reflect a dynamic equilibrium between damage and repair processes. Understanding how this balance is modulated in long-lived individuals may inform strategies to promote healthy aging and delay the onset of age-related diseases.

Humans↗

PubMed2026

Access to palliative care in rural settings: A mixed-methods systematic review.

BACKGROUND: Rural populations experience persistent inequities in access to palliative care. Existing evidence often describes individual barriers separately, with less attention to how access breaks down across the care pathway or how different service configurations shape access. OBJECTIVES: To synthesise evidence on access to palliative care in rural settings and examine how access barriers, service models, and implementation conditions interact across the care pathway. METHODS: A mixed-methods systematic review using a convergent integrated approach searched nine databases (PubMed, Embase, CINAHL, Web of Science, Scopus, PsycINFO, CNKI, WanFang, SinoMed) from inception to 15 March 2026, supplemented by hand-searching. Eligible studies were primary qualitative, quantitative, and mixed-methods studies on access to palliative care for adults in rural or non-urban settings. Two reviewers independently screened studies, extracted data, and assessed quality using the Mixed Methods Appraisal Tool. Findings were mapped to the Levesque access framework, analysed using the updated Consolidated Framework for Implementation Research, and integrated through mixed-methods synthesis, with additional coding of service models. RESULTS: Thirty-four studies were included, of which 26 were conducted in high-income countries and eight in low- and middle-income countries. Service configurations included specialist or hospice-oriented care, generalist or primary-care-oriented care, mixed specialist-generalist models, home-based and caregiver-centred care, nurse-coordinated services, telehealth-supported care, and community or implementation-oriented approaches. Access broke down cumulatively across four interdependent stages: recognition, entry, reach, and use and continuity, with affordability constraining every stage. Recognition was limited by low awareness, poor service visibility, and delayed identification of need. Entry was shaped by stigma, trust, family expectations, and unclear referral processes. Reach was constrained by distance, transport, workforce shortages, limited specialist capacity, and weak infrastructure. Use and continuity were affected by fragmented coordination, weak transitions, unstable follow-up, and reliance on family caregivers. Access problems varied across service configurations. Evidence on service innovations was methodologically less certain, and the overall evidence base remained concentrated in high-income countries. CONCLUSIONS: Access to palliative care in rural settings is best understood as a pathway and service-configuration problem rather than simply a deficit in service availability. Improving access requires earlier recognition, clearer referral routes, stronger specialist-generalist and nursing links, better support for family caregivers, and greater attention to affordability, continuity, and rural settings with limited resources. REGISTRATION: International Prospective Register of Systematic Reviews: CRD420261340783.

Health Services Accessibility↗

PubMed2026

Detectable C-Peptide and Diabetic Ketoacidosis Risk in Type 1 Diabetes.

OBJECTIVE: To investigate whether detectable C-peptide levels in type 1 diabetes is associated with a lower risk of diabetic ketoacidosis (DKA). RESEARCH DESIGN AND METHODS: We analyzed the Diabetes Control and Complications Trial publicly available data repository for the association between detectable stimulated C-peptide (>0.2 nmol/mL, measured annually) and DKA incidence over an average 6.5-year follow-up. We used crude and adjusted Andersen-Gill models for recurrent DKA events with time-dependent covariates. RESULTS: Of the 1,441 participants (53% male, median age 27 years), 129 (9%) experienced 180 DKA events. Of these events, 179 (99.44%) occurred after C-peptide was ≤0.2 nmol/L in the prior year and only 1 event occurred with C-peptide >0.2 nmol/L. C-peptide >0.2 nmol/L was associated with a DKA hazard ratio of 0.07 (95% CI 0.01-0.48; P = 0.007), consistent across adjusted models. CONCLUSIONS: Endogenous insulin production was significantly associated with lower DKA risk, suggesting that treatments preserving insulin production could decrease long-term DKA risk.

C-Peptide↗

PubMed2026

Analysis of end-stage renal disease mediated by cuproptosis-related genes.

OBJECTIVE: The complex pathophysiological mechanism of end-stage renal disease (ESRD) has not been fully understood. Cuproptosis is a newly discovered type of programmed cell death. Therefore, this study attempts to clarify the relationship between cuproptosis-related genes (CRGs) and the phenotype of ESRD. MATERIALS AND METHODS: The National Center for Biological Information Gene Expression Omnibus database was applied to obtain the GSE37171 dataset comprising whole-genome microarray analysis of peripheral blood samples. A 3 : 1 case-control design was employed with 75 ESRD patients and 20 healthy controls who were frequency-matched for age, sex, and ethnicity. Based on differentially expressed genes (DEGs) and genes related to cuproptosis, CRGs were identified. Thereafter, we explored two different subpopulations based on the cuproptosis gene and analyzed their expression and immune infiltration. Genes specific to the CRG cluster were identified through the weighted gene co-expression network analysis algorithm, and the best prediction model was determined and verified by four machine learning methods. RESULTS: The study identified 14 differentially expressed CRGs, among which ATP7B, SLC31A1, LIAS, LIPT1, DLD, MTF1, CDKN2A, DBT, and DLST had relatively high expression levels in the ESRD samples. Compared with the control group, expression levels of FDX1, DLAT, PDHA1, PDHB, and GLS were significantly lower in the ESRD group, and CRGs played a key role in the regulation of immune infiltration in ESRD. Two cuproptosis-related molecular clusters were identified in the ESRD samples. Cluster2 was more correlated with the immune infiltration of ESRD. By analyzing the intersection points between CRG cluster and key genes of ESRD, a total of 888 specific DEGs were identified. Functional differences related to specific DEGs were further explored using gene set variation analysis. Five significant genes (SMC5, USP47, USP53, AGA, and DMXL1) were identified by the support vector machine model as key predictors for ESRD disease risk, achieving an area under the curve (AUC) of 1.00 in internal validation. However, external validation in independent cohorts is required prior to clinical application. Individual gene analysis showed an AUC > 0.81 in discriminating ESRD patients from healthy controls, and the expression of all 5 genes in ESRD patients was significantly lower than in the control group. CONCLUSION: This study clarified the relationship between CRGs and the phenotype of ESRD, analyzed their specific roles in the immune microenvironment, and obtained a predictive model, providing new insights for the study of its potential therapeutic targets.

Humans↗

PubMed2026

Mechanisms of impact of mental health peer support in high-, middle- and low-income settings: mediation analysis of the UPSIDES randomised controlled trial.

AIMS: While there is growing evidence for the effectiveness of peer support (PS) in improving psychosocial outcomes among individuals with severe mental health conditions, the mechanisms through which these effects occur remain insufficiently understood. This study examines whether social inclusion, hope and empowerment mediate the relationship between PS, personal recovery and health and social functioning. METHODS: Data were collected from 565 adults with severe mental health conditions who participated in the multicentre UPSIDES randomised controlled trial across six sites in Germany, Uganda, Tanzania, India and Israel. Participants in the intervention group received structured PS from trained peer workers over a 6- to 8-month period. Standardised, self-report measures of social inclusion, hope, empowerment and personal recovery, as well as clinician-rated health and social functioning, were administered at baseline, 4 months, end of intervention (8 months) and 12-month follow-up. Cross-lagged panel modelling was used to explore longitudinal associations and mediating pathways. RESULTS: The cross-lagged models showed strong autoregressive effects across all variables, indicating high temporal stability. There were no significant direct effects of PS on recovery or health and social functioning. However, mediation analysis identified significant indirect effects of PS on personal recovery via social inclusion (β = 0.114, 95% confidence interval [CI] [0.049, 0.194], P < 0.05) and hope (β = 0.037, 95% CI [0.001, 0.086], P < 0.05). Similar indirect effects were observed for health and social functioning (via social inclusion: β = -0.035, 95% CI [-0.064, -0.013]; via hope: β = -0.026, 95% CI [-0.052, -0.006]; both P < 0.05). CONCLUSIONS: Findings suggest that PS affects recovery-related outcomes primarily through intermediate mechanisms of enhanced hope and social inclusion. These results support theoretical models positing indirect pathways of change in PS interventions and highlight the value of targeting social and psychological domains when designing and implementing PS in mental health services. Individuals with lower baseline levels of hope and social inclusion may particularly benefit from PS.

Humans↗