Evolution

BackgroundSubstance use initiation in adolescence is influenced by both genetic and environmental factors; however, large-scale genetic studies often treat initiation as a binary outcome and underuse longitudinal timing information. MethodsWe conducted time-to-event (survival) genome-wide association analyses (GWAS) of initiation for four outcomes--alcohol, nicotine, cannabis, and any substance use--using longitudinal follow-up data from the Adolescent Brain Cognitive Development (ABCD) Study. We performed ancestry-stratified GWAS within European (EUR), African (AFR), and Hispanic (HISP) groups, applying consistent quality control and covariate adjustment. Summary statistics were harmonized across ancestries and meta-analyzed using inverse-variance weighted fixed-effects and DerSimonian-Laird random-effects models. We evaluated genomic inflation and heterogeneity (Cochrans Q and I2), identified independent lead variants at genome-wide and suggestive significance thresholds, and assessed cross-trait overlap of associated loci. ResultsIn the multi-ancestry meta-analysis, we observed suggestive association signals across traits (minimum p-values: alcohol [~] 1 x 10-7, any [~] 1 x 10-7, cannabis [~] 5 x 10-8, nicotine [~] 1 x 10-8). Nicotine initiation showed one genome-wide significant variant in both fixed- and random-effects meta-analyses (p < 5 x 10-8). Across traits, suggestive loci demonstrated limited overlap, with the strongest concordance between alcohol and any substance use, consistent with shared liability. Heterogeneity statistics indicated that some loci exhibited cross-ancestry variation in effect estimates. ConclusionsSurvival GWAS leveraging initiation timing can identify genetic signals that may be missed by binary designs and enables principled multi-ancestry synthesis. Our results highlight both shared and trait-specific genetic contributions to early substance initiation and provide a foundation for downstream functional annotation and integrative modeling with environmental risk factors. These findings demonstrate the value of incorporating developmental timing into genetic discovery and provide a framework for integrating longitudinal risk modeling with genomic analyses.

Colorectal cancer (CRC) is the second leading cause of cancer death globally and the number one cause of cancer death in people under 50 years old. The reasons for the rise of early-onset CRC are unknown, and while anatomically distinct subtypes of CRC have substantial clinical and molecular associations, the etiology of region-specific disease, such as early-onset CRC's enrichment in the distal colon, remains unclear. Understanding regional mutagenesis may identify risk factors for this public health concern and CRC more broadly. To evaluate mutational dynamics across the premalignant colon, we performed whole-genome sequencing of 125 individual colon crypts taken from six standardized regions biopsied during colonoscopy, collected from 11 donors without polyps and 10 with polyps. We observed mutation spectra and accumulation rates consistent with previous whole-organ studies, with greater subclonal mutation capture enabled by experimental design. T>[A,C,G] mutations, which are associated with colibactin genotoxicity from pks+ Escherichia coli, were significantly enriched in the rectum of donors with and without polyps (adjusted p-values < 0.01). Moreover, when comparing findings to crypts from individuals with CRC and sequenced CRC tumors, we observed consistent enrichment of the colibactin-associated mutational signature "ID18" in the rectum in both normal colon crypts and CRC tumors, without significant difference in colibactin-specific single nucleotide variant or insertion-deletion burden in crypts across the three clinical groups (i.e., no polyp, polyp, and CRC). These findings argue against a causal or prognostic role for colibactin in CRC, instead indicating that the proposed association with early-onset disease reflects anatomic specificity rather than cancer-specific clinical relevance.

The worldwide rise in the prevalence of extended-spectrum beta-lactamase (ESBL) producing Escherichia coli is a major public health concern. In Europe, ESBL carriage frequency increased then stabilized at about 6-8 %. Past antibiotic use and travel in countries with high ESBL frequency, notably South-East Asia, have repeatedly been identified as risk factors of ESBL carriage. Yet, the relative contributions of these mechanisms to the observed maintenance of a stable low frequency of ESBL in Europe remains unknown. Here, we used comprehensive data on the risk factors for carriage of ESBL-producing E. coli in the French community, alongside detailed microbiological characterization of both resistant and overall E. coli, to develop a biologically plausible mathematical model of ESBL resistance spread in France. The model also includes several mechanisms previously showed to favor coexistence such as population structure, variability in carriage duration and within-host dynamics. The level of resistance in the community implies resistant strains transmit 14% less than sensitive (95% credible interval 0.6-38%), and are cleared at a +23% larger rate (0.9-62%). ESBL resistance is predicted to be strongly associated with factors prolonging residence in the gut. Both the rate of antibiotic treatment and transmission strongly impact the frequency of ESBL in the community. In contrast, travel has little impact on ESBL frequency. Whether reducing treatment or transmission is best to reduce resistance depends on community-specific parameters. Our study opens perspectives for the quantitative study of resistance evolution and argues for future work to improve the characterization of the duration of carriage of commensal bacterial strains.

Background: Pharmacogenomic testing (PGx) can optimise drug efficacy and minimise toxicity, but the extent of prescriber adherence to PGx recommendations remains unclear. We aimed to quantify clinician adherence to international genotype-guided prescribing recommendations in a cohort of paediatric oncology patients. Methods: We reviewed files of children enrolled in the MARVEL-PIC (NCT05667766) randomised control trial, who had PGx recommendations available. Patients were included if 12 weeks had passed since their PGx report was released to clinicians. Prescribing events were identified for actionable PGx recommendations, and classified as "explicitly followed", "inadvertently followed", or "not followed". Adherence was assessed by patient, drug, and recommendation. Results: 2,063 PGx recommendations were available for 216 patients. 64 (3.1%) recommendations were actionable for 44 patients and 10 drugs within the 12-week study period. Recommendations were explicitly followed in 57/288 (19.8%) of prescribing events, inadvertently followed in 145 (50.3%), and not followed in 86 (29.9%). Mercaptopurine demonstrated the highest rate of explicit adherence (87.5%). No significant associations were observed between adherence and age group, cancer type, drug type, or strength of recommendation. Conclusion: Adherence to pharmacogenomic recommendations was very low, highlighting the need to understand barriers to PGx implementation, and consideration of clinical decision supports to facilitate adherence.

The shared genetic liability between cortical morphology and psychiatric disorders remains unclear. We aimed to identify whether the genetic loci shared between cortical morphology and six psychiatric disorders show regional or global effects. We identified substantial pairwise genetic overlaps of cortical surface area or thickness with psychiatric disorders; however, these loci lacked a uniform direction (~50% concordance). Cross-trait analyses revealed distinct architectures: internalizing disorders and schizophrenia/bipolar disorder shared more genetic loci with localized effects, whereas neurodevelopmental disorders shared fewer loci but more with widespread effects. We identified 17 genomic loci shared across all disorders, most of which had opposing directional effects across cortical regions. Only one locus (rs2431112) had region-specific and unidirectional effects (reduced primary visual and posterior cingulate surface area). This directional heterogeneity within and across pleiotropic loci reveals complex shared genetic architectures and likely limits the genetic predictive performance of brain morphology for psychiatric disorders.

Genome-wide association studies (GWAS) have identified numerous genetic variants associated with complex traits. However, linkage disequilibrium (LD) confounds these associations, leading to false positives where non-causal variants appear associated because they are correlated with nearby causal variants. This is particularly the case in highly polygenic traits where the genome can be saturated in causal variants. To address this issue, we propose LDeconv a method based on truncated singular value decomposition (SVD) that adjust GWAS summary statistics without requiring individual-level genotype data. This approach accounts for LD structure, isolates causal variants in high-LD regions, and improve the reliability of effect size estimates. We assess its performance through simulations across various LD scenarios, conduct extensive sensitivity analyses, and apply them to real GWAS data from the UK Biobank. Our results demonstrate that LDeconv effectively reduces false discoveries while preserving true associations, offering a robust framework for post-GWAS analysis.

Introduction Lung cancer is rare before age 45, and its inherited genetic basis remains poorly defined. Methods We performed whole-genome sequencing in 171 predominantly young-onset lung cancer patients and integrated these data with whole-exome sequencing from six major lung cancer consortia, yielding 9,065 patients. After quality control, analyses focused on 6,545 individuals of European ancestry, the largest ancestral group. We compared the prevalence of rare pathogenic and likely pathogenic (P/LP) germline variants between 186 young-onset (age <45 years) and 6,359 older patients at gene and gene-set levels using Fisher's exact test, stratified by histology, sex, and smoking status. Polygenic risk scores (PRS) derived from common variants were also evaluated. Results Young-onset patients carried a higher burden of rare germline P/LP variants in DNA damage response (DDR) genes (including BRIP1, ERCC6, MSH5), and in cilia-related genes, notably GPR161. At the pathway level, DDR genes were significantly enriched (OR=1.66, p=0.007), with the strongest signal in the Fanconi Anemia pathway and among females (OR=1.96, p=0.01). Enrichment was also observed in inborn errors of immunity pathways, with strongest signals in antibody deficiency and the complement system genes. Young-onset patients additionally exhibited higher lung cancer PRS. Conclusion Young-onset lung cancer exhibits a distinct germline genetic architecture, characterized by enrichment of rare P/LP variants in DDR, cilia-related, and immune pathways, and an elevated lung cancer PRS. These findings support a greater role for inherited susceptibility in early-onset disease and have implications for risk stratification, earlier screening, and precision prevention.

Machine learning models trained on observational data from one environment frequently fail when deployed in another, because standard learning algorithms exploit spurious correlations alongside causal ones. Invariant learning methods address this problem by seeking representations that support stable prediction across training environments, but their behavior on tabular data remains poorly characterized. We present CausTab, a gradient variance regularization framework for causal invariant representation learning on mixed tabular data. CausTab penalizes the variance of parameter gradients across training environments, providing a richer invariance signal than the scalar penalty used by Invariant Risk Minimization (IRM). We provide formal results showing that the gradient variance penalty is zero at causally invariant solutions and positive at solutions that rely on spurious features. Through experiments on synthetic data across three spurious-correlation regimes, four cycles of the National Health and Nutrition Examination Survey (NHANES), and four hospital systems in the UCI Heart Disease dataset, we demonstrate that: (1) IRM consistently degrades relative to standard empirical risk minimization (ERM) on tabular data, losing up to 13.8 AUC points in spurious-dominant settings, a failure we trace mechanistically to penalty collapse during training; (2) CausTab matches or exceeds ERM in every experimental condition; (3) CausTab achieves consistently better probability calibration than both ERM and IRM; and (4) invariant learning methods fail when environments differ in outcome prevalence rather than in spurious feature correlations, a boundary condition we characterize both empirically and theoretically. We introduce the Spurious Dominance Index (SDI), a practical scalar diagnostic for determining whether a dataset requires invariant learning, and validate it across all experimental settings

Population ageing increases the importance of cognitive capacity for making decisions about retirement and living independently beyond it. We tested whether post-war educational expansion and working-life social mobility eliminate the association between social class of origin and cognition in early old age using the 1958 National Child Development Study. Two outcomes were analysed at age 62: standard episodic memory (immediate + delayed word recall) and long-term episodic memory, capturing accurate half-century recall of childhood household facts (rooms and people at age 11 validated against mothers' responses). Social mobility trajectories derived in prior work were classified into predominantly manual versus non-manual class trajectories. Models were estimated separately for women and men across three specifications: (i) social origin and controls, (ii) adding social mobility, and (iii) adding weighting to address healthy survivor bias. Education was consistently associated with both outcomes. For long-term episodic memory, social origin gradients were clearer than for short-term episodic memory, with men from service/professional origins showing a 13 percentage-point higher probability of accurate half-century recall than men from manual origins. These findings indicate that education expansion and working-life social mobility failed to release the grip of social origin on long-term episodic memory.

The etiology of autism is influenced by genetic and non-genetic factors, with observational studies suggesting associations between early maternal health diagnoses and offspring autism. However, these associations may partly reflect shared familial genetic liability rather than direct causal effects. Using comprehensive national health registers and individual-level genetic data from the iPSYCH cohort (N=117,542), we examined whether maternal health diagnoses are associated with offspring polygenic scores (PGS) for autism. Such associations between maternal health and offspring autism would indicate shared genetic factors and the possibility of genetic confounding in the observational associations. We also tested such associations with PGSs for other neuropsychiatric and neurodevelopmental conditions that are genetically correlated with autism, but with better-powered PGS (due to larger GWAS sample sizes and likely more polygenic genetic architecture), as well as height, a negative control. Several maternal diagnoses were nominally associated with autism PGS in the child, including, e.g., certain obstetric complications, asthma, and obesity. After adjustment for multiple testing, the only statistically significant results included those between maternal diagnoses, predominantly psychiatric, and other neuropsychiatric and neurodevelopmental PGSs in the child. Sensitivity analyses confirmed the robustness of our results across exposure windows, diagnostic settings, and socioeconomic adjustments. These findings indicate that maternal diagnoses associated with autism partially reflect shared genetic liabilities between mothers and their children. However, such genetic effects, as captured by child PGS do not fully explain the observed associations, suggesting additional factors, including e.g., non-genetic familial factors, rare variants, and indirect effects.

Genetic counselling outcome measures are increasingly adapted for diverse clinical contexts. While the Genetic Counselling Outcome Scale (GCOS-24) is available in Swedish, no autism-specific version has been developed. Therefore, we adapted the Swedish GCOS-24 using the English version of the modified GCOS-24 (mGCSOS-24) to create a Swedish autism-specific mGCOS-24. Thereafter, we evaluated both the Swedish autism mGCOS-24 and the Swedish general GCOS-24 using Rasch analysis to assess their psychometric properties. Both instruments exhibited structural challenges, including multidimensionality, disordered thresholds, local item dependence, and invariance issues. For the Swedish autism mGCOS-24, we were able to identify subscales with acceptable measurement properties. However, applying the same structure to the Swedish general GCOS-24 did not resolve its broader limitations. This study introduces the first Swedish autism-specific mGCOS-24 and represents the first Rasch-based evaluation of any GCOS-24 or mGCOS-24 in Swedish. Our findings highlight important opportunities for measure refinement but also indicate that new or more substantially adapted tools may be needed to capture outcomes of genetic counselling in autistic populations.

Female genital tract (FGT) polyps are common benign growths affecting up to half of all women. However, they carry malignant potential, and their genetic architecture remains poorly defined. We conducted a genome-wide association study (GWAS) meta-analysis across four biobanks (48,400 cases, 477,134 controls), identifying 26 risk loci for FGT polyps, 12 of which were previously unreported. Integrative gene prioritisation highlighted 193 candidate genes, revealing a potential convergent biological mechanism: where germline variation in DNA replication and maintenance (e.g., PRIM1, TERT and HMGA1) compromises genomic stability in the context of hormone-driven proliferation (e.g., ESR1 and GREB1). This susceptibility is further modulated by metabolic drivers of estrogen biosynthesis, underscored by specific adiposity-related loci (e.g. RSPO3 and PLCE1) and the aromatase gene CYP19A1. Mendelian randomisation demonstrated bidirectional causal relationships with endometriosis and fibroids, and endometrial cancer. Leveraging the shared genetic architecture of FGT polyps and other gynaecological disorders via multi-trait analysis revealed an additional 26 loci, validating sub-threshold regions encompassing HMGA1 and GREB1. In total, 52 risk loci were identified (36 novel), 39 of which replicated in an independent cohort. These findings reframe polyps not merely as local gynaecological overgrowths but as manifestations of a systemic proliferative syndrome characterised by dysregulated genome stability and estrogen signalling, which may also impact malignant transformation.

BackgroundLoneliness is a psychosocial stressor associated with elevated risk of severe mental illness (SMI), including major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD). Loneliness is theorized to become biologically embedded via inflammation-related mechanisms, yet its causal relationship with SMI and the role of inflammatory signaling remain unclear. AimsTo investigate whether loneliness causally influences SMI risk and whether inflammatory cytokines mediate this relationship. MethodWe applied univariable Mendelian randomization (MR) to estimate the causal effect of loneliness on SMI and multivariable MR (MVMR) to assess mediation by inflammatory signaling. We integrated genome-wide association study (GWAS) summary statistics for loneliness and SMI with genetic instruments for inflammatory cytokines. MVMR models estimated the direct effect of loneliness after accounting for inflammatory signaling using eQTL and pQTLs for interleukin-1 receptor antagonist (IL-1RA), interleukin-6 (IL-6), IL-6 receptor (IL-6R), tumor necrosis factor alpha (TNF-), and TNF receptors (TNF-R1/2). Bidirectional MR examined potential reverse causal pathways between inflammation, SMI, and loneliness. ResultsMR provided evidence consistent with a causal effect of loneliness on SCZ and MDD. Results were also consistent with inflammatory cytokine pathways for IL-1RA, IL-6R, and TNF-R1, partially mediating the loneliness-SCZ and loneliness-MDD causal effect. No significant effects were identified for BD in UVMR or MVMR models. Bidirectional MR suggested evidence of reverse causation between SCZ and loneliness. ConclusionsThe findings support a causal risk-increasing effect of loneliness on SCZ and MDD, partially mediated by systemic inflammatory signaling, implicating pathways as a plausible mechanistic link between psychosocial stress and mental illness risk and highlighting potential opportunities for prevention and targeted intervention through inflammation and social pathways.

Understanding depressive symptoms dynamics and their determinants is crucial for designing effective mental health support initiatives. This study compared two methods for describing youth depressive symptoms trajectories and investigated associations of early-life factors (maternal education, maternal perinatal depression, domestic violence, physical, emotional, or sexual abuse, bullying victimisation, psychiatric disorder) with trajectory features. Prospective data from 8,264 mostly White European participants (54% female), including self-reported Short Moods and Feelings Questionnaires on ten occasions between 10-25 years, were used. Trajectories were summarised using functional principal component analysis (FPCA) and P-splines linear mixed-effect (PLME) models. Estimated derivatives were used to obtain magnitude and age of peak symptoms and peak symptoms velocity. Both methods performed comparably, but PLME models tended to over-smooth trajectories. Peak symptoms and peak velocity were higher and occurred >1 year earlier in females than males. All early-life factors were associated with higher peak symptoms, and most associated with higher and earlier peak velocity. Abuse and bullying additionally associated with earlier age of peak symptoms. FPCA is a useful alternative for characterising depressive symptoms trajectories and informing time-sensitive preventative measures to reduce impact of depression before symptoms reach their peak. Early-life stressors may accelerate timeline and intensity of symptoms escalation during adolescence. Lay summaryUnderstanding development of depressive symptoms and factors shaping them is crucial for designing effective mental health support initiatives. This study used data from over 8,000 young people regularly followed up from before birth to compare two cutting-edge methods for describing depressive symptoms trajectories and examined how known risk factors for adulthood depression relate to the severity and rate of change of depressive symptoms in adolescence. We found that both methods performed well and that the peaks in depressive symptoms and their rate of change were, on average, higher and occurred over a year earlier in females than males. Our findings additionally suggest that early-life stressors (e.g., abuse, bullying) may accelerate the development of depression, highlighting the importance of early prevention.

PurposeAntibiotic use (ABU) is a major driver of antimicrobial resistance (AMR), but ABU patterns are poorly understood in low-income countries where the burden of AMR is great and ABU is insufficiently regulated. Here, we report ABU from ten sites ranging from rural villages to small cities in Madagascar, a country with high AMR levels, and present results from modeling to identify factors that may be associated with ABU in this setting. MethodsWe conducted surveys of 290 individuals from ten sites in the SAVA Region of northeast Madagascar to gather data on sociodemographic characteristics, agricultural and animal husbandry practices, recent antibiotic use, the antibiotics that participants recalled using in their lifetimes, and the sources of their antibiotics. Using these data, we conducted statistical analyses with a mixed-effects logistic model to determine which characteristics were associated with recent antibiotic use. ResultsNearly all respondents (N=283, 97.6%) reported ABU in their lifetimes, with amoxicillin being the most widely reported antibiotic (N=255, 90.1% of those reporting ABU). All recalled antibiotics were classified as frontline drugs except for ciprofloxacin. Most respondents who reported antibiotic use also reported obtaining antibiotics without prescriptions from local stores (N=273, 96.5%), while only 52.3% (N=148) reported obtaining antibiotics through a prescriptive route, such as from a health clinic or private doctor. Of the 127 individuals (44.9%) who reported recent ABU, men were found to be significantly less likely to have recently taken antibiotics than women. ConclusionsOur findings provide new insights into ABU in agricultural settings in low-income countries, which have historically been understudied in AMR and pharmacoepidemiologic research. Knowledge of ABU patterns supports understanding of AMR dynamics and AMR control efforts in these contexts, such as interventions on inappropriate antibiotic dispensing. Key pointsO_LIAntibiotic use (ABU) in Madagascar is largely unstudied despite its role in antimicrobial resistance (AMR), which Madagascar faces a high burden of. C_LIO_LIABU was widespread among livestock owners in northeast Madagascar, with the majority of study participants reporting ABU in their lifetimes and most people reporting ABU also having taken antibiotics in the previous three months. C_LIO_LIMost respondents reported obtaining their antibiotics from non-pharmaceutical stores, indicating high levels of unregulated ABU, though more than half also reported sourcing their antibiotics through prescriptive means (like doctors and health clinics). C_LIO_LIMen were less likely than women to have taken antibiotics in the previous three months. C_LIO_LIThese findings support the development of interventions to mitigate the burden of AMR in Madagascar and similar contexts while underscoring the need for more comprehensive research on the drivers and patterns of ABU. C_LI Plain language summaryIn this study, we provide basic information on antibiotic use (ABU) patterns in Madagascar, a country that experiences high levels of resistance but has been particularly understudied in AMR and pharmacological research. We surveyed 290 farmers with livestock from ten sites across northeast Madagascar about their ABU and found that nearly all study participants (N=283, 97.6%) have used antibiotics in their lifetimes, while a little under half of those who reported ABU also reported using antibiotics in the previous three months (N=127, 44.9%). The most used antibiotic was amoxicillin (N=255, 90.1%). Most people obtained their antibiotics from sources that do not require prescriptions, like general stores, indicating that most ABU is unregulated. Through modeling, we also found that men were less likely than women to have taken antibiotics in the previous three months (OR=0.50, CI 0.30-0.82). These findings help us better understand the dynamics of ABU in low-income countries, which have historically been understudied in AMR and pharmacological research. They also support efforts to mitigate the burden of AMR by revealing ABU dynamics that may contribute to the emergence and spread of AMR, as well as identifying targets for intervention to curb inappropriate ABU.

Human papillomavirus (HPV) testing is the primary method for cervical cancer screening, and a negative HPV test is associated with a very low subsequent risk of invasive cancer. Nevertheless, a small number of cervical cancers are diagnosed following an HPV-negative testing result, posing challenges within HPV-based screening pathways. Using nationwide Swedish registry data of HPV testing, we identified women diagnosed with invasive cervical cancer between 2019 and 2024 and reconstructed HPV testing histories from the National Cervical Screening Registry (NKCx). The most recent HPV test prior to diagnosis was defined as the index test, and longitudinal HPV testing trajectories were classified among women with an HPV-negative index test. Of 3,000 women diagnosed with invasive cancer, 243 (8.1%) had an HPV-negative index test. These women were older at diagnosis and more frequently diagnosed at advanced stages compared with women with an HPV-positive index test. Most HPV-negative index tests (66.3%) were performed in the peri-diagnostic period (+/- 30 days). Among women with an HPV-negative index test, 52.7% (128/243) had no prior HPV testing recorded, while the remainder had consistently HPV-negative histories (33.3%, 83/243) or evidence of prior HPV positivity before the index negative test (14%, 32/243). Possible recurrent HPV positivity following an intervening negative test was rare (0.4%, 1/243). HPV-negative screening results preceding invasive cancer reflect heterogeneous screening histories and cannot be explained solely by test failure. Findings highlighting the importance of reaching women earlier in screening programs and show that fluctuating HPV detectability is rare.

The global ambition to end the human immunodeficiency virus (HIV) epidemic requires understanding which system-level policy levers, enacted under the framework of Universal Health Coverage (UHC), are most effective in achieving both transmission reduction and diagnostic coverage. This study addresses an important evidence gap by quantifying the within-country association between measurable UHC policy indicators and the estimated rate of new HIV infections across nine Southeast Asian countries between 2013 and 2022. Employing a Fixed-Effects panel data methodology, the analysis controls for time-invariant national heterogeneity, ensuring reliable estimates of policy impact. We found that marginal changes in total current health expenditure (CHE) as a percentage of gross domestic product (GDP) were not statistically significantly associated with changes in HIV incidence. However, increases in the UHC Infectious Disease Service Coverage Index were statistically significantly associated with concurrent reductions in HIV incidence (p < 0.001), suggesting the efficacy of targeted service implementation as the principal driver of curbing new HIV infections. In addition, the UHC Reproductive, Maternal, Newborn, and Child Health Service Coverage Index exhibited a statistically significant positive association with changes in HIV incidence (p < 0.01), which is interpreted as a vital surveillance artefact resulting from expanded detection and reporting of previously undiagnosed HIV cases. Furthermore, out-of-pocket (OOP) health expenditure as a percentage of CHE showed a counter-intuitive negative association with changes in HIV incidence (p < 0.01), suggesting this metric primarily shows ongoing indirect cost burdens on the established patient cohort, or, alternatively, presents a diagnostic access barrier that results in lower case finding. These findings suggest that policymakers should prioritise investment in targeted infectious disease service efficacy over aggregate fiscal commitment and utilise integrated sexual health platforms for strengthened HIV surveillance and case identification.

Objectives: Longer lifespans lead to longer time on retirement, despite the efforts to raise the retirement age. Therefore, it is important to study how the retirement years can be spent without diseases. This study examined socioeconomic and sociodemographic differences in healthy years spent on retirement. Methods: We followed a cohort of retired Finnish municipal employees (N=4231, average follow-up 15.4 years) on national administrative registers for major chronic diseases: cancer, coronary heart disease, cerebrovascular disease, diabetes, asthma or chronic obstructive pulmonary disease, dementia, mental disorders, and alcohol-related disorders. Median healthy years on retirement and age at first occurrence of illness (ICD-10 and ATC-based) in each combination of sex, occupational class, and age of retirement were predicted using Royston-Parmar models. Prevalence rates for each diagnostic group were calculated. Results: Most healthy years on retirement were spent by women having worked in semi-professional jobs who retired at age 60-62 (median predicted healthy years 11.6, 95% CI 10.4-12.7). The least healthy years on retirement were spent by men having worked in routine non-manual jobs who retired after age 62 (median predicted healthy years 6.5, 95% CI 4.4-9.5). Diabetes was slightly more common among lower occupational class women, and dementia among manual working women having retired at age 60-62. Discussion: Healthy years on retirement are not enjoyed equally by women and men and those who retire early or later. Policies aiming to increase the retirement age should consider the effects of these gaps on retirees and the equitability of those effects.

Background Higher levels of sedentary behaviour, such as leisure screen time (LST), and lower levels of physical activity are associated with diseases across multiple body systems which contribute to a large global health burden. Whether these associations are causal is unclear. The primary aim of this study is to investigate the causal effects of higher LST (given greater power) and, secondarily, lower moderate-to-vigorous intensity physical activity (MVPA), on a wide range of diseases in a hypothesis-free approach. Methods A two-sample Mendelian randomisation phenome-wide association study was conducted for the main analyses. Genetic single nucleotide polymorphisms (SNPs) were first selected as exposure genetic instruments for LST (hours of television watched per day; 117 SNPs) and MVPA (higher vs. lower; 18 SNPs) based on the genome-wide significant threshold (p < 5*10-8) from the largest relevant genome-wide association study (GWAS). For disease outcomes, we used summary results from FinnGen GWAS, including 1,719 diseases defined by hospital discharge International Classification of Diseases (ICD) codes in 453,733 European participants. For the main analyses, we used the inverse-variance weighting method with a Bonferroni corrected p-value of p [&le;] 3.47*10-4. Sensitivity analyses included Steiger filtering, MR-Egger and weighted median analyses, and data from UK Biobank were used to explore replication. Findings Genetically predicted higher LST was associated with increased risk of 87 (5.1% of the 1,719) diseases. Most of these diseases were in musculoskeletal and connective tissue (n=37), genitourinary (n=12) and respiratory (n=8) systems. Genetic liability to lower MVPA was associated with six diseases: three in musculoskeletal and connective tissue and genitourinary systems (with greater risk of these diseases also identified with higher LST), and three in respiratory and genitourinary systems. Sensitivity analyses largely supported the main analyses. Results replicated in UK Biobank, where data available. Conclusions Higher levels of sedentary behaviour, and lower levels of physical activity, causally increase the risk of diseases across multiple body systems, making them promising targets for reducing multimorbidity.

BackgroundEarly-life adversity (ELA) is a risk factor for enduring pain in youth and is associated with alterations in brain morphology and function. However, it remains unclear whether ELA-related neurobiological changes contribute to the development of enduring pain in early adolescence. MethodsUsing data from the Adolescent Brain Cognitive Development (ABCD) Study, we examined multimodal magnetic resonance imaging (MRI) markers in children assessed at baseline (ages 9-11 years) and at 2-year follow-up (ages 11-13 years). ELA exposure was defined at baseline to maximise temporal separation between early adversity and later enduring pain. Participants with enduring pain at follow-up (n = 322) were compared to matched pain-free controls (n = 644). Structural MRI, diffusion MRI (fractional anisotropy, mean diffusivity), and resting-state functional connectivity data were analysed. Linear models tested main effects of enduring pain, ELA, and their interaction on brain metrics, controlling for relevant covariates. ResultsELA exposure was associated with smaller caudate and nucleus accumbens volumes, and reduced surface area of the left rostral middle frontal gyrus. No significant effects of enduring pain or ELA-by-enduring pain interaction were observed across grey matter, white matter, or functional connectivity measures. ConclusionsELA was associated with alterations in fronto-striatal regions in late childhood, but these changes were not linked to enduring pain in early adolescence. These findings suggest that ELA-related neurobiological alterations may represent early markers of vulnerability rather than concurrent correlates of enduring pain. Longitudinal follow-up is needed to determine whether these alterations contribute to later chronic pain risk.