Haematologica

Chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 has transformed outcomes for children with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), yet the influence of molecular subtype on outcomes remains unclear. We evaluated the impact of cytogenetic and molecular signatures on complete response (CR), overall survival (OS), and leukemia-free survival (LFS) after CD19 CAR-T therapy in eighty-six pediatric patients with R/R B-ALL treated with tisagenlecleucel. CR was assessed 30 days after infusion. Cytogenetic data were available for 84 patients and molecular profiling for 62. Survival analyses included 72 patients who received CD19 CAR-T as the sole cellular therapy. Seventy-seven patients achieved CR (89.5%). Pre-infusion bone marrow blasts of [&ge;]20% were associated with lower CR rates (53.8% vs 95.9%, p<0.0001) and significantly reduced OS and LFS (both p<0.0001). Among molecular markers, RAS mutations correlated with inferior OS (p=0.0222) and LFS (0.0402). In multivariate analysis, bone marrow blasts >20% and RAS mutations independently predicted inferior OS. Post CAR-T, CD19 negative relapses showed almost twice higher prevalence of RAS mutations (66% vs 37.5%). These findings highlight RAS mutations as a key molecular predictor of outcome after CD19 CAR-T therapy and suggest emergence of unique risk stratification for patients receiving CD19-targeting therapy.

Children with acute lymphoblastic leukemia (ALL) are treated with multiagent chemotherapy that causes profound changes to the immune system. There are limited data on how disease and therapy impact antigen-specific immune memory, leading to inconsistent guidelines on best practices for revaccination of this population. Here, to inform vaccine guidance, we investigated whether immunity derived from routine childhood measles and varicella zoster virus (VZV) vaccines is maintained during and after therapy for childhood ALL. We report that antibodies against measles and VZV were significantly reduced in children with ALL (n=45) compared to healthy controls (n=13), particularly in older children in whom a longer time had passed since their most recent vaccine dose. However, the avidity of the measles and VZV-specific antibodies was indistinguishable between groups. Despite changes to the composition of the T cell compartment, both overall and antigen-specific T cell function were preserved in children with ALL. These data provide compelling evidence for revaccination of children following ALL treatment. Intact T cell responses suggest that post-treatment revaccination would be effective.

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated condition linked to chronic inflammation and an increased risk of cardiovascular diseases and hematological malignancies. People with HIV (PWH) exhibit a higher prevalence of CHIP than the general population, but the mechanisms underlying this association remain unclear. In particular, it is unknown whether the excess burden of CHIP reflects earlier emergence of mutant clones, altered clonal expansion dynamics, or differences in selective pressures acting on hematopoietic stem cells. We reconstructed longitudinal trajectories of CHIP variant allele frequency (VAF) in 52 PWH using serial peripheral blood samples spanning up to 25 years from the Swiss HIV Cohort Study. We used spline-based modelling to estimate clone size and growth dynamics, and dynamic time warping to identify common trajectory patterns. Associations between clonal dynamics and longitudinal immune parameters were assessed using linear mixed-effects models. Trajectories in PWH were compared with publicly available longitudinal CHIP data from the SardiNIA population cohort. We identified heterogeneous clonal dynamics consistent with known gene-specific fitness patterns. Larger clone size was associated with lower CD4 T-cell count and lower CD4/CD8 ratio. Compared with the general population cohort, PWH showed higher VAF across the observed age range and steeper early trajectory increases, while long-term expansion rates were broadly similar. Greater variability in clonal dynamics among PWH suggests a stronger contribution of host environmental factors to clonal fitness. These findings support a model in which HIV-associated immune dysregulation alters the hematopoietic fitness landscape, contributing to earlier detectable clonal expansion and increased burden of CHIP in PWH.

Waldenstrom macroglobulinemia (WM) is a rare indolent neoplasm characterized by presence of more than 10% lymphoid cells in BM that exhibit plasmacytoid or plasma cell differentiation that secretes an IgM monoclonal protein. This is a retrospective analysis of 89 patients of WM that describes the clinical and laboratory characteristics, treatment patterns and outcome of patients of WM. The median age of the entire cophort was 66 years with male predominance (67.4%). Most common presentations were symptoms pertaining to anemia (77.5%) and constitutional symptoms (33.7%). Median bone marrow lymphoplasmacytic cells were 41%. Positivity for MYD88 and CXCR4 mutations were seen in 81.8% and 2.4% cases. BR was the most common regimen used (52.8%). Overall response rates were seen at 87.8%. Median overall survival, progression free survival and time to next treatment is 8.49 years, 2.15 years and 3.88 years. BR regimen was associated with highest event free survival.

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.

Pathogenic variants in TP53, the key tumour-suppressor gene underlying Li-Fraumeni syndrome (LFS), are among the best-established causes of inherited cancer predisposition. However, large-scale sequencing has revealed that many apparently pathogenic TP53 variants detected in blood are the result of somatic clonal expansions, complicating risk interpretation. Using blood-derived whole-exome data from 469,391 UK Biobank participants, we combined variant allele fraction (VAF) with haplotype-sharing analysis to distinguish germline and somatic TP53 variants. Germline variants were concentrated at sites linked to partial loss of p53 function and lower disease penetrance, whereas classic LFS alleles appeared almost entirely somatic. High-VAF carriers of classic LFS alleles conferred markedly increased risk of haematological malignancy but not solid tumours, consistent with large TP53-mutant clonal expansions. The prevalence of somatic clonal expansion also correlated with missense variant pathogenicity, suggesting that somatic activity provides an informative in vivo proxy for functional impact. These results provide new insights into TP53-associated cancer risk at the population level, demonstrate that somatic rather than germline risk predominates in middle-aged healthy adults and provide a scalable framework for variant classification in large-scale population genomics.

Children with relapsed or refractory acute lymphoblastic leukemia (ALL) require more effective and less toxic therapies. We established a prospective, multicenter Drug Response Profiling (DRP) registry (NCT06550102) integrating functional testing into precision-guided treatment. DRP was performed for 340 patients from 17 European countries with a turn-around time of two-weeks. Image-based drug screening with over 135000 unique perturbations revealed a heterogeneous landscape of ex vivo responses to 88 drugs on average. Ranking drug responses across the patient cohort defined individual drug fingerprints, identifying "DRP twins" by similarity in sensitivity and resistance independent of genetic ALL subtypes. Of 239 high-risk patients with follow-up, DRP-informed interventions were reported for 63 patients (26%). Patients received combination therapies based on venetoclax, tyrosine kinase inhibitors, trametinib, bortezomib or selinexor, resulting in objective clinical responses in 43 cases (68%). Precision-guided treatments allowed bridging to cellular therapies in 42 patients among whom 28 (67%) were still alive with a median follow-up of 21 months after DRP (IQR: 14.7-26.6 months). Top responders to venetoclax, ranked within the first tertile of the cohort, had superior 1-year event-survival compared to venetoclax non-responders (0.57 [95% CI, 0.39-0.85] vs. 0.25 [95% CI, 0.11-0.58]). Collectively, these findings demonstrate the feasibility and clinical relevance of functional profiling within an international network. This scalable framework enables individualized therapy selection for enrolment in adaptive precision trials for high-risk pediatric ALL.

PurposeIdiopathic hypogonadotropic hypogonadism (IHH) is characterized by impaired reproductive maturation, and approximately half of all cases lack an identified genetic cause. We investigated the genetic basis of IHH in two large cohorts to identify novel disease-causing genes. MethodsWe analyzed exome and genome sequencing data from 1,822 patients with IHH from two independent cohorts. Rare variants were filtered using pedigree-informed inheritance models. PLEKHA6 expression in the postmortem human hypothalamus were tested at the mRNA and protein level. Functional studies assessed kisspeptin secretion in cell-based assays. ResultsWe identified 18 distinct PLEKHA6 variants in 24 patients from 20 unrelated families (1.3% of cohort). Variants segregated with disease under autosomal recessive and autosomal dominant (with variable penetrance) inheritance patterns. PLEKHA6 was robustly expressed in the hypothalamus and showed clear colocalization with neurokinin B, which served as the marker for the GnRH pulse generator. Functional studies demonstrated that patient variants significantly impaired kisspeptin secretion. ConclusionPLEKHA6 is a novel IHH gene and the first reported regulator of kisspeptin secretion from the kisspeptin-neurokinin B-dynorphin (KNDy) neurons, which have recently been established as the GnRH pulse generator. These findings establish impaired kisspeptin release as a new disease mechanism in IHH and highlight the critical role of neuropeptide trafficking in reproductive function.

Rationale: Sepsis is a life-threatening syndrome causing significant morbidity and mortality especially in the aging population. Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition of clonal expansion of hematopoietic stem cells harboring somatic mutations associated with increased incidence of chronic illness and all-cause mortality. Objective: Evaluate the association of pre-illness CHIP with mortality and morbidity in patients admitted to the ICU with sepsis. Methods: We performed a retrospective study using a de-identified electronic health record linked with a DNA biorepository. We identified adult patients with sepsis who had DNA collected prior to ICU admission. We tested the association between CHIP status, determined from whole-genome sequencing, and ICU mortality, organ support-free days, and long-term survival adjusting for age, sex, race and Sequential Organ Failure Assessment (SOFA) score on ICU admission. Measurements and Main Results: Pre-illness CHIP was associated with increased sepsis mortality (OR = 1.54, 95% CI 1.13 to 2.07, P = 0.005) and fewer days alive and free of organ support (-1.7 days, 95% CI -3.2 to -0.2, P = 0.028) after adjusting for age, sex, race, and SOFA score. In sepsis survivors, CHIP was also associated with increased long-term mortality after discharge (HR 1.40, 95% CI 1.01 to 1.93, P = 0.041). Conclusions: Pre-illness CHIP was independently associated with increased mortality and morbidity in critically-ill adults with sepsis. These findings suggest that CHIP is a risk factor for sepsis severity. Elucidating the mechanism underlying this association could uncover new therapeutic interventions for sepsis.

Tourette Syndrome and other tic disorders (TD) are common, highly heritable neurodevelopmental conditions with complex genetic architectures. We conducted a genome-wide association study of 13,247 TD cases and 536,217 European ancestry controls and identified six independent genome-wide significant loci, including a pleiotropic signal at 3p21 shared with attention-deficit/hyperactivity disorder, among other traits. Gene prioritization highlighted 20 genes, including PCDH9, HCN1, NCKIPSD, WDR6, DALRD3, and CELSR3. Integrative analyses provide genetic support for the role of cortico-striato-thalamo-cortical circuits in TD pathophysiology and further localize TD genetic risk to specific cell types, including dopamine D1- and D2-receptor-positive medium spiny neurons, cortical pyramidal neurons, and oligodendrocyte-lineage cells. We further demonstrate extensive genetic correlations with neurodevelopmental and psychiatric traits, but not with neurological disorders. These findings advance our understanding of the genetic basis of TD, pinpointing specific genes and cell types that drive pathophysiology and providing a foundation for future mechanistic studies.

De novo mutations (DNMs) arising in the parental germline are a major cause of severe developmental disorders. While most DNMs originate in the paternal germline, it remains unclear whether fathers of affected children carry a systematically altered burden of transmissible germline risk, or whether disease largely reflects stochastic outcomes of shared population-wide mutational processes. Here, we combined whole-genome sequencing of 168 parent-child trios with ultra-accurate duplex sequencing of paternal sperm to directly relate transmitted DNMs to the broader mutational and selective landscape of the male germline. In 127 fathers, sperm mutation burden and mutational spectra were indistinguishable from population reference cohorts. Positive selection metrics were likewise concordant, with a global dN/dS of 1.56 (95% CI 1.45-1.67) compared to 1.44 (95% CI 1.17-1.77) in controls and 28 of 32 significantly selected genes overlapping with prior findings. Six fathers harboured a pathogenic early mosaic variant detectable in sperm at allele fractions that ranged from 0.7% to 14.8%. Although these variants generated substantial individual-level risk outliers, they accounted for only [~]11% of the aggregated exome pathogenic burden across the cohort. The remaining burden was distributed across low-VAF mutations, including positively selected driver variants and other rare mutations accumulating with paternal age. Together, these results show that transmissible de novo disease risk is governed primarily by universal germline mutational and selective processes, while early developmental mosaicism produces uncommon but clinically meaningful deviations. This integrated view clarifies how mutation timing, age-associated accumulation and germline selection jointly shape inheritance risk.

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.

Ewing sarcoma (EwS) is an aggressive, human-exclusive tumor typically driven by the EWS::FLI1 fusion protein. To assess whether the neomorphic functions of EWS::FLI1 are fundamentally dependent on evolutionarily recent cofactors such as ETS transcription factors (ETS-TFs), Plycomb group (PcG) proteins, CBP/p300, or specific subunits of the BAF complex, we expressed EWS::FLI1 in the model organism Saccharomyces cerevisiae. This minimal system was chosen because several key EWS::FLI 's cofactors possess greatly reduced sequence homology (e.g., BAF) or are lacking altogether (e.g., ETS-TFs, PcG, or CBP/p300). We used co-IP/MS to map the yeast interactome, Chip-Seq to identify gDNA binding sequences, RNA-Seq for global gene expression, and engineered reporters to test conversion of (GGAA) tandem repeats (GGAASat) into neoenhancers. We found that the yeast EWS::FLI1 interactome was more limited and qualitatively distinct from its human counterpart, sharing core machinery (e.g. RNA Polymerase II, FACT) but lacking the BAF/SWI-SNF and spliceosome complexes, and showing strong enrichment for the SAGA chromatin remodeling complex. We also found that EWS::FLI1 binds to hundreds of sites in the yeast genome with a clear preference for putative ETS-TF consensus sequences and (CA) dinucleotide repeats. Yet, EWS::FLI1 expressing cells presented only minimal transcriptional dysregulation, a stark contrast to the extensive changes observed in humans and Drosophila cells. Finally, we found that EWS::FLI1 successfully converted silent GGAASat sequences into active enhancers in yeast. This remarkable result occurs despite the absence of homologs for key human activators, such as CBP/p300, strongly suggesting that EWS::FLI1 can mobilize functionally related, non-homologous pathways to establish neoenhancers at GGAASat sites. Altogether, our results indicate that EWS::FLI1's core ability to drive GGAASat-dependent gene expression is a conserved, ancient property, while GGAASat-independent extensive transcriptome reprogramming is dependent on co-factors and pathways specific to animal cells.

ELF4 is an ETS family transcription factor involved in immune regulation, and germline loss-of-function mutations in ELF4 have been known as deficiency in ELF4, X-linked (DEX). To date, ELF4-related disease has been exclusively associated with germline mutations. Here, we report a pediatric patient with recurrent mucocutaneous inflammation and periodic fever caused by a somatic truncating mutation in ELF4. By directly comparing ELF4-mutant and wild-type immune cells within the same individual using full-length single-cell RNA sequencing, we identified mutation-associated transcriptional alterations across multiple immune cell types. Pathway analyses revealed cell type-specific immune alterations, characterized by reduced antiviral and interferon-related signaling in NK cells and enhanced inflammatory pathways related to Th17 differentiation and inflammatory bowel disease in CD16 monocytes. This study expands the disease spectrum of ELF4 deficiency by identifying somatic truncation of ELF4 as a genetic mechanism underlying autoinflammatory diseases and biased immune programs.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest human cancers. The current largest published PDAC Genome-Wide Association Study (GWAS) identified 23 genetic risk signals, but most lack sufficient characterization. This study aimed to functionally characterize the chr13q12.2 (PLUT/PDX1) PDAC GWAS risk locus. Fine-mapping, luciferase reporter assays, and electrophoretic mobility shift assays implicated rs9581943, a PDX1 promoter SNP, as a functional variant underlying this GWAS signal. GTEx expression QTL analyses identified rs9581943 as a significant PDX1 eQTL in pancreas, and CRISPR/Cas9 editing in PDAC-derived cell lines confirmed a functional relationship. PDX1 is a transcription factor involved in early pancreas development and {beta}-cell homeostasis, but its role in exocrine pancreatic cells is unclear. Single-nucleus RNA-seq analyses of pancreatic acinar and ductal cells from neonatal, adult, and chronic pancreatitis donors suggested PDX1 activity alleviates high secretory load and ER-stress in acinar and biases ducts toward homeostatic phenotypes. Similarly, scRNA-seq analyses of pancreatic tumors suggested PDX1 activity reduces biosynthetic and inflammatory stress and promotes epithelial differentiation. Our study therefore implicates rs9581943 as a causal variant for the chr13q12.2 PDAC GWAS signal wherein the risk allele reduces PDX1 expression, eroding PDX1's capacity to buffer stress and stabilize epithelial cell fate in the exocrine compartment.

Wearable-derived physiological features have been associated with disease risk, but most current studies focus on single conditions, limiting understanding of cross-disease patterns. This study adopts a trans-diagnostic approach to examine whether wearable data capture shared and condition-specific physiological signatures across multiple chronic conditions spanning physical and mental health, and then evaluates the utility of these features for disease classification. A total of 9,301 patients with at least 21 days of consecutive FitBit data from the All of Us Controlled Tier Dataset version 8 were analyzed. Disease subcohorts included cardiovascular disease (CVD), diabetes, obstructive sleep apnea (OSA), major depressive disorder (MDD), anxiety, bipolar disorder, and attention-deficit/ hyperactivity disorder (ADHD), chosen based on prevalence and relevance. Logistic regression and XGBoost models were fitted for each disease subcohort versus the control cohort. We found that compared to using just baseline demographic and lifestyle features, incorporating wearable-derived features enabled improved classification performance in all subcohorts for both models, except for ADHD where improvement was mainly observed for ROC-AUC in logistic regression model likely due to the smaller sample size in ADHD subcohort. The largest performance gains were observed in MDD (increase in ROC-AUC of 0.077 for Logistic regression, 0.071 for XGBoost; p < 0.001) and anxiety (increase in ROC-AUC of 0.077 for logistic regression, 0.108 for XGBoost; p < 0.001). This study provides one of the first comprehensive transdiagnostic evaluations of wearable-derived features for disease classification, highlighting their potential to enhance risk stratification in the real-world setting as a practical complement to clinical assessments and providing a foundation to explore more fine-grained wearable data. Author summaryWearable devices such as fitness trackers and smartwatches are becoming increasingly popular and affordable, providing continuous measurements of heart rate, physical activity, and sleep. Alongside the growing digitization of health records, this creates new opportunities for large-scale, real-world health studies. In this study, we analyzed wearable-derived physiological patterns across a range of chronic conditions spanning both physical and mental health to better understand how these signals relate to disease risk. We found that incorporating wearable-derived heart rate, activity and sleep features improved disease risk classification across several conditions, with particularly strong gains for major depressive disorder and anxiety. By examining how individual features contributed to model predictions, we also identified meaningful associations between physiological signals and disease risk. For example, both duration and day-to-day variation of deep and rapid eye movement (REM) sleep were associated with increased risk in certain conditions. Our study supports the development of real-time, automated tools to assess disease risk alongside clinical care.

Childhood socioeconomic position (SEP) can have lifelong effects on health. Many studies have used adult height as a surrogate marker for early-life conditions. In this study, we derived the non-genetic component of height, calculated as the residual from sex-specific standardized height regressed on genetically predicted height, as a surrogate for childhood SEP, using data from the Hispanic Community Healthy Study/Study of Latinos (2008-2011). A positive residual would indicate favorable early-life conditions promoting growth, while a negative residual indicates early-life adversity that may stunt the development. The height residual was associated with early-life variables such as parental education, year of birth, US nativity and age at first migration to the US (50 states/DC), supporting the validity of height residual as a surrogate for early-life conditions. Furthermore, a height residual was positively associated with better cardiovascular health (CVH) and cognitive function among middle-aged and older adults. Interestingly, among <35 years old, the height residual was negatively associated with the "Lifes Essential 8" clinical CVH scores. These results suggest the non-genetic component of height as a surrogate for childhood environment, with predictive value for CVH and cognitive function.

ObjectivesWe determined the frequency of sexually transmitted infection (STI) testing among people accessing sexual health services (SHS) in England. MethodsWe assessed STI testing frequency in face-to-face and online SHSs in England using data from the GUMCAD STI surveillance system. We quantified different combinations of tests (e.g. single chlamydia test or full STI screen), number of tests completed in 2024 and test positivity by sociodemographic and behavioural characteristics, as well as clinical setting and outcomes. ResultsOverall, there were 2,222,028 attendances at SHS in England in 2024 that involved tests for chlamydia, gonorrhoea, syphilis and/or HIV. Most of these attendances involved tests for all four of these STIs. Most people accessing SHS in England tested once (80.1%), and a small minority (1.9%) tested at least quarterly (4+ times). Some groups had a comparably larger proportion of quarterly testers; these included gay, bisexual, and other men who have sex with men (GBMSM) (6.7%), London residents (3.6%), online testers (2.5%), people using HIV-PrEP (13%), and people with 5+ partners in the previous 3 months (10.6%). Only 10.5% of GBMSM reporting higher-risk sexual behaviours tested quarterly despite recommendations for quarterly testing in this group. ConclusionsThe majority of those who tested for STIs in England in 2024 only tested once. The minority who tested at least quarterly had a higher proportion of GBMSM, people using HIV-PrEP, London residents and people reporting higher risk behaviours. Quarterly testing often appears to be aligned with current testing recommendations in England; however, we also observed that only a low proportion of behaviourally high-risk GBMSM and HIV-PrEP users are meeting these recommendations. It is important to acknowledge groups with lower or higher testing frequency when developing interventions and updating guidelines related to STI testing. WHAT IS ALREADY KNOWN ON THIS TOPICThe effectiveness of asymptomatic testing for chlamydia and gonorrhoea in gay, bisexual and other men who have sex with men (GBMSM), and the potential impact of the consequent increased antibiotic use on rising antimicrobial resistance and individual harm has recently been questioned. Testing and treatment remains a key pillar of STI prevention and management; despite this, there is limited evidence of STI testing frequency within sexual services (SHS) on a national level. WHAT THIS STUDY ADDSThis analysis shows that the majority of people attending SHSs in England in 2024 tested once, and only a small proportion of behaviourally high-risk people tested frequently. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYAwareness of groups that are behaviourally high risk but testing infrequently is important to guide interventions and messaging regarding STI testing. The low levels of frequent testing, even among those who would be recommended quarterly testing under UK guidelines, provides important context for wider discussion around asymptomatic STI screening.

BackgroundTimely cancer diagnosis in children and adolescents is critical to improving outcomes, yet substantial variation in diagnostic intervals persists across cancer types and care settings. We aimed to quantify time to diagnosis and assess variations by patient, demographic, and system-level factors. MethodsWe conducted a retrospective population-based study of children and adolescents aged 0-19 years diagnosed with one of 12 common cancers between 2010 and 2022 in Quebec, Canada. The diagnostic interval was defined as the time from first cancer-related healthcare encounter to diagnosis. We calculated medians and interquartile ranges (IQR) overall and by cancer type and used multivariable quantile regression to identify factors associated with time to diagnosis at the 25th, 50th, and 75th percentiles. ResultsAmong 2,927 individuals with cancer, diagnostic intervals varied by cancer type and age. Median intervals were longest for carcinomas (100 days; IQR 33-192) and shortest for leukemias (8 days; IQR 3-44). Compared with children living in Montreal, living in regional areas and other large urban centres was associated with longer 50th and 75th percentiles of time to diagnosis for hepatic and central nervous system (CNS) tumours. Diagnostic intervals were shorter in the post-pandemic period (2020-2022) across several cancer sites, with CNS tumours showing reductions across all quantiles. InterpretationDiagnostic timeliness differed by cancer type, age, and rurality, but not by sex, material, or social deprivation. The shorter diagnostic intervals observed in the post-pandemic period suggest that pandemic-related changes in care pathways may have expedited diagnosis for some cancers.

BackgroundAccelerometer-derived behavioral phenotype captures multidimensional aspects of human behavior extending well beyond physical activity, encompassing light exposure, step counts, physical activity patterns, sleep, and circadian rhythms. Whether these five domains constitute a unified behavioral architecture underlying cancer risk and whether circadian organization and light exposure confer incremental predictive value beyond movement volume alone remains to be comprehensively established. MethodsWe conducted an accelerometer-wide association study (AWAS) encompassing the complete accelerometer-derived behavioral exposome across five behavioral domains in UK Biobank participants with valid wrist accelerometry data. Incident solid cancers were designated as the primary endpoint, with prespecified site-specific solid cancers and hematological malignancy as secondary outcomes. Cox proportional hazards models with age as the timescale were used. The minimal covariate set served as the primary reporting tier, followed by sensitivity analyses additionally adjusting for adiposity/metabolic factors, independent activity patterns, shift work history, and accelerometry measurement quality. Nominal statistical significance was defined as two-sided P < 0.05 ResultsAmong 89,080 participants, 6,598 incident solid cancer events were observed over a median follow-up of 8.39 years. In the minimally adjusted model, the pan-solid-tumor association atlas was dominated by signals from activity volume, inactivity fragmentation, and circadian rhythm. Higher overall acceleration (HR per SD: 0.91, 95% CI: 0.89-0.94) and higher daily step counts (HR: 0.93, 95% CI: 0.90-0.95) were independently associated with reduced solid cancer risk, while inactivity fragmentation metrics were consistently linked to higher risk. Notably, circadian rhythms, most prominently cosinor mesor (Midline Estimating Statistic of Rhythm under cosinor model), emerged as leading inverse risk signals, underscoring the independent contribution of circadian behavioral architecture. Site-specific analyses revealed pronounced heterogeneity across tumor sites. Lung cancer exhibited a robust inverse activity-risk gradient, while breast cancer showed reproducible associations with MVPA. Most strikingly, nocturnal light exposure demonstrated a tumor-site-specific association confined to pancreatic cancer, a signal absent across all other sites examined. Associations for uterine cancer were predominantly inactivity-related and substantially attenuated following adjustment for adiposity and metabolic factors. ConclusionsAcross five accelerometer-derived behavioral domains, solid cancers as a whole were most consistently associated with a high-movement, low-fragmentation, and circadian-coherent behavioral profile. While site-specific heterogeneity exists, the broad cancer risk landscape is dominated by movement volume, inactivity fragmentation, and circadian rhythmicity. Light exposure, although more localized in its contribution, demonstrates a potentially novel and specific association with pancreatic cancer risk. These findings support a five-domain behavioral exposome framework for cancer epidemiology and, importantly, position circadian rhythm integrity and nocturnal light exposure as critically understudied dimensions warranting dedicated mechanistic investigation.