Clinical Epidemiology

Introduction Acute lower respiratory tract disease (aLRTD) is a leading cause of hospitalisation and death, particularly in older adults and adults with comorbidities, with acute lower respiratory tract infection (aLRTI; pneumonia and non-pneumonic LRTI) being a major component. Non-pulmonary complications and functional decline after aLRTI are recognised, but their pathogen-specific burden is poorly described. We aimed to quantify renal, hepatic, thromboembolic and functional complications, and mortality, after aLRTI hospitalisation, by clinical phenotype and pathogen. Methods We conducted a cohort study of adults (>18 years) admitted with aLRTD to two hospitals in Bristol, UK (01 August 2022-31 July 2024). aLRTD was classified as pneumonia, non-pneumonic LRTI (NP-LRTI) or no diagnosis of aLRTI. Pathogens were identified from standard-of-care and research microbiology. Outcomes were acute kidney injury (AKI), acute liver dysfunction, venous thromboembolism (VTE), in-hospital falls, reduced mobility at discharge, increased care requirements, and 30-day and 1-year mortality. Analyses were descriptive. Results Among 246,797 adult admissions, 21,456 aLRTD hospitalisations were included: 10,239 (47.7%) pneumonia, 7,742 (36.1%) NP-LRTI and 3,475 (16.2%) with no evidence of aLRTI. Of 19,152 tested aLRTD admissions, 8,503 (44.4%) had a positive microbiological/virological test, yielding 9,204 pathogen detections; 1,194 (6.2%) had co-infections, and SARS-CoV-2 was most frequent, with influenza the second most common in pneumonia and NP-LRTI. Pneumonia had greater severity than NP-LRTI and no diagnosis of aLRTI (median length of stay 6 vs 4 vs 4 days; ICU admission 3.4% vs 0.7% vs 0.5%, respectively). Overall, 22.2% developed AKI, 6.1% acute liver dysfunction, 0.6% DVT and 2.4% PE; 1.8% had a fall, 11.5% reduced mobility, and 16.6% required increased care at discharge. 30-day and 1-year mortality were highest for pneumonia (14.0% and 32.0%, respectively). Pathogen-specific analyses showed longer stays and higher complications and mortality rates for SARS-CoV-2 and Streptococcus pneumoniae, and shorter stays with lower complication and mortality rates for influenza and Haemophilus influenzae. Conclusions Non-cardiovascular complications and functional decline after aLRTI were common, particularly in pneumonic and SARS-CoV-2 or pneumococcal disease. These findings support routine surveillance for renal, hepatic, thromboembolic events, early mobilisation and rehabilitation, and consideration of multi-system outcomes when evaluating public health and economic value of vaccines and therapies.

Background: The relative merits of infrainguinal bypass and primary major lower limb amputation (MLLA) for chronic limb-threatening ischaemia (CLTI) remain uncertain, and the baseline profiles of patients selected for each strategy are poorly described. Methods: A systematic review and meta-analysis were undertaken in accordance with PRISMA 2020 and prospectively registered (PROSPERO: CRD42022356094). MEDLINE, Embase, CENTRAL, and CINAHL were searched from inception to March 2025. Prospective studies of adults with CLTI undergoing primary infrainguinal bypass or primary MLLA were eligible. Mortality, major adverse cardiovascular events (MACE) and subsequent amputation outcomes were synthesised using random-effects meta-analysis of proportions. Baseline comorbidity profiles were also extracted. Results: Twenty-seven studies involving 6,576 patients were included: 5,779 underwent infrainguinal bypass and 797 underwent MLLA. After bypass, pooled mortality was 3.7% at 30 days (95% CI 2.8%-4.9%, I2 = 49.4%), 18.5% at 1 year (95% CI 15.6%-21.9%, I2 = 62.3%), and 54.3% at 5 years (95% CI 50.5%-58.0%, I2 = 0%). After MLLA, pooled mortality was 9.2% at 30 days (95% CI 4.1%-19.3%, I2 = 73.5%), 28.5% at 1 year (95% CI 13.3%-51.0, I2 = 70.8%), and 39.9% at 2 years (95% CI 0.3%-99.3, I2 = 90.5%), although longer-term estimates were limited by sparse data and marked heterogeneity. Thirty-day MACE was 6.5% (95% CI 4.3%-9.7, I2 = 63.5%) after bypass and 2.8% after MLLA (95% CI 0.1%-37.6%, I2 = 0%). Early subsequent major amputation after bypass occurred in 3.9% of patients (95% CI 2.0%-7.7%, I2 = 91.2%), rising to 16.2% at 1 year (95% CI 12.6%-20.5%, I2 = 82.0%) and 33.3% at 3 years (95% CI 20.1%-49.8%, I2 = 0%). Early re-amputation after MLLA occurred in 10.9% of patients (95% CI 4.5%-24.4%, I2 = 40.3%). Baseline comorbidity burden was high in both groups, with substantial heterogeneity across studies. Conclusions: CLTI carries a poor prognosis regardless of treatment strategy. Infrainguinal bypass is associated with lower early mortality and better early limb preservation than primary MLLA, but long-term survival remains poor and later limb failure is common. Primary MLLA is not a low-risk alternative. Better contemporary comparative evidence utilising modern causal inference approaches is needed to support individualised decision-making.

Study design Retrospective cohort study. Objectives To correlate Hounsfield unit (HU) values, using elliptical regions of interest (ROI), that can be easily defined in routine clinical practice with magnetic resonance imaging (MRI) T2-hyperintense area fraction, as a surrogate for paraspinal muscle fat infiltration and to establish specific HU screening thresholds that may be applied with standard picture archiving and communication system (PACS). Methods We included 136 patients (71 men; 61.0 {+/-} 15.4 years) who underwent preoperative computed tomography (CT) and MRI within an 8-week period. Elliptical ROI HU values were measured at L2/3 and L4/5 for erector spinae, multifidus, and psoas major. MRI T2-hyperintense area fraction (Otsu thresholding) served as the fat infiltration reference. Linear mixed-effects (LME) models were used to assess the HU-T2 association and level-specific receiver operating characteristic (ROC) analyses (lower HU value side; n=136 per muscle-level) to identify thresholds for [≥]30% and [≥]50% infiltration criteria. Results Intraclass coefficients = 0.709 (HU) and 0.857 (T2 fraction); Goutallier weighted kappa = 0.579. In the overall LME, {beta} was -0.880 HU per 1% T2-fraction increase (95% confidence interval -0.935 to -0.825; marginal R2 =0.502); the association was steeper in multifidus ({beta} = -1.020) than in erector spinae ({beta} = -0.753). Psoas major (R = -0.226) was excluded from ROC analyses. Difference between L2/3 and L4/5 HU cutoffs was ~20 HU. The [≥]50% criterion revealed higher discrimination. Conclusions Elliptical ROI-based HU measurements may reliably screen paraspinal muscle fat infiltration in erector spinae and multifidus using standard PACS. Specific thresholds may allow practical preoperative evaluation without additional costs or radiation.

Large genomically annotated acute myeloid leukaemia (AML) datasets exist, but population-based contemporary cohorts remain scarce. Here we report clinicopathological, genomic, and outcome data from Danish AML patients. 2,512 AML patients were identified between 2015-2022, of whom 33.8% had available NGS data (NGS+). In patients [≤]70 years, baseline characteristics and outcomes were comparable between NGS+ and NGS- groups. In patients >70 years, more NGS+ patients received intensive treatment, but survival was similar among intensively treated patients. The distribution of mutations varied significantly by age and sex, with older age and male sex exhibiting higher frequencies of adverse-risk gene mutations. In intensively treated NGS+ patients, ELN2017 stratified 5-year OS: 58.4% (favorable), 43.4% (intermediate), and 28.2% (adverse), with hazard ratios (HRs) of 0.63 (favorable) and 1.45 (adverse) relative to intermediate. ELN2022 yielded corresponding OS rates of 56.9%, 51.8%, and 29.7%, with HRs of 0.78 and 1.86. The two models had comparable predictive performance for OS in a time-dependent model. In conclusion, outcomes of intensively treated AML patients were comparable irrespective of NGS status, underscoring the representativeness of the REFORM-AML database for the Danish AML population. Age and male sex correlated with adverse-risk mutations, and both ELN2017 and ELN2022 robustly predicted survival.

Background: Lumbar disc herniation, with or without concomitant disc degeneration, is a major cause of lumbar radiculopathy and low back pain, which also a key public musculoskeletal disorder without an exact pathophysiology. Studies have suggested that inflammatory cells and biochemical markers of inflammation also play an important role in lumbar radiculopathy in addition to nerve compression. The aim of the present study was to assess the association of selected circulatory inflammatory markers (CRP, hs-CRP and E-selectin) in patients with lumbar disc herniation without radiological degeneration (LDH) and lumbar disc herniation with radiological degeneration (LDHD). Materials & methods: This case-control study included 208 participants, comprising 104 patients with lumbar disc pathology and 104 controls. Patients were further stratified into LDH (n=67) and LDHD (n=37). Serum CRP, hs-CRP and E-selectin concentrations were measured. Results: Among the patients, 35.6 % presented with LDHD while 64.4 % had only LDH. Significantly increased median hs-CRP (p<0.001) and CRP (p<0.001) were observed in patients groups compared to controls, while CRP showing a consistent independent association across the combined disease (OR=1.68, 95% CI=1.33-2.14, p<0.001), LDHD (OR=1.62, 95% CI=1.16-2.20, p=0.005) and LDH (OR=1.69, 95% CI=1.30-2.20, p<0.001) multivariable models. No significant difference was observed in serum E-selectin between the study groups. Multivariable models incorporating inflammatory and clinical variables demonstrated substantially greater discriminatory performance than individual biomarkers alone. Conclusion: Elevated circulating CRP and hs-CRP concentrations were associated with lumbar disc pathology, with CRP showing a consistent independent association across the combined disease, LDH and LDHD multivariable models, whereas E-selectin showed no significant association. Multivariable models incorporating inflammatory and clinical variables demonstrated greater discriminatory performance than individual biomarkers. These findings support a potential systemic inflammatory component in lumbar disc pathology, although the cross-sectional nature of the measurements does not establish causality or a local inflammatory response within the disc.

Rationale: Pulmonary hypertension is defined by pulmonary hemodynamics, but diagnostic and prognostic biomarkers remain limited. Nuclear magnetic resonance (NMR) spectroscopy provides detailed insights, particularly in the lipid metabolism. Objectives: To explore circulating NMR-derived metabolites and lipoprotein-related parameters for their association with pulmonary hemodynamics and to analyse their prognostic properties in pulmonary arterial hypertension (PAH). Methods: Retrospective analysis of a PAH cohort with complete diagnostic workup including right heart catheterization and baseline serum samples, from the prospective GRaz Pulmonary Hypertension-Metabolism (GRAPH-M) registry. Measurements: NMR-derived metabolites and lipoprotein-related parameters were analyzed for their association with clinically relevant parameters of PAH. We defined PHIHDL, a score derived from high-density lipoprotein (HDL) related measures based on their strong association with pulmonary hemodynamics, and evaluated its prognostic value. Results: We included 100 patients with PAH treated at the PH clinic of LKH University Hospital, Medical University of Graz, between 2011 and 2021. Age was 61{+/-}15 years, female/male ratio 2.5, BMI 26 {+/-}7 kg/m2, mPAP 41{+/-}16 mmHg, PAWP 8.8{+/-}3.2 mmHg, PVR 8.0{+/-}4.9 WU, and median survival was 8.0 years. During follow-up, 46 patients died. We identified a cluster of 12 HDL-related measures that showed significant inverse association to pulmonary hemodynamics and derived PHIHDL from the reversed scaled average of these particles. PHIHDL was associated with all-cause mortality after adjustment for age and sex (HR 2.96, 95% CI 1.52-5.70), independent of the clinical risk scores COMPERA 2.0 and REVEAL Lite2. Conclusion: PHIHDL, a pulmonary hemodynamics-based metabolomic score, provides independent prognostic information beyond established risk scores in PAH.

Objectives To analyse the long-term effects of a cruciate ligament (CL) injury on health and socioeconomic outcomes. Methods We used a comprehensive national injury insurance database to identify CL injuries occurring in New Zealand between 2009 and 2022, and employed a doubly robust staggered difference-in-differences research design to identify the effects of these injuries on outcomes up to 10 years after injury. The outcomes of interest were healthcare use (hospitalisations, emergency department visits, medications, knee replacement surgery for osteoarthritis), associated healthcare costs, and labour market outcomes (employment rates, income, and government benefit payments). Results We identified 61 344 CL injuries for inclusion in the analysis. Over 10-year follow-up, a CL injury resulted in increased healthcare use (0.6 more hospitalizations [95%CI 0.4 to 0.7], 1.7 more days spent in hospital [95%CI 1.3 to 2.1], 0.4 more emergency department visits [95%CI 0.3 to 0.6], 2.5 more outpatient visits [95%CI 1.8 to 3.2], and 4.7 more medications dispensed [95%CI -1.8 to 11.2]) and public healthcare costs ($7 537; 95%CI 5 888 to 9 186), reduced income (-$6 060; 95%CI -11 644 to -475), and increased benefit payments ($1 152; 95%CI 542 to 1 761). Conclusion CL injuries have long-term impacts on healthcare use and socioeconomic outcomes. Strategies to reduce the incidence of CL injuries have the potential to realise large health and economic benefits.

Large Language Models (LLMs) are increasingly used by clinicians and patients for medical queries, yet their accuracy and safety at the specialist level in hematology remain insufficiently characterised. We benchmarked ten frontier proprietary and open-weight LLMs across two generations on 1,477 board-style hematology multiple-choice questions (MCQs) derived from five educational datasets spanning nine disease areas and six clinical skill domains, including text-only and multimodal case vignettes. Claude Opus 5 had the highest mean accuracy (92.7% text, 76.9% multimodal), followed closely by Gemini-3.1 Pro (91.4% and 78.7%), Gemini-3.6 Flash (91.0% and 74.8%) and GPT-5.6 Sol (89.9% and 76.7%). Accuracy significantly correlated with model size both for text-only and multimodal MCQs. Between model generations, the largest improvements in accuracy were seen for open-weight models whereas proprietary models showed only marginal gains. In error analysis, top-performing models exhibited highly concordant failure patterns, suggesting shared limitations on challenging cases. Frontier LLMs exhibit substantial specialist hematology knowledge across diverse subspecialist domains and clinical skill sets. Yet, despite high accuracy on board-style questions in hematology, continuous expert-on-the-loop output monitoring is paramount.

Background: Sickle cell anaemia (SCA) is characterised by chronic haemolysis, inflammation, platelet activation, and recurrent vaso-occlusive complications. Mean platelet volume (MPV) is a readily available platelet index, but evidence regarding its relationship with disease severity in paediatric SCA remains limited and inconsistent, particularly in African populations. Objective: To evaluate the relationship between MPV and disease severity among children with SCA in Kwara State, North-Central Nigeria. Methods: This hospital-based cross-sectional study included 51 clinically stable children with confirmed SCA consecutively recruited from the paediatric haematology clinic of Children Emergency Specialist Hospital, Ilorin. Complete blood count, including MPV, was performed using a Rayto RT-7600 automated haematology analyser. Disease severity was assessed using a composite clinical and laboratory scoring system based on a previously described method. Pearson's correlation, Spearman's rank correlation, simple linear regression, and the Kruskal-Wallis test were used as appropriate. Statistical significance was set at p < 0.05. Results: Of 51 participants, 14 (27.5%) had mild, 33 (64.7%) moderate, and 4 (7.8%) severe disease. Mean MPV was 9.34 +/- 0.76 fL (range, 8.0-11.2). Pearson's correlation showed a weak positive, non-significant linear relationship with severity score (r = 0.231, p = 0.103), whereas Spearman's analysis showed a weak positive monotonic association (rho = 0.286, p = 0.042). Regression explained 5.3% of severity-score variation (R2 = 0.053, p = 0.103). MPV did not differ significantly across severity categories (H = 2.163, p = 0.339). MPV correlated inversely with haemoglobin (r = -0.556, p < 0.001) and positively with platelet count (r = 0.307, p = 0.029). Conclusion: MPV showed a weak relationship with disease severity but inconsistent statistical evidence across analyses. The limited explained variance and absence of significant differences between severity categories do not support MPV as a standalone severity marker. Larger longitudinal studies are warranted. Keywords: Sickle cell anaemia; Mean platelet volume; Disease severity; Platelet indices; Paediatric haematology; Cross-sectional study; Nigeria.

Pneumococcal vaccination of older adults is primarily guided by age and clinical eligibility, despite substantial variation in individual risk of severe pneumonia. Here, we used longitudinal electronic health records from 787,538 adults aged [&ge;]65 years to evaluate the real-world effectiveness of the 20-valent pneumococcal conjugate vaccine (PCV20) and quantify clinical benefit according to baseline risk of pneumonia hospitalization. We developed and validated a machine-learning model using pre-PCV20 data to estimate individual 12-month hospitalization risk and integrated these predictions into a propensity score matching framework. Overall vaccine effectiveness against pneumonia hospitalization was 16.5% (95% CI, 10.6-22.1), but this population-level estimate masked substantial heterogeneity in clinical benefit. The 60% at lowest predicted risk, characterized by younger age and fewer pulmonary and other chronic conditions, showed no measurable reduction in hospitalization (VE, 3.1%; 95% CI, -14.4 to 18.0) and had an estimated 1-year number needed to vaccinate (NNV) of 7,423, compared with 184 and 115 in the intermediate- and high-risk groups, respectively. These findings suggest that incorporating baseline risk into adult pneumococcal vaccination strategies could enable more targeted and potentially better-timed vaccination.

Wearable (accelerometer) data and machine-learning allow objective assessment of the amount of daily physical activity. However, wearable-derived human activity is subject to measurement error. No studies have corrected the dose-response association between physical activity and survival time to chronic diseases, including cardiovascular disease (CVD). The objective is to estimate the measurement error-corrected association between CVD events and multiple measures of daily duration of light and total physical activity, derived from machine-learning and conventional accelerometer-processing methods. Our method combined an accelerated failure time model, spline, and simulation-extrapolation (SIMEX). The method recovered the true dose-response non-linear association in simulated data, while the naive model failed to capture it due to substantial attenuation. Application to the UK Biobank accelerometer cohort also showed an increased protective association of total physical activity after SIMEX correction (Time Ratio [TR] = 1.56, 95% CI: 1.28-1.82 vs. TR = 1.38, 95% CI: 1.24-1.54 for SIMEX-corrected vs. uncorrected dose-response association between the 95th and 5th percentiles of total activity), with a similar increase for light physical activity. Sensitivity analysis indicates that the female population experiences a substantially larger protective association after SIMEX correction than males. Dose-response survival analysis is a widely used analytical method in physical activity epidemiology and benefits from measurement error correction.

Background. Whether predictors of intraoperative hypotension (IOH) add information beyond the mean arterial pressure (MAP) already displayed on the monitor is contested: selection bias in common evaluation designs inflates apparent performance, and the field has called for comparisons against simple MAP-based references under bias-resistant protocols. Existing predictors also depend on proprietary waveform analysis or pulse-contour monitors, restricting both deployment and external validation. Methods. Using 807 non-cardiac surgery patients from the open VitalDB database, we derived an additive gradient boosting model (one split per tree: a learned shape function per variable, no interactions) from three variables computable from an arterial line alone: current MAP, its drift from the patient's own 20-minute baseline, and the growth of its rolling variance (critical slowing down). Evaluation used patient-level 5-fold cross-validation under a strict protocol - exclusion of the 65-75 mmHg grey zone and of all samples already hypotensive at prediction time - with MAP alone (same learner class) as comparator. The frozen model was then validated, without any refitting, on an independent cohort from another continent (MOVER, University of California Irvine) following a pre-registered plan sealed before external data access. Results. In development the pressure-only model reached AUROC 0.907 vs. 0.884 for MAP alone (Delta AUROC +0.023, 95% CI +0.017 to +0.029) at 5 min, with +0.031 and +0.032 at 10 and 15 min, and good calibration (Brier skill +0.418 vs. prevalence). In external validation on 3,069 patients (442,194 samples, 1-minute charting, event prevalence 5.8%), the advantage not only transferred but was larger than in development: AUROC 0.696 vs. 0.638, Delta AUROC +0.058 (95% CI +0.051 to +0.064), meeting both pre-registered gates. Discrimination transferred; calibration did not (external Brier skill -0.014), requiring local recalibration. In the unrestricted scenario, where samples already at threshold are retained, the advantage collapsed (+0.007), reproducing the selection effect this paper documents. A secondary model adding pulse-contour cardiac output and stroke volume variation improved development discrimination further (Delta AUROC +0.035) but could be externally validated in only 39 patients, because those signals are rarely recorded. Conclusions. The dynamics of arterial pressure itself - drift from a patient-specific baseline and variance growth - carry predictive information beyond its current value, in a fully interpretable additive model that requires only an arterial line, no waveform access and no proprietary hardware. The advantage is confirmed in a pre-registered frozen-model external validation of over three thousand patients, and is largest at coarse recording cadence, where instantaneous pressure is least informative.

Background. The clinical course of coronavirus disease 2019 (COVID-19), and the ability to anticipate which patients will require intensive care, were poorly characterized in Central Asia during the first pandemic wave. We aimed to describe the clinical features of hospitalized COVID-19 patients at the Tashkent State Medical University, Uzbekistan, and to identify risk factors for intensive care unit (ICU) admission. Methods. In this single-centre cross-sectional study, we reviewed the records of 2500 consecutive patients hospitalized between 11 April and 8 August 2020. Patients were grouped as asymptomatic or symptomatic, and symptomatic patients were compared by ICU versus non-ICU status. Groups were compared with chi-square or Fisher's exact and Mann-Whitney U tests. Univariable and multivariable logistic regression identified risk factors for ICU admission. Results. Of 2500 patients (median age 36 years; 60.9% male), 989 (39.6%) were asymptomatic and 1511 (60.4%) symptomatic. In total, 129 (5.2%) were admitted to the ICU and 38 (1.5%) died. ICU patients were older (median 56 vs 40.5 years) and more often had bilateral pneumonia, oxygen desaturation and cardiometabolic comorbidity. In the multivariable model (AUC 0.82), the independent predictors of ICU admission were ischemic heart disease (aOR 4.20), shortness of breath (aOR 3.22), hypertensive heart disease (aOR 2.93) and male sex (aOR 2.00). Conclusions. Older age, cardiometabolic comorbidity and respiratory compromise identified patients at high ICU risk. As one of the first clinical COVID-19 descriptions from Uzbekistan, these data provide a baseline for preparedness in Central Asia.

Background: Adult congenital heart disease (ACHD) patients are prone to HLA-antibody formation from multiple surgeries, transfusions, and prosthetic surgical material. Females with ACHD may accrue additional, non-surgical alloantigen exposure. Whether sex modifies the impact of allosensitization on heart transplant (HT) access and outcomes in ACHD remains unknown. Methods: We retrospectively analyzed the OPTN/UNOS registry of adults with ACHD listed for first-time HT (2018-2025). Sensitization was defined by calculated panel reactive antibodies (cPRA) at listing. We tested the sex x sensitization (highly sensitized, cPRA >50%) interaction on transplant access using Fine-Gray competing-risks regression, treating transplantation as the event of interest and death or removal from the waitlist as competing events, and on post-transplant survival using multivariable Cox proportional-hazards regression, both adjusted for age at listing, mechanical support at listing, and the number of distinct prior cardiac surgery categories. Results: Among 856 candidates (38% female), females were more often highly sensitized than males (23% vs 14%; age-adjusted OR 1.81, 95% CI 1.26-2.61), even after adjusting for surgical burden. Sensitization reduced transplant access in females (84% to 71%; median wait 60 to 110 days, p < 0.001) but not males (79% vs 79%, median wait 88 vs 98 days). In adjusted Fine-Gray models, the subdistribution hazard for transplant was reduced in sensitized females (sHR 0.54, 95% CI 0.41-0.72) with no effect in males (sHR 0.96, 95% CI 0.73-1.26), and the sex x sensitization interaction was significant (interaction sHR 0.64, 95% CI 0.44-0.94, p = 0.02). Post-transplant mortality was numerically higher in sensitized than non-sensitized candidates in both sexes and the sex x sensitization interaction on 1-year mortality was not significant. The sex-asymmetric effect persisted and was more pronounced in the multiorgan candidates. Conclusions: Allosensitization is not a sex-neutral barrier to transplant in HT candidates with ACHD. Females are more sensitized and have reduced transplant access without differences in 1-year mortality. The female excess in sensitization is not accounted for by surgical burden, and the exposures responsible remain to be defined. These findings warrant a sex-aware listing strategy and further studies.

Background: Endometriosis affects approximately 10% of reproductive-age women and is associated with substantial diagnostic delay and heterogeneous symptom presentation. Prior machine-learning prediction models have relied on comorbidity data alone or on small candidate-variant genetic scores, with inconsistent or incompletely reported performance. No study has combined a well-powered, multi-ancestry polygenic risk score (PRS) with environmental, reproductive, and symptom data in a single hybrid model. We developed and evaluated hybrid risk-prediction models integrating a genome-wide, multi-ancestry PRS with clinical and symptom data for endometriosis in the US-based All of Us Research Program. Methods: Among 69,376 participants (15,382 endometriosis cases, 53,994 controls) across six genetically inferred ancestry groups, we computed individual-level PRS values using PRS-CS weights derived from an independent, multi-ancestry GWAS. Five nested logistic regression, random forest, and XGBoost models progressively added age, ancestry, and within-ancestry genetic principal components (Model 1), environmental and reproductive factors (Model 2), symptom and comorbidity indicators (Model 3), all covariates combined (Model 4), and PRS x environment interactions (Model 5). Performance was assessed by AUROC in a held-out test set and 5-fold cross-validation, with class-weighted, Youden-optimized thresholds used for sensitivity, specificity, and predictive values; permutation importance identified top contributors. Pairwise AUROC differences were tested with a Holm-corrected DeLong-type test. Results: Discrimination improved from AUROC 0.63 (PRS, age, ancestry, principal components) to 0.72 for the full model, driven mainly by symptom and comorbidity data. XGBoost consistently outperformed logistic regression and random forest. The PRS ranked among the top individual predictors by permutation importance in nearly every model, alongside age, while genetic and demographic information alone gave only modest discrimination, and PRS x environment interactions did not improve on environmental factors alone. Threshold optimization yielded balanced sensitivity and specificity (~0.67/0.65) versus near-zero sensitivity at a default threshold. Conclusions: Combining the PRS with symptom and comorbidity data gave the best discrimination compared to solely a well-powered, multi-ancestry PRS as a predictor of endometriosis. This study clarifies both the promise and current limits of hybrid genetic-clinical prediction for endometriosis and points to symptom-based phenotyping, molecular subtyping, and external validation as priorities.

Background Elexacaftor-tezacaftor-ivacaftor (ETI) has been demonstrated to improve lung function in clinical trials; however, evidence describing effects on trajectories and whether long-term improvements are sustained (>1-year) is lacking. We estimated within-person lung clearance index (LCI) trajectories before and after ETI initiation, assessing changes in level and rate of change, alongside acute LCI change, up to three years after ETI initiation. Methods Prospective observational study of children at a tertiary hospital. Children aged 3-17 years with [&ge;]2 LCI testing occasions (i) before and (ii) after starting ETI were used to describe lung function trajectories. Children with [&ge;]1 pre-ETI and [&ge;]1 post-ETI LCI occasion(s) were used to describe acute LCI change after ETI initiation. Age-adjusted LCI trajectories for time periods (i) before and (ii) after ETI initiation were estimated using linear mixed-effects models, and pre- and post-ETI LCIs were compared using paired Wilcoxon tests. Results Mean pre-ETI and post-ETI longitudinal changes in LCI were -0.007 (95% CI: -0.28, 0.27; n=35) and 0.12 (95% CI: -0.17, 0.41; n=20) turnovers per year, respectively. Before ETI initiation, 57% (30/53) of patients had an LCI[&ge;]7.1 turnovers (indicating impaired lung function), compared to 26% (14/53) post-ETI, with a median LCI difference of -0.70 (95% CI -0.84, -0.46; p<0.001) turnovers. Within-individual variability in LCI decreased post-ETI. Conclusions Our real-world data within a unique longitudinal study provide a comprehensive picture of ETI benefit by outlining not only acute improvement in LCI but maintained stability in LCI trajectories and improved LCI stability sustained up to three years post-initiation.

Background: Percutaneous mechanical circulatory support (pMCS) is increasingly used in critically ill patients, yet its value in relation to cost and outcomes remains unclear. We evaluated national variation in utilization, outcomes, and cost, and introduced a value of care framework integrating risk-adjusted outcomes and expenditures. Methods: We performed a retrospective cohort study using the National Inpatient Sample to identify non-elective hospitalizations of critically ill patients undergoing intra-aortic balloon pump (IABP) or percutaneous left ventricular assist device (pLVAD) placement using ICD-10 codes. Multivariable logistic regression and generalized linear models were used to estimate expected outcomes and costs. Observed-to-expected (O/E) ratios were calculated, and a value index was derived to compare procedural strategies. Results: A total of 57,910 weighted hospitalizations were included (IABP 78%, pLVAD 22%). In-hospital mortality exceeded 30% across regions. Significant regional variation was observed, with the West demonstrating the highest costs and the Midwest the lowest (p<0.001). Mean hospital charges were higher for pLVAD compared with IABP ($403,731 vs $320,769). Both strategies achieved outcomes better than expected after risk adjustment (O/E 0.92); however, costs were higher than expected for both, with greater relative cost inflation observed for IABP (O/E 1.41) and higher absolute costs for pLVAD. In value-of-care analysis, IABP was associated with lower cost and comparable outcomes, while pLVAD demonstrated higher cost without proportional outcome improvement. Conclusion: Substantial variation exists in the cost, outcomes, and value of pMCS strategies. While both IABP and pLVAD achieve favorable risk-adjusted outcomes, pLVAD is associated with higher costs without commensurate clinical benefit.

Objective. To determine the publication rate of abstracts presented at the American Diabetes Association Scientific Sessions and to evaluate the association between statistical significance of study results and subsequent publication. Research Design and Methods. We conducted a retrospective cohort study of abstracts presented at the 2018 American Diabetes Association Scientific Sessions. The primary exposure was study result category (statistically significant vs. non-statistically significant findings), and the primary outcome was publication in an indexed journal within 5 years after conference presentation. Publication status was determined through PubMed/MEDLINE and Scopus searches. Adjusted relative risks (RRs) and 95% CIs were estimated using generalized linear models with Poisson distribution and robust variance. Results. Among 541 included abstracts, 321 (59.3%) were subsequently published in indexed journals. Abstracts reporting statistically significant findings had a higher publication rate than those reporting non-statistically significant findings (61.9% vs. 42.3%; p=0.002). In the adjusted analysis, abstracts with non-statistically significant findings had a lower likelihood of publication compared with those reporting statistically significant findings (adjusted RR 0.71 [95% CI 0.55-0.93]; p=0.013). Conclusions. Approximately four in ten abstracts presented at the ADA Scientific Sessions were not published within 5 years. Abstracts reporting non-statistically significant findings had a lower likelihood of subsequent publication, suggesting persistent publication bias in diabetology research. Future initiatives promoting the interpretation of effect estimates, confidence intervals and clinical relevance, rather than statistical significance alone, may help reduce selective dissemination of evidence

Background: Atrial fibrillation detected after stroke (AFDAS) is frequently diagnosed after embolic stroke of undetermined source (ESUS) and has important implications for secondary stroke prevention. Although prediction scores have been proposed to identify patients at increased risk of AFDAS, prospective evidence supporting their implementation to guide rhythm monitoring in routine clinical practice is limited. Methods: In this prospective, population-based implementation cohort study, adults with ESUS were enrolled between January 2022 and December 2024 across all stroke centers in Styria, Austria. The Graz AF Risk Score was prospectively implemented as part of a risk-adapted diagnostic pathway for cardiac rhythm monitoring. Patients with a score [&ge;]4 were recommended for implantable loop recorder monitoring, whereas monitoring in those with scores <4 remained at the treating physician's discretion. The primary outcome was AFDAS detection; recurrent ischemic stroke and recurrent stroke etiology were secondary outcomes. Results: Among 784 patients (median age 73 years [IQR 64-80], 45.7% women), AFDAS was detected in 166 patients (21.2%) during a median follow-up of 26.3 months (IQR 20-34). AFDAS detection was substantially higher in patients with a Graz AF Risk Score [&ge;]4 than <4 (38.1% vs. 3.9%; p<0.001). After adjustment for age, sex and ILR monitoring, a score [&ge;]4 independently predicted AFDAS (HR 6.3, 95% CI 3.5-11.2; p<0.001) and recurrent ischemic stroke (HR 2.2, 95% CI 1.1-4.1; p=0.023). Only one recurrent stroke in patients with a score <4 was attributable to atrial fibrillation (AF) (1/18, 5.6%). Conclusions: Prospective implementation of the Graz AF Risk Score identified patients with ESUS at markedly different risks of AFDAS. A Graz AF Risk Score [&ge;]4 was also independently associated with recurrent ischemic stroke. These findings support a risk-adapted approach to cardiac rhythm monitoring after ESUS.

Background Little evidence is available on the epidemiology of different knee injuries at a whole-of-population level. The objective of this article is to provide accurate estimates of knee injury incidence by harnessing the unique comprehensive, population-wide data of New Zealand's universal no-fault injury insurance provider, the Accident Compensation Corporation (ACC). Methods We obtained insurance claims data from ACC covering all knee injury insurance claims approved between 2015 and 2024. We calculated the number of injuries and the incidence rate per 100 000 population, by injury type, year, sex, ethnicity, and age. Results The total number of injuries increased from 184 710 (4 067 per 100 000 population) in 2015 to 244 155 (4 701 per 100 000) in 2024. The most common injuries were other/unspecified ligament sprains, contusions, and collateral ligament sprains. Ligament and cartilage injuries were more common for males than for females, while contusions were more common for females. Ligament tears and dislocations were more common in younger people (15 to 35 years of age), while cartilage injuries were more common at older ages (40 to 65 years). Discussion and Conclusions The rate of knee injuries observed in this study was higher than previously reported in other settings, probably due to broader coverage of injuries treated in primary and community care settings. A broad range of injuries were common, including those that have received less attention in the epidemiological literature to date. More research is needed on the prevention, burden, and outcomes of different knee injuries, beyond a narrow focus on cruciate ligament injuries.