RMD Open

Background Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease which can lead to progressive disability and damage to multiple organs. Obesity is associated with higher disease activity in RA and inadequate long-term outcomes, so better understanding of mechanisms linking adiposity to immune dysregulation might help to refine optimal treatments. Monocytes are important contributors to immune activation in RA through antigen presentation and costimulatory signaling. We hypothesized that adiposity enhances monocyte costimulatory programming in RA, thereby promoting adaptive immune activation. Methods Single-cell RNA sequencing was performed using the 10x Genomics Flex platform on purified circulating monocytes from 31 donors (16 RA participants fulfilling 2010 ACR/EULAR classification criteria and 15 non-RA controls) generating transcriptomic profiles for approximately 135,599 monocytes. Donor-level pathway enrichment scores were calculated for predefined immune activation pathways including antigen processing and presentation, interferon signaling, and regulation of T-cell costimulation. Analyses were performed at the donor level to avoid cell-level pseudoreplication. Associations with disease status and body mass index were evaluated using factorial linear models and Spearman correlation analyses. Results Single-cell transcriptomic profiling identified classical, intermediate-like, non-classical, and interferon-responsive monocyte populations. RA was associated with enrichment of antigen processing and presentation programs in circulating monocytes (p=0.0106), indicating a primed antigen-presenting state. In contrast, regulation of T-cell costimulation pathway enrichment did not differ by RA status alone. However, within RA participants, higher BMI was associated with increased enrichment of monocyte T-cell costimulatory pathways (Spearman {rho}=0.56, p=0.0248), unlike in non-RA controls. Gene-level analyses demonstrated strong baseline expression of CD86, while ICOSLG and TNFSF4 transcripts were expressed at low levels overall, consistent with inducible costimulatory signaling programs. Conclusions These findings support a model in which metabolic dysregulation amplifies monocyte-mediated immune activation and may contribute to worsened disease outcomes in RA.

Objective: The onset of juvenile idiopathic arthritis (JIA) in the early years ([≤]5 years) may negatively impact movement skill (encompassing related concepts of gross motor skills, fundamental movement skills, and functional ability) development. Few studies have explored the perceptions and needs of parents and physiotherapists towards children's difficulty with these movement skills, essential to identify potential areas for added support. The objective of this study is to understand the perceptions of physiotherapists and parents towards movement skills of children with JIA. Methods: Seventeen parents and 24 physiotherapists completed an online questionnaire consisting of multiple choice and open-ended questions about the movement skills of young children with JIA. Demographic and multiple choice questions were quantitively analysed using descriptive statistics. Open-ended responses were analyzed using qualitative conventional content analysis. Results: About half (47%) of parents perceived their children to have movement difficulties, and 75% of physiotherapists described the movement skills of children with JIA as worse than other children of the same age. Our qualitative analysis revealed three general themes including: functional task difficulties; clinical variability in movement skills; and psychosocial components of movement skill difficulties. Conclusion: This study provides an analysis of perceptions of physiotherapists and parents towards the movement skills of young children with JIA. A significant proportion of parents and physiotherapists identify movement difficulties among children with JIA that impact daily life. Future interventions co-designed with both parents and care providers targeting movement skills are needed.

Abstract Background Rheumatoid arthritis (RA) is an autoimmune inflammatory disease with complex and incompletely understood molecular mechanisms. Understanding circulating proteins associated with RA may improve understanding of disease biology and clarify its pathological links with cardiometabolic comorbidities. Methods A proteome-wide two-sample Mendelian randomisation (MR) drug target analysis was conducted using plasma proteins measured in 54,219 participants from the UK Biobank Pharma Proteomics Project as exposures and RA and cardiometabolic diseases as the outcomes. Summary statistics for RA included 53,663 cases and 1,070,200 controls. Colocalisation analysis was performed to confirm shared single causal variants and prioritise RA proteins supported by both MR and colocalisation. The prioritised proteins were then evaluated in the Accelerating Medicines Partnership RA Phase II synovial single-cell dataset for cell-type expression patterns. Druggability was then assessed followed by analysis of genetic overlap between RA-associated proteins and cardiometabolic diseases. Results 37 plasma proteins had a causal effect on RA risk, supported by combined evidence from MR and conditional colocalisation. In synovial tissue, TPPP3, RARRES2, AKAP12, and GGT5 were predominantly expressed in stromal and endothelial cell clusters. Druggability assessment identified IFNGR2, IL6R, CD40, and FCGR2B as Tier 1 targets. However, several biologically relevant proteins, including RARRES2, AKAP12, TPPP3, and SNX2, had limited available druggability data. Genetic overlap analysis demonstrated shared protein signals between RA and cardiovascular diseases, including overlap of RARRES2 and TPPP3 with coronary artery disease (CAD) and FCGR2B with atrial fibrillation (AF). To approximate the therapeutic effect of target inhibition, the direction of effect estimates for proteins showing overlap between RA-CAD and RA-AF was reversed. Conclusion This study identified circulating proteins involved in RA pathogenesis and reveals shared mechanisms between RA and cardiovascular diseases. While some proteins showed clear translational potential targets, several prioritised proteins had limited available druggability information and could not be confidently classified. Addressing these gaps may help identify new targets relevant to RA management. Future work should also use phenome-wide MR studies to evaluate potential on-target adverse effects of protein inhibition across RA-CAD and RA-AF.

Background and rationale: Knee osteoarthritis (KOA) is a leading cause of lower limb disability worldwide, characterized by functional limitations, stiffness and pain. The incidence of KOA is especially tied to age and obesity. It is a disabling disease that often makes patients less physically active, thus increasing the risk of other diseases and mortality1. The clinical diagnosis of KOA is based on the symptoms and functional limitations of the joint. The diagnosis is usually supported with a radiograph (X-ray) of the weight-bearing knee. Radiographic features, such as Kellgren-Lawrence grade, are used as eligibility criteria for clinical studies while other features, such as joint space width (JSW), are used as endpoints for structural KOA progression2,3. While the use of these radiographic features is standard in academia, the use of JSW as a structural biomarker has received criticism. Critics point out that JSW is an indirect and projection dependent measure of cartilage deterioration which is sensitive to technical factors such as the angulation of the X-ray beam and the positioning of the knee. Small differences in these factors can alter the measured joint space and may not reflect true disease progression4,5. Despite limitations, minimum joint space width (mJSW) remains as one of the most widely used structural biomarkers in KOA trials and is currently one of the only structural imaging accepted in regulatory guidance as evidence of disease modification in OA drug development3. For JSW to be reliable and consistent in determining the advancement of KOA, the use of fixed-flexion devices is crucial to reduce the risk of unwanted narrowing or widening of the radiographic joint space width6,7. The LOSEIT trial, which the present study is based on, acknowledges the angulation problem and uses a standard clinical fixed-flexion device in weight-bearing PA views to get reliable JSW results8. Historically, a radiologist would draw on and grade radiographs of the knee-joint to extract the features. However, manual reading and annotation is time consuming with notable interobserver variance9. With increasing computational power and the use of deep neural networks, off-the-shelf artificial intelligence (AI) tools have become available for automatic extraction of radiograph features. Automation would free up time from radiologists and provide more consistent measurements due to the reproducible nature of the models10. These tools have received regulatory approval for commercial use, however, regulatory approval does not guarantee uniform or bias free performance when used on real-world data11. Furthermore, in a large multi-hospital chest X-ray study, Zech et al., showed that convolutional neural networks achieved worse results on data from other hospitals than on the original hospitals in which it was tested12. This highlights the risk of overestimating the accuracy of AI tools when only internally validated. It is therefore apparent that external validation is required when testing these AI models. Objectives: The aim of this analysis is to evaluate the agreement of a commercially available AI tool for measuring JSW with the best practice radiologist annotation in the tibiofemoral joint of the knee in radiographs stabilized with a fixed-flexion device and acquired as part of a clinical trial. Methods: This study is a secondary analysis of the data from the LOSEIT trial, a randomized, double-blind, placebo-controlled, single-center trial, where patients were randomized to either liraglutide or identically appearing placebo after an initial weight-loss period to investigate the effects on KOA. Radiographs of the tibiofemoral joint were acquired at enrollment (week -8) and at end-of-trial (week 52) for a total acquisition-to-acquisition time of 60 weeks13. The primary analysis will assess agreement between AI-derived and reference-derived change in JSW from enrolment to follow-up. Change will be calculated as follow-up minus enrolment separately for the AI tool and the reference measurement. The main measure of interest will be the change in medial minimal JSW (mmJSW), with change in lateral minimal JSW (lmJSW), medial fixed JSW (mfJSW) and lateral fixed JSW (lfJSW) as secondary measures. This study will follow an equivalence framework using the two one-sided tests (TOST) approach with a Bland-Altman analysis as the main outcome. The equivalence margin will be set at {delta} = 0.5 mm. Agreement consistent with equivalence will be considered established if the upper limit of the 95% confidence interval (95% CI) for the upper limit of agreement (LoA) and the lower limit of the 95% CI for the lower LoA are within the established margins. The reference JSW will be the average measurement of two independent resident radiologists. If there is a mismatch in the measurements of more than 0.40 mm between the two radiologists, the radiologists will re-annotate the case independently. If the difference remains greater than 0.40 mm, a musculoskeletal radiology consultant will review the radiograph and establish the reference JSW. The index test will be the measurements output by the AI tool. Populations: Patients aged 18 to 74 with symptomatic knee osteoarthritis, radiographically confirmed KL grade 1-3, with a BMI [≥]27, motivated for weight loss and in accordance with the LOSEIT trial inclusion criteria Further statistical details Sample size: Not applicable as this is a secondary analysis. Framework: This is an agreement study assessing the equivalence of a commercially available AI tool for radiographic evaluation of knee osteoarthritis with best practice radiologist measurements. Confidence intervals and P values: All 95% confidence intervals and P-values will be two-sided. Statistical software: SAS Studio and/or R version 4.2.2 (or newer).

Context: Although knee extensor and flexor strength deficits are well-documented after anterior cruciate ligament reconstruction, limited data exist characterizing how strength recovery evolves over time. Understanding the temporal patterns of recovery, and how they differ by autograft type, is critical for optimizing rehabilitation and return-to-sport decision-making. Objective: To characterize temporal trends in knee extensor and flexor strength recovery during the first year post-ACLR and evaluate differences between patellar tendon and hamstring tendon autografts. Design: Case series. Setting: Sports physical therapy clinics within a large health system. Participants: Five hundred three patients (17.8 {+/-} 3.0 y) who underwent primary reconstruction with either patellar tendon or hamstring tendon autografts and completed a combined 730 return-to-sport tests within 12 months postoperatively. Main Outcome Measures: Normalized peak isokinetic concentric knee extension and flexion torques for involved and uninvolved limbs, and normalized symmetry indices for knee extension and flexion strength. Results: Knee extension strength on both limbs and extension strength symmetry improved over time. Patients with hamstring autografts demonstrated superior involved leg knee extension strength and better extension strength symmetry compared with those receiving patellar tendon autografts, although uninvolved leg strength was similar between autografts. Knee flexion strength on both limbs and flexion strength symmetry also improved over time. Patellar tendon autograft patients exhibited greater strength symmetry, despite no between autografts for flexion strength for the involved or uninvolved limb. Conclusions: Autograft significantly influences muscle strength recovery following anterior cruciate ligament reconstruction. Hamstring tendon autografts are associated with superior recovery of knee extension strength and strength symmetry compared to patellar tendon autografts. These findings underscore the need for graft-specific rehabilitation strategies and earlier identification of patients at risk for delayed recovery.

Objective: To characterize pregnancy outcomes and menstrual irregularities in Mexican women with systemic lupus erythematosus (SLE) and identify clinical factors associated with adverse pregnancy outcomes and early-onset menopause. Methods: We conducted a cross-sectional study of women with SLE enrolled in the Mexican Lupus Registry (LupusRGMX) between May 2021 and September 2024. Clinical and reproductive data were collected using standardized questionnaires. Menopause was defined as the absence of menstruation for [≥]12 consecutive months, and early menopause as onset before age 40. Univariable and multivariable logistic regression analyses were used to identify factors associated with pregnancy complications and early menopause. Results: A total of 210 women were included. Median age was 38 years (IQR 29-46) and median disease duration was 4 years (IQR 1-10). Among women with a history of pregnancy (47%), full-term delivery predominated (61%), while pregnancy loss occurred in 26% and preterm delivery in 13%. Pregnancy complications were reported in 9.6%, most commonly preeclampsia (6.7%). Younger maternal age was independently associated with pregnancy complications (OR 0.89, 95% CI 0.83-0.95) and adverse outcomes (OR 0.95, 95% CI 0.92-0.98). Higher disease activity was associated with complications in univariable analysis. Most pregnancies (68.3%) occurred before diagnosis. Early menopause was observed in 6.2% and independently associated with longer disease duration and older age. Conclusion: Younger maternal age was independently associated with adverse pregnancy outcomes, whereas disease activity showed an association in univariable analysis. Most pregnancies occurred prior to SLE diagnosis. Early menopause was associated with longer disease duration, suggesting impact of cumulative disease burden on ovarian function.

Postoperative resilience varies widely among older adults, yet the biological drivers of recovery remain unclear. We evaluated whether preoperative immune profiles, measured in plasma and through ex vivo whole blood stimulation, predict resilience to the acute stress of total knee arthroplasty. A total of 152 adults (greater or equal to 60 years) in the PRIME KNEE cohort underwent elective total knee arthroplasty and had available blood samples for measurement of 45 immune biomarkers, quantified in plasma and in whole blood stimulated ex vivo for 24 hours with lipopolysaccharide (LPS) or influenza antigen (FLU). Resilience was assessed using Expected Recovery Differential (ERD) and Resilience Trajectory (RT) across pain severity, pain interference, lower extremity physical activities of daily living (LE PADLs), and step counts. An exploratory stability selection framework using LASSO identified biomarker predictors of postoperative outcomes. Plasma and stimulated biomarkers showed broadly similar predictive performance. A shared set of biomarkers, including LBP, leptin, TNFR1, CD30, and LIF, was consistently selected across models. Immune predictors explained ~12-24% of the variance in resilience outcomes. Distinct immune signatures emerged for pain versus functional recovery: pain related predictors mapped to local inflammatory and neuroimmune pathways, whereas function related predictors reflected systemic inflammatory load and cytokine signaling. Preoperative immune biomarkers, whether measured in plasma or after ex vivo stimulation, capture meaningful variance in postoperative resilience. The divergence between pain related and function related immune signatures highlights biologically distinct pathways underlying different dimensions of recovery and supports further development of immune based perioperative risk assessment.

Background: Depression and heart disease frequently co-occur in the aging population and are associated with functional decline and poor health outcomes. Understanding how depressive symptoms relate to different aspects of physical function among adults with heart disease may help identify high-risk subgroups. Objective: To examine the association of depressive symptoms with self-reported and observed physical function measures among participants with heart disease in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study and assess whether associations differ by sex and race?sex groups. Methods: We conducted a cross-sectional analysis using data from REGARDS study second in-home visit (2013?2016). Depressive symptoms were measured with the 10-item Center for Epidemiologic Studies Depression scale (CES D 10), considering scores ?10 as clinically significant. Physical function measures were instrumental activities of daily living (IADL), activities of daily living (ADL), chair stand time (5 repetitions), and gait speed. Linear regression models estimated associations of depressive symptoms with function, adjusting for sociodemographic, health behavior, antidepressant medications, body mass index, and social support. Effect modification by sex and race?sex group was evaluated. Results: Among 3,055 participants, 11.7% had CES D 10 ?10. Compared to CES-D-10 scores <10, CES D 10 ?10 was associated with more limitations in IADL (1.84 points; 95% CI 1.62, 2.06), ADL (0.43 points; 95% CI 0.34, 0.52) and slower chair stand time (0.88 second; 95% CI 0.07, 1.69); associations with gait speed were modest (?0.04 meters/second; 95% CI ?0.08, -0.01). Women had a stronger association between CES-D-10 and ADL (0.49 points; 95% CI 0.35, 0.64) than men (0.33 points; 95% CI 0.21, 0.44; p for interaction = 0.01). Interaction between CES D 10 and race?sex groups was not statistically significant. Conclusions: Among adults with heart disease, clinically significant depressive symptoms were associated with lower physical function, particularly among women.

Background. Obesity is a modifiable risk factor for osteoarthritis and may contribute to pain, functional impairment, inflammation, and cartilage degradation. Resveratrol has potential anti-inflammatory and chondroprotective effects, but its efficacy as an adjunct to dietary intervention remains unclear. Objective. This study evaluated whether resveratrol supplementation provides additional benefits when combined with a low-calorie diet in postmenopausal women with obesity and knee osteoarthritis. Methods. A total of 97 postmenopausal women with obesity and knee osteoarthritis were included in this randomized controlled clinical study. Participants received either a 10-day low-calorie diet alone or the same diet combined with 150 mg/day trans-resveratrol. Anthropometric parameters, body composition, biochemical markers, pain intensity, functional status, and urinary CTX-II were assessed at baseline and follow-up. Results. Both interventions were associated with reductions in body weight, BMI, waist and hip circumferences, fat mass, glucose, HOMA-IR, lipid parameters, hsCRP, VAS, WOMAC, LAI, and urinary CTX-II. Compared with diet alone, resveratrol supplementation did not provide additional benefits for anthropometric parameters, glucose metabolism, lipid profile, or WOMAC score. However, the resveratrol group showed a greater reduction in hsCRP and urinary CTX-II. The obesity class did not modify the treatment effect. Conclusion. A short-term low-calorie diet improved metabolic, inflammatory, and osteoarthritis-related parameters in postmenopausal women with obesity and knee osteoarthritis. The addition of resveratrol did not enhance weight loss or improve most metabolic outcomes but was associated with greater reductions in hsCRP and urinary CTX-II. These findings suggest a potential anti-inflammatory and cartilage-related effect of resveratrol, which requires confirmation in longer randomized trials.

Abstract (already in the PDF; paste if a box is required): Injury risk prediction in elite football relies almost exclusively on external load metrics derived from GPS tracking, overlooking the molecular state of the athlete. We monitored 26 male players from FC Barcelona's first team across the 2025 calendar year, integrating GPS-derived training load with longitudinal blood-based immune monitoring (systemic inflammation and TCR-derived immune age). Immune age acceleration and inflammation were elevated in the 14 days preceding musculoskeletal injuries. A logistic regression model combining external load, inflammation, immune age acceleration, and career injury history reached an overall AUC of 0.678 and a mean per-player AUC of 0.754 (SD 0.146), improving on a GPS-only baseline of 0.541. Applied to 2026 data, the frozen model ranked players who later sustained non-contact musculoskeletal injuries high in the risk distribution. Together, our data suggest multimodal immune monitoring in elite football to reveal the athlete's internal physiological state, which carries injury-relevant information that external load alone does not capture.

Background. Tethered cord syndrome (TCS) is classically associated with a low-lying conus medullaris, yet many surgically treated children have a normally positioned conus (occult TCS). Large-scale normative data on conus position in children, and the diagnostic value of quantitative conus assessment, are limited. Purpose. To establish a large-cohort reference distribution for conus medullaris termination level in children, to quantify conus position in children surgically treated for presumed (occult) TCS, and to test whether automated conus segmentation and radiomics can distinguish TCS from normal. Materials and Methods. In this retrospective single-center study, conus termination level was extracted from structured radiology reports of consecutive pediatric lumbosacral MRI examinations and encoded numerically (L1 = 1, L2 = 2, etc.). Children surgically treated for tethered cord were identified by linkage to an operative registry (name and date of birth) and restricted to preoperative examinations. A deep-learning model (nnU-Net) was trained for conus segmentation on axial T2-weighted images. IBSI-compliant radiomic features were extracted; reproducibility was assessed by intra- and inter-observer intraclass correlation (ICC). A case-control radiomics analysis used batch-only ComBat harmonization and cross-validated L1-penalized logistic regression; discrimination was compared with conus level by paired bootstrap. Results. Among 9,808 examinations with a parseable conus level (98.5% of reports; parser validated against dual blinded annotation, 99.4% agreement, weighted kappa 0.946), the conus terminated in the L1 region in 85.7% and the L2 region in 14.3% of the reference cohort (postoperative examinations excluded, n = 9,655); a low-lying conus (>=L3) occurred in only 0.05% (5/9,655), and remained rare (0.14%, 14/9,808) including operated examinations (median L1; mean 1.13 +/- 0.33). A slightly more cephalad position was seen with increasing age (negligible correlation). Among 475 preoperative children surgically treated for tethered cord, 99.6% had a normally positioned conus (<=L2) and only 0.4% were low-lying. Automated conus segmentation achieved a held-out Dice of 0.85. Conus radiomics likewise did not distinguish TCS from controls (equivalence-tested null; full segmentation/radiomics pipeline reported in the companion methodological paper). Conclusion. In children, the conus medullaris terminates at L1-L2 in more than 99% of cases and is normally positioned in virtually all children surgically treated for TCS. Within the conus, neither position nor texture (radiomics) identifies tethered cord; whether the filum terminale carries a diagnostic signal was not tested here.

Chronic pelvic pain (CPP) affects up to 26% of women worldwide. While its pathophysiology is poorly understood, disturbances in body perception have been identified in various similar chronic musculoskeletal disorders. The Fremantle Perineal Awareness Questionnaire (FrePAQ) is a novel tool designed to specifically assess disturbed body perception in the pelvic region, but its structural validity and reliability require formal evaluation. Methods: Patient partners with lived experience contributed to study design. Participants with (n=417 and without (n=277) chronic pelvic pain completed the FrePAQ at baseline, as well as one week later. We assessed the validity and reliability of the FrePAQ following COSMIN guidelines for Classical Test Theory. Results: The validated FrePAQ comprises a two factor model, with a six item Distress & Disconnection (D&D) subscale and a two item Size & Shape (S&S) subscale. Confirmatory analysis showed excellent fit (CFI = .988; RMSEA = .048) and measurement invariance between diagnostic groups. Internal consistency was high (cronbach alpha = .838 CPP, .819 controls). Test retest reliability was high for D&D (ICC = .863) and acceptable for S&S (ICC = .695). FrePAQ scores showed a weak to moderate correlation with pain scores (r = .234 to .255), psychological distress (r = .226 to .443), and functional impact (r = .172 to .295), particularly for the D&D subscale. Conclusion: The FrePAQ is a reliable and valid instrument to measure perineal perceptual disturbances in CPP. Future research will evaluate the tools potential to support phenotyping and guide individualised interventions. Improved understanding of body perception disturbance in CPP can enhance diagnosis and treatment precision.

Background: Chronic low-grade inflammation drives cardiovascular-kidney-metabolic (CKM) syndrome. Clonal hematopoiesis of indeterminate potential (CHIP), an age-related driver of systemic inflammation, is linked to several cardiometabolic disorders. However, whether CHIP modifies CKM progression and contributes to heterogeneity in cardiovascular disease (CVD) risk within the CKM framework remains uninvestigated. Methods: This cohort study included 307,025 UK Biobank participants at CKM stages 0-3 free of baseline CVD. CHIP status was identified via whole-exome sequencing (WES). The association between CHIP and baseline CKM severity was examined, along with the independent and joint effects of CHIP and CKM stages on incident CVD risk. The joint effects of CHIP and polygenic risk scores (PRS) were further assessed, and the incremental predictive value of incorporating CHIP into the AHA PREVENT equations was evaluated. Results: CHIP carriers were more likely to present with advanced CKM stages [OR 1.14 (1.09-1.20), P < 0.001] and exhibited higher incident CVD risk during follow-up [HR 1.13 (1.08-1.18), P < 0.001]. Significant joint effects between CHIP and CKM stages were observed, with the highest risk among CHIP carriers at CKM stage 3 [HR 1.63 (1.50-1.78), P < 0.001]. Large or multiple CHIP mutations conferred greater hazards, with distinct gene-specific effects observed. Moreover, CHIP and high genetic risk also jointly amplified CVD susceptibility. Most importantly, incorporating CHIP into AHA PREVENT significantly improved risk discrimination. Conclusions: CHIP is a significant risk factor associated with more advanced CKM stages and amplifies incident CVD risk. Integrating CHIP into existing prevention strategies may refine CVD risk stratification.

Background: Patients with chronic hepatitis B (CHB) may have an increased risk of severe COVID-19. Tenofovir has been hypothesized to confer protection against severe disease, but evidence is inconclusive. We evaluated the risk of severe COVID-19 among CHB patients treated with tenofovir compared with other nucleos(t)ide analogues (NAs). Methods and findings: In this nationwide, registry-based cohort study, we included all adults with CHB and laboratory-confirmed COVID-19 in Sweden between February 2020 and July 2022. Data from national health and socioeconomic registers were linked using unique personal identification numbers (PINs). Patients with HIV, hepatitis C, or hepatitis D coinfection were excluded. Exposure was defined as tenofovir versus other NA therapy. The primary outcome was severe COVID-19, defined as hospitalization >2 days or death within 30 days of diagnosis. Logistic regression was used to estimate adjusted odds ratios (aOR) with 95% confidence intervals (CI), controlling for age, sex, comorbidities, vaccination, socioeconomic status, and region of birth. Among 5,877 CHB patients with COVID-19, 672 were receiving NA therapy (437 tenofovir, 235 other NAs). Severe COVID-19 occurred in 8.0% of tenofovir-treated patients and 14.5% of those receiving other NAs (unadjusted OR 0.52; 95% CI, 0.31-0.85). After adjustment, the association was attenuated and no longer significant (aOR 0.72; 95% CI, 0.39-1.31). Older age, comorbidities, and unvaccinated status were strongly associated with severe disease. Conclusions: The apparent protective effect of tenofovir against severe COVID-19 in unadjusted analyses was largely explained by confounding factors. The risk of severe disease was primarily driven by age, comorbidities, and vaccination status. Prevention of severe COVID-19 in patients with CHB should instead focus on vaccination and management of comorbidities.

Background: Adults with severe mental health conditions (often referred to as severe mental illness, SMI) experience 15 to 20 year mortality gap relative to the general population, with lung cancer a significant contributor. National cancer policy targets earlier diagnosis but does not explicitly address how pathways function for this group. Aims: This study aimed to describe lung cancer risk, prevalence, screening eligibility, referral activity and diagnostic pathway performance for adults with SMI in South East London (SEL), and to examine where along the pathway inequalities arise. Methods: Co-designed with experts with lived experience and voluntary sector, this exploratory mixed-methods service evaluation combined quantitative analysis of routinely collected data from the Quality Outcomes Framework (QOF), SMI Register and Cancer Waiting Times Record (April 2023-March 2024) with semi-structured qualitative interviews (n=11 clinical staff) and focus groups (n=6 adults with lived experience of SMI). Quantitative and qualitative data were analysed using descriptive statistics and framework-based thematic analysis respectively, and findings were integrated using a joint display approach, organised by the Consolidated Framework for Implementation Research (CFIR). Results: Lung cancer prevalence was approximately double among adults with SMI (0.17% vs 0.09% in the general population). Despite Urgent Suspected Cancer (USC) referral rates being more than twice as high in the SMI population (63 vs 28 per 100,000), fewer cancers were detected via planned general practice (GP) routes (11% vs 20%), the 28-day Faster Diagnosis Standard was not met for any SMI patient diagnosed with lung cancer during the study period; overall FDS performance was 76% in the SMI population compared with 84% in the general population; and appointment non-attendance was more than double that in the general population (6% vs 3%). Qualitative findings identified individual, service and system-level mechanisms, including stigma, diagnostic overshadowing, fragmented coordination, and rigid pathway protocols, that compound disadvantage across lung cancer pathway stages. Conclusions: Inequality in lung cancer outcomes for adults with SMI accumulates across the pathway rather than arising at a single point of failure. Addressing this requires proportionate adaptations within existing cancer pathways, alongside routine reporting of cancer outcomes stratified by SMI population. Keywords: severe mental health conditions, lung cancer, health inequalities, cancer screening, diagnostic pathway, mixed methods

Background: Alpha-1 antitrypsin deficiency (AATD) caused by the PI*ZZ mutation (Glu342Lys) results in hepatic accumulation of misfolded AAT-Z protein and reduced circulating AAT levels, leading to progressive liver disease and emphysema. Gene correction therapy represents a potentially curative approach by directly correcting the underlying genetic defect. We report the first case of successful hepatic gene correction with early histological and functional assessment. Methods/Case presentation: We report the case of a 66-year-old male patient with PI*ZZ AATD who underwent gene correction therapy within the YOLT-202 phase I/Ia clinical trial (clinical trial.gov ID NCT07193615). Ten weeks post treatment a liver biopsy was performed to re-evaluate pre-existing F2 liver fibrosis as measured by elastography before entering the study. Serum samples allowed functional assessment of the AAT-mediated elastase inhibition. Results: Liver biopsy did not show signs of hepatic inflammation and demonstrated 54% (Sanger) and 57% (Illumina) gene correction rate of the PI*ZZ variant on the DNA level with no bystander edits or off-target effects. Following a transient elevation of transaminases during the early post-treatment period, liver enzymes normalized. Monthly serum AAT measurements demonstrated biologically active and stable therapeutic levels throughout follow-up. Conclusions: This case demonstrates efficient and precise hepatic gene correction without concerning histological alterations and with substantial improvement of functional parameters, supporting the feasibility and safety of gene editing approaches for AATD.

INTRODUCTION Severe acute brain injury (stroke, traumatic brain injury or hypoxic-ischemic encephalopathy; SABI) is increasingly recognized as a chronic condition with care and communication needs beyond the initial hospitalization. This study aimed to characterize post-acute care patterns among SABI survivors, focusing on healthcare utilization and outpatient communication. METHODS Data were collected from a prospective cohort of hospitalized SABI patients using surveys, chart reviews, and the ED Information Exchange database. Socioeconomic disadvantage was assessed using the Area Deprivation Index (ADI), and qualitative analysis of outpatient notes examined conversations around palliative care needs and goals-of-care. RESULTS Two-thirds of patients (140/222) survived until discharge, primarily to nursing facilities (39%) or inpatient rehabilitation (38%). Among 109 with one-year follow-up, there were 89 hospitalizations, 104 ED visits, and 28 deaths. Patients from the most disadvantaged neighborhoods had significantly higher odds of rehospitalization or ED use within 30 days (OR 3.37, p=0.036). ADI was not linked to one-year utilization. seen outpatient by primary care (40%), neurology/neurosurgery (57%), and palliative care (1%), but conversations rarely revisited prognosis or goals-of-care. CONCLUSIONS Our findings highlight the need for improved long-term care planning and communication, particularly for socioeconomically disadvantaged survivors of SABI.

Background Continuous health monitoring enables early detection of diseases and improves therapeutic outcomes. Non-intrusive biosignal sensors, such as capacitive ECG (cECG), offer a practical solution for daily monitoring in private environments, such as smart homes and vehicles. However, artifacts reduce signal quality and compromise reliability. Methods Following a registered report protocol (Warnecke JM et al. Plos One. 2021; 16(7):e0254780), we record data of 44 subjects and develop an artifact index for cECG. We use three signal quality indices (SQIs): the correlation of QRS complexes (corSQI), the R-peak detection consistency (bSQI) and the absolute amplitude ratio (aSQI). Our index classifies overlapping 10s segments with a step-width of 2s into clean or artifact segments. We label a 2s interval as artifacts if all five overlapping segments indicate artifacts. We record cECGs using an armchair with integrated electrodes in a single-arm study involving 44 subjects performing two activities -- reading and watching television (TV); for 11 minutes each. We record a time-synchronized reference ECG with skin electrodes on the chest. To evaluate the artifact index, we compare it with manually generated ground truth. Moreover, we evaluate the clothing materials cotton, linen, jeans, and polyester in 5 subjects. Results Watching TV results in longer, continuously clean signal durations than reading. On average, 88.3% of the signal has a minimum continuous clean duration of 10s, versus 79.8% during reading. All clothing configurations achieve a clean signal duration exceeding 10s. Among the SQI metrics, bSQI performs best, achieving an accuracy of 90.7% and an F1 score of 79.9%. Combining the three SQI metrics in a voting approach improves accuracy to 92.0% and F1 score to 82.1%. Discussion Our artifact index automatically distinguishes clean from artifact cECG segments, promoting health monitoring in unsupervised real-world settings, earlier disease detection, and preventive health management. A limitation is the investigation of only two scenarios (reading and watching TV).

Whole-genome sequencing comprehensively captures coding, non-coding and structural variation in families with suspected inherited disorders, yet its clinical utility remains constrained by an interpretation bottleneck: selecting a handful of relevant variants from millions of candidates. Current rule-based pipelines, anchored in ACMG/AMP criteria, excel at identifying highly penetrant Mendelian alleles but frequently miss variants of low-to-moderate penetrance, non-coding alterations and germline-somatic interactions. Here we introduce PolyCLIP-T, a topology-guided multimodal framework that transforms variant selection from a classification problem into a geometric discovery task. By contrastively aligning DNA-sequence embeddings with functional annotations, PolyCLIP-T constructs a unified latent space in which the displacement between reference and alternate embeddings quantifies the molecular perturbation induced by each variant. Persistent homology then identifies stable topological components - coherent variant groups shared among affected relatives - that transcend single-variant scoring logic. Applied to six families with multi-morbid cancer, autoimmune and cardiovascular disease, PolyCLIP-T recovered non-coding and structural candidates overlooked by conventional pipelines and revealed pleiotropic networks spanning disease categories. This approach provides an interpretable, scalable solution for genome-first investigations of disorders driven by polygenic architectures that evade single-variant analysis. The framework was developed and benchmarked on deeply characterised familial cohorts selected for transgenerational multimorbidity; validation in larger, independent populations will be essential to establish its generalisability. An interactive web tool is freely available at https://www.polyclip-t.uma.es/.

Introduction: Early hospital presentation after stroke onset is necessary for rapid assessment and access to time-dependent acute management. This study examined the correlates of late presentation for stroke care among patients recorded at a tertiary hospital in Ondo State, Nigeria. Methods: A retrospective records review was conducted using secondary data from the Stroke Registry of the University of Medical Sciences Teaching Hospital, radiology department records, referral notes, and ambulance records. Records of stroke cases documented within the preceding 24 months were reviewed. Late presentation was defined as hospital presentation more than four hours after symptom onset. Frequencies, chi-square tests, and modified Poisson regression with robust standard errors were used to estimate adjusted prevalence ratios. Results: The analysis included 371 stroke cases. Of these, 317 (85.4%) presented after four hours, and the median time to presentation was 24 hours (interquartile range: 9-72 hours). Late presentation differed significantly by employment status, first-contact route, and pathway complexity at bivariate analysis. After adjustment, non-hospital first contact remained strongly associated with late presentation: patients whose first documented contact was non-hospital-based had almost 3 times the prevalence of delay compared with those whose first contact was hospital-based (adjusted prevalence ratio = 2.89; 95% confidence interval: 2.15-3.90; p < 0.001). Conclusion: Late presentation was pervasive in this tertiary hospital record cohort and was primarily associated with the initial direction of care-seeking. Stroke response interventions should emphasise immediate hospital presentation and strengthen urgent referral from non-hospital first-contact points.