Rheumatology

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.

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.

Background: Neurological, neuropsychiatric, and neurodevelopmental disorders cluster in ALS families, sharing a common genetic architecture with ALS. Pathogenic variants in genes associated with other neurological, neurodevelopmental, or neuropsychiatric disorders may also co-occur in ALS and modify phenotype. We have sought to determine the prevalence and clinical pattern of likely-pathogenic/pathogenic (LP/P) non-ALS neurological, neurodevelopmental, and neuropsychiatric variants, alone and in combination with ALS-gene variants, in two large ALS cohorts. Methods: Whole-genome sequencing (WGS) of 469 Irish and 774 Answer ALS people with ALS (pwALS) was analysed for ClinVar LP/P variants associated with other neurological (n = 15541), neurodevelopmental (n = 9761), and neuropsychiatric (n = 321) phenotypes. Inheritance patterns for associated genes (autosomal recessive/autosomal dominant) along with the associated phenotype were validated using OMIM. Standardised clinical data included family history, site and age of onset, El Escorial category, survival, motor decline, and cognitive and behavioural assessments. Known ALS-gene variants and C9orf72 repeat expansion status were included for each cohort. Results: Non-ALS neurological variants were identified in 47/469 (10.0%) Irish and 69/774 (8.9%) Answer ALS participants, most frequently in hereditary spastic paraplegia-associated genes (3.2% Irish; 2.8% Answer ALS). Irish neurological variant carriers showed higher frequency of respiratory onset (10.6% vs 1.2%, Fisher's exact p = 0.002, {Phi} = 0.20) and fewer premorbid behavioural symptoms (0.92 +/- 0.56 vs 3.08 +/- 0.97, Cohen's d = -0.40). Neurodevelopmental variants occurred in 12/469 (2.6%) Irish and 20/774 (2.6%) Answer ALS participants. In the Irish cohort, neurodevelopmental variant carriers had significantly shorter survival in Cox proportional hazards model (log-rank p = 0.005), corresponding to a more than two-fold increased hazard of death (HR = 2.25, 95% CI 1.26-4.00), and had significantly increased familial burden of neuropsychiatric disorders among first- and second-degree relatives (negative binomial IRR for carriers = 2.41, 95% CI: 1.12-5.18, p = 0.025). Across combined cohorts, 18 individuals (Irish n = 8; Answer ALS n = 10) carried [≥]2 LP/P variants spanning ALS and non-ALS genes. Conclusion: Rare LP/P variants in genes associated with other neurological and neurodevelopmental disorders occur in up to 12% of pwALS across two independent cohorts. Carriers show distinct phenotypes, shorter survival, and characteristic family history patterns. These findings suggest that extended pleiotropic and oligogenic architectures may contribute to ALS heterogeneity.

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 and Aims: MASLD has become the most prevalent chronic liver disease globally. Although MVPA and plasma fatty acids have been individually studied in relation to metabolic health, their independent and combined associations with MASLD incidence remain unclear. We aimed to investigate these associations. Methods: This study included 51,717 UK Biobank participants free of liver disease at baseline, with MVPA measured using wrist-worn accelerometers and plasma fatty acids quantified via NMR. Multivariable-adjusted Cox models and restricted cubic splines were used. Results: Over a median follow-up of 7.8 years, 472 incident cases were identified. In fully adjusted models, meeting recommended MVPA levels together with higher n-6 PUFA concentrations was associated with a 71% lower risk (HR 0.29, 95% CI 0.18-0.45). The MVPA-MASLD association was nonlinear, with risk reduction plateauing at approximately 189 minutes per week. Higher n-6 PUFA was associated with reduced risk, whereas n-3 PUFA showed no significant association. Conclusions: These findings suggest that behavioral and metabolic factors may jointly influence MASLD risk. Further studies in diverse populations are needed to confirm these associations.

Diabetic peripheral neuropathy (DPN) is a common and disabling condition for which no disease-modifying therapies are available. Glycemic and metabolic drivers do not fully explain why only a subset of individuals with diabetes develop DPN, and genetic contributors remain poorly defined. We aimed to perform a multi-population genome-wide association study (GWAS) of DPN to highlight potential new etiological pathways and therapeutic targets. Methods We performed a multi-population GWAS of neuropathy in people with and without diabetes using the VA Million Veteran Program and UK Biobank, followed by replication in the All of Us Research Program (AoU), and gene-based and gene-set analyses to identify implicated pathways. Causal relationships between circulating serine levels and DPN were further tested using two sample Mendelian randomization. To further evaluate pathogenic potential, we analyzed rare, high impact variants in GWAS implicated genes among individuals with unresolved inherited neuropathies using the GENESIS platform. Findings Among individuals with type 2 diabetes, we identified seven genome wide significant loci (p<5x10-): PHGDH and PSPH (key serine synthesis genes), TEAD1, CYP4F11, LARGE1, FTO, and COBLL1. No loci were significant in individuals without diabetes or with type 1 diabetes. Four loci (PHGDH, TEAD1, FTO and CYP4F11) replicated in AoU (p <0.05). Mendelian randomization demonstrated that higher genetically predicted serine levels were associated with lower DPN risk, consistent with a causal role of serine metabolism in disease pathogenesis. Rare-variant burden analyses revealed associations of predicted deleterious variants with inherited neuropathy case status in PHGDH (odds ratio [OR] 12.7 [95% CI 7.9, 20.4]), PSPH (OR 8.5 [7.2, 10.2]), PHKG1 (OR 4.8 [3.7, 6.3]), and LARGE1 (OR 0.007 [0.0004, 0.1]). Interpretation Convergent genetic evidence across common and rare variation implicates serine synthesis as a key pathway in DPN. These findings link diabetic and inherited neuropathies through a shared metabolic mechanism, identifying serine metabolism as a potential therapeutic target.

Background: Epic Cosmos is a relatively new centralized electronic health record dataset with high potential utility in perinatal epidemiologic research. Objectives: The study objectives were to develop replicable steps to create longitudinal, linked maternal-infant cohorts in Cosmos, assess completeness of key variables, evaluate potential selection bias with restrictions for longitudinal healthcare encounters, and provide an example epidemiologic analysis. Methods: We created maternal-infant cohorts by starting with live births during 2023-2024 recorded in the BirthFact data table and joining with additional data tables as needed. We selected and created variables for perinatal characteristics, common comorbidities, and routinely measured vital signs and laboratory values, and assessed variable completeness. We sequentially restricted the birth cohort for maternal-infant linkage and longitudinal healthcare from first-trimester prenatal care encounter through infant follow-up care within 12 weeks post-discharge from birth hospitalization. Finally, we conducted an example analysis of the association between high systolic blood pressure in the first trimester ([&ge;]140 mm Hg) and later onset of preeclampsia among those with chronic hypertension. Results: The total linked birth cohort included 2,624,186 pregnancies. Completeness was >90% for most variables assessed but was 77% for racial and ethnic group and 76% for body mass index at delivery. Characteristics of the cohort were similar to those reported for the entire United States birth population based on birth certificate data, including similar regional and racial-ethnic composition. Longitudinal cohort restriction requiring linked records from first trimester prenatal care through infant follow-up care reduced the cohort size to 509,148 pregnancies. However, restriction had minimal effects on cohort characteristics. In the example analysis, high systolic blood pressure was associated with increased risk of preeclampsia among those with chronic hypertension (aRR: 1.26; 95% CI: 1.22, 1.30). Conclusions: This study provides a rigorous and reproducible approach to creating longitudinal, linked maternal-infant cohorts in Epic Cosmos and the analytical findings suggest high data quality and representativeness.

BACKGROUND: Neuropsychiatric symptoms (NPS) are prevalent and debilitating in Alzheimer's disease (AD). Existing pharmacologic treatments are often ineffective and associated with serious adverse events. Identifying modifiable risk factors (MRFs) is critical for prevention and treatment. METHODS: Capitalizing on data from 14,497 individuals with AD from the National Alzheimer's Coordinating Center (NACC) database, we examined longitudinal associations between modifiable risk factors, APOE genotype and NPI-Q-assessed NPS using Cox proportional hazards models adjusted for demographics. RESULTS: Diabetes, alcohol consumption, smoking, and TBI were associated with an increased risk of specific NPS in AD. APOE{varepsilon}4 carrier status was linked to multiple NPS, showing a dose-response relationship. Education, LDL-C, and corrective lenses were protective; hypertension showed no associations. CONCLUSION: These findings strongly suggest that individual MRFs are associated with specific NPS in line with a complex etiology underlying these symptoms. Early detection and management of vascular, lifestyle and sensory factors could reduce NPS.

Large language models (LLMs) such as ChatGPT are rapidly reshaping healthcare education and simulation-based training in non-technical skills (NTS), yet no bibliometric analysis has mapped this landscape. We searched seven open-access databases (OpenAlex, PubMed, Europe PMC, Crossref, Semantic Scholar, CORE, DOAJ) for English-language publications from January 2020 to March 2026. From 100,277 initial records, a sequential keyword funnel yielded 830 candidate papers, which were screened by 83 independent Claude Sonnet 4.6 AI agents applying pre-specified inclusion criteria (PRISMA-trAIce compliant; Cohen's kappa = 0.86 pre-reconciliation, 1.0 post-reconciliation). The final AI-verified corpus comprised 551 papers with a compound annual growth rate of 109%, contributions from 2,398 authors across 279 journals in 58 countries, and an h-index of 41. ChatGPT dominated the model landscape (46% of papers), with open-source models virtually absent. Virtual patient chatbots were the leading simulation modality (106 papers). Among NTS domains, communication (145 papers) and decision-making (135 papers) were most studied, whereas teamwork, leadership, situational awareness, and crisis resource management were markedly underrepresented. Only 6 urology-relevant papers were identified, none examining LLM integration within boot camp training formats. The field is growing at extraordinary pace but remains concentrated in a narrow range of NTS domains and a single proprietary model. Critical gaps persist in team-based skills training, open-source model evaluation, and specialty-specific simulation. AI-assisted bibliometric screening using multiple independent agents is feasible, reliable, and scalable, offering a replicable methodology for mapping fast-evolving research fields.

Introduction: To investigate the epidemiological characteristics of chronic kidney diseases (CKD) in China in 2021 and its trends between 1990 and 2021, in the context of significant population growth and lifestyle changes over the past 30 years that have likely influenced the CKD spectrum. Methods: Data on CKD prevalence, mortality, disability-adjusted life-years (DALY), and risk factors were obtained from the Global Burden of Disease Study 2021. The estimated decadal percentage changes were calculated to evaluate changes in trends in prevalence, mortality and disease burden. Results: In 2021, an estimated 118.4 (95% UI 109.4 to 127.5) million people in China were affected by CKD, contributing to 204 230 (95% UI 164 736 to 246 372) deaths and 6.13 (95% UI 5.18 to 7.21) million DALY. Although CKD due to diabetes mellitus and hypertension accounted for less than a quarter of all cases, they were responsible for over 90% of CKD-related deaths. Over the past three decades, CKD mortality and DALY rates have steadily increased, although the prevalence has stabilized in the last decade. Diabetes mellitus type 2 and hypertension have emerged as key drivers of CKD burden in China. Conclusions: The CKD burden in China shows a dual pattern of rising incidence and high mortality from diabetes and hypertension-related chronic kidney disease, alongside persistently high years lived with disability from glomerulonephritis and other causes.

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.

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.

Cultural engagement is associated longitudinally with better mental health and reduced depression incidence, but evidence has largely relied on self-reported symptoms and diagnoses, leaving uncertainty about clinically recorded disorders, and residual confounding remains a concern. Here, we examined whether cultural engagement (including going to cinemas, museums, galleries, exhibitions, theatre, concerts, or opera) predicts hospital-treated mental disorders in 8,274 adults aged 50 years or older from the English Longitudinal Study of Ageing. Participant records were linked to ICD-10 diagnoses in Hospital Episode Statistics and mortality records with follow-up of up to 20 years. In fully adjusted Cox models accounting for sociodemographic, lifestyle, and social factors and multiple testing, frequent cultural engagement was associated with lower risk of any mental disorders (HR 0.71, 95% CI 0.62-0.82, FDR adjusted P value<0.001), dementia (0.71, 0.56-0.89, FDR adjusted P value=0.010), substance misuse (0.75, 0.59-0.95,FDR adjusted P value=0.040), and mood disorders (0.73, 0.56-0.95, FDR adjusted P value=0.044), but not neurotic disorders. Associations persisted after excluding early incident cases and adjusting for baseline depressive symptoms and cognition, and showed robustness to unmeasured confounders. To further probe causality, eye disease, ear disease, and traumatic brain injury, which share similar socio-demographic profiles to mental disorders, were prespecified as negative control outcomes. Cultural engagement was not associated with any negative control outcomes. These findings provide triangulated statistical data to suggest that cultural engagement is associated with reduced risk of several clinically recorded mental disorders and support further testing of cultural engagement as a population mental health strategy.

Abstract Purpose: Published clinical outcome data on preconception carrier screening (PCS) in Central Asia are limited. We report the first clinical implementation study from Uzbekistan of a whole-exome sequencing (WES)-based multi-platform PCS program combining exome sequencing with targeted SMA, FMR1, and DMD assays. Methods: We retrospectively analyzed anonymized data from 65 individuals (19 couples, 27 singletons) screened at IMC Genomics, Tashkent, between January 2024 and May 2026. WES covering the protein-coding regions of approximately 20,000 genes was followed by exome-wide bioinformatics filtering and clinical geneticist interpretation. Partly overlapping cohorts underwent SMA carrier screening (n=179), FMR1 CGG-repeat analysis in females (n=155), and DMD deletion/duplication testing in preconception females (n=29). Variants were classified by ACMG/AMP criteria against gnomAD v4.1. Results: Sixty-one of 65 WES-screened individuals (93.8%; 95% CI 85.2 - 97.6%) carried at least one reportable variant (152 instances across 126 genes). Four of 19 couples (21.1%; 95% CI 8.5 - 43.3%) were concordant for pathogenic or likely pathogenic variants in the same autosomal recessive gene; two were referred for preimplantation genetic testing for monogenic disease. SMA screening identified four carriers, including two 2+0 silent carriers; FMR1 analysis identified one intermediate allele; DMD MLPA identified no exonic rearrangements. Conclusion: This first reported WES-based multi-platform PCS program in Uzbekistan was feasible and clinically informative, identifying actionable couple-level reproductive risks and supporting structured implementation of reproductive genetic screening in Central Asia.

Background: Mono-allelic Dehydrodolichyl Diphosphate Synthase (DHDDS) variants are associated with juvenile Parkinsonism, developmental delay and seizures. Symptoms are progressive, and various mechanisms, such as defective glycosylation, lysosomal dysfunction and cholesterol accumulation have been hypothesized to underlie disease symptoms. There is no treatment for DHDDS-related disease. Methods: Patient-derived cortical forebrain organoids were created to elucidate disease mechanisms and evaluate potential treatments. In these neuronal models, glycosylation, lipidomics, proteomics, cholesterol/ganglioside accumulation, mitochondrial function and electrophysiological activity were assessed. Finally, we investigated the effects of nicotinamide mononucleotide (NMN), identified through a yeast-based drug screen, in neuronal cell models and in six patients in an off-label, N-of-1, observational series. Results: DHDDS-patient derived organoids showed visual signs of degeneration after four months of culturing. This was accompanied by significant cholesterol accumulation in astrocytes, decreased mitochondrial respiration and loss of deep-layer neurons. In addition, we identified glycosylation abnormalities, showing for the first time that glycosylation in human tissue is affected by monoallelic DHDDS variants. Proteomic analysis revealed altered protein expression of proteins involved in lipid metabolism, cytoskeletal organization and neuronal development. We found that oral Nicotinamide Mononucleotide supplementation led to significant improvement in mitochondrial respiration and electrophysiological parameters in organoids, concurring with clinical improvements in all of the treated patients, particularly regarding their ataxia and tremor. Conclusion: Our findings reveal a progressive phenotype in DHDDS-patient-derived brain organoids, with mitochondrial dysfunction and astrocyte-specific metabolic alterations contributing to disease pathology. Notably, NMN treatment led to clinical improvements in patients with heterozygous DHDDS variants, highlighting its potential as a therapeutic strategy.

Objective: Clinical phenotyping methods that rely on clinical and informatics expertise can be time-intensive and costly. We tested both manual and highly automated approaches using electronic health record (EHR) data to identify an FDA Sentinel Initiative health outcome of interest, acute pancreatitis. Materials and Methods: We trained and evaluated machine learning algorithms using EHR data with two approaches: a custom approach that included manually curated features and trained on outcomes data validated with medical record review, and a highly automated approach that greatly simplifies and automates feature engineering and relies on low-cost silver-standard outcomes for model training. Results: Custom algorithms using manually curated structured claims data discriminated cases from non-cases with a high degree of accuracy (cv-AUC 0.89 [95%CI 0.84-0.94]); the inclusion of natural language processing (NLP)-derived covariates from clinical notes increased performance slightly (cv-AUC 0.91[95%CI 0.86-0.97]). The automated algorithm trained on the outcome count of diagnosis codes performed less well (AUC 0.80 [95% CI 0.75-0.85]) but improved using maximum lipase value as an outcome (AUC 0.88 [95% CI 0.84-0.92]). At a positive predictive value of 90%, the custom algorithm had a sensitivity of 92%, the automated algorithm trained on diagnosis code count had a sensitivity of 45%, and the automated algorithm trained on maximum lipase value had a sensitivity of 84%. However, a prediction rule derived by clinicians during chart review was nearly as accurate (maximum lipase value [&ge;] 3 times upper limit of normal; AUC 0.86, PPV 85%, sensitivity 92%). Discussion: Machine learning algorithms with manually curated structured data and NLP features trained on validated outcomes data successfully identified validated events. Use of an outcome in the automated model based on specific phenotype knowledge (maximum lipase value) allowed for performance similar to the custom model and with considerably less resources.

Background: Mass gathering events (MGEs) are associated with several public health challenges and may cause a strain on healthcare services. Literature findings on the impact of MGEs on emergency departments (EDs) are heterogeneous. Objectives: To examine shifts in ED attendance characteristics during a major sporting tournament, namely the UEFA European Football Championship 2024 held in Germany. Methods: We conducted a retrospective observational study using ED data from the Emergency Department Data Registry. We compared baseline ED attendance characteristics between the tournament and the reference period, defined as two weeks before and two weeks after the tournament, and between Germany game days and non-Germany game days. Hourly attendance patterns were analysed for all Germany games using a reference range. Results: We included data from 41 EDs, totalling 253,493 attendances during the study period. A 1.57% increase in attendance was observed during the tournament compared to the reference period, with baseline characteristics remaining similar. The median daily attendance within all EDs was slightly lower on Germany game days (4066) compared to non-Germany game days (4128). Modest changes were observed in the hourly attendance on Germany game days, most notable during the last Germany game where a decrease in attendance below the reference range extended over three hours. Conclusions: The observed shifts in ED attendance were minimal, suggesting that no major changes of public health relevance occurred in ED attendance during the tournament. We highlight the utility of using ED data for monitoring and for enhancing the understanding of the public health risks and challenges associated with MGEs.

Background: Artemisinin-based combination therapies remain the mainstay of malaria control strategies; nevertheless, the advent of genetic markers linked to partial artemisinin resistance in Plasmodium falciparum has elicited substantial concern across African settings. To assess the prevalence, geographic distribution, and clinical associations of these molecular markers, we undertook a systematic review and meta-analysis of observational cohort studies.Methods: We conducted a search of cohort studies published between January 2015 and June 2025, following PRISMA 2020 guidelines. We queried databases including PubMed/MEDLINE, Scopus, Web of Science, and CINAHL. Eligibility required prospective enrollment of patients, longitudinal monitoring (therapeutic efficacy studies), and pfkelch13 propeller domain genotyping.Results: A meta-analytical synthesis of 888 isolates from six core prospective cohorts revealed a pooled prevalence of 6% (95% CI: 2.1%-11.8%) for validated pfkelch13 mutations. A profound geographic dichotomy was identified: while West and Central African cohorts maintained a 0% prevalence, East African hotspots showed significant expansion, with prevalence reaching 12.8% in Rwanda and up to 25.5% in Northern Uganda; high statistical heterogeneity (, ) reflects this biological divergence. Conclusions: These findings highlight the established and expanding presence of artemisinin partial resistance in East Africa. Standardized surveillance is essential to adapt malaria control policies across the continent. Keywords: Africa; artemisinin resistance; clinical indicators; pfkelch13 gene; molecular markers; partial resistance; Plasmodium falciparum.

Importance: As new treatments increase quality and length of life in people with multiple sclerosis (MS), effective prevention and management of common comorbidities, including Diabetes Mellitus (DM), is increasingly important. Objective: To compare incidence of DM and its associations with hospitalisation and mortality in adults with MS and matched controls. Design: Using English primary care data from the Clinical Practice Research Datalink (CPRD), linked to Hospital Episode Statistics and national mortality records, we matched adults with MS diagnosed between 2000 and 2023, with up to ten controls without MS by age, sex, and practice. We excluded individuals with preexisting DM, defined using diagnostic and management codes. Outcomes included all-cause hospitalisation (number and duration) and mortality. We used Poisson, negative binomial, linear, and Cox proportional hazards models, adjusting for demographic and socioeconomic factors, adding interaction terms to examine if ethnicity, deprivation, and urbanity were associated with outcomes. Results: We included 9,010 individuals with MS and 78,121 matched controls. Over a mean follow-up of 13.2 years, people with MS had over twice the incidence of DM compared with controls (adjusted incidence rate ratio [aIRR]=2.26, 95% CI: 1.96 to 2.61, p<0.001). Among people with MS, incident DM was associated with higher hospitalisation rates (aIRR=1.82, 95%CI: 1.47 to 2.28, p<0.001), longer hospitalisation duration (median 18 vs 4 days, adjusted beta;=0.53, 95%CI: 0.41 to 0.65, p<0.001), and increased all-cause mortality when incident DM was modelled as a time-varying exposure (adjusted hazard ratio=1.46, 95%CI: 1.17 to 1.82, p<0.001), compared to those who did not develop DM. Similar patterns were observed among controls (hospitalisation rates: aIRR = 2.96, 95% CI 2.63 to 3.23, p<0.001; hospitalisation duration: adjusted {beta} = 0.93, 95% CI: 0.86 to 0.99, p<0.001; mortality [time-varying]: HR = 1.50, 95% CI: 1.27 to 1.77, p<0.001). The relationship between DM and increased hospitalisation was stronger in rural areas among those with MS and stronger in White groups among controls. Conclusions: People with MS are more likely to be diagnosed with DM, resulting in greater all-cause hospitalisation and all-cause mortality. This highlights the importance of equitable screening, prevention, and management of DM in people living with MS, with particular attention to geographical health inequalities.

Background: The biological mechanisms linking generalized anxiety disorder (GAD) and COVID-19 remain poorly understood, despite substantial evidence of their comorbidity. To address this gap, we examined genetic and epigenetic factors underlying their co-occurrence. Methods: In a multi-ancestry sample of 893 participants, we conducted genome-wide and epigenome-wide analyses of GAD and COVID-19 severity. Integrating large-scale genome-wide datasets and information regarding methylation quantitative trait loci, complementary analytic approaches were used to identify regional methylation patterns, assess genetically regulated DNA methylation in blood and brain tissue, and evaluate causal loci shared between GAD and COVID-19. Results: GAD was associated with epigenome-wide significant variation in loci involved in chromatin regulation and synaptic signaling. Conversely, COVID-19-related epigenetic signals were enriched in immune-inflammatory and host-response pathways. Mild COVID-19 was epigenetically related to endothelial-inflammatory signals, while severe COVID-19 was linked to epigenetic changes implicated in myeloid and thrombo-inflammatory pathways. Epigenetic signals shared between GAD and COVID-19 implicated processes related to stress adaptation and tissue homeostasis. Genetically informed analyses identified 60 shared loci, including MAPT, ZFP57, and FBXL18, indicating pleiotropy between GAD and COVID-19 in genetically regulated DNA methylation variation. Brain-specific analyses further highlighted convergence in additional loci (i.e., MICB and HLA-DPB1), suggesting neuroimmune mechanisms underlying GAD-COVID-19 shared methylation patterns. Conclusions: These findings support that GAD and COVID-19 share epigenetic and genetic architecture involving pathways related to vascular integrity, immune function, and cellular adaptation, highlighting a potential neuroimmune basis for their co-occurrence.