British Journal of Clinical Pharmacology

Background: This study aimed to evaluate real-world adverse event (AE) signals of EV to provide evidence-based guidance for its safe clinical application. Methods: Data from the FDA Adverse Event Reporting System (FAERS) database from the period of 2019 Q1-2025 Q3 were analyzed. Disproportionality analysis algorithms, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayes geometric mean (EBGM), were utilized to mine safety signals.The time to onset (TTO) was evaluated using the Weibull distribution model. Results: Among 11,697,906 reports, 4,177 EV-treated patients experienced 14,511 AEs. The most common System Organ Classes (SOCs) were skin and subcutaneous tissue disorders (18.23%), general disorders and administration site conditions (13.17%).Multi-algorithm consensus identified 179 positive signals. Alongside known toxicities (rash, peripheral neuropathy, hyperglycemia), potential new signals emerged, including dysgeusia, atypical skin lesions, and myelosuppression. Median TTO was 14 days, with the Weibull {beta} of 0.736, confirming an "early failure" profile. Subgroup analysis revealed toxicity heterogeneity: patients aged [&ge;]65 and females exhibited stronger signals for fatal severe cutaneous adverse reactions, while patients aged < 65 and males showed higher susceptibility to neurological and metabolic toxicities. Conclusions: The real-world safety profile of EV confirms known toxicities, reveals new risks (e.g., dysgeusia), and shows toxicity concentrated in the first treatment cycle. Clinical practice requires proactive monitoring during the first two weeks using demographic-specific strategies: vigilance for fatal skin toxicity in elderly and female patients, and close follow-up of neurological and metabolic indicators in younger and male populations.

Purpose In deprescribing studies, a prescription-free gap is typically used to determine if patients discontinued their treatment. An appropriate gap depends on the typical time between prescriptions during continued use. This work aims to characterise the interval between prescriptions of chronic drugs using different methods for a cohort of older people in primary care in Ireland. Methods The empirical prescription interval was analysed for 38,154 patients for the twenty most common drug classes and the association between covariates and the interval was analysed using a multi-level model. Estimates were also compared to those obtained from the parametric waiting time distribution (pWTD) approach. Results Available covariates had consistent relationships with prescription intervals across drug classes. For example, each additional prescription issue was associated with an increase in the interval by 5.0 (NSAIDs) to 19.7 days ("Other antidepressants"). Full public health cover was associated with a -29.0 day (inhaled adrenergics) to -11.0 day (opioids) change relative to partial cover, while other/private cover had a -17.9 day (benzodiazepines and associated drugs) to -7.1 day (SSRI and SNRIs) change relative to partial cover. The pWTD also produced consistent estimates of the population interval for most drugs. Conclusions The interval varied substantially within drug classes, due to a mixture of patient, practice and unmodelled factors. Variation between practices was effectively explained, with residual variation between patients and within patients. The pWTD approach is useful for describing complex distributions of intervals, and may be more appropriate for inferring a gap than summarising truncated data.

Background: Endocrine-disrupting chemicals (EDCs) in consumer products are ubiquitously detected in human biospecimens, yet most epidemiological studies examine single chemicals rather than real-world co-exposures. We evaluated associations between a mixture of seven urinary chemical biomarkers and systemic inflammation. Methods: Survey-weighted log-log regression models adjusted for age, sex, race/ethnicity, poverty-income ratio, and survey cycle were conducted with Benjamini-Hochberg FDR correction (primary analysis, N=4,864). A sensitivity analysis additionally adjusted for body mass index and smoking status (N=4,494). Results: In the primary analysis, 5 of 7 chemicals showed significant associations after FDR correction: ethylparaben ({beta} = -0.056, FDR P < .001), propylparaben ({beta} = -0.026, FDR P = .007), bisphenol A ({beta} = +0.052, FDR P = .005), monoethyl phthalate ({beta} = +0.043, FDR P = .002), and monocyclohexyl phthalate ({beta} = +0.215, FDR P = .007). The WQS mixture index was significantly associated with CRP ({beta} = +0.056, 95% CI [0.031, 0.081], P < .001), with monocyclohexyl phthalate carrying the largest mixture weight (0.342). In the BMI- and smoking-adjusted sensitivity analysis, associations attenuated to null for all chemicals, though MCP preserved direction ({beta} = +0.129) and the WQS mixture direction was maintained ({beta} = +0.018). Two multiple imputation sensitivity analyses confirmed that monocyclohexyl phthalate was the only chemical to maintain a positive direction across all four analytical specifications (primary complete-case, BMI-adjusted complete-case, primary-aligned imputation, and BMI-adjusted imputation), reaching statistical significance in three of four specifications and providing convergent evidence of a robust MCP-inflammation association. Conclusions: The chemical mixture showed a significant collective association with systemic inflammation, consistent with a cumulative pro-inflammatory burden from co-exposure to multiple consumer product chemicals. These findings suggest that regulatory approaches should shift from single-chemical to mixture-based risk assessment frameworks for consumer product safety.

Background: Primary aldosteronism (PA) is increasingly recognized as a common cause of hypertension. The 2025 Endocrine Society guideline introduced a simplified diagnostic framework, but its real-world clinical implications remain unclear. Methods: We conducted a multicenter retrospective cohort study of hypertensive patients undergoing PA testing in Taiwan. PA was defined biochemically according to the 2025 Endocrine Society criteria. Multivariable logistic regression identified factors associated with PA diagnosis and aldosterone-targeted therapy. Among patients with suppressed renin (?1 ng/mL/h), restricted cubic splines evaluated the adjusted association between renin and PA probability. Results: Among 18,766 patients undergoing PA testing, 6,760 (36.0%) met diagnostic criteria for PA. PA was associated with older age, female sex, lower potassium, resistant hypertension, and a higher antihypertensive medication burden. Among patients with suppressed renin, lower renin remained significantly associated with higher adjusted PA probability. However, only 39.0% of patients with PA received aldosterone-targeted therapy, including 28.2% who received mineralocorticoid receptor antagonist therapy within 6 months and 9.4% who underwent adrenalectomy during follow-up. Lower renin, higher aldosterone, lower potassium, and resistant hypertension were associated with aldosterone-targeted therapy, while younger patients with fewer comorbidities were more likely to undergo adrenalectomy. Conclusions: Using the updated diagnostic framework, PA was highly prevalent among hypertensive patients undergoing PA testing. Nevertheless, many patients who met these biochemical criteria did not receive aldosterone-targeted therapy in routine care. These findings highlight the potential treatment implications of broader PA recognition and support the development of practical pathways to guide MRA therapy, adrenalectomy referral, and individualized management.

Background: Electrolyte replacement is ubiquitous in the acute care setting, but its familiarity cannot belie that even small dosing errors with potassium can cause lethal cardiac arrhythmias. Recently, MedAgentBench offered a benchmark for agentic artificial intelligence (AI) including the ability to correctly dose potassium based on a single rule; however, this does not adequately reflect the clinical complexity or safety concerns of an agent that has been used as the lethal injection. The purpose of this analysis was to a probe leaderboard large language model (LLM) capabilities to follow basic dosing rules to safely replace potassium in a series of clinician-annotated cases. Methods: Using a clinician panel, we developed a series of dosing principles and 20 clinical cases reflective of the complexity of potassium replacement. External clinicians were surveyed to assess practice variability and agreement to clinician panel answers. We tested GPT-5-chat with each case in triplicate, with and without the clinician curated dosing principles, and prompted the model to answer six questions involving potassium goals, dosing, route, lab frequency, concurrent interventions, and the model's perceived level of confidence for the output and complexity of the case. The primary outcome was the rate of appropriate recommendations in comparison to clinician answers. Results: A total of 54 clinicians reviewed the 20 hypokalemia cases and hypokalemia dosing guideline. Clinicians expressed "highly agree" or "somewhat agree" for 66.8% of the cases evaluated when asked if they agree with the guideline-recommended management. When given the potassium dosing guideline, total errors dropped from 165 to 104, and average accuracy improved from 45% to 65% with GPT-5-Chat. GPT-5-Chat conveyed a high level of confidence for 100% of responses, while labeling 80% and 76% of cases as highly complex with and without the criteria, respectively. Potential harm scores were considerable in both groups, however, a notable reduction in severity scores occurred with the dosing guidance document. Recommendations on concurrent interventions and dosing had the highest rate of errors in both groups. Conclusions: Benchmarks must appropriately reflect clinical complexity to be considered valuable for the deployment of agentic artificial intelligence tools in the healthcare domain. GPT-5-Chat assessment on a comprehensive medication management task for potassium replacement showed improvement with dosing guidance, yet unfit benchmarking performance.

Background: Cardiovascular-kidney-metabolic (CKM) syndrome is a leading driver of cardiovascular morbidity and mortality. Whole-body molecular imaging is well-positioned to phenotype such syndromes, yet no imaging biomarker quantifies cumulative CKM burden. Bone scintigraphy with 99mTc-labeled bisphosphonates is widely performed and expanding with transthyretin amyloidosis assessment, under which Perugini grade 0 (absent cardiac uptake) is considered clinically benign. Objective: We hypothesized that the soft tissue-to-bone ratio (STBR) on these scans captures CKM burden and is an independent prognostic biomarker. Methods: We retrospectively analyzed 8,769 consecutive patients without cardiac uptake on 99mTc-DPD whole-body planar scintigraphy. The primary endpoint was all-cause mortality. Secondary endpoints were major adverse cardiovascular events (MACE) and heart failure hospitalization. Cox models were adjusted for ten established cardiovascular risk factors. Imaging-phenotype association (IPA) analysis mapped STBR to 1,210 clinical traits. STBR distribution across CKM stages was assessed in four prespecified analyses, including a non-cancer subgroup. Results: During a median follow-up of 5.1 years (IQR 2.5-8.2), 2,418 deaths occurred. Patients with prespecified STBR >0.5 (n=772, 8.8%) had significantly higher mortality (adjHR 1.73, 95% CI 1.54-1.94, p<0.0001) with an adjHR of up to 3.42 at higher thresholds (95% CI 2.05-5.42, p<0.0001). Hazard increased monotonically with STBR. STBR >0.5 was independently associated with MACE (adjHR 1.51, 95% CI 1.11-2.05, p=0.008) and heart failure hospitalization (adjHR 1.31, 95% CI 1.02-1.67, p=0.03). The association was robust across all prespecified subgroups and sensitivity analyses, including continuous STBR and patients without renal insufficiency. IPA analysis identified significant associations with type 2 diabetes, chronic kidney disease, chronic ischaemic heart disease, heart failure, atrial fibrillation, liver disease, amyloidosis, and hypertension among binary traits, as well as with CRP, NT-proBNP, BUN, cholesterol (inverse), and hemoglobin (inverse) among continuous parameters. STBR increased monotonically across CKM stages in all sensitivity analyses (all p<0.0001). Conclusions: STBR derived from routine 99mTc-DPD bone scintigraphy in patients without cardiac uptake is an independent prognostic imaging biomarker associated with cumulative cardiovascular-kidney-metabolic burden. As an opportunistic measure from scans already acquired at scale, STBR could refine CKM risk stratification at no additional cost, radiation, or acquisition time.

Mosquito-borne diseases continue to pose significant public health challenges worldwide, particularly in densely populated regions of South Asia and parts of North America experiencing increasing vector prevalence due to climate and environmental changes. Commercial mosquito repellents are widely used as a primary preventive measure; however, their efficacy, safety, and public health impacts vary depending on formulation, active ingredients, environmental conditions, and user practices. This study presents a comparative evaluation of commonly used mosquito repellent products in South Asia and North America, including coils, vaporizers, sprays, creams, and Natural repellents. The research aims to assess repellent efficacy against major mosquito vectors, evaluate potential health and respiratory effects associated with prolonged exposure, and analyze consumer awareness and usage patterns across different regions. Laboratory-based efficacy testing and field observations were conducted to compare protection duration, repellency rate, and environmental performance under varying climatic conditions. Safety assessments included analysis of chemical composition, indoor air quality impact, and reported adverse health symptoms among users. The findings indicate significant differences in effectiveness and safety profiles among product categories and geographical regions. Synthetic repellents generally demonstrated higher repellency duration, while herbal formulations showed improved safety and environmental compatibility. The study highlights the importance of standardized evaluation protocols, regulatory oversight, and public awareness in promoting safe and effective mosquito control strategies. These findings may support policymakers, healthcare professionals, and manufacturers in improving mosquito repellent technologies and reducing the burden of mosquito-borne diseases globally.

Background One in four surgical patients carries a drug allergy label, of which an estimated 90% are incorrect. Avoidance of first-choice drug therapies may lead to worse postoperative outcomes. We sought to determine the nature and extent of any association between drug allergy labels and postoperative complications. Methods A multicentre observational study in 21 NHS hospitals. Eligible patients were 18 years or older, undergoing common surgical procedures: primary hip or knee replacement; internal fixation of closed long bone fracture; colorectal resection; trans-urethral resection of prostate or bladder tumour; caesarean section; hysterectomy. Exclusion criteria: use of antibiotics in the two weeks prior to surgery, previous participation in the study. Primary outcome was postoperative complications within 30 days following surgery, a composite outcome comprising: all postoperative infections, anastomotic leak, acute respiratory distress syndrome, myocardial infarction, postoperative bleed, pulmonary embolism, stroke, antimicrobial side effects, death. Results Among 13,646 patients, 3924 (29%) carried greater than or equal to1 drug allergy labels. Labelled patients were more likely to develop postoperative complications (989/3924 (25%) vs 1926/9722 (20%); OR 1.21 [1.10-1.34]; p<0.001). They were more likely to develop surgical site infections (337/3924 (9%) vs 760/9722 (8%); OR 1.19 [1.03 -1.38]; p<0.018), and any postoperative infection (750/3924 (19%) vs 1472/9722 (15%); OR 1.24 [1.11-1.38] p<0.001). Labelled patients experienced increased risk of allergic drug reactions (31/3924 (0.01%) vs 29/9722 (<0.01%); OR 3.00 [1.77-5.09]; p<0.001), but no increase in mortality. Conclusions Drug allergy labels are common, but often incorrect. Labelled patients experience worse postoperative outcomes, including infective and non-infective complications and increased risk of allergic drug reactions. Trial registration Registered with ISRCTN registry, ISRCTN15775657.

Background: Pathologic aldosteronism induces oxidative stress, tissue injury, and increases in hemoglobin. Conversely, aldosterone antagonist therapy decreases hemoglobin. Whether these effects are attributable to aldosterone-mediated changes in iron and oxygen metabolism is unknown. Methods: The plasma proteome of participants with overt primary aldosteronism (PA) (n=50) was compared with participants without overt PA (n=61). To isolate aldosterone-dependent effects, participants without overt PA underwent oral sodium suppression testing to quantify the magnitude of renin-independent aldosterone production, enabling monotonic dose-response analyses across the continuum of renin-independent aldosteronism (subclinical to overt PA). Differential abundance testing was performed using empirical Bayes linear modeling, followed by Reactome pathway enrichment analysis and covariate-adjusted sensitivity analyses. To validate clinical relevance, aldosterone dose-response trends with blood count parameters were examined in this cohort, and an independent population-based cohort of 5,713 people with hypertension. Results: 903 proteins in the peripheral circulation were differentially abundant in overt PA versus participants without PA. The most significantly increased protein in overt PA was CYBRD1, involved in iron reduction and absorption. Pathway enrichment identified 16 iron- and heme-related pathways, including erythropoietin signaling, heme biosynthesis and mitochondrial iron-sulfur cluster biogenesis, with increases in heme and erythroid proteins and decreases in mitochondrial iron-sulfur proteins. Linear aldosterone dose-dependent trend analyses across the PA continuum further supported this signature, identifying progressive increases in hemoglobin subunits (HBA1/HBB), heme-related proteins (HMBS, UROS, AMBP, HPX, GLO1) and erythrocyte oxygen handling enzymes (CA1/CA3), alongside progressive reductions in mitochondrial electron transport chain subunits (CYCS, ETFA). These proteomic changes corresponded with aldosterone dose-dependent increases in red blood cell count, hemoglobin, and hematocrit, in this cohort and another population-based cohort. Conclusion: The continuum of PA is characterized by a progressive shift away from mitochondrial oxidative phosphorylation and toward increased intestinal iron absorption, preferential iron transport over storage, and enhanced heme synthesis and recycling, possibly reflecting cellular pseudohypoxia and systemic adaptations to increase oxygen delivery. These findings provide a novel mechanistic basis for aldosterone-mediated tissue injury and the benefits of aldosterone-directed therapy.

Introduction: Preeclampsia (PE) is a leading cause of maternal and neonatal morbidity and mortality, and low-dose aspirin (LDA) prophylaxis is the cornerstone of evidence-based prevention. Despite guideline recommendations, LDA adherence remains poor, with 10-25% of moderate-risk patients taking aspirin. Objective personalized risk stratification using biomarkers has been shown to motivate behavior change in other disease contexts. Survey data suggest that patients are more motivated to take aspirin if informed by an objective predictive test. Here, we report real-world LDA adherence among patients who received a high-risk result from a cell-free RNA (cfRNA) PE risk prediction test. Methods: This retrospective, observational survey study included asymptomatic patients of advanced maternal age (AMA; [&ge;] 35 years at delivery) with singleton pregnancies without USPSTF-defined preexisting high-risk conditions for PE who received the cfRNA PE risk prediction test. Patients who opted in to receive text message surveys were asked about LDA use following receipt of test results. High adherence was defined as reporting LDA use on at least 6 of 7 days per week at least 85% of the time surveyed. The primary analysis included patients with a high-risk test result and at least one LDA frequency survey response following receipt of test result. The observed proportion of adherent patients was compared to a baseline estimate of 25% using an exact binomial test. Results: Of 166 patients who received a cfRNA PE risk prediction test result, 48 (28.9%) received a high-risk result. Of these, 29 (60%) opted in and responded to at least one survey, constituting the primary analysis population. Twenty-seven of the 29 (93.1%; 95% CI: 78.0-98.1%) were classified as highly adherent, significantly higher than the 25% baseline adherence estimate for moderate-risk patients (p < 0.0001). Conclusion: Among surveyed patients who received a high-risk cfRNA PE test result, the proportion classified as highly adherent to LDA (93%) substantially exceeded published estimates of adherence in a similar patient population and met the clinically meaningful threshold of [&ge;] 80% associated with reduced risk of preterm preeclampsia. These findings indicate that objective and personalized biomarker risk testing may be a powerful driver of behavior change that current guidelines have failed to produce.

Abstract Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated cardiovascular benefit in type 2 diabetes and obesity, with recent observational data suggesting favorable associations after transcatheter aortic valve replacement. Whether similar associations exist after surgical aortic valve replacement (SAVR) is unknown. Methods: Retrospective propensity-matched cohort analysis using the TriNetX U.S. Collaborative Network. Adults with type 2 diabetes or obesity (BMI [&ge;]30 kg/m2) undergoing SAVR were categorized by GLP-1 RA exposure (any use within 3 months before through 1 year after SAVR) versus no use. One-to-one matching was performed on 44 covariates. Primary outcomes were 1-year all-cause mortality, heart failure, acute kidney injury, acute myocardial infarction, cerebral infarction, and atrial fibrillation. Sensitivity analyses included 30-day landmark restriction and falsification outcomes. Results: After matching, 1,984 patients were retained per cohort. GLP-1 RA use was associated with lower 1-year risks of all-cause mortality (4.8% vs 10.4%; HR, 0.44; 95% CI, 0.34-0.56), acute kidney injury (6.9% vs 10.1%; HR, 0.65; 95% CI, 0.49-0.85), myocardial infarction (3.0% vs 5.1%; HR, 0.57; 95% CI, (0.40-0.82), heart failure (11.3% vs 15.7%; HR, 0.68; 95% CI, (0.51-0.90), and atrial fibrillation or flutter (10.1% vs 13.9%; HR, 0.69; 95% CI, 0.54-0.90; all P[&le;]006). Cerebral infarction did not differ. In landmark analysis, mortality, heart failure, and acute kidney injury associations persisted; myocardial infarction and atrial fibrillation associations were attenuated. Falsification outcomes were null. Conclusions: Perioperative GLP-1 RA use was associated with lower 1-year cardiovascular event rates after SAVR. These hypothesis-generating findings support prospective randomized investigation.

BACKGROUND: Coronary artery disease (CAD) and Impaired Cognitive (IC) disease share sociodemographic, genetic, and clinical factors, but the association of IC with statin use in CAD remains unclear. OBJECTIVES: To determine the association between IC and statin use in CAD based on APO (e) genotype, sex, and lipid levels. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective study of AllofUS (AoU) participants with CAD (Age [&ge;]60 yrs) enrolled from 2017 to 2023. We defined CAD as having a history of angina/myocardial infarction/chronic ischemic heart disease or having percutaneous coronary intervention/CABG, and IC defined as mild cognitive impairment or all cause dementia, using ICD/SNOMED codes. MEASURES: We assessed the association between IC and statin use using logistic regression analysis, while adjusting for clinical factors, sociodemographics, and APO (e) genotypes before and after propensity score matching. We further performed stratified analysis by sex, and APO (e) genotypes. We finally assessed the association between IC and statin users, based magnitude on the change in lipid levels before CAD and after IC (TC: Total cholesterol, LDL: low density lipoprotein, HDL: High Density Lipoprotein). Significance was defined at p < 0.05. RESULTS: The cohort included 22,089 participants with CAD and 1343 with IC. Thirty-nine percent of participants were females, 77% were European, 13% were African American, and 9% were of Admixed American ancestry. The proportion of IC was higher (6.8% vs 3.5%, p<0.001) in statin users (n=17,191) vs non-statin users (n=4,898). IC was significantly associated with statin use (OR:1.70;1.40-2.10, p = 4.9e-7) after adjustment for clinical factors, sociodemographics, and APO (e) genotypes. After propensity-score matching between IC and CAD, we observed an association between IC and statin use (OR:1.55;1.24-1.94, p =1e-4). In stratified analysis, the association between IC and statin use was strongest in the APO e3/e3 group (OR:2.04;1.53-2.75, p = 1e-6), and in females (OR:2.20;1.60-3.06, p = 2.e-6) compared to males (OR:1.43;1.10-1.90, p = 0.01). We finally observed an increased magnitude of association between IC and statin users having higher HDL increase (> 10 mg/dl: OR:1.95;1.44-2.66, p=1e-5) as compared to statin users with lesser HDL increase (<=; 10mg/dl: OR:1.61;1.22-2.15, p=8e-4). CONCLUSION: In the AllofUS cohort, IC was significantly associated with statin use in CAD participants. We observed the strongest association in the APO e3/e3 group, among females, and with a greater increase in HDL levels in statin users.

Background Blood pressure (BP) regulation in individuals with sickle cell disease (SCD) is influenced by a complex interplay of genetic and physiological factors. While SCD has traditionally been associated with lower BP, there is an increased risk of hypertension. Emerging BP research suggests significant heterogeneity across genotypes, age groups, and sex. Objectives: This study investigated the longitudinal effects of population-level characteristics and continuous clinical and laboratory predictors on systolic (SBP) and diastolic blood pressure (DBP) in individuals with SCD, with emphasis on the interactions between baseline and predicted blood pressure slopes over time. Methods We retrospectively analyzed longitudinal data from a cohort of 2,739 patients with diverse SCD genotypes. Descriptive statistics were documented across sex, age range, genotype, health status and relative systemic hypertension risk categories (rHTN-risk). Linear mixed-effects models provided estimates of fixed- and random-effects of baseline BP and of time-related BP effects, respectively. Post-estimation margins provided contrasts of baseline-adjusted BP means and of pre-specified time effects on BP patterns. Results Males had significantly higher baseline SBP ({beta} = 6.64, p < 0.001) but lower baseline DBP ({beta} = -2.61, p < 0.001) compared with age-matched HbSS females. Baseline SBP was more unstable compared with baseline DBP and baseline DBP was more predictive of future BP trends than baseline SBP. Genotype was a consistent predictor of DBP (p < 0.05), but not of SBP. Similarly, we observed increased risks of relative diastolic hypertension across most genotypes, while the prevalence and magnitude of systolic hypertension was lower across all genotype compared with HbSS. Conclusions Blood pressure trajectories in SCD patients are not uniform and are significantly related to genotype, age group and sex over time. Baseline diastolic levels were less heterogenous and exhibited clear upward trajectories over time. These findings support the need for patient-specific BP surveillance in the care and management of SCD.

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.

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.

Background: Red cell distribution width (RDW), a readily available hematological parameter reflecting erythrocyte size heterogeneity, has been increasingly recognized as a prognostic marker in congestive heart failure (CHF), with elevated levels independently associated with adverse outcomes. However, RDW-derived composite indices-particularly the RDW-to-platelet ratio (RPR) and RDW-to-hemoglobin ratio (RHR), which integrate inflammatory, hemostatic, and oxygen-delivery pathways-remain largely unexplored in CHF populations. Whether these indices provide incremental prognostic value beyond RDW alone in critically ill patients with CHF has not been established. Methods: This retrospective cohort study included 30,409 participants from the MIMIC-IV and eICU-CRD databases. Multivariable logistic regression, restricted cubic spline (RCS) analysis, and subgroup analyses were employed to evaluate the associations between RDW, RDW-derived indices (RPR and RHR), and in-hospital mortality in patients with congestive heart failure. Results: Based on a pooled cohort of 30,409 patients with CHF from the MIMIC-IV and multi-center eICU-CRD databases (15,983 and 14,426, respectively), 16,295 (53.6%) were male and 14,114 were female, with a median age of 71.7 years. The mean RDW was 16.0 {+/-} 2.5, and the overall in-hospital mortality rate was 12.6%. Higher RDW quintiles were associated with progressively increased in-hospital mortality. In the fully adjusted model, RDW, RPR, and RHR were all significantly associated with increased in-hospital mortality, with adjusted odds ratios (ORs) of 2.46 (95% CI: 2.17-2.79) for RDW, 1.55 (95% CI: 1.38-1.73) for RPR, and 2.43 (95% CI: 2.09-2.82) for RHR. Sensitivity analyses using restricted cubic splines demonstrated that the association between RDW and RHR with in-hospital mortality was linear (P for nonlinearity > 0.05), whereas that for RPR exhibited a non-linear pattern (P = 0.02 for non-linearity). Conclusions. Elevated RDW, RPR, and RHR were independently associated with increased in-hospital mortality in patients with congestive heart failure. Notably, RPR exhibited a non-linear threshold association with in-hospital mortality.

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.

Introduction: Hypertension is the world's leading cause of death, and depression its leading cause of disability. Control rates for these noncommunicable diseases (NCDs) are low in low and middle-income countries (LMICs). Many LMICs have programs to screen and treat underserved communities for infectious diseases, but evidence to adapt them to treat NCDs is limited. We developed and tested a non-communicable disease program through Ghana's Community-Based Health Planning and Services (CHPS) primary care initiative. Methods: We trained 8 CHPS nurses to diagnose and treat hypertension and depression through door-to-door screening and pharmacotherapy. Physician assistants provided telehealth supervision. We combined this treatment with volunteer counseling to boost medication adherence, improve mood, and change health behaviors. We called the 90-day intervention the CHPS Opportunity for Mentally and Behaviorally Integrated NCD Engagement (COMBINE). Results: We recruited 60 adults from 580 screened: 37 with hypertension (mean blood pressure (BP) of 149/91 mm Hg) and 23 with depression (mean physician health questionnaire (PHQ-9) score of 13.3). After 90 days, 57/60 (95%) completed the intervention: 32/37 (86%) achieved blood pressure control (mean BP 122/75 mm Hg), and 19 of 20 (95%) achieved depression control (mean PHQ-9 score 2.0). After 12 months, 51/60 were retained: 33/37 with hypertension (89%) and 18/23 with depression (78%), with a mean BP of 121/75 and PHQ-9 score of 1.4 respectively. All 51 (100%) achieved disease control at 12 months. 5 persons left by migration and 4 by escalation to higher-level care. Conclusions: The COMBINE model achieved high levels of diagnosis, care retention, and disease control, with minimal adverse events, in a remote setting with limited usual NCD care. This model suggests a novel means to improve the care cascade for these and other noncommunicable diseases through existing non-physician care models in LMICs, warranting further controlled testing at scale.

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 [&ge;]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.

Purpose: To evaluate the incidence and baseline predictors of intraocular pressure (IOP)-lowering treatment following detection of referable glaucoma by teleretinal screening. Design: Retrospective cohort study. Methods: Participants were derived from a safety-net teleretinal diabetic retinopathy screening program (2013-2024). Participants included individuals who screened positive for referable glaucoma (cup-to-disc ratio [CDR] [&ge;]0.6 or CDR asymmetry [&ge;]0.2) and completed in-office diagnostic evaluation. The primary outcome was initiation of IOP-lowering treatment (medication, laser, or surgery) and the secondary outcome was intervention with surgery. Cumulative incidence functions were estimated, accounting for loss to follow-up. Fine-Gray models were used to identify baseline screening predictors to risk stratify each outcome. Glaucoma diagnosis was approximated using diagnostic codes and chart review. Results: 2,367 participants were included. The cumulative incidence of treatment was 19.6% (95% CI: 18.0-21.2) at Year 1 and 45.1% (42.1-48.1) at Year 8. Early treatment occurred primarily in glaucoma cases, whereas treatment accumulated longitudinally in glaucoma suspects, reaching 36.5% (31.6-41.5) by Year 8. Surgery was less common (8-year incidence: 5.3%). Baseline screening data predicted treatment and surgery, enabling risk stratification. At Year 8, cumulative incidence differed substantially between high- and low-risk groups (treatment: 59.9% vs. 31.2%; surgery: 9.7% vs. 1.0%). Older age (sub-distribution hazard ratio [SHR] 1.03 per year, p<0.001), Black race (SHR 1.50, p<0.001), and personal history of glaucoma (SHR 1.90, p<0.001) were associated with treatment; Asian race was protective (0.71, p=0.03). Older age (SHR 1.06, p<0.001), worse visual acuity (SHR 5.11 per logMAR unit, p<0.001), and screening at a hospital-based site (SHR 2.46, p=0.003) were associated with surgical treatment. Conclusion: Nearly half of safety-net diabetic patients screening positive for referable glaucoma initiated IOP-lowering treatment over 8 years, while few received surgery. Baseline screening characteristics enabled risk stratification of treatment and surgery. These findings address an evidence gap about longitudinal consequences of screening and suggest that its impact extends beyond detection of prevalent glaucoma to include identification of high-risk glaucoma suspects who warrant ongoing surveillance.