Frontiers in 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.

Background: Histological examination of mucosal tissue in inflammatory bowel diseases (IBD) is a sensitive tool to measure disease activity, and histological remission is emerging as a potentially important treatment target. There are several existing histopathological indices, but they often encompass caveats such as not primarily having been designed to measure the degree of inflammation, encompassing subjective components with poor intra- and interindividual reproducibility, and requiring expert pathologists who are scarce, thus resulting in extended response times. Aim: To construct a new computerized, automated index to objectively measure histological disease activity in the ileal and colonic mucosa, applicable to both Crohn's disease (CD) and ulcerative colitis (UC). Materials and methods: Ileocolonic biopsies were collected from control subjects and patients with CD or UC. A group of CD patients was sampled before and after 12 weeks of anti-TNF therapy. Another group of CD and UC patients functioned as a small validation cohort. Epithelial cells, neutrophils, macrophages, and T cells were immunohistochemically stained, followed by digitalization of the color signal and computerized delineation of the epithelial and lamina propria compartments. The various immune cell types within the epithelium and the lamina propria, respectively, were enumerated, and the numbers were compared between control subjects and patients with CD or UC. Results: The numbers of neutrophils and macrophages in the epithelium, and neutrophils in the lamina propria, showed the highest sensitivity and specificity for distinguishing control-subject tissues from CD and UC tissues. These three parameters were thus chosen to construct a new index, named QiC3 1.0, that could separate tissues from control subjects and patients with CD or UC with high precision. It performed equally well in a small validation cohort of patients. The QiC3 index correlated well with previously described histopathological indices, fecal calprotectin, and endoscopic scores in UC, but showed worse correlation with endoscopic scores in CD and symptomatic scores. When applying the new index to tissues from CD patients before and after therapy, it showed good responsiveness, demonstrating a distinct amelioration in the microscopic inflammatory status that corresponded well to improvements in histopathological scores. Conclusion: We describe a new quantitative, computerized, automated, non-subjective, and response-sensitive immunohistological index (QiC3) for measuring disease activity in ileal and colonic mucosal biopsies, suitable for both CD and UC.

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.

Use of fungal mycelia, which has antiviral properties, constitutes a novel strategy for addressing existing and newly emerging viral diseases. We evaluated safety and feasibility of fungal mycelia (Fomitopsis officinalis and Trametes versicolor, FoTv) for treatment of COVID-19 and assessed its antiviral effects and potential to reduce symptoms. In a randomized, double-blind, placebo-controlled, dual site (UCSD/UCLA medical centers) clinical trial we examined non-hospitalized patients who contracted mild-to-moderate COVID-19 [&le;] 96 hours, and experienced symptom onset [&le;] nine days, before enrollment. FoTv was safe, well-tolerated, and feasible for COVID-19 treatment. Minor differences in biochemical markers were observed between groups (26 FoTv, 24 Placebo). FoTv significantly reduced the number and severity of symptoms, particularly sore throat/cough, and in vitro SARS-CoV-2 (pseudovirus) cellular infection. In conclusion, FoTv was safe and reduced COVID-19 symptoms and cellular viral infection. Future studies should investigate therapeutic benefits of fungal mycelia for SARS-CoV-2 and other viruses. Clinicaltrials.gov registration:NCT04667247.

Background: Obesity is a global health crisis, contributing to chronic diseases such as diabetes, cardiovascular disease, and metabolic syndrome. Traditional Chinese Medicine (TCM) has been used in East Asia to manage obesity, but evidence on its efficacy and safety remains limited. This systematic review and meta-analysis assess clinical evidence from randomized controlled trials (RCTs) on TCM for obesity treatment. Methods: We systematically searched PubMed, EMBASE, Cochrane Library, and Web of Science from inception to April 2026. Eligible RCTs compared TCM interventions with placebo or conventional treatments in obese patients. Two reviewers independently conducted screening, data extraction, and quality assessment. Meta-analysis was conducted using a random-effects model to calculate pooled weighted mean differences (WMD) and odds ratios (OR) for body weight, BMI, waist-to-hip ratio (WHR), lipid profiles, and adverse events. Results: A total of 33 randomized controlled trials (RCTs) involving 3,053 participants were included in the analysis. TCM significantly reduced body weight (WMD = -5.86 kg, 95% CI: -7.51 to -4.21), BMI (WMD = -2.82 kg/m{superscript 2}, 95% CI: -3.38 to -2.25), and WHR (WMD = -0.04, 95% CI: -0.06 to -0.02). Lipid profiles improved, with reductions in total cholesterol (WMD = -0.82 mmol/L), triglycerides (WMD = -0.65 mmol/L), LDL-C (WMD = -0.39 mmol/L), and increased HDL-C (WMD = 0.29 mmol/L) (all p < 0.001). Adverse events were infrequent, with no significant difference observed between TCM and control groups (OR = 0.51, 95% CI: 0.24 to 1.08). Funnel plots indicated no publication bias. Conclusion: TCM appears effective in reducing body weight and improving lipid profiles in obese patients, with a low incidence of adverse events. It may serve as a complementary treatment for obesity, though further high-quality RCTs are needed to confirm these findings and assess long-term outcomes.

Abstract Objective: The onset of hypertension occurs at a younger age in China, and the relationship between health literacy and quality of life among middle-aged and older hypertensive patients remains unclear. This study explored whether perceived social support and self-efficacy mediate the association between health literacy and quality of life in middle-aged and older hypertensive patients. Methods: A questionnaire was administered to 1,015 middle-aged and older hypertensive adults from communities in six central provinces of China. The EQ-5D scale, Perceived Social Support (PSS) scale, Self-Efficacy Scale (SES), and Health Literacy Scale (HLS) were used to assess quality of life, social support, self-efficacy, and health literacy, respectively. Mplus 8.3 software was used to construct a structural equation model for path analysis. Results: The mean PSS, SES, HLS, EQ-5D, and EQ-VAS scores were 15.57{+/-}3.45, 10.61{+/-}2.41, 9.49{+/-}2.86, 0.88{+/-}0.18, and 71.06{+/-}17.49, respectively. Health literacy and quality of life scores significantly differed among middle-aged and older hypertensive patients, and both showed positive correlations with perceived social support and self-efficacy (both P<0.001). Perceived social support and self-efficacy exhibited a chain mediated effect on the relationship between health literacy and quality of life (EQ-5D utility index and EQ-VAS), accounting for 28.57% of the total effect of the EQ-5D utility index and 27.26% of that of the EQ-VAS. This study is the first to elucidate the mechanism by which health literacy influences quality of life in middle-aged and older hypertensive patients through the chain-mediated effect of perceived social support and self-efficacy. Conclusion : Health literacy is significantly correlated with quality of life in middle-aged and older hypertensive patients. This correlation can directly or indirectly explain the impact on quality of life through mediating pathways involving perceived social support and self-efficacy. Keywords: hypertensive patients, perceived social support, self-efficacy, health literacy, quality of life, mediating effect

Background and Aims: Fatigue is a prevalent and disabling symptom in inflammatory bowel disease (IBD), yet its underlying biological mechanisms remain poorly understood. We aimed to characterize fatigue-associated molecular signatures in IBD patients by integrating DNA methylation and mRNA expression analyses. Methods: Peripheral blood was collected from 40 patients with Crohn's disease (CD), 29 with ulcerative colitis (UC), and 10 healthy controls. Fatigue severity was assessed continuously using the Multidimensional Fatigue Inventory (MFI). Epigenome-wide DNA methylation profiling and mRNA sequencing were performed, identifying differentially methylated regions (DMRs) and differentially expressed genes (DEGs) for active and quiescent CD and UC, adjusting for age, sex, and smoking status. Pathway enrichment analysis was performed on genes with differential methylation and expression. Results: In active CD, more severe fatigue was associated with transcriptional suppression of immune and metabolic pathways (246 DMRs; 1,090 DEGs), versus upregulation of mitochondrial and metabolic processes in quiescent CD (200 DMRs; 1,619 DEGs). In active UC, fatigue was associated with anabolic pathway upregulation and epigenetic silencing of neuroactive pathways (6,927 DMRs; 343 DEGs; 56 concordant genes). Quiescent UC showed transcriptional changes without significant epigenetic pathway enrichment (1,710 DMRs; 3,224 DEGs). Healthy controls exhibited a distinct profile spanning metabolic, immune, and neuronal pathways (8,621 DMRs; 395 DEGs). Fatigue-associated signatures were largely non-overlapping across all five groups. Conclusions: Fatigue-associated molecular profiles differed substantially by disease subtype and activity state, highlighting the biological heterogeneity of IBD-related fatigue and laying the foundation for multi-omics approaches to identify biomarkers and potential therapeutic targets.

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.

Introduction: Synthetic oligopeptides provide a rapid and cost-efficient approach to developing antibodies and diagnostics for emerging viral variants. Methods: This study computationally and experimentally characterized a synthetic peptide analog of the SARS-CoV-2 spike subdomain 2 major disulfide loop (SD2MDL), designated S621 (CPVAIHADQLTPTWRVYSTC). Binding affinity was computationally estimated using the Heuristic Affinity Prediction Tool for Immune Complexes (HAPTIC), while experimental validation was performed using enzyme-linked immunosorbent assay (ELISA) with rabbit-derived antipeptide antibodies. Clinical diagnostic accuracy testing was done using plasma samples from RT-PCR-confirmed COVID-19 patients and pre-COVID-19 controls. Results: S621 demonstrated nanomolar binding affinity (Kdapp = 1.14 nM) and high avidity (3.67 nM), closely matching HAPTIC predictions (3.54 nM). Diagnostic evaluation yielded a sensitivity of 89.92% and specificity of 27.79%, corresponding to an overall accuracy of 71.79%. Discussion: These findings demonstrate that a single synthetic peptide derived from a conserved spike subdomain can function as a high-affinity surrogate for full-length antigens, supporting its potential application in rapid peptide-based immunodiagnostics.

As genetic testing becomes increasingly integrated into Parkinson disease (PD) research, including targeted testing for variants in LRRK2 and GBA1, the return of individual research results is becoming more common. However, limited qualitative data exists regarding how research participants experience genetic results disclosure and post-test genetic counseling in PD research settings. We conducted semi-structured qualitative interviews with participants (n=13) enrolled in the Parkinson Precision Medicine Initiative (formerly Parkinson Progression Markers Initiative; PPMI) who had received PD-related genetic test results and post-test genetic counseling. Interviews were conducted 1 to 3 weeks following result disclosure and analyzed using thematic analysis with a primarily deductive coding approach informed by study aims and inductive identification of emergent themes. Four primary themes were identified: (1) personal connection and motivations for participation, (2) centrality of result disclosure and information preferences, (3) emotional experiences and support needs, and (4) communication quality and alignment with participant needs. Overall, our findings underscore the importance of person-centered genetic counseling within PD research. As return of genetic and biomarker results in research and clinical trial contexts expand, thoughtful integration of relational, informational, and communication-focused practices will be essential to support participant engagement and trust.

Aims: Sarcopenia and sarcopenic obesity are associated with increased risks of cardiovascular (CV) disease and mortality. This study examined the associations of body composition and daily physical activity with mortality, CV events and cancer in patients with diabetes. Methods: This prospective cohort study included patients with diabetes treated at a specialised clinic in Japan between January 2018 and March 2023. Body composition, including visceral adipose tissue (VAT), was assessed by bioelectrical impedance analysis. Daily physical activity was evaluated using the non-exercise activity thermogenesis (NEAT) questionnaire, and handgrip strength (HGS) was measured by dynamometry. Cox proportional hazards models were used to assess associations with mortality, CV events, and cancer. Results: Among 2,024 patients (mean age 63.0 years, BMI 24.6 kg/m^2, HbA1c 7.8%), NEAT, HGS, and VAT were not independently associated with all-cause mortality. Higher VAT was associated with increased cancer risk (HR 1.485; 95% CI 1.101-2.003; p = 0.009). Higher HGS was inversely associated with CV event risk (HR 0.951; 95% CI 0.919-0.984; p = 0.004). NEAT was not associated with any outcome. Conclusions: Higher VAT was associated with increased cancer risk, whereas higher HGS was protective against CV events. Incorporating body composition and HGS assessments into clinical practice may improve risk stratification and management in patients with diabetes.

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.

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.

Heart transplantation (HT) is the durable therapy for end-stage heart failure (HF). Despite advances in immunosuppression, cardiac allograft vasculopathy (CAV) remains a leading cause of late graft failure and mortality in the modern era. Prior studies have established donor age and immunological phenomena, such as acute cellular rejection (ACR), antibody-mediated rejection (AMR), and development of donor-specific antibodies (DSAs) as risk factors for CAV. However, it remains unclear whether acute rejection (AR) that occurs early post-HT, when individuals experience the highest degree of immunosuppression, reflects higher baseline immune activity and confers a higher risk of future CAV compared to later AR, when immunosuppression is minimized. We therefore examined whether AR occurring during pre-specified early and intermediate intervals compared to those who did not experience AR in the first post-HT year was associated with future CAV among recipients without CAV at 1 year.

Background The European Association for the Study of the Liver (ESAL) - Steatotic Liver Disease (SLD) screening algorithm involves two steps; initial screening with FIB-4 followed by referral for vibration-controlled transient elastography (VCTE) in patients likely to have significant fibrosis (SF). However, VCTE is not widely available in resource-limited settings. Aim To optimise the EASL SLD screening algorithm for resource-poor settings using machine learning (ML). Methods We analysed data from 964 adults aged [&ge;]35 years who underwent VCTE at a tertiary referral centre in Sri Lanka between November 2024 and 2025. Multiple ML models using different methods and variable combinations were trained on 80% of the dataset and tested on the remaining 20%. Best models were selected based on performance and externally validated using data from 430 patients who underwent VCTE before November 2024. Model performance was compared with the FIB-4 using confusion matrices. Results A Random Forest model incorporating age, AST, ALT, and platelet count separately, rather than using FIB-4, outperformed. The all-variable ML model showed the best predictive performance for SF, with accuracy of 77.2%, recall of 0.762, precision of 0.778, and AUC-ROC of 0.818. The variables used in the model, in descending order of feature importance, were AST, platelet count, BMI, ALT, age, diabetes mellitus, hypertension, dyslipidaemia, sex, family history, hypothyroidism, diabetes complication and smoking. External validation demonstrated 75.1% accuracy and an AUC of 0.779. When used as the first step of the SLD screening algorithm, the all-variable ML model identified 37 (17.1%) additional true positives and reduced false-negative diagnoses by 50% compared with FIB-4. Conclusions ML-based models were more effective than the FIB-4 score as the first-line screening tool for VCTE referral, substantially improving the identification of patients with significant fibrosis in this South Asian cohort.

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: 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: 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 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.

This cross-sectional study aimed to examine the prevalence of alcohol use and its sociodemographic correlates among adults with cardiovascular disease (CVD). We analyzed data from two large US cohorts: the All of Us Research Program (2017-2023) and the National Health and Nutrition Examination Survey (NHANES, 1999-2016). Both CVD diagnosis and past-year alcohol consumption were self-reported. Risky drinking was defined as exceeding moderate drinking or binge drinking (All of Us), or moderate/heavy drinking (NHANES). Multivariable logistic regression was used to exam associations with sociodemographic and lifestyle factors. Among 32,788 current drinkers with CVD in the All of Us cohort, 15% exceeded moderate drinking thresholds and 26% reported binge drinking. Older age, female sex, and higher socioeconomic status were inversely associated with risky drinking, while smoking was positively associated. In NHANES, moderate drinking rose from 47.3% to 57.2% and heavy drinking from 6.7% to 7.2%. Moderate/heavy drinking was positively associated with age <65 but inversely with age [&ge;]65. Higher education and income were linked to moderate drinking, while current smoking was strongly associated with heavy drinking. These results highlight the need to integrate holistic screening for alcohol use, tobacco use, and social context into routine cardiovascular care.