Citations

Background: Noninvasive tests are well validated in metabolic dysfunction–associated steatotic liver disease, but evidence in metabolic dysfunction and alcohol-associated liver disease (MetALD) and alcohol-associated liver disease (ALD) is limited. We evaluated noninvasive test–based clinical care pathways for fibrosis risk stratification in MetALD and ALD. Methods: This is a multinational, multicenter, cross-sectional study across 35 centers in 16 countries (2013–2025), including adults with MetALD or ALD. Fibrosis was assessed by liver biopsy and/or vibration-controlled transient elastography (VCTE). In biopsy-proven participants, we analyzed the sequential pathway (Fibrosis-4 [FIB-4] first, followed by VCTE for indeterminate FIB-4) to identify advanced fibrosis (≥F3). Diagnostic accuracy was assessed using the AUC. Results: Among 893 participants (41.3% MetALD and 58.7% ALD), the median age was 52 [43.0–61.0] years, and 79.4% were male. The estimated prevalence of advanced fibrosis was 45% (32.2% in MetALD and 54.0% in ALD). Participants with MetALD had a more dysmetabolic profile but lower fibrosis stages than ALD. Among biopsy-proven participants, FIB-4 AUC was 0.720, and VCTE AUC was 0.833. FIB-4 performed better in MetALD than ALD (AUC 0.773 vs. 0.540), while VCTE accuracy was similar across groups. In the sequential pathways, the false-negative rate for advanced fibrosis (misclassified as low risk) was 6.8% (4.9% MetALD and 11.3% ALD). Conclusions: In biopsy-proven patients, FIB-4 performance was acceptable in MetALD but substantially weaker in ALD. The standard 2-step pathway performed adequately in MetALD but missed a clinically meaningful proportion of advanced fibrosis in ALD.

Background: Rural communities face worsening surgical access because of hospital closures and workforce shortages. Although osteopathic physicians have historically practiced in rural settings, their contribution to the contemporary rural surgical workforce remains poorly defined. Study Design: Cross-sectional analysis of 74,404 US attending surgeons across seven specialties using the 2023 Centers for Medicare & Medicaid Services Doctors and Clinicians database. Practice addresses were linked to 2020 Rural-Urban Commuting Area codes, Area Deprivation Index quintiles, and census tract population density. Rural practice (mean Rural-Urban Commuting Area score ≥4) was modeled using multivariable logistic regression adjusted for specialty, graduation cohort, sex, Census division, and state urbanization, with state-clustered standard errors. Results: Rural practice was more common among DO than MD surgeons (18.3% vs 9.7%; risk difference, 8.6 percentage points; 95% CI, 7.6–9.6). Across all specialties, DO surgeons practiced in more socioeconomically deprived communities. After adjustment, DO surgeons had twice the odds of rural practice compared with MD surgeons (OR, 2.05; 95% CI, 1.85–2.28). Rural areas had 13.8 surgeons per 100,000 residents versus 23.6 per 100,000 in metropolitan areas. Surgeons graduating in 2010 or later had approximately half the odds of rural practice compared with those graduating in 1979 or earlier (adjusted OR, 0.48; 95% CI, 0.42–0.56). Conclusions: Osteopathic surgeons disproportionately practice in rural and socioeconomically disadvantaged communities, identifying an important workforce component for maintaining rural surgical access. The declining likelihood of rural practice among more recent training cohorts raises concerns regarding the future rural surgical workforce.

Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

Objective Lennox–Gastaut syndrome (LGS) is a severe treatment‐resistant epilepsy. Although vagus nerve stimulation (VNS) and deep brain stimulation (DBS) are established therapies, comparative data and the impact of dual neuromodulation remain limited. We compared seizure outcomes across VNS, DBS, and combined DBS + VNS therapy in LGS. Methods This retrospective cohort study at Mayo Clinic (2005–2024) included LGS patients treated with VNS and/or DBS . Seizure frequency was assessed at 6, 12, and 24 months post‐stimulation. Responder was defined as 50% or more seizure reduction. Results Forty patients were included (42% female, median, 150 seizures/month). Eleven patients underwent sequential VNS followed by DBS and contributed data to 2 treatment epochs, yielding 3 treatment groups: VNS alone (n = 29), DBS alone (n = 12), and DBS + VNS (n = 10). At 24 months, median seizure reduction rate was comparable between VNS (50%; 95% confidence interval [ CI], 44–75%) and the overall DBS cohort (59%, 95% CI, 33–86%) ( p = 0.54). However, a significant difference emerged when comparing the 3 treatment arms ( p = 0.027). Specifically, DBS + VNS therapy yielded significantly greater median reduction rate (81%, 95% CI, 60–99%) than DBS alone (43%, 95% CI, 0–58%) ( p adj = 0.027) or VNS alone (50%, 95% CI, 44.4–75.0%) ( p adj = 0.048). Four patients attained sustained seizure freedom above 1 year at last follow‐up. Interpretation VNS and DBS provide comparable seizure reduction in LGS over a 2‐year follow‐up period. DBS + VNS was associated with further improvements in seizure reduction in this small, retrospective dataset. This possibility warrants further investigation. ANN NEUROL 2026

Abstract Background and Aims EUS-guided gastroenterostomy (EUS-GE) is an effective option to palliate symptoms of gastric outlet obstruction (GOO). While the jejunum is conventionally targeted (EUS-GJ), targeting the duodenum (EUS-GD) may offer clinical advantages. Outcomes were compared for EUS-GJ and EUS-GD. Methods Adult patients who underwent EUS-GE for GOO between 2020 and 2024 were included and categorized as an EUS-GD if the stent entered the transverse or ascending duodenum or an EUS-GJ if the stent entered more distally. The primary outcome was clinical success (soft diet tolerance at 7 days). Secondary outcomes included adverse events (AEs), stent misdeployment, and unplanned endoscopic reintervention. Baseline demographic variables and outcomes were compared with statistical significance at p < 0.05. Results Of the 139 included patients (median age 67 years (IQR 61–74); 41% female), 105 underwent EUS-GJ and 34 underwent EUS-GD. Clinical success was 98% for EUS-GJ and 94% for EUS-GD (p = 0.25). The misdeployment rate was 7% for EUS-GJ and 0% for EUS-GD (p = 0.19). The AE rate was 22% for EUS-GJ and 12% for EUS-GD (p = 0.23). There were no significant differences for stent obstruction (EUS-GJ 12% vs. EUS-GD 6%), bleeding (2% vs. 6%), perforation (4% vs. 0%), stent migration (1% vs. 0%), infection (3% vs. 0%), and unplanned reintervention (14% vs. 9%). Conclusion Both EUS-GJ and EUS-GD demonstrate high clinical success with no significant differences in adverse event rates. These data can support intraprocedural decision-making for endoscopists performing EUS-GE.

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome comprising multiple pathophysiological phenotypes. HFpEF trials have largely enrolled diverse populations and reported average treatment effects, consistently yielding neutral results that may obscure drug-specific benefits within distinct subgroups. To address this issue, we employ an interaction-based that incorporates treatment-by-variable interactions to uncover drug-specific responses. Methods We leveraged four HFpEF clinical trials (TOPCAT, RELAX, NEAT-HFpEF, INDIE-HFpEF) and developed a framework comprising two complementary approaches. The first employed a prognostic responder model to evaluate whether conventional responder definitions reflect treatment-specific benefit or instead capture favorable clinical trajectories common to both treatment and placebo groups. The second used an interaction-based individual treatment effect (ITE) modeling to identify baseline variables that modify therapy effect, distinguishing drug-specific response from prognostic phenotypes. Results Although the prognostic responder model demonstrated good discrimination, further analisys suggested it primarily captured a prognostic signal associated with favorable clinical trajectories common to both treatment and placebo arms. In contrast, the ITE model identified distinct, drug-specific effect modifiers across trials (cardiorenal-inflammatory for spironolactone (TOPCAT), NO-mediated anti-inflammatory for isosorbide mononitrate (NEAT-HFpEF), afterload-reducing for inorganic nitrite (INDIE-HFpEF), and anti–volume-overload for sildenafil (RELAX). Each ITE model demonstrated significance only within its own trial suggesting drug-specific signal. Conclusions The proposed method identifies mechanism-specific effect modifiers, and uncovers clinically meaningful heterogeneity in treatment response, which is not captured by conventional MCID-based approaches. Although exploratory, these findings support phenotype-guided therapy in HFpEF and argue for phenotype-informed trial design to enhance treatment-effect detection and therapy targeting. Graphical Abstract

Immune-mediated epilepsies represent an etiologically unique category defined by immune activation within the central nervous system that initiates a pathophysiological cascade resulting in seizures, encephalopathy, and sometimes epileptogenesis with long-term epilepsy. Once considered rare and largely confined to paraneoplastic or postinfectious syndromes, immune-mediated and inflammatory mechanisms are now recognized across a broad spectrum ranging from acute autoimmune encephalitis with reversible seizures, new-onset refractory status epilepticus, or febrile illness-related refractory status epilepticus, to chronic autoimmune-associated epilepsy and drug-refractory structural epilepsies. This review integrates historical perspectives, mechanistic insights from animal and human studies, and contemporary clinical frameworks. It synthesizes advances in neuroimmunology, clinical phenotyping, diagnostics, immunomodulatory and antiseizure therapies, neuromodulation, and patient and family centered outcomes, and outlines future directions focused on biomarker-driven precision medicine, disease-modifying strategies, and interdisciplinary care models.

Importance Anhydramnios from fetal kidney failure causes lethal pulmonary hypoplasia. Serial amnioinfusions have shown promise in mitigating pulmonary disease from bilateral renal agenesis, but efficacy and safety for other causes of fetal kidney failure are unproven. Objective To assess the efficacy of serial amnioinfusions initiated before 26 weeks’ gestation to mitigate lethal pulmonary hypoplasia in cases of anhydramnios due to fetal kidney failure. Design, Setting, and Participants Prospective, nonrandomized clinical trial conducted at 13 US fetal therapy centers from December 2018 to February 2025. Outcomes for maternal-fetal pairs with anhydramnios before 22 weeks’ gestation due to fetal kidney failure without bilateral renal agenesis are reported; data collection for surviving infants continued until February 13, 2026. Exposure Thirty-two participants underwent serial amnioinfusions with isotonic fluid beginning before 26 weeks’ gestation. Main Outcomes and Measures The primary end point was neonatal survival for 14 days or longer with dialysis access placement. Secondary outcome measures of survival to discharge home and kidney transplant are reported. Results Twenty-nine of 32 participants (91%) had a live birth, with a median (IQR) gestational age at delivery of 34 weeks 1 day (31 weeks 5 days to 34 weeks 6 days). All participants delivered before 37 weeks’ gestation. No unexpected serious maternal adverse events occurred, and the most common maternal complications were preterm prelabor rupture of membranes in 19 participants (56%) and chorioamniotic separation in 10 (29%). The primary outcome occurred in 19 (65.5%) of 29 live-born neonates (95% CI, 45.7%-82.1%). Factors associated with survival to the primary outcome included receiving more amnioinfusions (median [IQR], 14 [9-18] in survivors vs 7 [4-11] in nonsurvivors; P = .01), longer time interval from first amnioinfusion to preterm prelabor rupture of membranes (63.5 [60.5-74.5] days in survivors vs 29.0 [22.0-56.0] days in nonsurvivors; P = .01), gestational age greater than 32 weeks (79% of survivors vs 38% of nonsurvivors; P = .03), and higher birth weight (2029 [1770-2250] g in survivors vs 1635 [1185-1915] g in nonsurvivors; P = .01). Fourteen live-born infants (48%) survived to hospital discharge at a median (IQR) age of 4.7 (3.4-5.7) months. Of the 11 infants surviving to date, 7 (64%) have undergone kidney transplant between ages 2 years to 5 years. Conclusions and Relevance Serial amnioinfusions mitigated lethal pulmonary hypoplasia in neonates with anhydramnios due to fetal kidney failure. Significant neonatal morbidity and mortality independent of early lung function was noted. Factors associated with survival were consistent with the Renal Anhydramnios Fetal Therapy trial’s bilateral renal agenesis cohort, suggesting common mechanistic pathways for mitigating pulmonary hypoplasia. Trial Registration ClinicalTrials.gov Identifier: NCT03101891

Objective: To examine changes in weight status after initiating zonisamide in children with epilepsy and elevated body mass index (BMI). Study Design: Retrospective chart review of children aged 2 to ≤18 years with epilepsy treated with zonisamide, assessing BMI changes over 2 years. Results: A total of 140 children were included; mean age (SD) at initiation was 9.60 years (3.93). BMI categories included 28 children with severe obesity, 28 with mild–moderate obesity, 28 with overweight, and 56 with healthy weight. Participants were 56.6% female, 91.4% non-Hispanic/Latino, and 88.6% White. At 2 years, BMI z score decreased significantly across all BMI groups: severe obesity −0.38 ( N = 13, 95% CI −0.64 to −0.13; p = 0.003), mild-moderate obesity −0.39 ( N = 15, 95% CI −0.62 to −0.16; p = 0.001), overweight −0.60 ( N = 14, 95% CI −0.84 to −0.36; p < 0.001), and healthy weight −0.46 ( N = 21, 95% CI −0.63 to −0.28; p < 0.001). Significant BMI z score reductions were also observed across age groups: 2–10 years −0.48 ( N = 40, 95% CI −0.62 to −0.34), >10–13 years −0.27 ( N = 15, 95% CI −0.50 to −0.04), and ≥13 years −0.63 ( N = 12, 95% CI 0.89 to −0.36). Conclusions: BMI reduction persisted up to 2 years following zonisamide initiation in children with epilepsy. Further prospective studies are needed to evaluate the weight loss effect and safety of zonisamide in children with epilepsy and elevated BMI.