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Abstract Background Recent studies suggested that treating obesity and its comorbidities with glucagon-like peptide-1 (GLP-1) receptor agonists may improve outcomes in patients with heart failure with preserved ejection fraction (HFpEF). The randomized SUMMIT trial found that tirzepatide use was associated with a lower risk of heart failure (HF) events or cardiovascular death in adults with HFpEF and obesity compared with placebo. Purpose We aimed to examine whether tirzepatide use in clinical practice was associated with risks of HF events and all-cause mortality among adults with HFpEF and obesity. Methods This was a retrospective cohort study leveraging the Optum Labs Data Warehouse (OLDW), a de-identified administrative claims database of commercial and Medicare Advantage enrollees across the United States. We identified all adults with HFpEF and obesity from January 1, 2022, to December 31, 2024. Our primary exposure was tirzepatide use, and our primary outcome was a composite of a HF event (ED visits or hospitalization for HF) or mortality. Secondary outcomes included hospitalization for angina, atrial fibrillation or atrial flutter (AF/AFL), acute myocardial infarction (MI), cardiac arrest, and cardiogenic shock. Patients were followed from the index date, defined as the tirzepatide treatment start date after HFpEF diagnosis or pseudo-index date in tirzepatide non-users, to the end of enrollment or death using the intention-to-treat framework. Inverse probability of treatment weighting (IPTW) was used to balance groups. Fracture, conjunctivitis, ear infection, and fungal skin infection were used as falsification endpoints. Cox-proportional and Fine-Gray subdistribution hazard models were used to estimate a hazard ratio (HR) and subdistribution hazard ratio (SHR), respectively. Results Among our total cohort of 99,270 patients, the mean age was 73 years, 58,616 (59.1%) were female, 8,839 (8.9%) used tirzepatide, and the mean follow-up time was about 385 days. Patients using tirzepatide had a significantly lower risk of a HF event or mortality (HR=0.73; 95% confidence interval [CI]=0.66–0.80; p<0.001) compared to patients not using tirzepatide. Patients using tirzepatide had a lower risk of a HF event (SHR=0.80; 95% CI=0.73–0.88; p<0.001) and all-cause mortality (HR=0.48; 95% CI=0.38–0.60; p<0.001). Tirzepatide use was associated with lower risks of hospitalization for acute MI (SHR=0.67; 95% CI=0.52–0.85; p=0.001) and cardiogenic shock (SHR=0.56; 95% CI=0.38–0.83; p=0.003), but not angina, AF/AFL, or cardiac arrest (Figure 1). Conclusion Among adults with HFpEF and obesity, tirzepatide use in real-world clinical practice was associated with a lower risk of HF events, hospitalizations for acute cardiovascular disease, and all-cause mortality.For image description, please refer to the figure legend and surrounding text.

Abstract Current genomic assays provide prognostic information and guide chemotherapy decisions in early-stage hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) breast cancer, but limited tissue sampling may incompletely capture tumor heterogeneity. We developed and validated an image-based artificial intelligence (AI) model integrating dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and clinicopathologic features to predict recurrence risk in early-stage HR+/HER2 − breast cancer. In this retrospective multi-institutional study, the model was trained using pre-treatment imaging and clinicopathologic data from 522 patients and independently validated in 550 additional patients treated between 2010 and 2023. By analyzing spatial tumor characteristics, the model generated individualized recurrence risk scores that outperformed clinicopathologic features alone. In the validation cohort, median age was 53 years (range, 24–90), 15.6% of patients self-identified as African American, 89.7% had clinical T1–T2 disease, and 34.4% had 1–3 positive lymph nodes. Five-year recurrence-free survival was 93.8% (95% CI, 90.0–96.2%) among patients classified as low risk compared with 82.6% (95% CI, 74.8–88.1%) among those classified as high risk, corresponding to an adjusted hazard ratio of 2.28. Prognostic performance was maintained across clinically relevant subgroups, including age and nodal status. These findings support the potential of a noninvasive image-based AI approach for real-time prognostication and treatment personalization in early-stage HR+/HER2 − breast cancer.

Purpose To investigate outcomes among patients undergoing total hip arthroplasty after hip arthroscopy (HA‐THA) compared with a matched cohort undergoing primary THA without prior arthroscopy (Only‐THA). Methods Patients who underwent THA after primary hip arthroscopic labral repair from 2009 to 2022 at a single institution were identified. Cases were propensity‐matched 1:4 to primary THA controls by age at THA, sex, body mass index (BMI), surgical approach, and year of surgery. At minimum 2‐year follow‐up, patient‐reported outcomes (PROs)—Forgotten Joint Score (FJS), modified Harris Hip Score (mHHS), and Hip Disability and Osteoarthritis Outcome Score Pain (HOOS‐Pain)—were analyzed. Results Sixty‐two hips (age: 47.5 ± 9.3 years, BMI: 29.7 ± 6.2 kg/m 2 ) were matched to 248 Only‐THA hips (age: 47.9 ± 10 years, BMI: 29.5 ± 5.8 kg/m 2 ). Although both HA‐THA and Only‐THA patients showed significant ( P < .001) postoperative improvements in PROs, HA‐THA patients reported significantly lower postoperative FJS, mHHS, HOOS‐Pain, and inferior Visual Analog Scale pain scores ( P < .001) compared with Only‐THA controls. A cohort‐specific minimal clinical important difference for mHHS was calculated as 9.6 points, with 75.7% of HA‐THA and 87.5% Only‐THA patients achieving this threshold ( P = . 077). At mean 6.6 ± 3.3 years follow‐up, HA‐THA patients with preoperative Tönnis grades 1 reported significantly decreased FJS, mHHS, and HOOS‐Pain compared with HA‐THA patients with preoperative Tönnis grade 2‐3 ( P ≤ .05). HA‐THA patients with Tönnis grade 1 also exhibited worse PROs ( P < .001) compared with Only‐THA controls. Although there were no differences in complication rates between HA‐THA and Only‐THA patients (8% vs. 5%, P = .49), all‐cause reoperation was greater amongst HA‐THA (10% vs. 2%, P = .01). Conclusions Patients undergoing THA after prior hip arthroscopy showed modestly inferior subjective outcomes at mid‐term follow up compared with an age‐matched cohort without prior arthroscopy. Although both groups showed meaningful improvement, a smaller proportion of HA‐THA patients achieved the cohort‐specific MCID for mHHS compared with Only‐THA controls. Level of Evidence Level III, retrospective cohort study.

ABSTRACT Background Disparities in management of atrial fibrillation in rural and urban hospitals across the U.S. have been reported. However, studies investigating disparities regarding outcomes and complications after left atrial appendage occlusion (LAAO) based on hospital location are lacking. Objective To evaluate differences in outcomes and complications related to LAAO among rural and urban hospitals. Methods The National Inpatient Sample was used to identify patients who underwent LAAO implantations in the U.S. from 2016−2020. Study endpoints assessed included inpatient complications, outcomes, and resource utilization after LAAO procedures among rural and urban hospitals. Results From 2016−2020, there were a total of 87 315 and 1985 LAAO device placements in urban and rural hospitals, respectively. Baseline characteristics were similar among both groups, with a few exceptions. After multivariable adjustment for confounders, odds of inpatient complications and mortality were similar among both groups. However, rural LAAO recipients experienced greater rates of discharge to an acute care facility (3.3% vs 2.4%, p = 0.01), as well as lower costs (aOR: 0.58, 95% CI: 0.49–0.69) and length of stay (aOR: 0.89, 95% CI: 0.81–0.98). Conclusions A majority of LAAO implantations occurred in urban hospitals in the U.S. Baseline characteristics and adjusted odds of inpatient complications and mortality were similar in rural and urban recipients. However, important differences were described regarding resource utilization and disposition. Further investigation into the specific factors driving these inequities is encouraged to promote improved access to and outcomes of cardiovascular care for rural residents.

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.

Abstract Objective The upper frequency limit of human brain activity remains unknown. Using ultrahigh sampling rate (≥20 kHz) intracranial microelectroencephalography, this study aimed to systematically explore and quantitatively characterize brain field oscillations beyond the established high‐frequency oscillation range (>2 kHz), and to determine their relationship to epileptogenic tissue. Methods We analyzed intracranial electroencephalographic recordings from 15 patients with drug‐resistant epilepsy, comprising 466 microcontacts and 434 macrocontacts implanted in mesiotemporal structures across four international epilepsy centers. A custom spectrogram‐based detector optimized for ultrahigh frequencies was developed to identify ultrafast oscillations (UFOs; >2 kHz). UFO rates were assessed in epileptic (successfully resected) and nonepileptic hippocampi and compared with established electrophysiological biomarkers, including interictal epileptiform discharges, ripples, and fast ripples. Statistical comparisons were performed using mixed‐effects models to account for intersubject and interelectrode variability. Results We identified a previously undescribed class of short‐duration oscillatory events spanning 2–8 kHz. UFOs occurred at significantly higher rates in epileptic compared with nonepileptic mesiotemporal regions, with the strongest differentiation observed in the 2–3‐kHz band. Two distinct UFO phenotypes were consistently observed: (1) spindlelike, narrow‐band oscillations and (2) sharp‐onset, rapidly decaying bursts. Both forms were prevalent within epileptic hippocampi but were exceedingly rare in nonepileptic structures. UFOs exhibited pronounced temporal intermittency and spatial focality and frequently arose independently of ripples, fast ripples, and very high‐frequency oscillations, indicating that they represent a distinct electrophysiological phenomenon. Macrocontacts detected UFOs only exceptionally, highlighting the necessity of microelectrode recordings to capture activity in this ultrahigh‐frequency regime. Significance These findings substantially extend the known frequency range of human brain field activity and identify ultrafast oscillations as a novel biomarker of neuronal hyperexcitability. UFOs likely reflect pathological microcircuit dynamics inaccessible to conventional clinical recordings and provide new insights into the organization and pathophysiology of epileptogenic networks.

Iron is an important metal element regulating biological processes such as gene expression, electron transport, cell proliferation, differentiation and division, and cellular respiration. Regulation of iron levels is therefore critical, with excess iron accumulation leading to iron-dependent lipid peroxidation and cell death (ferroptosis). Factors such as aging and environmental exposures (e.g., high/low oxygen, particulate iron) can disrupt iron homeostasis. Iron-dependent processes influence downstream pathways such as inflammation, mitochondrial energetics, and remodeling (proliferation, fibrosis), pathways involved in lung diseases particularly at the extremes of age, from hyperoxic lung injury in neonates to chronic diseases such as asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis (PF) that increase with age. Although these diseases involve structural and functional changes in bronchial versus alveolar compartments, including airway hyperreactivity, altered mucus production, cell proliferation and migration, increased extracellular matrix (ECM) remodeling, senescence, and metabolic dysregulation, the casual or consequential links between iron dysregulation and disease pathology, particularly with aging, are still being investigated. The aim of this topical review is to 1) highlight current knowledge regarding iron regulation in normal lung versus lung diseases, 2) identify known roles of iron in lung homeostasis and the contribution of iron dysregulation in lung diseases with aging, and 3) explore the potential benefit of targeting iron regulation and/or ferroptosis in lung diseases.

Abstract Background N‐methyl‐D‐aspartate receptor antibody encephalitis (NMDAR‐Ab‐E) is an autoantibody‐mediated disorder, characterized by acute development of neuropsychiatric symptoms, seizures, movement disorders, and autonomic instability. Objectives To describe acute seizure semiology and electroencephalogram (EEG) findings in patients with a first episode of NMDAR‐Ab‐E. Methods Medical records and EEG results were retrospectively evaluated from 14 adult patients with definite NMDAR‐Ab‐E, recruited between April 2009 and September 2017, and followed up until October 2024. Results A total of 92.8% (13/14) were women with a mean age of 29.6 years. 85.7% (12/14) patients experienced seizures. Focal and/or generalized seizures were described at presentation or in the first days of the illness in 57% (8/14). EEGs showed diffuse slowing in 13/14 and this coexisted with epileptiform activity in 10/13; fast frequencies in 7/13 (potentially owing to a benzodiazepine effect); and asymmetric focal slowing in 6/13. Six patients had periods of rhythmic slow activity (focal or diffuse), without evolution to electrographic seizures. An extreme delta brush (EDB) pattern was recorded in 2/13 patients, and this was associated with non‐convulsive status epilepticus in one of these individuals. Significance Most patients in this case series of NMDAR‐Ab‐E were young adult females with early focal and/or generalized seizures. Diffuse slowing in theta/delta range was the most common EEG finding, with or without epileptiform discharges, focal slowing, superimposed fast activities, and focal or diffuse rhythmic slowing. An EDB pattern was rare. Even with non‐specific findings, EEG seems to be a sensitive tool to aid diagnosis and decision‐making in NMDAR‐Ab‐E.

Abstract Aims Prognosis in tricuspid regurgitation (TR) is shaped by complex clinical and haemodynamic interactions, complicating risk stratification. We aimed to use explainable artificial intelligence (EAI) to model these relationships and identify key predictors of outcomes. Methods and results We analysed long-term all-cause mortality in a large prospective registry of patients with native TR across the full severity spectrum. Patients underwent detailed clinical evaluation and quantitative Doppler-echocardiography. Supervised EAI models were applied to identify and rank predictors of mortality under medical therapy, capturing non-linear associations and interactions among baseline characteristics. Among 9761 patients [mean age 73 ± 15 years; 56.9% women; effective regurgitant orifice area (EROA) 40 (30–56) mm2; regurgitant volume 39 (29–53) mL/beat; 42% severe TR], 2676 deaths occurred during 3.8 ± 4.6 years of follow-up. EAI identified and ranked 20 prognostic determinants of survival. Haemodynamic measures, led by elevated pulmonary-artery systolic and right-atrial pressures, were strongest, followed by age and comorbidity. TR-related variables ranked next, led by right ventricular dysfunction and EROA, which outperformed integrative TR grade and TRIScore. Left-ventricular parameters were less influential. Non-linear effects, including those involving ejection fraction, and interactions such as higher EROA-related risk with elevated pulmonary pressures or lower TRIScore (both P &lt; 0.03) were observed. Proportional hazards models confirmed EROA as the strongest TR severity marker (P &lt; 0.0001), with excess mortality beginning at 40 mm2 and increasing further at 60 mm2. Conclusion EAI ranked mortality predictors in TR, highlighting patient factors, haemodynamics, TR-specific measures, and left-ventricular function. Among TR-specific measures, EROA and TRIScore were most prognostic. Recognizing their impact can refine risk stratification, guide intervention timing, and inform long-term management.