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Importance Classifying disease based on underlying pathobiology rather than clinical phenotype has implications for the development of biomarkers and therapy development. Observations Transactive response DNA-binding protein 43 kDa (TDP-43) pathology is observed across a range of clinically defined neurodegenerative disorders including limbic predominant age-related encephalopathy (LATE), most cases of amyotrophic lateral sclerosis (ALS), inclusion body myositis, multisystem proteinopathy, and approximately half the cases of frontotemporal dementia (FTD). Despite this shared biology, the current nosology for these neurodegenerative disorders is based on their distinct clinical phenotypes. An alternative approach recognizes the central role of TDP-43 pathology in disease pathogenesis, reserving the use of clinical terms like ALS, FTD, or LATE to describe phenotypic manifestations of underlying pathobiology. This approach also recognizes the converging biomarker and neuropathological data indicating that pathology begins presymptomatically, before the overt clinical manifestations of disease appear. Conclusions and Relevance In proposing a pathobiological definition of disease, the goal is to provide a road map for developing biomarkers that accurately reflect the underlying pathobiology of disease and for advancing therapeutic candidates that effectively target fundamental disease mechanisms.

Importance Recent case reports suggest that B antigen–containing blood products may be associated with anaphylactic transfusion reactions in recipients with preformed immunoglobulin E to galactose- α -1,3-galactose (alpha-gal). Objective To test the association of local alpha-gal syndrome (AGS) prevalence and allergic transfusion reaction (ATR) in patients with blood type O. Design, Setting, and Participants In this international, multicenter, retrospective cohort study at academic medical centers, sites were assigned to AGS high- or low-prevalence clusters based on the known geographic distribution of AGS. Data were collected on platelet or plasma transfusions and ATRs during 2020 to 2024. Consecutive patients receiving platelet or plasma transfusions were included. Exposures Patients with blood type O who received B or AB units and patients with blood type O who received O units (reference group) in AGS high- and low-prevalence clusters were compared. Main Outcomes and Measures Before data collection, the hypothesis was that if transfusion-related alpha-gal syndrome (TRAGS) is a true clinical entity, excess ATRs to group B or AB units would be detected in AGS high-prevalence regions exclusively. The main measure was the overall risk ratio (RR) for ATRs to B or AB plasma or platelets in AGS high- vs low-prevalence clusters. Results In total, 558 823 platelet and plasma transfusions at 40 sites in 5 countries were analyzed, of which ATRs occurred in 1744 transfusions (0.3%). In the US AGS high-prevalence cluster (9 sites), significantly more ATRs of any severity occurred among patients with blood type O who received B or AB units vs patients with blood type O who received O units (overall RR, 3.93; 95% CI, 2.96-5.21; P < .001). In contrast, in the primary analysis of the AGS low-prevalence cluster (15 sites), excess ATRs to B or AB units were not detected. In subgroup analyses among patients with blood type O receiving B units, the RR for moderate to severe ATRs was 9.14 (95% CI, 5.39-15.52; P < .001) in the AGS high-prevalence cluster vs 2.15 (95% CI, 1.34-3.47; P = .002) in the AGS low-prevalence cluster. Outside the US, a signal consistent with TRAGS was not detected. Conclusions and Relevance This cohort study provides provocative epidemiologic evidence that TRAGS may be a unique manifestation of AGS and a previously unrecognized risk associated with transfusion. In AGS high-prevalence regions, blood collectors and hospital transfusion services should consider approaches to preventing severe ATRs from B or AB plasma or platelet units.

Objectives: Women with a history of breast cancer are at increased risk of developing subsequent breast cancer, including ipsilateral recurrence and contralateral new primary breast cancer. This study evaluated the discriminatory performance of a mammogram-based artificial intelligence (AI) risk model for predicting subsequent breast cancer within one year after a negative screening mammogram. Methods: This enriched retrospective case–control study included women with a prior history of breast cancer who underwent screening digital breast tomosynthesis between January 2018 and December 2023 at three affiliated academic breast imaging centers. Digital breast tomosynthesis examinations classified as BI-RADS 1 or 2 were retrospectively analyzed using the ProFound AI® Risk model version 1.0 to estimate 1-year breast cancer risk. Patients were classified according to whether they developed subsequent breast cancer within one year of the index screening examination. Model discrimination was evaluated using receiver operating characteristic analysis. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated at an exploratory cutoff selected by maximizing the Youden index. Results: The study included 96 women (mean age, 65.3 ± 8.7 years), of whom 32 developed subsequent breast cancer within one year, and 64 did not. The mean AI risk score was significantly higher in the subsequent breast cancer group than in the control group (1.18 ± 0.59 vs. 0.49 ± 0.41; p < 0.001). The AI model demonstrated an AUC of 0.824 (95% CI: 0.728–0.921). At an exploratory cutoff of 0.39, sensitivity was 81.3%, specificity was 76.6%, PPV was 63.4%, and NPV was 89.1%. In separate exploratory analyses, the AUC was 0.790 (95% CI: 0.641–0.939) for ipsilateral recurrence and 0.860 (95% CI: 0.752–0.974) for contralateral new primary breast cancer. AI risk scores were not significantly correlated with tumor size or age at subsequent breast cancer diagnosis. Conclusions: In this enriched retrospective case–control study, higher mammogram-based AI risk scores were associated with subsequent breast cancer within one year after a negative screening examination. The model demonstrated discriminatory performance for both ipsilateral recurrence and contralateral new primary breast cancer; however, these analyses were exploratory. Because the cohort was enriched for subsequent breast cancer events, the reported predictive values are specific to the study sample and should not be extrapolated to routine surveillance populations. Larger prospective cohorts are needed to validate discrimination, calibration, and clinical utility.

Low protein (LP) diets improve metabolic health in rodents and humans. In rodents, LP diets are typically implemented by replacing protein with carbohydrates like sucrose or cornstarch, keeping diets isocaloric. However, humans can choose from many different types of carbohydrate, and how dietary carbohydrate quality - the precise composition of the dietary sugars - impacts the response to dietary protein remains largely unexplored. Here, mice were fed control (21% protein) or LP (7% protein) diets with four different carbohydrate sources: sucrose, a 1:1 glucose/fructose mixture, glucose, or fructose. While LP diets improved metabolic health across all groups in male mice, carbohydrate quality also significantly altered specific health outcomes, with fructose-fed mice having the lowest body weight and adiposity of all control diets. In female mice, responses to LP diets were influenced by carbohydrate quality, with certain sugars inducing a stronger metabolic response to LP diets than previously seen. Finally, in female APP/PS1 mice, a model of Alzheimer's disease, we find that although LP diets reduce A-beta; plaque burden irrespective of carbohydrate type, dietary sugar type does influence spatial memory. Together, these results demonstrate that while dietary protein is a critical determinant of metabolic and neurological health, carbohydrate quality influences these outcomes in a sex-specific manner.

Abstract Objective To assess the efficacy and safety of fenfluramine in patients with Dravet syndrome (DS) stratified by age, number of previously attempted antiseizure medications (ASMs), and SCN1A pathogenic variant status. Methods In this post hoc analysis, data from three randomized controlled trials (RCTs) in patients with DS (2–18 years) were pooled and stratified by age (<4; ≥4 years), number of previous ASMs (1–3; 4–6; ≥7), and SCN1A pathogenic variant status ( SCN1A +; SCN1A −). Stratified groups were assessed and compared with the pooled placebo group (change in monthly convulsive seizure frequency [MCSF], longest convulsive seizure‐free interval, and Clinical Global Impression–Improvement [CGI–I] scale scores rated by parents/caregivers and investigators), and safety (treatment‐emergent adverse events [TEAEs]: frequency, days to onset, and proportion resolved). Results Among 348 patients included in the RCTs, 216 were randomized to fenfluramine (0.7 mg/kg/day, n = 88; 0.4 mg/kg/day [with stiripentol], n = 43; 0.2 mg/kg/day, n = 85) and 132 to placebo. Compared with placebo, fenfluramine treatment (all doses combined) resulted in greater MCSF reductions, greater increases in longest convulsive seizure‐free intervals, and a higher proportion of parents/caregivers and investigators reporting clinically meaningful improvement (“Much Improved”, “Very Much Improved”) on CGI–I scores across all stratified groups. CGI–I scores were consistent across fenfluramine doses in most stratified groups, but patients with the fewest number of previous ASMs had the greatest frequency of clinically meaningful improvement on investigator‐rated CGI–I scores. Safety outcomes were similar across all strata. Most TEAEs resolved by end‐of‐study. Significance Fenfluramine treatment was associated with improved seizure outcomes and global functioning compared with placebo regardless of age, number of previous ASMs, and SCN1A status in patients with DS. Fenfluramine was well‐tolerated; no new safety signals were identified. Further studies with larger sample sizes (including adults) and a priori inferential analyses of stratified groups are warranted. Plain Language Summary Patients with Dravet syndrome struggle with seizures and everyday life. In three studies, patients aged 2–18 years received fenfluramine or placebo (sugar pill). Fenfluramine lowered seizures without many side effects. Researchers combined results from these studies to see how fenfluramine worked in different patient groups based on age, number of previous medications, and a gene called SCN1A . They looked at seizure reduction and whether doctors felt patients had improved. In all groups, fenfluramine worked better than placebo, with similar side effects. Researchers believe fenfluramine helped these patients, but some groups were small, so these results need to be confirmed.

Abstract Topic Benign Disease: Eosinophilic Esophagitis Background Active inflammation in eosinophilic esophagitis (EoE) disrupts the mucosal barrier, leading to dilated intercellular spaces and decreased transepithelial electrical resistance. Mucosal impedance (MI) has been used to assess mucosal integrity in EoE. We evaluated whether baseline MI measured by high-resolution impedance manometry (HRIM) distinguishes active and inactive EoE. Methods We retrospectively reviewed data from patients with EoE who underwent endoscopic esophageal biopsies within three months of HRIM from 2018-2026 at our tertiary referral center and had no treatment changes between studies. We excluded patients with a history of foregut surgery, erosive esophagitis, or Barrett’s esophagus. Demographics, endoscopy and pathology results were collected by chart review. Active EoE was histologically defined as ≥15 eosinophils per high-power field. Esophageal baseline MI was measured in the 30-second landmark period for the whole esophagus (from 2 cm above LES to 2 cm below UES), distal esophagus (from 2–7 cm above LES), and mid/proximal esophagus (from 10 cm above LES to 2 cm below UES). Mann–Whitney U or T tests were used for comparisons . Optimal MI thresholds were identified by Youden index with 10,000 bootstrap validations, and interrater reliability was assessed using two-way mixed effects intraclass correlation coefficients. Results Seventy-three patients were included: 37 (51%) female, median age 52 years, median BMI 27.2 kg/m2. Fifty-seven patients (78%) had atopic history, including seasonal allergies (38, 52%), asthma (31, 42%), eczema (21, 29%), and food allergies (19, 26%). Thirty-nine patients (53%) were receiving proton pump inhibitors, 25 (34%) were not on EoE therapy, 5 (6.8%) were on swallowed topical steroids, 3 (4.1%) were on dupilumab, and 1 (1.4%) was on an elimination diet. Esophageal strictures were present in 23 patients (32%), and 45 (62%) had active EoE. Baseline MI measurement showed high interrater reliability (n=50, 2 raters; intraclass correlation coefficient 0.937–0.963, p&lt;0.001). Basal mean and minimal impedance were significantly lower in active EoE across all segments, greatest in the distal esophagus (all p&lt;0.05; Figure 1). ROC analysis showed high discrimination of distal mean MI, with a cutoff ≤1.91 kΩ (AUC=0.837, sensitivity 67.9%, specificity 86.7%, Youden 0.545; Figure 2). Conclusion Baseline mucosal impedance during HRIM distinguishes active from inactive EoE, with strongest discrimination in the distal esophagus, supporting MI as a potential, minimally-invasive physiologic marker of mucosal inflammation and disease activity. Clinically, MI may serve as an adjunct tool in dysphagia evaluation, prompting EoE-directed biopsy when abnormal, aiding management in biopsy–symptom discordance, and potentially supporting disease monitoring in selected patients. Larger prospective studies are warranted.

Abstract Topic Benign Disease: Gastro-Esophageal Reflux and Hiatal Hernia Background Ambulatory reflux monitoring (wireless pH or catheter-based pH-impedance) performed off acid suppression is the gold standard for diagnosing gastroesophageal reflux disease (GERD). Barium esophagram (BE), commonly used to evaluate esophageal symptoms, routinely assesses reflux, yet its diagnostic accuracy relative to ambulatory monitoring remains unclear. Existing studies are limited, relied on outdated reflux criteria, and demonstrated poor concordance with BE-based GERD diagnoses. We aimed to determine whether BE reliably identifies GERD compared with ambulatory reflux monitoring interpreted using updated Lyon 2.0 consensus criteria. Methods Retrospective analysis of adult patients that underwent BE and ambulatory reflux monitoring (wireless pH or pH-impedance) off PPI within an 8-month interval. Patients with a history of fundoplication were excluded. Esophagram was performed with standard technique and reported by radiology, considered positive for GERD if there was reflux above the thoracic inlet with or without provocative maneuvers. Reflux monitoring studies were considered positive or negative for GERD based on Lyon consensus 2.0 recommendations. Inter-rater reliability, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and received operating characteristic (ROC) curve analysis were calculated for esophagram, with reflux monitoring diagnosis as the gold standard. Results 64 patients were included, 31 % male, mean age = 60 years, mean Body Mass Index = 26. GERD was diagnosed by esophagram in 20 patients (31%), and by reflux monitoring in 19 (30%). Compared to reflux monitoring, BE had sensitivity: 47%, specificity: 76%, PPV: 45%, NPV: 77%, and area under the ROC curve: 0.61 (Figure 1). Inter-rater reliability between BE and ambulatory reflux monitoring was poor (Cohen's Kappa = 0.226). Conclusion There was poor concordance between BE and ambulatory reflux monitoring for diagnosing GERD. BE overall had suboptimal diagnostic performance, with low sensitivity, and moderate specificity. Furthermore, the area under the ROC curve indicates limited ability to distinguish correctly between patients with and without GERD. These findings indicate that barium esophagram should not be relied upon as a diagnostic tool for GERD.

Abstract Topic Benign Disease: Gastro-Esophageal Reflux and Hiatal Hernia Background Ambulatory reflux monitoring off acid suppression is the gold standard for diagnosing gastroesophageal reflux disease (GERD). Barium esophagram (BE) routinely evaluates reflux, but its diagnostic accuracy remains uncertain. We assessed whether BE reliably identifies GERD compared with ambulatory reflux monitoring interpreted using updated Lyon 2.0 consensus criteria. Methods Retrospective analysis of adult patients that underwent BE and ambulatory reflux monitoring (wireless pH or pH-impedance) off PPI within an 8-month interval. Patients with a history of fundoplication were excluded. Esophagram was performed with standard technique and reported by radiology, considered positive for GERD if there was reflux above the thoracic inlet with or without provocative maneuvers. Reflux monitoring studies were considered positive or negative for GERD based on Lyon consensus 2.0 recommendations. Inter-rater reliability, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and received operating characteristic (ROC) curve analysis were calculated for esophagram, with reflux monitoring diagnosis as the gold standard. Results 64 patients were included, 31 % male, mean age = 60 years, mean Body Mass Index = 26. GERD was diagnosed by esophagram in 20 patients (31%), and by reflux monitoring in 19 (30%). Compared to reflux monitoring, BE had sensitivity: 47%, specificity: 76%, PPV: 45%, NPV: 77%, and area under the ROC curve: 0.61 (Figure 1). Inter-rater reliability between BE and ambulatory reflux monitoring was poor (Cohen's Kappa = 0.226). Conclusion There was poor concordance between BE and ambulatory reflux monitoring for diagnosing GERD. BE overall had suboptimal diagnostic performance, with low sensitivity, and moderate specificity. Furthermore, the area under the ROC curve indicates limited ability to distinguish correctly between patients with and without GERD. These findings indicate that barium esophagram should not be relied upon as a diagnostic tool for GERD.

Primary mediastinal B-cell lymphoma (PMBCL) is a rare form of large B-cell lymphoma (LBCL) with around 90% of patients cured with frontline treatment. For relapsed or refractory (R/R) disease, the optimal treatment is unclear. CD19 chimeric antigen receptor-T cell (CAR-T) has been established as the preferred second line (2L) treatment for primary refractory or early relapsing LBCL based on the overall survival benefits observed in the landmark phase III trials. However, PMBCL patients were underrepresented on these pivotal studies. This study evaluated outcomes of 252 patients treated with 2L therapies for R/R PMBCL at 14 US institutions between 2001 and 2025. Platinum-based salvage with intent to proceed to high dose therapy and autologous stem cell transplant (HDT/ASCT) (platinum cohort) and CD19 CAR-T (CAR-T cohort) were given as 2L therapy in the real-world setting in 157 and 26 patients, respectively. Overall response rate (ORR), complete response (CR) rate and median progression-free survival (PFS) were significantly higher in the CAR-T cohort compared with the platinum cohort (ORR: 91.3% vs 44.2%, p &lt;0.001; CR 65.2% vs 14.7%, p&lt;0.001; median PFS not reached vs 3.5 months, hazard ratio (HR) 0.28, 95% CI 0.15-0.54, p=0.001). No significant difference was observed in overall survival. This study demonstrated superior response rate and PFS of CD19 CAR-T over platinum-based salvage with intent to proceed to HDT/ASCT as 2L treatment for R/R PMBCL.