Citations

Abstract The apolipoprotein E ε4 ( APOE4 ) allele is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), yet the mechanistic underpinnings by which it alters human microglial function remain poorly understood. Here, we utilize CRISPR/Cas9-engineered isogenic human induced pluripotent stem cell-derived microglia-like cells (iMGs) expressing APOE3 or APOE4 to systematically interrogate genotype-dependent effects on microglial proteomes and their secreted extracellular vesicles (EVs) under basal and fibrillar amyloid-β (fAβ)-challenged conditions. Quantitative proteomics revealed that APOE4 iMGs exhibit downregulated RNA processing, impaired phagocytosis, and exacerbated pro-inflammatory signaling, particularly upon fAβ exposure. Functionally, APOE4 iMGs demonstrated increased NF-κB activation, enhanced neuronal apoptosis and tau pathology in 2D and 3D co-culture systems. Interestingly, APOE4 iMGs released greater amount of EVs enriched in proteasomal components over APOE3 iMG. Integrated proteomic analyses further highlighted APOE4 -specific selective packaging of EV cargo linked to neuron-glia communication, inflammatory signaling, and proteostasis dysregulation, suggesting a potent, non-cell-autonomous mechanism driving neuronal damage. Consistently, these APOE4 iMGEVs were preferentially internalized by neurons, leading to disrupted neuronal proteostasis, impaired neuronal firing, and increased tau phosphorylation, particularly under pathological stress. Notably, pharmacologic inhibition of NF-κB in APOE4 iMGs reduced EV cargo-loading of proteasomal molecules and mitigated iMGEV-driven neuronal dysfunction and tau pathology. These findings establish a mechanistic link between APOE4 , dysregulated microglial homeostasis, and microglial EV-mediated propagation of proteostatic dysfunction and neurodegeneration, advancing our understanding of how APOE4 contributes to AD pathogenesis.

Abstract Topic Esophageal Cancer: Barrett‘s Esophagus: High-Grade Dysplasia and Early Invasive Cancer Background Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) delay gastric emptying and are linked to increased gastroesophageal reflux, a recognized risk factor for Barrett’s esophagus (BE) progression to esophageal cancer (EC). Extended use of GLP-1 RAs facilitates weight loss, mitigating reflux, possibly offering a protective effect against EC. This large retrospective study aimed to assess the association between GLP-1 use with the development of dysplastic Barrett’s esophagus (BE) and EC in patients with non-dysplastic BE (NDBE). Methods We used ICD and CPT codes within the TriNetX (a large multicenter claims based) database to identify NDBE patients. The cohort was then categorized as GLP-1 users vs. non-users based on ATC code A10BJ. A 1:1 propensity matched analysis was performed with balancing of confounders (Table 1). Primary outcomes included incidence of dysplastic BE and EC. Time to event analyses were performed. Results A total of 4,534 patients were identified in the GLP-1 cohort and 55,621 in the non-GLP-1 cohort. After 1:1 matching, 4,530 patients were included in each cohort. Mean follow-up was 3.57 years in GLP-1 cohort and 3.30 years in non-GLP-1 cohort. Incidence of dysplastic BE/EC in the GLP 1 cohort was 1.24% (N=56) compared to 0.54% (N=24) in non-GLP 1 cohort. GLP-1 users demonstrated significantly higher risk of developing dysplastic BE/EC compared to non-users (RR: 2.30; 95% CI: 1.47–3.70, P = 0.0004. The cumulative incidence of dysplastic BE/EC was higher among GLP-1 cohort at 3 and 5 years—0.90 %, and 1.11%, respectively—compared to 0.47%, and 0.49 % in the non-GLP-1 group. Conclusion Our findings indicate that GLP-1 therapy was associated with an increased risk of progression to dysplastic BE/EC in patients with non-dysplastic BE. Further prospective studies are warranted to validate these results.

Abstract Topic Benign Disease: Other Background Lichen planus is a chronic immune-mediated skin disease that may involve the esophagus. Esophageal lichen planus (ELP) is considered rare, but likely underdiagnosed. Lack of published guidelines for ELP results in significant treatment variability. Given heterogeneous practice patterns and emerging treatments, further outcome data are needed. Methods A retrospective cohort of ELP patients was assembled from 3 academic centers. Patients ≥ 18 years old were identified by ICD10 code search (L43.8) in the electronic health record, from 2006 to 2025. Patients were included if they had initial endoscopy, histology, and follow-up endoscopy showing features of LP, and excluded if there was diagnostic uncertainty, unavailable procedural documentation, or other esophageal diseases. Endoscopic findings were assessed qualitatively by manual review of reports. Data abstracted included demographics, presenting symptoms, endoscopic/histologic findings, treatment, and clinical outcomes. Statistical analysis was performed in R. Results 193 patients met inclusion criteria. Mean age at index endoscopy was 65 years, 86% were female, 98% were non-Hispanic Caucasian, 39% were ever smokers, and mean BMI was 26. Dysphagia was the most common presenting symptom (90%). Strictures were common (73%), 58% underwent dilation during initial endoscopy. Endoscopic findings included presence of sloughing (20%), exudate (22%) and friability (23%). Histology showed lymphocytic infiltrate (47%), parakeratosis/dyskeratosis (42%) and Civatte bodies (17%). Topical steroids (71%) and PPIs (63%) were used most frequently for treatment. Immunosuppressives (tacrolimus, systemic steroids, mycophenolate, methotrexate, hydroxychloroquine, cyclosporine, azathioprine, JAK inhibitor) were used in 54% of patients. Endoscopic improvement was seen in 66%, with highest response rates in tacrolimus (100%), hydroxychloroquine (100%), and a JAK inhibitor (100%). Symptom improvement was seen in 63%, with the greatest benefit seen in patients treated with a JAK inhibitor (100%) and hydroxychloroquine (86%). Conclusion In this large, multisite cohort, ELP demonstrated significant morbidity, with high rates of dysphagia, strictures, and inflammatory changes. Dilation appeared to be safe, with only a single iatrogenic perforation identified. Esophageal squamous cell cancer risk was low but present, at 4%. Despite heterogeneous treatment practices, several therapies – tacrolimus, hydroxychloroquine, and JAK inhibitors – were associated with marked endoscopic and symptomatic improvement. Prospective studies are needed to clarify the optimal approach to pharmacological management of ELP.

Abstract Background Breast cancer is etiologically heterogeneous, but which risk factors differ in their associations across tumor subtypes remains unclear. We conducted a large, pooled analysis to evaluate independent, dose-response associations between breast cancer risk factors and quantitative tumor features. Methods Analyses of 15,731 invasive breast cancers from 24 studies evaluated associations (p-trend) between reproductive and hormonal factors, body mass index (BMI), alcohol, smoking, and family history in relation to quantitative immunohistochemistry measures on tissue microarrays (ER, PR, HER2, KI67, TP53) and tumor grade. Analyses in a subset of 10 population-based studies estimated subtype-specific odds ratios (ORs) comparing cases to controls. A Bayesian False Discovery Probability (BFDP) <0.2 was used to identify associations with strong statistical evidence. Results Nulliparity and later age at menopause were associated with higher ER-positivity (p-trend=0.021 and 0.001, respectively), with corresponding OR[ER+] (95% CI) = 1.49 (1.16-1.90) for nulliparous vs. parous and 1.07 (1.03-1.11) per 5 years. Current combined menopausal hormone therapy (MHT) use was associated with lower grade (p-trend<0.001), with OR [grade1] = 3.37 (2.69-4.21) for current vs. never users. Higher BMI was associated with lower ER-positivity and higher grade in premenopausal women (p-trend<0.001 and <0.001), with OR[ER+] = 0.80 (0.74-0.87) and OR[grade1] = 0.75 (0.63-0.88) per 5 units, and with higher PR-positivity and higher grade in postmenopausal women (p-trend<0.001 and <0.001), with OR[PR+] = 1.08 (1.03-1.14) and OR[grade 3] = 1.10 (1.04-1.17) per 5 units. Conclusion This pooled analysis of 15,731 cases showed that nulliparity, age at menopause, MHT, and BMI have independent, dose-response associations with ER, PR, and grade, clarifying patterns of etiologic heterogeneity. Associations with HER2, KI67 and TP53, or other risk factors did not meet our threshold for strong evidence.

Objective Vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic syndrome (VEXAS) syndrome is characterized by a complex spectrum of inflammatory and hematologic manifestations. Clinical research to identify effective therapies is urgently needed but is hindered by the lack of validated outcome measures. A VEXAS‐specific disease activity index (DAI) is an essential tool for reliably capturing changes in disease activity over time, thereby supporting clinical research and informing patient care in this emerging disease. This study aimed to develop a comprehensive DAI to assess disease‐related inflammation across affected organ systems in patients with VEXAS syndrome. Methods Inflammatory manifestations of VEXAS were previously identified through a systematic literature review and expert input. A multinational expert advisory committee developed the VEXAS‐DAI using modified Delphi methodology until consensus (defined as ≥75% concurrence) was reached. Item grading was adapted from the Common Terminology Criteria for Adverse Events. Scoring criteria were developed based on 158 test cases using the Physician Global Assessment of Inflammation. Results Consensus on the VEXAS‐DAI was achieved after four Delphi rounds. The index assesses inflammatory activity at the time of evaluation across 12 domains: inflammatory rash, chondritis, periorbital, ophthalmologic, joint, pulmonary, cardiovascular, genitourinary, neurologic, oral and gastrointestinal, renal, and constitutional symptoms. The total score ranges from 0 to 40. Conclusion The VEXAS‐DAI is a novel instrument designed to quantify active inflammation over time in patients with VEXAS. Prospective validation within a clinical trial setting is ongoing. image

Abstract Background New-onset atrial fibrillation (AF) is common in patients who are hospitalized with acute illness and is associated with overall poor outcomes. Current clinical and demographic predictors of new-onset AF have limitations. Electrocardiogram (ECG) waveforms, combined with these factors as part of multimodal approach could help improve prediction of new-onset AF. Purpose The purpose of our study was to develop a multimodal, deep-learning system that combines ECG waveforms with clinical data for prediction of new-onset AF in hospitalized patients. Methods We developed and compared two separate 1-dimensional models with a fusion model for prediction of new-onset AF. (a): one-dimensional convolutional neural network (1D-CNN) that learns patterns from the raw ECG waveforms. (b): a Multi-Layer Perceptron (MLP), unsupervised machine learning model which utilizes data from structured variables such as: age, heart rate, routinely obtained laboratory data and medications. The two modules each produce latent feature vectors, which are then placed end-to-end and fed into a final Multi- MLP head that outputs the probability of New-onset AF during hospitalization. We then compared this fused MLP model with the two simpler unimodal models based solely on ECG waveforms and clinical data respectively. Results On the held-out test set data, the feature-level fused model achieved an Area Under the Curve (AUC) of 0.81. This significantly outperformed both the ECG-alone model (0.77) and the clinical-alone model (0.74). By adjusting the threshold, we can fine-tune the tool at a threshold of 0.5, it flags 83% of patients who later develop AF (207 of 248) with a precision of 10%, a setting that could be useful for wider screening. By adjusting the threshold of 0.98 for a high-precision alert configuration, it has the ability to predict 46% of future occurrence of AF cases (113 of 248) while reducing false alarms by 81% (from 1,797 to 328), increasing precision to 26% and achieving an overall accuracy of 89%, a setting useful when resources for follow-up are limited. Conclusions Combining ECG signals with clinical data significantly enhances the model’s ability to detect new-onset AF in hospitalized patients as compared to a uni-dimensional CNN model. The dynamic nature of ML model also allows for adjustment of its decision threshold which can aid in broader screening and improving adverse outcomes related to occurrence of AF.ROC Curve for Fusion model

Expert consensus recommendations from 21 academic centers were established for appropriate radiography utilization at 12 potentially low-yield anatomic sites through a multidisciplinary process endorsed by six major American medical societies.

Abstract Background and aims BotulinumtoxinA (BoNT-A) is a guideline-recommended treatment for spasticity following stroke. We evaluated BoNT-A treatment persistence drivers of discontinuation and predictors of non-persistence in patients with stroke. Methods Eligible adults had received ≥1 treatment cycle with BoNT-A at the Mayo Clinic (January 2010–June 2023) and had an International Classification of Diseases (ICD9/10) code for stroke. Patients with ICD9/10 codes for migraine, cerebral palsy, cervical dystonia, or bladder dysfunction were excluded. Index date (baseline) was the date of first BoNT-A treatment; follow-up was 2 years post-index. Patients were persistent if all treatment intervals post-index were ≤the 80th percentile of all patients. Reasons for discontinuation were identified by AI natural language processing analysis of physicians’ free-text notes. Baseline characteristics associated with non-persistence were identified using step-wise logistic regression analyses. Results Overall, 407 patients were included. The 80th percentile of the BoNT-A treatment interval was 154 days; 5.7% of patients were persistent. Mean (95%CI) number of BoNT-A treatments over the 2-year follow-up was 2.43 (2.24–2.63) cycles. Comorbidity burden was high (Table 1). The most common reasons for BoNT-A discontinuation were patient- and physician-reported lack of treatment effectiveness (Table 2). Older age, Hispanic/Latino/unknown/undisclosed ethnicity, presence of comorbidities, and use of medications of interest at baseline (skeletal muscle relaxants, antidepressants, anticonvulsants, opiates, sedatives/hypnotics, NSAIDs) were significantly associated with non-persistence (Table 3). Conclusions Over 2 years, BoNT-A treatment persistence was low. Lack of treatment effectiveness was the most common reason for discontinuation. Addressing drivers of non-persistence may help improve BoNT-A treatment outcomes. Conflict of interest Funding: Ipsen. Disclosure of Conflicts of Interest: Michael Wainberg: has received consulting fees from Ipsen. Billie Schultz: has received consulting fees from Ipsen. Jinming Zhang, Simon Page, Jonathan Bouchard, Amandeep Mann, Mathieu Beneteau are employees of Ipsen. Table 1 - belongs to Conclusions Table 2 - belongs to Conclusions Table 3 - belongs to Conclusions

Importance Adjuvant chemotherapy regimens may be administered after pancreatic resection for adenocarcinoma arising from intraductal papillary mucinous neoplasms (A-IPMNs), although the evidence supporting their use is limited. Objective To evaluate the survival benefit associated with contemporary adjuvant chemotherapy regimens after resection in A-IPMNs between 2017 and 2023. Design, Setting, and Participants This retrospective cohort study was an international, multicenter study with 69 participating centers across Europe, North America, South America, and the Asia-Pacific region. Patients undergoing resection for A-IPMNs were included. Data were analyzed from May to August 2025. Intervention Contemporary adjuvant chemotherapy regimens, such as gemcitabine-capecitabine (GemCap); 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX), modified FOLFIRINOX (mFOLFIRINOX), and S-1. Main Outcome and Measure Overall survival (months). Results Among 1321 patients (median [IQR] age 70 [63 to 76] years; 713 males [54.0%] and 608 females [46.0%]), 781 patients (59.1%) received adjuvant chemotherapy, while in 181 patients (13.7%) it was omitted due to poor patient fitness. Of patients who received adjuvant chemotherapy, 568 patients (72.6%) received contemporary regimens, including GemCap (232 patients [29.7%]), FOLFIRINOX (176 patients [22.5%]), mFOLFIRINOX (71 patients [9.1%]), and S-1 (70 patients [9.0%]). The median (IQR) follow-up for the cohort was 64.2 (40.4 to 85.0) months, and the median overall survival was 73.8 months (95% CI, 66.4 to 81.9 months). After 90-day landmark analysis and exclusion of patients ineligible for chemotherapy, adjuvant chemotherapy vs no adjuvant chemotherapy (propensity score–matched populations, 243:243 patients) was not associated with improved overall survival (median, 82.3 months; 95% CI, 78.2 months to not applicable [NA] vs not reached; 95% CI, 75.3 months to NA; P = .58). Contemporary regimens vs no adjuvant chemotherapy (propensity score–matched populations, 309:309 patients) was not associated with longer survival, and a mean survival benefit greater than 4.2 months over 5 years was excluded (difference in restricted mean survival, 1.26 months; 95%, −1.72 to 4.24 months). Treatment outcomes did not vary by chemotherapy regimen or disease characteristic (eg, N stage or carbohydrate antigen 19-9 level). Conclusions and Relevance In this study, contemporary adjuvant chemotherapy was not associated with improved overall survival in A-IPMNs, and a randomized clinical trial is indicated.