Citations

139 Background: Statins have been shown to reduce the risk of HCC in high-risk populations with metabolic diseases. However, emerging data suggests that GLP-1 RA’s may also offer hepatoprotection by reversing metabolic and inflammatory drivers contributing to HCC development. Patients with T2DM are at an increased risk of metabolic associated steatotic liver disease (MASLD) and HCC. To our knowledge, no real-world studies have directly compared the effectiveness of GLP-1 RA’s and statins for prevention of HCC in patients with T2DM. In this study, we aim to compare the incidence of HCC and hepatic decompensation events in patients with T2DM treated with GLP-1 RA’s vs statins. Methods: We performed a retrospective cohort study using data from TriNetX, a healthcare database of over 150 million patients in the United States. Adult patients with T2DM were identified and stratified by use of GLP-1 RA (semaglutide, dulaglutide, tirzepatide, exenatide, liraglutide, and lixisenatide) or statin (pitavastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin or lovastatin). Exposure groups were mutually exclusive with no overlap in GLP-1 RA or statin use. Propensity score matching was conducted between cohorts, matching for age, sex, race, tobacco use, alcohol use, hypertension, hyperlipidemia, obesity, MASLD, aspirin use, non-steroidal anti-inflammatory analgesic drug use, and other T2DM medications. Five-year incidence of HCC was compared between the GLP-1 RA and statin cohorts. In a subsequent analysis, hepatic decompensation events of ascites, hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), and esophageal varices (EV) were compared. Results: We identified 1,411,022 patients with T2DM, including 254,832 GLP-1 RA users and 1,156,190 statin users. After PSM, 219,984 patients were included in the analysis. There was no significant difference in the five-year incidence of HCC between the GLP-1 RA and statin cohorts (0.14% vs 0.15%, odds ratio (OR) 0.95, 95% confidence interval (CI)0.81-1.11, p =0.5). In the subsequent analysis, GLP-1 RA use was associated with a lower incidence of ascites (0.98% vs 1.99%, OR 0.84, 95% CI 0.46-0.51, p <0.001), HE (0.18% vs 0.22%, OR 0.84, 95% CI 0.74-0.96, p =0.01), and SBP (0.05% vs 0.1%, OR 0.52, 95% CI 0.42-0.65, p <0.001). There was no difference in incidence of EV (0.33% vs 0.35%, OR 0.94, 95% CI 0.85-1.04, p =0.25). Conclusions: In patients with T2DM at elevated risk for MASLD and HCC, we found that GLP-1 RA use was associated with significantly lower incidence of hepatic decompensation events compared to statin use. However, there was no significant difference in HCC incidence between the cohorts. Prospective studies are warranted to confirm the hepatoprotective effect of GLP-1 RA medications and evaluate long-term oncologic outcomes.

138 Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RA’s) have advanced the treatment of type 2 diabetes mellitus (T2DM), yet their association with cancer risk remains subject of ongoing research. Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a well-established risk factor for colorectal cancer (CRC). Studies have shown a reduced risk of CRC with GLP-1 RA use however, the impact of GLP-1 RA therapy in the high-risk IBD population is unknown. In this study, we aim to evaluate the association between GLP-1 RA use and CRC incidence among patients with IBD, and among those with IBD and T2DM. Methods: We performed a retrospective cohort study using data from TriNetX, a healthcare database of over 150 million patients in the United States. In the first analysis, adult patients with pre-existing IBD were identified and stratified by use of a GLP-1 RA (semaglutide, dulaglutide, tirzepatide, exenatide, liraglutide, and lixisenatide) or not. Propensity score matching (PSM) was conducted between GLP1-RA users and non-users, matching for age, sex, race, tobacco use, alcohol use, hypertension, hyperlipidemia, obesity, IBD subtype (CD or UC), steroid use, immunosuppressive use including biologics, and other T2DM medications. Five-year incidence of CRC was compared between GLP-1 RA users and non-users in the matched cohort between 2015 and 2025. We then restricted the cohort to patients with IBD and T2DM and repeated this analysis. Results: We identified 1,137,300 patients with IBD, including 70,303 GLP-1 RA users and 1,066,997 non-users. After PSM with all variables adequately matched, 69,221 patients were included in the analyses. GLP-1 RA use was associated with a lower 5-year incidence of CRC (0.2% vs. 0.43%, odds ratio (OR) 0.49, 95% confidence interval (CI) 0.3-0.57, p <0.001). We then identified 209,649 patients with IBD and T2DM, including 38,567 GLP-1 RA users and 171,082 non-users. After matching for all variables, 37,740 patients were included in the analyses. Among patients with IBD and T2DM, GLP-1 RA use was associated with a lower 5-year incidence of CRC (0.31% vs. 0.57%, OR 0.54, 95% CI 0.43-0.68, p <0.001). Conclusions: GLP-1 RA use was associated with a significantly reduced incidence of CRC in all patients with IBD, as well as the subpopulation with both IBD and T2DM. Given the elevated CRC risk in IBD, these findings suggest a potential protective effect of GLP-1 RA use in this high-risk population. Prospective studies will be important to further analyze and confirm this potential benefit.

Abstract Patients with atypical variants of Alzheimer's disease (AD) often present at a younger age with predominantly non‐amnestic impairments and a more aggressive disease course. Historically, individuals with atypical presentations have not been included in large‐scale clinical trials, which typically focus on late‐onset, sporadic amnestic‐predominant AD. Consequently, treatment options and research efforts specific to atypical AD remain limited. The emergence of amyloid‐targeting therapies that slow disease progression underscores these challenges, as evidence supporting their efficacy in early‐onset amnestic and non‐amnestic AD variants is scarce. This perspective article argues that atypical AD represents an excellent disease model for clinical trials and proposes strategies to address critical gaps in clinical trial design for this population. Key considerations include optimizing participant selection approaches, establishing syndrome‐specific or surrogate biological and clinical endpoints, and fostering advocacy to enhance early and accurate diagnosis, equitable representation, and outcomes for these populations.

Abstract Background SWI/SNF chromatin remodeling complexes are frequently mutated across human cancers, including biliary tract cancers (BTC). Within the SWI/SNF complexes, loss-of-function (LOF) mutations in ARID1A and PBRM1 are the most common and frequently co-occur alongside PI3K/AKT pathway activation. Yet, how those mutations affect the intracellular signaling landscape and transcriptomic programs is underexplored and may yield novel therapeutic opportunities. Methods Clinicodemographic parameters and mutation profiles of 250 patients with BTC were retrospectively collected through electronic medical records. Advanced overall survival (OS) was assessed in a multivariable analysis. Transcriptomic data were obtained and differentially expressed genes (DEGs) and pathways associated with SWI/SNF mutation status were analyzed. Changes in the transcriptomic landscape were compared to a murine syngeneic model of intrahepatic cholangiocarcinoma (CCA) initiated by loss of ARID1A and/or PBRM1 for cross-species validation. Results After adjusting for age, sex, and anatomical subtype, patients with SWI/SNF LOF mutations were found to have a 30% reduction in mortality risk (HR = 0.70, 95% CI: 0.50-0.98, p = 0.037). The transcriptomic cohort of 233 BTC patients included 71 (30%) with SWI/SNF LOF mutations, 21 (9%) with variants of uncertain significance, and 141 (61%) with SWI/SNF wild-type tumors. Differential gene expression and pathway analysis revealed changes in adaptive immune response, extracellular matrix, and cancer-associated proteoglycans. RNA-sequencing of murine tumors revealed the dominant effect of ARID1A loss in single and double knock-out tumors and conserved pathway alterations between mouse and human tumors. Conclusion Both murine and human primary tumors with either ARID1A alone or ARID1A/PBRM1 co-mutations exhibited altered expression of critical genes and pathways associated with proteoglycan synthesis and extracellular matrix. Ongoing research is investigating how CCA cells depend on those pathways and their canonical regulators for tumor formation and progression.

Abstract Background & Objectives Cholangiocarcinoma (CCA) is a highly aggressive malignancy arising from the bile duct epithelium. Despite advancements in diagnostic techniques, the diagnosis of cholangiocarcinoma (CCA) remains challenging. Currently, CA19-9 is the best available blood-based marker for detection of CCA, which has a sensitivity of 50-60% and a specificity of 80%. Moreover, individuals who are Lewis-antigen-negative (∼20% in some populations) have undetectable CA 19–9 levels resulting in false negative diagnoses. Therefore, there is a critical need for developing novel blood-based diagnostic approach for improving the sensitivity of diagnosis of CCA to improve clinical outcomes. Glycosylation, one of the most prevalent post-translational modifications, plays a crucial role in regulating biological functions such as cell-cell communication, protein folding and receptor signaling and is frequently dysregulated in cancer. Cell surface proteins, including glycoproteins, are overexpressed in CCA are likely to be shed into the blood and we investigated development of mass spectrometry-based methods to measure changes in glycosylation in patients with CCA. Methods Mass spectrometry data were acquired in parallel reaction monitoring mode using Orbitrap Eclipse Tribrid mass spectrometers. In addition, we tested the use of heavy glycopeptides for absolute quantitation of each glycopeptide. Mass spectrometry data were analyzed using Skyline to estimate glycopeptide abundance. Results First, we performed tandem mass tag-based quantitative proteomics and glycoproteomics of tumor tissues and serum collected from CCA patients using high-resolution mass spectrometry. From these experiments, a number of glycopeptides were found to be increased in abundance in CCA patients. We subsequently developed a targeted mass spectrometry–based assay to monitor four candidate glycopeptides derived from polymeric immunoglobulin receptor and aminopeptidase N to validate their performance in a large patient cohort from 269 patients with CCA and 100 healthy individuals. Conclusion We anticipate that this finding will lay the foundation for novel diagnostics that could benefit patients with this aggressive malignancy.

Importance TMEM106B is a frontotemporal lobar degeneration (FTLD) genetic susceptibility factor, and TMEM106B protein aggregates are a feature of aging and neurodegeneration. Whether TMEM106B protein levels are associated with clinical features is unknown. Objective To investigate the clinical associations of cerebrospinal fluid (CSF) TMEM106B in FTLD. Design, Setting, and Participants This cross-sectional study was conducted in 2 independent frontotemporal dementia (FTD) cohorts (recruitment from April 2009 through July 2023, with analyses from January 2025 through April 2026), with a 2-year follow up. This multicenter clinical study integrated clinical, genetic, biomarker, and neuroimaging data. Individuals were recruited through the University of California, San Francisco (n = 3733), or ALLFTD (n = 2343). Participants with available CSF were included. A discovery cohort (n = 271) included participants with sporadic neuropathology-confirmed FTLD; presymptomatic or symptomatic carriers of pathogenic variants in C9orf72 , GRN , or MAPT ; or controls. An independent validation cohort (n = 383) included participants with clinically diagnosed sporadic FTD, Alzheimer disease (AD), and controls. Exposures CSF samples for TMEM106B quantification with aptamer proteomics (SomaScan version 3.0 [discovery cohort] and SomaScan version 4.1 [validation cohort]). Main Outcomes and Measures Parametric tests compared the primary outcome, CSF TMEM106B, by disease severity, TMEM106B rs1990622 genotype, sex, clinical syndrome, pathological diagnosis, and pathogenic variant and determined associations with brain volume. Results In the discovery (n = 271; 136 women [51%]; median [IQR] age, 59 [38-80] years) and validation (n = 383; 183 women [48%]; median [IQR] age, 64 [50-78] years) cohorts, lower CSF TMEM106B was associated with more severe disease (β, −0.15; 95% CI, −0.24 to −0.04; P = .003), lower frontotemporal brain volumes (β, 0.42; 95% CI, 0.24-0.61; P &amp;lt; .001), and faster clinical progression (β, −2.21; 95% CI, −3.70 to −0.72; P = .001). Associations of TMEM106B with clinical disease severity were independent of those with neurofilament light chain. TMEM106B levels were influenced by TMEM106B rs1990622 genotype, where individuals with the protective G/G genotype had lower levels than the risk A/A genotype. CSF TMEM106B levels did not differentiate between FTLD subtypes or between FTLD and AD. Conclusions and Relevance Per the results of this cross-sectional study, TMEM106B is detectable in CSF and levels reflect disease severity in sporadic and genetic FTLD and AD, but levels are also influenced by the TMEM106B rs1990622 genotype. CSF TMEM106B could support further studies to understand the mechanisms of disease and develop clinical tools in FTLD and other neurodegenerative diseases.

Abstract Purpose Bronchiectasis is a condition characterized by chronic cough, recurrent infections, and progressive airway damage that is rising in prevalence. While often idiopathic, a subset of patients have a genetic cause such as cystic fibrosis (CF), primary ciliary dyskinesia (PCD), or alpha-1-antitrypsin deficiency (A1ATD). Genetic causes for bronchiectasis should be considered in patients with diffuse bronchiectasis involving ≥2 lobes, especially in those with early onset of symptoms, recurrent otitis media or chronic rhinosinusitis, infertility, organ laterality defects (e.g., situs inversus), exocrine pancreatic insufficiency or family history of bronchiectasis. Genetic testing may impact management decisions. Methods The Mayo Clinic Center for Individualized Medicine developed the Program for Rare and Undiagnosed Diseases (PRaUD) Genetic Testing and Counseling Unit (GTAC) provides abbreviated, point-of-care genetic counseling, and DNA sequencing-based testing. Patients with bronchiectasis evaluated by GTAC underwent exome or genome-based 52-gene panels which included PCD, CF, and A1ATD (SERPINA1)-associated genes. Sequencing panes results were reviewed and interpreted by a multidisciplinary team including genetic counselors, geneticists, and pulmonologists. Results From July 2022 to December 2025, 203 patients were identified; 163 patients completed testing (74% female, 93% white). A molecular diagnosis was confirmed in 10.4% (17/163) of cases, with known pathogenic variants identified in RSPH4A, SERPINA1 (A1ATD), and CFTR (CF). Variants of uncertain significance (VUS) were identified in 24% of patients. Notably, 11.6% (19/163) were identified as CF carriers, a rate significantly higher than the general European-ancestry population (∼4%). Clinical management was impacted for two patients, including the initiation of targeted CFTR modulator therapy in one patient with CF-related disorder (CFTRD) and one CFTR pathogenic variant heterozygote. Conclusions Genetic counselor-supported DNA sequencing for bronchiectasis led to an increased identification of genes that cause bronchiectasis. Interestingly, we found a high rate of CFTR heterozygote variant carriers in our clinic cohort, this aligns with the findings of other studies that CFTR variant carriers can have an increased frequency of bronchiectasis. The identification of pathogenic variants and VUS helps facilitate a diagnosis or potential genetic cause in a significant proportion of patients and highlights the need for further research in understanding the epidemiology of CF, PCD, and A1ATD-related variant genotypes in patients with bronchiectasis. Clinical Implications Comprehensive DNA sequencing, combined with genetic counseling and support from genetic counselors in partnership with pulmonologists can advance precision diagnostics and care for patients with bronchiectasis. This abstract is funded by: None

ABSTRACT Background The Academy for Women in Academic Emergency Medicine (AWAEM) within the Society for Academic Emergency Medicine was established to advance the recruitment, promotion, retention, and career satisfaction of women in academic emergency medicine (AEM). Despite progress, persistent gender disparities remain in several areas, including compensation, promotion, and leadership representation. Objective To better assess and evaluate current AWAEM programming, we developed a logic model to visually and systematically map AWAEM activities and initiatives with current and future metrics for evaluation. Methods The logic model was guided by AWAEM’s strategic plan and developed through an iterative process involving feedback from AWAEM members and leaders. Results The model outlines key inputs, describes activities categorized across five thematic areas, and identifies tangible outputs with corresponding metrics for those activities. The model concludes with short‐, intermediate‐, and long‐term outcomes that speak to the likely impact of AWAEM’s programming. Discussion The proposed logic model serves as a practical framework to align AWAEM’s efforts to outcomes while also embedding evaluation into ongoing programming. It provides a visual tool for identifying gaps and incorporating data‐driven modifications, as well as facilitating collaboration across the academy. While there are limitations to this logic model, it provides an initial roadmap and foundation for strategic planning and evaluation. It also provides an opportunity to periodically revise the model as AWAEM’s needs evolve to ensure continued relevance and alignment with the needs of the entire membership. Additionally, this model can serve as a framework for other professional development groups, academies, and societies external to SAEM.

Abstract The Tau Global Conference 2025, hosted by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation, convened international experts from academia, industry, government, and philanthropy to explore advances and challenges in tauopathy research. The meeting highlighted progress across tau biology, including emerging models of tau regulation, degradation, and propagation; advances in biomarker development for the diagnosis and staging of tauopathies; and evolving therapeutic strategies targeting diverse aspects of tau pathophysiology. Discussions also emphasized the importance of cross‐sector collaboration, and global initiatives to address disparities in tau research. This report synthesizes key insights from the conference and underscores the critical role of interdisciplinary, biomarker‐driven, and globally inclusive approaches in accelerating the translation of tau research into effective clinical applications.

ABSTRACT Prior surveys of chronic automated red blood cell exchange (RCE) for patients with sickle cell disease (SCD) have identified considerable procedural variability, especially with the use of isovolemic hemodilution red blood cell exchange (IHD‐RCE). We conducted a survey of chronic RCE practices among American Society for Apheresis (ASFA) members to identify opportunities for practice harmonization and future studies. The ASFA SCD Research Subcommittee developed a 72‐item survey of chronic RCE practices, with a focus on IHD‐RCE. The survey was validated internally and distributed by email to all ASFA members from September 2024 to February 2025. One survey response from each institution was retained for data analysis. Descriptive statistics were performed. Sixty‐two survey responses, including three from international institutions, were retained for analysis. Sixty‐one percent of respondents (38/62) reported using at least one fixed RCE target, with end hematocrit being the most common fixed parameter (40%, 25/62), followed by fraction of cells remaining (31%, 19/62) and hemoglobin S% (27%, 17/62). Most respondents (60%, 37/61) performed IHD‐RCE at their institution, though other details such as the minimum hematocrit, exclusion criteria, and response to adverse effects were variable. Consistent pre‐ and post‐RCE laboratory monitoring practices were reported. Consistent with earlier surveys, procedural variability in chronic RCE practices for patients with SCD is observed. This highlights opportunities to compare outcomes where practice variability exists. Consensus guidelines based on institutional practices with optimal outcomes should be developed.