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SummaryBackgroundRacial and ethnic disparities exist for hepatitis C virus (HCV) treatment and hepatocellular carcinoma (HCC) survival.AimTo evaluate the impact of HCV treatment on such disparities.MethodsIn a retrospective cohort study, we analysed 6069 patients with HCV‐related HCC (54.2% Asian, 30.1% White, 8.5% Black, and 7.3% Hispanic) from centres in the United States and Asia.ResultsThe mean age was 61, 60, 59 and 68, respectively, for White, Black, Hispanic and Asian patients. Black patients were most likely to have Barcelona Clinic Liver Cancer stage D, vascular invasion and distant metastasis (23% vs. 5%–15%, 20% vs. 10%–17% and 10% vs. 5%–7%, respectively; all p < 0.0001). Treatment rate with direct‐acting antiviral agents (DAA) was 35.9% for Asian, 34.9% for White, 30.3% for Hispanic (30.3%), and 18.7% for Black patients (p < 0.0001). Among those untreated or without sustained virologic response (SVR), 10‐year survival rates were 35.4, 27.5, 19.3 and 14.0, respectively, for Asian, Hispanic, White and Black patients (p < 0.0001). There were no statistically significant differences among those with SVR (p = 0.44). On multivariable analysis adjusted for relevant confounders, there was no statistically significant association between survival and being Hispanic (aHR: 0.68, p = 0.26) or Black (aHR: 1.18, p = 0.60) versus White. There was a significant association between being Asian American and survival (aHR: 0.24, p = 0.001; non‐U.S. Asian: aHR: 0.66, p = 0.05), and for SVR (aHR: 0.30, p < 0.0001).ConclusionDAA treatment rates were suboptimal. Racial and ethnic disparities resolved with HCV cure. Early diagnosis and improved access to HCV treatment is needed for all patients with HCV infection.

Abstract Microglia, the major resident immune cells in the central nervous system, serve as the frontline soldiers against cerebral ischemic injuries, possibly along with metabolic alterations. However, signaling pathways involved in the regulation of microglial immunometabolism in ischemic stroke remain to be further elucidated. In this study, using single‐nuclei RNA sequencing, a microglial subcluster up‐regulated in ischemic brain tissues is identified, with high expression of Igf1 and Trem2, neuroprotective transcriptional signature and enhanced oxidative phosphorylation. Microglial depletion by PLX3397 exacerbates ischemic brain damage, which is reversed by repopulating the microglia with high Igf1 and Trem2 phenotype. Mechanistically, Igf1 serves as one of the major down‐stream molecules of Trem2, and Trem2‐Igf1 signaling axis regulates microglial functional and metabolic profiles, exerting neuroprotective effects on ischemic stroke. Overexpression of Igf1 and supplementation of cyclocreatine restore microglial glucometabolic levels and cellular functions even in the absence of Trem2. These findings suggest that Trem2‐Igf1 signaling axis reprograms microglial immunometabolic profiles and shifts microglia toward a neuroprotective phenotype, which has promising therapeutic potential in treating ischemic stroke.

AbstractBackgroundRepetitive head impacts (RHI) from American football can lead to tau and non‐tau pathologies that might present as white matter hyperintensities (WMH) on FLAIR MRI. In 2022, we published a study in Alzheimer’s & Dementia that examined WMH and their association with risk factors and clinical function in former elite football players. That study will be presented during this symposium along with new unpublished data that used imaging and fluid biomarkers to examine etiological correlates (tau, amyloid, neurodegeneration, axonal injury, neuroinflammation) of WMH in the same cohort.MethodsThe multi‐site DIAGNOSE CTE Research Project recruited 180 football players and 60 asymptomatic males without RHI (“controls”), all 45‐74 years (Table 1). Participants completed MRI, lumbar puncture, and neuropsychological testing. Lesion Segmentation Toolbox estimated FLAIR WMH, FreeSurfer derived total cortical thickness, and a diffusion pipeline derived average global FA. CSF was analyzed for p‐tau181, Aβ1‐42, NfL, and sTREM2. Tobit regressions compared football players (n = 149) and controls (n = 53) on total and regional log‐WMH and estimated the effects of years of football and age of first exposure (AFE) to football on log‐WMH. Linear regressions evaluated log‐WMH and clinical associations in football players. Structural equation modeling (SEM) examined effects between log‐WMH and cortical thickness, FA, and the CSF biomarkers. Analyses accounted for age, race, revised Framingham Stroke Risk Profile (rFSRP), body mass index, APOE ε4, and evaluation site.ResultsAlosco et al. (2022) found older (i.e., 60+) but not younger football players had greater total, frontal, temporal and parietal log‐WMH compared to controls (FDR‐adjusted p‐values<0.05; Table 2). Among older football players, younger AFE was associated with greater log‐WMH (beta = ‐0.13, 95% CI = ‐0.23,‐0.02). Greater log‐WMH corresponded to worse Trails A‐B (beta = ‐4.32, 95% CI = ‐8.59,‐0.05) and List Learning Long Delay scores (beta = ‐0.56, 95% CI = ‐0.93,‐0.19). Subsequent unpublished SEM analyses in football players (Figure 1) showed the following direct effects on log‐WMH: higher rFSRP, higher CSF p‐tau181, lower FA, and reduced cortical thickness. There were no indirect effects. Compared to controls, SEM associations were stronger in football players exception for cortical thickness.ConclusionsFLAIR WMH might have unique imaging characteristics, risk factors, and pathological underpinnings in people exposed to RHI.

AbstractBackgroundTriggering receptor expressed on myeloid cell 2 (TREM2) is a surface receptor that, in the central nervous system, is exclusively expressed on microglia. TREM2 variants have been linked to increased risk for neurodegenerative diseases, but the functional effects of microglial TREM2 in TAR‐DNA binding protein 43 kDa (TDP‐43)‐related neurodegeneration remain largely unknown.MethodWe investigated TDP‐43 neurodegeneration via viral‐mediated expression of hTDP‐43 protein in mice or inducible expression of hTDP43 with defective nuclear localization signals in transgenic mice. Mass cytometry analysis, mass spectrometry, surface plasmon resonance, and computational simulation were used to study the interaction between TREM2 and TDP‐43.ResultWe found that TREM2 deficiency impaired microglia phagocytic clearance of pathological TDP‐43, and enhanced neuronal damage and motor function impairments. hTDP‐43 induced a TREM2‐dependent subpopulation of microglia with high CD11c expression and higher phagocytic ability. We further demonstrated an interaction between TDP‐43 and TREM2, in vitro and in vivo, in hTDP‐43‐expressing transgenic mouse brains. We computationally identified the region within hTDP‐43 that interacts with TREM2 and observed the potential interaction in ALS patient tissues.ConclusionOur data reveal the novel interaction between TREM2 and TDP‐43, highlighting that TDP‐43 is a potential ligand for microglial TREM2 and the interaction mediates neuroprotection of microglial TREM2 in TDP‐43‐related neurodegeneration.

Background: Impaired left ventricular (LV) global longitudinal strain (GLS) is associated with worse outcomes in patients with severe aortic stenosis (AS). However, its prognostic value in patients with moderate AS is still unknown. The aim of this study is to investigate the impact of LV GLS on outcomes of patients with moderate AS. Methods: PubMed/Medline, Scopus, and Google Scholar databases were systematically reviewed to find relevant studies through June 2023 reporting data on the relationship between the LV GLS and long-term mortality in patients with moderate AS. Binary random effects models were used to estimate pooled odds ratios (OR) and 95% confidence intervals (CI). I2 statistics were used to interpret heterogeneity, with I2>75% indicating substantial inter-study variation. Leave-one-out meta-analysis was performed to evaluate the effect of each study on the overall estimate. A p<0.05 was considered statistically significant. Results: A total of 172 studies were reviewed, and 4 studies between 2000-2023 were included in our meta-analysis with a median follow-up of 48.5 months and GLS cut-off varying from 11% to 16%. The pooled univariate analysis revealed a significant association between LV GLS and long-term mortality in patients with moderate AS with a pooled OR of 2.02 (95CI 1.04-3.93) p=0.04, I2=94.25%. The multivariate analysis, after adjusting for overall modifiable risk factors, yielded significant results, with an adjusted odds ratio (aOR) of 1.56 (95CI 1.21-2.01) p<0.01, I2=89.48%. Sensitivity analysis, using leave-one-out method, demonstrated robustness and stability of the results with aOR 1.56 (95CI 1.21-2.01) p<0.01. Conclusions: In patients with moderate AS, impaired LV GLS is associated with an increased risk for all-cause mortality. If further randomized studies confirm the prognostic ability of impaired GLS, moderate AS can be redefined, and GLS can be considered in determining the optimal timing for aortic valve intervention.

Aim: Studies in the past have linked obesity as a risk factor for atrial fibrillation (AF). However, there is a paucity of data on this influence in young adult males. This meta-analysis aims to evaluate and stratify the association between BMI and AF among young men. Methods: PubMed, Scopus, and Google Scholar databases were systematically reviewed for studies reporting long term-incidence of atrial fibrillation in young male adults (18-49 years) with obesity (BMI>30 kg/m 2 ), and overweight BMI (BMI 20-25 kg/m 2 ). Random effects models were used for the meta-analyses and subgroup analyses. I 2 statistics were used to identify (>50%) heterogeneity. A sensitivity analysis was performed using leave-one-out method. Results: Six studies with a total of 21,856,538 individuals were screened, out of which 6,732,531 young males with higher BMI and obesity were evaluated for the risk of Atrial fibrillation for a median follow-up duration of 6.3 years (3.3 - 29 years range). South Korean and Japanese studies together constituted 99.86% of the study population. Most commonly associated comorbidities were hypertension, diabetes mellitus type 2, dyslipidemia and smoking. The unadjusted HR showed a significant association between overweight (BMI 25-30) [OR:1.42, (95%CI:1.28-1.58, I 2 : 75.86%; p< 0.01] and obesity (BMI >30) and AF [OR: 2.02, (95%CI: 1.77-2.29, I 2 :64.3%; p=0.02] in young adult males. After multivariable analysis, the association remained significant for overweight [OR:1.22, 95%CI: 1.14-1.32, I 2 : 82.74%; p< 0.01] and obesity [OR:1.48, 95%CI: 1.29-1.71, I 2 : 90.43%; p< 0.01]. Sensitivity analysis indicated that no single study unduly influenced the pooled estimates. Conclusion: This meta-analysis revealed that higher BMI (overweight and obese) in young males is associated with an increased long-term risk of AF over a median follow-up duration of 6.3 years.

Introduction: Over 100 FDA-approved medications, electrolyte perturbations, and many disease states can prolong the QT interval in up to 10% of patients. In contrast, approximately 1 in 2,000 people have congenital long QT syndrome (LQTS) hallmarked by pathological QT prolongation secondary to LQTS-causative mutations. Hypothesis: an artificial intelligence (AI) deep neural network (DNN) analysis of the 12-lead ECG can distinguish patients with LQTS from those with acquired QT prolongation. Methods: The study cohort included 1599 patients with genetically confirmed LQTS and over 2.5 million controls from Mayo Clinic’s ECG data vault. Every patient/control with ≥ 1 ECG above age- and sex- specific 99 th percentile values for QTc [> 460 ms for all patients (male/female) < 13 years of age, or > 470 ms for men and > 480 ms for women above this age] was included. An AI-DNN involving a multi-layer convolutional neural network was developed. To simulate screening conditions, patients were matched at a ratio of 1:2,000 (incidence of LQTS) or 1:200 (balance of LQTS vs acquired QT prolongation in a tertiary referral center). Results: Among the 1,599 patients with LQTS, 808 (> 50%) had ≥ 1 ECG with QTc above the aforementioned QTc thresholds (2,987 ECGs) compared to 361,069/2.5M controls (14% of Mayo Clinic patients getting an ECG, 989,313 ECGs). Following age- and sex- matching and splitting, the model successfully distinguished LQTS from those with acquired QT prolongation at 1:2,000 matching with an AUC of 0.937 (accuracy 89%, sensitivity 81%, specificity 90%, PPV 0.05, NPV 0.99). Furthermore, when matching at a rate that genetically-mediated QT prolongation would be encountered in clinic (1:200), the model still successfully separated the two groups (AUC 0.912, accuracy 88%, sensitivity 78%, specificity 89%, PPV 0.1, NPV 0.99). Conclusion: For patients with a QTc exceeding its 99 th percentile values seen in health, this novel AI-DNN 12-lead ECG distinguishes abnormal QT prolongation stemming from LQTS versus acquired QT prolongation with high performance characteristics (AUC > 0.93). Even when scaled to referral center and LQTS incidence ratios, a negative AI-DNN signal rules out the presence of a LQTS disease-causative mutation with 99% negative predictive value.

Introduction: Long-term outcomes of young patients with chest pain and normal epicardial coronary arteries (NECA) in angiography remain understudied. Methods: We conducted a prospective study in a tertiary heart hospital between 2004-2020, enrolling men<45 and women<55 years presenting with symptoms or objective findings of coronary artery disease (CAD) and confirmed NECA in angiography. Patients with cardiomyopathy, coronary anomaly, and significant valvular, renal, pulmonary, or liver diseases were excluded. The primary outcome was MACCE, defined as the composite of death, CCU admission (for MI or unstable angina), stroke, and revascularization. Follow-ups were done every 5 years using a standardized questionnaire and a committee of experts reviewed all the events. Expected age and sex-adjusted mortality rates were estimated using national data. The association between exposures and MACCE was studied using multivariable Cox-proportional hazard models. Results: 1257 patients, 340 (27.05%) men (38.34±5.46 years), and 917 (72.95%) women (48.41±4.94 years) were included. 698 (55.53%) had acute and 559 (44.47%) had chronic symptoms. Over the median 9.4 (8.5-11.0) years of follow-up, 134 (10.66%) events happened. CCU admission (6.33%) was the most common event (Figure). The 10-year mortality rate (per 100,000-person-years) was 265 for men and 174 for women, which were 1.6 and 2.5 times higher than the age-sex-matched rate of the normal population, respectively. Diabetes, hypertension, and presenting with acute symptoms were associated with higher MACCE with the hazard ratios (95% CI) of 1.87 (1.05-3.31, P:0.03), 1.72 (1.13-2.61, P:0.01), and 1.56 (1.03-2.36, P:0.04), respectively. During follow-up, 192 (15.27%) repeated angiographies were done and 19.8% developed obstructive CAD. Conclusions: In young patients with chest pain and NECA, approximately 10% experienced MACCE during a 10-year follow-up, and the mortality is higher than expected.

INTRODUCTION: The relentless toll of cardiovascular disease in the United States demands a breakthrough in reliable and cost-effective prognostic markers. Amidst the limited knowledge surrounding the role of adiponectin in stable coronary artery disease (CAD), this study aims to unveil its power in predicting all-cause mortality and major adverse cardiovascular events (MACE) among patients with stable coronary artery disease (CAD). METHODS: We systematically screened PubMed, Scopus, and Google Scholar for articles until May 2023 to identify relevant studies. Random-effects model estimated the pooled odds ratio (OR) with 95% confidence intervals (CI), and I2 statistics assessed heterogeneity. The leave-one-out method was used for sensitivity analysis. RESULTS: Following the screening, five prospective studies involving 3225 patients with a median follow-up duration of 3.8 years were included. In the study population, hypertension, diabetes, hyperlipidemia, and smoking were prevalent risk factors, and common medications included angiotensin-converting enzyme inhibitors, beta-blockers, and statins. The pooled adjusted OR for all-cause mortality was 2.51 (95%CI: 1.36-4.62), with moderate heterogeneity (I2=65.51%, p=0.03), and the pooled adjusted OR for MACE was 1.04 (95%CI: 1.02-1.06), with no significant heterogeneity (I2=0%, p=0.68) (Fig. 1) . The leave-one-out sensitivity analysis showed that no single study significantly influenced the meta-analysis results, indicating robustness. CONCLUSION: Higher adiponectin levels were associated with higher odds of long-term mortality and MACE in stable CAD patients, highlighting its potential as a cost-effective marker for risk stratification and guiding management strategies. Further studies exploring the role of adiponectin can significantly impact clinical decision-making and resource allocation in cardiovascular care.