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Abstract Introduction: Brexu-cel is a highly effective treatment for R/R B-ALL, with complete responses achieved in 71% of patients (pts) treated in the pivotal ZUMA-3 trial. Patients with B-ALL with high-risk (HR) genetics are known to have inferior outcomes with chemotherapy, but little is known about the influence of HR ALL genetics on responses to chimeric antigen receptor (CAR)-T in adults. In this study, we assessed the impact of HR ALL genetics on outcomes in a large cohort of adult patients treated with brexu-cel for R/R Philadelphia chromosome (Ph)-negative B-ALL. Methods: Patient characteristics and outcomes were obtained from the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) database which includes data from 40 U.S. centers. NCCN guidelines (NCCN Guidelines in Oncology, ALL v2.2025) were used to define HR B-ALL genetics; lack of HR genetics was defined as standard-risk (SR). The primary outcome was event-free survival (EFS), defined as lack of response, disease progression, or death from any cause. Secondary outcomes were overall survival (OS), relapse free survival (RFS) and response rates including complete response (CR), CR incomplete count recovery (CRi), measurable residual disease negative CR (MRD-) by flow or NGS and progressive disease (PD). Multivariable models were adjusted for age, pre-infusion blast percentage, prior allo-HCT, and post CAR-T allo-HCT (modeled as a time-varying covariate). Results: The cohort included 286 pts: 169 with HR and 117 with SR B-ALL. The HR cohort included TP53m (n=24, 14%), KMT2Ar (n=16, 9%), CRLF2r (n=65, 39%) and other HR genetics such as JAK2 and other Ph-like, IKZF1, complex cytogenetics (n=64, 38%). Relative to SR pts, HR pts were more commonly Hispanic (50% vs 28%). HR and SR pts had similar disease burden pre-apheresis (>5% blasts: 58% vs 53%), prior blinatumomab (60% vs 58%), prior inotuzumab (42% vs 46%), and prior allo HCT (27% vs 37%). The presence of CNS disease (11% HR vs 12% SR) and extramedullary disease (EMD, 22% HR vs 29% SR) at apheresis was also similar. CR/CRi was achieved in 90.5% of evaluable HR pts (n=147) and 90.2% of evaluable SR pts (n=102); MRD- rates were also similar between HR and SR pts at 78.9% and 78.2% respectively. In unadjusted analyses, EFS did not significantly differ between HR pts (median 9.6 mos; 1-yr: 46%, 95% CI 38%-54%) and SR pts (median 11.6 mos; 1-yr: 48%, 95% CI 38%- 58%). Median RFS (HR: 12.2 mos, SR: 13.3 mos) and median OS (HR: 22.4 mos, SR: 21.0 mos) were also similar. Multivariable models demonstrated no significant associations between HR B-ALL and EFS (HR 1.09, 95% CI 0.73-1.63), RFS (HR 1.13, 95% CI 0.71-1.80), or OS (HR 0.96, 95% CI 0.62- 1.48) relative to SR ALL. 28% of HR patients and 21% of SR patients underwent consolidative allo-HCT. Among the HR subgroup, CR/CRi rate was lowest in KMT2Ar (71%) relative to TP53m (95%), CRLF2r (95%), and other HR genetics (89%). The median EFS was lowest in KMT2Ar (4.1 mos), followed by TP53m (6.9 mos), CRLF2r (11.6 mos), and other HR (11.1 mos). Median OS was also lowest in KMT2Ar (6.8 mos) vs 22.4 mos in TP53m and not reached in CRLF2r or other HR. PD was highest in KMT2Ar pts (29%), as compared to 11% HR other, 10% SR, and 5% TP53 and CRLF2r. The rate of relapse among those that achieved CR across the groups was similar and ranged between 28% -40%. Rates of CD19 negative relapse were similar between all subgroups (13%-15%), however 21% of KMT2A pts underwent myeloid transformation as compared 0% for TP53 and CRLF2 pts, and 2% among other HR and SR pts. 25% of KMT2Ar patients underwent consolidative allo-HCT as compared to 32% CRLF2 pts, 29% TP53 pts, 25% other HR pts and 21% SR pts. Multivariable models evaluating the different genomic subgroups demonstrated that relative to SR B-ALL, only KMT2Ar was associated with inferior OS (HR 3.17, 95% CI 1.53-6.58, p=0020). No associations were seen between HR subgroups and EFS. Conclusion: To our knowledge, this analysis represents the largest examination of adult B-ALL recipients of CAR-T assessed by genomic risk group. We found that response rates and survival outcomes following brexu-cel were similar among HR and SR B-ALL pts, including pts with TP53m and CRLF2r. However, pts with KMT2Ar had lower response rates and dismal EFS and OS, with higher rates of PD and myeloid transformation at relapse, suggesting that alternative strategies are necessary to improve outcomes for patients with R/R KMT2Ar B-ALL.

Background The natural history of asymptomatic moderate or severe aortic regurgitation (AR) remains uncertain, with conflicting reports about its progression and surgical timing. We aimed to quantify adverse outcomes under conservative management and evaluate the association of aortic valve replacement/repair (AVR) with mortality. Methods Systematic searches (inception–July 2025) identified cohort studies of asymptomatic moderate/severe AR. Random-effects models estimated pooled incidence rates of adverse events; fixed-effects models were used for hazard ratios (HRs) of AVR vs conservative management. Results Twenty-seven studies (4720 patients; mean age 49 years; mean follow-up 3.9 years) were included. Pooled incidence rates per 100 person-years were 1.75 (95% CI 1.27 to 2.41) for all-cause mortality, 1.29 for cardiac death, 0.29 for sudden death, 4.30 for new symptoms and 7.01 for AVR. Asymptomatic low left ventricular ejection fraction occurred in only 0.9 per 100 person-years. Mortality rates were more than double those of the general population across age groups—2.45 (1.90 to 3.18) per 100 person-years for cohorts with mean age ≥50 years versus 0.59 (0.29 to 1.21) for younger cohorts. Early AVR was associated with lower mortality (pooled HR 0.33; 95% CI 0.30 to 0.37). Conclusion Asymptomatic moderate/severe AR carries significant excess mortality irrespective of age, contradicting its historically benign reputation. Given the rarity of asymptomatic LV dysfunction, earlier intervention guided by more sensitive markers of LV damage may improve outcomes, although heterogeneity and study quality warrant cautious interpretation. PROSPERO registration number CRD42024522683.

Viral hepatitis (VH) remains a leading cause of preventable mortality in the United States (US). Despite advancements in antiviral therapies, disparities in VH-related mortality persist across demographic, racial, and geographic groups. This study analyzes trends in VH-related mortality among US adults between 1999 and 2020 to identify high-risk subgroups and inform public health interventions. This retrospective cohort study analyzed VH-related deaths among US adults (≥25 years). Data were obtained from the CDC WONDER database, with cases identified using the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes B15–B19. Age-adjusted mortality rates (AAMRs) were calculated per 1,00,000 individuals and stratified by age, gender, race and geographical location. Temporal trends in mortality were analyzed by estimating annual percentage changes (APCs) in the AAMRs using the joinpoint regression model. A total of 3,59,035 VH-related deaths were recorded among US adults during 1999 to 2020 with a cumulative overall AAMR of 7.36 (95% CI: 7.33–7.38). Overall, the AAMRs increased significantly from 1999 to 2013 (APC: +3.21; P < .01), followed by a significant decline until 2020 (APC: −5.61; P < .01). Men exhibited higher AAMRs than women, with middle-aged adults (45–64 years) most affected compared to young (25–44 years) and older adults (65 to 85+ years). Non-Hispanic (NH) American Indians/Alaska experienced the highest AAMRs followed by NH Blacks/African Americans, Hispanics, NH Asians/Pacific Islanders and NH Whites populations. Geographically, mortality rates were higher in urban areas than in rural areas, in the Western region relative to other regions and in the District of Columbia compared to other states. Significant disparities in VH-related mortality persist across demographic and geographic subgroups, with particularly higher rates among men, NH American Indian/Alaska Native population, middle-aged adults, and residents of urban and Western US regions. Targeted public health strategies are essential to address these inequities and improve outcomes.

Introduction: In patients with type 2 diabetes (T2D) at high cardiovascular risk, glucagon-like peptide-1 receptor agonists (GLP1-RAs) have been shown to reduce major adverse cardiovascular events. However, patients with valvular heart disease, including those undergoing transcatheter aortic-valve implantation (TAVI), have been largely excluded from randomized trials. Hypothesis: We investigated whether GLP1-RA use is associated with improved one-year cardiovascular outcomes in patients with T2D undergoing TAVI. Methods: We conducted a retrospective cohort study using the TriNetX network. Adults (≥18 years) with T2D who underwent TAVI between 2015 and 2023 were included and stratified based on GLP1-RA initiation within 14 days post-TAVI. Baseline characteristics, comorbidities, medications, and laboratory data were balanced using 1:1 propensity score matching (PSM). The primary outcome was a composite of all-cause mortality or hospitalization at 1 year. Secondary outcomes included acute heart failure (HF) exacerbation, acute myocardial infarction (AMI), cardiac arrest, and ischemic stroke. Outcomes were assessed from 1 month to 1 year after TAVI. Survival probabilities were estimated using Kaplan-Meier analysis, and hazard ratios (HRs) were calculated with Cox proportional hazards models. Results: Among 20,454 patients with T2D undergoing TAVI from 2015-2023, 937 received GLP1-RAs. After PSM, 930 patients were included in each cohort, with a mean age of 73 years and 37% female. The mean follow-up duration was 342 days for GLP1-RA users and 325 days for non-users. GLP1-RA cohort exhibited a higher 1-year survival probability (93.8%) compared to non-users (89.5%) (HR 0.573 [95% CI, 0.410-0.801]; p=0.001). GLP1-RA use was also associated lower rates of all-cause hospitalization (HR 0.762 [95% CI, 0.652-0.891]; p=0.001), acute HF exacerbation (HR 0.687 [95% CI, 0.566-0.834]; p<0.001), and cardiac arrest (HR 0.452 [95% CI, 0.213-0.960]; p=0.034). No differences were observed in AMI (HR 1.033 [95% CI, 0.750-1.423]; p=0.844), or ischemic stroke (HR 0.875 [95% CI, 0.659-1.162]; p=0.356). Conclusions: In patients with T2D undergoing TAVI, GLP1-RA use is associated with significant survival benefits and improved cardiovascular outcomes, including reductions in acute HF exacerbation, all-cause hospitalization, and cardiac arrest. These findings highlight the need for prospective clinical trials to confirm these results.

Introduction: Preeclampsia is a multisystem progressive disease of pregnancy, characterized by a new onset of hypertension (≥ 140/90 mm Hg) with proteinuria after the 20th week of gestation. There is a conflict between United States guidelines that recommend Low-dose aspirin (LDA) and United Kingdom guidelines that recommend High-dose aspirin (HDA) for the prevention of preeclampsia in high-risk pregnant women. After the latest study that recommends HDA and the absence of pairwise meta-analyses comparing two doses, we aimed to conduct a comprehensive pairwise meta-analysis to assess whether HDA is better than LDA in the prevention of preeclampsia. Methods: We conducted a systematic search on PubMed, Scopus, Cochrane Central, and Web of Science (WOS) from inception until June 2025. All randomized controlled trials (RCTs) comparing LDA and HDA in high-risk pregnant women were included. Our primary outcome was the incidence of preeclampsia (PE), while secondary outcomes were Placental abruption, Pre-term delivery, and Intrauterine Growth Restriction (IUGR). Using random-effects models, we calculated risk ratios (RR) with 95% confidence intervals (CIs). Results: A total of 8 RCTs with 1,290 patients from the United States, Canada, England, and different Asian countries were included, among whom 642 (49.8%) patients were randomized to HDA. All studies compared HDA (≥ 150 mg) and LDA (75 mg to 81 mg). Patients with LDA had a higher risk of Preeclampsia (RR: 1.71, 95% CI: 1.19 to 2.44, p<0.001) compared to HDA. There was no significant difference between the LDA and HDA regarding Placental abruption, Pre-term delivery, and IUGR. With a pooled RR with a 95% CI (1.8, [0.91 to 3.54], P = 0.09), (1.25, [0.79 to 1.97], P = 0.34), (1.5, [0.93 to 2.42], P = 0.1), respectively. Conclusion: Among high-risk pregnant women, LDA was associated with a 71% higher incidence of preeclampsia than HDA. These results support the use of HDA as a preventive medication for preeclampsia in high-risk pregnant women.

Background: Heart failure (HF) continues to be a major cause of morbidity and mortality worldwide, placing a significant burden on healthcare systems. Differences in the outcomes of HF hospitalizations for adults in teaching vs. non-teaching hospitals in urban settings are uncertain. Research Question: Do outcomes of HF hospitalizations differ between patients hospitalized in urban teaching vs. non-teaching hospitals in the United States? Methods: HF hospitalizations were abstracted from the 2016 through 2022 Nationwide Readmissions Database and stratified into urban teaching vs. urban non-teaching hospital settings. Propensity-score matching was used to control for baseline differences between teaching and non-teaching hospital cohorts. Logistic regression and lognormal models were estimated to assess differences in inpatient mortality, length of stay (LOS), total costs, complications, and 30-day and 90-day all-cause readmissions. Odds ratios (OR) with associated 95% Confidence intervals (CI) and p-values were reported. Analyses were conducted via SAS v. 9.4. Results: A total of 7,558,299 weighted HF hospitalizations were included in the analysis, of which 76.3% involved urban teaching hospitalizations. Compared to urban non-teaching, HF hospitalizations in urban teaching hospitals were associated with higher odds of in-hospital mortality (OR 1.24, 95% CI:1.21-1.27); had higher complications, including cardiogenic shock (OR 2.58, 95% CI, 2.46, 2.70), cardiac arrest (OR 1.31, 95% CI, 1.27, 1.36), CPR (OR 1.28, 95% CI, 1.22, 1.34), and use of extracorporeal membrane oxygenation (OR 20.13, 95% CI, 13.0, 31.2), intra-aortic balloon pump (OR 4.46, 95% CI, 3.90, 5.10) and mechanical ventilation (OR 1.27, 95% CI, 1.23, 1.33); higher hospitalization cost (Ratio 1.18, 95% CI: 1.17,1.20), longer length of stay (OR 1.16, 95% CI: 1.15, 1.17) and a greater palliative care consultation rate (Ratio 1.35 (95% CI 1.30, 1.40) (all p<0.001) ( Figure 1 ). 30-day (OR 1.03, 95% CI: 1.02, 1.04) and 90-day (OR 1.05, 95% CI: 1.02, 1.07) all-cause readmission rates were also statistically higher (p<0.001), though the difference was clinically non-significant ( Figure 2 ). The home discharge rate was similar for teaching and non-teaching hospitals ( Figure 2 ). Conclusion: HF hospitalizations in urban teaching hospitals were associated with higher inpatient mortality, complication rates, resource utilization, and palliative care consult rates than urban non-teaching hospitals.

Introduction: As the global elderly population grows, so does the incidence of acute coronary syndrome (ACS) requiring urgent intervention. Emergency coronary artery bypass grafting (CABG) may offer a survival benefit, but concerns remain about its feasibility and safety in critically ill elderly patients with multiple comorbidities. Description of Case: This single-surgeon case series includes eight patients >65 years old who underwent emergency CABG for ACS between September 2023 and September 2024. Comorbidities included diabetes, hypertension, CKD, COPD, and previous stroke. All patients were critically ill, requiring combinations of inotropes, intra-aortic balloon pump (IABP), and mechanical ventilation. Ejection fractions ranged from 20–45%, and EuroSCOREs ranged from 10.86 to 30.45. Standard cardiopulmonary bypass with moderate hypothermia and a single aortic cross-clamp was used. Postoperatively, complications included transient ischemic attacks, dialysis-requiring renal dysfunction, atrial fibrillation, and infections. All patients survived; extubation times ranged from 7 to 70 hours, and hospital stays from 5 to 12 days. Discussion: This case series examines outcomes of CABG in elderly patients, emphasizing that despite multiple comorbidities, through physiological assessment, CABG can safely be performed in critically ill patients Although the LVEF was low and multiple comorbidities like diabetes and chronic kidney disease, signify the importance of a comprehensive assessment of physiology beyond standard biomarkers is necessary to determine readiness for surgery. Ventilation times variations highlighted the consequences of pulmonary and hematological challenges encountered in these patients. Recent advances in surgical techniques and perioperative care have improved outcomes, and most patients showed enhanced quality of life and physical function within a year post-surgery. Conclusion: Emergency CABG can be a lifesaving therapy in critically ill elderly ACS patients. With careful perioperative management, advanced age and comorbidity burden should not preclude surgical intervention.

Introduction: Valvular heart disease (VHD) poses a growing global burden, particularly in aging populations. While transcatheter interventions have expanded rapidly over the past two decades, the extent to which trial populations reflect real-world demographics—especially age and sex—is unclear. Understanding enrollment trends and representation gaps is essential to ensure equitable, generalizable evidence for clinical decision-making. Methods: We systematically reviewed VHD interventional trials (2000–2024) indexed in PubMed. Surgical and percutaneous trials across aortic, mitral, tricuspid, and pulmonic valves were included. Trial characteristics, demographics, and interventions were analyzed using descriptive and nonparametric statistics. Results: We included 487 trials enrolling 87,412 participants (45% women). Median trial size increased over time (z = 4.98, p < 0.01), and the mean age of participants also rose significantly (z = 10.08, p < 0.01). Trials involving percutaneous (11% to 45%), bioprosthetic (22% to 53%), aortic valve (27% to 62%), and multinational (2% to 16%) interventions increased over time. Older participants were more commonly enrolled in percutaneous, industry-funded, multinational, bioprosthetic, and aortic valve trials. Female representation remained unchanged across time (median 47%, z = -0.48, p = 0.63), but trials enrolling older participants tended to include more women (ρ = 0.196, p < 0.01). Female representation was highest in mitral (59%) and tricuspid (59%) valve trials, and more common in percutaneous (52%) than surgical (42%) interventions. Conclusion: Over the past two decades, VHD trials have expanded in size and geographic scope, with increased enrollment of older adults, particularly in percutaneous and industry-sponsored studies. However, sex disparities and demographic variability persist. Future trials should prioritize inclusive designs to ensure equitable, generalizable evidence for evolving valve interventions.

Background: Despite obesity being a major cardiovascular risk factor, studies in heart failure populations have reported an inverse association between body mass index and mortality—a phenomenon termed the "obesity paradox." However, the consistency and shape of this relationship across different HF phenotypes and clinical subgroups remain unclear. This meta-analysis aimed to quantify the dose-response relationship between BMI and mortality in HF patients and assess potential variations across subgroups. Hypothesis: Higher BMI is associated with reduced mortality in patients with heart failure, and that this relationship varies across clinical subgroups and U-shaped relationship. Methods: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A search strategy was developed, and studies were extracted from Cochrane and PubMed databases through December 2023. The main outcomes were all-cause mortality, cardiovascular deaths, and heart failure hospitalizations. Data were summarized as hazard ratios with 95% confidence intervals, and a spline model was used to assess non-linear relationships, with 21.7 kg/m2 as the reference point in the dose-response curve. PROSPERO: CRD42023455124 Results: Thirty-three studies (457,124 person-years) showed that each 5 kg/m2 increase in BMI was significantly associated with a 6% reduction in all-cause mortality (HR 0.94; 95% CI 0.92–0.96). Significant reductions were observed in acute decompensated heart failure (7%), HFpEF (9%), HFrEF (8%), diabetes (9%), males (9%), and females (8%). Cardiovascular mortality declined by 5% per 5 kg/m2 increase. Non-linear analysis revealed a significant U-shaped relationship, with lowest all-cause mortality between BMI 21.7 and 39 kg/m2. Subgroup analysis showed significant non-linear all-cause mortality reductions in acute decompensated heart failure (23.5–26 kg/m2), HFpEF (21.7–31 kg/m2), HFrEF (21.7–43 kg/m2), females (24–25.5 kg/m2), diabetes (21.7–36 kg/m2), and non-diabetics (21.7–33 kg/m2). Conclusion: Higher BMI is significantly associated with lower all-cause and cardiovascular mortality in patients with heart failure, supporting the presence of an obesity paradox. This protective effect was consistent across clinical subgroups, including HFpEF, HFrEF, males, females, and individuals with diabetes. The BMI paradox was evident in patients with acute decompensated heart failure, HFpEF, HFrEF, females, and both with and without diabetes.