Citations

Introduction: Sex-based differences in outcomes among patients with heart failure with reduced ejection fraction (HFrEF) treated with sodium-glucose cotransporter 2 inhibitors (SGLT2is) remain underexplored. This study aimed to evaluate sex-specific differences in cardiovascular outcomes in patients with HFrEF receiving SGLT2 inhibitors alongside guidelinedirected medical therapy (GDMT). Methods: We conducted a retrospective cohort study using the TriNetX global research network. Adults with HFrEF treated with SGLT2is and GDMT were stratified by sex. Propensity score matching (PSM) was used to balance baseline demographics, comorbidities, medications, and laboratory data. Primary outcomes were all-cause mortality and acute heart failure (HF) events; secondary outcomes included hospitalizations, arrhythmias, renal outcomes, and advanced therapies. Results: After PSM, 17,408 male and 17,408 female patients were analyzed. Male patients had lower odds of acute HF events (aOR: 0.949; 95% CI: 0.909–0.991), all-cause hospitalizations (aOR: 0.933; 95% CI: 0.895–0.973), and renal failure (aOR: 0.915; 95% CI: 0.870–0.962). No significant differences were observed in all-cause mortality (aOR: 1.003; 95% CI: 0.926–1.087) or heart transplantation, although LVAD use was more frequent in males (aOR: 1.416; 95% CI: 1.053–1.905). Discussion: The findings highlighted potential sex-based disparities in outcomes for patients with HFrEF on SGLT2is. Differential prescribing patterns, comorbidity burden, or timing of therapy initiation may contribute to observed differences. Conclusion: Among HFrEF patients treated with SGLT2is, males experienced lower risks of HF events, hospitalizations, and renal failure compared to females, despite similar mortality. Further research is needed to understand and address sex-specific disparities in HFrEF management.

PURPOSE Ziftomenib—a potent, highly selective, oral menin inhibitor—was well tolerated and demonstrated encouraging clinical activity as monotherapy for relapsed/refractory NPM1 -mutated ( NPM1 -m) and KMT2A -rearranged AML in the KOMET-001 phase I trial. METHODS In the registration-enabling phase II part of KOMET-001, patients with relapsed/refractory NPM1 -m AML received ziftomenib 600 mg once daily. The primary end point was the rate of complete remission with full hematologic recovery (CR)/CR with partial hematologic recovery (CRh). RESULTS From January 26, 2023, to May 13, 2024, 92 patients (median age, 69 years [range, 33-84]) were treated. The primary end point was met, with a CR/CRh rate of 22% (95% CI, 14 to 32; P = .0058); 61% were negative for measurable residual disease. Overall response rate was 33% (95% CI, 23 to 43), with a median duration of 4.6 months (95% CI, 2.8 to 7.4). Prespecified subgroup analyses showed comparable CR/CRh regardless of previous therapy, including venetoclax, or type of comutations. Median overall survival was 6.6 months (95% CI, 3.6 to 8.6). Common grade ≥3 treatment-emergent adverse events were febrile neutropenia (26%), anemia (20%), and thrombocytopenia (20%). Differentiation syndrome occurred in 25% of patients (15% grade 3; no grade 4-5) and was manageable with protocol-defined mitigation. Three patients (3%) discontinued treatment because of ziftomenib-related adverse events. CONCLUSION Ziftomenib demonstrated significant clinical benefit and deep responses in patients with heavily pretreated, relapsed/refractory NPM1 -m AML. Ziftomenib was well tolerated with a safety profile consistent with previous studies, including manageable differentiation syndrome, lack of clinically significant QTc prolongation, and low rates of myelosuppression.

Background/Objectives: Pediatric heart failure (HF) is a complex clinical syndrome with diverse etiologies and presentations. Primary care providers (PCPs) are critical in early recognition, family education, and coordination of ongoing care in collaboration with pediatric cardiologists. This review provides a comprehensive guide for PCPs to understand the causes, symptoms, treatments, and longitudinal considerations for children with HF. Methods: We conducted a narrative review synthesizing published evidence and expert consensus guidelines, focusing on the clinical presentation, treatment options, and longitudinal care strategies in children with HF. Results: HF in children most commonly results from congenital heart disease and cardiomyopathy, but includes a wide range of etiologies. Presenting symptoms differ by age, with subtle signs often mistaken for common pediatric illnesses. Treatments range from disease-modifying medications to surgical and transplant therapies. Psychosocial support, mental health, and family-centered care are critical components of long-term management. Conclusions: PCPs are essential partners in the care of children with HF. A proactive, collaborative, and informed approach can improve quality of life, reduce hospitalizations, and support families navigating this challenging diagnosis.

Objectives Directly compare the brain glucose patterns seen with [F‐18] fluorodeoxyglucose (FDG) positron emission tomography (PET) between 2 genetically determined forms of Alzheimer's disease: Down syndrome (DS) and autosomal dominant Alzheimer's disease (ADAD). Methods Cross‐sectional analyses of FDG were performed in individuals with DS (n = 76) from the Alzheimer Biomarker Consortium‐Down Syndrome (ABC‐DS), ADAD (n = 297), and neurotypical familial controls (n = 188) from the Dominantly Inherited Alzheimer Network (DIAN). Within‐group linear regression models and generalized additive models were performed for select regional FDG uptake measures (isthmus cingulate and inferior parietal, precuneus, middle temporal gyrus, and precentral gyrus). Age, sex, apolipoprotein (APOE) ε4 carrier status, and cortical amyloid burden were included within these analyses. Results Even 20 years before expected onset of clinical symptoms, FDG uptake was lower for DS compared to neurotypical familial controls ( p < 0.01). ADAD baseline FDG was similar to neurotypical familial controls until 7 years before expected symptom onset. Both symptomatic individuals with DS and ADAD had lower FDG compared to neurotypical familial controls ( p < 0.01). A higher amyloid burden was associated with lower FDG for both genetic forms, with similar rates of decline in FDG uptake for DS and ADAD who were amyloid positive. Interpretation Brain glucose metabolism is substantially lower for people with DS, even in individuals who are cognitively stable. The patterns of FDG decline are distinct in these 2 genetically determined forms of AD. The diagnostic utility of FDG‐PET is specific to the genetic form of AD. ANN NEUROL 2025;98:1237–1248

Objective To establish a framework for validating candidate biomarkers of cerebral small vessel diseases (SVD) associated with cognitive impairment and characterize individuals enrolled by the MarkVCID2 consortium under this framework. Methods Participants age 60 to 90 years were enrolled across 17 MarkVCID2 sites. Recruitment was targeted to enrich in cognitive symptoms (mild dementia, mild cognitive impairment, subjective cognitive decline), defined risk factors (diabetes mellitus, advanced hypertension), and Black/African American, White, and Hispanic/Latino subgroups. Enrolled participants underwent baseline visits that included cognitive testing, multimodal magnetic resonance imaging (MRI), and biofluid collection. Provisional risk for SVD‐related cognitive decline was estimated primarily by baseline cognitive symptoms plus SVD risk factors. Adjudicated risk status was estimated by cognitive symptoms plus presence of moderate‐to‐severe white matter hyperintensities, microbleeds, or lacunes on baseline MRI. Results MarkVCID2 enrolled 1883 individuals age 73.4 ± 7.5 years, 65.0% female, 24.2% Hispanic, and 27.1% non‐Hispanic Black. Among enrollees, 44.8% were provisionally designated high‐risk. After baseline MRI, 48.5% were categorized as adjudicated high‐risk status, with substantial recategorization both from low‐ to high‐risk (primarily because of MRI lesions without SVD risk factors) and high‐ to low‐risk (primarily suspected cognitive impairment at screening not confirmed by baseline testing). Interpretation MarkVCID2 baseline data indicate successful enrollment of diverse individuals enriched in factors associated with SVD‐related cognitive decline. Changes over 3 years of longitudinal follow‐up will be analyzed to validate the candidate biomarkers for 2 projected contexts of use: subject selection (identifying likelihood of future SVD progression) and study outcome (efficiently measuring SVD progression). ANN NEUROL 2026;99:449–458

Abstract Objectives Hepatic steatosis impacts the quality of grafts, affecting transplant outcomes. Rising obesity rates and subsequent donor graft steatosis further influence the organ shortage crisis in pediatric liver transplantation (LT). Our study aimed to evaluate how donor steatosis modulates the outcomes of pediatric LT. Methods We analyzed the United Network of Organ Sharing database for transplanted donor grafts from January 01, 2004, to April 30, 2024. We stratified pediatric (≤18 years) LT recipients into steatotic grafts, subdivided into <30% and ≥30%. Graft failure was assessed using Kaplan–Meier curves, and Cox proportional hazards models, with Lasso regression identifying key predictive variables. Gradient‐boosting decision tree was used to assess the level of likelihood importance for post‐LT survival. Results Five hundred and ninety‐five pediatric LT recipients were included; 62 (10.4%) received donors with steatosis levels ≥30%. Survival rates for steatotic grafts ≥30% were 93.5% at 1 year, 89.9% at 5 years, and 84.4% at 10 years, compared to 94.7%, 89.5%, and 85.2% respectively, among steatotic grafts <30% ( p = 0.72, p = 0.92, and p = 0.92). Donor age (adjusted hazard ratio [aHR]: 1.01, 95% confidence interval [CI]: 1.01–1.03), donation after cardiac death (DCD) (aHR: 10.68, 95% CI: 3.27–34.86), and recipient life support (aHR: 1.95, 95% CI: 1.19–3.20) were associated with an increased risk of mortality. Conclusion Steatotic grafts in pediatric patients had acceptable outcomes. Predictors of mortality in steatotic grafts, including donor age, DCD, and recipient life support, underscore the complex interplay of multiple factors in post‐LT outcomes.

Abstract Introduction: Despite treatment advances, ovarian cancer (OC) remains the deadliest gynecological cancer, with a ∼70% mortality rate. OCs initially respond to platinum chemotherapy but often develop resistance. While PARP inhibitors improve relapse-free survival in responsive cases, they do not extend overall survival. This underscores the need for effective combination therapies beyond BRCA status. The lysosomal protein cathepsin L (CTSL) can traffic to the nucleus, where it can regulate DNA repair and serve as a chromatin modifier. We found that nucleoside analog clofarabine (CLF) induces CTSL nuclear trafficking in OC cells. Here we tested the hypothesis that accumulation nuclear CTSL (nCTSL) is a biomarker of sensitivity to DNA damaging therapy in OCs for improved therapeutic options. Methods: To determine the role of CLF induced nuclear CTSL in DNA damage and its synergy with PARP and CRM1 inhibitors in PARP inhibitor–sensitive and –resistant ovarian cancer (OC) cell lines, ex vivo cultures of ascites-derived patient OC cells (OVA-3D spheroids), primary ovarian tumors, and patient-derived xenograft (PDX) models and validated by colony formation assays. Nuclear CTSL localization was determined in subcellular fractionated lysates by western blots and immunofluorescence cytometry (IFC). Tumor regression was determined in vivo using ex vivo cultures of PDX derived cells. Results: In ovarian cancer (OC) cell lines, CLF monotherapy induced nuclear CTSL (nCTSL) in a subset of models classified as CLF-responsive (CLF-r), sensitizing them to the PARP inhibitors olaparib and rucaparib. In CLF-non-responsive (CLF-nr) models, nCTSL induction and therapeutic synergy were observed only with the CLF+olaparib combination. Synergy was detected in 47% of CLF-r and 24% of CLF-nr patient-derived ascites samples (OVA). Mechanistically, CLF induced nuclear import of CTSL via KPNB1 in CLF-r cells, while this import was triggered by the CLF+olaparib combination in CLF-nr cells. CLF also downregulated the nuclear export protein CRM1 (XPO1) in both groups. Knockdown of CTSL in either CLF-r or CLF-nr cells abrogated sensitivity to the combination. Notably, in 29% of OVA samples classified as CLF-resistant (CLF-Res), CLF failed to suppress CRM1 expression. In these cases, CRM1 inhibition with KPT8602 restored CLF+PARP inhibitor synergy. In vivo, CLF-r and CLF-nr PDX models treated with the combination exhibited increased DNA damage, reduced tumor burden, and extended survival. Conclusion: These findings identify nuclear CTSL (nCTSL) induction as a potential biomarker of response to DNA-damaging therapies. The combination of CLF and olaparib represents a promising strategy to overcome drug resistance in ovarian cancer by promoting CTSL nuclear localization and enhancing DNA damage. Citation Format: Prabhu Thirusangu, Ling Jin, Upasana Ray, Anya Zhao, Julie Staub, Xinyan Wu, Xiaonan Hou, Jamison L. VanBlaricom, Syed Mohamed Musheer Aalam, Sun-Hee Lee, Ann Oberg, Nagarajan Kannan, John Weroha, Jeremy Chien, Scott H. Kaufmann, Jamie N. Bakkum-Gamez, Viji Shridhar. Role of drug induced nuclear CTSL (nCTSL) in DNA damage response in cancer- therapeutic implications [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A050.