Citations

Hypoplastic left heart syndrome (HLHS) is the most lethal congenital heart disease (CHD). The pathogenesis of HLHS is poorly understood, and due to the likely oligogenic complexity of the disease, definitive HLHS-causing genes have not yet been identified. Postulating impaired cardiomyocyte proliferation as a likely important contributing mechanism to HLHS pathogenesis, and we conducted a genome-wide siRNA screen to identify genes affecting proliferation of human iPSC-derived cardiomyocytes (hPSC-CMs). This yielded ribosomal protein (RP) genes as the most prominent class of effectors of CM proliferation. In parallel, whole genome sequencing and rare variant filtering of a cohort of 25 HLHS proband-parent trios with poor clinical outcome revealed enrichment of rare variants of RP genes. In addition, in a familial CHD case we identified a rare, predicted-damaging promoter variant affecting RPS15A that was shared between the HLHS proband and a distant relative with CHD. Functional testing with an integrated multi-model system approach reinforced the idea that RP genes are major regulators of cardiac growth and proliferation, thus potentially contributing to the hypoplastic phenotype observed in HLHS patients. Cardiac knockdown (KD) of RP genes with promoter or coding variants (RPS15A, RPS17, RPL26L1, RPL39, RPS15) reduced proliferation in generic hPSC-CMs and caused malformed hearts, heart-loss or even lethality in Drosophila. In zebrafish, diminished rps15a function caused reduced CM numbers, heart looping defects, or weakened contractility, while reduced rps17 or rpl39 function caused reduced ventricular size or systolic atrial dysfunction of the atrium, respectively. Importantly, genetic interactions between RPS15A and core cardiac transcription factors TBX5 in CMs, Drosocross, pannier and tinman in flies, and tbx5 and nkx2-7 (nkx2-5 paralog) in fish, support a specific role for RP genes in heart development. Furthermore, RPS15A KD-induced heart/CM proliferation defects were significantly attenuated by p53 KD in both hPSC-CMs and zebrafish, and by Hippo activation (YAP/yorkie overexpression) in developing fly hearts. Based on these findings, we conclude that RP genes play novel critical roles in cardiogenesis and constitute an emerging class of gene candidates likely involved in HLHS.

Positive inotropic agents have an important role in the management of acute decompensated heart failure patients with reduced cardiac output and poor end-organ perfusion. However, despite their acute hemodynamic benefits, the role of inotropes in the management of chronic advanced heart failure remains limited to palliative therapy or as a bridging strategy to mechanical support or heart transplantation. Milrinone is one of the most common inotropic agents used in advanced heart failure to provide symptomatic relief and improved hemodynamics. This review discusses the current evidence of milrinone’s efficacy, indications, outcomes in advanced heart failure, evidence gap, and future directions.

Importance Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have become substantially more popular as a medication to treat obesity and type 2 diabetes (T2D). Despite their known association with gastroesophageal reflux disease and vagal nerve stimulation, the association between GLP-1RAs and chronic cough has not been previously studied. Objective To assess the clinical association between GLP-1RAs and chronic cough. Design, Setting, and Participants This large, multicenter cohort study used clinical records from a US-based collection of electronic medical record data from April 28, 2005, to April 15, 2025, from 70 health care organizations. Adults (≥18 years) with T2D and prescription of a GLP-1RA were identified. Additionally, groups with T2D and prescription of another second-line diabetes medication, including dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and sulfonylureas were created. After propensity score matching for various demographic and clinical characteristics, adjusted hazard ratios (aHRs) and 95% CIs were calculated using Cox regression analyses to estimate the risk of new chronic cough or gastroesophageal reflux disease diagnosis. Exposure GLP-1RAs or other second-line diabetes medication. Main Outcomes and Measures Chronic cough. Results Cohorts included 427 555 individuals (mean [SD] age, 55.8 [13.8] years; 251 928 female individuals [58.9%]) with T2D who were prescribed a GLP-1RA and 1 614 495 individuals (mean [SD] age, 63.7 [13.3] years; 712 946 female individuals [44.4%]) with T2D who were prescribed another second-line diabetes medication. After propensity score matching, individuals prescribed a GLP-1RA had significantly increased risk of new chronic cough compared with individuals prescribed any non–GLP-1RA second-line medication (aHR, 1.12; 95% CI, 1.08-1.16), DPP-4 inhibitor (aHR, 1.18; 95% CI, 1.11-1.26), or sulfonylurea (aHR, 1.32; 95% CI, 1.24-1.40) but not compared with SLGT2 inhibitors (aHR, 1.03; 95% CI, 0.98-1.09). After removing patients with a previous diagnosis of gastroesophageal reflux disease from analysis, patients prescribed GLP-1RAs had significantly increased risk of chronic cough compared with those prescribed any non–GLP-1RA (aHR, 1.29; 95% CI, 1.17-1.42), DPP4 inhibitor (aHR, 1.36; 95% CI, 1.17-1.58), SGLT2 inhibitor (aHR, 1.14; 95% CI, 1.02-1.28), or sulfonylurea (aHR, 1.25; 95% CI, 1.09-1.42). Conclusions and Relevance This cohort study suggests an association between GLP-1RA use and chronic cough. Further research is needed to confirm the existence, strength, and mechanisms of this association.

Background Mechanical thrombectomy (MT) is a well-established treatment for acute ischemic stroke (AIS) due to large vessel occlusion (LVO). However, its role in cervical artery dissection-related (CeAD) LVO remains debated due to anatomical complexities and procedural challenges. This systematic review and meta-analysis aims to evaluate the safety, efficacy, and clinical outcomes of MT in patients with AIS due to CeAD-related LVO compared with other AIS etiologies. Methods PubMed, Embase, and Scopus were systematically searched from inception to March 2025. Comparative observational studies evaluating the use of MT in adult patients with AIS due to LVO were included, specifically those comparing outcomes in patients with CeAD versus non-CeAD etiologies. Results MT for CeAD-related AIS showed no statistically significant difference in successful recanalization compared with non-CeAD cases (OR 0.81 (95% CI 0.63 to 1.04), P=0.10). However, patients with CeAD-related AIS had significantly higher rates of 90-day functional independence (modified Rankin Scale score 0–2) (OR 2.17 (95% CI 1.55 to 3.05), P<0.01) and lower 90-day mortality (OR 0.34 (95% CI 0.22 to 0.53), P<0.01). Rates of distal embolization (OR 1.60 (95% CI 0.69 to 3.70), P=0.27), symptomatic intracranial hemorrhage (OR 0.84 (95% CI 0.51 to 1.38), P=0.49), or iatrogenic dissection (OR 1.58 (95% CI 0.59 to 4.22), P=0.36) did not differ significantly between patient groups. Conclusions MT in patients with CeAD-related LVO is safe, effective, and associated with improved functional outcomes and lower mortality compared with patients with non-CeAD acute ischemic causes.

Abstract Description A subset of follicular lymphoma patients has an early relapse with a poor outcome. We showed that this unfavorable group displays increased expression of IRF4, dysregulated immune signaling and an immunosuppressive microenvironment. However, little is known on the molecular mechanisms whereby IRF4 controls the crosstalk between B and T cells. To this aim, we leveraged Cγ1cre;irf4fl/fl mice that yield conditional deletion of irf4 (cKO) in germinal center B cells (GCB). After 10 days of immunization, cKO GCB showed significant increase of HLA-DR and CD40 expression, a skewed LZ:DZ ratio towards increased DZ, and suppression of plasma cells compared to WT. Upon irf4 deletion, we also found a significant increase of total CD4 and TFH cells and a decrease in Treg cells. To test if this effect was antigen-dependent, we cocultured sorted GCB from NP-OVA-immunized cKO and WT mice with CSFE-labeled OVA-specific OT-II CD4 T cells at a ratio of 2:1 for 5 days. We observed increased antigen specific proliferation of CD4 T cells with cKO GCB compared to WT. We then performed seahorse assay and mass spectrometry of the same GCB to define if IRF4-dependent B cell metabolic reprogramming influences immune responses. GCB cKO had lower glycolytic ECAR and increased intracellular glucose and non-essential amino acids than WT cells, suggesting a metabolic shift from glycolysis to the TCA cycle. Thus, IRF4 controls immune and metabolic signaling with functional effects on the B-T cell crosstalk. Funding Sources NCI K08CA279652, LRF Clinical Investigator Award (CDA 1020588), the Gerstner Family Career Development Award, the ASH Junior Faculty Scholar Award. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Background: Qualification of non-invasive tests (NITs) and blood biomarkers for fibrosis severity and risk assessment is an unmet need in clinical care for cirrhosis. The paucity of reproducibility data for imaging and blood biomarkers in cirrhosis hinders their application for longitudinal monitoring. The aim of this study was to evaluate the reproducibility of imaging and blood biomarkers in a prospective cohort of adults with cirrhosis. Methods: We prospectively enrolled adults with cirrhosis in an observational, longitudinal cohort study. Participants completed a research visit with vibration-controlled transient elastography (VCTE) with liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) and blood testing, including AST, ALT, platelets, alpha-fetoprotein (AFP), and the Fibrosis-4 Index (FIB-4). Biomarkers were repeated a median of 3 months apart without any interim intervention. The primary outcome was the reproducibility of each biomarker as assessed by the reproducibility coefficient (RDC%), within-participant coefficient of variation (wCV), intraclass correlation coefficient (ICC), and Bland–Altman analysis. Results: In total, 40 participants (mean age 62, 60% female, mean BMI 28.6 kg/m 2 ) had VCTE/CAP, 38 AST/ALT, and 26 had AFP at both time points. The RDC% for VCTE-LSM was 54.4, wCV 0.19, and ICC 0.91. VCTE CAP had an RDC% of 56, a wCV of 0.30, and ICC 0.47. AFP had an RDC% of 58, a wCV of 0.21, and an ICC of 0.95. RDC% for AST, ALT, and FIB-4 ranged from 70% to 79%. On Bland–Altman analyses, VCTE-LSM demonstrated the lowest relative bias (0.4%). Conclusions: Prospective assessment of repeat biomarkers in adults with cirrhosis found that VCTE-LSM and CAP provide consistent assessments across individuals but may yield substantial within-individual variation. Blood-based biomarkers had poor reproducibility within individuals but were consistent in detecting between-patient variability. These data can inform ultrasound-based non-invasive testing qualification by defining thresholds that may reflect measurement variability rather than true biologic change over time.

Foundation models can streamline imaging workflows, improve diagnostic accuracy, enable personalized treatment, and, via integrated generative artificial intelligence, create synthetic images to augment scarce real-world data; however, successful adoption requires explainability, trust, and workflow integration.