CYP2C19 Genotype-Guided Antiplatelet Therapy and Clinical Outcomes in Patients Undergoing a Neurointerventional Procedure.

In neurovascular settings, including treatment and prevention of ischemic stroke and prevention of thromboembolic complications after percutaneous neurointerventional procedures, dual antiplatelet therapy with a P2Y12 inhibitor and aspirin is the standard of care. Clopidogrel remains the most commonly prescribed P2Y12 inhibitor for neurovascular indications. However, patients carrying CYP2C19 no-function alleles have diminished capacity for inhibition of platelet reactivity due to reduced formation of clopidogrel's active metabolite.

E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.

The carboxyl terminus of Hsc70-interacting protein (CHIP) is pivotal for managing misfolded and aggregated proteins via chaperone networks and degradation pathways. In a preclinical rodent model of CHIP-related ataxia, we observed that CHIP mutations lead to increased levels of phosphodiesterase 9A (PDE9A), whose role in this context remains poorly understood. Here, we investigated the molecular mechanisms underlying the role of PDE9A in CHIP-related ataxia and demonstrated that CHIP binds to PDE9A, facilitating its polyubiquitination and autophagic degradation.

Rural-urban disparity in survival and use of PCI in patients who develop STEMI while hospitalized for a non-cardiac condition.

Background: The development of ST-segment elevation myocardial infarction (STEMI) in patients hospitalized for non-cardiac indications carries a high mortality rate.

Objectives: Determine the impact of rural vs. urban hospital location and hospital percutaneous coronary intervention (PCI) volumes on clinical outcomes.

X-Chromosome-Linked miRNAs Regulate Sex Differences in Cardiac Physiology.

Background: Males and females exhibit distinct anatomic and functional characteristics of the heart, predisposing them to specific disease states.

Methods: We identified microRNA (miRNAs/miR) with sex-differential expression in mouse hearts.

Results: Four conserved miRNAs are present in a single locus on the X-chromosome and are expressed at higher levels in females than males.

Inhibition of nitric oxide synthase transforms carotid occlusion-mediated benign oligemia into large cerebral infarction.

It remains unclear why unilateral proximal carotid artery occlusion (UCAO) causes benign oligemia in mice, yet leads to various outcomes (asymptomatic-to-death) in humans. We hypothesized that inhibition of nitric oxide synthase (NOS) both transforms UCAO-mediated oligemia into full infarction and expands pre-existing infarction. Using 900 mice, we i) investigated stroke-related effects of UCAO with/without intraperitoneal administration of the NOS inhibitor (NOSi) N-nitro-L-arginine methyl ester (L-NAME, 400 mg/kg); ii) examined the rescue effect of the NO-donor, molsidomine (200 mg/kg at 30 minutes); and iii) tested the impact of antiplatelet medications.

Decoding aging in the heart via single cell dual omics of non-cardiomyocytes.

To understand heart aging at the single-cell level, we employed single-cell dual omics (scRNA-seq and scATAC-seq) in profiling non-myocytes (non-CMs) from young, middle-aged, and elderly mice. Non-CMs, vital in heart development, physiology, and pathology, are understudied compared to cardiomyocytes. Our analysis revealed aging response heterogeneity and its dynamics over time.

Direct cardiac reprogramming via combined CRISPRa-mediated endogenous Gata4 activation and exogenous Mef2c and Tbx5 expression.

Direct cardiac reprogramming of fibroblasts into induced cardiomyocytes (iCMs) can be achieved by ectopic expression of cardiac transcription factors (TFs) via viral vectors. However, risks like genomic mutations, viral toxicity, and immune response limited its clinical application. Transactivation of endogenous TFs emerges as an alternative approach that may partially mitigate some of the risks.

Sox17 and Erg synergistically activate endothelial cell fate in reprogramming fibroblasts.

Sox17-Erg direct reprogramming is a potent tool for the in vitro and in vivo generation of arterial-like induced-endothelial cells from fibroblasts. In this study, we illustrate the pioneering roles of both Sox17 and Erg in the endothelial cell reprogramming process and demonstrate that emergent gene expression only occurs when both factors are co-expressed. Bioinformatic analyses and molecular validation reveal both Bach2 and Etv4 as integral mediators of Sox17-Erg reprogramming with different roles in lung and heart fibroblast reprogramming.

Establishing best practices in large language model research: an application to repeat prompting.

Objectives: We aimed to demonstrate the importance of establishing best practices in large language model research, using repeat prompting as an illustrative example.

Materials And Methods: Using data from a prior study investigating potential model bias in peer review of medical abstracts, we compared methods that ignore correlation in model outputs from repeated prompting with a random effects method that accounts for this correlation.

Results: High correlation within groups was found when repeatedly prompting the model, with intraclass correlation coefficient of 0.

Photothrombolytics: A light-driven technology for the targeted lysis of thrombi.

Occlusive blood clots remain a significant global health challenge and result in emergencies that are main causes of death and disability worldwide. Thrombolytic agents (including tissue plasminogen activator, tPA) are the only pharmacological means to dissolve blood clots. However, these drugs have modest efficacy and severe safety concerns persist.

GRAF1 deficiency leads to defective brown adipose tissue differentiation and thermogenic response.

Adipose tissue, which is crucial for the regulation of energy within the body, contains both white and brown adipocytes. White adipose tissue (WAT) primarily stores energy, while brown adipose tissue (BAT) plays a critical role in energy dissipation as heat, offering potential for therapies aimed at enhancing metabolic health. Regulation of the RhoA/ROCK pathway is crucial for appropriate specification, differentiation and maturation of both white and brown adipocytes.

Flagellum Pumping Efficiency in Shear-Thinning Viscoelastic Fluids.

Microorganism motility often takes place within complex, viscoelastic fluid environments, e.g., sperm in cervicovaginal mucus and bacteria in biofilms.

In situ-crosslinked Zippersomes enhance cardiac repair by increasing accumulation and retention.

Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) are a promising treatment for myocardial infarction (MI), but their therapeutic efficacy is limited by inefficient accumulation at the target site. A minimally invasive MSC EV therapy that enhances EV accumulation at the disease site and extends EV retention could significantly improve post-infarct cardiac regeneration. Here, we show that EVs decorated with the next-generation of high-affinity (HiA) heterodimerizing leucine zippers, termed HiA Zippersomes, amplify targetable surface areas through in situ crosslinking and exhibited ~7-fold enhanced accumulation within the infarcted myocardium in mice after 3 days and continued to be retained up to Day 21, surpassing the performance of unmodified EVs.

Recommendations for Clinicians, Technologists, and Healthcare Organizations on the Use of Generative Artificial Intelligence in Medicine: A Position Statement from the Society of General Internal Medicine.

Generative artificial intelligence (generative AI) is a new technology with potentially broad applications across important domains of healthcare, but serious questions remain about how to balance the promise of generative AI against unintended consequences from adoption of these tools. In this position statement, we provide recommendations on behalf of the Society of General Internal Medicine on how clinicians, technologists, and healthcare organizations can approach the use of these tools. We focus on three major domains of medical practice where clinicians and technology experts believe generative AI will have substantial immediate and long-term impacts: clinical decision-making, health systems optimization, and the patient-physician relationship.

P300 Modulates Endothelial Mechanotransduction of Fluid Shear Stress.

Purpose: P300 is a lysine acetyltransferase that plays a significant role in regulating transcription and the nuclear acetylome. While P300 has been shown to be required for the transcription of certain early flow responsive genes, relatively little is known about its role in the endothelial response to hemodynamic fluid stress. Here we sought to define the role of P300 in mechanotransduction of fluid shear stress in the vascular endothelium.

Optimism mitigated impacts of pre-operative depression and anxiety on post-operative distress in cardiac patients.

Both anxiety and depression are comorbid mortality risks in middle-aged and older patients with heart diseases. Open-heart surgery (OHS), a life-altering procedure, can induce psychological distress that impedes postoperative recovery. Extensive research has shown the health benefit of optimism, an indicator of a Character Strength in positive psychology.

Transcatheter Aortic-Valve Replacement for Asymptomatic Severe Aortic Stenosis.

Background: For patients with asymptomatic severe aortic stenosis and preserved left ventricular ejection fraction, current guidelines recommend routine clinical surveillance every 6 to 12 months. Data from randomized trials examining whether early intervention with transcatheter aortic-valve replacement (TAVR) will improve outcomes in these patients are lacking.

Methods: At 75 centers in the United States and Canada, we randomly assigned, in a 1:1 ratio, patients with asymptomatic severe aortic stenosis to undergo early TAVR with transfemoral placement of a balloon-expandable valve or clinical surveillance.

Cardiac Aging in the Multi-Omics Era: High-Throughput Sequencing Insights.

Cardiovascular diseases are a leading cause of mortality worldwide, and the risks of both developing a disease and receiving a poor prognosis increase with age. With increasing life expectancy, understanding the mechanisms underlying heart aging has become critical. Traditional techniques have supported research into finding the physiological changes and hallmarks of cardiovascular aging, including oxidative stress, disabled macroautophagy, loss of proteostasis, and epigenetic alterations, among others.