Prognostic Value of Coronary CT Angiography-Derived Quantitative Flow Ratio in Suspected Coronary Artery Disease.

Background The prognostic value of coronary CT angiography (CTA)-derived quantitative flow ratio (CT-QFR) remains unknown. Purpose To determine the prognostic value of CT-QFR in predicting the long-term outcomes of patients with suspected coronary artery disease (CAD) in comparison with invasive coronary angiography (ICA)/SPECT and to determine the influence of prior percutaneous coronary intervention (PCI) on the prognostic value of CT-QFR. Materials and Methods In this secondary analysis of the prospective international CORE320 study, 379 participants who underwent coronary CTA and SPECT within 60 days before ICA between November 2009 and July 2011 were included for follow-up.

Sex differences and determinants of coronary microvascular function in asymptomatic adults with type 2 diabetes.

Background: Coronary microvascular dysfunction (CMD) is a significant complication in type 2 diabetes (T2D) and may be more common in women. We aimed to evaluate the sex differences and sex-specific clinical determinants of CMD in adults with T2D without prevalent cardiovascular disease.

Methods: Single center pooled analysis of four prospective studies comparing asymptomatic people with T2D and controls.

Reactivation of mTOR signaling slows neurodegeneration in a lysosomal sphingolipid storage disease.

Sandhoff disease, a lysosomal storage disorder, is caused by pathogenic variants in the HEXB gene, resulting in the loss of β-hexosaminidase activity and accumulation of sphingolipids including GM2 ganglioside. This accumulation occurs primarily in neurons, and leads to progressive neurodegeneration through a largely unknown process. Lysosomal storage diseases often exhibit dysfunctional mTOR signaling, a pathway crucial for proper neuronal development and function.

Safety and efficacy of mitapivat in sickle cell disease (RISE UP): results from the phase 2 portion of a global, double-blind, randomised, placebo-controlled trial.

Background: Sickle cell disease, a debilitating, inherited haemolytic anaemia with premature morbidity and mortality, affects millions globally. Mitapivat, a first-in-class, oral, allosteric activator of pyruvate kinase, improves red blood cell survival by increasing ATP and diminishes sickling by decreasing 2,3-diphosphoglycerate. We aimed to evaluate the efficacy and safety of mitapivat in patients with sickle cell disease.

BCL11A +58/+55 enhancer-editing facilitates HSPC engraftment and HbF induction in rhesus macaques conditioned with a CD45 antibody-drug conjugate.

Editing the +58 region of the BCL11A erythroid enhancer has shown promise in treating β-globin disorders. To address variations in fetal hemoglobin (HbF) response, we investigated editing both +58 and +55 enhancers. Rhesus macaques transplanted with edited hematopoietic stem/progenitor cells (HSPCs) following busulfan conditioning exhibited durable, high-level (∼90%) editing frequencies post transplantation with sustained HbF reactivation over 4 years, without hematological perturbations.

Sickle Trait and Alpha Thalassemia Increase NOS-Dependent Vasodilation of Human Arteries Through Disruption of Endothelial Hemoglobin-eNOS Interactions.

Background: Severe malaria is associated with impaired nitric oxide (NO) synthase (NOS)-dependent vasodilation, and reversal of this deficit improves survival in murine models. Malaria might have selected for genetic polymorphisms that increase endothelial NO signaling and now contribute to heterogeneity in vascular function among humans. One protein potentially selected for is alpha globin, which, in mouse models, interacts with endothelial NOS (eNOS) to negatively regulate NO signaling.

Predictors of plasma HDL-C concentrations in the Coronary Artery Risk Development in Young Adults (CARDIA) study.

HDL-C is an established risk marker for coronary heart disease. We investigated sociodemographic, lifestyle, anthropometric/physiologic, and other predictors of HDL-C over 30 years of follow-up in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a multicenter, longitudinal cohort with a baseline exam in 1985-86 and follow-up exams at least every five years through 2016. During exams, participants completed various questionnaires, anthropometric measurements, and blood collection.

Proteomics in Acute Heart Transplant Rejection, On Behalf of the GRAfT Investigators.

Background: Proteomic phenotyping can provide insights into rejection pathophysiology, novel biomarkers, and therapeutic targets.

Methods: Within the prospective, multicenter Genomic Research Alliance for Transplantation study, 181 proteins were evaluated from blood drawn at the time of endomyocardial biopsy; protein fold change, logistic regression, and pathway analyses were conducted, with protein discovery adjusted for a 5% false discovery rate.

Results: Among 104 adult heart transplant patients (31% female sex, 53% Black race, median age 52 y), 74 had no rejection, 18 developed acute cellular rejection (ACR), and 12 developed antibody-mediated rejection (AMR).

Multicamera simultaneous total internal reflection and interference reflection microscopy.

Interference Reflection Microscopy (IRM) is an optical technique that relies on the interference between the reflected light from an incident beam as it passes through materials of different refractive indices. This technique has been successfully used to image microtubules, biologically important biofilaments with a diameter of 25 nm. However, it is often desirable to image both the microtubule and microtubule interacting proteins simultaneously.

Fostamatinib for Hospitalized Adults With COVID-19 and Hypoxemia: A Randomized Clinical Trial.

Importance: Fostamatinib, a spleen tyrosine kinase inhibitor, has been reported to improve outcomes of COVID-19.

Objective: To evaluate the efficacy and safety of fostamatinib in adults hospitalized with COVID-19 and hypoxemia.

Design, Setting, And Participants: This multicenter, phase 3, placebo-controlled, double-blinded randomized clinical trial was conducted at 41 US sites and 21 international sites between November 17, 2021, and September 27, 2023; the last follow-up visit was December 31, 2023.

DNA Methylation Signatures of Cardiovascular Health Provide Insights into Diseases.

Background: The association of overall cardiovascular health (CVH) with changes in DNA methylation (DNAm) has not been well characterized.

Methods: We calculated the American Heart Association's Life's Essential 8 (LE8) score to reflect CVH in five cohorts with diverse ancestry backgrounds. Epigenome-wide association studies (EWAS) for LE8 score were conducted, followed by bioinformatic analyses.

Targeting GOF p53 and c-MYC through LZK Inhibition or Degradation Suppresses Head and Neck Tumor Growth.

The worldwide frequency of head and neck squamous cell carcinoma (HNSCC) is approximately 800,000 new cases, with 430,000 deaths annually. We determined that LZK (encoded by ) is a therapeutic target in HNSCC and showed that inhibition with small molecule inhibitors decreases the viability of HNSCC cells with amplified . A drug-resistant mutant of LZK blocks decreases in cell viability due to LZK inhibition, indicating on-target activity by two separate small molecules.

Role of STING Deficiency in Amelioration of Mouse Models of Lupus and Atherosclerosis.

Objective: Systemic lupus erythematosus (SLE) is a systemic autoimmune syndrome characterized by autoreactive responses to nucleic acids, dysregulation of the type I interferon (IFN-I) pathway, and accelerated atherosclerosis. The stimulator of IFN genes (STING), a cytosolic DNA sensor, has pathogenic implications in various inflammatory diseases. However, its specific role in SLE pathogenesis, particularly in tissue damage, remains unclear.

Phenotypic findings associated with variation in elastin.

Variation in the elastin gene (ELN) may contribute to connective tissue disease beyond the known disease associations of supravalvar aortic stenosis and cutis laxa. Exome data from MyCode Community Health Initiative participants were analyzed for ELN rare variants (mean allele frequency <1%, not currently annotated as benign). Participants with variants of interest underwent phenotyping by dual chart review using a standardized abstraction tool.

Overexpression of enhanced yellow fluorescent protein fused with Channelrhodopsin-2 causes contractile dysfunction in skeletal muscle.

Skeletal muscle activation using optogenetics has emerged as a promising technique for inducing noninvasive muscle contraction and assessing muscle function both in vivo and in vitro. Transgenic mice overexpressing the optogenetic fusion protein, Channelrhodopsin 2-EYFP (ChR2-EYFP) in skeletal muscle are widely used; however, overexpression of fluorescent proteins can negatively impact the functionality of activable tissues. In this study, we characterized the contractile properties of ChR2-EYFP skeletal muscle and introduced the ChR2-only mouse model that expresses light-responsive ChR2 without the fluorescent EYFP in their skeletal muscles.