Bleeding disorder of unknown cause: an illustrated review on current practice, knowledge gaps, and future perspectives.

In more than half of the individuals with a clinically relevant bleeding tendency who are referred to hemostasis experts, no biological etiology can be found after extensive laboratory testing. These persons are diagnosed with an unexplained bleeding tendency or "bleeding disorder of unknown cause" (BDUC). The mucocutaneous bleeding phenotype of individuals with BDUC is generally comparable to that of individuals with inherited bleeding disorders such as von Willebrand disease or platelet function disorders.

Investigating How Lysophosphatidylcholine and Lysophosphatidylethanolamine Enhance the Membrane Permeabilization Efficacy of Host Defense Peptide Piscidin 1.

Lysophospholipids (LPLs) and host defense peptides (HDPs) are naturally occurring membrane-active agents that disrupt key membrane properties, including the hydrocarbon thickness, intrinsic curvature, and molecular packing. Although the membrane activity of these agents has been widely examined separately, their combined effects are largely unexplored. Here, we use experimental and computational tools to investigate how lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE), an LPL of lower positive spontaneous curvature, influence the membrane activity of piscidin 1 (P1), an α-helical HDP from fish.

Comparative Kidney Uptake of Nanobody-Based PET Tracers Labeled with Various Fluorine-18-Labeled Prosthetic Groups.

Nanobodies, or single-domain antibody fragments, are promising candidates for molecular imaging due to their small size, rapid tissue penetration, and high target specificity. However, a significant challenge in their use is high renal uptake and retention, which can limit the therapeutic efficacy and complicate image interpretation. This study compares five different fluorine-18-labeled prosthetic groups for nanobodies, aiming to optimize pharmacokinetics and minimize kidney retention while maintaining tumor targeting.

Unveiling Tissue-Specific RNA Landscapes in Mouse Organs During Fasting and Feeding Using Nanopore Direct RNA Sequencing.

Understanding tissue-specific RNA landscapes is essential for uncovering the functional mechanisms of key organs in mammals. However, current knowledge remains limited, as short-read RNA sequencing-the predominant method for assessing gene expression-depends on incomplete gene annotations and struggles to resolve the diverse transcripts produced by genes. To address these limitations, an integrative approach combining nanopore direct RNA sequencing (DRS), ATAC-Seq, and short-read RNA-seq is used.

Exploring CRISPR-Cas9 HNH-Domain-Catalyzed DNA Cleavage Using Accelerated Quantum Mechanical Molecular Mechanical Free Energy Simulation.

The target DNA (tDNA) cleavage catalyzed by the CRISPR Cas9 enzyme is a critical step in the Cas9-based genome editing technologies. Previously, the tDNA cleavage from an active SpyCas9 enzyme conformation was modeled by Palermo and co-workers (Nierzwicki et al., , 912) using ab initio quantum mechanical molecular mechanical (ai-QM/MM) free energy simulations, where the free energy barrier was found to be more favorable than that from a pseudoactive enzyme conformation.

Extended Quality (eQual): Radial threshold clustering based on n-ary similarity.

We are transforming Radial Threshold Clustering (RTC), an algorithm, into Extended Quality Clustering, an algorithm with several novel features. Daura et al's RTC algorithm is a partitioning clustering algorithm that groups similar frames together based on their similarity to the seed configuration. Two current issues with RTC is that it scales as making it inefficient at high frame counts, and the clustering results are dependent on the order of the input frames.

Genomic Landscape of Thrombosis Recurrence Risk Across Venous Thromboembolism Subtypes.

Venous thromboembolism (VT) is a frequent (annual incidence of 1 to 2 per 1,000) and potentially life-threatening (case-fatality rate up to 10%) disease. VT is associated with serious short-term and long-term complications including a recurrence rate of approximately 20% within five years. Anticoagulant therapy, the mainstay of VT treatment, drastically reduces the risk of early VT recurrence, but it exposes patients to a substantial risk of bleeding.

Empagliflozin to prevent worsening of left ventricular volumes and systolic function after myocardial infarction (EMPRESS-MI).

Aims: Patients with a reduced left ventricular ejection fraction (LVEF) following an acute myocardial infarction (MI) are considered to be at risk of progressive adverse cardiac remodelling which can lead to the development of heart failure and death. The early addition of a sodium-glucose cotransporter 2 (SGLT2) inhibitor to standard treatment may delay or prevent progressive adverse remodelling in these patients.

Methods And Results: We performed a randomized, double-blind, placebo-controlled, multicentre trial using cardiovascular magnetic resonance imaging (MRI), in patients with left ventricular systolic dysfunction following MI.

Oxidation of CaMKIIα cysteines inhibits autonomous activation induced by phosphorylation.

Ca/calmodulin-dependent protein kinase II α (CaMKIIα) "autonomous" activation induced by Thr286 phosphorylation has a crucial role in synaptic plasticity. Previous studies showed that in Alzheimer's disease brain, CaMKIIα autophosphorylation at Thr286 is reduced while the level of cysteine-oxidized CAMKIIα is elevated. We performed tryptic mapping of the oxidized CaMKIIα and discovered the formation of a disulfide between the N-terminal Cys6 and the regulatory domain Cys280.

Epidemiology and Outcomes of Antibiotic De-escalation in Patients with Suspected Sepsis in US Hospitals.

Background: Little is known about the frequency, hospital-level variation, predictors, and clinical outcomes of antibiotic de-escalation in suspected sepsis.

Methods: We retrospectively analyzed all adults admitted to 236 US hospitals between 2017-2021 with suspected sepsis (defined by a blood culture draw, lactate measurement, and intravenous antibiotic administration) who were initially treated with ≥2 days of anti-MRSA and anti-pseudomonal antibiotics but had no resistant organisms requiring these agents identified through hospital day 4. De-escalation was defined as stopping anti-MRSA and anti-pseudomonal antibiotics or switching to narrower antibiotics by day 4.

Awareness of heart failure, blood pressure management and self-efficacy: The Research Goes Red for Women Registry.

Background: Heart failure (HF) is increasing in the United States, and awareness is needed for prevention. Hypertension is the leading cause of HF, and adherence to antihypertensive medication is critical for reducing HF risk. Self-efficacy positively influences health-promoting behaviors.

Effectiveness of electronic medical record-based strategies for death and hospital admission endpoint capture in pragmatic clinical trials.

Objective: Event capture in clinical trials is resource-intensive, and electronic medical records (EMRs) offer a potential solution. This study develops algorithms for EMR-based death and hospitalization capture and compares them with traditional event capture methods.

Materials And Methods: We compared the effectiveness of EMR-based event capture and site-captured events adjudicated by a clinical endpoint committee in the multi-center INfluenza Vaccine to Effectively Stop cardio Thoracic Events and Decompensated heart failure (INVESTED) trial for participants from the Veterans Affairs healthcare system.

Identification of Amino Acid Residues Critical for the Interaction of Fibrin with N-Cadherin.

We recently identified N-cadherin as a novel receptor for fibrin and localized complementary binding sites within the fibrin βN-domains and the third and fifth extracellular domains (EC3 and EC5) of N-cadherin. We also hypothesized that the His16 and Arg17 residues of the βN-domains and the (Asp/Glu)-X-(Asp/Glu) motifs present in the EC3 and EC5 domains may play roles in the interaction between fibrin and N-cadherin. The primary objectives of this study were to test these hypotheses and to further clarify the structural basis for this interaction.

Structure of apolipoprotein B100 bound to the low-density lipoprotein receptor.

Apolipoprotein B100 (apoB100) is a structural component of low-density lipoprotein (LDL) and a ligand for the LDL receptor (LDLR). Mutations in apoB100 or in LDLR cause familial hypercholesterolaemia, an autosomal dominant disease that is characterized by a marked increase in LDL cholesterol (LDL-C) and a higher risk of cardiovascular disease. The structure of apoB100 on LDL and its interaction with LDLR are poorly understood.

Associations of plasma extracellular microRNAs with new-onset breast cancer in the Framingham heart study.

Breast cancer is the second leading cause of cancer deaths among women. Multiple microRNAs (miRNAs) have been reported to be associated with breast cancer progression or metastasis. The purpose of the current study was to identify plasma extracellular miRNAs associated with incident breast cancer.

Relationships Between Markers of Iron Status and Hematological Parameters in Patients With Sickle Cell Disease.

Based on the relationship between the intracellular concentration of sickle hemoglobin S (HbS) and the delay that occurs prior to the onset of sickling following deoxygenation, targeting the intracellular HbS concentration is a recognized therapeutic approach for sickle cell disease (SCD). We and others have shown that restricting iron by dietary or pharmacologic means improves hematologic parameters, inflammation, and organ damage in mouse models of SCD. Clinical evidence corroborating these findings is confined to case reports and small case series studies, none of which account for treatment or -thalassemia.

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.

Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma.

Background: Daratumumab, an anti-CD38 monoclonal antibody, has been approved for the treatment of multiple myeloma. Data are needed regarding the use of daratumumab for high-risk smoldering multiple myeloma, a precursor disease of active multiple myeloma for which no treatments have been approved.

Methods: In this phase 3 trial, we randomly assigned patients with high-risk smoldering multiple myeloma to receive either subcutaneous daratumumab monotherapy or active monitoring.

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.