ECM Modifications Driven by Age and Metabolic Stress Directly Promote the Vascular Smooth Muscle Cell Osteogenic Processes.

Background: The ECM (extracellular matrix) provides the microenvironmental niche sensed by resident vascular smooth muscle cells (VSMCs). Aging and disease are associated with dramatic changes in ECM composition and properties; however, their impact on the VSMC phenotype remains poorly studied.

Methods: Here, we describe a novel in vitro model system that utilizes endogenous ECM to study how modifications associated with age and metabolic disease impact the VSMC phenotype.

Association between triglyceride-glucose (TyG) related indices and cardiovascular diseases and mortality among individuals with metabolic dysfunction-associated steatotic liver disease: a cohort study of UK Biobank.

Background: Triglyceride-glucose (TyG) related indices, which serve as simple markers for insulin resistance, have been closely linked to metabolic dysfunction-associated steatotic liver disease (MASLD), cardiovascular disease (CVD), and mortality. However, the prognostic utility of TyG-related indices in predicting the risk of CVD and mortality among patients with MASLD remains unclear.

Methods: Data of 97,331 MASLD patients, with a median age of 58.

Refining PREVENT prediction models for 10-year risk of cardiovascular disease using measures of anxiety and depression.

Background: Anxiety and depression are associated with cardiovascular disease (CVD). We aimed to investigate whether adding measures of anxiety and depression to the American Heart Association Predicting Risk of Cardiovascular Disease Events (PREVENT) predictors improves the prediction of CVD risk.

Methods: We developed and internally validated risk prediction models using 60% and 40% of the cohort data from the UK Biobank, respectively.

Identifying biomarker-driven subphenotypes of cardiogenic shock: analysis of prospective cohorts and randomized controlled trials.

Background: Cardiogenic shock (CS) is a heterogeneous clinical syndrome, making it challenging to predict patient trajectory and response to treatment. This study aims to identify biological/molecular CS subphenotypes, evaluate their association with outcome, and explore their impact on heterogeneity of treatment effect (ShockCO-OP, NCT06376318).

Methods: We used unsupervised clustering to integrate plasma biomarker data from two prospective cohorts of CS patients: CardShock (N = 205 [2010-2012, NCT01374867]) and the French and European Outcome reGistry in Intensive Care Units (FROG-ICU) (N = 228 [2011-2013, NCT01367093]) to determine the optimal number of classes.

Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma.

Human tumors are diverse in their natural history and response to treatment, which in part results from genetic and transcriptomic heterogeneity. In clinical practice, single-site needle biopsies are used to sample this diversity, but cancer biomarkers may be confounded by spatiogenomic heterogeneity within individual tumors. Here we investigate clonally expressed genes as a solution to the sampling bias problem by analyzing multiregion whole-exome and RNA sequencing data for 450 tumor regions from 184 patients with lung adenocarcinoma in the TRACERx study.

Safety and Efficacy of Remote Ischemic Conditioning in Patients With Intravenous Thrombolysis: The SERIC-IVT Trial.

Background: Approximately half of the patients with acute ischemic stroke who receive intravenous thrombolysis (IVT) do not achieve an excellent outcome. Remote ischemic conditioning (RIC) as a promising neuroprotective treatment may improve clinical outcomes in this population. This study aimed to assess the efficacy and safety of RIC in patients with IVT.

COLOFIT: Development and Internal-External Validation of Models Using Age, Sex, Faecal Immunochemical and Blood Tests to Optimise Diagnosis of Colorectal Cancer in Symptomatic Patients.

Background: Colorectal cancer (CRC) is the third most common cancer in the United Kingdom and the second largest cause of cancer death.

Aim: To develop and validate a model using available information at the time of faecal immunochemical testing (FIT) in primary care to improve selection of symptomatic patients for CRC investigations.

Methods: We included all adults (≥ 18 years) referred to Nottingham University Hospitals NHS Trust between 2018 and 2022 with symptoms of suspected CRC who had a FIT.

Single-cell RNA sequencing identifies CXADR as a fate determinant of the placental exchange surface.

The placenta is the critical interface between mother and fetus, and consequently, placental dysfunction underlies many pregnancy complications. Placental formation requires an adequate expansion of trophoblast stem and progenitor cells followed by finely tuned lineage specification events. Here, using single-cell RNA sequencing of mouse trophoblast stem cells during the earliest phases of differentiation, we identify gatekeepers of the stem cell state, notably Nicol1, and uncover unsuspected trajectories of cell lineage diversification as well as regulators of lineage entry points.

Development of an individualized dementia risk prediction model using deep learning survival analysis incorporating genetic and environmental factors.

Background: Dementia is a major public health challenge in modern society. Early detection of high-risk dementia patients and timely intervention or treatment are of significant clinical importance. Neural network survival analysis represents the most advanced technology for survival analysis to date.

Science of Learning Strategy Series: Article 6, Elaboration.

The science of learning (learning science) is an interprofessional field that concerns itself with how the brain learns and remembers important information. Learning science has compiled a set of evidence-based strategies, such as distributed practice, retrieval practice, and interleaving, which are quite relevant to continuing professional development. Spreading out study and practice separated by cognitive breaks (distributed practice), testing oneself to check mastery and memory of previously learned information (retrieval practice), and mixing the learning of separate but associated information (interleaving) represent strategies that are underutilized in continuing professional development.

Genetic Variants Associated With Preeclampsia and Maternal Serum sFLT1 Levels.

Background: Elevated maternal serum sFLT1 (soluble fms-like tyrosine kinase 1) has a key role in the pathophysiology of preeclampsia. We sought to determine the relationship between the maternal and fetal genome and maternal levels of sFLT1 at 12, 20, 28, and 36 weeks of gestational age (wkGA).

Methods: We studied a prospective cohort of nulliparous women (3968 mother-child pairs).

Methylammonium Lead Iodide across Physical Space: Phase Boundaries and Structural Collapse.

Hybrid perovskites exhibit complex structures and phase behavior under different thermodynamic conditions and chemical environments, the understanding of which continues to be pivotally important for tailoring their properties toward improved operational stability. To this end, we present for the first time a comprehensive neutron and synchrotron diffraction investigation over the pressure-temperature phase diagram of the paradigmatic hybrid organic-inorganic perovskite methylammonium lead iodide (MAPbI). This ambitious experimental campaign down to cryogenic temperatures and tens of kilobars was supported by extensive molecular dynamics simulations validated by the experimental data, to track the structural evolution of MAPbI under external physical stimuli at the atomic and molecular levels.

Dual Antiplatelet Treatment up to 72 Hours After Ischemic Stroke Stratified by Risk Profile: A Post Hoc Analysis.

Background: Risk profile of recurrence may influence the effect of antiplatelet therapy. This study aimed to evaluate the efficacy and safety of clopidogrel-aspirin initiated within 72 hours after symptom onset for acute mild stroke or high-risk transient ischemic attack stratified by risk profile.

Methods: This is a secondary post hoc analysis of the INSPIRES (Intensive Statin and Antiplatelet Therapy for Acute High-risk Intracranial or Extracranial Atherosclerosis) randomized clinical trial that enrolled patients 35 to 80 years old with acute mild ischemic stroke or high-risk transient ischemic attack between 2018 and 2022.

Talin1 dysfunction is genetically linked to systemic capillary leak syndrome.

Systemic capillary leak syndrome (SCLS) is a rare life-threatening disorder due to profound vascular leak. The trigger and the cause of the disease are currently unknown and there is no specific treatment. Here, we identified a rare heterozygous splice-site variant in the TLN1 gene in a familial SCLS case, suggestive of autosomal dominant inheritance with incomplete penetrance.

Clinical and Biomarker Determinants for Recurrent Stroke in Patients With Atrial Fibrillation: A Systematic Review and Meta-Analysis.

Background And Objectives: Despite effective secondary prevention, including oral anticoagulant (OAC) therapy, the risk of recurrent stroke (RS) in patients with atrial fibrillation (AF) remains substantial with an annualized risk of 3.2%-6.5% per year.

Consensus Recommendations for Studies of Outflow Facility and Intraocular Pressure Regulation Using Ex Vivo Perfusion Approaches.

Intraocular pressure (IOP) elevation is the primary risk factor and currently the main treatable factor for progression of glaucomatous optic neuropathy. In addition to direct clinical and living animal in vivo studies, ex vivo perfusion of anterior segments and whole eyes is a key technique for studying conventional outflow function as it is responsible for IOP regulation. We present well-tested experimental details, protocols, considerations, advantages, and limitations of several ex vivo model systems for studying IOP regulation.

Relationship Between Severity of Ischemia and Coronary Artery Disease for Different Stress Test Modalities in the ISCHEMIA Trial.

Background: The relationship between the extent and severity of stress-induced ischemia and the extent and severity of anatomic coronary artery disease (CAD) in patients with obstructive CAD is multifactorial and includes the intensity of stress achieved, type of testing used, presence and extent of prior infarction, collateral blood flow, plaque characteristics, microvascular disease, coronary vasomotor tone, and genetic factors. Among chronic coronary disease participants with site-determined moderate or severe ischemia, we investigated associations between ischemia severity on stress testing and the extent of CAD on coronary computed tomography angiography.

Methods: Clinically indicated stress testing included nuclear imaging, echocardiography, cardiac magnetic resonance imaging, or nonimaging exercise tolerance test.

Current State and New Horizons in Applications of Physiologically Based Biopharmaceutics Modeling (PBBM): A Workshop Report.

This report summarizes the proceedings for Day 3 of the workshop titled "". This day focused on the current and future drug product quality applications of PBBM from the innovator and generic industries as well as the regulatory agencies perspectives. The presentations, which included several case studies, covered the applications of PBBM in generic drug product development, applications of virtual bioequivalence trials to support formulation bridging and the utility of absorption modeling in clinical pharmacology assessments.

Development, validation, and prognostic evaluation of LiverPRO for the prediction of significant liver fibrosis in primary care: a prospective cohort study.

Background: Clinically significant liver fibrosis is associated with future adverse events in patients with steatotic liver disease. We designed a software tool for detection of clinically significant liver fibrosis in primary care.

Methods: In this prospective cohort study, we developed and validated LiverPRO using six independent cohorts from Denmark, Germany, and England that included patients from primary and secondary care with steatotic liver disease related to alcohol or metabolic dysfunction.

Exploring Sex Differences in Outcomes of Dual Antiplatelet Therapy for Patients With Noncardioembolic Mild-to-Moderate Ischemic Stroke or High-Risk Transient Ischemic Attack: A Propensity-Matched Analysis of the READAPT Study Cohort.

Background: Sex may impact clinical outcomes in patients with stroke treated with dual antiplatelet therapy (DAPT). We aimed to investigate the sex differences in the short-term outcomes of DAPT within a real-world population of patients with noncardioembolic mild-to-moderate ischemic stroke or high-risk transient ischemic attack.

Methods: We performed a propensity score-matched analysis from a prospective multicentric cohort study (READAPT [Real-Life Study on Short-Term Dual Antiplatelet Treatment in Patients With Ischemic Stroke or Transient Ischemic Attack]) by including patients with noncardioembolic mild-to-moderate stroke (National Institutes of Health Stroke Scale score of 0-10) or high-risk transient ischemic attack (age, blood pressure, clinical features, duration of transient ischemic attack, presence of diabetes [ABCD] ≥4) who initiated DAPT within 48 hours of symptom onset.

Excess weight by degree and duration and cancer risk (ABACus2 consortium): a cohort study and individual participant data meta-analysis.

Background: Elevated body mass index (BMI) ≥25 kg/m is a major preventable cause of cancer. A single BMI measure does not capture the degree and duration of exposure to excess BMI. We investigate associations between adulthood overweight-years, incorporating exposure time to BMI ≥25 kg/m and cancer incidence, and compare this with single BMI.

Twice-Yearly Lenacapavir for HIV Prevention in Men and Gender-Diverse Persons.

Background: Twice-yearly subcutaneous lenacapavir has been shown to be efficacious for prevention of HIV infection in cisgender women. The efficacy of lenacapavir for preexposure prophylaxis (PrEP) in cisgender men, transgender women, transgender men, and gender-nonbinary persons is unclear.

Methods: In this phase 3, double-blind, randomized, active-controlled trial, we randomly assigned participants in a 2:1 ratio to receive subcutaneous lenacapavir every 26 weeks or daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF).

In Vivo Activity Profiling of Biosynthetic Darobactin D22 against Critical Gram-Negative Pathogens.

In recent years, naturally occurring darobactins have emerged as a promising compound class to combat infections caused by critical Gram-negative pathogens. In this study, we describe the in vivo evaluation of derivative D22, a non-natural biosynthetic darobactin analogue with significantly improved antibacterial activity. We found D22 to be active in vivo against key critical Gram-negative human pathogens, as demonstrated in murine models of thigh infection, peritonitis/sepsis, and urinary tract infection (UTI).

Spleen tyrosine kinase: a novel pharmacological target for sepsis-induced cardiac dysfunction and multi-organ failure.

Sepsis is a systemic condition caused by a dysregulated host response to infection and often associated with excessive release of proinflammatory cytokines resulting in multi-organ failure (MOF), including cardiac dysfunction. Despite a number of effective supportive treatments (e.g.