Dynamic Importance of Genomic and Clinical Risk for Coronary Artery Disease Over the Life Course.

Background: Earlier identification of high coronary artery disease (CAD) risk individuals may enable more effective prevention strategies. However, existing 10-year risk frameworks are ineffective at earlier identification. We sought to understand how the variable importance of genomic and clinical factors across life stages may significantly improve lifelong CAD event prediction.

Biogeographic Insights Into the Late Miocene Diversification of the Giant Deep-Ocean Amphipod .

Mechanisms driving the spatial and temporal patterns of species distribution in the Earth's largest habitat, the deep ocean, remain largely enigmatic. The late Miocene to the Pliocene (~23-2.58 Ma) is a period that was marked by significant geological, climatic, and oceanographic changes.

Effects of vitamin D supplementation on cardiac biomarkers: Results from the STURDY trial.

Objectives: In observational studies, older adults with low serum vitamin D levels are at higher risk of cardiovascular disease (CVD), but randomized trials have failed to demonstrate reduction in CVD risk from vitamin D supplementation, possibly because the doses of vitamin D supplements tested were too low. Our objective was to determine if higher doses of vitamin D supplementation reduce high-sensitivity cardiac troponin (hs-cTnI) and N-terminal pro-b-type natriuretic peptide (NT-proBNP), markers of subclinical CVD.

Methods: The Study to Understand Fall Reduction and Vitamin D in You (STURDY) was a double-blind, randomized, response-adaptive trial that tested the effects of 4 doses of vitamin D3 supplementation (200, 1000, 2000, 4000 IU/day) on fall risk among older adults with low serum 25-hydroxyvitamin D concentrations (10-29 ng/mL).

Coronavirus Disease 2019 (COVID-19) Real World Data Infrastructure: A Big-Data Resource for Study of the Impact of COVID-19 in Patient Populations With Immunocompromising Conditions.

Background: We developed a United States-based real-world data resource to better understand the continued impact of the coronavirus disease 2019 (COVID-19) pandemic on immunocompromised patients, who are typically underrepresented in prospective studies and clinical trials.

Methods: The COVID-19 Real World Data infrastructure (CRWDi) was created by linking and harmonizing de-identified HealthVerity medical and pharmacy claims data from 1 December 2018 to 31 December 2023, with severe acute respiratory syndrome coronavirus 2 virologic and serologic laboratory data from major commercial laboratories and Northwell Health; COVID-19 vaccination data; and, for patients with cancer, 2010 to 2021 National Cancer Institute Surveillance, Epidemiology, and End Results registry data.

Results: The CRWDi contains 4 cohorts: patients with cancer; patients with rheumatic diseases receiving pharmacotherapy; noncancer solid organ and hematopoietic stem cell transplant recipients; and people from the general population including adults and pediatric patients.

Prime Editing by Lipid Nanoparticle Co-delivery of Chemically Modified pegRNA and Prime Editor mRNA.

Prime editing has gained significant attention as a next-generation gene editing technology, owing to its unique advantages. However, realizing its potential requires effective delivery strategies. While adeno-associated virus (AAV) has been employed for delivery of prime editors in research settings, it presents inherent limitations related to vector size, ongoing expression, and inability to re-dose patients.

Synthetic data in generalizable, learning-based neuroimaging.

Synthetic data have emerged as an attractive option for developing machine-learning methods in human neuroimaging, particularly in magnetic resonance imaging (MRI)-a modality where image contrast depends enormously on acquisition hardware and parameters. This retrospective paper reviews a family of recently proposed methods, based on synthetic data, for generalizable machine learning in brain MRI analysis. Central to this framework is the concept of domain randomization, which involves training neural networks on a vastly diverse array of synthetically generated images with random contrast properties.

Population Pharmacokinetics of Pegcetacoplan in Patients with Geographic Atrophy or Neovascular Age-related Macular Degeneration.

Objective: To develop a population pharmacokinetic (PK) model to characterize serum pegcetacoplan concentration-time data after intravitreal administration in patients with geographic atrophy (GA) or neovascular age-related macular degeneration (nAMD).

Design: Pharmacokinetic modeling.

Participants: Two hundred sixty-one patients with GA or nAMD enrolled in 4 clinical studies of pegcetacoplan.

Machine learning for antimicrobial peptide identification and design.

Artificial intelligence (AI) and machine learning (ML) models are being deployed in many domains of society and have recently reached the field of drug discovery. Given the increasing prevalence of antimicrobial resistance, as well as the challenges intrinsic to antibiotic development, there is an urgent need to accelerate the design of new antimicrobial therapies. Antimicrobial peptides (AMPs) are therapeutic agents for treating bacterial infections, but their translation into the clinic has been slow owing to toxicity, poor stability, limited cellular penetration and high cost, among other issues.

Integrated SegFlow, µSIA, and UPLC for Online Sialic Acid Quantitation of Glycoproteins Directly from Bioreactors.

This study emphasizes the critical importance of closely monitoring and controlling the sialic acid content in therapeutic glycoproteins, including EPO, interferon-γ, Orencia, Enbrel, and others, as the level of sialylation directly impacts their pharmacokinetics (PK), immunogenicity, potency, and overall clinical performance due to its influence on protein clearance via hepatic asialoglycoprotein receptors (ASGPR). The ASGPR recognizes and binds to glycoproteins exposed to terminal galactose or N-acetylgalactosamine residues, leading to receptor-mediated endocytosis. Recent studies have demonstrated that sialylation of O-linked glycan plays a role in protecting against macrophage galactose lectin (MGL)-mediated clearance.

Impaired Visuospatial Processing in Cerebral Visual Impairment Revealed by Performance on a Conjunction Visual Search Task.

Cerebral visual impairment (CVI) is a brain-based visual disorder associated with injury and/or maldevelopment of central visual pathways. Visuospatial processing impairments are a cardinal feature of the complex clinical profile of individuals with CVI. Here, we assessed visuospatial processing abilities using a classic conjunction search task.

Incremental Cost-Effectiveness Ratios (ICERs) and Revised Metformin Cost-Effectiveness Conclusions in the Diabetes Prevention Program/ Diabetes Prevention Program Outcomes Study.

Based on previously published US Diabetes Prevention Program (DPP) cost-effectiveness analyses (CEAs), metformin continues to be promoted as "cost-effective." We reviewed a 10-year CEA to assess this. Treatment alternatives included placebo, branded metformin and individual lifestyle modification.

Age- and sex-specific care cascades to detect gaps in the care of children with tuberculosis in Bangladesh: a cohort study.

Background: Programmatic interventions to increase the detection of children with tuberculosis (TB) are rarely evaluated to understand age- and sex-specific completion rates. We applied modified TB screening and treatment cascade frameworks to assess indicators of effective implementation by age and sex of a TB screening program for children (zero to 14 years) in Bangladesh.

Methods: We implemented an intensified screening program for paediatric TB detection in 119 health care facilities (2018-21).

Reinforcement Learning is Impaired in the Sub-acute Post-stroke Period.

Background: In humans, most spontaneous recovery from motor impairment after stroke occurs in the first 3 months. Studies in animal models show higher responsiveness to training over a similar time-period. Both phenomena are often attributed to a milieu of heightened plasticity, which may share some mechanistic overlap with plasticity associated with normal motor learning.

Evaluating the impact of ESICM 2023 guidelines and the new global definition of ARDS on clinical outcomes: insights from MIMIC-IV cohort data.

Background: In 2023, the European Society of Intensive Care Medicine (ESICM) recommended updated criteria for acute respiratory distress syndrome (ARDS). In 2024, Matthay et al. updated the global ARDS definition in AJRCCM, titled "A New Global Definition of Acute Respiratory Distress Syndrome.

Social-structural barriers to primary care among sex workers: findings from a community-based cohort in Vancouver, Canada (2014-2021).

Background: Due to social-structural marginalization, sex workers experience health inequities including a high prevalence of sexually transmitted and blood-borne infections, mental health disorders, trauma, and substance use, alongside a multitude of barriers to HIV and substance use services. Given limited evidence on sex workers' broader primary healthcare access, we aimed to examine social-structural factors associated with primary care use among sex workers over 7 years.

Methods: Data were derived from An Evaluation of Sex Workers Health Access (AESHA), a community-based open prospective cohort of women (cis and trans) sex workers in Metro Vancouver, from 2014 to 2021.

Effects of movement behaviors on preschoolers' cognition: a systematic review of randomized controlled trials.

Background: Movement behaviors, including physical activity (PA), sedentary behavior (SB), and sleep, are fundamental to early childhood development. These behaviors interact dynamically within a 24-hour period, creating a complex balance that influences not only physical health but also cognitive and emotional well-being in young children. While the physical health benefits of movement behaviors are well-documented, systematic evaluations of how interventions targeting these behaviors affect cognitive development in preschool-aged children remain limited.

Developing a comprehensive inventory to define harm reduction housing.

Background: The City of Boston has faced unprecedented challenges with substance use amidst changes to the illicit drug supply and increased visibility of homelessness. Among its responses, Boston developed six low threshold harm reduction housing (HRH) sites geared towards supporting the housing needs of people who use drugs (PWUD) and addressing health and safety concerns around geographically concentrated tent encampments. HRH sites are transitional supportive housing that adhere to a "housing first" approach where abstinence is not required and harm reduction services and supports are co-located.

Multi-ancestry genome-wide association analyses: a comparison of meta- and mega-analyses in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study.

Background: There is increasing need for effective incorporation of high-dimensional genetics data from individuals with varied ancestry in genome-wide association (GWAS) analyses. Classically, multi-ancestry GWAS analyses are performed using statistical meta-analysis to combine results conducted within homogeneous ancestry groups. The emergence of cosmopolitan reference panels makes collective preprocessing of GWAS data possible, but impact on downstream GWAS results in a mega-analysis framework merits investigation.

Using Classifiers To Predict Catalyst Design for Polyketone Microstructure.

We applied a classifier method to predict palladium catalysts for the formation of nonalternating polyketones via the copolymerization of CO and ethylene; current examples are limited to using phosphine sulfonate and diphosphazane monoxide supporting ligands. With the reported workflow, we discovered two new classes of palladium complexes capable of achieving the synthesis of nonalternating polyketones with a lower CO content than those made by known palladium catalysts. Our results show that we doubled the number of classes of palladium compounds that can catalyze the formation of this type of polymer.

Screening and Referral for Social Needs Among Veterans: A Randomized Controlled Trial.

Background: Healthcare-based social need screening and referral (S&R) among adult populations has produced equivocal results regarding social need resource connection.

Objective: Assess the efficacy of S&R on resource connection (primary outcome) and unmet need reduction (secondary outcome).

Design: Intention-to-treat randomized controlled trial.

Rapid human oogonia-like cell specification via transcription factor-directed differentiation.

The generation of germline cells from human induced pluripotent stem cells (hiPSCs) represents a milestone toward in vitro gametogenesis. Methods to recapitulate germline development beyond primordial germ cells in vitro have relied on long-term cell culture, such as 3-dimensional organoid co-culture for ~four months. Using a pipeline with highly parallelized screening, this study identifies combinations of TFs that directly and rapidly convert hiPSCs to induced oogonia-like cells (iOLCs).

Prenatal Diagnosis of Congenital Heart Disease in Liveborn Infants in the New England Region.

Prenatal diagnosis of congenital heart disease requiring early cardiac catheterization or surgical intervention enables optimal delivery planning for appropriate postnatal cardiovascular intervention and care. This allows for improved morbidity and mortality. Prior national data reported prenatal diagnosis rates of 32% for congenital heart disease requiring intervention in infants in the first 6 months of life in the New England region.

Associations of inferior frontal sulcal hyperintensities on brain MRI with cerebral small vessel disease, cognitive function, and depression symptoms.

Inferior frontal sulcal hyperintensities (IFSH) observed on fluid-attenuated inversion recovery (FLAIR) MRI have been proposed as indicators of elevated cerebrospinal fluid waste accumulation in cerebral small vessel disease (CSVD). However, to validate IFSH as a reliable imaging biomarker, further replication studies are required. The objective of this study was to investigate associations between IFSH and CSVD, and their potential repercussions, i.