Composite endpoints in health technology assessment: Part 1 - an illustration of best modeling practice.

Composite endpoints amalgamate multiple clinical outcomes into a single measure, offering efficiency gains in clinical trials through increased event rates and reduced sample sizes, thus accelerating clinical development and regulatory approval. However, employing composite endpoints introduces complexities into health technology assessments (HTAs), particularly in economic modeling, due to the varying clinical significance and cost implications of the components. In this paper, we explore best modeling practice for HTAs that are based on clinical trials that employ composite endpoints.

Epidemiology, pathophysiology, diagnosis and management of atrial functional mitral regurgitation: An expert opinion paper.

Atrial functional mitral regurgitation (AFMR) is an increasingly recognized subtype of mitral regurgitation, characterized by left atrial remodelling and mitral annular dilation in the absence of primary mitral valve disease or left ventricular dysfunction. Closely linked to chronic atrial fibrillation and heart failure with preserved ejection fraction, AFMR is associated with poor clinical outcomes and represents a growing therapeutic challenge. This expert opinion paper summarizes current evidence on the epidemiology, pathophysiology, diagnosis and management strategies, including medical therapy and emerging data supporting surgical and transcatheter interventions in selected patients.

Genome sequencing reveals the impact of pseudoexons in rare genetic disease.

Purpose: Advancements in sequencing technologies have significantly improved clinical genetic testing, yet the diagnostic yield remains around 30-40%. Emerging technologies are now being deployed to address the remaining diagnostic gap.

Methods: We tested whether short-read genome sequencing could increase the diagnostic yield in individuals enrolled into the UCI-GREGoR research study, who had suspected Mendelian conditions and prior inconclusive testing.

Systematic analyses uncover plasma proteins linked to incident cardiovascular diseases.

Cardiovascular disease (CVD) research is hindered by limited comprehensive analyses of plasma proteome across disease subtypes. Here, we systematically investigated the associations between plasma proteins and cardiovascular outcomes in 53,026 UK Biobank participants over a 14-year follow-up. Association analyses identified 3,089 significant associations involving 892 unique protein analytes across 13 CVD outcomes.

Modeling Musculoskeletal Combat Casualty Care: NATO Trauma System Performance in Large Scale Combat Operations.

Background: It is unclear whether the current North Atlantic Treaty Organization (NATO) trauma system will be effective in the setting of Large-Scale Combat Operations (LSCO). We sought to model the efficacy of the NATO trauma system in the setting of LSCO. We also intended to model novel scenarios that could better adapt the current system to LSCO.

Anterior-posterior and medial-lateral balance metrics are unchanged when two-dimensional pseudorandom motion perturbations are provided in semicircular canal coordinates.

Introduction: External continuous perturbations using a motion platform have been developed by employing either sum-of-sines (SoS) or a pseudorandom ternary sequence (PRTS) of numbers to quantify body sway evoked in the medial-lateral (ML) or anterior-posterior (AP) directions, which ultimately helps understand the human postural control system. These stimuli have been provided via pitch tilts of the motion platform for evaluations of AP balance responses or roll tilts for ML balance responses. However, little is known about whether a healthy postural control system responds to 2-dimensional (2D) perturbations similarly when the perturbation stimuli are provided in semicircular canal coordinates (i.

Call to action: recognize and prevent the effects of extreme heat on early childhood development and health.

The frequency and severity of heat waves are expected to worsen with climate change. Exposure to extreme heat, or prolonged unusually high temperatures, are associated with increased morbidity and mortality. The fetus, infant, and young child are more sensitive to higher temperatures than older children and most adults given that they are rapidly developing.

Prenatal environmental risk for adolescent attention, thought, and substance use problems: A mixtures approach to coexposure and psychiatric comorbidities.

Background: Prospective studies suggest that prenatal exposure to chemical neurotoxicants and maternal stress increase risk for psychiatric problems. However, most studies have focused on childhood outcomes, leaving adolescence-a critical period for the emergence or worsening of psychiatric symptoms-relatively understudied. The complexity of prenatal coexposures and adolescent psychiatric comorbidities, particularly among structurally marginalized populations with high exposure burdens, remains poorly understood.

Don't know much about geography? Decision support for the evaluation of patients with suspected high consequence infectious diseases.

EvalHCID is a clinical decision support system integrating outbreak intelligence, symptom onset, and epidemiologic risk factors to identify high consequence infectious diseases (HCIDs) (eg, Ebola). Tested among 20 emergency department (ED) providers, it significantly reduced assessment time, lowered misclassification, and scored "excellent" usability. EvalHCID may improve institutional preparedness and patient outcomes for emerging infectious disease threats.

Individual, Social and Environmental Influences on Sleep in Latino Pre-Adolescents: A Qualitative Analysis.

A community-based qualitative study identified multilevel influences on sleep duration, quality, and timing in 10 to 12-year-old Latino pre-adolescents via 11 focus groups with 46 children and 15 interviews with parents. An iterative content analysis revealed three themes negatively and positively impacted sleep: (1) Individual-level; (2) Social-level; and (3) Environmental-level influences. At the individual level, use of technology (e.

Ensuring Biosecurity and Research Agility for Outbreak Response: A Researcher's Perspective on the Federal Nucleic Acid Screening Framework.

The Framework for Nucleic Acid Synthesis Screening (FNASS), introduced by the U.S. White House Office of Science and Technology Policy, establishes new biosecurity measures to address emerging concerns about the potential misuse of synthetic nucleic acid sequences.

Fostering Safety, Support, and Hope: A Qualitative Study of Multistakeholder Perspectives on Designing Health Care Services for Women Who Use Drugs in Seattle, Washington, 2023.

Background: Women who use drugs (WWUD) experience increasingly worse outcomes from drug use as compared to men. Additionally, transactional sex, unstable housing, and unmet needs may further complicate their ability to get needed health care. To inform the design of gender-based, mobile health services, we sought perspectives on health care service delivery from WWUD and health care and harm reduction professionals (HHRPs) in Seattle, WA.

Single-Cell and Plasma Proteomics Do Not Differentiate Patients With and Without SARS-CoV-2 Antigenemia in Convalescence in a Cohort of 100 Patients.

Plasma samples obtained approximately 3 ( = 100) and 12 months ( = 78) after acute SARS-CoV-2 infection were tested for S1, spike, and N antigens. There were no significant differences in plasma proteins or single-cell protein expression levels on immune cells between those with and without plasma antigen detected.

Are Sex-Specific Cutoffs Needed With a Next-Generation Urine Tenofovir Lateral Flow Assay for Antiretroviral Adherence Monitoring?

Accurate point-of-care tools are needed to detect early nonadherence to daily HIV regimens and support timely transitions to long-acting options. Emerging evidence suggests that females may require higher adherence than males to achieve equivalent protection. Our next-generation urine tenofovir assay showed high accuracy across sexes but lower urine drug levels among female participants.

How perceptual learning rewires brain connectivity: lessons from the visual system in a top-down perspective.

Neural circuits sculpt their structure and modify the strength of their connections to effectively adapt to the external stimuli throughout life. In response to practice and experience, the brain learns to distinguish previously undetectable stimulus features recurring in the external environment. The unconscious acquisition of improved perceptual abilities falls into a form of implicit learning known as perceptual learning.

Abnormal choline transporter immunohistochemical staining in older children with chronic constipation not associated with Hirschsprung disease.

Objective: Choline transporter (ChT) immunohistochemistry (IHC) is a new ancillary test that aids in the diagnosis of Hirschsprung disease in newborns and infants. The behavior of this stain in older children (greater than 1 year of age) with chronic constipation, where Hirschsprung disease is clinically unlikely, has not been investigated. The aim of our study was to determine the behavior of ChT IHC in rectal biopsies performed on older children with chronic constipation.

Effect of Hepatic Arterial Reconstruction prior to On-Site Normothermic Machine Perfusion in Donation after Circulatory Death Liver Transplant.

Objectives: On-site normothermic machine perfusion of the liver may require hepatic arterial reconstruction. The effect of arterial reconstruction on the deve-lopment of primary ischemic cholangiopathy has not been fully elucidated in liver transplants with organs donated after circulatory death. The aim of this study was to evaluate the effect of normothermic machine perfusion with arterial reconstruction at the onset of ischemic cholangiopathy in liver transplants with organs donated after circulatory death.

Congenital hearing loss in Palestine: Mapping the socioeconomic and clinical factors on infant health in Gaza.

Introduction: Congenital hearing loss (CHL) is a significant chronic condition affecting children's development and communication skills. Globally, its incidence is 1.33 per 1000 newborns, but data from Gaza is limited, this study aims to investigate clinical profile, and risk factors associated with congenital hearing loss (CHL) in infants within the Gaza Strip, focusing on the period before the 2023 military escalation.

Brain network signatures of spatial memory in adolescents at risk for substance use.

Background: Examining youth before engagement in risky behaviors may help identify neurobiological signatures that prospectively predict susceptibility to initiating and escalating alcohol and other substance use. Given that frontal and medial temporal (e.g.

Whole genome sequence analysis of low-density lipoprotein cholesterol across 246 K individuals.

Background: Rare genetic variation provided by whole genome sequence datasets has been relatively less explored for its contributions to human traits. Meta-analysis of sequencing data offers advantages by integrating larger sample sizes from diverse cohorts, thereby increasing the likelihood of discovering novel insights into complex traits. Furthermore, emerging methods in genome-wide rare variant association testing further improve power and interpretability.

Medicolegal landscape of prostate cancer ablative therapy: a national legal database analysis of malpractice claims (1970-2024).

Background: With the advancement of MR-based imaging, prostate cancer ablative therapies have seen increased interest to reduce complications of prostate cancer treatment. Although less invasive, they do carry procedural risks, including rectal injury. To date, the medicolegal aspects of ablative therapy remain underexplored.

Emerging strategies, applications and challenges of targeting NAD in the clinic.

Beyond their classical functions as redox cofactors, recent fundamental and clinical research has expanded our understanding of the diverse roles of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) in signaling pathways, epigenetic regulation and energy homeostasis. Moreover, NAD and NADP influence numerous diseases as well as the processes of aging, and are emerging as targets for clinical intervention. Here, we summarize safety, bioavailability and efficacy data from NAD-related clinical trials, focusing on aging and neurodegenerative diseases.

Learning ecosystem-scale dynamics from microbiome data with MDSINE2.

Although dynamical systems models are a powerful tool for analysing microbial ecosystems, challenges in learning these models from complex microbiome datasets and interpreting their outputs limit use. We introduce the Microbial Dynamical Systems Inference Engine 2 (MDSINE2), a Bayesian method that learns compact and interpretable ecosystems-scale dynamical systems models from microbiome timeseries data. Microbial dynamics are modelled as stochastic processes driven by interaction modules, or groups of microbes with similar interaction structure and responses to perturbations, and additionally, noise characteristics of data are modelled.

The multi-kingdom cancer microbiome.

Microbial influence on cancer development and therapeutic response is a growing area of cancer research. Although it is known that microorganisms can colonize certain tissues and contribute to tumour initiation, the use of deep sequencing technologies and computational pipelines has led to reports of multi-kingdom microbial communities in a growing list of cancer types. This has prompted discussions on the role and scope of microbial presence in cancer, while raising the possibility of microbiome-based diagnostic, prognostic and therapeutic tools.

Mechanisms and treatment of cancer therapy-induced peripheral and central neurotoxicity.

Neurotoxicity is a common and potentially severe adverse effect from conventional and novel cancer therapy. The mechanisms that underlie clinical symptoms of central and peripheral nervous system injury remain incompletely understood. For conventional cytotoxic chemotherapy or radiotherapy, direct toxicities to brain structures and neurovascular damage may result in myelin degradation and impaired neurogenesis, which eventually translates into delayed neurodegeneration accompanied by cognitive symptoms.