A Statistically-Robust Model of the Axomyelin Unit under Normal Physiologic Conditions with Application to Disease States.

Despite tremendous progress in characterizing the myriad cellular structures in the nervous system, a full appreciation of the interdependent and intricate interactions between these structures is as yet unfulfilled. Indeed, few more so than the interaction between the myelin internode and its ensheathed axon. More than a half-century after the ultrastructural characterization of this axomyelin unit, we lack a reliable understanding of the physiological properties, the significance and consequence of pathobiological processes, and the means to gauge success or failure of interventions designed to mitigate disease.

Cryo-EM structure of AAV2 Rep68 bound to integration site AAVS1: insights into the mechanism of DNA melting.

The Rep68 protein from Adeno-Associated Virus (AAV) is a multifunctional SF3 helicase that performs most of the DNA transactions necessary for the viral life cycle. During AAV DNA replication, Rep68 assembles at the origin of replication, catalyzing the DNA melting and nicking reactions during the hairpin rolling replication process to complete the second-strand synthesis of the AAV genome. We report the cryo-electron microscopy structures of Rep68 bound to the adeno-associated virus integration site 1 in different nucleotide-bound states.

Costimulation blockade: the next generation.

Purpose Of The Review: Calcineurin inhibitors (CNIs) are central to immunosuppression in kidney transplantation (KT), improving short-term outcomes but falling short in enhancing long-term outcomes due to cardiovascular, metabolic, and renal complications. Belatacept, an FDA-approved costimulation blocker, offers a less toxic alternative to CNIs but is limited by its intravenous administration and reduced efficacy in high-immunological-risk patients.

Recent Findings: Emerging therapies target more specific pathways to improve efficacy and accessibility.

Increased serum GM-CSF at diagnosis of biliary atresia is associated with improved biliary drainage.

Background: The immune heterogeneity of biliary atresia (BA) presents a challenge for development of prognostic biomarkers. This study aimed to identify early immune signatures associated with biliary drainage after Kasai Portoenterostomy (KPE).

Methods: Serum samples, liver slides, and clinical data were obtained from patients enrolled in the NIDDK-supported Childhood Liver Disease Research Network.

Fabrication of heteroatom-doped graphene-porous organic polymer hybrid materials via femtosecond laser writing and their application in VOCs sensing.

Graphene, a two-dimensional material featuring densely packed sp-hybridized carbon atoms arranged in a honeycomb lattice, has revolutionized material science. Laser-induced graphene (LIG) represents a breakthrough method for producing graphene from both commercial and natural precursors via direct laser writing, offering advantages such as simplicity, efficiency, and cost-effectiveness. This study demonstrates a novel approach to synthesize a composite material exclusively from a porous organic polymer (POP) by direct femtosecond laser writing on a compressed imide-linked porous organic polymer substrate.

Posterior urethral valves: Examining the relationship of socioeconomic factors in disease presentation and progression.

Introduction: A significant portion of posterior urethral valve patients continue to progress to end stage renal disease despite improvements in medical care. Socioeconomic status has been connected to various healthcare outcomes but has not been evaluated in relation to longitudinal outcomes of posterior urethral valves.

Objective: To evaluate the effect of socioeconomic status on the progression to renal failure among patients with posterior urethral valves.

Non-atherosclerotic coronary causes of myocardial infarction in women.

Ischemic heart disease is the most common cardiovascular cause of death in women worldwide. Obstructive coronary atherosclerosis is the primary cause of myocardial infarction (MI), however, non-atherosclerotic mechanisms of MI, such as spontaneous coronary artery dissection, vasospasm, microvascular dysfunction, embolization, inflammation, coronary anomalies, infectious and infiltrative causes are increasingly being recognized. Emerging data suggest that women are two to five times more likely to have an MI in the absence of coronary atherosclerosis compared to men, but they continue to remain underdiagnosed and undertreated, partly due to underdiagnosis and limited understanding of these mechanisms.

Outpatient Total Knee Arthroplasty Has Become More Frequent Since the Onset of the COVID-19 Pandemic Without an Increase in Early Post-Operative Complications.

Introduction: Outpatient total knee arthroplasty (TKA) has quickly grown in popularity, largely driven by policy shifts and the recent coronavirus disease 2019 (COVID-19) pandemic. The aim of this study was to compare 30-day complications between outpatient TKA (oTKA) versus inpatient TKA (iTKA) before and after the COVID-19 pandemic to elucidate the effect of the pandemic on utilization and short-term outcomes.

Methods: Patients who underwent primary TKA between 2008 and 2021 were identified through Current Procedural Terminology codes in a national database.

Development of a predictive model for pediatric intranasal drug delivery with nasal sprays: Leveraging intersubject variability in anatomical dimensions, administration-related parameters, and airway patency.

In this study, we examined the correlation between anatomical dimensions, spray administration parameters, pressure drop across 40 pediatric nasal cavities, and in vitro posterior drug delivery (PDD) using Nasacort ALLERGY 24HR and FLONASE SENSIMIST nasal suspensions sprays, with different nozzle and actuation designs. The importance of each parameter and their interaction in the outcome (PDD) was evaluated. To do so, initially we measured anatomical and administration-related parameters, and the pressure drop of each cavity.

New PPARα Agonist A190-Loaded Microemulsion for Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect of anticancer agents with limited effective preventive or therapeutic interventions. Although fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPARα) agonist, has demonstrated neuroprotective and analgesic properties, its clinical utility is hindered by low receptor affinity, poor subtype selectivity, and suboptimal bioavailability. A190, a highly selective and potent nonfibrate PPARα agonist, offers a promising alternative but is limited by poor aqueous solubility, resulting in reduced oral bioavailability and therapeutic efficacy.

Clustering Sequence Data with Mixture Markov Chains with Covariates Using Multiple Simplex Constrained Optimization Routine (MSiCOR).

Mixture Markov Model (MMM) is a widely used tool to cluster sequences of events coming from a finite state-space. However, the MMM likelihood being multi-modal, the challenge remains in its maximization. Although Expectation-Maximization (EM) algorithm remains one of the most popular ways to estimate the MMM parameters, however, convergence of EM algorithm is not always guaranteed.

Perceptions and Attitudes of People With Cancer and Diabetes Towards Patient Guidelines: A Mixed Methods Study.

Objective: To explore patients' perceptions and attitudes towards patient guidelines (PGs) and to identify specific factors related to PG content, design, presentation, and management that may influence patients' use or adoption of PGs.

Methods: An exploratory sequential mixed-methods design was employed. Initial semi-structured interviews were conducted with a diverse group of individuals, including people with diabetes or oncology, and clinicians.

Using capacity assessments and tailored technical assistance to advance trauma informed care integration at the organizational level.

Background: The prevalence of trauma among individuals with HIV has prompted efforts to integrate trauma-informed care (TIC) into HIV care and treatment to improve health outcomes. A TIC Implementation Model, developed by a US capacity-building organization focuses on organizational changes, aligning cultural and physical environments, emphasizing values like safety and trustworthiness, engaging leadership, and training staff in skills-based TIC services. Despite growing research, gaps remain in understanding the relationship between organizational capacity, provider knowledge, and the dosage of technical assistance (TA) required to sustain TIC integration.

SARS-CoV-2 S-protein expression drives syncytia formation in endothelial cells.

SARS-CoV-2 is a viral infection, best studied in the context of epithelial cell infection. Epithelial cells, when infected with SARS-CoV-2 express the viral S-protein, which causes host cells to fuse together into large multi-nucleated cells known as syncytia. Because SARS-CoV-2 infections also frequently present with cardiovascular phenotypes, we sought to understand if S-protein expression would also result in syncytia formation in endothelial cells.

Corticosteroids in severe alcohol-associated hepatitis? Not so fast: A systematic review of randomized controlled trials.

Background: Severe alcohol-associated hepatitis (AH) is rising in incidence with a high mortality burden. While corticosteroids are recommended for eligible patients with severe AH, no guidance exists for the timing of steroid initiation, tapering regimens, and surveillance of adverse events.

Objective: We aim to systematically review these variables and provide evidence-based recommendations for the inpatient and outpatient management of severe AH.

Care Recipients' Cognitive Trajectories and Caregivers' Depressive Symptoms: The Mediating Role of Caregiving Burden.

Background And Objectives: The heterogeneity of population-based trajectories of care recipients' (CRs) cognitive functioning and how they are associated with their caregivers' mental health is less studied in the United States. Informed by the stress process model, this study examines the relationship between care recipients' cognitive trajectories and caregivers' depressive symptoms, and the mediating role of caregiving burden.

Research Design And Methods: Data were from the National Health and Aging Trends Study (2011-2020) for 1,086 care recipients and their 1,675 caregivers from the 2021 National Study of Caregiving.

Ablation of LRP6 in alpha-smooth muscle actin-expressing cells abrogates lung inflammation and fibrosis upon bleomycin-induced lung injury.

Tissue fibrosis is a progressive pathological process with excessive deposition of extracellular matrix proteins (ECM). Myofibroblasts, identified by alpha-smooth muscle actin (αSMA) expression, play an important role in tissue fibrosis by producing ECM. Here, we found that the Wnt antagonist Dickkopf1 (DKK1) induced gene expressions associated with inflammation and fibrosis in lung fibroblasts.

The talk and walk in Black families: Exploring racial socialization content and competency in the context of parental worries about racial profiling and adolescents' internalizing outcomes.

Although many parents worry that their child will be the target of racial profiling, there is a dearth of literature on how parental worries about children facing racism are linked to racial socialization (RS) practices and youth internalizing symptoms. Additionally, it is unclear how RS content relative to competency may uniquely influence whether and how parental worries influence youth internalizing outcomes. Using data from 203 Black parents (M = 44.

Environment scan of generative AI infrastructure for clinical and translational science.

This study reports a comprehensive environmental scan of the generative AI (GenAI) infrastructure in the national network for clinical and translational science across 36 institutions supported by the CTSA Program led by the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) at the United States. Key findings indicate a diverse range of institutional strategies, with most organizations in the experimental phase of GenAI deployment. The results underscore the need for a more coordinated approach to GenAI governance, emphasizing collaboration among senior leaders, clinicians, information technology staff, and researchers.

Skin tone and academic readiness among young Mexican-origin children: Testing the moderating role of ethnic-racial identity attitudes and centrality.

Skin tone-based social stratification is an enduring part of the U.S. racial landscape.

Supporting Unhealthy Substance use care Through a whole person Approach and user centered INtegration into primary care (SUSTAIN): Study protocol for a type 2 hybrid effectiveness-implementation trial.

Background: Unhealthy substance use (USU) is common and ranges from use above guideline-recommended levels to severe substance use disorder. USU results in substantial morbidity and mortality yet primary care practices rarely systematically screen, diagnose, and treat USU. Supporting Unhealthy Substance use care Through a whole person Approach and user centered INtegration into primary care (SUSTAIN) tests whether the implementation of a co-designed change package for USU improves patient function.

Long-Term Cognitive Outcomes in Adult Patients Receiving Chimeric Antigen Receptor T-Cell Therapies.

Background: CAR T-cell therapy (CAR-T) is leading to durable responses in patients with cancer but there is concern that cytokine release syndrome (CRS) and neurotoxicity may impact survivors' cognitive function. We assessed long-term cognitive function in CAR-T recipients and examine factors associated with change in cognition over time.

Methods: We assessed perceived cognition (Functional Assessment of Cancer Therapy - Cognition) and neurocognitive performance (standardized neuropsychological battery) in adult patients prior to receiving CAR-T and at 6 month follow-up.