Patient and Healthcare Professional Perspectives on Crohn's Perianal Fistula Treatment: Results From a Discrete Choice Experiment.

Background: Crohn's perianal fistulas (CPF) are difficult to manage and often require multiple interventions. This study aimed to assess the preferences of patients and healthcare professionals (HCPs) for attributes of CPF-related procedures/surgeries to better inform CPF management.

Methods: This US cross-sectional, observational study was conducted via a web-enabled questionnaire (October 2021-January 2022) among patients aged 21-89 years with a self-reported physician diagnosis of CPF (with or without CPF-related surgery experience) and HCPs (gastroenterologists and colorectal surgeons who managed ≥3 patients with CPF in the past 12 months).

Impulsivity behaviors and white matter mediate the relationship between genetic risk for cannabis use disorder and early cannabis use in adolescents.

Background And Aim: Cannabis use disorder (CUD) is strongly influenced by genetic factors; however the mechanisms underpinning this association are not well understood. This study investigated whether a polygenic risk score (PRS) based on a genome-wide association study for CUD in adults predicts cannabis use in adolescents and whether the association can be explained by inter-individual variation in structural properties of brain white matter or risk-taking behaviors.

Design And Setting: Longitudinal and cross-sectional analyses using data from the IMAGEN cohort, a European longitudinal study integrating genetic, neuroimaging and behavioral measures.

Biophysical mapping of TREM2-ligand interactions reveals shared surfaces for engagement of multiple Alzheimer's disease ligands.

TREM2 is a signaling receptor expressed on microglia that has emerged as an important drug target for Alzheimer's disease and other neurodegenerative diseases. While a number of TREM2 ligands have been identified, little is known regarding the structural details of how they engage. To better understand this, we created a protein library of 28 different TREM2 variants that could be used to map interactions with various ligands using biolayer interferometry.

Effect of daily alcohol intake on sex hormone levels among postmenopausal breast cancer survivors on aromatase inhibitor therapy: a randomized controlled crossover pilot study.

Background: Alcohol intake is associated with a higher risk of estrogen receptor-positive (ER+) breast cancer (BC), presumably through its confirmed ability to increase sex hormone levels. Whether consuming alcohol within the recommended limit of one serving per day increases sex hormone levels among postmenopausal women taking aromatase inhibitors (AI) to inhibit estrogen production remains unknown. Therefore, we compared sex hormone levels following white wine to levels following white grape juice among ER + BC survivors taking AIs.

Unraveling the genetic architecture of blueberry fruit quality traits: major loci control organic acid content while more complex genetic mechanisms control texture and sugar content.

Background: Fruit quality traits, including taste, flavor, texture, and shelf-life, have emerged as important breeding priorities in blueberry (Vaccinium corymbosum). Organic acids and sugars play crucial roles in the perception of blueberry taste/flavor, where low and high consumer liking are correlated with high organic acids and high sugars, respectively. Blueberry texture and appearance are also critical for shelf-life quality and consumers' willingness-to-pay.

Non-Caucasian Race/Ethnicity Predisposes to Unfavorable Stage and Grade at Upper Tract Urothelial Carcinoma Diagnosis.

Objective: To test whether race/ethnicity affects stage or grade distribution at upper tract urothelial carcinoma (UTUC) diagnosis.

Methods: Within the Surveillance, Epidemiology, and End Results (SEER) database 2004-2020, UTUC patients were identified. Multivariable logistic regression models tested for the association between race/ethnicity and stage as well as grade at diagnosis according to renal pelvis vs.

Global profiling of alternative splicing in non-small cell lung cancer reveals novel histological and population differences.

Lung cancer is one of the most frequently diagnosed cancers in the US. African-American (AA) men are more likely to develop lung cancer with higher incidence and mortality rates than European-American (EA) men. Herein, we report high-confidence alternative splicing (AS) events from high-throughput, high-depth total RNA sequencing of lung tumors and non-tumor adjacent tissues (NATs) in two independent cohorts of patients with adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC).

Divergent roles of mA in orchestrating brown and white adipocyte transcriptomes and systemic metabolism.

N-methyladenosine (mA) is among the most abundant mRNA modifications, yet its cell-type-specific regulatory roles remain unclear. Here we show that mA methyltransferase-like 14 (METTL14) differentially regulates transcriptome in brown versus white adipose tissue (BAT and WAT), leading to divergent metabolic outcomes. In humans and mice with insulin resistance, METTL14 expression differs significantly from BAT and WAT in the context of its correlation with insulin sensitivity.

Effect of Dietary Ketosis and Nicotinamide Riboside on Hippocampal Krebs Cycle Intermediates and Mitochondrial Energetics in a DNA Repair-Deficient 3xTg/POLβ Alzheimer Disease Mouse Model.

Alzheimer disease is a neurodegenerative pathology-modifying mitochondrial metabolism with energy impairments where the effects of biological sex and DNA repair deficiencies are unclear. We investigated the therapeutic potential of dietary ketosis alone or with supplemental nicotinamide riboside (NR) on hippocampal intermediary metabolism and mitochondrial bioenergetics in older male and female wild-type (Wt) and 3xTgAD-DNA polymerase-β-deficient (3xTg/POLβ) (AD) mice. DNA polymerase-β is a key enzyme in DNA base excision repair (BER) of oxidative damage that may also contribute to mitochondrial DNA repair.

Implementation of Ambulatory Kidney Supportive Care in a Safety Net Hospital.

Context: Chronic kidney disease (CKD) disproportionately impacts lower socioeconomic groups and is associated with many symptoms and complex decisions. Integration of Kidney Supportive Care (KSC) with CKD care can address these needs. To our knowledge, this approach has not been described in an underserved population.

Design, synthesis, and biological evaluation of novel thiourea derivatives as small molecule inhibitors for prostate specific membrane antigen.

Prostate cancer (PCa) has emerged to be the second leading cause of cancer-related deaths in men. Molecular imaging of PCa using targeted radiopharmaceuticals specifically to PCa cells promises accurate staging of primary disease, detection of localized and metastasized tumours, and helps predict the progression of the disease. Glutamate urea heterodimers have been popularly used as high-affinity small molecules in the binding pockets of popular and well-characterized PCa biomarker, prostate specific membrane antigen (PSMA).

Pulsed Ultrasound-Mediated Drug Delivery Enhancement Through Human Sclera.

Purpose: The purpose of this study was to characterize whether pulsed ultrasound (PUS) affects transscleral drug delivery.

Methods: Fluorescein sodium (NaF, 376 Da) and fluorescein isothiocyanate-conjugated dextran 40 (FD-40, 40 kDa) were used as model drugs. Human sclera grafts were placed in modified Franz diffusion cells and were treated by PUS (1 megahertz [MHz], 0.

Understanding the Role of Trust in Healthcare and Intentions to Pursue Live Donor Kidney Transplant Among African American End Stage Kidney Disease Patients.

African Americans (AAs) with end-stage kidney disease (ESKD) experience significant barriers to accessing living donor kidney transplantation (LDKT), largely due to individual and systemic factors, including a lack of trust in healthcare systems resulting from a legacy of and continued experiences with medical racism. This cross-sectional study analyzed survey data from 416 AA patients with ESKD undergoing transplant evaluation in 2019-2023 at two kidney transplant centers in the Southeast United States, examining whether trust (specifically trust in kidney doctors, hospitals, and healthcare) modifies the relationship between attitudes towards LDKT and behavioral intentions to discuss LDKT with family and friends. Multivariable analyses revealed significant interactions.

Central Nervous System Metastases in Breast Cancer.

Breast cancer metastasizing to the central nervous system (CNS) encompasses two distinct entities: brain metastases involving the cerebral parenchyma and infiltration of the leptomeningeal space, i.e., leptomeningeal disease.

Antibody-Drug Conjugates in Breast Cancer: The Road Towards Biologically-Informed Selection and Sequencing.

Purpose Of Review: In this review, we discuss evidence supporting the use of antibody-drug conjugates (ADCs) in breast cancer treatment, describe novel ADCs and combination regimens under development, and examine our current understanding of resistance mechanisms and biomarkers to guide ADC selection and sequencing.

Recent Findings: Three ADCs have proven benefit in patients with metastatic breast cancer: trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan (SG). There are over two hundred investigational ADCs on the horizon, as pre-clinical studies work to identify novel ADC targets and structures.

CD4+ T helper 2 cell-macrophage crosstalk induces IL-24-mediated breast cancer suppression.

CD4+ T cells contribute to antitumor immunity and are implicated in the efficacy of cancer immunotherapies. In particular, CD4+ T helper 2 (Th2) cells were recently found to block spontaneous breast carcinogenesis. However, the antitumor potential of Th2 cells in targeting established breast cancer remains uncertain.

COMT and MTHFR Genetic Variants Combined Effects on Adolescent Idiopathic Scoliosis Progression.

Genetic variants encoding both low COMT and MTHFR activity are associated with idiopathic scoliosis. The combined impact of and on progression of adolescent idiopathic scoliosis (AIS) is unknown. This study investigated if and low activity variants are associated with AIS progression.

Arachidonic acid synergizes with aspirin preventing myocardial ischemia-reperfusion injury and mitigates bleeding risk.

Aims: The therapeutic efficacy of coronary revascularization is compromised by myocardial ischemia-reperfusion (MI/R) injury. Higher levels of circulating arachidonic acid (AA) are reportedly associated with lower risk of cardiovascular disease. The cyclooxygenase (COX) pathway metabolizes AA into prostaglandins (PGs) and the platelet-activating thromboxane A2 (TXA2), which is inhibited by aspirin.

The Role of Double-Zero-Event Studies in Evidence Synthesis: Evaluating Robustness Using the Fragility Index.

Rationale: Zero-event counts are common in clinical studies, particularly when assessing rare adverse events. These occurrences can result from low event rates, short follow-up periods, and small sample sizes. When both intervention and control groups report zero events in a clinical trial, the study is referred to as a double-zero-event study, which presents methodological challenges for evidence synthesis.

Impact of Social Determinants of Health on Pre-exposure Prophylaxis Care for HIV Prevention.

Background: HIV continues to disproportionately impact men who have sex with men (MSM) in the United States (US). Pre-exposure prophylaxis (PrEP) is effective, but disparities persist. Limited studies have conducted systematic evaluations of social determinants of health (SDOH) and their effects on PrEP persistence among MSM.

evoke and evoke+: design of two large-scale, double-blind, placebo-controlled, phase 3 studies evaluating efficacy, safety, and tolerability of semaglutide in early-stage symptomatic Alzheimer's disease.

Background: Disease-modifying therapies targeting the diverse pathophysiology of Alzheimer's disease (AD), including neuroinflammation, represent potentially important and novel approaches. The glucagon-like peptide-1 receptor agonist semaglutide is approved for the treatment of type 2 diabetes and obesity and has an established safety profile. Semaglutide may have a disease-modifying, neuroprotective effect in AD through multimodal mechanisms including neuroinflammatory, vascular, and other AD-related processes.

Network analysis combined with genome-wide association study helps identification of genes related to amino acid contents in soybean.

Background: Additional to total protein content, the amino acid (AA) profile is important to the nutritional value of soybean seed. The AA profile in soybean seed is a complex quantitative trait controlled by multiple interconnected genes and pathways controlling the accumulation of each AA. With a total of 621 soybean germplasm, we used three genome-wide association study (GWAS)-based approaches to investigate the genomic regions controlling the AA content and profile in soybean.

Medical large language models are vulnerable to data-poisoning attacks.

The adoption of large language models (LLMs) in healthcare demands a careful analysis of their potential to spread false medical knowledge. Because LLMs ingest massive volumes of data from the open Internet during training, they are potentially exposed to unverified medical knowledge that may include deliberately planted misinformation. Here, we perform a threat assessment that simulates a data-poisoning attack against The Pile, a popular dataset used for LLM development.

Toward expert-level medical question answering with large language models.

Large language models (LLMs) have shown promise in medical question answering, with Med-PaLM being the first to exceed a 'passing' score in United States Medical Licensing Examination style questions. However, challenges remain in long-form medical question answering and handling real-world workflows. Here, we present Med-PaLM 2, which bridges these gaps with a combination of base LLM improvements, medical domain fine-tuning and new strategies for improving reasoning and grounding through ensemble refinement and chain of retrieval.