Biologically-targeted discovery-replication scan identifies G×G interaction in relation to risk of Barrett's esophagus and esophageal adenocarcinoma.

Inherited genetics represents an important contributor to risk of esophageal adenocarcinoma (EAC), and its precursor Barrett's esophagus (BE). Genome-wide association studies have identified ∼30 susceptibility variants for BE/EAC, yet genetic interactions remain unexamined. To address challenges in large-scale G×G scans, we combined knowledge-guided filtering and machine learning approaches, focusing on genes with (A) known/plausible links to BE/EAC pathogenesis (n=493) or (B) prior evidence of biological interactions (n=4,196).

The impact of weight loss after bariatric surgeries on the patient's body image, quality of life, and self-esteem.

Objectives: The objective of this web-based study is to analyze the attributes of bariatric surgery cases ensuing health implications. Additionally, the study seeks to delve into the factors influencing post-bariatric psychological evaluations and the impact of various bariatric surgeries on weight loss and psycho-social assessment scores for patients who had undergone bariatric surgeries within a specific bariatric surgery center in Egypt between January 2017 and January 2024.

Methods: An analytical cross-sectional study recruited 411 adults who had undergone different bariatric procedures by the same surgical team.

A word of caution in the functional monitoring of patients after rectal cancer surgery: a multicentre observational study.

Background: Patients with rectal cancer often experience adverse effects on urinary, sexual, and digestive functions. Despite recognised impacts and available treatments, they are not fully integrated into follow-up protocols, thereby hindering appropriate interventions. The aim of the study was to discern the activities conducted in our routine clinical practice outside of clinical trials.

Measuring the uptake of clinic-based HIV treatment and prevention services following HIV testing and referral at private pharmacies in Kenya.

Background: Despite their ubiquity across sub-Saharan Africa, private pharmacies are underutilized for HIV service delivery beyond the sale of HIV self-test kits. To understand what uptake of HIV prevention and treatment services might look like if private pharmacies offered clients free HIV self-testing and referral to clinic-based HIV services, we conducted a pilot study in Kenya.

Methods: At 20 private pharmacies in Kisumu County, Kenya, pharmacy clients (≥ 18 years) purchasing sexual health-related products (e.

Metabolic reprogramming, malignant transformation and metastasis: lessons from chronic lymphocytic leukaemia and prostate cancer.

Metabolic reprogramming is a hallmark of cancer, crucial for malignant transformation and metastasis. Chronic lymphocytic leukaemia (CLL) and prostate cancer exhibit similar metabolic adaptations, particularly in glucose and lipid metabolism. Understanding this metabolic plasticity is crucial for identifying mechanisms contributing to metastasis.

Associations between maternal plasma concentrations of corticotrophin releasing hormone and the placental transcriptome.

Introduction: The placenta produces corticotrophin releasing hormone (CRH), which rises exponentially in maternal plasma across pregnancy. CRH plays a functional role in fetal development, labor initiation, and the regulation of gestational length. We aimed to understand how maternal plasma CRH during pregnancy reflects placental physiology during parturition by characterizing placental transcriptomic signatures of maternal plasma CRH and comparing to transcriptomic signatures of gestational age at birth.

A cross-sectional study assessing barriers and facilitators to the sustainability of physical activity and nutrition interventions in early childhood education and care settings.

Background: Effective evidence-based physical activity and nutrition interventions to prevent overweight and obesity and support healthy child development need to be sustained within Early Childhood Education and Care (ECEC) services. Despite this, little is known about factors that influence sustainability of these programs in ECEC settings. Therefore, the aim of this study was to describe the factors related to sustainability of physical activity and nutrition interventions in ECEC settings and examine their association with ECEC service characteristics.

Evolutionary study and structural basis of proton sensing by Mus GPR4 and Xenopus GPR4.

Animals have evolved pH-sensing membrane receptors, such as G-protein-coupled receptor 4 (GPR4), to monitor pH changes related to their physiology and generate adaptive reactions. However, the evolutionary trajectory and structural mechanism of proton sensing by GPR4 remain unresolved. Here, we observed a positive correlation between the optimal pH of GPR4 activity and the blood pH range across different species.

β-Triketones from Leptospermum scoparium (mānuka) oil show potential as scabicides.

Background: Scabies is a debilitating and neglected infectious disease with limited effective treatment options and affecting millions of people worldwide, mainly in poor and overcrowded settings. Essential oils from Australasian Myrtaceae are known to have parasiticidal properties, often attributed to the presence of β-triketones, which are known inhibitors of the tyrosine catabolism pathway through inhibition of hydroxyphenylpyruvate dioxygenase (HPPD).

Purpose: In this study, essential oils from mānuka (Leptospermum scoparium) were evaluated in vitro for miticidal and ovicidal activities and their active β-triketone constituents (flavesone, leptospermone, and isoleptospermone) were identified.

Klp2-mediated Rsp1-Mto1 colocalization inhibits microtubule-dependent microtubule assembly in fission yeast.

Microtubule assembly takes place at the centrosome and noncentrosomal microtubule-organizing centers (MTOCs). However, the mechanisms controlling the activity of noncentrosomal MTOCs are poorly understood. Here, using the fission yeast as a model organism, we demonstrate that the kinesin-14 motor Klp2 interacts with the J-domain Hsp70/Ssa1 cochaperone Rsp1, an inhibitory factor of microtubule assembly, and that Klp2 is required for the proper localization of Rsp1 to microtubules.

Uncovering NK cell sabotage in gut diseases via single cell transcriptomics.

The identification of immune environments and cellular interactions in the colon microenvironment is essential for understanding the mechanisms of chronic inflammatory disease. Despite occurring in the same organ, there is a significant gap in understanding the pathophysiology of ulcerative colitis (UC) and colorectal cancer (CRC). Our study aims to address the distinct immunopathological response of UC and CRC.

Antibiotic prescribing patterns at outpatient clinics in Western and Coastal Kenya.

Antimicrobial resistant pathogens are a leading cause of morbidity and mortality worldwide, with overuse and misuse of antimicrobials being key contributors. We aimed to identify factors associated with antibiotic prescriptions among patients presenting to clinics in Kenya. We performed a retrospective, descriptive cohort study of persons presenting to outpatient clinics in Western and Coastal Kenya, including symptoms, physical exams, clinician assessments, laboratory results and prescriptions.

Basic Science and Pathogenesis.

Background: Alzheimer's Disease (AD) is the most prevalent form of dementia globally. While some familial cases are observed, sporadic AD cases are more common and reflect a high level of complexity, with individual risk determined by the interaction of polygenic and environmental factors.

Objective: To characterize polygenic genetic risk factors in individuals with cognitive impairment and Alzheimer's Disease across four regions of Peru.

Basic Science and Pathogenesis.

Background: Published data have highlighted associations between Alzheimer's disease (AD) susceptibility loci and AD-related brain changes. The amyloid imaging to prevent AD (AMYPAD) consortium is a European collaboration consisting of several parent cohorts, four of which had raw genotype array data available. We sought to integrate and harmonise the genetic data, calculate AD polygenic risk scores (PRS), and investigate their association with global amyloid deposition.

Basic Science and Pathogenesis.

Background: Recently, there has been substantial interest in investigating the role of short-chain fatty acids (SCFAs) and, medium chain fatty acids (MCFA) in the neuroinflammation associated with Alzheimer's disease (AD). Specifically, butyrate (SCFA) and lauric acid (MCFA) have demonstrated potential in alleviating neuroinflammation and reducing toxicity associated with amyloid proteins. Additionally, they have been found to enhance mitochondrial function and reduce neuronal hyperactivity.

Clinical Manifestations.

Background: Subjective Cognitive Decline (SCD) may represent the initial symptom of Alzheimer's disease (AD), but SCD may be absent and/or unrelated to actual cognitive decline. Objective Subtle Cognitive Decline (obj-SCD) can be identified through longitudinal standardized neuropsychological tests in individuals not yet meeting criteria for Mild Cognitive Impairment (MCI). We argue that the relationship between SCD and obj-SCD might help to inform clinical and research criteria in pre-MCI stages.

Clinical Manifestations.

Background: Objective Subtle Cognitive Decline (obj-SCD) can be identified through standardized neuropsychological tests and may precede the development of Mild Cognitive Impairment (MCI). Nevertheless, current clinical and research criteria lack a standardized protocol for identifying obj-SCD. This study introduces cutting-edge sensitive methods to characterize obj-SCD, defined through Alzheimer's disease (AD) biomarker-based longitudinal cognitive performance in episodic memory.

Clinical Manifestations.

Background: Cognitive abilities, notably memory, typically decline with age, but a subset of individuals known as superagers defy this trend by exhibiting memory functions akin to those 20-30 years younger in late life. Recognizing the interconnection between physical performance, health outcomes, and cognitive function in older adults, our aim was to explore whether superagers demonstrate superior physical performance compared to typical agers.

Methods: Forty-nine cognitively unimpaired older adults underwent comprehensive assessments, including cognitive function tests using the Seoul Neuropsychological Screening Battery, Brain MRI, and the Short Physical Performance Battery (SPPB), a prominent tool for evaluating physical function.

Fatty acids and telomere length.

Purpose Of Review: This narrative review includes the latest clinical and preclinical evidence on fatty acid exposure and telomere length, a widely accepted hallmark of aging.

Recent Findings: A large body of literature focused on n-3 (omega-3) polyunsaturated fatty acids (PUFAs). Observational studies reported beneficial associations with telomere length for self-reported consumption of n-3 PUFA-rich foods; for estimated intake of n-3 PUFAs; and for n-3 PUFAs blood-based biomarkers in most (but not all) studies involving lipidomics, a promising tool in the field.

The African Initiative for Bioinformatics Online Training in Neurodegenerative Diseases (AI-BOND): Investing in the next generation of African neuroscientists.

Unlabelled: Neurodegenerative disorders, including Alzheimer's disease and AD-related dementias (AD/ADRD), pose significant challenges to health care systems globally, particularly in Africa. With the advances in medical technology and research capabilities, especially in next-generation sequencing and imaging, vast amounts of data have been generated from AD/ADRD research. Given that the greatest increase in AD/ADRD prevalence is expected to occur in Africa, it is critical to establish comprehensive bioinformatics training programs to help African scientists leverage existing data and collect additional information to untangle AD/ADRD heterogeneity in African populations.

Clinical Pharmacology and Approach to Dose Selection of Emestedastat, a Novel Tissue Cortisol Synthesis Inhibitor for the Treatment of Central Nervous System Disease.

This review demonstrates the value of central pharmacodynamics (PD), including positron emission tomography (PET) and computerized cognitive testing, to supplement pharmacokinetic (PK) and peripheral PD for determining the target dose range for clinical efficacy testing of emestedastat, an 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitor. Combined data from 6 clinical trials in cognitively normal volunteers and patients with Alzheimer disease included a population PK model, endocrine PD, a human PET trial (11β-HSD1 brain imaging), and computerized cognitive testing. PK and PET findings were similar in volunteers and patients with Alzheimer disease.

The β Common Cytokine Receptor Family Reveals New Functional Paradigms From Structural Complexities.

Cytokines are small proteins that are critical for controlling the growth and activity of hematopoietic cells by binding to cell surface receptors and transmitting signals across membranes. The β common (βc) cytokine receptor family, consisting of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5 cytokine receptors, is an architype of the heterodimeric cytokine receptor systems. We now know that signaling by cytokine receptors is not always an "all or none" phenomenon.

Association of Mycobacterium tuberculosis aerosolization and HIV coinfection in the index case with T cell responses in household contacts.

Exposure to pulmonary tuberculosis (PTB) culminates in heterogeneous outcomes, including variation in Mtb antigen-specific interferon-gamma (IFN-γ) T-cell responses. IFN-γ-independent cytokines, including tumor necrosis factor (TNF) and interleukin (IL-2), offer potential diagnostic improvements and insights into pathogenesis. We hypothesized that ESAT6/CFP10 TNF and IL-2 responses improve Mtb infection detection among exposed household contacts (HHCs) and are associated with index case Mtb aerosolization (i.

Deep learning and genome-wide association meta-analyses of bone marrow adiposity in the UK Biobank.

Bone marrow adipose tissue is a distinct adipose subtype comprising more than 10% of fat mass in healthy humans. However, the functions and pathophysiological correlates of this tissue are unclear, and its genetic determinants remain unknown. Here, we use deep learning to measure bone marrow adiposity in the femoral head, total hip, femoral diaphysis, and spine from MRI scans of approximately 47,000 UK Biobank participants, including over 41,000 white and over 6300 non-white participants.