Evidence that extracellular HSPB1 contributes to inflammation in alcohol-associated hepatitis.

Background: Alcohol-associated hepatitis (AH) is the most life-threatening form of alcohol-associated liver disease (ALD). AH is characterized by severe inflammation attributed to increased levels of ethanol, microbes or microbial components, and damage-associated molecular pattern (DAMP) molecules in the liver. HSPB1 [Heat Shock Protein Family B (Small) Member 1; also known as Hsp25/27] is a DAMP released from stressed cells, including hepatocytes.

Metabolic syndrome as a modifiable risk factor for complications after epilepsy surgery.

Objective: Metabolic syndrome (MetS) is a growing public health concern in what has been called a "global epidemic." The aim of this study was to investigate how MetS influences postoperative seizure freedom outcomes and complications following elective neurosurgical intervention for drug-resistant epilepsy (DRE), offering an opportunity to uncover modifiable outcome drivers.

Methods: Adult patients with DRE who underwent a first resective epilepsy surgery from 2000 to 2017 were identified retrospectively from a prospectively collected institutional outcomes registry.

Neurobeachin (NBEA) is a novel gene associated with GLP-1 receptor agonist associated weight loss.

Aims: Nearly 42% of adults in the United States have obesity, a significant risk factor for many cardiometabolic diseases and cancers. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are promising interventions for weight loss, but their efficacy varies significantly across individuals. This study investigates the role of neurobeachin (NBEA), a gene that encodes a protein kinase A anchor protein, on weight loss response in two large, real-world cohorts.

Preventing Microglial Reactivity Protects from Acute and Progressive Neuronal Dysfunction, Motor Impairments and Sedation following Alcohol Abuse.

Alcohol abuse is the primary risk factor for alcohol use disorder (AUD), a leading cause of preventable morbidity and mortality, characterized by systemic inflammation, multi-organ damage, and neurological impairments. While direct effects of alcohol on brain function are well-established, the role of microglia in acute and chronic neurological dysfunction in AUD remains unclear. Using longitudinal imaging in mice during acute and repeated alcohol abuse, we found that microglia exhibit dynamic morphological responses that precede but parallel ethanol-induced sedation.

Mitochondria-derived dsRNA-induced stress granules promote IRF3-mediated fibrotic responses.

Nucleic acid-induced activation of the anti-viral transcription factor interferon regulatory factor 3 (IRF3) promotes transforming growth factor-beta (TGFβ)-induced fibrotic responses of hepatic stellate cells . Herein, we identified molecular mechanisms underlying TGFβ-induced IRF3 activation. Gene silencing of with short interfering RNA (siRNA) in LX2 human hepatic stellate cells decreased TGFβ-induced fibrotic responses.

Macrovascular and microvascular complications in US Medicare enrollees with type 2 diabetes with and without atherosclerotic cardiovascular disease.

Aims: To assess the incidence of macrovascular and microvascular complications in US Medicare enrollees diagnosed with T2D with and without established ASCVD.

Materials And Methods: We conducted a retrospective cohort study using Medicare fee-for-service claims data from 1 January 2006, through 31 December 2021. Baseline demographic and clinical characteristics were assessed in the 1-year prior to indexing.

Peri-operative anti-inflammatory drug use and seizure recurrence after resective epilepsy surgery: Target trials emulation.

We conducted a retrospective observational study to examine whether anti-inflammatory medications prescribed peri-operatively of resective brain surgery can reduce long-term seizure recurrence for individuals with drug-resistant focal epilepsy. We used insurance-claims data from across the United States to screen medications prescribed to 1,993 individuals undergoing epilepsy. We then validated the results in a well-characterized cohort of 671 epilepsy patients from a major surgical center.

Pain Assessment in Osteoarthritis: Present Practices and Future Prospects Including the Use of Biomarkers and Wearable Technologies, and AI-Driven Personalized Medicine.

Osteoarthritis (OA) is a highly prevalent chronic joint disorder affecting ~600 million individuals worldwide and is characterized by complex pain mechanisms that significantly impair patient quality of life. Challenges exist in accurately assessing and measuring pain in OA due to variations in pain perception among individuals and the heterogeneous nature of the disease. Conventional pain assessment methods, such as patient-reported outcome measures and clinical evaluations, often fail to fully capture the heterogeneity of pain experiences among individuals with OA.

Newer Glucagon-Like Peptide-1 Receptor Agonists Are Associated With Improved Glycemic Control in US Adults With Type 2 Diabetes: A Population-Level Time Series Analysis.

Objectives: The population-level impact of newer glucagon-like peptide-1 receptor agonist (GLP-1 RA) treatments on patients with type 2 diabetes remains unclear. Therefore, this study investigated the association of newer GLP-1 RAs with population-level diabetes-related outcomes in US adults with type 2 diabetes.

Methods: This was a noninterventional, retrospective analysis of administrative insurance claims data obtained from Optum's deidentified Clinformatics® Data Mart Database between January 2004 and December 2022.

A genome-wide association study identifies genetic determinants of hemoglobin glycation index with implications across sex and ethnicity.

Introduction: We investigated the genetic determinants of variation in the hemoglobin glycation index (HGI), an emerging biomarker for the risk of diabetes complications.

Methods: We conducted a genome-wide association study (GWAS) for HGI in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial ( = 7,913) using linear regression and additive genotype encoding on variants with minor allele frequency greater than 3%. We conducted replication analyses of top findings in the Atherosclerosis Risk in Communities (ARIC) study with inverse variance-weighted meta-analysis.

Biomarker Discovery in Liver Disease Using Untargeted Metabolomics in Plasma and Saliva.

Chronic liver diseases, including non-alcoholic fatty liver disease (NAFLD), cirrhosis, and hepatocellular carcinoma (HCC), continue to be a global health burden with a rise in incidence and mortality, necessitating a need for the discovery of novel biomarkers for HCC detection. This study aimed to identify novel non-invasive biomarkers for these different liver disease states. We performed untargeted metabolomics in plasma (Healthy = 9, NAFLD = 14, Cirrhosis = 10, HCC = 34) and saliva samples (Healthy = 9, NAFLD = 14, Cirrhosis = 10, HCC = 22) to test for significant metabolite associations with each disease state.

Circulating Gut Microbe-Derived Metabolites Are Associated with Hepatocellular Carcinoma.

Unlabelled: Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. The gut microbiome has been implicated in outcomes for HCC, and gut microbe-derived products may serve as potential non-invasive indices for early HCC detection. This study evaluated differences in plasma concentrations of gut microbiota-derived metabolites.

Evidence that extracellular HSPB1 contributes to inflammation in alcohol-associated hepatitis.

Background And Aims: Alcohol-associated hepatitis (AH) is the most life-threatening form of alcohol-associated liver disease (ALD). AH is characterized by severe inflammation attributed to increased levels of ethanol, microbes or microbial components, and damage-associated molecular pattern (DAMP) molecules in the liver. HSPB1 (Heat Shock Protein Family B (Small) Member 1; also known as Hsp25/27) is a DAMP that is rapidly increased in and released from cells experiencing stress, including hepatocytes.

Multi-omics machine learning to study host-microbiome interactions in early-onset colorectal cancer.

The incidence of early-onset colorectal cancer (eoCRC) is rising, and its pathogenesis is not completely understood. We hypothesized that machine learning utilizing paired tissue microbiome and plasma metabolome features could uncover distinct host-microbiome associations between eoCRC and average-onset CRC (aoCRC). Individuals with stages I-IV CRC (n = 64) were categorized as eoCRC (age ≤ 50, n = 20) or aoCRC (age ≥ 60, n = 44).

Polygenic subtype identified in ACCORD trial displays a favorable type 2 diabetes phenotype in the UKBiobank population.

Introduction: We previously identified a genetic subtype (C4) of type 2 diabetes (T2D), benefitting from intensive glycemia treatment in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Here, we characterized the population of patients that met the C4 criteria in the UKBiobank cohort.

Research Design And Methods: Using our polygenic score (PS), we identified C4 individuals in the UKBiobank and tested C4 status with risk of developing T2D, cardiovascular disease (CVD) outcomes, and differences in T2D medications.

Proteomics identifies complement protein signatures in patients with alcohol-associated hepatitis.

Diagnostic challenges continue to impede development of effective therapies for successful management of alcohol-associated hepatitis (AH), creating an unmet need to identify noninvasive biomarkers for AH. In murine models, complement contributes to ethanol-induced liver injury. Therefore, we hypothesized that complement proteins could be rational diagnostic/prognostic biomarkers in AH.

An interpretable predictive deep learning platform for pediatric metabolic diseases.

Objectives: Metabolic disease in children is increasing worldwide and predisposes a wide array of chronic comorbid conditions with severe impacts on quality of life. Tools for early detection are needed to promptly intervene to prevent or slow the development of these long-term complications.

Materials And Methods: No clinically available tools are currently in widespread use that can predict the onset of metabolic diseases in pediatric patients.

Plasma metabolomic differences in early-onset compared to average-onset colorectal cancer.

Deleterious effects of environmental exposures may contribute to the rising incidence of early-onset colorectal cancer (eoCRC). We assessed the metabolomic differences between patients with eoCRC, average-onset CRC (aoCRC), and non-CRC controls, to understand pathogenic mechanisms. Patients with stage I-IV CRC and non-CRC controls were categorized based on age ≤ 50 years (eoCRC or young non-CRC controls) or  ≥ 60 years (aoCRC or older non-CRC controls).

GLI1+ perivascular, renal, progenitor cells: The likely source of spontaneous neoplasia that created the AGMK1-9T7 cell line.

The AGMK1-9T7 cell line has been used to study neoplasia in tissue culture. By passage in cell culture, these cells evolved to become tumorigenic and metastatic in immunodeficient mice at passage 40. Of the 20 x 106 kidney cells originally plated, less than 2% formed the colonies that evolved to create this cell line.

Combined Liver Transplant and Cardiac Surgery: Long-term Outcomes and Predictors of Success.

Objective: We aim to report our institutional outcomes of single-staged combined liver transplantation (LT) and cardiac surgery (CS).

Background: Concurrent LT and CS is a potential treatment for combined cardiac dysfunction and end-stage liver disease, yet only 54 cases have been previously reported in the literature. Thus, the outcomes of this approach are relatively unknown, and this approach has been previously regarded as extremely risky.

Molecular subtypes of epilepsy associated with post-surgical seizure recurrence.

Approximately 50% of individuals who undergo resective epilepsy surgery experience seizure recurrence. The heterogenous post-operative outcomes are not fully explained by clinical, imaging and electrophysiological variables. We hypothesized that molecular features may be useful in understanding surgical response, and that individuals with epilepsy can be classified into molecular subtypes that are associated with seizure freedom or recurrence after surgical resection.

Genomic approaches to explore susceptibility and pathogenesis of alcohol use disorder and alcohol-associated liver disease.

Excessive alcohol use is a major risk factor for the development of an alcohol use disorder (AUD) and contributes to a wide variety of other medical illnesses, including alcohol-associated liver disease (ALD). Both AUD and ALD are complex and causally interrelated diseases, and multiple factors other than alcohol consumption are implicated in the disease pathogenesis. While the underlying pathophysiology of AUD and ALD is complex, there is substantial evidence for a genetic susceptibility of both diseases.