Joint Hypermobility, Autonomic Dysfunction, Gastrointestinal Dysfunction, and Autoimmune Markers: Clinical Associations and Response to Intravenous Immunoglobulin Therapy.

Introduction: We examined autoimmunity markers (AIM) and autonomic dysfunction in patients with chronic neurogastroenterological symptoms and their relationship to joint hypermobility/hypermobility spectrum disorder (JH/HSD).

Methods: AIM positivity was defined as a diagnosis of known autoimmune/autoinflammatory disorder with at least 1 positive seromarker of autoimmunity or at least 2 positive seromarkers by themselves. Three cohorts were studied: (i) retrospective (n = 300), (ii) prospective validation cohort (n = 133), and (iii) treatment cohort (n = 40), administered open-label intravenous immunoglobulin (IVIG).

Gastrointestinal syndromes preceding a diagnosis of Parkinson's disease: testing Braak's hypothesis using a nationwide database for comparison with Alzheimer's disease and cerebrovascular diseases.

Objective: Braak's hypothesis states that Parkinson's disease (PD) originates in the gastrointestinal (GI) tract, and similar associations have been established for Alzheimer's disease (AD) and cerebrovascular diseases (CVD). We aimed to determine the incidence of GI syndromes and interventions preceding PD compared with negative controls (NCs), AD and CVD.

Design: We performed a combined case-control and cohort study using TriNetX, a US based nationwide medical record network.

Human primary liver cancer organoids reveal intratumor and interpatient drug response heterogeneity.

Liver cancer is the fourth leading cause of cancer-related mortality and is distinguished by a relative paucity of chemotherapy options. It has been hypothesized that intratumor genetic heterogeneity may contribute to the high failure rate of chemotherapy. Here, we evaluated functional heterogeneity in a cohort of primary human liver cancer organoid lines.

Functional variants in the gene confer shared effects on risk for Crohn's disease and Parkinson's disease.

Crohn's disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewish than in non-Jewish European populations. To define the role of nonsynonymous mutations, we performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2066 CD cases and 3633 healthy controls. We detected association signals in the gene that conferred risk for CD (N2081D variant, = 9.

A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition.

Background & Aims: Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA).

Methods: Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls.

A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF.

Background & Aims: Crohn's disease (CD) has the highest prevalence in Ashkenazi Jewish populations. We sought to identify rare, CD-associated frameshift variants of high functional and statistical effects.

Methods: We performed exome sequencing and array-based genotype analyses of 1477 Ashkenazi Jewish individuals with CD and 2614 Ashkenazi Jewish individuals without CD (controls).

Defects in NADPH Oxidase Genes and in Very Early Onset Inflammatory Bowel Disease.

Background & Aims: Defects in intestinal innate defense systems predispose patients to inflammatory bowel disease (IBD). Reactive oxygen species (ROS) generated by nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases in the mucosal barrier maintain gut homeostasis and defend against pathogenic attack. We hypothesized that molecular genetic defects in intestinal NADPH oxidases might be present in children with IBD.

Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins.

The Ashkenazi Jewish (AJ) population is a genetic isolate close to European and Middle Eastern groups, with genetic diversity patterns conducive to disease mapping. Here we report high-depth sequencing of 128 complete genomes of AJ controls. Compared with European samples, our AJ panel has 47% more novel variants per genome and is eightfold more effective at filtering benign variants out of AJ clinical genomes.

Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases.

Effector CD4+ T cell expression signatures and immune-mediated disease associated genes.

Genome-wide association studies (GWAS) in immune-mediated diseases have identified over 150 associated genomic loci. Many of these loci play a role in T cell responses, and regulation of T cell differentiation plays a critical role in immune-mediated diseases; however, the relationship between implicated disease loci and T cell differentiation is incompletely understood. To further address this relationship, we examined differential gene expression in naïve human CD4+ T cells, as well as in in vitro differentiated Th1, memory Th17-negative and Th17-enriched CD4+ T cells subsets using microarray and RNASeq.

Gene selection using iterative feature elimination random forests for survival outcomes.

Although many feature selection methods for classification have been developed, there is a need to identify genes in high-dimensional data with censored survival outcomes. Traditional methods for gene selection in classification problems have several drawbacks. First, the majority of the gene selection approaches for classification are single-gene based.

Time-motion analysis of health care workers' contact with patients and workers' hand hygiene: open vs closed units.

Background: The effects of open (care provided by general medicine teams with a pulmonary intensivist consultant) vs closed (care provided by a dedicated critical care team) intensive care units on health care workers' contact with patients and their hand hygiene is uncertain.

Objective: To determine if closed intensive care units have fewer visits of patients by health care providers and greater hand-washing compliance among providers than do open units.

Methods: Time-motion analysis was used to observe 2 rooms in a medical intensive care unit at a teaching hospital affiliated with Indiana University School of Medicine, Indianapolis, for 96 hours before and after closure of the unit.