The role of cGAS in epithelial dysregulation in inflammatory bowel disease and gastrointestinal malignancies.

The gastrointestinal tract is lined by an epithelial monolayer responsible for selective permeability and absorption, as well as protection against harmful luminal contents. Recognition of foreign or aberrant DNA within these epithelial cells is, in part, regulated by pattern recognition receptors such as cyclic GMP-AMP synthase (cGAS). cGAS binds double-stranded DNA from exogenous and endogenous sources, resulting in the activation of stimulator of interferon genes (STING) and a type 1 interferon response.

Ouch, my pouch! a clinician's guide to pouchitis.

Pouchitis is defined as inflammation of the ileal pouch created during a restorative proctocolectomy with ileal pouch-anal anastomosis. Although the incidence of this inflammatory condition is high, the exact etiology often remains unclear and the management challenging. In this review, we summarize the clinical presentation, pathogenesis, diagnosis, and management of this common complication.

Epithelial NAD depletion drives mitochondrial dysfunction and contributes to intestinal inflammation.

Introduction: We have previously demonstrated that a pathologic downregulation of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1α) within the intestinal epithelium contributes to the pathogenesis of inflammatory bowel disease (IBD). However, the mechanism underlying downregulation of PGC1α expression and activity during IBD is not yet clear.

Methods: Mice (male; C57Bl/6, /+; mice, and ) were subjected to experimental colitis and treated with nicotinamide riboside.

Studying the Epithelial Effects of Intestinal Inflammation In Vitro on Established Murine Colonoids.

The intestinal epithelium plays an essential role in human health, providing a barrier between the host and the external environment. This highly dynamic cell layer provides the first line of defense between microbial and immune populations and helps to modulate the intestinal immune response. Disruption of the epithelial barrier is a hallmark of inflammatory bowel disease (IBD) and is of interest for therapeutic targeting.

Validity of the American College of Radiology Thyroid Imaging Reporting and Data System in Children.

Objective: To assess the validity of the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) for evaluating thyroid nodules in children.

Methods: Patients aged <19 years with thyroid nodule(s) evaluated by ultrasound (US) from 2007-2018 at a tertiary children's hospital were included. Two radiologists scored de-identified thyroid US images using ACR TI-RADS (from 1, "benign" to 5, "highly suspicious").

Cyclic GMP-AMP synthase contributes to epithelial homeostasis in intestinal inflammation via Beclin-1-mediated autophagy.

Inflammatory bowel disease (IBD) represents a set of idiopathic and chronic inflammatory diseases of the gastrointestinal tract. Central to the pathogenesis of IBD is a dysregulation of normal intestinal epithelial homeostasis. cGAS is a DNA-sensing receptor demonstrated to promote autophagy, a mechanism that removes dysfunctional cellular components.

Eicosatetraynoic Acid and Butyrate Regulate Human Intestinal Organoid Mitochondrial and Extracellular Matrix Pathways Implicated in Crohn's Disease Strictures.

Background: Perturbagen analysis of Crohn's disease (CD) ileal gene expression data identified small molecules including eicosatetraynoic acid (ETYA), which may exert an antifibrotic effect. We developed a patient-specific human intestinal organoid (HIO) model system to test small molecule regulation of mitochondrial and wound-healing functions implicated in stricturing behavior.

Methods: HIOs were made from CD induced pluripotent stem cells with and without a loss-of-function haplotype in the DUOX2 gene implicated in ileal homeostasis and characterized under basal conditions and following exposure to butyrate and ETYA using RNA sequencing, flow cytometry, and immunofluorescent and polarized light microscopy.

Inactivation of RIP3 kinase sensitizes to 15LOX/PEBP1-mediated ferroptotic death.

Ferroptosis and necroptosis are two pro-inflammatory cell death programs contributing to major pathologies and their inhibition has gained attention to treat a wide range of disease states. Necroptosis relies on activation of RIP1 and RIP3 kinases. Ferroptosis is triggered by oxidation of polyunsaturated phosphatidylethanolamines (PUFA-PE) by complexes of 15-Lipoxygenase (15LOX) with phosphatidylethanolamine-binding protein 1 (PEBP1).

Inclusion and representation in the pediatric surgery workforce: Strategies to mitigate bias in the fellowship application process.

Diverse perspectives are critical components of effective teams in every industry. Underrepresentation of minorities in medicine leads to worse outcomes for minority patients, and efforts to increase diversity in the health care workforce are critical. Presently, about 70% of the pediatric surgery workforce is white, and pediatric surgeons at large do not reflect the racial or ethnic diversity of the populations they serve.

High Sugar-Sweetened Beverage Consumption Is Associated with Increased Health Care Utilization in Patients with Inflammatory Bowel Disease: A Multiyear, Prospective Analysis.

Background: Dietary factors like sugar-sweetened beverage (SSB) consumption are known to influence disease course in a variety of illnesses; however, long-term outcomes are not well documented for inflammatory bowel disease.

Objective: Does high consumption of SSBs lead to high healthcare utilization (ie, hospitalizations and emergency department visits), inflammation, and disease severity in patients with inflammatory bowel disease?

Design: A prospective cohort study was conducted from 2015 to 2019. Patients enrolled in the discovery study cohort were followed for 3 years, whereas patients in the validation cohort were followed for 2 years.

Unique Molecular Signatures Are Associated with Aggressive Histology in Pediatric Differentiated Thyroid Cancer.

Molecular testing (MT) enhances the diagnostic accuracy of thyroid fine-needle aspiration biopsy, reducing the need for diagnostic lobectomy in adult patients with indeterminate nodules (Bethesda class III/IV). However, little is known about genetic alterations in pediatric thyroid carcinoma (TC). Our aim was to analyze MT results of pediatric differentiated TC (DTC) cases to determine associations with histological and clinical features.

Chronic Lymphocytic Thyroiditis and Aggressiveness of Pediatric Differentiated Thyroid Cancer.

Objectives/hypothesis: Hashimoto's Thyroiditis (HT) is a common cause of hypothyroidism. Among adults with differentiated thyroid cancer (DTC), HT appears to be associated with less severe disease burden. In the absence of information regarding HT and disease burden among children with DTC, we assessed the relationship between pediatric DTC severity and HT.

Depletion of gut microbiota is associated with improved neurologic outcome following traumatic brain injury.

Signaling between intestinal microbiota and the brain influences neurologic outcome in multiple forms of brain injury. The impact of gut microbiota following traumatic brain injury (TBI) has not been well established. Our objective was to compare TBI outcomes in specific pathogen-free mice with or without depletion of intestinal bacteria.

An Evidence-Based Care Protocol Improves Outcomes and Decreases Cost in Pediatric Appendicitis.

Background: Appendicitis is a common indication for urgent abdominal surgery in the pediatric population. The postoperative management varies significantly in time to discharge and cost of care. The objective of this study was to investigate whether implementation of an evidence-based protocol after an appendectomy would lead to decreased length of stay and cost of care.

Nix-Mediated Mitophagy Modulates Mitochondrial Damage During Intestinal Inflammation.

Mitochondrial stress and dysfunction within the intestinal epithelium are known to contribute to the pathogenesis of inflammatory bowel disease (IBD). However, the importance of mitophagy during intestinal inflammation remains poorly understood. The primary aim of this study was to investigate how the mitophagy protein BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like (BNIP3L/NIX) mitigates mitochondrial damage during intestinal inflammation in the hopes that these data will allow us to target mitochondrial health in the intestinal epithelium as an adjunct to immune-based treatment strategies.

Effect of dietary cellulose supplementation on gut barrier function and apoptosis in a murine model of endotoxemia.

The gut plays a vital role in critical illness, and alterations in the gut structure and function have been reported in endotoxemia and sepsis models. Previously, we have demonstrated a novel link between the diet-induced alteration of the gut microbiome with cellulose and improved outcomes in sepsis. As compared to mice receiving basal fiber (BF) diet, mice that were fed a non-fermentable high fiber (HF) diet demonstrated significant improvement in survival and decreased organ injury in both cecal-ligation and puncture (CLP) and endotoxin sepsis models.

The Pediatric Surgeon-Scientist: Succeeding in Today's Academic Environment.

Background: Pediatric surgeons have long been advocates of basic science research. However, new challenges facing the scientific community have threatened the success of academic surgeons pursuing basic science careers. The purpose of this study was to compare academic pediatric surgeons' perceptions of their ability to effectively conduct basic science research to those of other surgical subspecialties.

Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response.

Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants.

Calcium/calmodulin-dependent protein kinase IV (CaMKIV) activation contributes to the pathogenesis of experimental colitis via inhibition of intestinal epithelial cell proliferation.

The incidence and prevalence of inflammatory bowel disease (IBD) are increasing worldwide. IBD is known to be multifactorial, but inflammatory signaling within the intestinal epithelium and a subsequent failure of the intestinal epithelial barrier have been shown to play essential roles in disease pathogenesis. CaMKIV is a multifunctional protein kinase associated with inflammation and cell cycle regulation.

Management and Outcome of Pediatric Patients With Transient Small Bowel-Small Bowel Intussusception.

Objective: The aim of this study was to assess the management and outcomes of healthy pediatric patients diagnosed radiologically with transient and benign small bowel-small bowel intussusception (SB-SBI).

Methods: Retrospective cohort study of healthy patients 0 to 18 years of age who presented to a children's hospital emergency department from January 1, 2005, to June 30, 2015, and had transient and benign SB-SBI characterized by spontaneous resolution (ie, transient), diameter of less than 2.5 cm, no lead point, normal bowel wall thickness, nondilated proximal small bowel, and no colonic involvement (ie, benign radiographic features).

Pediatric Sepsis Update: How Are Children Different?

Background: Although there are some commonalities between pediatric and adult sepsis, there are important differences in pathophysiology, clinical presentation, and therapeutic approaches. The recognition and diagnosis of sepsis is a significant challenge in pediatric patients as vital sign aberrations and examination findings are often subtle as compared to those observed in adults. Gaps in knowledge that have been studied in depth in adult sepsis are still being investigated in pediatric patients such as best practices in ventilation, invasive monitoring, and resuscitation.

Management of acute severe ulcerative colitis in children.

The incidence of pediatric-onset ulcerative colitis (UC) is rising. Children often present with a more severe disease phenotype as compared to adults with over a third requiring hospitalization for the management of acute severe ulcerative colitis (ASUC). Further, in pediatric patients presenting with inflammatory bowel disease (IBD) limited to the colon, a definitive diagnosis of UC vs.

Treatment with a Catalytic Superoxide Dismutase (SOD) Mimetic Improves Liver Steatosis, Insulin Sensitivity, and Inflammation in Obesity-Induced Type 2 Diabetes.

Oxidative stress and persistent inflammation are exaggerated through chronic over-nutrition and a sedentary lifestyle, resulting in insulin resistance. In type 2 diabetes (T2D), impaired insulin signaling leads to hyperglycemia and long-term complications, including metabolic liver dysfunction, resulting in non-alcoholic fatty liver disease (NAFLD). The manganese metalloporphyrin superoxide dismustase (SOD) mimetic, manganese (III) meso-tetrakis (-ethylpyridinium-2-yl) porphyrin (MnP), is an oxidoreductase known to scavenge reactive oxygen species (ROS) and decrease pro-inflammatory cytokine production, by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation.