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. Mitochondrial activity was measured using high-resolution respirometry and tissue stiffness using atomic force microscopy. RESULTS: HIOs expressed core mitochondrial and extracellular matrix (ECM) genes and enriched biologic functions implicated in CD ileal strictures; ECM gene expression was suppressed by both butyrate and ETYA, with butyrate also suppressing genes regulating epithelial proliferation. Consistent with this, butyrate, but not ETYA, exerted a profound effect on HIO epithelial mitochondrial function, reactive oxygen species production, and cellular abundance. Butyrate and ETYA suppressed HIO expression of alpha smooth muscle actin expressed by myofibroblasts, type I collagen, and collagen protein abundance. HIOs exhibited tissue stiffness comparable to normal human ileum; this was reduced by chronic ETYA exposure in HIOs carrying the DUOX2 loss-of-function haplotype. CONCLUSIONS: ETYA regulates ECM genes implicated in strictures and suppresses collagen content and tissue stiffness in an HIO model. HIOs provide a platform to test personalized therapeutics, including small molecules prioritized by perturbagen analysis.

A subset of pediatric Crohn's disease patients develop intestinal strictures requiring surgery. The microbial metabolite butyrate and eicosatetraynoic acid regulate pathways implicated in stricture formation in a human intestinal organoid model system, which may be used to test new therapies.

Trends in United States emergency department visits and associated charges from 2010 to 2016.

BACKGROUND: Demographic shifts and care delivery system evolution affect the number of Emergency Department (ED) visits and associated costs. Recent aggregate trends in ED visit rates and charges between 2010 and 2016 have not been evaluated. METHODS: Data from the National Emergency Department Sample, comprising approximately 30 million annual patient visits, were used to estimate the ED visit rate and charges per visit from 2010 to 2016. ED visits were grouped into 144 mutually exclusive clinical categories. Visit rates, compound annual growth rates (CAGRs), and per visit charges were estimated. RESULTS: From 2010 to 2016, the number of ED visits increased from 128.97 million to 144.82 million; the cumulative growth was 12.29% and the CAGR was 1.95%, while the population grew at a CAGR of 0.73%. Expressed as a population rate, ED visits per 1000 persons increased from 416.92 in 2010 to 448.19 in 2016 (p value <0.001). The mean charges per visit increased from $2061 (standard deviation $2962) in 2010 to $3516 (standard deviation $2962) in 2016; the CAGR was 9.31% (p value <0.001). Of 144 clinical categories, 140 categories had a CAGR for mean charges per visit of at least 5%. CONCLUSION: The rate of ED visits per 1000 persons and the mean charge per ED visit increased significantly between 2010 and 2016. Mean charges increased for both high- and low-acuity clinical categories. Visits for the 5 most common clinical categories comprise about 30% of ED visits, and may represent focus areas for increasing the value of ED care.