ASO silencing of a glycosyltransferase, Poglut1 , improves the liver phenotypes in mouse models of Alagille syndrome.

BACKGROUND AND AIMS: Paucity of intrahepatic bile ducts (BDs) is caused by various etiologies and often leads to cholestatic liver disease. For example, in patients with Alagille syndrome (ALGS), which is a genetic disease primarily caused by mutations in jagged 1 ( JAG1) , BD paucity often results in severe cholestasis and liver damage. However, no mechanism-based therapy exists to restore the biliary system in ALGS or other diseases associated with BD paucity. Based on previous genetic observations, we investigated whether postnatal knockdown of the glycosyltransferase gene protein O -glucosyltransferase 1 ( Poglut1) can improve the ALGS liver phenotypes in several mouse models generated by removing one copy of Jag1 in the germline with or without reducing the gene dosage of sex-determining region Y-box 9 in the liver. APPROACH AND RESULTS: Using an ASO established in this study, we show that reducing Poglut1 levels in postnatal livers of ALGS mouse models with moderate to profound biliary abnormalities can significantly improve BD development and biliary tree formation. Importantly, ASO injections prevent liver damage in these models without adverse effects. Furthermore, ASO-mediated Poglut1 knockdown improves biliary tree formation in a different mouse model with no Jag1 mutations. Cell-based signaling assays indicate that reducing POGLUT1 levels or mutating POGLUT1 modification sites on JAG1 increases JAG1 protein level and JAG1-mediated signaling, suggesting a likely mechanism for the observed in vivo rescue. CONCLUSIONS: Our preclinical studies establish ASO-mediated POGLUT1 knockdown as a potential therapeutic strategy for ALGS liver disease and possibly other diseases associated with BD paucity.

Total Hip Arthroplasty for Developmental Dysplasia of Hip vs Osteoarthritis: A Propensity Matched Pair Analysis.

BACKGROUND: The purpose of this study was to use the American College of Surgeons National Surgical Quality Improvement Program to compare the perioperative and postoperative outcomes after total hip arthroplasty (THA) for DDH and primary OA via a propensity-matched pair analysis and the valuation of THA between both groups. MATERIAL AND METHODS: All patients who underwent THA between 2008 and 2016 were identified from National Surgical Quality Improvement Program database via the current procedural terminology (CPT) code. Patients were further identified and stratified based on International Statistical Classification of Diseases and Related Health Problems-9/International Statistical Classification of Diseases and Related Health Problems-10 diagnosis codes for primary OA (n = 115,166) and DDH (n = 603), which included codes for congenital hip dislocation, hip dysplasia, or juvenile osteochondrosis. Demographic variables were used to create 557 propensity-matched pairs. RESULTS: The DDH group was associated with a significantly longer operative time (120.3 vs 95.9 min), higher postoperative transfusion rate (12% vs 6.6%), and longer hospital length of stay (2.8 vs 2.5 days) compared with the primary OA group (P < .001, P < .001, and P = .002, respectively). There were no statistically significant differences found between the two groups with respect to inpatient complications, discharge disposition (P = .123), readmissions (P = .615), or reoperations (P = .404). CONCLUSIONS: Health policy makers should be cognizant of the higher complexity of THA for DDH when determining whether DDH and primary OA should be in the same bundle. Owing to the limitations of our data set, all the observed associations are likely an underestimate of the true risk posed to patients with severe DDH, as these patients were unable to be stratified in the present analysis.