Helmrath, Michael A.

Objective: To identify child-, surgeon-, and hospital-specific factors at the time of primary cleft lip repair that are associated with the use of secondary cleft lip surgery. Design: Retrospective cohort study. Setting: Forty-nine pediatric hospitals. Participants: Children who underwent cleft lip repair between 1999 and 2015. Main outcome measure: Time from primary cleft lip repair to secondary lip surgery. Results: By 5 years after primary lip repair, 24.0% of children had undergone a secondary lip surgery. In multivariable analysis, primary lip repair before 3 months had a 1.22-fold increased hazard of secondary surgery (95% confidence interval [CI]: 1.02-1.46) compared to repair at 7 to 12 months of age, and children with multiple congenital anomalies had a 0.77-fold decreased hazard of secondary surgery (95% CI: 0.68-0.87). After adjusting for cleft type, age at repair, presence of multiple congenital anomalies, and procedure volume, there remained substantial variation in secondary surgery use among surgeons and hospitals ( P < .01). For children with unilateral cleft lip repaired at 3 to 6 months of age, the predicted proportion of children undergoing secondary surgery within 5 years of primary repair ranged from 4.9% to 21.8% across surgeons and from 4.5% to 24.7% across hospitals. Conclusions: There are substantial differences among surgeons and hospitals in the rates of secondary lip surgery. Further work is needed to identify causes for this variation among providers.

Objective: To identify child-, surgeon- and hospital-specific factors at the time of primary cleft palate repair that are associated with the use of secondary palate surgery. Design: Retrospective cohort study. Setting: Forty-nine pediatric hospitals. Participants: Children who underwent cleft palate repair between 1998 and 2015. Main Outcome Measure: Time from primary cleft palate repair to secondary palate surgery. Results: By 5 years after the primary palate repair, 27.5% of children had undergone secondary palate surgery. In multivariable analysis, cleft type and age at primary palate repair were both associated with secondary surgery ( P < .01). Children with unilateral cleft lip and palate had a 1.69-fold increased hazard of secondary surgery (95% confidence interval [CI]: 1.54-1.85) compared to children with cleft palate alone. Primary palate repair before 9 months had a 3.99-fold increased hazard of secondary surgery (95% CI: 3.39-4.07) compared to repair at 16 to 24 months of age. After adjusting for cleft type, age at repair, and procedure volume, there remained substantial variation in secondary surgery use among surgeons and hospitals ( P < .01). For children with isolated cleft palate, the predicted proportion of children undergoing secondary surgery within 5 years of primary repair ranged from 8.5% to 46.0% across surgeons and 9.1% to 49.4% across hospitals. Conclusions: There are substantial differences among surgeons and hospitals in the rates of secondary palate surgery. Further work is needed to identify causes for this variation among providers and develop interventions to reduce the need for secondary surgery.

Altered response to the intestinal microbiota strongly associates with inflammatory bowel disease (IBD); however, how commensal microbial cues are integrated by the host during the pathogenesis of IBD is not understood. Epigenetics represents a potential mechanism that could enable intestinal microbes to modulate transcriptional output during the development of IBD. Here, we reveal a histone methylation signature of intestinal epithelial cells isolated from the terminal ilea of newly diagnosed pediatric IBD patients. Genes characterized by significant alterations in histone H3-lysine 4 trimethylation (H3K4me3) showed differential enrichment in pathways involving immunoregulation, cell survival and signaling, and metabolism. Interestingly, a large subset of these genes was epigenetically regulated by microbiota in mice and several microbiota-sensitive epigenetic targets demonstrated altered expression in IBD patients. Remarkably though, a substantial proportion of these genes exhibited H3K4me3 levels that correlated with the severity of intestinal inflammation in IBD, despite lacking significant differential expression. Collectively, these data uncover a previously unrecognized epigenetic profile of IBD that can be primed by commensal microbes and indicate sensitive targets in the epithelium that may underlie how microbiota predispose to subsequent intestinal inflammation and disease.