Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression.

An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications.

Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn's Disease: A Pragmatic Randomized Trial.

BACKGROUND & AIMS: Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy. METHODS: Patients with pediatric Crohn's disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected. RESULTS: Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs. CONCLUSIONS: Among adalimumab but not infliximab initiators, patients with pediatric Crohn's disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile. CLINICALTRIALS: gov, Number: NCT02772965.

Multicenter Cohort Study of Infliximab Pharmacokinetics and Therapy Response in Pediatric Acute Severe Ulcerative Colitis.

BACKGROUND & AIMS: We aimed to model infliximab (IFX) pharmacokinetics (PK) in pediatric acute severe ulcerative colitis (ASUC) and assess the association between PK parameters, including drug exposure, and clinical response. METHODS: We studied a multicenter prospective cohort of hospitalized children initiating IFX for ASUC or IBD-unclassified. Serial IFX serum concentrations over 26 weeks were used to develop a PK model. We tested the association of PK parameter estimates with day 7 clinical response, week 8 clinical remission, week 26 corticosteroid-free clinical remission (CSF-CR) (using the Pediatric Ulcerative Colitis Activity Index), and colectomy-free survival. RESULTS: Thirty-eight participants received IFX (median initial dose, 9.9 mg/kg). Day 7 clinical response, week 8 clinical remission, and week 26 CSF-CR occurred in 71%, 55%, and 43%, respectively. Albumin, C-reactive protein, white blood cell count, platelets, weight, and antibodies to IFX were significant covariates incorporated into a PK model. Week 26 non-remitters exhibited faster IFX clearance than remitters (P = .013). However, cumulative IFX exposure did not differ between clinical response groups. One (2.7%) and 4 (10.8%) participants underwent colectomy by week 26 and 2 years, respectively. Day 3 IFX clearance >0.02 L/h was associated with colectomy (hazard ratio, 58.2; 95% confidence interval, 6.0-568.6; P < .001). CONCLUSIONS: At median higher-than-label IFX dosing for pediatric ASUC, baseline faster IFX CL was associated with colectomy and at week 26 with lack of CSF-CR. IFX exposure was not predictive of clinical outcomes. Higher IFX dosing may sufficiently optimize early outcomes in pediatric ASUC. Larger studies are warranted to determine whether sustained intensification can overcome rapid clearance and improve later outcomes. CLINICALTRIALS: gov identifier: NCT02799615.

Outcomes for Standardized Home and Hospital-Based Infusions of Infliximab for Children With Inflammatory Bowel Disease.

BACKGROUND: Pediatric inflammatory bowel disease (IBD) is commonly treated with infliximab in a hospital setting. Utilization of home infusions (HI) is increasing due to insurance mandates, travel time savings, and convenience. We evaluated adverse outcomes (AOs) of infliximab infusions in children with IBD receiving HI compared to hospital-based infusions. METHODS: Children receiving HI between September 2016 and September 2018 were retrospectively matched based on age, race, ethnicity, sex, and disease type to a cohort receiving infliximab at a hospital-based center. A survival analysis evaluated the hazard ratio for AOs in HI relative to hospital-infused children over 2 years. AOs were defined as discontinuation of therapy for clinically relevant reasons, IBD-related hospitalizations, and emergency department visits. RESULTS: We included 102 children (51 pairs) (63% male, 91% White, 92% Crohn disease). Disease location, behavior, growth status, and disease severity were similar between the 2 cohorts. Quiescent disease increased from 3% to 93% after 2 years without cohort differences. At baseline, 94% of HI patients and 88% of controls were on 5 mg/kg every 8 weeks as standard maintenance therapy. Within 2 years, only 19% remained on 5 mg/kg and the remainder required increased dosing or decreased interval. The HI cohort had fewer labs obtained ( P < 0.001), though laboratory values, number of clinic visits, and frequency of AOs were similar. CONCLUSION: Drug durability, AOs, and laboratory values were similar between HI and hospital-based infusions. These findings suggest HI may be as effective as hospital-based infusions, provided a standardized care approach is utilized.

Biosimilars for Pediatric Patients With Inflammatory Bowel Disease: Pediatric Gastroenterology Clinical Practice Survey.

BACKGROUND: Biosimilars are biological agents that have been demonstrated to have similar safety and efficacy profiles as the originator. The objective of this study was to evaluate the perspectives of pediatric gastroenterologists in the United States (U.S.) toward biosimilar use and to explore factors that impact their comfort level with prescribing infliximab biosimilars. METHODS: A cross-sectional survey was developed and distributed to pediatric gastroenterology physicians from the U.S. via a listserv (Pediatric gastroenterology Bulletin Board). Respondent's demographics were recorded. Using a 6-point Likert scale, the survey assessed the respondent's perceptions toward biosimilars and initiating switches from the originator to biosimilar agent along with factors impacting provider's comfort level. Fischer exact tests were used to detect statistically significant differences in responses for hypotheses of interest. RESULTS: One hundred thirty-nine pediatric gastroenterologists completed the online survey (response rate 5.4%). Eighty-seven percent of respondents reported being comfortable prescribing infliximab biosimilars to anti-tumor necrosis factor naive patients, and 69% reported being comfortable doing a one-time switch if the patient was in clinical remission. Factors that negatively impacted a respondent's comfort level included respondents not practicing at an ImproveCareNow (ICN) center and managing less than 50 patients with inflammatory bowel diseases (IBD). CONCLUSIONS: Nearly 90% of pediatric gastroenterologists felt comfortable prescribing an infliximab biosimilar, and 70% felt comfortable with a one-time switch to the biosimilar if the patient was in clinical remission. Involvement in ICN a learning health system and caring for higher numbers of patients with IBD was associated with increased provider comfort with biosimilar use.

Early Change in Fecal Calprotectin Predicts One-Year Outcome in Children Newly Diagnosed With Ulcerative Colitis.

INTRODUCTION: While fecal calprotectin (FC) is used to assess disease activity in ulcerative colitis (UC) there are little data concerning the role of serial FC levels at diagnosis in predicting clinical course. We sought to determine whether FC at diagnosis or early change following therapy predicts clinical outcomes in pediatric UC.Methods: Children with newly diagnosed UC were treated with standardized regimens of mesalamine or corticosteroids (CS). CS tapering and escalation to additional therapy or colectomy were by protocol. Patients with baseline or week 4 or week 12 FC levels were included in the analysis. Our primary outcome was CS-free remission on mesalamine at week 52. We compared the prognostic value of a baseline FC as well as a change in FC by week 4 or week 12 in predicting clinical outcomes. RESULTS: The study included 352 children (113 initial mesalamine, 239 initial CS, mean age 12.6 years) with UC. At Week 52, 135 (38.3%), 84 (23.8%), and 19 (5.4%) children achieved CS-free remission, needed anti-tumor necrosis factor therapy or had colectomy respectively. Baseline FC was not associated with CS-free remission at week 52. However, both week 4 (odds ratio [OR] 0.95, 95% confidence interval [CI] 0.901.00) and week 12 FC levels (OR 0.91, 95% CI 0.87-0.96) were associated with outcomes, with the latter having a stronger association with CS-free remission. Patients with a >75% decrease by 12 weeks, had a 3-fold increased likelihood of CS-free remission at 1 year. DISCUSSION: Longitudinal changes in FC may predict 1 year outcomes better than values at diagnosis in children with a new diagnosis of UC.

Predicting Suboptimal Transitions in Adolescents With Inflammatory Bowel Disease.

OBJECTIVES: Adolescents and young adults (AYAs) are at risk for disease exacerbations and increased health care utilization around the time of transition to adult care. Our aim was to identify risk factors predictive of a suboptimal transition for AYA with inflammatory bowel disease. MATERIALS AND METHODS: We performed a retrospective chart review of patients with pediatric inflammatory bowel disease transferred to adult care from our institution in 2016 and 2017, recording demographic, psychosocial, and disease-specific data. Post-transfer data were obtained via the health care information exchange from the adult provider within our electronic medical record. We defined suboptimal transition as either a return to pediatric care or requiring care escalation within 1 year of transfer. RESULTS: Out of 104 subjects 37 (36%) were found to have had a suboptimal transition. Our models suggest that a suboptimal transition is associated with several risk factors including any mental health diagnosis (odds ratio [OR] = 4.15; 95% confidence interval [95% CI]: 1.18-14.59), history of medication nonadherence (OR = 5.15 [95% CI: 1.52-17.42]), public insurance (OR = 6.60 [95% CI: 1.25-34.96]), higher Physician Global Assessment score at time of transition (OR = 6.64 [95% CI: 1.60-27.58], and short Pediatric Crohn Disease Activity Index scores (OR = 1.17 [95% CI: 1.03-1.33]). Higher hemoglobin levels at transition were protective (OR = 0.69 [95% CI: 0.48-0.98]). Age at time of transition, disease duration, and medication type at transition were not found to be associated with transition outcomes. CONCLUSION: AYA with public insurance, a mental health history, medication nonadherence, and evidence of active disease may be at greater risk for suboptimal and poor health outcomes at transition.

Incorporation of a chiral gem-disubstituted nitrogen heterocycle yields an oxazolidinone antibiotic with reduced mitochondrial toxicity.

gem-Disubstituted N-heterocycles are rarely found in drugs, despite their potential to improve the drug-like properties of small molecule pharmaceuticals. Linezolid, a morpholine heterocycle-containing oxazolidinone antibiotic, exhibits significant side effects associated with human mitochondrial protein synthesis inhibition. We synthesized a gem-disubstituted linezolid analogue that when compared to linezolid, maintains comparable (albeit slightly diminished) activity against bacteria, comparable in vitro physicochemical properties, and a decrease in undesired mitochondrial protein synthesis (MPS) inhibition. This research contributes to the structure-activity-relationship data surrounding oxazolidinone MPS inhibition, and may inspire investigations into the utility of gem-disubstituted N-heterocycles in medicinal chemistry.

Creatively Improving Care Delivery.

The medical community has been challenged to improve upon deficiencies in the delivery of patient care. Quality improvement methods are therefore increasingly used in everyday clinical practice. As demonstrated in this review, creative and impactful improvement projects within pediatric gastroenterology can be successfully achieved as either multicenter projects or single-center efforts. Through our willingness to accept the challenge to improve, practitioners within the pediatric gastroenterology community have become leaders in using quality improvement to change practice and improve clinical outcomes.

Prevalence and Impact of Functional Abdominal Pain Disorders in Children With Inflammatory Bowel Diseases (IBD-FAPD).

OBJECTIVES: We sought to describe the prevalence of the overlap of functional abdominal pain disorders (FAPDs) in children with inflammatory bowel diseases (IBDs), a condition we have designated as IBD-FAPD. We also aimed to describe the psychological profile of this group, and to assess predictors of disease and the impact of IBD-FAPD on quality of life. METHODS: This cross-sectional prospective study included patients ages 8 to 18 years with a diagnosis of IBD. Disease activity was assessed by physician's global assessment, laboratory studies, and abbreviated Pediatric Crohn's Disease Activity Index or Pediatric Ulcerative Colitis Activity Index scoring. Age-appropriate validated questionnaires were used to diagnose FAPDs according to the Rome III criteria, depression, anxiety symptoms, and quality of life. RESULTS: There were 128 patients recruited. Eighty-one (63%) completed questionnaires (36 girls; 45 boys; mean age 14.4 ±â€Š2.6 years) (62 Crohn disease, 19 ulcerative colitis). The prevalence of IBD-FAPD in clinical remission was 26% (17 Crohn disease, 4 ulcerative colitis; 95% confidence interval: 20.6%-79.4%), with significantly more girls having IBD-FAPD (P = 0.038). Anxiety symptoms were in 14.3% of patients with IBD-FAPD (P = 0.06) and depression in 23.8% (P = 0.006). The average Pediatric Quality of Life Inventory Gastrointestinal Symptoms score for the IBD-FAPD group was significantly lower than those without FAPDs (71 vs 86.5, P = 0.008). CONCLUSIONS: In our cohort, the prevalence of IBD-FAPD was 26%. This is the first study to assess all FAPDs using the Rome III criteria and to demonstrate increased anxiety, depression, and worse quality of life in children with IBD-FAPD. The identification of patients predisposed to IBD-FAPD may allow implementing strategies that could improve symptoms and quality of life.

Complementary and Alternative Medicine Use in Children With Inflammatory Bowel Diseases: A Single-Center Survey.

OBJECTIVES: The prevalence of inflammatory bowel diseases (IBD) and use of complementary and alternative medicine (CAM) are both common and increasing. The definition of CAM therapy among both practitioners and patients is variable. The aim of our study was to update our understanding of how pediatric IBD patients use, perceive, and define CAM therapies. METHODS: We surveyed families of patients with IBD followed in the Gastroenterology Division at Nationwide Children's Hospital in summer 2014 during a routine clinic visit. The survey included questions about the following demographic and disease information; use and side effects associated with prior conventional therapies (CT); and attitudes toward, and use of CAM. RESULTS: The questionnaire was completed by 104 of 118 patients approached (14 ±â€Š3 years; 43% women). Patients had previously used an average of 3 CT. CAM therapy was used by 84% of patients surveyed, although only 24% of patients/families considered themselves to be using CAM. Common CAM therapies included vitamins/supplements, stress management techniques, and/or dietary changes. Factors associated with using specific CAM therapies included self-reported prior CT-related side effects (P < 0.01) and moderate/severe disease activity (P < 0.01). Most families (77%) desired to learn more about CAM. CONCLUSIONS: Patients seen in a tertiary care center for pediatric IBD frequently integrated CAM therapies into their treatment regimen. Patients with prior side effects from CT or more severe disease were more likely to use CAM. Given the high prevalence of CAM use, pediatric gastrointestinal physicians should be knowledgeable and open to discussions about CAM therapies with their patients.

Incidence, pattern, and etiology of elevated liver enzymes in pediatric inflammatory bowel disease.

OBJECTIVES: Patients with inflammatory bowel disease (IBD) often develop elevated liver enzymes (ELE), which are frequently a benign, transient finding, but may be related to treatment or IBD-associated liver diseases. Distinguishing benign from pathologic ELE is crucial for focused diagnostic and therapeutic interventions. We sought to characterize the incidence, character, chronicity, degree, and etiology of ELE in children with IBD. METHODS: Institutional review board-approved retrospective review of all of the patients with IBD (2-21 years) seen between October 2009 and October 2012 with >9 months of follow-up were included in the study. We examined body mass index, disease activity, extent, phenotype, concurrent medications, and character, chronicity, degree of enzyme elevation, and final diagnosis. RESULTS: A total of 219 of 514 patients with IBD had ≥1 episode of ELE. Five patients were excluded for preexisting liver disease, leaving 214 patients (Crohn disease [CD]: 14.8 ±â€Š3.5 years, 46% girls; ulcerative colitis [UC]: 14.4 ±â€Š4.2 years, 37% girls). One hundred forty-eight patients (69%) had a hepatic, 17 (8%) cholestatic, and 49 (23%) mixed character of ELE. There were no significant differences in character, chronicity, or degree of ELE between CD and UC (P = 0.71, P = 0.58, P > 0.33). Of the 128 patients with sufficient data to determine chronicity, 98 (77%) had transient elevations, (CD: n = 66, 75% and UC: n = 32, 80%). Episodes of ELE were idiopathic in 87% of patients with IBD. A final diagnosis of idiopathic ELE was associated with a lower degree of ELE elevation (P < 0.0001). CONCLUSIONS: Pediatric patients with IBD commonly experience transient, idiopathic ELE. Our findings suggest that higher degrees of ELE, specifically alanine aminotransferase, are associated with an etiology that requires more extensive evaluation.

Linking microbial genes to plasma and stool metabolites uncovers host-microbial interactions underlying ulcerative colitis disease course.

Understanding the role of the microbiome in inflammatory diseases requires the identification of microbial effector molecules. We established an approach to link disease-associated microbes to microbial metabolites by integrating paired metagenomics, stool and plasma metabolomics, and culturomics. We identified host-microbial interactions correlated with disease activity, inflammation, and the clinical course of ulcerative colitis (UC) in the Predicting Response to Standardized Colitis Therapy (PROTECT) pediatric inception cohort. In severe disease, metabolite changes included increased dipeptides and tauro-conjugated bile acids (BAs) and decreased amino-acid-conjugated BAs in stool, whereas in plasma polyamines (N-acetylputrescine and N1-acetylspermidine) increased. Using patient samples and Veillonella parvula as a model, we uncovered nitrate- and lactate-dependent metabolic pathways, experimentally linking V. parvula expansion to immunomodulatory tryptophan metabolite production. Additionally, V. parvula metabolizes immunosuppressive thiopurine drugs through xdhA xanthine dehydrogenase, potentially impairing the therapeutic response. Our findings demonstrate that the microbiome contributes to disease-associated metabolite changes, underscoring the importance of these interactions in disease pathology and treatment.

Mucosal transcriptomics highlight lncRNAs implicated in ulcerative colitis, Crohn's disease, and celiac disease.

Ulcerative colitis (UC), Crohn's disease (CD), and celiac disease are prevalent intestinal inflammatory disorders with nonsatisfactory therapeutic interventions. Analyzing patient data-driven cohorts can highlight disease pathways and new targets for interventions. Long noncoding RNAs (lncRNAs) are attractive candidates, since they are readily targetable by RNA therapeutics, show relative cell-specific expression, and play key cellular functions. Uniformly analyzing gut mucosal transcriptomics from 696 subjects, we have highlighted lncRNA expression along the gastrointestinal (GI) tract, demonstrating that, in control samples, lncRNAs have a more location-specific expression in comparison with protein-coding genes. We defined dysregulation of lncRNAs in treatment-naive UC, CD, and celiac diseases using independent test and validation cohorts. Using the Predicting Response to Standardized Pediatric Colitis Therapy (PROTECT) inception UC cohort, we defined and prioritized lncRNA linked with UC severity and prospective outcomes, and we highlighted lncRNAs linked with gut microbes previously implicated in mucosal homeostasis. HNF1A-AS1 lncRNA was reduced in all 3 conditions and was further reduced in more severe UC form. Similarly, the reduction of HNF1A-AS1 ortholog in mice gut epithelia showed higher sensitivity to dextran sodium sulfate-induced colitis, which was coupled with alteration in the gut microbial community. These analyses highlight prioritized dysregulated lncRNAs that can guide future preclinical studies for testing them as potential targets.

Development of a flexible strategy towards FR900482 and the mitomycins.

FR900482 and the mitomycins are two intriguing classes of alkaloid natural products that have analogous biological mechanisms and obvious structural similarity. Both classes possess potent anticancer activity, a feature that has led to their investigation and implementation for the clinical treatment of human cancer. Given the structural similarity between these natural products, we envisioned a common synthetic strategy by which both classes could be targeted through assembling the mitomycin skeleton prior to further oxidative functionalization. Realization of this strategy with respect to FR900482 was accomplished through the synthesis of 7-epi-FR900482, which displayed equal potency relative to the natural product against two human cancer cell lines. With the challenging goal of a synthesis of either mitomycin or FR900482 in mind, several methodologies were explored. While not all of these methods ultimately proved useful for our synthetic goal, a number of them led to intriguing findings that provide a more complete understanding of several methodologies. In particular, amination via π-allyl palladium complexes for the synthesis of tetrahydroquinolines, eight-membered heterocycle formation via carbonylative lactamization, and amination through late-stage C-H insertion via rhodium catalysis all featured prominently in our synthetic studies.

Achieving Target Infliximab Drug Concentrations Improves Blood and Fecal Neutrophil Biomarkers in Crohn's Disease.

BACKGROUND: The neutrophil fecal biomarkers, calprotectin (FCP) and lactoferrin (LCT), and peripheral blood neutrophil CD64 surface receptor (nCD64) are biomarkers for mucosal inflammation in inflammatory bowel disease (IBD). Although FCP has been evaluated as a biomarker for mucosal healing, cut points for LCT and nCD64 are less known. We aimed to identify the cut points for LCT and nCD64 that were associated with FCP remission, with a secondary aim to evaluate the relationship between biochemical outcomes and infliximab (IFX) trough concentrations. METHODS: We analyzed FCP, LCT, and nCD64 before and after IFX induction in a pediatric Crohn's disease (CD) cohort study. Week-14 FCP biomarker remission was defined as FCP <250 µg/g, with clinical response defined as a weighted Pediatric Crohn's Disease Activity Index <12.5 or Δ>17.5 improvement. Predictive outcomes were calculated by receiver operating characteristics (ROCs). RESULTS: Among 56 CD patients, ROC analysis identified an infusion 4 LCT <8.06 (area under the receiver operator characteristics [AUROC], 0.934, P < 0.001) and nCD64 <6.12 (AUROC, 0.76, P = 0.02) as the ideal cut points for week-14 FCP biomarker remission. End of induction IFX-trough of >9.4 µg/mL (AUROC, 0.799, P = 0.002) and >11.5 µg/mL (AUROC, 0.835, P = 0.003) were associated with a FCP <250 and FCP <100, respectively. We found patients achieving end of induction trough >5 µg/mL had a median FCP improvement (dose 1 to dose 4) of 90% compared with a median of 35% with levels <5 µg/mL (P = 0.024) with a similar median reduction in nCD64 (48% vs 20%, P = 0.031). CONCLUSIONS: This study establishes cut points in neutrophil stool and blood biomarkers for both biochemical remission and therapeutic trough levels following induction therapy. Further studies that evaluate pharmacodynamic biomarker targets for endoscopic and histologic healing are warranted.

Similar Long-Term Outcomes in Children Presenting With Abscess vs Phlegmon at Diagnosis of Crohn Disease.

Background: Limited data are available for long-term outcomes of pediatric patients with abdominal abscess or phlegmon at diagnosis of Crohn disease. Methods: We performed a retrospective chart review of such children over a recent 6-year period at 5 pediatric inflammatory bowel diseases. Results: Fifty-two patients (mean age 15.9 ± 1.8 years) were reviewed. Thirty-six had an abscess and 27 (75%) required resectional therapy compared to 16 with phlegmon which 10 (63%) requiring surgery. Overall (37/52) 71% had surgery which was performed within 6 months in 32 (86%). Conclusions: A similar high surgical rate exists whether pediatric patients with Crohn disease present with abscess or phlegmon.

Total synthesis and stereochemical assignment of (-)-ushikulide A.

We report the determination of the full stereostructure of (-)-ushikulide A (1), a spiroketal containing macrolide by total synthesis. Ushikulide A (1) was isolated from a culture broth of Streptomyces sp. IUK-102 and exhibits potent immunosuppressant activity (IC(50) = 70 nM). To embark upon an ushikulide A synthesis, a tentative assignment was made based on analogy to cytovaricin (2), a related macrolide isolated from a culture of Streptomyces diastatochromogenes whose full structure was previously established via synthesis and X-ray crystallography. This report delineates studies on several key steps, namely a direct aldol reaction catalyzed by the dinuclear zinc ProPhenol complex, a metal catalyzed spiroketalization, as well as application of an unprecedented asymmetric alkynylation of a simple saturated aldehyde with methyl propiolate to prepare the nucleophilic partner for a Marshall-Tamaru propargylation. These studies culminated in the first total synthesis and stereochemical assignment of (-)-ushikulide A and significantly extended the scope of the above-mentioned methodologies.

Quality of health care in the United States: implications for pediatric inflammatory bowel disease.

The Institute of Medicine's publications To Error is Human and Crossing the Quality Chasm publicized the widespread deficits in US health care quality. Emerging studies continue to reveal deficits in the quality of adult and pediatric care, including subspecialty care. In recent years, key stakeholders in the health care system including providers, purchasers, and the public have been applying various quality improvement methods to address these concerns. Lessons learned from these efforts in other pediatric conditions, including asthma, cystic fibrosis, neonatal intensive care, and liver transplantation may be applicable to the care of children with inflammatory bowel disease (IBD).This review is intended to be a primer on the quality of care movement in the United States, with a focus on pediatric IBD. In this article, we review the history, rationale, and methods of quality measurement and improvement, and we discuss the unique challenges in adapting these general strategies to pediatric IBD care.

Challenges in IBD Research: Pragmatic Clinical Research.

Pragmatic clinical research is part of five focus areas of the Challenges in IBD research document, which also includes preclinical human IBD mechanisms, environmental triggers, novel technologies, and precision medicine. The Challenges in IBD research document provides a comprehensive overview of current gaps in inflammatory bowel diseases (IBD) research and delivers actionable approaches to address them. It is the result of multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient centric research prioritization. In particular, the pragmatic clinical research section is focused on highlighting gaps that need to be addressed in order to optimize and standardize IBD care. Identified gaps include: 1) understanding the incidence and prevalence of IBD; 2) evaluating medication positioning to increase therapeutic effectiveness; 3) understanding the utility of therapeutic drug monitoring (TDM); 4) studying pain management; and 5) understanding healthcare economics and resources utilization. To address these gaps, there is a need to emphasize the use of emerging data sources and real-world evidence to better understand epidemiologic and therapeutic trends in IBD, expanding on existing data to better understand how and where we should improve care. Proposed approaches include epidemiological studies in ethnically and geographically diverse cohorts to estimate incidence and prevalence of IBD and impact of diversity on treatment patterns and outcomes. The implementation of new clinical trial design and methodologies will be essential to evaluate optimal medication positioning, appropriate use of TDM in adults and children, and multidisciplinary approaches to IBD pain management and its impact on healthcare resources.