Development of Clinical Prediction Models for Surgery and Complications in Crohn’s Disease

Background and Objective: Crohn’s disease (CD)-related complications account for a substantial proportion of IBD-related healthcare expenditure. Identifying patients at risk for complications may allow for targeted use of early therapeutic interventions to alter this natural course. The objective of this project was to develop risk prediction models of CD-related surgery and complications. Methods: Using data from the REACT cluster-randomized clinical trial (N=1898 from 41 community practices), prediction models were developed and internally validated for CD-related surgery and CD-related complications, defined as the first CD-related surgery, hospitalization or complication within 24 months. Performance of each model was assessed in terms of discrimination and calibration, as well as decision curves and net benefit analyses. Results: There were 130 (6.8%) CD-related surgeries and 504 (26.6%) CD-related complications during the 24-month follow-up period. Selected baseline predictors for predicting surgery included age, gender, disease location, HBI score, stool frequency, antimetabolite or 5-aminosalicylates use, and the presence of a fistula, abscess or abdominal mass. Selected predictors of complications included those same factors for surgery, corticosteroid and TNF-antagonist use and excluded 5-aminosalicylate use. The discrimination ability, as measured by optimism-corrected c-statistic, was 0.70 for the surgery model, and 0.62 for the complication model. Score charts and nomograms were developed to facilitate future risk score calculation. Conclusions: Risk prediction models for CD-related surgery and CD-related complications were developed using clinical trial data involving community gastroenterology practices. These models need to be externally validated before being used to guide management of CD

Novel Mechanisms In The Sorting Of Proglucagon To The Secretory Granules Of The Regulated Secretory Pathway

The prohormone proglucagon encodes for multiple peptide hormones, including glucagon, glucagon-like peptide-1 (GLP-1), and GLP-2, produced through tissue-specific processing by prohormone convertase (PC) 1/3 and PC2. In alpha cells, PC2 yields glucagon, the major counter-regulatory hormone to insulin, which together, control glucose homeostasis. In contrast, GLP-1 and GLP2 are mainly produced in intestinal L-cells by PC1/3. GLP-1 stimulates insulin secretion following a meal, and therefore has opposing function to glucagon regulating glucose homeostasis; in contrast, GLP-2 enhances gut nutrient absorption. Efficient sorting of proglucagon to secretory granules is required for nutrient-regulated secretion. The aim of this thesis is to discover the molecular mechanisms by which proglucagon is targeted to secretory granules, which ensures that proglucagon is correctly processed to mature hormones, and is necessary for prompt physiologic response to nutrient status. In this thesis, we identify several sorting signals within the hormone domains of proglucagon that encode targeting information. Using quantitative immunofluorescence microscopy and co-localization analyses, I was able to determine the molecular nature by which glucagon and GLP-1 enter granules. Despite these two hormones sharing a large degree of structural homology, it is their particular alpha-helix structures that enable the sorting of proglucagon. Further, I provide evidence that proglucagon is first sorted to granules prior to being processed to active hormones. Furthermore, I have identified carboxypeptidase E in the mechanism by which glucagon sorts within alpha cells. Together, each hormone carries with it a unique sorting “signature” to efficiently reach its destination, and allows alpha and L-cells to tightly regulate nutrient homeostasis

Cholinergic receptor pathways involved in apoptosis, cell proliferation and neuronal differentiation

Acetylcholine (ACh) has been shown to modulate neuronal differentiation during early development. Both muscarinic and nicotinic acetylcholine receptors (AChRs) regulate a wide variety of physiological responses, including apoptosis, cellular proliferation and neuronal differentiation. However, the intracellular mechanisms underlying these effects of AChR signaling are not fully understood. It is known that activation of AChRs increase cellular proliferation and neurogenesis and that regulation of intracellular calcium through AChRs may underlie the many functions of ACh. Intriguingly, activation of diverse signaling molecules such as Ras-mitogen-activated protein kinase, phosphatidylinositol 3-kinase-Akt, protein kinase C and c-Src is modulated by AChRs. Here we discuss the roles of ACh in neuronal differentiation, cell proliferation and apoptosis. We also discuss the pathways involved in these processes, as well as the effects of novel endogenous AChRs agonists and strategies to enhance neuronal-differentiation of stem and neural progenitor cells. Further understanding of the intracellular mechanisms underlying AChR signaling may provide insights for novel therapeutic strategies, as abnormal AChR activity is present in many diseases

Recommendations for Standardizing MRI-based Evaluation of Perianal Fistulizing Disease Activity in Pediatric Crohn's Disease Clinical Trials

BACKGROUND: Perianal fistulas and abscesses occur commonly as complications of pediatric Crohn's disease (CD). A validated imaging assessment tool for quantification of perianal disease severity and activity is needed to evaluate treatment response. We aimed to identify magnetic resonance imaging (MRI)-based measures of perianal fistulizing disease activity and study design features appropriate for pediatric patients. METHODS: Seventy-nine statements relevant to MRI-based assessment of pediatric perianal fistulizing CD activity and clinical trial design were generated from literature review and expert opinion. Statement appropriateness was rated by a panel (N = 15) of gastroenterologists, radiologists, and surgeons using modified RAND/University of California Los Angeles appropriateness methodology. RESULTS: The modified Van Assche Index (mVAI) and the Magnetic Resonance Novel Index for Fistula Imaging in CD (MAGNIFI-CD) were considered appropriate instruments for use in pediatric perianal fistulizing disease clinical trials. Although there was concern regarding the use of intravascular contrast material in pediatric patients, its use in clinical trials was considered appropriate. A clinically evident fistula tract and radiologic disease defined as at least 1 fistula or abscess on pelvic MRI were considered appropriate trial inclusion criteria. A coprimary clinical and radiologic end point and inclusion of a patient-reported outcome were also considered appropriate. CONCLUSION: Outcomes of treatment of perianal fistulizing disease in children must include MRI. Existing multi-item measures, specifically the mVAI and MAGNIFI-CD, can be adapted and used for children. Further research to assess the operating properties of the indices when used in a pediatric patient population is ongoing