Mucosal Expression of Type 2 and Type 17 Immune Response Genes Distinguishes Ulcerative Colitis From Colon-Only Crohn's Disease in Treatment-Naive Pediatric Patients

Background & Aims There is controversy regarding the role of the type 2 immune response in the pathogenesis of ulcerative colitis (UC)?few data are available from treatment-naive patients. We investigated whether genes associated with a type 2 immune response in the intestinal mucosa are up-regulated in treatment-naive pediatric patients with UC compared with patients with Crohn's disease (CD)-associated colitis or without inflammatory bowel disease (IBD), and whether expression levels are associated with clinical outcomes. Methods We used a real-time reverse-transcription quantitative polymerase chain reaction array to analyze messenger RNA (mRNA) expression patterns in rectal mucosal samples from 138 treatment-naive pediatric patients with IBD and macroscopic rectal disease, as well as those from 49 children without IBD (controls), enrolled in a multicenter prospective observational study from 2008 to 2012. Results were validated in real-time reverse-transcription quantitative polymerase chain reaction analyses of rectal RNA from an independent cohort of 34 pediatric patients with IBD and macroscopic rectal disease and 17 controls from Cincinnati Children's Hospital Medical Center. Results We measured significant increases in mRNAs associated with a type 2 immune response (interleukin [IL]5 gene, IL13, and IL13RA2) and a type 17 immune response (IL17A and IL23) in mucosal samples from patients with UC compared with patients with colon-only CD. In a regression model, increased expression of IL5 and IL17A mRNAs distinguished patients with UC from patients with colon-only CD (P =.001; area under the receiver operating characteristic curve, 0.72). We identified a gene expression pattern in rectal tissues of patients with UC, characterized by detection of IL13 mRNA, that predicted clinical response to therapy after 6 months (odds ratio [OR], 6.469; 95% confidence interval [CI], 1.553?26.94), clinical response after 12 months (OR, 6.125; 95% CI, 1.330?28.22), and remission after 12 months (OR, 5.333; 95% CI, 1.132?25.12). Conclusions In an analysis of rectal tissues from treatment-naive pediatric patients with IBD, we observed activation of a type 2 immune response during the early course of UC. We were able to distinguish patients with UC from those with colon-only CD based on increased mucosal expression of genes that mediate type 2 and type 17 immune responses. Increased expression at diagnosis of genes that mediate a type 2 immune response is associated with response to therapy and remission in pediatric patients with UC

Serologic Reactivity Reflects Clinical Expression of Ulcerative Colitis in Children

Background In contrast to pediatric Crohn's disease (CD), little is known in pediatric ulcerative colitis (UC) about the relationship between disease phenotype and serologic reactivity to microbial and other antigens. Aim The aim of this study was to examine disease phenotype and serology in a well-characterized inception cohort of children newly diagnosed with UC during the PROTECT Study (Predicting Response to Standardized Pediatric Colitis Therapy). Methods Patients were recruited from 29 participating centers. Demographic, clinical, laboratory, and serologic (pANCA, ASCA IgA/IgG, Anti-CBir1, and Anti-OmpC) data were obtained from children 4-17 years old with UC. Results Sixty-five percent of the patients had positive serology for pANCA, with 62% less than 12 years old and 66% 12 years old or older. Perinuclear anti-neutrophil cytoplasmic antibodies did not correspond to a specific phenotype though pANCA ò100, found in 19%, was strongly associated with pancolitis (P = 0.003). Anti-CBir1 was positive in 19% and more common in younger children with 32% less than 12 years old as compared with 14% 12 years old or older (P < 0.001). No association was found in any age group between pANCA and Anti-CBir1. Relative rectal sparing was more common in +CBir1, 16% versus 7% (P = 0.02). Calprotectin was lower in Anti-CBir1+ (Median [IQR] 1495 mcg/g [973-3333] vs 2648 mcg/g [1343-4038]; P = 0.04). Vitamin D 25-OH sufficiency was associated with Anti-CBir1+ (P = 0.0009). Conclusions The frequency of pANCA in children was consistent with adult observations. High titer pANCA was associated with more extensive disease, supporting the idea that the magnitude of immune reactivity may reflect disease severity. Anti-CBir1+ was more common in younger ages, suggesting host-microbial interactions may differ by patient age

Variation in care in the management of children with Crohn's disease: Data from a multicenter inception cohort study

Background: Variation in care is common in medical practice. Reducing variation in care is shown to improve quality and increase favorable outcomes in chronic diseases. We sought to identify factors associated with variation in care in children with newly diagnosed Crohn's disease (CD). Methods: Prospectively collected data from a 28-site multicenter inception CD cohort were analyzed for variations in diagnostic modalities, treatment, and follow-up monitoring practices, along with complicated disease outcomes over 3 years in 1046 children. Generalized linear mixed effects models were used to investigate the intercenter variations in each outcome variable. Results: The mean age at diagnosis was 12 years, and 25.9% were nonwhite. The number of participants ranged from 5 to 112 per site. No variation existed in the initial diagnostic approach. When medication exposure was analyzed, steroid exposure varied from 28.6% to 96.9% (P 0.99). Use of immunomodulators (IMs) varied among centers both within 90 days (P < 0.01) and during 3 years of follow-up (P < 0.01). A significant variation was seen at the geographic level with follow-up small bowel imaging and colonoscopy surveillance after initial therapy. Conclusions: Intercenter variation in care was seen with the initial use of steroids and anti-TNF, but there was no difference in total 3-year exposure to these drugs. Variation in the initiation and long-term use of IMs was significant among sites, but further research with objective measures is needed to explain this variation of care. Small bowel imaging or repeat colonoscopy in CD patients was not uniformly performed across sites. As our data show the widespread existence of variation in care and disease monitoring at geographic levels among pediatric CD patients, future implementation of various practice strategies may help reduce the variation in care

OpenPathSampling: A Python Framework for Path Sampling Simulations. 1. Basics

Transition path sampling techniques allow molecular dynamics simulations of complex systems to focus on rare dynamical events, providing insight into mechanisms and the ability to calculate rates inaccessible by ordinary dynamics simulations. While path sampling algorithms are conceptually as simple as importance sampling Monte Carlo, the technical complexity of their implementation has kept these techniques out of reach of the broad community. Here, we introduce an easy-to-use Python framework called OpenPathSampling (OPS) that facilitates path sampling for (bio)molecular systems with minimal effort and yet is still extensible. Interfaces to OpenMM and an internal dynamics engine for simple models are provided in the initial release, but new molecular simulation packages can easily be added. Multiple ready-to-use transition path sampling methodologies are implemented, including standard transition path sampling (TPS) between reactant and product states and transition interface sampling (TIS) and its replica exchange variant (RETIS), as well as recent multistate and multiset extensions of transition interface sampling (MSTIS, MISTIS). In addition, tools are provided to facilitate the implementation of new path sampling schemes built on basic path sampling components. In this paper, we give an overview of the design of this framework and illustrate the simplicity of applying the available path sampling algorithms to a variety of benchmark problems

OpenPathSampling: A Python Framework for Path Sampling Simulations. 2. Building and Customizing Path Ensembles and Sample Schemes

The OpenPathSampling (OPS) package provides an easy-to-use framework to apply transition path sampling methodologies to complex molecular systems with a minimum of effort. Yet, the extensibility of OPS allows for the exploration of new path sampling algorithms by building on a variety of basic operations. In a companion paper [Swenson et al. J. Chem. Theory Comput. 2018, 10.1021/acs.jctc.8b00626] we introduced the basic concepts and the structure of the OPS package, and how it can be employed to perform standard transition path sampling and (replica exchange) transition interface sampling. In this paper, we elaborate on two theoretical developments that went into the design of OPS. The first development relates to the construction of path ensembles, the what is being sampled. We introduce a novel set-based notation for the path ensemble, which provides an alternative paradigm for constructing path ensembles and allows building arbitrarily complex path ensembles from fundamental ones. The second fundamental development is the structure for the customization of Monte Carlo procedures; how path ensembles are being sampled. We describe in detail the OPS objects that implement this approach to customization, the MoveScheme and the PathMover, and provide tools to create and manipulate these objects. We illustrate both the path ensemble building and sampling scheme customization with several examples. OPS thus facilitates both standard path sampling application in complex systems as well as the development of new path sampling methodology, beyond the default

BAC Overlap Identification Based on Bit-Vectors

Abstract. There is no software that accurately calculates the overlap of two BACs fast enough for application to thousands of cases in turn. The problems include unacceptably low speed of dynamic programming algorithms for sequences of the considered size and failure of the faster local alignment methods to identify complete sequence overlaps. Lower sequence quality at both BAC ends and internal difference blocks, being small enough to not significantly increase relative error rates but large enough to terminate local alignments, cause output of multiple overlapping local matches which do not extend to both sequence ends. Based on Myers ’ bit-vector algorithm for fast edit distance calculation, we developed the program BACOLAP, that identifies overlapping BACs just as sensitive as global dynamic programming alignment and as fast as local heuristic alignment.