Publications by authors named "Harland S Winter"

74 Publications

Interactions between the intestinal microbiota and epigenome in individuals with autism spectrum disorder.

Dev Med Child Neurol 2021 Sep 15. Epub 2021 Sep 15.

Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by variable impairment of cognitive function and interpersonal relationships. Furthermore, some individuals with ASD have gastrointestinal disorders that have been correlated with impairments in intestinal microbiota. Gut microbiota are important not only for intestinal health, but also for many other functions including food digestion, energy production, immune system regulation, and, according to current data, behavior. Disruption of the indigenous microbiota, microbial dysbiosis (imbalance between microorganisms present in the gut), overgrowth of potentially pathogenic microorganisms, a less diverse microbiome, or lower levels of beneficial bacteria in children with ASD can affect behavior. Metabolome analysis in children with ASD has identified perturbations in multiple metabolic pathways that might be associated with cognitive functions. Recent studies have shown that the intestinal microbiome provides environmental signals that can modify host response to stimuli by modifying the host epigenome, which affects DNA methylation, histone modification, and non-coding RNAs. The most studied microbiota-produced epigenetic modifiers are short-chain fatty acids, although other products of intestinal microbiota might also cause epigenetic modifications in the host's DNA. Here we review evidence suggesting that epigenetic alterations caused by modification of gene expression play an important role in understanding ASD.
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http://dx.doi.org/10.1111/dmcn.15052DOI Listing
September 2021

Importance of early detection of infantile inflammatory bowel disease with defective IL-10 pathway: A case report.

Medicine (Baltimore) 2021 May;100(21):e25868

Department of Pediatric Gastroenterology, Hepatology and Nutrition, MacKay Children's Hospital, Taipei.

Rationale: Infantile inflammatory bowel disease (IBD) is an extremely rare subgroup of IBD that includes patients whose age of onset is younger than 2 years old. These patients can have more surgical interventions, and a severe and refractory disease course with higher rates of conventional treatment failure. Monogenic defects play an important role in this subgroup of IBD, and identification of the underlying defect can guide the therapeutic approach.

Patient Concerns: In 2007, a 4-month-old girl from a nonconsanguineous family presenting with anal fistula, chronic diarrhea, and failure to thrive. She underwent multiple surgical repairs but continued to have persistent colitis and perianal fistulas.

Diagnosis: Crohn's disease was confirmed by endoscopic and histologic finding.

Intervention: Conventional pediatric IBD therapy including multiple surgical interventions and antitumor necrosis factor alpha agents were applied.

Outcomes: The patient did not respond to conventional pediatric IBD therapy. Interleukin-10 (IL-10) receptor mutation was discovered by whole-exome sequencing and defective IL-10 signaling was proved by functional test of IL-10 signaling pathway by the age of 12. The patient is currently awaiting hematopoietic stem cell transplantation.

Lessons: Early detection of underlying genetic causes of patients with infantile-IBD is crucial, since it may prevent patients from undergoing unnecessary surgeries and adverse effects from ineffective medical therapies. Moreover, infantile-IBD patients with complex perianal disease, intractable early onset enterocolitis and extraintestinal manifestations including oral ulcers and skin folliculitis, should undergo genetic and functional testing for IL-10 pathway defect.
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http://dx.doi.org/10.1097/MD.0000000000025868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154448PMC
May 2021

Bacterial dysbiosis predicts the diagnosis of Crohn's disease in Saudi children.

Saudi J Gastroenterol 2021 May-Jun;27(3):144-148

Department of Pediatrics, Gastroenterology Division, Supervisor, Prince Abdullah Bin Khalid Celiac Disease Research Chair, King Saud University, Riyadh, Kingdom of Saudi Arabia.

Background: Studies have reached different conclusions regarding the accuracy of dysbiosis in predicting the diagnosis of Crohn's disease (CD). The aim of this report is to assess the utility of mucosal and fecal microbial dysbiosis as predictors in the diagnosis of this condition in Saudi children.

Methods: Tissue and fecal samples were collected prospectively from children with final diagnosis of CD and from controls. Bacterial DNA was extracted and sequenced using Illumina MiSeq chemistry. The abundance and diversity of bacteria in tissue and fecal samples were determined in relation to controls. Sparse logistic regression was calculated to predict the diagnosis of CD based on subject's microbiota profile.

Results: There were 17 children with CD and 18 controls. All children were Saudis. The median age was 13.9 and 16.3 years for children with CD and controls respectively. Sex distribution showed that 11/17 (65%) of the CD and 12/18 (67%) of the control subjects were boys. The mean area under the curve (AUC) was significantly higher in stool (AUC = 0.97 ± 0.029) than in tissue samples (AUC = 0.83 ±0.055) (P < 0.001).

Conclusions: We found high AUC in mucosal and fecal samples. The higher AUC for fecal samples suggests higher accuracy in predicting the diagnosis of CD.
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http://dx.doi.org/10.4103/sjg.SJG_409_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265402PMC
August 2021

Lymphoma in Pediatric-Onset Inflammatory Bowel Disease Treated with Infliximab Monotherapy: A Case Series.

Dig Dis Sci 2021 Feb 17. Epub 2021 Feb 17.

Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital, CRPZ 5-560, 175 Cambridge Street, Boston, MA, 02114, USA.

Background: Inflammatory bowel diseases (IBD) are often treated with anti-tumor necrosis factor alpha (anti-TNFα) medications. Concomitant treatment of IBD with anti-TNFα agents and immunomodulators appears to be associated with an increased risk for lymphoma.

Methods: Patients who developed lymphoma while on monotherapy with an anti-TNFα agent were identified at three centers. Institutional Review Board approval was obtained.

Results: Five adolescents and young adult patients with pediatric-onset IBD who were treated with infliximab (IFX) without exposure to thiopurines were subsequently diagnosed with lymphoma. Three of the five patients had bone involvement at presentation. Epstein-Barr virus was positive in 2 cases. Median time from diagnosis of IBD and exposure to IFX prior to diagnosis of lymphoma was 5 and 4.3 years, respectively.

Conclusions: This case series reports long-term follow-up for young patients with IBD who were treated with IFX monotherapy and developed lymphoma. Three of the five patients had bone involvement. In general, the risk of lymphoma following exposure to anti-TNFα medications alone remains low, but the incidence of primary bone lymphomas in IBD has not been reported. Studies examining longer exposure times may be needed to determine the true lymphoma risk in patients treated with IFX monotherapy.
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http://dx.doi.org/10.1007/s10620-021-06884-9DOI Listing
February 2021

Gut Microbiota and Gender in Autism Spectrum Disorders.

Curr Pediatr Rev 2020 ;16(4):249-254

Department of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital, Harvard Medical School, Boston, United States.

Gender dimorphism in autism spectrum disorders (ASD) is well known; however, the reasons for gender differences in autism are poorly understood. There are several hypotheses that might explain male prevalence in ASD, including increased levels of androgens, "extreme male brain," and a combination of elevated levels of prenatal testosterone in conjunction with prenatal stress. In this comprehensive review, differences in the gut microbiome and metabolome in humans and animals are described to explain gender differences in individuals with ASD, effects on behavior and social interactions and the impact of antibiotics, probiotics and fecal transplants. The bidirectional relationship between sex hormones and intestinal microbiota could also be relevant. Such interactions have been described in autoimmune diseases, but thus far, are not implicated in ASD. Since intestinal microbiota may affect behavior, it is possible that the prevalence of ASD in boys may be associated with more significant changes in the intestinal microbiome than in affected girls.
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http://dx.doi.org/10.2174/1573396316999200727123026DOI Listing
January 2020

Outcomes Following Pouch Formation in Paediatric Ulcerative Colitis: A Study From the Porto Group of ESPGHAN.

J Pediatr Gastroenterol Nutr 2020 09;71(3):346-353

Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel.

Introduction: Contemporary pediatric data on pouch outcomes are sparse, especially in the era of laparoscopic surgeries. We aimed to assess outcomes and predictors in children with ulcerative colitis/inflammatory bowel disease (IBD)-unclassified who underwent colectomy and ileal pouch-anal anastomosis.

Methods: This was a multicenter retrospective cohort study from 17 IBD centers affiliated with the pediatric IBD Porto group of ESPGHAN. An electronic REDcap system was used to collate baseline characteristics, demographic, clinical, management and surgical data, short- and long-term outcomes, and to identify potential predictors of pouch outcome.

Results: Of the 129 patients included, 86 (67%) developed pouchitis during follow-up of median 40 months (interquartile range 26-72), of whom 33 (26%) with chronic pouchitis. Patients operated on by surgeons performing <10 pouch surgeries/year had a higher rate of chronic pouchitis (11/27 [41%] vs 8/54 [15%], P = 0.013) on both univariable and multivariable analyses and also associated with time to pouchitis (P = 0.018) and chronic pouchitis (P = 0.020). At last follow-up, overall pouch performance was rated good/excellent in 86 (74%) patients. Time from colectomy to pouch formation was not associated with pouch outcomes. Despite higher rate of nonsevere surgical complications among children undergoing colectomy at <10 years of age (7/16 [44%] vs 10/92 [11%], P = 0.003), functional outcome and pouchitis rate did not differ.

Conclusions: Pouchitis rate in children with ulcerative colitis/IBD unclassified is high. Surgeon experience is the major modifiable risk factor for pouch outcome. Our analyses suggest that pouch surgery can also be performed successfully in young children.
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http://dx.doi.org/10.1097/MPG.0000000000002805DOI Listing
September 2020

Additional Intestinal Mucosal Biopsy Sampling for Research Is Safe During Pediatric Endoscopic Procedures.

Clin Gastroenterol Hepatol 2020 05 4;18(5):1233-1234. Epub 2019 Jul 4.

Division of Pediatric Gastroenterology, Department of Pediatrics, MassGeneral Hospital for Children, Harvard Medical School, Boston, Massachusetts.

Advancing the understanding of inflammatory bowel disease (IBD) pathogenesis has been facilitated by mechanistic studies that require human intestinal tissue. Enrolling pediatric subjects into these studies improves our knowledge of IBD in this underserved population. Given the additional research protections granted to children, institutional review boards (IRBs) must weigh the benefit of obtaining research biopsies against perceived risks. Although obtaining clinical biopsies from children is generally considered safe, there are only limited data on the safety of obtaining research biopsies in children..
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http://dx.doi.org/10.1016/j.cgh.2019.06.040DOI Listing
May 2020

Performance of Surveillance MR Enterography (MRE) in Asymptomatic Children and Adolescents With Crohn's Disease.

J Magn Reson Imaging 2019 12 30;50(6):1955-1963. Epub 2019 May 30.

Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Background: MR enterography (MRE) is the primary modality for evaluating small bowel disease in pediatric Crohn's patients. Standard clinical practice includes imaging patients at diagnosis and during symptomatic recurrence. The role for MRE in surveillance of asymptomatic Crohn's patients has not yet been established.

Purpose: To determine whether MRE imaging features are associated with clinical recurrence.

Study Type: Retrospective.

Populations: Pediatric Crohn's patients who underwent MRE while asymptomatic, defined by pediatric gastroenterologists using a physician global assessment; 35 MREs were identified.

Field Strength/sequence: 1.5T including T -weighted single-shot fast spin echo, balanced steady-state free precession, diffusion-weighted, and contrast-enhanced multiphase T -weighted gradient recalled echo sequences.

Assessment: MREs were reviewed by three radiologists independently for mural thickening, T -weighted hyperintensity, diffusion restriction, hyperenhancement, vasa recta engorgement, and overall assessment of disease activity. Two pediatric gastroenterologists reviewed patient medical records for 6 months following MRE to evaluate for recurrence, defined as Crohn's-related treatment escalation, surgery, or hospitalization.

Statistical Tests: Fisher's exact test, Wald chi-square test, and model selection by Akaike information criterion minimization were used to assess statistical significance of MRE imaging features.

Results: Of 35 MREs identified, seven cases demonstrated clinical recurrence at 6 months (20%); 28 cases remained in remission (80%). Imaging features of active disease were present in 86% of patients with recurrence compared to 29% of patients in remission (P = 0.01). Wall thickening, T -weighted hyperintensity, hyperenhancement, and diffusion restriction were significantly associated with recurrence. Multivariate regression analysis determined diffusion restriction to be the best predictor of recurrence within 6 months (P = 0.001, area under the curve 0.786).

Data Conclusion: MRE performed on young asymptomatic Crohn's patients can identify patients who have a high probability of developing clinical recurrence in a 6-month period, indicating a potential role for surveillance imaging to assess for subclinical active disease.

Level Of Evidence: 3 Technical Efficacy Stage 5 J. Magn. Reson. Imaging 2019;50:1955-1963.
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http://dx.doi.org/10.1002/jmri.26811DOI Listing
December 2019

Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases.

Nature 2019 05 29;569(7758):655-662. Epub 2019 May 29.

Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.

Inflammatory bowel diseases, which include Crohn's disease and ulcerative colitis, affect several million individuals worldwide. Crohn's disease and ulcerative colitis are complex diseases that are heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to this dysregulation. The study's infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi'omics Database ( http://ibdmdb.org ), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases.
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http://dx.doi.org/10.1038/s41586-019-1237-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650278PMC
May 2019

Long-term Outcomes of Paediatric Patients Admitted With Acute Severe Colitis- A Multicentre Study From the Paediatric IBD Porto Group of ESPGHAN.

J Crohns Colitis 2019 Dec;13(12):1518-1526

Department of Pediatric Gastroenterology, Hepatology and Nutrition, Hospital Sant Joan de Déu, Barcelona, Spain.

Background And Aim: Acute severe colitis [ASC] is associated with significant morbidity in paediatric patients with ulcerative colitis [UC]. Most outcome studies in ASC since tumour necrosis factor alpha [TNFα] antagonists became available have focused on the first year after admission. The aim of this study was to characterise the longer-term outcomes of paediatric patients admitted with ASC.

Methods: This retrospective study was conducted in 25 centres across Europe and North America. Data on patients with UC aged <18 years, admitted with ASC (defined as paediatric ulcerative colitis activity index [PUCAI] score ≥65) between 2009 and 2011, were collected at discharge and 1, 3 and 5 years after admission. The primary outcome was colectomy-free rates at each time point.

Results: Of the 141 patients admitted with ASC, 137 [97.1%] were treated with intravenous corticosteroids. Thirty-one [22.6%] patients were escalated to second-line therapy, mainly to infliximab. Sixteen patients [11.3%] underwent colectomy before discharge. Long-term follow-up showed colectomy-free rates were 71.3%, 66.4% and 63.6% at 1, 3 and 5 years after initial ASC admission, respectively, and were similar across different age groups. Sub-analysis of colectomy rates in patients with new-onset disease [42.5% of the cohort] yielded similar results. In a multivariate analysis, use of oral steroids in the 3 months before admission, erythrocyte sedimentation rate >70 mm/h, and albumin <2.5 g/dL, were significantly associated with 5-year colectomy risk.

Conclusions: High colectomy rates were demonstrated in paediatric UC patients admitted with ASC. Additional studies are required to determine whether intensification of anti-TNFα treatment, close therapeutic drug monitoring, and use of new drugs alter this outcome.
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http://dx.doi.org/10.1093/ecco-jcc/jjz092DOI Listing
December 2019

Measurement of Microvascular Function in Pediatric Inflammatory Bowel Disease.

J Pediatr Gastroenterol Nutr 2019 05;68(5):608-609

Harvard Medical School, MassGeneral Hospital for Children, Boston, MA.

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http://dx.doi.org/10.1097/MPG.0000000000002299DOI Listing
May 2019

Microbiota profile in new-onset pediatric Crohn's disease: data from a non-Western population.

Gut Pathog 2018 29;10:49. Epub 2018 Nov 29.

7Physics Department, Boston University, Boston, USA.

Background: The role of microbiota in Crohn's disease (CD) is increasingly recognized. However, most of the reports are from Western populations. Considering the possible variation from other populations, the aim of this study was to describe the microbiota profile in children with CD in Saudi Arabia, a non-Western developing country population.

Results: Significantly more abundant genera in children with CD included and whereas the most significantly-depleted genera included and Alpha diversity was significantly reduced in stool (p = 0.03) but not in mucosa (p = 0.31). Beta diversity showed significant difference in community composition between control and CD samples (p = 0.03).

Conclusion: In this developing country, we found a pattern of microbiota in children with CD similar to Western literature, suggesting a role of recent dietary lifestyle changes in this population on microbiota structure.
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http://dx.doi.org/10.1186/s13099-018-0276-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6263052PMC
November 2018

Fungal dysbiosis predicts the diagnosis of pediatric Crohn's disease.

World J Gastroenterol 2018 Oct;24(39):4510-4516

Department of Pediatrics, Supervisor of Prince Abdullah Bin Khalid Celiac Disease Research Chair, King Saud University, Riyadh 11461, Saudi Arabia.

Aim: To investigate the accuracy of fungal dysbiosis in mucosa and stool for predicting the diagnosis of Crohn's disease (CD).

Methods: Children were prospectively enrolled in two medical centers: one university hospital and one private gastroenterology clinic in the city of Riyadh, Kingdom of Saudi Arabia. The children with confirmed diagnosis of CD by standard guidelines were considered cases, and the others were considered non-inflammatory bowel disease controls. Mucosal and stool samples were sequenced utilizing Illumina MiSeq chemistry following the manufacturer's protocols, and abundance and diversity of fungal taxa in mucosa and stool were analyzed. Sparse logistic regression was used to predict the diagnosis of CD. The accuracy of the classifier was tested by computing the receiver operating characteristic curves with 5-fold stratified cross-validation under 100 permutations of the training data partition and the mean area under the curve (AUC) was calculated.

Results: All the children were Saudi nationals. There were 15 children with CD and 20 controls. The mean age was 13.9 (range: 6.7-17.8) years for CD children and 13.9 (3.25-18.6) years for controls, and 10/15 (67%) of the CD and 13/20 (65%) of the control subjects were boys. CD locations at diagnosis were ileal (L1) in 4 and colonic (L3) in 11 children, while CD behavior was non-stricturing and non-penetrating (B1) in 12 and stricturing (B2) in 3 children. The mean AUC for the fungal dysbiosis classifier was significantly higher in stools (AUC = 0.85 ± 0.057) than in mucosa (AUC = 0.71 ± 0.067) ( < 0.001). Most fungal species were significantly more depleted in stools than mucosal samples, except for and , which were significantly more abundant. Diversity was significantly more reduced in stools than in mucosa.

Conclusion: We found high AUC of fungal dysbiosis in fecal samples of children with CD, suggesting high accuracy in predicting diagnosis of CD.
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http://dx.doi.org/10.3748/wjg.v24.i39.4510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196340PMC
October 2018

Development of a Brief Parent-Report Screen for Common Gastrointestinal Disorders in Autism Spectrum Disorder.

J Autism Dev Disord 2019 Jan;49(1):349-362

Department of Pediatrics, Division of Gastroenterology, Mass-General Hospital for Children, Boston, MA, USA.

Gastrointestinal dysfunction in children with autism spectrum disorder (ASD) is common and associated with problem behaviors. This study describes the development of a brief, parent-report screen that relies minimally upon the child's ability to report or localize pain for identifying children with ASD at risk for one of three common gastrointestinal disorders (functional constipation, functional diarrhea, and gastroesophageal reflux disease). In a clinical sample of children with ASD, this 17-item screen identified children having one or more of these disorders with a sensitivity of 84%, specificity of 43%, and a positive predictive value of 67%. If found to be valid in an independent sample of children with ASD, the screen will be useful in both clinical practice and research.
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http://dx.doi.org/10.1007/s10803-018-3767-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857533PMC
January 2019

Colonic Inhibition of Phosphatase and Tensin Homolog Increases Colitogenic Bacteria, Causing Development of Colitis in Il10-/- Mice.

Inflamm Bowel Dis 2018 07;24(8):1718-1732

Department of Biological Sciences, Oakland University, Rochester, Michigan.

Background: Phosphatase and tensin homolog (Pten) is capable of mediating microbe-induced immune responses in the gut. Thus, Pten deficiency in the intestine accelerates colitis development in Il10-/- mice. As some ambient pollutants inhibit Pten function and exposure to ambient pollutants may increase inflammatory bowel disease (IBD) incidence, it is of interest to examine how Pten inhibition could affect colitis development in genetically susceptible hosts.

Methods: With human colonic mucosa biopsies from pediatric ulcerative colitis and non-IBD control subjects, we assessed the mRNA levels of the PTEN gene and the gene involved in IL10 responses. The data from the human tissues were corroborated by treating Il10-/-, Il10rb-/-, and wild-type C57BL/6 mice with Pten-specific inhibitor VO-OHpic. We evaluated the severity of mouse colitis by investigating the tissue histology and cytokine production. The gut microbiome was investigated by analyzing the 16S ribosomal RNA gene sequence with mouse fecal samples.

Results: PTEN and IL10RB mRNA levels were reduced in the human colonic mucosa of pediatric ulcerative colitis compared with non-IBD subjects. Intracolonic treatment of the Pten inhibitor induced colitis in Il10-/- mice, characterized by reduced body weight, marked colonic damage, and increased production of inflammatory cytokines, whereas Il10rb-/- and wild-type C57BL/6 mice treated with the inhibitor did not develop colitis. Pten inhibitor treatment changed the fecal microbiome, with increased abundance of colitogenic bacteria Bacteroides and Akkermansia in Il10-/- mice.

Conclusions: Loss of Pten function increases the levels of colitogenic bacteria in the gut, thereby inducing deleterious colitis in an Il10-deficient condition.
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http://dx.doi.org/10.1093/ibd/izy124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231371PMC
July 2018

Genetic Variation Affects C-Reactive Protein Elevations in Crohn's Disease.

Inflamm Bowel Dis 2018 08;24(9):2048-2052

Division of Pediatric Gastroenterology, Hepatology, and Nutrition, MassGeneral Hospital for Children, Boston, Massachusetts.

Background: C-reactive protein (CRP) is a serum marker that is used to measure disease activity in Crohn's disease (CD). However, a subset of CD patients have normal CRP during flares. In rheumatoid arthritis and lupus, genetic variants can restrict CRP elevations during flares. This study sought to determine if common CRP genetic variants affect CRP values during active CD.

Methods: Subjects with CD who participated in the Partners HealthCare BioBank were genotyped for 5 common CRP genetic variants (rs2794520, rs3122012, rs3093077, rs2808635, and rs1800947). Medical records were reviewed to determine disease activity and the highest CRP value during active CD. CRP values during active infection or malignancy at the time of the test were excluded. CRP values were compared by genotype using the Mann-Whitney test.

Results: The study included 199 subjects with active CD (21 to 86 years of age). Subjects with the rs2794520 TT genotype had a lower CRP than subjects with the CC genotype (58.3 mg/L vs 28.4 mg/L, P = 0.008). Subjects with the rs1800947 CG genotype had a lower CRP than those with the CC genotype (54.3 mg/L vs 22.4 mg/L, P < 0.0001); 41.6% of TT subjects had a normal CRP compared with 24.1% of CT subjects and 16.5% of CC subjects (P = 0.041).

Conclusions: This study demonstrates that rs2794520 and rs1800947 are associated with a restriction of CRP elevations during active CD. While CRP is typically a reliable biomarker in CD, there is a subset of CD patients with a genetically determined restriction of CRP in whom other disease markers should be utilized.
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http://dx.doi.org/10.1093/ibd/izy100DOI Listing
August 2018

Genetic variants in cellular transport do not affect mesalamine response in ulcerative colitis.

PLoS One 2018 26;13(3):e0192806. Epub 2018 Mar 26.

Division of Pediatric Gastroenterology, Hepatology, & Nutrition, MassGeneral Hospital for Children, Boston, Massachusetts, United States of America.

Background And Aims: Mesalamine is commonly used to treat ulcerative colitis (UC). Although mesalamine acts topically, in vitro data suggest that intracellular transport is required for its beneficial effect. Genetic variants in mucosal transport proteins may affect this uptake, but the clinical relevance of these variants has not been studied. The aim of this study was to determine whether variants in genes involved in cellular transport affect the response to mesalamine in UC.

Methods: Subjects with UC from a 6-week clinical trial using multiple doses of mesalamine were genotyped using a genome-wide array that included common exome variants. Analysis focused on cellular transport gene variants with a minor allele frequency >5%. Mesalamine response was defined as improvement in Week 6 Physician's Global Assessment (PGA) and non-response as a lack of improvement in Week 6 PGA. Quality control thresholds included an individual genotyping rate of >90%, SNP genotyping rate of >98%, and exclusion for subjects with cryptic relatedness. All included variants met Hardy-Weinberg equilibrium (p>0.001).

Results: 457 adults with UC were included with 280 responders and 177 non-responders. There were no common variants in transporter genes that were associated with response to mesalamine. The genetic risk score of responders was similar to that of non-responders (p = 0.18). Genome-wide variants demonstrating a trend towards mesalamine response included ST8SIA5 (p = 1x10-5).

Conclusions: Common transporter gene variants did not affect response to mesalamine in adult UC. The response to mesalamine may be due to rare genetic events or environmental factors such as the intestinal microbiome.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192806PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868763PMC
June 2018

Identification and characterization of a novel missense mutation associated with congenital diarrhea.

J Lipid Res 2017 06 3;58(6):1230-1237. Epub 2017 Apr 3.

Harvard Medical School, Boston, MA 02115

Acyl-CoA:diacylglycerol acyltransferase (DGAT)1 and DGAT2 catalyze triglyceride (TG) biosynthesis in humans. Biallelic loss-of-function mutations in human result in severe congenital diarrhea and protein-losing enteropathy. Additionally, pharmacologic inhibition of DGAT1 led to dose-related diarrhea in human clinical trials. Here we identify a previously unknown mutation in identical twins of South Asian descent. These male patients developed watery diarrhea shortly after birth, with protein-losing enteropathy and failure to thrive. Exome sequencing revealed a homozygous recessive mutation in , c.314T>C, p.L105P. We show here that the p.L105P DGAT1 enzyme produced from the mutant allele is less abundant, resulting in partial loss of TG synthesis activity and decreased formation of lipid droplets in patient-derived primary dermal fibroblasts. Thus, in contrast with complete loss-of-function alleles of , the p.L105P missense allele partially reduces TG synthesis activity and causes a less severe clinical phenotype. Our findings add to the growing recognition of DGAT1 deficiency as a cause of congenital diarrhea with protein-losing enteropathy and indicate that mutations result in a spectrum of diseases.
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http://dx.doi.org/10.1194/jlr.P075119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454518PMC
June 2017

Analysis of the Duodenal Microbiome in Autistic Individuals: Association With Carbohydrate Digestion.

J Pediatr Gastroenterol Nutr 2017 05;64(5):e110-e116

*Department of Pediatrics, Massachusetts General Hospital, Boston, MA †Research and Testing Laboratory ‡Department of Biological Sciences, Texas Tech University, Lubbock §Department of Molecular Biology ||Department of Botany, University of Wyoming, Laramie.

Objectives: There is evidence that symptoms of maldigestion or malabsorption in autistic individuals are related to changes in the indigenous microbiota. Analysis of colonic bacteria has revealed microbial dysbiosis in children with autism; however, characteristics of the duodenal microbiome are not well described. In the present study the microbiome of the duodenal mucosa of subjects with autism was evaluated for dysbiosis, bacteria overgrowth, and microbiota associated with carbohydrate digestion. The relationship between the duodenal microbiome and disaccharidase activity was analyzed in biopsies from 21 autistic subjects and 19 children without autism.

Methods: Microbiota composition was determined by 16S ribosomal RNA gene sequencing, and disaccharidase activity via biochemical assays.

Results: Although subjects with autism had a higher frequency of constipation (P < 0.005), there was no difference in disaccharidase activity between groups. In addition, no differences in microbiome diversity (species richness and evenness) were observed. Bacteria belonging to the genus Burkholderia were more abundant in subjects with autism, whereas members of the genus Neisseria were less abundant. At the species level, a relative decrease in abundance of 2 Bacteroides species and Escherichia coli was found in autistic individuals. There was a positive correlation between the abundance of Clostridium species, and disaccharidase activity, in autistic individuals.

Conclusions: There are a variety of changes at the genus and species level in duodenal microbiota in children with autism that could be influenced by carbohydrate malabsorption. These observations could be affected by variations in individual diets, but also may represent a more pervasive dysbiosis that results in metabolites that affect the behavior of autistic children.
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http://dx.doi.org/10.1097/MPG.0000000000001458DOI Listing
May 2017

Improving Clinical Remission Rates in Pediatric Inflammatory Bowel Disease with Previsit Planning.

BMJ Qual Improv Rep 2016 29;5(1). Epub 2016 Jul 29.

MassGeneral Hospital for Children, United States of America.

Inflammatory Bowel Disease (IBD) is a chronic autoimmune inflammatory disease of the intestine which can lead to malnutrition, poor quality of life, and colon cancer.(1-4) Although there is no cure for the disease, clinical remission is the primary goal.(5) The Center for Inflammatory Bowel Disease at MassGeneral Hospital for Children (MGHfC) adopted a Previsit Planning (PVP) model to identify and discuss symptomatic patients prior to their appointments to identify specific issues that impact disease management.(6-8) The Registry from ImproveCareNow (ICN), the international Quality Improvement Collaborative for the management of Crohn's Disease and Ulcerative Colitis in pediatric and adolescent patients, was used to capture information from each ambulatory visit and hospitalization. Using the Model for Improvement framework, the team began a weekly review and made care recommendations of patients with active disease who were cared for by one physician. Interventions were modified over multiple Plan-Do-Study-Act (PDSA) improvement cycles to increase the number of providers and to include patients with mild or moderate disease activity.(9) Feedback from the providers regarding this process was elicited via a REDCap survey and the clinical remission rate was tracked using the ICN Registry. The clinical remission rate for the Center's patients increased from 77% (n=597) in September 2014 to 83% (n=585) in August 2015 and has been maintained. 78% of responding providers indicated that they found the PVP recommendations helpful "all of the time". One hundred percent who responded to the survey said that they have used at least one recommendation provided to them. PVP for management of a chronic disease in pediatrics is feasible, even in a high volume practice. This process at MGHfC has resulted in the improvement of clinical remission rate. PDSA cycles were used to document successes and failures to help guide the work. Ongoing expansion of this PVP practice to all providers continues with the anticipation of including input from patients and their families, as well.
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http://dx.doi.org/10.1136/bmjquality.u211063.w4361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4994092PMC
August 2016

Health Care Infrastructure for Financially Sustainable Clinical Genomics.

J Mol Diagn 2016 09 25;18(5):697-706. Epub 2016 Jul 25.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Next-generation sequencing has evolved technically and economically into the method of choice for interrogating the genome in cancer and inherited disorders. The introduction of procedural code sets for whole-exome and genome sequencing is a milestone toward financially sustainable clinical implementation; however, achieving reimbursement is currently a major challenge. As part of a prospective quality-improvement initiative to implement the new code sets, we adopted Agile, a development methodology originally devised in software development. We implemented eight functionally distinct modules (request review, cost estimation, preauthorization, accessioning, prebilling, testing, reporting, and reimbursement consultation) and obtained feedback via an anonymous survey. We managed 50 clinical requests (January to June 2015). The fraction of pursued-to-requested cases (n = 15/50; utilization management fraction, 0.3) aimed for a high rate of preauthorizations. In 13 of 15 patients the insurance plan required preauthorization, which we obtained in 70% and ultimately achieved reimbursement in 50%. Interoperability enabled assessment of 12 different combinations of modules that underline the importance of an adaptive workflow and policy tailoring to achieve higher yields of reimbursement. The survey confirmed a positive attitude toward self-organizing teams. We acknowledge the individuals and their interactions and termed the infrastructure: human pipeline. Nontechnical barriers currently are limiting the scope and availability of clinical genomic sequencing. The presented human pipeline is one approach toward long-term financial sustainability of clinical genomics.
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http://dx.doi.org/10.1016/j.jmoldx.2016.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5397703PMC
September 2016

MR Enterographic Findings as Biomarkers of Mucosal Healing in Young Patients With Crohn Disease.

AJR Am J Roentgenol 2016 Oct 28;207(4):896-902. Epub 2016 Jun 28.

1 Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Objective: The purpose of this study was to investigate the MR enterographic findings that best correlate with mucosal healing assessed with ileocolonoscopy.

Materials And Methods: Patients with Crohn disease who underwent two ileocolonoscopic examinations and also underwent MR enterography close in time to the second endoscopic examination were included in a retrospective study. Two pediatric gastroenterologists blinded to the imaging findings reviewed the endoscopic examinations to assess for mucosal healing, defined as resolution of inflammation within a bowel segment at subsequent ileocolonoscopy. Two radiologists blinded to endoscopic and clinical data interpreted the MR enterographic images. Sensitivity, specificity, and accuracy for mucosal healing were calculated for several imaging features.

Results: A total of 30 patients (15 female patients, 15 male patients; age range, 8-24 years; mean, 17.2 ± 3.2 years) with pediatric-onset Crohn disease were examined. The average time between MR enterography and the second ileocolonoscopic examination was 12.7 ± 7.9 days. A total of 202 bowel segments from the terminal ileum to rectum were evaluated in the 60 ileocolonoscopic examinations. Forty-four bowel segments exhibited mucosal healing, and 37 segments exhibited persistent inflammation. At imaging, the MR index of activity score in mucosal healing segments was 6.6 ± 3.4, compared with 13.7 ± 9.7 in segments without mucosal healing (p = 0.0001). The average bowel wall thickness in healing segments was 2.7 ± 0.9 mm compared with 4.7 ± 3.1 mm in persistently inflamed segments (p = 0.0004). An MR index of activity score less than 8 had the highest accuracy for mucosal healing (accuracy, 74%; sensitivity, 84%; specificity, 62%; p < 0.0001). Mucosal hyperenhancement (72%, 98%, 41%), mesenteric hypervascularity (72%, 98%, 41%), bowel wall edema (72%, 93%, 46%), and bowel wall thickness less than 4 mm (72%, 84%, 57%) were also strongly associated with mucosal healing (p < 0.0003).

Conclusion: In this study MR enterography was accurate for assessing mucosal healing, an important therapeutic endpoint in pediatric patients with Crohn disease.
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http://dx.doi.org/10.2214/AJR.16.16079DOI Listing
October 2016

Evaluation of Intestinal Function in Children With Autism and Gastrointestinal Symptoms.

J Pediatr Gastroenterol Nutr 2016 05;62(5):687-91

*Department of Pediatrics, Mass General Hospital for Children, Harvard Medical School, Boston †Department of Biology, Boston College, Chestnut Hill, MA.

Objective: Alterations in intestinal function, often characterized as a "leaky gut," have been attributed to children who are on the autism spectrum. Disaccharidase activity, intestinal inflammation, and permeability were analyzed in 61 children with autism and 50 nonautistic individuals with gastrointestinal symptoms.

Methods: All patients had duodenal biopsies assayed for lactase, sucrase, maltase, and palatinase activity. Intestinal permeability was evaluated by rhamnose/lactulose test and measured by high-performance liquid chromatography-mass spectrometry. Intestinal inflammation was evaluated by fecal calprotectin and lactoferrin levels using enzyme-linked immunosorbent assay and histology.

Results: Some children with autism had mild levels of mucosal inflammation on intestinal biopsy. Disaccharidase activity was not different in autistic and nonautistic individuals. Fecal calprotectin and lactoferrin were similar in both groups. Differences between lactulose and rhamnose recovery and lactulose/rhamnose ratio in urine were not statistically different in patients with and without autism.

Conclusions: The present study supports the observation that children with autism who have symptoms of gastrointestinal disorders have objective findings similar to children without autism. Neither noninvasive testing nor endoscopic findings identify gastrointestinal pathology specific to autism, but may be of benefit in identifying children with autism who have atypical symptoms.
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http://dx.doi.org/10.1097/MPG.0000000000001174DOI Listing
May 2016

Role of percutaneous abscess drainage in the management of young patients with Crohn disease.

Pediatr Radiol 2016 May 29;46(5):653-9. Epub 2016 Jan 29.

Division of Abdominal Imaging, Massachusetts General Hospital, Boston, MA, USA.

Background: Intra-abdominal abscess is a common complication of Crohn disease in children. Prior studies, primarily in adults, have shown that percutaneous abscess drainage is a safe and effective treatment for this condition; however, the data regarding this procedure and indications in pediatric patients is limited.

Objective: Our aim was to determine the success rate of percutaneous abscess drainage for abscesses related to Crohn disease in pediatric patients with a focus on treatment endpoints that are relevant in the era of biological medical therapy.

Materials And Methods: We retrospectively reviewed 25 cases of patients ages ≤20 years with Crohn disease who underwent percutaneous abscess drainage. Technical success was defined as catheter placement within the abscess with reduction in abscess size on post-treatment imaging. Clinical success was defined as (1) no surgery within 1 year of drainage or (2) surgical resection following drainage with no residual abscess at surgery or on preoperative imaging. Multiple clinical parameters were analyzed for association with treatment success or failure.

Results: All cases were classified as technical successes. Nineteen cases were classified as clinical successes (76%), including 7 patients (28%) who required no surgery within 1 year of percutaneous drainage and 12 patients (48%) who had elective bowel resection within 1 year. There was a statistically significant association between resumption of immunosuppressive therapy within 8 weeks of drainage and both clinical success (P < 0.01) and avoidance of surgery after 1 year (P < 0.01).

Conclusion: Percutaneous abscess drainage is an effective treatment for Crohn disease-related abscesses in pediatric patients. Early resumption of immunosuppressive therapy is statistically associated with both clinical success and avoidance of bowel resection, suggesting a role for percutaneous drainage in facilitating prompt initiation of medical therapy and preventing surgical bowel resection.
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http://dx.doi.org/10.1007/s00247-015-3533-3DOI Listing
May 2016

Detecting Microbial Dysbiosis Associated with Pediatric Crohn Disease Despite the High Variability of the Gut Microbiota.

Cell Rep 2016 Feb 21;14(4):945-955. Epub 2016 Jan 21.

Bioinformatics Graduate Program, Boston University, Boston, MA 02215, USA; Department of Physics, Boston University, Boston, MA 02215, USA. Electronic address:

The relationship between the host and its microbiota is challenging to understand because both microbial communities and their environments are highly variable. We have developed a set of techniques based on population dynamics and information theory to address this challenge. These methods identify additional bacterial taxa associated with pediatric Crohn disease and can detect significant changes in microbial communities with fewer samples than previous statistical approaches required. We have also substantially improved the accuracy of the diagnosis based on the microbiota from stool samples, and we found that the ecological niche of a microbe predicts its role in Crohn disease. Bacteria typically residing in the lumen of healthy individuals decrease in disease, whereas bacteria typically residing on the mucosa of healthy individuals increase in disease. Our results also show that the associations with Crohn disease are evolutionarily conserved and provide a mutual information-based method to depict dysbiosis.
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http://dx.doi.org/10.1016/j.celrep.2015.12.088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740235PMC
February 2016

Commentary on "The Use of Placebo in Pediatric Inflammatory Bowel Diseases".

Authors:
Harland S Winter

J Pediatr Gastroenterol Nutr 2016 Jan;62(1):5-7

Pediatric IBD Program, MassGeneral Hospital for Children, Boston, Massachusetts.

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http://dx.doi.org/10.1097/MPG.0000000000001047DOI Listing
January 2016

Authors' Response.

J Pediatr Gastroenterol Nutr 2016 Mar;62(3):e31-2

*Division of Pediatric Gastroenterology, Hepatology, and Nutrition†Department of Pediatric Surgery, Massachusetts General Hospital Boston.

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http://dx.doi.org/10.1097/MPG.0000000000001060DOI Listing
March 2016

Exome sequencing analysis reveals variants in primary immunodeficiency genes in patients with very early onset inflammatory bowel disease.

Gastroenterology 2015 Nov 17;149(6):1415-24. Epub 2015 Jul 17.

Division of Human Genetics, The Children's Hospital of Philadelphia; Department of Pediatrics, Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania; Department of Molecular Medicine, University Sapienza, Rome, Italy.

Background & Aims: Very early onset inflammatory bowel disease (VEO-IBD), IBD diagnosed at 5 years of age or younger, frequently presents with a different and more severe phenotype than older-onset IBD. We investigated whether patients with VEO-IBD carry rare or novel variants in genes associated with immunodeficiencies that might contribute to disease development.

Methods: Patients with VEO-IBD and parents (when available) were recruited from the Children's Hospital of Philadelphia from March 2013 through July 2014. We analyzed DNA from 125 patients with VEO-IBD (age, 3 wk to 4 y) and 19 parents, 4 of whom also had IBD. Exome capture was performed by Agilent SureSelect V4, and sequencing was performed using the Illumina HiSeq platform. Alignment to human genome GRCh37 was achieved followed by postprocessing and variant calling. After functional annotation, candidate variants were analyzed for change in protein function, minor allele frequency less than 0.1%, and scaled combined annotation-dependent depletion scores of 10 or less. We focused on genes associated with primary immunodeficiencies and related pathways. An additional 210 exome samples from patients with pediatric IBD (n = 45) or adult-onset Crohn's disease (n = 20) and healthy individuals (controls, n = 145) were obtained from the University of Kiel, Germany, and used as control groups.

Results: Four hundred genes and regions associated with primary immunodeficiency, covering approximately 6500 coding exons totaling more than 1 Mbp of coding sequence, were selected from the whole-exome data. Our analysis showed novel and rare variants within these genes that could contribute to the development of VEO-IBD, including rare heterozygous missense variants in IL10RA and previously unidentified variants in MSH5 and CD19.

Conclusions: In an exome sequence analysis of patients with VEO-IBD and their parents, we identified variants in genes that regulate B- and T-cell functions and could contribute to pathogenesis. Our analysis could lead to the identification of previously unidentified IBD-associated variants.
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http://dx.doi.org/10.1053/j.gastro.2015.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853027PMC
November 2015

A microRNA signature in pediatric ulcerative colitis: deregulation of the miR-4284/CXCL5 pathway in the intestinal epithelium.

Inflamm Bowel Dis 2015 May;21(5):996-1005

*Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California; †Pediatric IBD Center, MassGeneral Hospital for Children, Boston, Massachusetts; ‡Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California; and §Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.

Background: Twenty to 25% of the patients with inflammatory bowel disease (IBD) present the disease before the age of 18 to 20, with worse extent and severity, compared with adult-onset IBD. We sought to identify the differential expression of microRNAs in pediatric ulcerative colitis (UC) and their association with different clinical phenotypes.

Methods: MicroRNA expression analysis was performed in colonic tissues derived from pediatric patients with UC and controls without IBD. MiR-4284 levels were verified by real-time quantitative polymerase chain reaction in 2 additional cohorts of pediatric patients with UC. Bioinformatics analysis was performed to predict the targets of miR-4284. In vitro experiments using luciferase reporter assays and real-time polymerase chain reaction evaluated the direct effect of miR-4284 on CXCL5 mRNA. In vivo experiments were performed in 2 mouse models of experimental colitis.

Results: A 24-microRNA signature was identified in colonic tissues derived from pediatric patients with UC. The most downregulated microRNA in the tissue of pediatric patients UC, relative to non-IBD controls, was miR-4284. In situ hybridization revealed that miR-4284 is present in colonic epithelial cells, and its levels correlate with the disease activity. Furthermore, we found that miR-4284 regulates CXCL5 mRNA expression through binding to its 3'UTR. CXCL5 had increased mRNA levels in colonic tissue from pediatric patients with UC and correlated with disease activity. Furthermore, we found an inverse correlation between miR-4284 and CXCL5 levels in the colonic pediatric UC tissues and in 2 mouse models of experimental colitis.

Conclusions: Our data reveal a novel microRNA pediatric UC signature and provide evidence that miR-4284 directly regulates CXCL5 and correlates with the disease activity.
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http://dx.doi.org/10.1097/MIB.0000000000000339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402238PMC
May 2015

Occult Blood and Perianal Examination: Value Added in Pediatric Inflammatory Bowel Disease Screening.

J Pediatr Gastroenterol Nutr 2015 Jul;61(1):52-55

Department of Pediatrics, Harvard Medical School.

Objectives: Pediatric inflammatory bowel disease (IBD) often presents insidiously and standard blood tests are normal in 20% of patients. We hypothesize that fecal occult blood testing (FOBT) and the perianal examination in addition to blood tests provide important information during the screening process for IBD. The aim of the present study was to measure the diagnostic value of adding FOBT and perianal examination to standard screening laboratories in evaluating children and adolescents for IBD.

Methods: The medical records of consecutive patients undergoing ileocolonoscopy for IBD were reviewed. Laboratory test results, FOBT, and perianal examination before the decision to perform the ileocolonoscopy were recorded. Standard limits of laboratory tests were used. Multivariate logistic regression was performed on a discovery cohort and applied to an independent validation cohort.

Results: The discovery cohort included 335 patients (85 IBD and 250 non-IBD). A total of 61.2% had FOBT and perianal examination performed before the decision to perform the ileocolonoscopy. A total of 119 patients had complete blood testing, FOBT, and perianal examination available for full analysis. The sensitivity of the laboratory testing was 80.5% for IBD, and the sensitivity of FOBT with perianal examination was 66.9%. The combined sensitivity of laboratory testing and FOBT with perianal examination was, however, 97.6%. The most predictive model included C-reactive protein, platelet counts, and FOBT with perianal examination and was superior to the laboratory value-only model (P < 0.001) that was validated in a separate cohort.

Conclusions: Perianal examination and FOBT improve sensitivity in screening children for IBD.
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http://dx.doi.org/10.1097/MPG.0000000000000754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4736714PMC
July 2015
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