Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.

Lubiprostone for Pediatric Functional Constipation: Randomized, Controlled, Double-Blind Study With Long-term Extension.

BACKGROUND & AIMS: Pediatric functional constipation (PFC) is a common problem in children that causes distress and presents treatment challenges to health care professionals. We conducted a randomized, placebo-controlled trial (study 1) in patients with PFC (6-17 years of age) to evaluate the efficacy and safety of lubiprostone, followed by an open-label extension for those who completed the placebo-controlled phase (study 2). METHODS: Study 1 (NCT02042183) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 12-week study evaluating the efficacy and safety of lubiprostone 12 µg twice daily (BID) and 24 µg BID. Study 2 (NCT02138136) was a phase 3, long-term, open-label extension of study 1. In both studies, lubiprostone doses were based on patients' weight. Efficacy was assessed solely based on study 1, with a primary endpoint of overall spontaneous bowel movement (SBM) response (increase of ≥1 SBM/wk vs baseline and ≥3 SBMs/wk for ≥9 weeks, including 3 of the final 4 weeks). RESULTS: 606 patients were randomized to treatment (placebo: n = 202; lubiprostone: n = 404) in study 1. No statistically significant difference in overall SBM response rate was observed between the lubiprostone and placebo groups (18.5% vs 14.4%; P = .2245). Both the 12-µg BID and 24-µg BID doses of lubiprostone were well tolerated in the double-blind and extension phases, with a safety profile consistent with that seen in adult studies. CONCLUSIONS: Lubiprostone did not demonstrate statistically significant effectiveness over placebo in children and adolescents with PFC but did demonstrate a safety profile similar to that in adults. (ClinicalTrials.gov: Number: NCT02042183; Number: NCT02138136).

Safety of Lubiprostone in Pediatric Patients With Functional Constipation: A Nonrandomized, Open-Label Trial.

OBJECTIVES: Pediatric functional constipation (PFC) affects up to 30% of children. Current treatments often do not sustain symptomatic relief. Lubiprostone is a locally acting chloride channel activator that promotes fluid secretion into the small bowel without affecting serum electrolyte concentrations. We assessed the safety/tolerability of oral lubiprostone as treatment for PFC in a 24-week study. METHODS: This phase 3 open-label safety trial conducted from April-November 2016 at 13 US sites included patients (ages 6-17 years) diagnosed with PFC (Rome III criteria). Patients <50 and ≥50 kg received lubiprostone 12 or 24 mcg twice daily, respectively, for 24 weeks. Safety endpoints included incidence of treatment-emergent adverse events (TEAEs) and changes from baseline in clinical laboratory parameters and vital signs. RESULTS: Overall, 87 patients receiving lubiprostone, 64.3% (36/56) in the 12-mcg group and 54.8% (17/31) in the 24-mcg group, completed the study. Of 12 TEAEs leading to discontinuation, only upper abdominal pain occurred in >1 patient. TEAEs were mostly mild in intensity, with gastrointestinal disorders (diarrhea, vomiting) most frequently reported. No safety concerns were found in vital signs, abbreviated physical examinations, and laboratory tests. Subgroup analyses assessed an impact of age, sex, and race categories on TEAEs and treatment-related adverse events. Mean investigators' assessments of treatment effectiveness (scale of 0-4) for lubiprostone 12- and 24-mcg groups, respectively, were 2.8 and 2.9 at week 12, and 2.7 and 2.2 at week 24. CONCLUSIONS: Lubiprostone was well tolerated in the pediatric population. The incidence of TEAEs was comparable to that observed in previous clinical trials and in adults.

Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease.

BACKGROUND & AIMS: The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. METHODS: We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P < 5.0 × 10-8 in meta-analysis with a nominal evidence (P < .05) in each scan were considered to have genome-wide significance. RESULTS: We detected SNPs at HLA-DRB1, and African-specific SNPs at ZNF649 and LSAMP, with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication (P < 1.6 × 10-6): ADCY3, CXCR6, HLA-DRB1 to HLA-DQA1 (genome-wide significance on conditioning), IL12B,PTGER4, and TNC for IBD; IL23R, PTGER4, and SNX20 (in strong linkage disequilibrium with NOD2) for CD; and KCNQ2 (near TNFRSF6B) for UC. Several of these genes, such as TNC (near TNFSF15), CXCR6, and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles. CONCLUSIONS: We performed a genome-wide association study of African Americans with IBD and identified loci associated with UC in only this population; we also replicated IBD, CD, and UC loci identified in European populations. The detection of variants associated with IBD risk in only people of African descent demonstrates the importance of studying the genetics of IBD and other complex diseases in populations beyond those of European ancestry.

Biliary Dyskinesia in Children: A Systematic Review.

Cholecystectomy rates for biliary dyskinesia in children are rising in the United States, but not in other countries. Biliary dyskinesia is a validated functional gallbladder disorder in adults, requiring biliary colic in the diagnosis. In contrast, most studies in children require upper abdominal pain, absent gallstones on ultrasound, and an abnormal gallbladder ejection fraction (GBEF) on cholecystokinin-stimulated cholescintigraphy for diagnosis. We aimed to systematically review existing literature in biliary dyskinesia in children, determine the validity and reliability of diagnostic criteria, GBEF, and to assess outcomes following cholecystectomy. We performed a systematic review following the PRISMA checklist and searched 7 databases including PubMed, Scopus, Embase, Ovid, MEDLINE, ProQuest, Web of Science, and the Cochrane library. Bibliographies of articles were screened for additional studies. Our search terms yielded 916 articles of which 28 were included. Three articles were manually added from searched references. We reviewed 31 peer-reviewed publications, all retrospective chart reviews. There was heterogeneity in diagnostic criteria and GBEF values. Outcomes after laparoscopic cholecystectomy varied from 34% to 100% success, and there was no consensus concerning factors influencing outcomes. The observational, retrospective study designs that comprised our review limited interpretation of safety and efficacy of the investigations and treatment in biliary dyskinesia in children. Symptoms of biliary dyskinesia overlapped with functional dyspepsia. There is a need for consensus on symptoms defining biliary dyskinesia, validation of testing required for diagnosis of biliary dyskinesia, and randomized controlled trials comparing medical versus surgical management in children with upper abdominal pain.

Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) has familial aggregation in African Americans (AAs), but little is known about the molecular genetic susceptibility. Mapping studies using the Immunochip genotyping array expand the number of susceptibility loci for IBD in Caucasians to 163, but the contribution of the 163 loci and European admixture to IBD risk in AAs is unclear. We performed a genetic mapping study using the Immunochip to determine whether IBD susceptibility loci in Caucasians also affect risk in AAs and identify new associated loci. METHODS: We recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the United States; additional controls were collected from 4 other Immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease, 361 with ulcerative colitis, 62 with IBD type unknown, and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed. RESULTS: The strongest associations were observed between ulcerative colitis and HLA rs9271366 (P = 7.5 × 10(-6)), Crohn's disease and 5p13.1 rs4286721 (P = 3.5 × 10(-6)), and IBD and KAT2A rs730086 (P = 2.3 × 10(-6)). Additional suggestive associations (P < 4.2 × 10(-5)) were observed between Crohn's disease and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2orf43; and between ulcerative colitis and SNPs near HDAC11 and near LINC00994. The latter 3 loci have not been previously associated with IBD, but require replication. Established Caucasian associations were replicated in AAs (P < 3.1 × 10(-4)) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P < 3.9 × 10(-4)) was observed for 17q12-17q21.31 (IZKF3 through STAT3), 10q11.23-10q21.2, 15q22.2-15q23, and 16p12.2-16p12.1. Network analyses showed significant enrichment (false discovery rate <1 × 10(-5)) in genes that encode members of the JAK-STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles. CONCLUSIONS: In a genetic analysis of 3308 AA IBD cases and controls, we found that many variants associated with IBD in Caucasians also showed association evidence with these diseases in AAs; we also found evidence for variants and loci not previously associated with IBD. The complex genetic factors that determine risk for or protection against IBD in different populations require further study.

Psychotropic medications for pediatric functional gastrointestinal disorders.

We describe the use of psychotropic medications in the treatment of functional gastrointestinal disorders (FGIDs) in children based on available data. We address their safety and efficacy. Most pediatric gastroenterologists do not or are not able to collaborate with child psychiatrists, so it may be beneficial for pediatric gastroenterologists to have a working knowledge of off-label psychotropic drugs to improve functional symptoms. We recommend that efforts be made to involve both the children and their families from the beginning, adverse effects be mentioned, and the treatment plan be explained.

Safety and efficacy of delayed release rabeprazole in 1- to 11-month-old infants with symptomatic GERD.

AIM: : The efficacy and safety of rabeprazole, a proton pump inhibitor, were studied in infants with gastroesophageal reflux disease (GERD). METHODS: Infants ages 1 to 11 months, with symptomatic GERD resistant to conservative therapy and/or previous exposure to acid-suppressive medications, were screened. After scoring >16 on a GERD symptom score (Infant Gastroesophageal Reflux Questionnaire-Revised [I-GERQ]), 344 infants were enrolled in a 1- to 3-week open-label (OL) phase and received rabeprazole 10 mg/day. Following caregiver-rated clinical improvement during the OL phase, patients were randomized to placebo, rabeprazole 5 mg, or rabeprazole 10 mg in the ensuing 5-week double-blind (DB) withdrawal phase. Primary endpoints evaluated from DB baseline to the end of the DB withdrawal phase included frequency of regurgitation, weight-for-age z score, and daily and weekly GERD symptom scores. RESULTS: Overall, 231 (86%) of the 268 randomized infants (placebo: 90; rabeprazole 5 mg: 90; rabeprazole 10 mg: 88) completed the study. Efficacy endpoints were similarly improved during the OL phase in all of the groups, and continued improving during the DB withdrawal phase with no difference between the placebo and combined rabeprazole groups. Mean decrease in frequency of regurgitation (-0.79 vs -1.20 times per day; P = 0.168), in I-GERQ-Revised scores (-3.6 [-25%] vs -3.9 points [-27%]; P = 0.960), in I-GERQ-Daily Diary scores (-1.87 [-19%] vs -1.85 [-19%]; P = 0.968), and increase in weight-for-age z scores (mean [standard deviation]: 0.11 [0.329] vs 0.14 [0.295]; P = 0.440) indicated equal improvement. Equal percentages (47%) reported adverse events in placebo and combined rabeprazole groups, with no new safety signals emerging. CONCLUSIONS: In those infants with GERD who improved with rabeprazole during the OL phase, improvements in symptoms and weight were similar in those who continued rabeprazole and those withdrawn to placebo during a 5-week DB phase.

Management of ingested magnets in children.

We describe a comprehensive algorithm for the management of ingested rare-earth magnets in children. These newer and smaller neodymium magnets sold as adult toys are much stronger than the traditional magnets, and can attract each other with formidable forces. If >1 magnet is swallowed at the same time, or a magnet is co-ingested with another metallic object, the loops of intestine can be squeezed between them resulting in bowel damage including perforations. An algorithm that uses the number of magnets ingested, location of magnets, and the timing of ingestion before intervention helps to delineate the roles of the pediatric gastroenterologists and surgeons in the management of these cases.

Morphometric histology for infant gastroesophageal reflux disease: evaluation of reliability in 497 esophageal biopsies.

OBJECTIVES: We sought to determine the reliability of morphometric measurements on infant esophageal biopsies using a light microscope with eyepiece micrometer. METHODS: We measured epithelial thickness, basal layer thickness (B), papillary height (P) and epithelial lymphocyte and eosinophil numbers on approximately 500 existing esophageal suction biopsies from infants previously evaluated for reflux esophagitis. We tested these measurements for interobserver, test-retest and internal consistency reliability. RESULTS: Infants ages 0.25 to 23.75 (median, 6.25) months provided 497 biopsies. Both investigators scoring the biopsies independently judged 93% of them scorable. Of the biopsies scored by both, the 2 readings were within 0.15 of each other for P in 97% and for B in 81%. In addition to these correlative measures of consistency, categoric measures demonstrated that 373 (89%) of the 420 scorable biopsies with visible papillae produced agreement as to P being abnormal (317, 85%) or normal (56, 15%). Similarly, 360 (78%) of the 463 scorable biopsies produced agreement as to B being abnormal (339, 94%) or normal (21, 6%). P values were 0.17 to 0.94 (median, 0.67), and B values were 0.13 to 0.91 (median, 0.34). Lymphocytes numbered 0 to 40 (median 5) per high-power field. Only 12% had any eosinophils; none of those with completely normal morphometrics had any eosinophils; and only 2% had >5 eosinophils per high-power field. CONCLUSIONS: Simple quantitative esophageal histological morphometric parameters are reliably measurable on suction biopsies from infants using a light microscope fitted with an ocular micrometer, even by nonpathologists.

IBD Serology and Disease Outcomes in African Americans With Crohn's Disease.

Backgrounds: Recent studies have identified the role of serologic markers in characterizing disease phenotype, location, complications, and severity among Northern Europeans (NE) with Crohn's disease (CD). However, very little is known about the role of serology in CD among African Americans (AA). Our study explored the relationship between serology and disease phenotype in AA with CD, while controlling for genetic ancestry. Methods: AAs with CD were enrolled as participants through multicenter collaborative efforts. Serological levels of IgA anti-Saccharomyces cervisiae antibody (ASCA), IgG ASCA, E. coli outermembrane porin C, anti-CBir1, and ANCA were measured using enzyme-linked immunosorbent assays. Genotyping was performed using Illumina immunochip technology; an admixture rate was calculated for each subject. Multiple imputation by chained equations was performed to account for data missing at random. Logistic regression was used to calculate adjusted odds ratio (OR) for associations between serological markers and both complicated disease and disease requiring surgery. Results: A total of 358 patients were included in the analysis. The majority of our patients had inflammatory, noncomplicated disease (58.4%), perianal disease (55.7%), and documented colonic inflammation (86.8%). On multivariable analysis, both IgG ASCA and OmpC were associated with complicated disease (OR, 2.67; 95% CI, 1.67-4.28; OR, 2.23; 95% CI, 1.41-3.53, respectively) and disease requiring surgery (OR, 2.51; 95% CI, 1.49-4.22; OR, 3.57; 95% CI, 2.12-6.00). NE admixture to the African genome did not have any associations or interactions in relation to clinical outcome. Conclusions: Our study comprises the largest cohort of AAs with CD. The utility of serological markers for the prognosis of CD in NE applies equally to AA populations.

Motility disorders. Diagnosis and treatment for the pediatric patient.

Motility disorders are common in children and may affect any area of the GI tract. The past decade has brought significant advances in the understanding of motility disorders in pediatrics. More sophisticated testing techniques have helped to differentiate normal from abnormal motility in children of different ages. Manometry now may be used to clarify the pathophysiologic defect underlying chest pain, dysphagia, rumination, gastroparesis, chronic intestinal pseudo-obstruction, and colonic neuromuscular disorders. Motility testing also may be used to identify the motor defect responsible for persistence of symptoms after surgery for GER or HD. New investigational techniques and prokinetic agents likely to be available in the future also were discussed.

Surgical reconstruction of the double lumen esophagus.

We describe an unusual case of iatrogenic double lumen esophagus in a young female who underwent a Nissen fundoplication surgery for gastroesophageal reflux disease (GERD) in infancy. The patient suffered from refractory symptoms, including dysphagia and failure to thrive before she was evaluated and noted to have a double-lumen in the distal esophagus leading to the stomach with both lumina being extremely narrow. This condition has only rarely been described in the literature. Her symptoms were reversed after surgical reconstruction of the distal esophagus using a novel stapling technique through a gastrotomy. This is the first report of successful surgical reconstruction of a double lumen esophagus.

Significance of screening electrocardiogram before the initiation of amitriptyline therapy in children with functional abdominal pain.

Amitriptyline (AMT) is commonly used in the management of children with irritable bowel syndrome. AMT is pro-arrhythmogenic and increases the risk of sudden cardiac death. However, there is not enough data regarding the cardiac toxicity in therapeutic doses of AMT in children and the need for screening electrocardiogram (EKG). Errors in computer EKG interpretation are not uncommon. In a risk-prevention study, the authors sought to identify the true incidence of prolonged corrected QT (QTc) interval and other arrhythmias in children with irritable bowel syndrome before the initiation of AMT. Out of the 760 EKGs screened, 3 EKGs demonstrated a true prolonged QTc after the careful manual reading by a pediatric cardiologist and they were not picked by computer-generated reading. The authors conclude that screening EKG should always be performed on children before initiating AMT therapy. Also, the computer-generated EKG needs to be verified by a pediatric cardiologist to avoid serious misinterpretations.

Rectocele in children: a case report.

Rectocele is an abnormal protrusion of the anterior wall of the rectum into the vagina. When symptomatic, it will typically cause obstructed defecation. It is almost exclusively found in females with rare reports in males and never been described in the literature in children younger than 18 years of age so far. We are presenting 3 cases of rectocele with obstructed defecation in the pediatric population. These children presented with the complaints of constipation along with refractory straining. They were diagnosed by defecography. Two were treated surgically and one conservatively. Surgical intervention completely cured the problem with uneventful postoperative course. Further multicenter studies with the aid of radiologic studies on children with "hard to treat" constipation should be considered to better define that disorder in the pediatric age group. A more vigilant approach may have implications in the prevention of more severe rectal and uterovaginal prolapse in the future.

Side population cells derived from adult human liver generate hepatocyte-like cells in vitro.

We sought to determine whether hepatic side population (SP) cells derived from adult human liver possess the potential of a novel candidate hepatic stem cell. Human cadaveric donor liver was subjected to collagenase perfusion and hepatocytes were separated from nonparenchymal cells by differential centrifugation. SP cells were isolated from the nonparenchymal portion after Hoechst 33342 staining. Since CD45 is a panleukocyte antigen, CD45-negative SP cells were separated from the vast majority of CD45-positive SP cells (90%), and hepatic growth medium was used to culture both groups. Both CD45-negative and CD45-positive hepatic SP cells generated colonies in the hepatic growth medium in 2-3 weeks. The colonies yielded large cells morphologically consistent with human hepatocytes, demonstrating granule-rich cytoplasm, dense, often double nuclei, and intracellular lipofuscin pigment. The cultured cells from both sources were positive for markers of human hepatocytes: HepPar, cytokeratin 8 (CK8), and human albumin. Reverse transcriptase-polymerase chain reaction (RT-PCR) performed on both groups demonstrated positivity for additional liver markers including human albumin, CK18, alpha-1 anti-trypsin, and the human cytochrome P450 enzyme CYP2B6. Double immunostaining (CD45 and HepPar) and RT-PCR confirmed that the hepatocyte-like cells derived from the CD45-negative SP cells acquired HepPar positivity but had no detectable CD45 antigen expression. In contrast, the cultured cells derived from the CD45-positive SP cells also acquired HepPar positivity, but only a minimal fraction expressed the CD45 antigen. We conclude that hepatic SP cells derived from the nonparenchymal portion of human liver are a potential source of human hepatocytes irrespective of their CD45 status, and further animal studies will be required to assess their regenerative potential.