William E. Bennett

Patterned progression of bacterial populations in the premature infant gut

Significance It is increasingly apparent that bacteria in the gut are important determinants of health and disease in humans. However, we know remarkably little about how this organ transitions from a sterile/near-sterile state at birth to one that soon harbors a highly diverse biomass. We show in premature infants a patterned progression of the gut bacterial community that is only minimally influenced by mode of delivery, antibiotics, or feeds. The pace of this progression is most strongly influenced by gestational age, with the microbial population assembling slowest for infants born most prematurely. These data raise the possibility that host biology, more than exogenous factors such as antibiotics, feeds, and route of delivery, drives bacterial populations in the premature newborn infant gut. In the weeks after birth, the gut acquires a nascent microbiome, and starts its transition to bacterial population equilibrium. This early-in-life microbial population quite likely influences later-in-life host biology. However, we know little about the governance of community development: does the gut serve as a passive incubator where the first organisms randomly encountered gain entry and predominate, or is there an orderly progression of members joining the community of bacteria? We used fine interval enumeration of microbes in stools from multiple subjects to answer this question. We demonstrate via 16S rRNA gene pyrosequencing of 922 specimens from 58 subjects that the gut microbiota of premature infants residing in a tightly controlled microbial environment progresses through a choreographed succession of bacterial classes from Bacilli to Gammaproteobacteria to Clostridia, interrupted by abrupt population changes. As infants approach 33–36 wk postconceptional age (corresponding to the third to the twelfth weeks of life depending on gestational age at birth), the gut is well colonized by anaerobes. Antibiotics, vaginal vs. Caesarian birth, diet, and age of the infants when sampled influence the pace, but not the sequence, of progression. Our results suggest that in infants in a microbiologically constrained ecosphere of a neonatal intensive care unit, gut bacterial communities have an overall nonrandom assembly that is punctuated by microbial population abruptions. The possibility that the pace of this assembly depends more on host biology (chiefly gestational age at birth) than identifiable exogenous factors warrants further consideration.

Enteric infections and diagnostic testing.

Purpose of review Gastrointestinal pathogens profoundly affect human health and well being. The providers ability to render optimal care often highly depends on diagnostic microbiologic support. We aim to provide a clinically pertinent assessment of the current state of our ability to diagnose human gastrointestinal pathogens and describe (and decry) the unsophistication of many current diagnostic methods and strategies. Recent findings Recent advances involve improved stool polymerase chain reaction assays and application of this technology to a broader panel of pathogens, stool antigen assays, and improved culture techniques, but there is little penetration of such diagnostic advances into clinical practice. Many such techniques remain limited to research or epidemiologic use and are not typically available in the clinical laboratory. Summary Multiple clinical and laboratory factors need to be considered when attempting to diagnose the wide variety of gastrointestinal pathogens afflicting humans. Careful interpretation of diagnostic tests with attention to the population studied and the characteristics of each test is necessary.

Increased Length of Stay and Costs Associated With Weekend Admissions for Failure to Thrive

OBJECTIVE: To evaluate whether admission day of the week affects the length of stay (LOS) and health care costs for failure to thrive (FTT) admissions. METHODS: Administrative data were obtained for all children aged <2 years (N = 23 332) with a primary admission diagnosis of FTT from 2003-2011 from 42 freestanding US hospitals. Demographic characteristics, day of admission, LOS, costs per stay, number of discharge diagnoses, primary discharge diagnoses, primary procedure code, number of radiologic and laboratory units billed during admission were obtained for each admission. Linear regression and zero-truncated Poisson regression were used for analysis. RESULTS: Weekend admission was significantly correlated with increased LOS and increased average cost (P < .002). This finding was also true for children with both admission and discharge diagnoses of FTT (P < .001). The number of procedures for children admitted on the weekend was not significantly different compared with children admitted on the weekdays (incident rate ratio [IRR]:1.04 [95% confidence interval (CI): 0.99–1.09]). However, weekend admissions did have more radiologic studies (IRR: 1.13 [95% CI: 1.10–1.16]) and laboratory tests (IRR: 1.39 [95% CI: 1.38–1.40]) performed. If one-half of weekend admissions in 2010 with both admission and discharge diagnoses of FTT were converted to Monday admissions, total savings in health care dollars for 2010 would be

Hypothyroidism is a rare cause of isolated constipation.

534, 145. CONCLUSIONS: Scheduled FTT admissions on weekends increased LOS and health care costs compared with weekday admissions of similar levels of complexity. Reduction in planned weekend admissions for FTT could significantly reduce health care costs.

Ibuprofen-Induced Liver Injury in an Adolescent Athlete

ABSTRACT The prevalence of constipation in children is high and accounts for a large percentage of pediatric and pediatric gastroenterology visits. Thyroid testing is frequently ordered to evaluate constipation and other gastrointestinal complaints in children. We reviewed all of the patients with thyroid testing ordered by our pediatric gastroenterology division during a 5-year period. We found 873 patients on whom thyroid testing was performed, and 56 patients had evidence of hypothyroidism. Nine patients had constipation and clinically significant hypothyroidism in this group; however, only 1 child had constipation as their sole presenting symptom. The contribution of occult hypothyroidism to isolated constipation in children may have been previously overestimated.

A Method for Isolating and Analyzing Human mRNA from Newborn Stool

The patient is a 16-year-old previously healthy Caucasian male who presented with the acute onset of jaundice and dark urine. Six weeks prior to this, he was seen by his primary care doctor for chronic shoulder pain related to pitching in baseball. At that time, he began scheduled dosing of ibuprofen at ∼1.2 g/day for a 2-week period. Subsequent to that, he took an average of 200 to 400 mg/day sporadically for the next 4 weeks. He first noticed dark-colored urine and scleral icterus, which were followed by jaundice 2 days later. He presented to his pediatrician, where initial laboratory workup included a total bilirubin of 3.2 mg/dL, an aspartate aminotransferase (AST) of 41 U/L, an alanine aminotransferase (ALT) of 65 U/L, an alkaline phosphatase of 409 U/L, Epstein-Barr virus and cytomegalovirus titers, which were negative, and a hepatitis A, B, and C viral titers, which were also negative. Two days later, he had a computed tomography (CT) of his abdomen which showed moderate pericholecystic fluid, but no evidence of biliary obstruction and a normal-appearing liver. His laboratory data are summarized in Table 1. On day of illness 9, he came for consultation at our tertiary institution, where further workup was initiated. Repeat laboratory values showed a total bilirubin of 5.8, an AST of 43, an ALT of 76, an alkaline phosphatase of 510, and a normal γ-glutamyl transpeptidase. An international normalization ratio (INR) was first performed then, which was normal at Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the commoner causes of druginduced cholestasis, accounting for between 3 and 23 cases per 10 000 patient years. Reports of hepatic injury range from insignificant and transient liver enzyme elevation to severe and fulminant hepatitis. Meanwhile, ibuprofen remains one of the most commonly taken over-the-counter medications, and its gastrointestinal side effects are well-described, but its hepatoxicity remains poorly understood. A recent meta-analysis of 64 randomized control trials of NSAID use in adults with arthritis showed no difference between ibuprofen and placebo in the rate of hypertransaminasemia, liver-related hospitalizations, or liver-related deaths. However, although the reviewed trials were powered to achieve a result for arthritis outcomes, none were sufficiently powered to evaluate rare but serious adverse events such as liver injury. Case reports of patients with ibuprofen-induced Stevens–Johnson syndrome with hepatic involvement have shown severe cholestasis, usually with marked hepatitis and occasional hepatic failure. Additionally, several cases linked to ibuprofen use have shown progression to fulminant hepatic failure at both therapeutic dosages and overdosage. More recently, ibuprofen has been implicated in the socalled acute vanishing bile duct syndrome in children and in cases of acute hepatitis in patients with established stable, chronic hepatitis C infection.

Proinflammatory fecal mRNA and childhood bacterial enteric infections

Efforts to characterize the human transcriptome have largely been limited to blood, urine, and tissue analyses (i.e., normally sterile materials). We report here an extraction protocol using commercially available reagents to obtain high-yield, reverse-transcribable RNA from human stool. Quantitative reverse transcriptase polymerase chain reactions demonstrated minimal intra-specimen but considerable intra-subject variability over time of transcripts for interleukin-6 (IL-6), IL-8, epidermal growth factor (EGF), calprotectin, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). This technique now expands opportunities to use the human fecal transcriptome to characterize gastrointestinal pathophysiology.

Robin sequence: what the multidisciplinary approach can do

Introduction: Assessment of specific mRNAs in human samples is useful in characterizing disease. However, mRNA in human stool has been understudied. Methods: We purified fecal RNA from 46 children infected with Campylobacter jejuni, Escherichia coli O157:H7, Salmonella spp., or Shigella sonnei and 26 controls, and compared the proportions of IL-1β, IL-8, osteoprotegerin, and calprotectin mRNA between groups using qRT-PCR. We determined the concentrations of calprotectin, IL-8, and osteoprotegerin by enzyme immunoassays in cognate specimens. Results: Compared to controls, infected stools showed increased transcripts of IL-1β, IL-8, and calprotectin. mRNA and protein concentrations correlated for IL-8, but not for calprotectin. Discussion: Stool mRNA quantification offers a potentially useful, noninvasive way to assess inflammation in the gastrointestinal tract, and may be more sensitive than EIA.

Incidence of Low Seroimmunity to Hepatitis B Virus in Children With Inflammatory Bowel Disease

Robin sequence (RS) is a commonly encountered triad of micrognathia, glossoptosis, and airway obstruction, with or without a cleft palate. The management of airway obstruction is of paramount importance, and multiple reviews and retrospective series outline the diagnosis and treatment of RS. This article focuses on the multidisciplinary nature of RS and the specialists’ contributions and thought processes regarding the management of the RS child from birth to skeletal maturity. This review demonstrates that the care of these children extends far beyond the acute airway obstruction and that thorough monitoring and appropriate intervention are required to help them achieve optimal outcomes.

Probiotics and infant colic

Objectives: Patients with inflammatory bowel disease (IBD) often receive immunosuppressive therapy, which may make them vulnerable to infections such as hepatitis B. We hypothesized that hepatitis B virus titers are low in the vaccinated pediatric population with IBD. The aims of our study were to identify the incidence of lower titers of hepatitis B surface antibody (HBsAb) and determine which patient factors may be associated with lower HBsAb titers. Methods: Patients with diagnosis of IBD, ages 5 to 18 years, were prospectively enrolled. Patients were confirmed to have had a full series of hepatitis B vaccination. Quantitative serum HBsAb titers were measured and logistic regression analysis with independent variables of age, sex, race, disease phenotype, surgery, medications and a dependent variable of adequate HBsAb titers (> 10 mIU/mL) was performed. Results: Of the 116 patients enrolled, 57 were boys and 59 were girls. 75 patients had a diagnosis of Crohn disease; 32 had a diagnosis of ulcerative colitis; and 9 patients had been diagnosed as having indeterminate colitis. At the time of the study, 15 patients were taking corticosteroid, 66 on an immunomodulator, and 53 on a biologic. Sixty percent of patients in the 5- to 10-year age group had protective titers versus 22% to 27% in the older groups, P = 0.04. Only 28% of the 116 patients had HBsAb titers of >10m IU/mL. Twenty percent of the patients taking corticosteroids, 27% taking immunomodulators, and 24% taking biologics were found to be seroimmune. Conclusions: Nearly two-thirds of pediatric patients with IBD have low titers against hepatitis B virus. Titers were highest in the younger patients. No patient-specific variable, such as the use of immunosuppressants, appeared to influence these low titers.