Hasbro Children's Hospital

BACKGROUND: The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis result from alterations in intestinal microbes and the immune system. However, the precise dysfunctions of microbial metabolism in the gastrointestinal microbiome during IBD remain unclear. We analyzed the microbiota of intestinal biopsies and stool samples from 231 IBD and healthy subjects by 16S gene pyrosequencing and followed up a subset using shotgun metagenomics. Gene and pathway composition were assessed, based on 16S data from phylogenetically-related reference genomes, and associated using sparse multivariate linear modeling with medications, environmental factors, and IBD status. RESULTS: Firmicutes and Enterobacteriaceae abundances were associated with disease status as expected, but also with treatment and subject characteristics. Microbial function, though, was more consistently perturbed than composition, with 12% of analyzed pathways changed compared with 2% of genera. We identified major shifts in oxidative stress pathways, as well as decreased carbohydrate metabolism and amino acid biosynthesis in favor of nutrient transport and uptake. The microbiome of ileal Crohn's disease was notable for increases in virulence and secretion pathways. CONCLUSIONS: This inferred functional metagenomic information provides the first insights into community-wide microbial processes and pathways that underpin IBD pathogenesis.

OBJECTIVE: Childhood obesity has contributed to an increased incidence of type 2 diabetes mellitus and metabolic syndrome (MS) among children. Intrauterine exposure to diabetes and size at birth are risk factors for type 2 diabetes mellitus, but their association with MS in childhood has not been demonstrated. We examined the development of MS among large-for-gestational-age (LGA) and appropriate-for-gestational age (AGA) children. STUDY DESIGN: The major components of MS (obesity, hypertension, dyslipidemia, and glucose intolerance) were evaluated in a longitudinal cohort study of children at age 6, 7, 9, and 11 years who were LGA (n = 84) or AGA (n = 95) offspring of mothers with or without gestational diabetes mellitus (GDM). The cohort consisted of 4 groups, ie, LGA offspring of control mothers, LGA offspring of mothers with GDM, AGA offspring of control mothers, and AGA offspring of mothers with GDM. Biometric and anthropometric measurements were obtained at 6, 7, 9, and 11 years. Biochemical testing included measurements of postprandial glucose and insulin levels and high-density lipoprotein (HDL) cholesterol levels at 6 and 7 years and of fasting glucose, insulin, triglyceride, and HDL cholesterol levels at 9 and 11 years. We defined the components of MS as (1) obesity (BMI >85th percentile for age), (2) diastolic or systolic blood pressure >95th percentile for age, (3) postprandial glucose level >140 mg/dL or fasting glucose level >110 mg/dL, (4) triglyceride level >95th percentile for age, and (5) HDL level <5th percentile for age. RESULTS: There were no differences in baseline characteristics (gender, race, socioeconomic status, and maternal weight gain during pregnancy) for the 4 groups except for birth weight, but there was a trend toward a higher prevalence of maternal obesity before pregnancy in the LGA/GDM group. Obesity (BMI >85th percentile) at 11 years was present in 25% to 35% of the children, but rates were not different between LGA and AGA offspring. There was a trend toward a higher incidence of insulin resistance, defined as a fasting glucose/insulin ratio of <7, in the LGA/GDM group at 11 years. Analysis of insulin resistance at 11 years in a multivariate logistic regression revealed that childhood obesity and the combination of LGA status and maternal GDM were associated with insulin resistance, with odds ratios of 4.3 (95% confidence interval [CI]: 1.5-11.9) and 10.4 (95% CI: 1.5-74.4), respectively. The prevalence at any time of > or =2 components of MS was 50% for the LGA/GDM group, which was significantly higher than values for the LGA/control group (29%), AGA/GDM group (21%), and AGA/control group (18%). The prevalence of > or =3 components of MS at age 11 was 15% for the LGA/GDM group, compared with 3.0% to 5.3% for the other groups. Cox regression analysis was performed to determine the independent hazard (risk) of developing MS attributable to birth weight, gender, maternal prepregnancy obesity, and GDM. For Cox analyses, we defined MS as > or =2 of the following 4 components: obesity, hypertension (systolic or diastolic), glucose intolerance, and dyslipidemia (elevated triglyceride levels or low HDL levels). LGA status and maternal obesity increased the risk of MS approximately twofold, with hazard ratios of 2.19 (95% CI: 1.25-3.82) and 1.81 (95% CI: 1.03-3.19), respectively. GDM and gender were not independently significant. To determine the cumulative hazard of developing MS with time, we plotted the risk according to LGA or AGA category for the control and GDM groups from 6 years to 11 years, with Cox regression analyses. The risk of developing MS with time was not significantly different between LGA and AGA offspring in the control group but was significantly different between LGA and AGA offspring in the GDM group, with a 3.6-fold greater risk among LGA children by 11 years. CONCLUSIONS: We showed that LGA offspring of diabetic mothers were at significant risk of developing MS in childhood. The prevalence of MS in the other groups was similar to the prevalence (4.8%) among white adolescents in the 1988-1994 National Health and Nutrition Examination Survey. This effect of LGA with maternal GDM on childhood MS was previously demonstrated for Pima Indian children but not the general population. We also found that children exposed to maternal obesity were at increased risk of developing MS, which suggests that obese mothers who do not fulfill the clinical criteria for GDM may still have metabolic factors that affect fetal growth and postnatal outcomes. Children who are LGA at birth and exposed to an intrauterine environment of either diabetes or maternal obesity are at increased risk of developing MS. Given the increased obesity prevalence, these findings have implications for perpetuating the cycle of obesity, insulin resistance, and their consequences in subsequent generations.

BACKGROUND/AIMS: On behalf of the Drug and Therapeutics, and Ethics Committees of the Pediatric Endocrine Society, we sought to update the guidelines published in 2003 on the use of growth hormone (GH). Because idiopathic short stature (ISS) remains a controversial indication, and diagnostic challenges often blur the distinction between ISS, GH deficiency (GHD), and primary IGF-I deficiency (PIGFD), we focused on these three diagnoses, thereby adding recombinant IGF-I therapy to the GH guidelines for the first time. METHODS: This guideline was developed following the GRADE approach (Grading of Recommendations, Assessment, Development, and Evaluation). RESULTS: This guideline provides recommendations for the clinical management of children and adolescents with growth failure from GHD, ISS, or PIGFD using the best available evidence. CONCLUSION: The taskforce suggests that the recommendations be applied in clinical practice with consideration of the evolving literature and the risks and benefits to each individual patient. In many instances, careful review highlights areas that need further research.

BACKGROUND: Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management. METHODS: We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization. RESULTS: Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P=2.11×10(-38)). Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant (Spearman correlation coefficient, 0.66; P<0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P<0.001), and mothers were more likely than fathers to transmit second-site copy-number variants to their offspring (P=0.02). CONCLUSIONS: Multiple, large copy-number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation, and secondary copy-number variants are preferentially transmitted from maternal carriers. (Funded by the Simons Foundation Autism Research Initiative and the National Institutes of Health.).

As a traditionally underserved population that faces numerous health disparities, youth who identify as transgender and gender diverse (TGD) and their families are increasingly presenting to pediatric providers for education, care, and referrals. The need for more formal training, standardized treatment, and research on safety and medical outcomes often leaves providers feeling ill equipped to support and care for patients that identify as TGD and families. In this policy statement, we review relevant concepts and challenges and provide suggestions for pediatric providers that are focused on promoting the health and positive development of youth that identify as TGD while eliminating discrimination and stigma.

Cholestatic jaundice in infancy affects approximately 1 in every 2500 term infants and is infrequently recognized by primary providers in the setting of physiologic jaundice. Cholestatic jaundice is always pathologic and indicates hepatobiliary dysfunction. Early detection by the primary care physician and timely referrals to the pediatric gastroenterologist/hepatologist are important contributors to optimal treatment and prognosis. The most common causes of cholestatic jaundice in the first months of life are biliary atresia (25%-40%) followed by an expanding list of monogenic disorders (25%), along with many unknown or multifactorial (eg, parenteral nutrition-related) causes, each of which may have time-sensitive and distinct treatment plans. Thus, these guidelines can have an essential role for the evaluation of neonatal cholestasis to optimize care. The recommendations from this clinical practice guideline are based upon review and analysis of published literature and the combined experience of the authors. The committee recommends that any infant noted to be jaundiced after 2 weeks of age be evaluated for cholestasis with measurement of total and direct serum bilirubin, and that an elevated serum direct bilirubin level (direct bilirubin levels >1.0 mg/dL or >17 μmol/L) warrants timely consideration for evaluation and referral to a pediatric gastroenterologist or hepatologist. Of note, current differential diagnostic plans now incorporate consideration of modern broad-based next-generation DNA sequencing technologies in the proper clinical context. These recommendations are a general guideline and are not intended as a substitute for clinical judgment or as a protocol for the care of all infants with cholestasis. Broad implementation of these recommendations is expected to reduce the time to the diagnosis of pediatric liver diseases, including biliary atresia, leading to improved outcomes.

PURPOSE: Pediatric Oncology Group (POG) studies 9426 and 9425 evaluated dexrazoxane (DRZ) as a cardiopulmonary protectant during treatment for Hodgkin's disease (HD). We evaluated incidence and risk factors of acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and second malignant neoplasms (SMNs). PATIENTS AND METHODS: Treatment for low- and high-risk HD with doxorubicin, bleomycin, vincristine, and etoposide (ABVE) or dose-intensified ABVE with prednisone and cyclophosphamide (ABVE-PC), respectively, was followed by low-dose radiation. The number of chemotherapy cycles was determined by rapidity of the initial response. Patients were assigned randomly to receive DRZ (n = 239) or no DRZ (n = 239) concomitantly with chemotherapy to evaluate its potential to decrease adverse cardiopulmonary outcomes. RESULTS: Ten patients developed SMN. Six of eight patients developed AML/MDS, and both solid tumors (osteosarcoma and papillary thyroid carcinoma) occurred in recipients of DRZ. Eight patients with SMN were first events. With median 58 months' follow-up, 4-year cumulative incidence rate (CIR) for AML/MDS was 2.55% +/- 1.0% with DRZ versus 0.85% +/- 0.6% in the non-DRZ group (P = .160). For any SMN, the CIR for DRZ was 3.43% +/- 1.2% versus CIR for non-DRZ of 0.85% +/- 0.6% (P = .060). Among patients receiving DRZ, the standardized incidence rate (SIR) for AML/MDS was 613.6 compared with 202.4 for those not receiving DRZ (P = .0990). The SIR for all SMN was 41.86 with DRZ versus 10.08 without DRZ (P = .0231). CONCLUSION: DRZ is a topoisomerase II inhibitor with a mechanism distinct from etoposide and doxorubicin. Adding DRZ to ABVE and ABVE-PC may have increased the incidence of SMN and AML/MDS.

OBJECTIVE: To examine the impact of a 30-minute delay in school start time on adolescents' sleep, mood, and behavior. DESIGN: Participants completed the online retrospective Sleep Habits Survey before and after a change in school start time. SETTING: An independent high school in Rhode Island. PARTICIPANTS: Students (n = 201) in grades 9 through 12. Intervention Institution of a delay in school start time from 8 to 8:30 am. MAIN OUTCOME MEASURES: Sleep patterns and behavior, daytime sleepiness, mood, data from the Health Center, and absences/tardies. RESULTS: After the start time delay, mean school night sleep duration increased by 45 minutes, and average bedtime advanced by 18 minutes (95% confidence interval, 7-29 minutes [t(423) = 3.36; P < .001]); the percentage of students getting less than 7 hours of sleep decreased by 79.4%, and those reporting at least 8 hours of sleep increased from 16.4% to 54.7%. Students reported significantly more satisfaction with sleep and experienced improved motivation. Daytime sleepiness, fatigue, and depressed mood were all reduced. Most health-related variables, including Health Center visits for fatigue-related complaints, and class attendance also improved. CONCLUSIONS: A modest delay in school start time was associated with significant improvements in measures of adolescent alertness, mood, and health. The results of this study support the potential benefits of adjusting school schedules to adolescents' sleep needs, circadian rhythm, and developmental stage.

OBJECTIVE: To investigate the relationship between specific television-viewing habits and both sleep habits and sleep disturbances in school children. METHODS: The parents of 495 children in grades kindergarten through fourth grade in three public elementary schools completed two retrospective survey questionnaires, one assessing their children's sleep behaviors and the other examining television-viewing habits of both the child and the family. Sleep domains assessed included bedtime resistance, sleep onset delay, sleep duration, anxiety around sleep, parasomnias, night wakings, and daytime sleepiness. Teachers from all three schools also completed daytime sleepiness questionnaires (N = 402) for the sample. RESULTS: Most of the television-viewing practices examined in this study were associated with at least one type of sleep disturbance. Despite overall close monitoring of television-viewing habits, one quarter of the parents reported the presence of a television set in the child's bedroom. The television-viewing habits associated most significantly with sleep disturbance were increased daily television viewing amounts and increased television viewing at bedtime, especially in the context of having a television set in the child's bedroom. The sleep domains that appeared to be affected most consistently by television were bedtime resistance, sleep onset delay, and anxiety around sleep, followed by shortened sleep duration. The parent's threshold for defining "problem sleep behavior" in their child was also important in determining the significance of the association between sleep disturbance and television-viewing habits. CONCLUSION: Health care practitioners should be aware of the potential negative impact of television viewing at bedtime. Parents should be questioned about their children's television-viewing habits as part of general screening for sleep disturbances and as part of anticipatory guidance in regards to healthy sleep habits in children. In particular, the presence of a television set in the child's bedroom may be a relatively underrecognized, but important, contributor to sleep problems in school children.

OBJECTIVE: Adolescence is an important period of risk for the development of lifelong smoking behaviors. Compelling, although inconsistent, evidence suggests a relationship between parental smoking and the risk of smoking initiation during adolescence. This study investigates unresolved issues concerning the strength and nature of the association between parent smoking and offspring smoking initiation. METHODS: We enrolled 564 adolescents aged 12 to 17, along with 1 of their parents, into the New England Family Study between 2001 and 2004. Lifetime smoking histories were obtained from parents and their adolescent offspring. Discrete-time survival analysis was used to investigate the influence of parental smoking histories on the risk of adolescent smoking initiation. RESULTS: Parental smoking was associated with a significantly higher risk of smoking initiation in adolescent offspring. In addition, the likelihood of offspring smoking initiation increased with the number of smoking parents and the duration of exposure to parental smoking, suggesting a dose-response relationship between parental smoking and offspring smoking. Offspring of parents who had quit smoking were no more likely to smoke than offspring of parents who had never smoked. The effects of parental smoking on offspring initiation differed by sex (with a stronger effect of fathers' smoking on boys than girls), developmental period (with a stronger effect of parental smoking before the adolescent was age 13 than afterward), and residence of parents (with effects of fathers' smoking being dependent on living in the same household as the adolescent). Parental smoking was also associated with stronger negative reactions to adolescents' first cigarette, a potential marker of the risk of progression to higher levels of use. CONCLUSIONS: Parental smoking is an important source of vulnerability to smoking initiation among adolescents, and parental smoking cessation might attenuate this vulnerability.

PURPOSE: Current American Urological Association treatment guidelines for vesicoureteral reflux do not include any recommendations pertaining to endoscopic therapy (subureteral injection of bulking agent). We performed a meta-analysis of the existing literature pertaining to endoscopic treatment to allow comparison with reports of open surgical correction. MATERIALS AND METHODS: We searched all peer reviewed articles published through 2003 pertaining to endoscopic treatment of vesicoureteral reflux. A total of 63 articles were double reviewed by 9 pediatric urologists, and the data were tabulated on data retrieval sheets. A mixed effects logistic regression model was used to obtain overall estimates of event probabilities (eg reflux resolution, ureteral obstruction) together with their 95% confidence intervals. Individual study estimates were obtained with overall estimate and observation characteristics using empirical Bayes calculations. Differences between or among specific groups were assessed using the F-test. RESULTS: The database included 5,527 patients and 8,101 renal units. Following 1 treatment the reflux resolution rate (by ureter) for grades I and II reflux was 78.5%, grade III 72%, grade IV 63% and grade V 51%. If the first injection was unsuccessful, the second treatment had a success rate of 68%, and the third treatment 34%. The aggregate success rate with 1 or more injections was 85%. The success rate was significantly lower for duplicated (50%) vs single systems (73%), and neuropathic (62%) vs normal bladders (74%). The success rate was similar among children and adults. Following a previous failed open reimplantation endoscopic treatment was successful in 65% of patients. After endoscopic treatment with variable followup pyelonephritis developed in 0.75% of patients and cystitis in 6%. There were few reports of renal scarring following treatment. CONCLUSIONS: Endoscopic treatment provides a high rate of success in children with reflux that decreases with increasing grade, although multiple treatments may be necessary. Future reports of endoscopic therapy should include rates of urinary tract infection and renal scarring.

Abstract Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α 4 β 7 integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.

Rotavirus infection is the most common cause of severe diarrhea disease in infants and young children worldwide and continues to have a major global impact on childhood morbidity and mortality. Vaccination is the only control measure likely to have a significant impact on the incidence of severe dehydrating rotavirus disease. In 1999, a highly efficacious rotavirus vaccine licensed in the United States, RotaShield, was withdrawn from the market after 14 months because of its association with intussusception. Two new live, oral, attenuated rotavirus vaccines were licensed in 2006: the pentavalent bovine-human reassortant vaccine (RotaTeq) and the monovalent human rotavirus vaccine (Rotarix). Both vaccines have demonstrated very good safety and efficacy profiles in large clinical trials in western industrialized countries and in Latin America. Careful surveillance has not revealed any increased risk of intussusception in the vaccinated groups with either vaccine. The new rotavirus vaccines are now introduced for routine use in a number of industrialized and developing countries. These new safe and effective rotavirus vaccines offer the best hope of reducing the toll of acute rotavirus gastroenteritis in both developed and developing countries.

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA that produces the farnesylated aberrant lamin A protein, progerin. This multisystem disorder causes failure to thrive and accelerated atherosclerosis leading to early death. Farnesyltransferase inhibitors have ameliorated disease phenotypes in preclinical studies. Twenty-five patients with HGPS received the farnesyltransferase inhibitor lonafarnib for a minimum of 2 y. Primary outcome success was predefined as a 50% increase over pretherapy in estimated annual rate of weight gain, or change from pretherapy weight loss to statistically significant on-study weight gain. Nine patients experienced a ≥50% increase, six experienced a ≥50% decrease, and 10 remained stable with respect to rate of weight gain. Secondary outcomes included decreases in arterial pulse wave velocity and carotid artery echodensity and increases in skeletal rigidity and sensorineural hearing within patient subgroups. All patients improved in one or more of these outcomes. Results from this clinical treatment trial for children with HGPS provide preliminary evidence that lonafarnib may improve vascular stiffness, bone structure, and audiological status.

Importance: In young febrile infants, serious bacterial infections (SBIs), including urinary tract infections, bacteremia, and meningitis, may lead to dangerous complications. However, lumbar punctures and hospitalizations involve risks and costs. Clinical prediction rules using biomarkers beyond the white blood cell count (WBC) may accurately identify febrile infants at low risk for SBIs. Objective: To derive and validate a prediction rule to identify febrile infants 60 days and younger at low risk for SBIs. Design, Setting, and Participants: Prospective, observational study between March 2011 and May 2013 at 26 emergency departments. Convenience sample of previously healthy febrile infants 60 days and younger who were evaluated for SBIs. Data were analyzed between April 2014 and April 2018. Exposures: Clinical and laboratory data (blood and urine) including patient demographics, fever height and duration, clinical appearance, WBC, absolute neutrophil count (ANC), serum procalcitonin, and urinalysis. We derived and validated a prediction rule based on these variables using binary recursive partitioning analysis. Main Outcomes and Measures: Serious bacterial infection, defined as urinary tract infection, bacteremia, or bacterial meningitis. Results: We derived the prediction rule on a random sample of 908 infants and validated it on 913 infants (mean age was 36 days, 765 were girls [42%], 781 were white and non-Hispanic [43%], 366 were black [20%], and 535 were Hispanic [29%]). Serious bacterial infections were present in 170 of 1821 infants (9.3%), including 26 (1.4%) with bacteremia, 151 (8.3%) with urinary tract infections, and 10 (0.5%) with bacterial meningitis; 16 (0.9%) had concurrent SBIs. The prediction rule identified infants at low risk of SBI using a negative urinalysis result, an ANC of 4090/µL or less (to convert to ×109 per liter, multiply by 0.001), and serum procalcitonin of 1.71 ng/mL or less. In the validation cohort, the rule sensitivity was 97.7% (95% CI, 91.3-99.6), specificity was 60.0% (95% CI, 56.6-63.3), negative predictive value was 99.6% (95% CI, 98.4-99.9), and negative likelihood ratio was 0.04 (95% CI, 0.01-0.15). One infant with bacteremia and 2 infants with urinary tract infections were misclassified. No patients with bacterial meningitis were missed by the rule. The rule performance was nearly identical when the outcome was restricted to bacteremia and/or bacterial meningitis, missing the same infant with bacteremia. Conclusions and Relevance: We derived and validated an accurate prediction rule to identify febrile infants 60 days and younger at low risk for SBIs using the urinalysis, ANC, and procalcitonin levels. Once further validated on an independent cohort, clinical application of the rule has the potential to decrease unnecessary lumbar punctures, antibiotic administration, and hospitalizations.

The present study examined whether parenting and child characteristics of 2- and 3 1/2-year-old children had common paths of influence on their 4 1/2-year independent cognitive and social functioning. Structural equation modeling was guided by hypotheses that assumed children's later independence is facilitated by specialized parental support in early social interactions. To address the importance of variability in early development for understanding children's later independence, we included 104 term and 185 preterm children, as they are known to differ in early skills. As predicted, mothers' maintaining of children's interests indirectly supported 4 1/2-year cognitive and social independence through a direct, positive influence on 2- and 3 1/2-year skills. Directiveness positively supported children's early cognitive and responsiveness skills but by 3 1/2 years, high levels of this behavior had a direct, negative influence on their cognitive and social independence at 4 1/2 years. Whereas high levels of maintaining interests across these ages support later independence, directiveness needs to decrease in relation to children's increasing competencies. Results support a theoretical framework that emphasizes the importance of the social context for understanding the origins of children's later independent functioning.

Selvaraj S, Arnone D, Job D, Stanfield A, Farrow TFD, Nugent AC, Scherk H, Gruber O, Chen X, Sachdev PS, Dickstein DP, Malhi GS, Ha TH, Ha K, Phillips ML, McIntosh AM. Grey matter differences in bipolar disorder: a meta‐analysis of voxel‐based morphometry studies. Bipolar Disord 2012: 14: 135–145. © 2012 The Authors. Journal compilation © 2012 John Wiley &amp; Sons A/S. Objective: Several neuroimaging studies have reported structural brain differences in bipolar disorder using automated methods. While these studies have several advantages over those using region of interest techniques, no study has yet estimated a summary effect size or tested for between‐study heterogeneity. We sought to address this issue using meta‐analytic techniques applied for the first time in bipolar disorder at the level of the individual voxel. Methods: A systematic review identified 16 voxel‐based morphometry (VBM) studies comparing individuals with bipolar disorder with unaffected controls, of which eight were included in the meta‐analysis. In order to take account of heterogeneity, summary effect sizes were computed using a random‐effects model with appropriate correction for multiple testing. Results: Compared with controls, subjects with bipolar disorder had reduced grey matter in a single cluster encompassing the right ventral prefrontal cortex, insula, temporal cortex, and claustrum. Study heterogeneity was widespread throughout the brain; though the significant cluster of grey matter reduction remained once these extraneous voxels had been removed. We found no evidence of publication bias (Eggers p = 0.63). Conclusions: Bipolar disorder is consistently associated with reductions in right prefrontal and temporal lobe grey matter. Reductions elsewhere may be obscured by clinical and methodological heterogeneity.

OBJECTIVES: The objective of this study was to characterize emergency department (ED) visits for pediatric sport-related concussion (SRC) in pre-high school- versus high school-aged athletes. METHODS: A stratified probability sample of US hospitals that provide emergency services in the National Electronic Injury Surveillance System (1997-2007) and All Injury Program (2001-2005) was used. Concussion-related ED visits were analyzed for 8- to 13- and 14- to 19-year-old patients. Population data were obtained from the US Census Bureau; sport participation data were obtained from National Sporting Goods Association. RESULTS: From 2001 to 2005, US children who were aged 8 to 19 years had an estimated 502 000 ED visits for concussion. The 8- to 13-year-old group accounted for approximately 35% of these visits. Approximately half of all ED visits for concussion were SRC. The 8- to 13-year-old group sustained 40% of these, which represents 58% of all concussions in this group. Approximately 25% of all SRC visits in the 8- to 13-year-old group occurred during organized team sport (OTS). During the study period, approximately 4 in 1000 children aged 8 to 13 years and 6 in 1000 children aged 14 to 19 years had an ED visit for SRC, and 1 in 1000 children aged 8 to 13 years and 3 in 1000 children aged 14 to 19 years had an ED visit for concussion sustained during OTS. From 1997 to 2007, although participation had declined, ED visits for concussions in OTS in 8- to 13-year-old children had doubled and had increased by >200% in the 14- to 19-year-old group. CONCLUSIONS: The number of SRCs in young athletes is noteworthy. Additional research is required.

BACKGROUND: Poor neurodevelopmental outcomes and recurrences of cutaneous lesions remain unacceptably frequent among survivors of neonatal herpes simplex virus (HSV) disease. METHODS: We enrolled neonates with HSV disease in two parallel, identical, double-blind, placebo-controlled studies. Neonates with central nervous system (CNS) involvement were enrolled in one study, and neonates with skin, eye, and mouth involvement only were enrolled in the other. After completing a regimen of 14 to 21 days of parenteral acyclovir, the infants were randomly assigned to immediate acyclovir suppression (300 mg per square meter of body-surface area per dose orally, three times daily for 6 months) or placebo. Cutaneous recurrences were treated with open-label episodic therapy. RESULTS: A total of 74 neonates were enrolled--45 with CNS involvement and 29 with skin, eye, and mouth disease. The Mental Development Index of the Bayley Scales of Infant Development (in which scores range from 50 to 150, with a mean of 100 and with higher scores indicating better neurodevelopmental outcomes) was assessed in 28 of the 45 infants with CNS involvement (62%) at 12 months of age. After adjustment for covariates, infants with CNS involvement who had been randomly assigned to acyclovir suppression had significantly higher mean Bayley mental-development scores at 12 months than did infants randomly assigned to placebo (88.24 vs. 68.12, P=0.046). Overall, there was a trend toward more neutropenia in the acyclovir group than in the placebo group (P=0.09). CONCLUSIONS: Infants surviving neonatal HSV disease with CNS involvement had improved neurodevelopmental outcomes when they received suppressive therapy with oral acyclovir for 6 months. (Funded by the National Institute of Allergy and Infectious Diseases; CASG 103 and CASG 104 ClinicalTrials.gov numbers, NCT00031460 and NCT00031447, respectively.).

PURPOSE: We report a multicenter experience using tubularized incised plate urethroplasty for proximal hypospadias. MATERIALS AND METHODS: From August 1993 to December 1996 tubularized incised plate urethroplasty was performed in 27 boys 6 months to 3 years old with mid shaft and penoscrotal hypospadias. In 7 other boys complex reconstruction combined the tubularized incised plate technique for the glanular urethra with other repairs for the proximal urethra. RESULTS: Tubularized incised plate surgery created a functional neourethra even in penoscrotal hypospadias. Complications of the primary repair developed in only 3 of 27 patients (11%). No complications were attributed to use of the technique for the glanular urethra in complex repairs. CONCLUSIONS: Tubularized incised plate urethroplasty is a versatile operation that corrects proximal hypospadias defects with few complications and superior cosmetic results.