Zoledronic Acid vs Placebo in Pediatric Glucocorticoid-induced Osteoporosis: A Randomized, Double-blind, Phase 3 Trial.

CONTEXT: Glucocorticoids (GCs) prescribed for chronic pediatric illnesses are associated with osteoporotic fractures. OBJECTIVE: This study aims to determine the efficacy and safety of intravenous (IV) zoledronic acid (ZA) compared with placebo to treat pediatric GC-induced osteoporosis (GIO). METHODS: Children aged 5 to 17 years with GIO were enrolled in this multinational, randomized, double-blind, placebo-controlled phase 3 trial (ClinicalTrials.gov NCT00799266). Eligible children were randomly assigned 1:1 to 6 monthly IV ZA 0.05 mg/kg or IV placebo. The primary end point was the change in lumbar spine bone mineral density z score (LSBMDZ) from baseline to month 12. Incident fractures and safety were assessed. RESULTS: Thirty-four children were enrolled (mean age 12.6 ±â€…3.4 years [18 on ZA, 16 on placebo]), all with low-trauma vertebral fractures (VFs). LSBMDZ increased from -2.13 ±â€…0.79 to -1.49 ±â€…1.05 on ZA, compared with -2.38 ±â€…0.90 to -2.27 ±â€…1.03 on placebo (least squares means difference 0.41 [95% CI, 0.02-0.81; P = .04]); when corrected for height z score, the least squares means difference in LBMDZ was 0.75 [95% CI, 0.27-1.22; P = .004]. Two children on placebo had new low-trauma VF vs none on ZA. Adverse events (AEs) were reported in 15 of 18 children (83%) on ZA, and in 12 of 16 (75%) on placebo, most frequently within 10 days after the first infusion. There were no deaths or treatment discontinuations due to treatment-emergent AEs. CONCLUSION: LSBMDZ increased significantly on ZA compared with placebo over 1 year in children with GIO. Most AEs occurred after the first infusion.

Early prenatal use of a multivitamin diminishes the risk for inadequate vitamin D status in pregnant women: results from the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort study.

BACKGROUND: Reports on the adequacy of vitamin D status of pregnant women are not available in Canada. OBJECTIVES: The objectives of this study were to examine vitamin D status across pregnancy and identify the correlates of vitamin D status of pregnant women in Canada. METHODS: Pregnant women (≥18 years) from 6 provinces (2008-2011) participating in a longitudinal cohort were studied. Sociodemographic data, obstetrical histories, and dietary and supplemental vitamin D intakes were surveyed. Plasma 25-hydroxyvitamin D (25OHD) was measured using an immunoassay standardized to LC-MS/MS from samples collected during the first (n = 1905) and third trimesters (n = 1649) and at delivery (n = 1543). The proportion of women with ≥40 nmol/L of plasma 25OHD (adequate status) was estimated at each time point, and factors related to achieving this cut point were identified using repeated-measures logistic regression. Differences in 25OHD concentrations across trimesters and at delivery were tested a using repeated-measures ANOVA with a post hoc Tukey's test. RESULTS: In the first trimester, 93.4% (95% CI: 92.3%-94.5%) of participants had 25OHD ≥40 nmol/L. The mean plasma 25OHD concentration increased from the first to the third trimester and then declined by delivery (69.8 ± 0.5 nmol/L, 78.6 ± 0.7 nmol/L, and 75.7 ± 0.7 nmol/L, respectively; P < 0.0001). A lack of multivitamin use early in pregnancy reduced the odds of achieving 25OHD ≥40 nmol/L (ORadj = 0.33; 95% CI: 0.25-0.42) across all time points. Factors associated with not using a prenatal multivitamin included multiparity (ORadj = 2.08; 95% CI: 1.42-3.02) and a below-median income (ORadj = 1.39; 95% CI: 1.02-1.89). CONCLUSIONS: The results from this cohort demonstrate the importance of early multivitamin supplement use to achieve an adequate vitamin D status in pregnant women.

Effect of high dose vitamin D3 therapy on serum vitamin D3 levels in vitamin D insufficient adults with cystic fibrosis.

BACKGROUND: The effect of a high dose oral cholecalciferol repletion strategy in Vitamin D insufficient adults with CF is still unknown. Therefore, we assessed the effectiveness of our current approach, giving oral vitamin D3 supplementation at a dose of 10,000 IU from Monday to Friday for a total of 50,000 IU D3 weekly in vitamin D insufficient adult with CF. METHODS: We performed a retrospective chart review of all 59 adult CF patients between the ages of 17 and 64 years routinely followed at the CF Adult Program of Winnipeg Health Sciences Centre. Through consultation with the endocrinologist, our clinic vitamin D repletion protocol for treating CF adult patients who have serum 25-hydroxyvitamin D (25-OHD) < 30 ng/ml (<75 nmol/L) was to prescribe vitamin D3 10,000 IU orally from Monday to Friday (or the weekly equivalent of 50,000 IU) for 12 weeks in addition to their regular CF vitamin that supplied from 800 to 2000 IU vitamin D3 daily. Cholecalciferol was conveniently administered orally as either one capsule (oil-based) 10,000 IU or one tablet (powder-based) 10,000 IU. All patients were instructed to obtain follow-up serum 25-OHD levels post completion of treatment. RESULTS: Of the 59 adult patients at our CF Clinic, 35 patients (59%) had below optimal serum 25-OHD levels. Of the 35 patients identified, 10 patients with insufficient serum 25-OHD levels between 10 and 30 ng/ml (25-75 nmol/L) fulfilled the inclusion criteria. A significant increase in serum 25-OHD levels was observed (P < 0.01) from mean value of 21.6 ± 5.9 ng/ml (54.1 ± 14.8 nmol/L) at baseline to 31.7 ± 9.1 ng/ml (79.3 ± 22.8 nmol/L) ≥ 2 months post intervention. The current treatment approach was successful in treating Vitamin D insufficiency in 70% of the patients with low 25-OHD levels. CONCLUSION: The results of this study demonstrate that a large number of adults attending Winnipeg Health Sciences Centre CF Clinic have serum 25-OHD levels below 30 ng/ml (75 nmol/L). This supports the need for dedicated and individualized approach to manage this condition. High dose therapy of vitamin D3, although a more aggressive treatment approach, may result in achieving optimal levels of serum 25-OHD in adults with CF.

Effect of Hydrolyzed Infant Formula vs Conventional Formula on Risk of Type 1 Diabetes: The TRIGR Randomized Clinical Trial.

Importance: Early exposure to complex dietary proteins may increase the risk of type 1 diabetes in children with genetic disease susceptibility. There are no intact proteins in extensively hydrolyzed formulas. Objective: To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of type 1 diabetes in young children. Design, Setting, and Participants: An international double-blind randomized clinical trial of 2159 infants with human leukocyte antigen-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1081 were randomized to be weaned to the extensively hydrolyzed casein formula and 1078 to a conventional formula. The follow-up of the participants ended on February 28, 2017. Interventions: The participants received either a casein hydrolysate or a conventional adapted cow's milk formula supplemented with 20% of the casein hydrolysate. The minimum duration of study formula exposure was 60 days by 6 to 8 months of age. Main Outcomes and Measures: Primary outcome was type 1 diabetes diagnosed according to World Health Organization criteria. Secondary outcomes included age at diabetes diagnosis and safety (adverse events). Results: Among 2159 newborn infants (1021 female [47.3%]) who were randomized, 1744 (80.8%) completed the trial. The participants were observed for a median of 11.5 years (quartile [Q] 1-Q3, 10.2-12.8). The absolute risk of type 1 diabetes was 8.4% among those randomized to the casein hydrolysate (n = 91) vs 7.6% among those randomized to the conventional formula (n = 82) (difference, 0.8% [95% CI, -1.6% to 3.2%]). The hazard ratio for type 1 diabetes adjusted for human leukocyte antigen risk group, duration of breastfeeding, duration of study formula consumption, sex, and region while treating study center as a random effect was 1.1 (95% CI, 0.8 to 1.5; P = .46). The median age at diagnosis of type 1 diabetes was similar in the 2 groups (6.0 years [Q1-Q3, 3.1-8.9] vs 5.8 years [Q1-Q3, 2.6-9.1]; difference, 0.2 years [95% CI, -0.9 to 1.2]). Upper respiratory infections were the most common adverse event reported (frequency, 0.48 events/year in the hydrolysate group and 0.50 events/year in the control group). Conclusions and Relevance: Among infants at risk for type 1 diabetes, weaning to a hydrolyzed formula compared with a conventional formula did not reduce the cumulative incidence of type 1 diabetes after median follow-up for 11.5 years. These findings do not support a need to revise the dietary recommendations for infants at risk for type 1 diabetes. Trial Registration: clinicaltrials.gov Identifier: NCT00179777.

Maternal Concentrations of Perfluoroalkyl Substances and Fetal Markers of Metabolic Function and Birth Weight.

Perfluoroalkyl substances (PFAS) are ubiquitous, persistent chemicals that have been widely used in the production of common household and consumer goods for their nonflammable, lipophobic, and hydrophobic properties. Inverse associations between maternal or umbilical cord blood concentrations of perfluorooctanoic acid and perfluorooctanesulfonate and birth weight have been identified. This literature has primarily examined each PFAS individually without consideration of the potential influence of correlated exposures. Further, the association between PFAS exposures and indicators of metabolic function (i.e., leptin and adiponectin) has received limited attention. We examined associations between first-trimester maternal plasma PFAS concentrations and birth weight and cord blood concentrations of leptin and adiponectin using data on 1,705 mother-infant pairs from the Maternal Infant Research on Environmental Chemicals (MIREC) Study, a trans-Canada birth cohort study that recruited women between 2008 and 2011. Bayesian hierarchical models were used to quantify associations and calculate credible intervals. Maternal perfluorooctanoic acid concentrations were inversely associated with birth weight z score, though the null value was included in all credible intervals (log10 ß = −0.10, 95% credible interval: −0.34, 0.13). All associations between maternal PFAS concentrations and cord blood adipocytokine concentrations were of small magnitude and centered around the null value. Follow-up in a cohort of children is required to determine how the observed associations manifest in childhood.

Air Pollution Exposure During Pregnancy and Fetal Markers of Metabolic function: The MIREC Study.

Previous evidence suggests that exposure to outdoor air pollution during pregnancy could alter fetal metabolic function, which could increase the risk of obesity in childhood. However, to our knowledge, no epidemiologic study has investigated the association between prenatal exposure to air pollution and indicators of fetal metabolic function. We investigated the association between maternal exposure to nitrogen dioxide and fine particulate matter (aerodynamic diameter ≤2.5 µm) and umbilical cord blood leptin and adiponectin levels with mixed-effects linear regression models among 1,257 mother-infant pairs from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, conducted in Canada (2008-2011). We observed that an interquartile-range increase in average exposure to fine particulate matter (3.2 µg/m(3)) during pregnancy was associated with an 11% (95% confidence interval: 4, 17) increase in adiponectin levels. We also observed 13% (95% confidence interval: 6, 20) higher adiponectin levels per interquartile-range increase in average exposure to nitrogen dioxide (13.6 parts per billion) during pregnancy. Significant associations were seen between air pollution markers and cord blood leptin levels in models that adjusted for birth weight z score but not in models that did not adjust for birth weight z score. The roles of prenatal exposure to air pollution and fetal metabolic function in the potential development of childhood obesity should be further explored.

Exposure to organophosphorus and organochlorine pesticides, perfluoroalkyl substances, and polychlorinated biphenyls in pregnancy and the association with impaired glucose tolerance and gestational diabetes mellitus: The MIREC Study.

BACKGROUND: Studies report increases in rates of gestational diabetes mellitus (GDM) over recent decades. Environmental chemicals may increase the risk of diabetes through impacts on glucose metabolism, mitochondrial dysfunction, and endocrine-disrupting mechanisms including effects on pancreatic ß-cell function and adiponectin release. OBJECTIVES: To determine the associations between pesticides, perfluoroalkyl substances (PFASs) and polychlorinated biphenyls (PCBs) measured in early pregnancy and impaired glucose tolerance (IGT) and GDM in a Canadian birth cohort. METHODS: Women enrolled in the Maternal-Infant Research on Environmental Chemicals (MIREC) Study were included if they had a singleton delivery and did not have pre-existing diabetes. Exposure variables included three organophosphorus (OP) pesticide metabolites detected in first-trimester urine samples, as well as three organochlorine (OC) pesticides, three PFASs, and four PCBs in first-trimester blood samples. Gestational IGT and GDM were assessed by chart review in accordance with published guidelines. Adjusted logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CI) for the association between quartiles of environmental chemicals and both gestational IGT and GDM. RESULTS: Of the 2001 women recruited into the MIREC cohort, 1274 met the inclusion criteria and had outcome and biomonitoring data available. Significantly lower odds of GDM were observed in the third and fourth quartiles of dimethylphosphate (DMP) and in the fourth quartile of dimethylthiophosphate (DMTP) in adjusted analyses (DMP Q3: OR=0.2, 95% CI=0.1-0.7; DMP Q4: OR=0.3, 95% CI=0.1-0.8; DMTP: OR=0.3, 95% CI=0.1-0.9). Significantly elevated odds of gestational IGT was observed in the second quartile of perfluorohexane sulfonate (PFHxS) (OR=3.5, 95% CI=1.4-8.9). No evidence of associations with GDM or IGT during pregnancy was observed for PCBs or OC pesticides. CONCLUSIONS: We did not find consistent evidence for any positive associations between the chemicals we examined and GDM or IGT during pregnancy. We observed statistical evidence of inverse relationships between urine concentrations of DMP and DMTP with GDM. We cannot rule out the influence of residual confounding due to unmeasured protective factors, such as nutritional benefits from fruit and vegetable consumption, also associated with pesticide exposure, on the observed inverse associations between maternal OP pesticide metabolites and GDM. These findings require further investigation.

Maternal and Neonatal Levels of Perfluoroalkyl Substances in Relation to Gestational Weight Gain.

Perfluoroalkyl substances (PFASs) are ubiquitous, persistent pollutants widely used in the production of common household and consumer goods. There is a limited body of literature suggesting that these chemicals may alter metabolic pathways and growth trajectories. The relationship between prenatal exposures to these chemicals and gestational weight gain (GWG) has received limited attention. One objective was to analyze the associations among maternal plasma levels of three common perfluoroalkyl substances (perfluorooctanoate (PFOA), perfluorooctanesulfonate (PFOS), perfluorohexanesulfanoate (PFHxS)) and GWG. Additionally, we explored whether GWG was associated with cord blood PFAS levels. This study utilized data collected in the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a trans-Canada cohort study of 2001 pregnant women. Our analysis quantified associations between (1) maternal PFAS concentrations and GWG and (2) GWG and cord blood PFAS concentrations. Maternal PFOS concentrations were positively associated with GWG (ß = 0.39 95% CI: 0.02, 0.75). Interquartile increases in GWG were significantly associated with elevated cord blood PFOA (OR = 1.33; 95% CI: 1.13 to 1.56) and PFOS (OR = 1.20; 95% CI: 1.03 to 1.40) concentrations. No statistically significant associations were observed between GWG and either measure of PFHxS. These findings warrant elucidation of the potential underlying mechanisms.

Maternal blood metal levels and fetal markers of metabolic function.

Exposure to metals commonly found in the environment has been hypothesized to be associated with measures of fetal growth but the epidemiological literature is limited. The Maternal-Infant Research on Environmental Chemicals (MIREC) study recruited 2001 women during the first trimester of pregnancy from 10 Canadian sites. Our objective was to assess the association between prenatal exposure to metals (lead, arsenic, cadmium, and mercury) and fetal metabolic function. Average maternal metal concentrations in 1st and 3rd trimester blood samples were used to represent prenatal metals exposure. Leptin and adiponectin were measured in 1363 cord blood samples and served as markers of fetal metabolic function. Polytomous logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between metals and both high (≥ 90%) and low (≤ 10%) fetal adiponectin and leptin levels. Leptin levels were significantly higher in female infants compared to males. A significant relationship between maternal blood cadmium and odds of high leptin was observed among males but not females in adjusted models. When adjusting for birth weight z-score, lead was associated with an increased odd of high leptin. No other significant associations were found at the top or bottom 10th percentile in either leptin or adiponectin models. This study supports the proposition that maternal levels of cadmium influence cord blood adipokine levels in a sex-dependent manner. Further investigation is required to confirm these findings and to determine how such findings at birth will translate into childhood anthropometric measures.

A birth cohort study to investigate the association between prenatal phthalate and bisphenol A exposures and fetal markers of metabolic dysfunction.

BACKGROUND: Obesity and type-2 diabetes are on the rise and in utero exposure to environmental contaminants is a suspected contributing factor. Our objective was to examine associations between prenatal exposure to potential endocrine disrupting chemicals and markers of fetal metabolic dysfunction. METHODS: The Maternal-Infant Research on Environmental Chemicals Study (MIREC) recruited 2001 women during the first trimester of pregnancy from 10 Canadian sites. First trimester maternal urine was measured for 11 phthalate metabolites and bisphenol A (BPA). Leptin and adioponectin measured in 1,363 available umbilical cord blood samples served as markers of metabolic function. Restricted cubic spline curves were used to assess the relationship between continuous measures of phthalate and BPA levels and cord blood adipokines. Polytomous logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between phthalates and BPA and both high (≥90th percentile) and low (≤10th percentile) fetal adiponectin and leptin, adjusting for confounding factors. Analyses were conducted for all subjects, overall, and separately by fetal sex. RESULTS: Leptin was significantly higher in female than male infants. We observed an inverse, non-linear relationship between BPA and adiponectin among males in the restricted cubic spline and linear regression analysis. Mono-(3-carboxypropyl) (MCPP) was associated with increased odds of high leptin among males in the polytomous logistic regression models (4th quartile OR = 3.5 95% CI: 1.1-11.6). CONCLUSION: Our findings contribute to the growing body of evidence examining the influence of early life exposure on metabolic regulation and function. Associations between maternal exposure to chemicals and markers of metabolic function appear to be potentially sex specific. However, further investigation is required to determine whether in utero and childhood exposure to BPA and phthalates are associated with metabolic dysfunctions later in life.

Use of vitamin D supplements during infancy in an international feeding trial.

OBJECTIVE: To examine the use of vitamin D supplements during infancy among the participants in an international infant feeding trial. DESIGN: Longitudinal study. SETTING: Information about vitamin D supplementation was collected through a validated FFQ at the age of 2 weeks and monthly between the ages of 1 month and 6 months. SUBJECTS: Infants (n 2159) with a biological family member affected by type 1 diabetes and with increased human leucocyte antigen-conferred susceptibility to type 1 diabetes from twelve European countries, the USA, Canada and Australia. RESULTS: Daily use of vitamin D supplements was common during the first 6 months of life in Northern and Central Europe (>80% of the infants), with somewhat lower rates observed in Southern Europe (> 60%). In Canada, vitamin D supplementation was more common among exclusively breast-fed than other infants (e.g., 71% v. 44% at 6 months of age). Less than 2% of infants in the U.S.A. and Australia received any vitamin D supplementation. Higher gestational age, older maternal age and longer maternal education were study-wide associated with greater use of vitamin D supplements. CONCLUSIONS: Most of the infants received vitamin D supplements during the first 6 months of life in the European countries, whereas in Canada only half and in the U.S.A. and Australia very few were given supplementation.

Cohort profile: the maternal-infant research on environmental chemicals research platform.

BACKGROUND: The Maternal-Infant Research on Environmental Chemicals (MIREC) Study was established to obtain Canadian biomonitoring data for pregnant women and their infants, and to examine potential adverse health effects of prenatal exposure to priority environmental chemicals on pregnancy and infant health. METHODS: Women were recruited during the first trimester from 10 sites across Canada and were followed through delivery. Questionnaires were administered during pregnancy and post-delivery to collect information on demographics, occupation, life style, medical history, environmental exposures and diet. Information on the pregnancy and the infant was abstracted from medical charts. Maternal blood, urine, hair and breast milk, as well as cord blood and infant meconium, were collected and analysed for an extensive list of environmental biomarkers and nutrients. Additional biospecimens were stored in the study's Biobank. The MIREC Research Platform encompasses the main cohort study, the Biobank and follow-up studies. RESULTS: Of the 8716 women approached at early prenatal clinics, 5108 were eligible and 2001 agreed to participate (39%). MIREC participants tended to smoke less (5.9% vs. 10.5%), be older (mean 32.2 vs. 29.4 years) and have a higher education (62.3% vs. 35.1% with a university degree) than women giving birth in Canada. CONCLUSIONS: The MIREC Study, while smaller in number of participants than several of the international cohort studies, has one of the most comprehensive datasets on prenatal exposure to multiple environmental chemicals. The biomonitoring data and biological specimen bank will make this research platform a significant resource for examining potential adverse health effects of prenatal exposure to environmental chemicals.

Glucocorticoid-related changes in body mass index among children and adolescents with rheumatic diseases.

OBJECTIVE: To examine the temporal and dose-related effects of glucocorticoids (GCs) on body mass index (BMI) in children with rheumatic diseases. METHODS: Children initiating GCs for a rheumatic disease (n = 130) were assessed every 3 months for 18 months. BMI, weight, and height Z score trajectories were described according to GC starting dosage in prednisone equivalents: high (≥1.0 mg/kg/day), low (<0.2 mg/kg/day to a maximum of 7.5 mg/day), and moderate (between high and low) dosage. The impact of GC dosing, underlying diagnosis, pubertal status, physical activity, and disease activity on BMI Z scores and on percent body fat was assessed with longitudinal mixed-effects growth curve models. RESULTS: The GC starting dose was high in 59% and moderate in 39% of patients. The peak BMI Z score was +1.29 at 4 months with high-dose GCs and +0.69 at 4.2 months with moderate-dose GCs (P < 0.001). Overall, 50% (95% confidence interval 41-59%) of the children returned to within +0.25 SD of their baseline BMI Z score. Oral GC dose over the preceding 3 months was the most significant determinant of BMI Z score and percent body fat. The proportion of days in receipt of GCs, disease activity, and a diagnosis of systemic-onset juvenile idiopathic arthritis were also associated with BMI Z scores. The correlation between changes in BMI and changes in percent body fat was 0.09. CONCLUSION: In children with rheumatic diseases starting moderate and high doses of GCs, BMI Z scores peaked at 4 months, and only half returned to within +0.25 SD of their baseline BMI Z score after 18 months.

High incidence of vertebral fractures in children with acute lymphoblastic leukemia 12 months after the initiation of therapy.

PURPOSE: Vertebral fractures due to osteoporosis are a potential complication of childhood acute lymphoblastic leukemia (ALL). To date, the incidence of vertebral fractures during ALL treatment has not been reported. PATIENT AND METHODS: We prospectively evaluated 155 children with ALL during the first 12 months of leukemia therapy. Lateral thoracolumbar spine radiographs were obtained at baseline and 12 months. Vertebral bodies were assessed for incident vertebral fractures using the Genant semiquantitative method, and relevant clinical indices such as spine bone mineral density (BMD), back pain, and the presence of vertebral fractures at baseline were analyzed for association with incident vertebral fractures. RESULTS: Of the 155 children, 25 (16%; 95% CI, 11% to 23%) had a total of 61 incident vertebral fractures, of which 32 (52%) were moderate or severe. Thirteen (52%) of the 25 children with incident vertebral fractures also had fractures at baseline. Vertebral fractures at baseline increased the odds of an incident fracture at 12 months by an odds ratio of 7.3 (95% CI, 2.3 to 23.1; P = .001). In addition, for every one standard deviation reduction in spine BMD Z-score at baseline, there was 1.8-fold increased odds of incident vertebral fracture at 12 months (95% CI, 1.2 to 2.7; P = .006). CONCLUSION: Children with ALL have a high incidence of vertebral fractures after 12 months of chemotherapy, and the presence of vertebral fractures and reductions in spine BMD Z-scores at baseline are highly associated clinical features.

Incident vertebral fractures among children with rheumatic disorders 12 months after glucocorticoid initiation: a national observational study.

OBJECTIVE: To determine the frequency of incident vertebral fractures (IVF) 12 months after glucocorticoid (GC) initiation in children with rheumatic diseases and to identify children at higher risk. METHODS: Children with rheumatic diseases initiating GC were enrolled in a prospective observational study. Annual spine radiographs were evaluated using the Genant semiquantitative method. Spine areal bone mineral density (aBMD) was measured every 6 months. Clinical features, including cumulative GC dose, back pain, disease and physical activity, calcium and vitamin D intake, and spine aBMD Z scores, were analyzed for association with IVF. RESULTS: Seven (6%) of 118 children (95% confidence interval 2.9-11.7%) had IVF. Their diagnoses were: juvenile dermatomyositis (n = 2), systemic lupus erythematosus (n = 3), systemic vasculitis (n = 1), and mixed connective tissue disease (n = 1). One child was omitted from the analyses after 4 months because of osteoporosis treatment for symptomatic IVF. Children with IVF received on average 50% more GC than those without (P = 0.030), had a greater increase in body mass index (BMI) at 6 months (P = 0.010), and had greater decrements in spine aBMD Z scores in the first 6 months (P = 0.048). Four (67%) of 6 children with IVF and data to 12 months had spine aBMD Z scores less than -2.0 at 12 months compared to 16% of children without IVF (P = 0.011). CONCLUSION: The incidence of VF 12 months following GC initiation was 6%; most children were asymptomatic. Children with IVF received more GC, had greater increases in BMI, and had greater declines in spine aBMD Z scores in the first 6 months.

Blastomycosis of the central nervous system in a child: a rare cause of hypopituitarism.

Blastomyces dermatitidis is a dimorphic fungus that can cause granulomatous lesions. Typically, children present with respiratory symptoms. Central nervous system involvement is unusual, and almost always associated with involvement of other organs. This case report, to our knowledge, is the first published case of an adolescent male presenting with panhypopituitarism secondary to a blastomycosis infection.

Health-related quality of life of young adults with Turner syndrome following a long-term randomized controlled trial of recombinant human growth hormone.

BACKGROUND: There are limited long-term randomized controlled trials of growth hormone (GH) supplementation to adult height and few published reports of the health-related quality of life (HRQOL) following treatment. The present follow-up study of young adults from a long-term controlled trial of GH treatment in patients with Turner syndrome (TS) yielded data to examine whether GH supplementation resulted in a higher HRQOL (either due to taller stature or from the knowledge that active treatment and not placebo had been received) or alternatively a lower HRQOL (due to medicalization from years of injections). METHODS: The original trial randomized 154 Canadian girls with TS aged 7-13 years from 13 centres to receive either long-term GH injections at the pharmacologic dose of 0.3 mg/kg/week or to receive no injections; estrogen prescription for induction of puberty was standardized. Patients were eligible for the follow-up study if they were at least 16 years old at the time of follow-up. The instrument used to study HRQOL was the SF-36, summarized into physical and mental component scales (PCS and MCS); higher scores indicate better HRQOL. RESULTS: Thirty-four of the 48 eligible participants (71%) consented to participate; data were missing for one patient. Both groups (GH and no treatment) had normal HRQOL at this post-treatment assessment. The GH group had a (mean ± SD) PCS score of 56 ± 5; the untreated group 58 ± 4; mean score for 16-24 year old females in the general population 53.5 ± 6.9. The GH group had a mean MCS score of 52 ± 6; the untreated group 49 ± 13; mean score for 16-24 year old females in the general population 49.6 ± 9.8. Secondary analyses showed no relationship between HRQOL and height. CONCLUSIONS: We found no benefit or adverse effect on HRQOL either from receiving or not receiving growth hormone injections in a long-term randomized controlled trial, confirming larger observational studies. We suggest that it remains ethically acceptable as well as necessary to maintain a long-term untreated control group to estimate the effects of pharmacological agents to manipulate adult height. Young adult women with TS have normal HRQOL suggesting that they adjust well to their challenges in life. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00191113.

Obesity and type 2 diabetes mellitus in a birth cohort of First Nation children born to mothers with pediatric-onset type 2 diabetes.

BACKGROUND: Children who are born to mothers with pediatric-onset type 2 diabetes mellitus are exposed to a hyperglycemic intra-uterine environment throughout pregnancy. The growth patterns and risk of type 2 diabetes in these offspring may be influenced by unique gene-environment interactions during intra-uterine and postnatal life. SUBJECTS: We established a cohort of offspring of First Nation mothers with onset of type 2 diabetes before age 18 years in Manitoba, Canada. METHODS: We measured height or length and weight at study entry and annually thereafter with fasting blood glucose in offspring aged ≥ 7 years. We collected birth and breastfeeding history and determined the population-specific hepatic nuclear factor-1α (HNF-1α) G319S genotype of offspring at age 7 years. RESULTS: From July 2003 to April 2008, we enrolled 76 offspring of 37 mothers. Sixty-four percent (23/36) of the offspring aged 2-19 years were obese at initial assessment. The rates of obesity remained constant throughout the 5 years. As of April 2008, 7/28 (25%) of the offspring aged 7-19 years have diabetes including 6/14 (43%) aged 10-19 years. Most offspring with diabetes (5/7, 71%) were obese at diagnosis. All of the 7 offspring with diabetes have 1 or 2 copies of the G319S polymorphism. CONCLUSIONS: The prevalence of type 2 diabetes in this cohort of offspring of First Nation women with pediatric-onset type 2 diabetes is the highest ever reported. Obesity is an important postnatal risk factor for type 2 diabetes in this population and may result from a unique gene-environment interaction.

WITHDRAWN: Metoclopramide, thickened feedings, and positioning for gastro-oesophageal reflux in children under two years.

BACKGROUND: Gastro-esophageal reflux (GER) is the refluxing of gastric contents into the esophagus. Fifty per cent of all infants 0 to 3 months regurgitate at least once a day. This drops to 5% once infants are 10 to 12 months old. Three per cent of parents of 10 to 12 month old infants view this as a problem. OBJECTIVES: To investigate the effectiveness of thickened feeds, positioning, and metoclopramide as compared to placebo in improving the outcome of GER in developmentally normal infants aged one month to two years. SEARCH STRATEGY: Trials were identified by searching Cochrane Central Register of Controlled Trials (The Cochrane Library 2003), MEDLINE (January 1966 to 23 January 2003), EMBASE (January 1985 to 27 January 2003), and reference lists of articles. Searches in all databases were updated in April 2009. SELECTION CRITERIA: Randomised studies (parallel or cross over) which evaluated thickened feeds, positional alternations or metoclopramide for the treatment of GER in children between the age of one month and two years who were developmentally normal. DATA COLLECTION AND ANALYSIS: All three reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials. MAIN RESULTS: Twenty trials involving 771 children met the inclusion criteria: eight dealt with thickened feeds, five with positioning, and seven with metoclopramide. Few comparisons could be made, and so summary measures were often made with two or three studies. Thickened feeds reduce the regurgitation severity score (standardized mean difference (SMD) -0.94;95% confidence interval -1.35 to -0.52), as well as the frequency of emesis (SMD -0.91; confidence interval -1.22 to -0.61). The reflux index was not reduced (weighted mean difference (WMD) 0.48%; 95% confidence interval -3.27 to 4.23). All five positioning studies utilized esophageal pH monitoring as their outcome measure. Elevating the head of the crib for treating reflux in the supine position is not justifiable. The seven metoclopramide studies used a variety of outcomes. Compared to placebo, metoclopramide appears to reduce daily symptoms ( SMD -0.73; 95% confidence interval -1.16 to -0.30), and reduce the reflux index (WMD -2.80%; 95% confidence interval -5.58 to -0.01). It does increase side effects. AUTHORS' CONCLUSIONS: Thickened feeds are helpful in reducing the symptoms of GER. Elevating the head of the crib in the supine position does not have any effect. Metoclopramide may have some benefit in comparison to placebo in the symptomatic treatment for GER, but that must be weighed against possible side effects. .

Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function.

BACKGROUND: Hydroxyethyl starches (HES) are synthetic colloids commonly used for fluid resuscitation, yet controversy exists about their impact on kidney function. OBJECTIVES: To examine the effects of HES on kidney function compared to other fluid resuscitation therapies in different patient populations. SEARCH STRATEGY: We searched the Cochrane Renal Group's specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL, in The Cochrane Library), MEDLINE, EMBASE, MetaRegister and reference lists of articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs in which HES was compared to an alternate fluid therapy for the prevention or treatment of effective intravascular volume depletion. Primary outcomes were renal replacement therapy (RRT), author-defined kidney failure and acute kidney injury (AKI) as defined by the RIFLE criteria. Secondary outcomes included serum creatinine and creatinine clearance. DATA COLLECTION AND ANALYSIS: Screening, selection, data extraction and quality assessments for each retrieved article were carried out by two authors using standardised forms. Authors were contacted when published data were incomplete. Preplanned sensitivity and subgroup analyses were performed after data were analysed with a random effects model. MAIN RESULTS: The review included 34 studies (2607 patients). Overall, the RR of author-defined kidney failure was 1.50 (95% CI 1.20 to 1.87; n = 1199) and 1.38 for requiring RRT (95% CI 0.89 to 2.16; n = 1236) in HES treated individuals compared with other fluid therapies. Subgroup analyses suggested increased risk in septic patients compared to non-septic (surgical/trauma) patients. Non-septic patient studies were smaller and had lower event rates, so subgroup differences may have been due to lack of statistical power in these studies. Only limited data was obtained for analysis of kidney outcomes by the RIFLE criteria. Overall, methodological quality of studies was good but subjective outcomes were potentially biased because most studies were unblinded. AUTHORS' CONCLUSIONS: Potential for increased risk of AKI should be considered when weighing the risks and benefits of HES for volume resuscitation, particularly in septic patients. Large studies with adequate follow-up are required to evaluate the renal safety of HES products in non-septic patient populations. RIFLE criteria should be applied to evaluate kidney function in future studies of HES and, where data is available, to re-analyse those studies already published. There is inadequate clinical data to address the claim that safety differences exist between different HES products.