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Ode KL, Frohnert B, Laguna T, Phillips J, Holme B, Regelmann W, Thomas W, Moran A. Oral glucose tolerance testing in children with cystic fibrosis. Background: Cystic fibrosis (CF) related diabetes is the most common comorbidity in persons with CF. International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines recommend annual oral glucose tolerance testing (OGTT) screening starting at age 10. The OGTT might be recommended in younger children if, as in adults, it provided clinically relevant prognostic information. A database review was performed to determine whether OGTT findings in children with CF predict subsequent clinical course. Methods: A retrospective matched-pair cohort study was based on OGTTs performed during 1998-2003. Children aged 6-9 were classified as having normal glucose tolerance (NGT) or abnormal glucose tolerance (AGT). Children with AGT were matched by age and gender to those with NGT. Clinical status was assessed at baseline and 5 yr later. In a separate investigation, diabetes and prior AGT status of children aged 10-18 were used to assess predictions derived from the cohort study. Results: In 1998-2003, 39 of 94 children had AGT. Of these, 31 had sufficient follow-up data to be included. Both at baseline and 5 yr later there was no significant difference in height, weight, body mass index BMI) or lung function between AGT and NGT. Diabetes developed in 13 AGT (42%) and one NGT (3%) [odds ratio (OR) 11, p = 0.0009]. Age of diabetes onset was 12 ± 1 yr in boys and 11 ± 1 yr in girls, compared to approximately 23 yr in the general CF population. Fifteen current children age 10-18 who had AGT before age 10 have diabetes, close to the prediction of 19. Conclusions: AGT in children with CF age 6-9 yr identifies those at high risk for progression to early onset diabetes. [ABSTRACT FROM AUTHOR]

Given the differential risk of type 1 diabetes (T1D) in offspring of affected fathers versus affected mothers and our observation that T1D cases have differential DNA methylation near the imprinted DLGAP2 gene compared to controls, we examined whether methylation near DLGAP2 mediates the association between T1D family history and T1D risk. In a nested case-control study of 87 T1D cases and 87 controls from the Diabetes Autoimmunity Study in the Young, we conducted causal mediation analyses at 12 DLGAP2 region CpGs to decompose the effect of family history on T1D risk into indirect and direct effects. These effects were estimated from two regression models adjusted for the human leukocyte antigen DR3/4 genotype: a linear regression of family history on methylation (mediator model) and a logistic regression of family history and methylation on T1D (outcome model). For 8 of the 12 CpGs, we identified a significant interaction between T1D family history and methylation on T1D risk. Accounting for this interaction, we found that the increased risk of T1D for children with affected mothers compared to those with no family history was mediated through differences in methylation at two CpGs (cg27351978, cg00565786) in the DLGAP2 region, as demonstrated by a significant pure natural indirect effect (odds ratio (OR) = 1.98, 95% confidence interval (CI): 1.06-3.71) and nonsignificant total natural direct effect (OR = 1.65, 95% CI: 0.16-16.62) (for cg00565786). In contrast, the increased risk of T1D for children with an affected father or sibling was not explained by DNA methylation changes at these CpGs. Results were similar for cg27351978 and robust in sensitivity analyses. Lastly, we found that DNA methylation in the DLGAP2 region was associated ( P <0:05) with gene expression of nearby protein-coding genes DLGAP2 , ARHGEF10 , ZNF596 , and ERICH1 . Results indicate that the maternal protective effect conferred through exposure to T1D in utero may operate through changes to DNA methylation that have functional downstream consequences., Competing Interests: Conflicts of Interest The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Objective: Large-scale screening of the general population for islet autoantibodies (IAbs) to detect type 1 diabetes (T1D) has started worldwide. The standard screening method of separate radio-binding assay (RBA) for each IAb is an inefficient bottleneck. Furthermore, most positive results by RBA in screening of general population individuals without a clinical diagnosis of T1D are low-affinity and not predictive of future diabetes. Research Design and Methods: We have developed and validated a novel 6-Plex assay based on electrochemiluminescence (ECL) technology that combines in a single well high-affinity IAbs (to insulin, GAD, IA-2, and ZnT8), transglutaminase autoantibodies for celiac disease, and severe acute respiratory syndrome coronavirus 2 antibodies. The Autoimmunity Screening for Kids (ASK) provided 880 serum samples, from 828 children aged 1-17 years without diabetes who were previously tested for IAbs using single ECL assays and RBA assays. Results: Levels of all six antibodies in the 6-Plex ECL assay correlated well with respective single ECL assay levels. Similar to single ECL assays, the 6-Plex ECL assay positivity was congruent with the RBA in 95% (35/37) of children who later developed T1D and in 88% (105/119) high-risk children with multiple IAbs. In contrast, only 56% (86/154, P  < 0.0001) of children with persistent single IAb by RBA were found to be positive by 6-Plex ECL assay. Of 555 samples negative for all IAbs by RBA, few (0.2%-0.5%) were positive at low levels in the 6-Plex ECL assay. Conclusions: The study demonstrated that the 6-Plex ECL assay compares favorably to the standard RBAs in terms of disease specificity for general population screening in children. The 6-Plex ECL assay was therefore adopted as the primary screening tool in the general population screening ASK program with advantages of high efficiency, low cost, and low serum volume.

Aims: In June 2014, the American Diabetes Association lowered recommended hemoglobin A1c (HbA1c) targets from <8.5% (69mmol/mol) for children <6years of age and from <8.0% (64mmol/mol) for children 6-12years of age to <7.5% (58mmol/mol). Lower target HbA1c may lead to better glycemic control but could increase the risk of severe hypoglycemia., Methods: Patients with type 1 diabetes >1year duration, age 0-12years and seen in our center between January 1 and June 30, 2014 or between January 1 and June 30, 2015 were included. 1013 unique patients had 2684 encounters. We analyzed first quarterly HbA1c (January-March, April-June) and self-reported severe hypoglycemia at all clinic encounters., Results: HbA1c across the age span and within the 0-<6, 6-12, and 0-12year old groups did not differ in the insurance adjusted mixed-effects model. Least squares means for all patients' HbA1c in 2014 was 8.59±0.04 (70±0.5mmol/mol); for 2015, 8.60±0.04 (70±0.5mmol/mol) (p=0.90). Severe hypoglycemia data fields were more complete in 2015 (43% vs 50%). Logistic regression adjusting for follow up showed no difference in severe hypoglycemia for all ages (p=0.80)., Conclusions: HbA1c did not change 1year after the updated guidelines despite adoption of the new targets. Assessing changes in severe hypoglycemia may require larger, prospective datasets or longer observation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In 1992, the U.S. Public Health Service recommended that all women capable of becoming pregnant consume 400 µg of folic acid daily to prevent neural tube defects (NTDs). NTDs are major birth defects of the brain and spine that occur early in pregnancy as a result of improper closure of the embryonic neural tube, which can lead to death or varying degrees of disability. The two most common NTDs are anencephaly and spina bifida. Beginning in 1998, the United States mandated fortification of enriched cereal grain products with 140 µg of folic acid per 100 g. Immediately after mandatory fortification, the birth prevalence of NTD cases declined. Fortification was estimated to avert approximately 1,000 NTD-affected pregnancies annually. To provide updated estimates of the birth prevalence of NTDs in the period after introduction of mandatory folic acid fortification (i.e., the post-fortification period), data from 19 population-based birth defects surveillance programs in the United States, covering the years 1999-2011, were examined. After the initial decrease, NTD birth prevalence during the post-fortification period has remained relatively stable. The number of births occurring annually without NTDs that would otherwise have been affected is approximately 1,326 (95% confidence interval = 1,122-1,531). Mandatory folic acid fortification remains an effective public health intervention. There remain opportunities for prevention among women with lower folic acid intakes, especially among Hispanic women, to further reduce the prevalence of NTDs in the United States.

Aim: To assess predictability of bone mineral density (BMD) of the lumbar spine (LS) determined by dual-energy x-ray absorptiometry (DXA) using by ultrasound speed of sound of the right and left radii (SOS-R and SOS-L) in patients with growth problems., Methods: Ultrasound and DXA were compared in patients with advanced, normal and delayed bone ages assessed by Greulich and Pyle (GP) and Tanner and Whitehouse (TW3) methods., Results: There was a strong correlation (r), of raw scores, between SOS-R and SOS-L, r = 0.81, p = 0.000 and their respective Z-scores, r = 0.78, p = 0.000. Z-score correlations were poor between SOS-R or SOS-L and LS-BMD. Sensitivity, specificity, positive and negative predictive values of SOS-R and Z-scores for predicting normal (>-1 to <1) and low (<-1) LS-BMD were poor. For high (>1) LS-BMD, Z-scores were 22%, 93%, 29% and 90%, respectively, for SOS-R and for SOS-L, 25%, 89%, 20% and 91%. For very low (<-2) LS-BMD, SOS-R and SOS-L were the same, respectively, 29%, 91%, 40% and 86%., Conclusion: Ultrasound of the radius is a poor predictor of radiologically assessed BMD at the LS, especially with delayed bone age., (©2013 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Childhood cancer survivors (CCS) are at risk for growth hormone (GH) deficiency. CCS are also at increased risk for early mortality from cardiovascular (CV) disease, but the association between GH levels and CV risk remains poorly understood. The goal of this study was to examine the cross-sectional association between stimulated GH levels and CV risk factors in CCS younger than 18 years., Procedure: A total of 276 CCS (147 males, 14.4 ± 2.6 years) ≥5 years after cancer diagnosis, and 208 sibling controls (112 males, 13.6 ± 2.4 years) participated in this cross-sectional study, which included anthropometry, body composition, and metabolic studies. Blunted response (BR) was defined as peak GH level <7 µg/L after clonidine and arginine. Insulin sensitivity (M(lbm) ) was measured by euglycemic hyperinsulinemic clamp. Statistical analyses used linear and logistic regression accounting for sibling clustering, adjusted for age, sex, Tanner stage, and adiposity., Results: Thirty-four (12%) CCS showed BR to GH stimulation. BR CCS were shorter and had a lower IGF-1 than controls; only 6 of 34 received cranial radiation therapy. CCS with normal stimulated GH response were similar to controls for CV risk factors. Conversely, BR CCS had greater adiposity, higher lipids, and lower M(lbm) than controls. Differences in lipids and M(lbm) between BR CCS and controls remained significant after adjustment for BMI or visceral fat., Conclusions: BR to GH stimulation is prevalent in CCS youth and is associated with an unfavorable CV risk factor profile. Further studies are needed to establish the mechanisms of these associations., (Copyright © 2012 Wiley Periodicals, Inc.)