Time spent outside of target glucose range for young children with type 1 diabetes: a continuous glucose monitor study.

AIM: To assess the associations between demographic and clinical characteristics and sensor glucose metrics in young children with type 1 diabetes, using masked, continuous glucose monitoring data from children aged 2 to < 8 years. RESEARCH DESIGN AND METHODS: The analysis included 143 children across 14 sites in the USA, enrolled in a separate clinical trial. Eligibility criteria were: age 2 to <8 years; type 1 diabetes duration ≥3 months; no continuous glucose monitoring use for past 30 days; and HbA1c concentration 53 to <86 mmol/mol (7.0 to <10.0%). All participants wore masked continuous glucose monitors up to 14 days. RESULTS: On average, participants spent the majority (13 h) of the day in hyperglycaemia (>10.0 mmol/l) and a median of ~1 h/day in hypoglycaemia (<3.9 mmol/l). Participants with minority race/ethnicity and higher parent education levels spent more time in target range, 3.9-10.0 mmol/l, and less time in hyperglycaemia. More time in hypoglycaemia was associated with minority race/ethnicity and younger age at diagnosis. Continuous glucose monitoring metrics were similar in pump and injection users. CONCLUSIONS: Given that both hypo- and hyperglycaemia negatively impact neurocognitive development, strategies to increase time in target glucose range for young children are needed.

Improvement in lipids after switch to boosted atazanavir or darunavir in children/adolescents with perinatally acquired HIV on older protease inhibitors: results from the Pediatric HIV/AIDS Cohort Study.

OBJECTIVES: Dyslipidaemia is common in perinatally HIV-infected (PHIV) youth receiving protease inhibitors (PIs). Few studies have evaluated longitudinal lipid changes in PHIV youth after switch to newer PIs. METHODS: We compared longitudinal changes in fasting lipids [total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and TC:HDL-C ratio] in PHIV youth enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS) Adolescent Master Protocol (AMP) study who switched to atazanavir/ritonavir (ATV/r)- or darunavir/ritonavir (DRV/r)-based antiretroviral therapy (ART) from an older PI-based ART and those remaining on an older PI. Generalized estimating equation models were fitted to assess the association of a switch to ATV/r- or DRV/r-based ART with the rate of change in lipids, adjusted for potential confounders. RESULTS: From 2007 to 2014, 47 PHIV children/adolescents switched to ATV/r or DRV/r, while 120 remained on an older PI [primarily lopinavir/r (72%) and nelfinavir (24%)]. Baseline age ranged from 7 to 21 years. After adjustment for age, Tanner stage, race/ethnicity, and HIV RNA level, a switch to ATV/r or DRV/r was associated with a more rapid annual rate of decline in the ratio of TC:HDL-C. (ß = -0.12; P = 0.039) than remaining on an older PI. On average, TC declined by 4.57 mg/dL/year (P = 0.057) more in the switch group. A switch to ATV/r or DRV/r was not associated with the rate of HDL-C, LDL-C, or TG change. CONCLUSIONS: A switch to ATV/r or DRV/r may result in more rapid reduction in TC and the TC:HDL-C ratio in PHIV youth, potentially impacting long-term cardiovascular disease risk.

Initial findings: primary diabetes care responsibility among emerging adults with type 1 diabetes post high school and move out of parental home.

BACKGROUND: Emerging adults with diabetes are assuming diabetes care responsibility, graduating from high school and leaving their parental homes. We examined: (1) how diabetes care responsibility changed in relation to time (high school to post high school) and living situation (living independently or not of parents) and (2) the association of diabetes self-efficacy, worry about hypoglycaemia, gender and glycaemic control with these changes in responsibility among emerging adults with type 1 diabetes. METHODS: During the last 6 months in high school (T1), 113 participants completed diabetes care responsibility (total, daily and non-daily), diabetes self-efficacy and worry about hypoglycaemia scales. Participants again completed the responsibility scales post high school graduation (T2). We used a linear mixed-effects model with diabetes self-efficacy, worry about hypoglycaemia, time since graduation, living situation, gender and glycaemic control as independent variables; and diabetes care responsibility (total, daily and non-daily) as dependent variables. Moderation involving diabetes self-efficacy, worry about hypoglycaemia, gender and glycaemic control was also tested. FINDINGS: Diabetes care responsibility increased over time for total (P < 0.001), daily (P= 0.002) and non-daily (P < 0.001), but the associations of self-efficacy and gender with diabetes care responsibility were moderated by living situation. Self-efficacy was negatively related to total (P= 0.006), daily (P= 0.010) and non-daily (P= 0.030) responsibility for those not living independently while positively related only to total responsibility (P= 0.028) for those living independently. Being female was positively related to total (P= 0.007) and non-daily (P= 0.001) responsibility for those living independently. CONCLUSION: Diabetes care responsibility increased from high school to post high school among these emerging adults with diabetes. There is a complex relationship between self-efficacy, gender and responsibility related to living independently of parents for these youth.

Metabolic abnormalities and viral replication are associated with biomarkers of vascular dysfunction in HIV-infected children.

OBJECTIVES: HIV-infected children may be at risk for premature cardiovascular disease. We compared levels of biomarkers of vascular dysfunction in HIV-infected children (with and without hyperlipidaemia) with those in HIV-exposed, uninfected (HEU) children enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS), and determined factors associated with these biomarkers. METHODS: A prospective cohort study was carried out. Biomarkers of inflammation [C-reactive protein (CRP), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP1)], coagulant dysfunction (fibrinogen and P-selectin), endothelial dysfunction [soluble intracellular cell adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM) and E-selectin], and metabolic dysfunction (adiponectin) were measured in 226 HIV-infected and 140 HEU children. Anthropometry, body composition, lipids, glucose, insulin, HIV disease severity, and antiretroviral therapy were recorded. RESULTS: The median ages of the children were 12.3 years in the HIV-infected group and 10.1 years in the HEU group. Body mass index (BMI) z-scores, waist and hip circumferences, and percentage body fat were lower in the HIV-infected children. Total and non-high-density lipoprotein (HDL) cholesterol and triglycerides were higher in HIV-infected children. HIV-infected children also had higher MCP-1, fibrinogen, sICAM and sVCAM levels. In multivariable analyses in the HIV-infected children alone, BMI z-score was associated with higher CRP and fibrinogen, but lower MCP-1 and sVCAM. Unfavourable lipid profiles were positively associated with IL-6, MCP-1, fibrinogen, and P- and E-selectin, whereas increased HIV viral load was associated with markers of inflammation (MCP-1 and CRP) and endothelial dysfunction (sICAM and sVCAM). CONCLUSIONS: HIV-infected children have higher levels of biomarkers of vascular dysfunction than do HEU children. Risk factors associated with higher biomarkers include unfavourable lipid levels and active HIV replication.

Insulin dose changes in children attending a residential diabetes camp.

AIMS: To examine the effects of insulin dose adjustments on rates of hypoglycaemia for school-aged children with Type 1 diabetes attending camp. METHODS: Camp records for 256 children aged 7-15 years (55% on continuous subcutaneous insulin infusion) attending a week-long residential summer camp were analysed. RESULTS: In anticipation of increased physical activity, basal insulin was decreased for all children on continuous subcutaneous insulin infusion and injection therapy by 10% upon arrival at camp. During the first day, children on continuous subcutaneous insulin infusion received 11.1±6.3% less basal insulin than home doses, whereas children on injections decreased intermediate/long-acting insulin by 8.2±12.8%. Despite these decreases, 60% had at least one blood sugar level <70 mg/dl (3.9 mmol/l) during the first day. Children on continuous subcutaneous insulin infusion were more likely to have hypoglycaemia during the first day than those on injections. The number of episodes of hypoglycaemia increased with increasing camper age. Overall, children did not have further significant reductions in their total daily insulin dose by the last day of camp. However, on the last day, children had fewer episodes of hypoglycaemia than during the first day (0.7±0.9 vs. 1.1±1.2, P<0.001) and 51% had no low blood sugar levels that day. CONCLUSIONS: An empiric 10% reduction in basal insulin appears reasonable, as nearly equal numbers of children required dose increases as dose decreases as camp progressed. However, hypoglycaemia was still common in all age groups. Prospective studies characterizing individual variables are needed in order to facilitate tailored insulin dose adjustments that minimize glycaemic variability while optimizing control in the diabetes camp setting.

A comparison of oral and intravenous bisphosphonate therapy for children with osteogenesis imperfecta.

Bone mineral density and fracture rates in children with osteogenesis imperfecta improve with intravenous bisphosphonates. The efficacy of oral bisphosphonates has not been established. This report is an analysis of an open-label, prospective, randomized clinical trial of oral compared to intravenous bisphosphonate medications in children with osteogenesis imperfecta. Children were stratified according to bone age, pubertal stage, and type of osteogenesis imperfecta and then randomized to receive intravenous pamidronate, 3 mg/kg over 3 days every 4 months, or oral alendronate 1 mg/kg, from a minimum of 10 mg to a maximum of 20 mg daily. The primary efficacy outcome was change in bone mineral density. Secondary outcomes included change in biomarkers of bone turnover, fracture incidence, and growth rate. Ten children were randomized (6 oral and 4 intravenous). Two other children were assigned to intravenous treatment due to chronic abdominal pain. In each group, three patients had type III/IV osteogenesis imperfecta, while three had type I. All 12 children completed 8 months of therapy; nine completed 12 months. Bone mineral density increased in both oral and intravenous groups equally and beyond that expected with normal growth. All children had a decrease in biochemical markers of bone turnover. Linear growth showed a moderate increase above that for age. There was a non-significant decrease in fracture incidence in both groups.

Intravenous pamidronate treatment of children under 36 months of age with osteogenesis imperfecta.

INTRODUCTION: Bone mineral density (BMD) and fracture rates in children with osteogenesis imperfecta (OI) have been shown to improve with bisphosphonate therapy. There are limited data available on the efficacy of this therapy in children with OI under the age of 3 years. To examine this, we instituted a prospective clinical trial of intravenous bisphosphonate to study safety, feasibility, and efficacy of this therapy. MATERIALS AND METHODS: Nine infants and young children with osteogenesis imperfecta (age range 1-35 months) were treated with intravenous pamidronate. Six had type II OI, two had type I, and one had type IV. Pamidronate was administered in cycles of 3 consecutive days. The total duration of therapy ranged from 11 to 29 months (mean 17 months). RESULTS: During treatment, the mean annualized percent change in total body areal BMD was 25% (range 11-40%). Pamidronate therapy resulted in sustained and significant decreases in serum calcium and bone-specific alkaline phosphatase and in urine calcium/creatinine and NTX/creatinine. Fracture rate in the group decreased from 80 fractures in 111 months before treatment to 25 fractures in 152 months after treatment (P<0.01). Linear growth and weight gain were maintained. Other than fevers in several infants following the initial dose of intravenous bisphosphonate no adverse effects of therapy were noted. CONCLUSIONS: Our data support that intravenous pamidronate therapy is safe, increases BMD, and reduces fracture rates in very young children with OI. Currently, it would seem to be the best available treatment for these children.

A missense mutation encoding cys(67) --> gly in neurophysin ii is associated with early onset autosomal dominant neurohypophyseal diabetes insipidus.

Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is an inherited disorder in which progressive degeneration of magnocellular neurons of the hypothalamus impairs production of arginine vasopressin (AVP). ADNDI is caused by mutations in the arginine vasopressin-neurophysin II (AVP-NPII) gene. These mutations are hypothesized to trigger neurodegeneration via disruption of preproAVP-NPII processing. Affected individuals usually develop diabetes insipidus between 1 and 6 years of age. Here we report a novel mutation of the AVP-NPII gene in a family with unusually early presentation of ADNDI. The index case developed symptoms of diabetes insipidus at 1 month of age, her mother at 9 months of age, and the maternal grandfather in early childhood. Each was found to be heterozygous for the missense mutation 1665T > G encoding the amino acid substitution C67G within NPII. This mutation helps to define two homologous regions of the AVP-NPII precursor bounded by disulfide bridges between C13 and C27 and between C61 and C73 that have structural homology and contain the majority of amino acid substitutions associated with ADNDI. The early onset of symptomatic diabetes insipidus in this family suggests that the C67G substitution may be particularly deleterious to magnocellular neurons and may provide a valuable model for study of dominantly inherited neurodegeneration.

Height outcome in congenital adrenal hyperplasia caused by 21-hydroxylase deficiency: a meta-analysis.

OBJECTIVE: To investigate adult heights attained by patients with 21-hydroxylase deficiency and to perform a meta-analysis of height outcomes reported in this population. STUDY DESIGN: A retrospective chart review of our patients >5 years of age (n = 65) who were followed up from 1978 to 1998 for 21-hydroxylase deficiency was conducted. Final height (FH) SD scores and target height (TH) SD scores were determined. The impact of sex, time of diagnosis, and compliance was assessed. Meta-analysis of results from 18 studies was performed; TH was available for 204 of 561 patients. RESULTS: Mean FH SD score-TH SD score for our 65 patients was -1.03. For the meta-analysis, mean weighted FH SD score for all 561 patients was -1.37, whereas weighted mean FH SD score-TH SD score for the 204 patients for whom TH was available was -1.21. No difference in outcome was seen for males compared with females, although a statistically significant difference was seen for patients identified early versus late. CONCLUSIONS: Adult height in patients with 21-hydroxylase deficiency is often within 1 SD of TH. Early diagnosis and good compliance appear to improve the outcome. Rather than pursuing alternate therapies for congenital adrenal hyperplasia, efforts may instead be focused on early detection and improved compliance with traditional medical therapy.

Disorders of phosphate metabolism.

Correct identification of the disorders of hypophosphatemia and hyperphosphatemia is important for determining therapy. Further research will provide insights into normal phosphate homeostasis, a complex and fascinating process.

Disorders of puberty: inactivating and activating molecular mutations.

Recent developments have increased our understanding of the molecular mechanisms that are responsible for several disorders of puberty. Specific gene mutations have been identified in three syndromes, one that is associated with delayed puberty (Kallmann syndrome) and two that are associated with precocious puberty (McCune-Albright syndrome and familial male precocious puberty). Mutations in the KAL gene have been shown to be responsible for cases of X-linked Kallmann syndrome. This gene encodes a protein that is believed to be involved in neural target recognition and protease inhibition. In McCune-Albright syndrome, heterozygous, postzygotic somatic mutations of the alpha-subunit of the stimulatory guanine nucleotide binding protein Gs have been shown to stimulate constitutive G protein activation and long-term cyclic adenosine monophosphate production. Similarly, familial male precocious puberty has been linked to gain-in-function mutations that result in increased levels of cyclic adenosine monophosphate; however, these mutations are found in the luteinizing hormone receptor gene itself. The clinical manifestations and the recent molecular advances in each of these three syndromes are explored.