Outcomes of hybrid closed-loop insulin delivery activated 24/7 versus evening and night in free-living prepubertal children with type 1 diabetes: A multicentre, randomized clinical trial.

AIM: To assess the safety and efficacy of hybrid closed-loop (HCL) insulin delivery 24/7 versus only evening and night (E/N), and on extended 24/7 use, in free-living children with type 1 diabetes. MATERIALS AND METHODS: Prepubertal children (n = 122; 49 females/73 males; age, 8.6 ± 1.6 years; diabetes duration, 5.2 ± 2.3 years; insulin pump use, 4.6 ± 2.5 years; HbA1c 7.7% ± 0.7%/61 ± 5 mmol/mol) from four centres were randomized for 24/7 versus E/N activation of the Tandem Control-IQ system for 18 weeks. Afterwards, all children used the activated system 24/7 for 18 more weeks. The primary outcome was the percentage of time spent in the 70-180 mg/dL glucose range (TIR). RESULTS: HCL was active 94.1% and 51.1% of the time in the 24/7 and E/N modes, respectively. TIR from baseline increased more in the 24/7 versus the E/N mode (52.9% ± 9.5% to 67.3% ± 5.6% [+14.4%, 95% CI 12.4%-16.7%] vs. 55.1% ± 10.8% to 64.7% ± 7.0% [+9.6%, 95% CI 7.4%-11.6%]; P = .001). Mean percentage time below range was similarly reduced, from 4.2% and 4.6% to 2.7%, and the mean percentage time above range decreased more in the 24/7 mode (41.9% to 30.0% [-11.9%, 95% CI 9.7%-14.6%] vs. 39.8% to 32.6% [-7.2%, 95% CI 5.0%-9.9%]; P = .007). TIR increased through the whole range of baseline levels and always more with 24/7 use. The results were maintained during the extension phase in those initially on 24/7 use and improved in those with initial E/N use up to those with 24/7 use. Neither ketoacidosis nor severe hypoglycaemia occurred. CONCLUSIONS: The current study shows the safety and efficacy of the Tandem Control-IQ system in free-living children with type 1 diabetes for both E/N and 24/7 use; 24/7 use shows better outcomes, sustained for up to 36 weeks with no safety issues.

Time trend in excess mortality in children with type 1 diabetes from 1987 to 2016 in mainland France.

BACKGROUND: Mortality risk for children with type 1 diabetes (T1D) is unknown in France and their causes of death are not well documented. AIM: To determine the standardized mortality ratios (SMRs) and causes of death in children aged 1-14 years with T1D from 1987 to 2016. METHODS: The French Center for Epidemiology on Medical Causes of Death collected all death certificates in mainland France. SMRs, corrected SMRs (accounting for missing cases of deaths unrelated to diabetes), and 95% confidence intervals were calculated. RESULTS: Of 146 deaths with the contribution of diabetes, 97 were due to T1D. Mean age at death of the subjects with T1D was 8.8 ± 4.1 years (54% males). The cause of death was diabetic ketoacidosis (DKA) in 58% of the cases (70% in subjects 1-4 years), hypoglycemia or dead-in-bed syndrome in 4%, related to diabetes but not described in 24%, and unrelated to diabetes in 14%. The SMRs showed a significant decrease across the years, except for the 1-4 age group. In the last decade (2007-2016), the crude and corrected SMRs were significantly different from 1 in the 1-4 age group (5.4 [2.3; 10.7] and 6.1 [2.8; 11.5]), no longer significant in the 5-9 age group (1.7 [0.6; 4.0] and 2.1 [0.8; 4.5]) and borderline significant in the 10-14 age group (1.7 [0.8; 3.2] and 2.3 [1.2; 4.0]). CONCLUSIONS: Children with T1D aged 1-4 years still had a high mortality rate. Their needs for early recognition and safe management of diabetes are not being met.

Insufficient Bone Mineralization to Sustain Mechanical Load of Weight in Obese Boys: A Cross-Sectional Study.

CONTEXT: The increase in bone mineral content (BMC) and density (BMD) measured by dual-energy x-ray absorptiometry (DXA) in obese children may not sustain the mechanical load associated with weight, and the factors influencing bone mineralization are not well known. OBJECTIVE: We described bone mineralization in boys with overweight/obesity and leanness in relation to body composition. METHODS: Cross-sectional study in the Pediatric Endocrinology Unit of Angers University Hospital with 249 overweight/obese boys aged 8-18 who underwent DXA and insulin, testosterone, and IGF-1 measurements. Bone mineralization was compared with data from 301 lean boys of similar age and height from NHANES 2011-2015, using the same DXA model. Path analyses were performed to evaluate factors associated with total body less head (TBLH) BMC. RESULTS: The mean age- and height-adjusted difference in TBLH BMC between obese and lean boys was 241 ± 20 g/cm2. Each 1 kg/m2 increase in BMI was associated with +39 ± 6 g of TBLH BMC in lean subjects vs + 25 ± 3 g in obese subjects (P < .05). Each 1 kg/m2 increase in lean BMI (LBMI) was associated with +78 ± 5 g of TBLH BMC in lean and obese boys, and each 1 kg/m2 increase in fat mass index (FMI) was associated with a decrease of 9 ± 3 g of TBLH BMC. The TBLH BMC was directly positively influenced by LBMI and indirectly and positively influenced by IGF-1, testosterone, and insulin (mediated through height and LBMI). FMI indirectly influenced TBLH BMC, both positively through LBMI and negatively through its negative impact on IGF-1 and testosterone. CONCLUSION: The increase in bone mineralization in obese children does not adapt to the increase in body mass.

Factors Associated With Weight Loss After Laparoscopic Adjustable Gastric Banding in Adolescents With Severe Obesity.

Childhood obesity is associated with many comorbidities. Bariatric surgery is known to be efficient for reducing weight in adolescents. Objectives: The primary outcome was to identify somatic or psychosocial factors associated with success at 24 months after a laparoscopic adjustable gastric banding (LAGB) procedure in our cohort of adolescents with severe obesity. Secondary endpoints were to describe weight loss outcomes, comorbidity resolution, and complications. Methods: We have retrospectively reviewed medical records of patients who had LAGB placed between 2007 and 2017. Factors associated with success at 24 months after LAGB were researched, with success being defined as positive percentage of excess weight loss (%EWL) at 24 months. Results: Forty-two adolescents underwent a LAGB procedure, the mean %EWL was 34.1% at 24 months, with improvement in most comorbidities and without major complications. Having lost weight before surgery was associated with success, whereas a high body mass index at surgery was associated with a higher risk of failure. No other factor was found to be associated with success. Conclusion: Comorbidities mostly improved 24 months after LAGB and no major complication occurred. Having lost weight before surgery was associated with a successful surgery, whereas a high body mass index at surgery increases the risk of failure.

Hybrid Closed Loop Overcomes the Impact of Missed or Suboptimal Meal Boluses on Glucose Control in Children with Type 1 Diabetes Compared to Sensor-Augmented Pump Therapy.

Background: It is unclear whether hybrid closed-loop (HCL) therapy attenuates the metabolic impact of missed or suboptimal meal insulin bolus compared with sensor-augmented pump (SAP) therapy in children with type 1 diabetes in free-living conditions. Methods: This is an ancillary study from a multicenter randomized controlled trial that compared 24/7 HCL with evening and night (E/N) HCL for 36 weeks in children between 6 and 12 years old. In the present study, the 60 children from the E/N arm underwent a SAP phase, an E/N HCL for 18 weeks, then a 24/7 phase for 18 weeks, extended for 36 more weeks. The last 28-30 days of each of the four phases were analyzed according to meal bolus management (cumulated 6817 days). The primary endpoint was the percentage of time that the sensor glucose was in the target range (TIR, 70-180 mg/dL) according to the number of missed boluses per day. Findings: TIR was 54% ± 10% with SAP, 63% ± 7% with E/N HCL, and steadily 67% ± 7% with 24/7 HCL. From the SAP phase to 72 weeks of HCL, the percentage of days with at least one missed meal bolus increased from 12% to 22%. Estimated marginal (EM) mean TIR when no bolus was missed was 54% (95% confidence intervals [CI] 53-56) in SAP and it was 13% higher (95% CI 11-15) in the 24/7 HCL phase. EM mean TIR with 1 and ≥2 missed boluses/day was 49.5% (95% CI 46-52) and 45% (95% CI 39-51) in SAP, and it was 15% (95% CI 14-16) and 17% higher (95% CI 6-28), respectively, in the 24/7 HCL phase (P < 0.05 for all comparisons vs. SAP). Interpretation: HCL persistently improves glycemic control compared with SAP, even in case of meal bolus omission. ClinicalTrials.gov (NCT03739099).

The Severity of Congenital Hypothyroidism With Gland-In-Situ Predicts Molecular Yield by Targeted Next-Generation Sequencing.

INTRODUCTION: Congenital hypothyroidism with gland-in-situ (CH-GIS) is usually attributed to mutations in the genes involved in thyroid hormone production. The diagnostic yield of targeted next-generation sequencing (NGS) varied widely between studies. We hypothesized that the molecular yield of targeted NGS would depend on the severity of CH. METHODS: Targeted NGS was performed in 103 CH-GIS patients from the French national screening program referred to the Reference Center for Rare Thyroid Diseases of Angers University Hospital. The custom targeted NGS panel contained 48 genes. Cases were classified as solved or probably solved depending on the known inheritance of the gene, the classification of the variants according to the American College of Medical Genetics and Genomics, the familial segregation, and published functional studies. Thyroid-stimulating hormone at CH screening and at diagnosis (TSHsc and TSHdg) and free T4 at diagnosis (FT4dg) were recorded. RESULTS: NGS identified 95 variants in 10 genes in 73 of the 103 patients, resulting in 25 solved cases and 18 probably solved cases. They were mainly due to mutations in the TG (n = 20) and TPO (n = 15) genes. The molecular yield was, respectively, 73% and 25% if TSHsc was ≥ and < 80 mUI/L, 60% and 30% if TSHdg was ≥ and < 100 mUI/L, and 69% and 29% if FT4dg was ≤ and > 5 pmol/L. CONCLUSION: NGS in patients with CH-GIS in France found a molecular explanation in 42% of the cases, increasing to 70% when TSHsc was ≥ 80 mUI/L or FT4dg was ≤ 5 pmol/L.

Lower Circulating Sertoli and Leydig Cell Hormone Levels During Puberty in Obese Boys: A Cross-sectional Study.

CONTEXT: Alterations in semen characteristics and circulating Sertoli and Leydig cell hormones have been described in obese male adults. Whether hormonal alterations occur before adulthood has not been fully evaluated. OBJECTIVE: We describe circulating Sertoli and Leydig cell hormone levels in overweight-obese (ow/ob) boys through childhood and adolescence in a cross-sectional study. METHODS: Monocentric study in the Pediatric Endocrinology Unit of Angers University Hospital. Three hundred and fifty-one obese and overweight boys aged 5-19 years underwent physical examination, dual-energy X-ray absorptiometry for body composition, oral glucose tolerance test on insulin and glucose, and measurements of follicle-stimulating hormone, luteinizing hormone, anti-Müllerian hormone (AMH), inhibin B, testosterone, and estradiol. Hormonal levels were compared with normative data obtained from 652 healthy nonoverweight nonobese boys of similar age or Tanner stage. RESULTS: Median inhibin B and testosterone levels during puberty were significantly lower in ow/ob than in healthy boys (1) from age >12 years and thereafter for inhibin B, and (2) from age >14 years and thereafter for testosterone. At Tanner stages 4 and 5, 26%, 31%, and 18% of inhibin B, testosterone, and AMH values were below the 5th percentile in ow/ob subjects (P < .01). In multiple regression analyses, estradiol and total bone mineral density Z-score were negative predictors of inhibin B, fat mass percentage was a negative predictor of testosterone, and insulin was a negative predictor of AMH. CONCLUSION: Lower Sertoli and Leydig cell hormone levels during puberty were observed in the ow/ob boys.

Presenting features and molecular genetics of primary hyperparathyroidism in the paediatric population.

AIM: To describe the presenting features and molecular genetics of primary hyperparathyroidism (PHPT) in the paediatric population. METHODS: Retrospective study of 63 children diagnosed with primary PHPT from 1998 to 2018. RESULTS: Compared to older children, infants were often asymptomatic (54% vs 15%, P = 0.002) with a milder form of PHPT. When symptomatic, children and adolescents mostly presented with non-specific complaints such as asthenia, depression, weight loss, vomiting or abdominal pain. A genetic cause of PHPT was identified in about half of this cohort (52%). The infancy period was almost exclusively associated with mutation in genes involved in the calcium-sensing receptor (CaSR) signalling pathway (i.e. CaSR and AP2S1 genes, 'CaSR group'; 94% of infants with mutations) whereas childhood and adolescence were associated with mutation in genes involved in parathyroid cell proliferation (i.e. MEN1, CDC73, CDKN1B and RET genes, 'cell proliferation group'; 69% of children and adolescents with mutations). Although serum calcium levels did not differ between the two groups (P = 0.785), serum PTH levels and the urinary calcium/creatinine ratio were significantly higher in 'cell proliferation group' patients compared to those in the 'CaSR group' (P = 0.001 and 0.028, respectively). CONCLUSION: Although far less common than in adults, PHPT can develop in children and is associated with significant morbidity. Consequently, this diagnosis should be considered in children with non-specific complaints and lead to monitoring of mineral homeostasis parameters. A genetic cause of PHPT can be identified in about half of these patients.