Delayed-Onset Transient Hyperinsulinism in Infants with Very Low and Extremely Low Birth Weights: A Cohort Study.

We describe 16 infants born preterm with birth weights <1500 g and transient hyperinsulinism. The onset of hyperinsulinism was delayed and often coincident with clinical stabilization. We hypothesize that postnatal stress caused by prematurity and associated problems may contribute to development of delayed-onset transient hyperinsulinism.

Reliability and Observer Dependence of Signs of Neonatal Hypoglycemia.

OBJECTIVES: To evaluate, using video documentation, the sensitivity, specificity, and interobserver reliability of visualizable signs of neonatal hypoglycemia at different glucose concentrations in neonates. STUDY DESIGN: In a prospective cohort study of 145 neonates with and without risk factors for hypoglycemia, 430 videos were recorded before blood glucose measurements and analyzed by 10 blinded investigators of different professions. The primary outcome measures were sensitivity and specificity for clinical detection of hypoglycemia. RESULTS: The overall sensitivity to detect low blood glucose (<55 mg/dL [<3.1 mmol/L]) based on signs was 30%, and the specificity was 82%. Significantly more investigators suspected hypoglycemia while viewing videos of infants with blood glucose levels of 46-54 mg/dL (2.6-3.0 mmol/L) and 30-45 mg/dL (1.7-2.5 mmol/L) compared with ≥55 mg/dL (≥3.1 mmol/L) (29 ± 3% and 31 ± 4% vs 18 ± 1%; P = .001; P = .007). After 48 hours of life, significantly more investigators suspected hypoglycemia in videos of infants with blood glucose levels of ≤45 mg/dL (≤2.5 mmol/L) compared with blood glucose levels of >45 mg/dL (>2.5 mmol/L) (28.9 ± 8.1% vs 10.9 ± 1.8%; P = .007). For blood glucose levels 30-45 mg/dL (1.7-2.5 mmol/L), sensitivity varied widely between investigators, ranging from 5% to 62%. Three hypoglycemic episodes <30 mg/dL (<1.7 mmol/L) were only partially recognized. CONCLUSIONS: Clinical observation of signs is neither sensitive nor specific to detect neonatal hypoglycemia, and there are large interobserver differences. Thus, guidelines on neonatal hypoglycemia should reconsider whether distinguishing between asymptomatic and symptomatic hypoglycemia provides useful information for the management of neonatal hypoglycemia, because it may pose a risk for systematic under-recognition and undertreatment, leading to an increased risk for neurodevelopmental impairment. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00021500 www.drks.de/drks_web/setLocale_EN.do.

Three-Variate Longitudinal Patterns of Metabolic Control, Body Mass Index, and Insulin Dose during Puberty in a Type 1 Diabetes Cohort: A Group-Based Multitrajectory Analysis.

OBJECTIVE: To analyze the interrelationship of metabolic control, age- and sex-adjusted body mass index, and daily insulin dose and to identify heterogeneous multivariate developmental curves from childhood to young adulthood in a large cohort of children with type 1 diabetes (T1D) STUDY DESIGN: Data were extracted from the diabetes follow-up registry DPV. Longitudinal data from 9239 participants with T1D age 8-18 years with diabetes duration ≥2 years and ≥5 years of follow-up were analyzed. We applied group-based multitrajectory modeling to identify latent groups of subjects following similar developmental curves across outcomes (hemoglobin A1c [HbA1c], age/sex-standardized body mass index [BMI-SDS], daily insulin dose per kg). Group number was based on Bayes information criterion and group size (≥5%). RESULTS: The group-based multitrajectory approach revealed 5 heterogeneous 3-variate trajectories during puberty. Individuals with stable good metabolic control, high-normal increasing BMI-SDS, and rising insulin dose patterns were classified as group 1 (33%). Group 2 (20%) comprised youths with intermediate-increasing HbA1c, low BMI-SDS, and steeply increasing insulin dose trajectories. Group 3 (11%) followed intermediate-rising HbA1c and high-normal increasing BMI-SDS developmental curves, while insulin dose increased steeply. In group 4 (14%), both high-increasing HbA1c and insulin dose trajectories were observed, while BMI-SDS was stable-normal. Group 5 (22%) included subjects with intermediate-rising HbA1c patterns, high-increasing BMI-SDS, and increasing insulin dose patterns. CONCLUSIONS: This study identified 5 distinct 3-variate curves of HbA1c, BMI-SDS, and insulin dose during puberty among youths with T1D. This approach demonstrates a considerable heterogeneity highlighting the importance of personalized medical care.

Acceptability of Multiple Uncoated Minitablets in Infants and Toddlers: A Randomized Controlled Trial.

OBJECTIVES: To assess the acceptability and swallowability of several minitablets when administered as a unit dose compared with an equivalent dose of syrup in children aged 6 months to 5 years. STUDY DESIGN: The acceptability and swallowability of multiple drug-free minitablets in comparison with glucose syrup was assessed in 372 children of 2 age groups (186 in age group 1 [6-23 months of age] and 186 in age group 2 [2-5 years of age]) in a randomized, 3-way, single administration cross-over study. Age group 1 received 25 minitablets, 100 minitablets, and 5 mL syrup. Age group 2 received 100 minitablets, 400 minitablets, and 10 mL syrup. RESULTS: Superiority was demonstrated in age group 1 for acceptability (25 minitablets, P < .017; 100 minitablets, P < .0001) and swallowability (25 minitablets and 100 minitablets, both P < .0001) compared with syrup. In age group 2, noninferiority of acceptability was found only for 400 minitablets (P < .0003), not for 100 minitablets. Subgroup analysis revealed a strong sequential effect. For swallowability, noninferiority could be demonstrated for 100 minitablets (P < .01) but not for 400 minitablets. CONCLUSIONS: Administration of ≥25 minitablets is well-tolerated, feasible, and safe in children aged from 6 months, and was superior to the equivalent dose of syrup. Children aged >1 year accept ≤400 minitablets even better than the equivalent dose of syrup. Minitablets open the perspective for introducing small-sized solid drug formulations for all children, thus, further shifting the paradigm from liquid toward small-sized solid drug formulations. TRIAL REGISTRATION: German Clinical Trials Register (DRKS): DRKS00008843.

Inflammatory Markers in Obese Adolescents with Type 2 Diabetes and Their Relationship to Hepatokines and Adipokines.

OBJECTIVES: To analyze inflammatory markers, adipokines, and hepatokines in obese adolescents with and without type 2 diabetes mellitus (T2DM). STUDY DESIGN: We studied high sensitivity C-reactive protein (hsCRP), tumor necrosis factor (TNF)-α, interleukin-1ß, and interferon-γ, the hepatokines (fetuin-A and fibroblast growth factor [FGF]-21), and the adipokines (adiponectin and leptin) in a cross-sectional study of 74 predominately Caucasian adolescents with T2DM aged 12-18 years and in 74 body mass index (BMI)-, age-, and sex-matched controls. RESULTS: Adolescents with T2DM had significantly higher concentrations of hsCRP, TNF-α, and interleukin-1ß compared with obese controls without T2DM. Interferon-γ was not detectable in obese adolescents with or without T2DM. In multiple linear regression analysis, hsCRP was significantly associated with FGF-21 and BMI, but not with hemoglobin A1c, adiponectin, leptin, fetuin-A, sex, or age. TNF-α was significantly related negatively to leptin, positively to BMI, but not to hemoglobin A1c, adiponectin, fetuin-A, FGF-21 sex, or age in multiple linear regression analysis. CONCLUSIONS: Increased inflammatory markers are associated with T2DM in adolescents. Because hsCRP was related to FGF-21 and TNF-α was associated with leptin, these findings suggest a link between increased levels of these adipokines and hepatokines and chronic inflammation. Future longitudinal studies in humans are necessary to confirm these hypotheses.

Acceptability of Uncoated Mini-Tablets in Neonates--A Randomized Controlled Trial.

OBJECTIVE: To evaluate the suitability of drug-free solid dosage forms (2 mm mini-tablets) as an alternative administration modality in neonates in comparison with syrup. STUDY DESIGN: A total of 151 neonates (inpatients; aged 2-28 days; median 4 days) were recruited. An open, randomized, prospective cross-over study was conducted to compare the acceptability and swallowability of 2 mm uncoated mini-tablets compared with .5 mL syrup. RESULTS: All neonates (N = 151) accepted the uncoated mini-tablet as well as the syrup (both formulations 100%; 95% CI 97.6%-100.0%; primary objective). The level of swallowability of uncoated mini-tablets was not inferior (P < .0001), in fact even higher (difference in proportions 10.0%; 95% CI 1.37%-19.34%; P = .0315) compared with syrup. Both pharmaceutical formulations were well tolerated, and in none of the 151 neonates, serious adverse events occurred; particularly none of the neonates inhaled or coughed in either of the formulations. CONCLUSIONS: The administration of uncoated mini-tablets proved to be a valuable alternative to syrup for term neonates. Our data on neonates close the age gap of prior findings in toddlers and infants: uncoated mini-tablets offer the potential of a single formulation for all age groups. These findings further shift the paradigm from liquid toward small-sized solid drug formulations for children of all age groups, as the World Health Organization proposes. TRIAL REGISTRATION: German Clinical Trials Register (Deutsches Register Klinischer Studien [DRKS; germanctr.de]): DRKS00005609.

Favorable acceptance of mini-tablets compared with syrup: a randomized controlled trial in infants and preschool children.

OBJECTIVE: To evaluate acceptability of 2 mm solid dosage forms (mini-tablets) as an alternative administration modality in young children in comparison with syrup. STUDY DESIGN: Three hundred six pediatric in- and outpatients aged 6 months-5 years (51 in each of 6 age groups) were recruited. An open, randomized cross-over study was conducted to compare acceptability and capability to swallow 2 mm uncoated or coated mini-tablets vs 3 mL syrup. RESULTS: In the overall patient population of 306 children, the acceptability of uncoated mini-tablets was superior to syrup (difference in proportions 14.8%, 95% CI 10.2-19.4; P < .0001). In line with this finding, the level of capability to swallow was higher for uncoated mini-tablets compared with syrup as well (difference in proportions 12.3%, 95% CI 5.4-19.3; P = .0008). All 3 pharmaceutical formulations were well tolerated, and none of the 306 children inhaled or coughed because of the syrup or the uncoated mini-tablet; only 2 of the 306 children (both in age group 0.5-1 year) coughed because of the coated mini-tablet, in both cases without clinical relevance. CONCLUSIONS: Mini-tablets are a valuable alternative to syrup for children 6 months-6 years of age and are more acceptable compared with liquid formulation. Regulatory bodies such as Food and Drug Administration and European Medicine Agency are encouraged to take our data into account for guideline updates and future drug approval processes.