BACKGROUND:Achieving optimal glycemic control in type 1 diabetes (T1D) is challenging. Automated insulin delivery (AID) systems have improved outcomes, yet data on open-source systems-particularly in low-resource, low technological literacy settings-remain limited. This study compared the efficacy and safety of an open-source system with a regulatory-approved system in a heterogeneous real-world pediatric cohort. METHODS:This longitudinal observational study included 61 children with T1D treated at Shaare Zedek Medical Center: 30 using the regulatory-approved Medtronic 780G and 31 using the open-source AndroidAPS AID system. Socioeconomic status (SES) was determined by residential address. Glycemic outcomes were compared between AID use and prior sensor-augmented pump therapy. Primary endpoints included changes in time in range (TIR), average glucose, glucose management indicator (GMI), and hypoglycemia/hyperglycemia duration. Safety outcomes included rates of severe hypoglycemia and diabetic ketoacidosis (DKA). RESULTS:Both groups demonstrated significant glycemic improvements after transitioning to AID, including an increase in %TIR (56.6 ± 14.1 vs 69.3 ± 8.8) and reduction in average blood glucose (173.3 ± 31.7 vs 149.9 ± 18.3), GMI and % time in hyperglycemia. No significant differences in glycemic outcomes were observed between groups, although a trend toward greater reduction in average blood glucose and GMI was observed in the regulatory-approved group. No episodes of severe hypoglycemia or DKA occurred in either group. CONCLUSIONS:In a heterogeneous real-world pediatric cohort including a low-resource population with limited technological access, both AID systems significantly improved glycemic outcomes without compromising safety. These findings suggest AID benefits transcend socioeconomic barriers, supporting patient autonomy in system selection.

AIMS:To evaluate the outcomes of prolonged religious Jewish fasting in individuals with type 1 diabetes using automated insulin delivery (AID) systems. METHODS:This cross-sectional, non-interventional study assessed the effects of a 25-hour Jewish fast in individuals using AID systems. Data was collected on the day of the fast, one week before, and one week after. RESULTS:The study included data from 109 fasting days involving 80 adolescents and young adults with type 1 diabetes. The mean age of participants was 17.4 ± 4.1 years; 47.5% were male, and the average duration of diabetes was 7.2 ± 4.3 years. A total of 67.6% of participants modified their AID system settings during the fasting period, with the most common modification being a change in the target glucose level. Overall, 71.5% completed the fast without complications. Fasts were primarily broken because of sensor-detected hypoglycemia. No cases of severe hypoglycemia or diabetic ketoacidosis were reported during or after the fasting period. During the fast, the mean blood glucose level was 135 ± 28.6 mg/dL, time in range (70-180 mg/dL) was 80.7%, and time spent in hypoglycemia (<70 mg/dL) was 2.6%. CONCLUSIONS:Prolonged fasting appears to be safe for adolescents and young adults with type 1 diabetes using AID systems. However, individualized adjustments to system settings are often necessary to maintain glycemic stability during fasting. To our knowledge, this is the first report of the effects of using an AID system during Jewish religious fasting.

Objective To evaluate the incidence and severity of ketoacidosis (DKA) at type 1 diabetes diagnosis during the first wave of the coronavirus disease 2019 (COVID-19) pandemic in Israel. Research Design and Methods A population-based study the product of a national collaboration of Israeli pediatric diabetes centers investigated the presentation of childhood-onset type 1 diabetes. The frequencies of DKA and severe DKA observed during the COVID-19 period from March 15, 2020 (commencement of the first nationwide lockdown) until June 30, 2020 were compared with the same periods in 2019, 2018, and 2017 using multivariable logistic regression, adjusting for age, sex, and socioeconomic position. Results During the COVID-19 period, DKA incidence was 58.2%, significantly higher than in 2019 (adjusted OR [aOR] 2.18 [95% CI, 1.31-3.60], P = 0.003); 2018 (aOR 2.05 [95% CI, 1.26-3.34], P = 0.004); and 2017 (aOR, 1.79 [95% CI, 1.09-2.93], P = 0.022). The incidence of severe DKA was 19.9%, significantly higher than in 2018 (aOR, 2.49 [95% CI, 1.20-5.19], P = 0.015) and 2017 (aOR, 2.73 [95% CI, 1.28-5.82], P = 0.009). In 2020, admissions and duration of stay in the intensive care unit were higher than in previous years (P = 0.001). During the COVID-19 pandemic, children aged 6-11 years had higher incidences of DKA (61.3% vs. 34.0%, 40.6%, and 45.1%, respectively, P = 0.012), and severe DKA (29.3% vs. 15.1%, 10.9%, and 5.9%, respectively, P = 0.002). Conclusions The dramatic increase in DKA at presentation of childhood-onset type 1 diabetes during the COVID-19 pandemic mandates targeted measures to raise public and physician awareness.

Context: NKX2-2 is a crucial transcription factor that enables specific beta-cell gene expression. Nkx2-2((-/-)) mice manifest with severe neonatal diabetes and changes in beta-cell progenitor fate into ghrelin-producing cells. In humans, recessive NKX2-2 gene mutations have been recently reported as a novel etiology for neonatal diabetes, with only 3 cases known worldwide. This study describes the genetic analysis, distinctive clinical features, the therapeutic challenges, and the unique pathophysiology causing neonatal diabetes in human NKX2-2 dysfunction. Case Description: An infant with very low birth weight (VLBW) and severe neonatal diabetes (NDM) re presented with severe obesity and developmental delay already at age 1 year.The challenge of achieving 3 glycemic control in a VLBW infant was unexpectedly met by a regimen of 3 daily doses of long-acting insulin analogues. Sanger sequencing of known NDM genes (such as ABCC8 and EIF2AK3) was followed by whole-exome sequencing that revealed homozygosity of a pathogenic frameshift variant, c.356delG, p.P119fs64*, in the islet cells transcription factor, NKX2-2. To elucidate the cause for the severe obesity, an oral glucose tolerance test was conducted at age 3.5 years and revealed undetectable C-peptide levels with a paradoxically unexpected 30% increase in ghrelin levels. Conclusion: Recessive NKX2-2 loss of function causes severe NDM associated with VLBW, childhood obesity, and developmental delay. The severe obesity phenotype is associated with postprandial paradoxical ghrelin secretion, which may be related to human p-cell fate change to ghrelin-secreting cells, recapitulating the finding in Nkx2-2((-/-)) mice islet cells.

This study aimed to evaluate liver involvement in patients with Carney complex (CNC) based on a large cohort and to analyze any germline PRKAR1A genotype-phenotype association of liver disease. The study included 83 patients with CNC, followed between 1995 and 2018 at a tertiary research center. We reviewed liver images, recorded types and number of lesions and analyzed per genotype: all patients were sequenced for the PRKAR1A gene. A total of 29/83 patients (24.0%) had liver radiological findings. Patients with liver lesion had a significantly higher rate of pathogenic variants detected in the PRKAR1A gene (72.4 vs 38.9%, P = 0.005, respectively). Patients with a pathogenic variant detected on germline PRKAR1A analysis had a higher risk for having a liver lesion compared with patients with wild-type (WT) PRKAR1A alleles (21/42 (50.0%) vs 8/41 (19.5%), respectively, P = 0.004). Among patients with liver lesions, those with a nonsense PRKAR1A pathogenic-variant had more liver lesions (7/7) than among those with other pathogenic-variant types (8/22, P = 0.001). In multivariable analysis, detection of liver lesion(s) was associated with an odds ratio of 5.2 for cardiac myxomas (95% CI 1.55-17.49, P = 0.008). In conclusion, patients with CNC, particularly with a PRKAR1A pathogenic variant, have a higher rate of liver lesions. Additionally, liver lesions are associated with a high risk for cardiac myxomas in this population.

OBJECTIVE:To evaluate the variability of growth hormone stimulation tests results and factors affecting it in short children suspected of having growth hormone deficiency. DESIGN:The cohort included patients with short stature suspected of having growth hormone deficiency, and who underwent a second stimulation test, after the first stimulation test was positive. Testing was done at a single center from May 2014 to October 2017. Patients' weight, height, age, sex, stimulating agents and test results were recorded. RESULTS:The study population comprised 200 patients, 108 males and 92 females, average age 9.2 years (2.2-16.6 years). The average peak growth hormone was 5.2 μg/L and 7.8 μg/L in the first and second tests respectively and the concordance rate was 56.5%. The probability of a second positive test was increased if the peak growth hormone level in the first test was below 5 μg/L. In the second test, Clonidine and Glucagon led to higher peak growth levels than Arginine with averages of 9.02, 9.97 and 6.88 μg/L respectively. Younger children and children with higher BMI SDS only had lower peaks of growth hormone in the second test. The effect of height SDS on peak growth hormone levels was equivocal. CONCLUSION:The reproducibility rate of GH simulation tests in our study was low. A few factors may affect the peak levels of growth hormone in the second test, the most prominent being the peak of growth hormone in the first test.

We describe an 8-week-old infant with severe gastrointestinal symptoms, significant hypoalbuminemia, and mild carditis following asymptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infant’s symptoms, including their temporal appearance, were consistent with multisystem inflammatory syndrome in children (MIS-C). A unique finding on colonic histology which may shed light on the pathogenesis of MIS-C was identified. The patient improved significantly following several anti-inflammatory treatments. The lag between the presentation of MIS-C and initial SARS-CoV-2 exposure, which may often be asymptomatic, together with the young age of our patient, makes this a challenging diagnosis. Clinicians should be aware of this entity, even in the neonatal and infantile age groups, to facilitate timely identification and treatment.

Background/Aims: Carney complex (CNC) is a rare syndrome associated with multiple tumors and several other unique manifestations. We describe the clinical, genetic, and laboratory findings in a cohort of patients with CNC and failure to thrive (FTT). Methods: A retrospective case series of pediatric patients with CNC presenting with FTT. Results: We describe a patient with infantile Cushing syndrome (CS) who presented with severe FTT and liver disease; the patient was subsequently diagnosed with CNC. This led to the realization that at least 10 other patients with CNC and FTT have been investigated in the last 22 years at the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Four of those had primary pigmented nodular adrenocortical disease (PPNAD), 2 had cardiac myxomas, and 3 had liver disease. Conclusion: Pediatric patients with CNC may present with FTT whose primary cause is variable and includes CS due to PPNAD, hepatic involvement, and other manifestations of CNC. FTT due to liver disease and/or other causes is a unique new presentation of this rare syndrome with which clinicians need to be familiar.

BackgroundHypermutable Pseudomonas aeruginosa (HPA) with high mutation rate due to defects in the DNA mismatch repair genes are frequently isolated in the sputum of cystic fibrosis (CF) patients. These isolates tend to be multidrug resistant and may be better adapted to the CF lung environment. However, the clinical significance of this infection has not been determined.MethodsThis prospective study enrolled patients with PA infection attending CF clinics in Jerusalem between 2010 and 2011. Mutation frequency of pseudomonas isolates was determined by quantification of colonies resistant to rifampicin.ResultsOf the 73 patients enrolled, 22 (30%) were infected with HPA. Average mutation frequency was 2.95 × 10−4 in HPA and 1 × 10−7 in non-HPA.Pulmonary function tests, number of pulmonary exacerbations and the response to antibiotic therapy were similar between patients infected with HPA and non-HPA isolates. The only predictors for infection with HPA were resistance to multiple antimicrobial categories (OR = 4.8, 95% CI: 1.8–12.4) and previous use of inhaled colistin (OR = 8.1, 95% CI: 2–30). Resistant mutant subpopulation analysis was a poor screening test for identifying HPA isolates.ConclusionsInfection with hypermutable strains represents the marked ability of PA to adapt to the lung environment, but was not associated with worse clinical outcome.

Objective To assess the association between severe intraventricular hemorrhage (IVH) and blood glucose variables during the first 96 hours of life in preterm infants.Study design Preterm infants with IVH grade 3-4 (n = 70) were compared with matched infants of similar gestational age and birth weight, but with no IVH (n = 108). Studied variables included the frequency and duration of hyper/hypoglycemic (>6.9/<3.3 mmol/L, respectively) events, the extreme slope of an event evolution, the maximal glucose value observed, and the "hyper/hypoglycemic index" representing a weighted average of the hyper/hypoglycemic amplitude.Results The IVH group had significantly more hyperglycemic events (2.9 +/- 1.7 vs 2.4 +/- 1.8 events, P < .05) with longer duration (22.2 +/- 14.2 vs 14.1 +/- 12.5 hours, P < .001) and a higher hyperglycemic index (1.0 +/- 0.9 vs 1.4 +/- 1.0, P = .003) compared with the non-IVH controls. Respiratory distress syndrome, hypotension, and thrombocytopenia increased the adjusted OR for IVH. Hypoglycemia was not independently associated with IVH. Conversely, the increase in hyperglycemic duration was most prominently increasing the aOR for severe IVH (OR = 10.33, 95% CI = 10.0-10.6, P = .033).Conclusion Longer duration of hyperglycemia in the first 96 hours of life was most strongly associated with severe IVH in preterm infants. Consequently, interventional studies to determine the selective effect of continuous control of long-lasting hyperglycemia by appropriate and timed insulin treatment on the incidence of severe IVH are warranted.