Multicenter, Randomized Trial of a Bionic Pancreas in Type 1 Diabetes.

BACKGROUND: Currently available semiautomated insulin-delivery systems require individualized insulin regimens for the initialization of therapy and meal doses based on carbohydrate counting for routine operation. In contrast, the bionic pancreas is initialized only on the basis of body weight, makes all dose decisions and delivers insulin autonomously, and uses meal announcements without carbohydrate counting. METHODS: In this 13-week, multicenter, randomized trial, we randomly assigned in a 2:1 ratio persons at least 6 years of age with type 1 diabetes either to receive bionic pancreas treatment with insulin aspart or insulin lispro or to receive standard care (defined as any insulin-delivery method with unblinded, real-time continuous glucose monitoring). The primary outcome was the glycated hemoglobin level at 13 weeks. The key secondary outcome was the percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter; the prespecified noninferiority limit for this outcome was 1 percentage point. Safety was also assessed. RESULTS: A total of 219 participants 6 to 79 years of age were assigned to the bionic-pancreas group, and 107 to the standard-care group. The glycated hemoglobin level decreased from 7.9% to 7.3% in the bionic-pancreas group and did not change (was at 7.7% at both time points) in the standard-care group (mean adjusted difference at 13 weeks, -0.5 percentage points; 95% confidence interval [CI], -0.6 to -0.3; P<0.001). The percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter did not differ significantly between the two groups (13-week adjusted difference, 0.0 percentage points; 95% CI, -0.1 to 0.04; P<0.001 for noninferiority). The rate of severe hypoglycemia was 17.7 events per 100 participant-years in the bionic-pancreas group and 10.8 events per 100 participant-years in the standard-care group (P = 0.39). No episodes of diabetic ketoacidosis occurred in either group. CONCLUSIONS: In this 13-week, randomized trial involving adults and children with type 1 diabetes, use of a bionic pancreas was associated with a greater reduction than standard care in the glycated hemoglobin level. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT04200313.).

A centennial review of discoveries and advances in diabetes: Children and youth.

Diabetes is an increasingly common chronic metabolic disorder in children worldwide. The discovery of insulin in 1921 resulted in unprecedented advancements that improved the lives of children and youth with diabetes. The purpose of this article is to review the history of diabetes in children and youth over the last century and its implications for future developments in the field. We identified 68 relevant events between 1921 and 2021 through literature review and survey of pediatric endocrinologists. Basic research milestones led to the discovery of insulin and other regulatory hormones, established the normal physiology of carbohydrate metabolism and pathophysiology of diabetes, and provided insight into strategies for diabetes prevention. While landmark clinical studies were initially focused on adult diabetes populations, later studies assessed etiologic factors in birth cohort studies, evaluated technology use among children with diabetes, and investigated pharmacologic management of youth type 2 diabetes. Technological innovations culminated in the introduction of continuous glucose monitoring that enabled semi-automated insulin delivery systems. Finally, professional organizations collaborated with patient groups to advocate for the needs of children with diabetes and their families. Together, these advances transformed type 1 diabetes from a terminal illness to a manageable disease with near-normal life expectancy and increased our knowledge of type 2 diabetes and other forms of diabetes in the pediatric population. However, disparities in access to insulin, diabetes technology, education, and care support remain and disproportionately impact minority youth and communities with less resources. The overarching goal of diabetes management remains promoting a high quality of life and improving glycemic management without undermining the psychological health of children and youth living with diabetes.

Impact of the COVID-19 pandemic on management of children and adolescents with Type 1 diabetes.

BACKGROUND: The coronavirus disease-2019 (COVID-19) pandemic had widespread impacts on the lives of parents and children. We determined how the pandemic affected Type 1 diabetes patients at a large urban pediatric teaching hospital. METHODS: We compared patient characteristics, glycemic control, PHQ-9 depression screen, in person and virtual outpatient encounters, hospitalizations and continuous glucose monitor (CGM) utilization in approximately 1600 patients in 1 year periods preceding and following the local imposition of COVID-related restrictions on 3/15/2020 ("2019" and "2020" groups, respectively). RESULTS: In a generalized linear model, increasing age, non-commercial insurance, Black and Hispanic race/ethnicity, and non-utilization of CGMs were all associated with higher hemoglobin A1c (HbA1c), but there was no difference between the 2019 and 2020 groups. The time in range in CGM users was lower with non-commercial insurance and in Black and Hispanic patients; it improved slightly from 2019 to 2020. CGM utilization by patients with non-commercial insurance (93% of such patients were in government programs, 7% uninsured or "other") increased markedly. In 2020, patients with commercial insurance (i.e., private-pay or provided by an employer) had fewer office visits, but insurance status did not influence utilization of the virtual visit platform. There was no change in hospitalization frequency from 2019 to 2020 in either commercially or non-commercially insured patients, but patients with non-commercial insurance were hospitalized at markedly higher frequencies in both years. PHQ-9 scores were unchanged. CONCLUSIONS: Hospitalization frequency, glycemic control and depression screening were unchanged in our large urban pediatric teaching hospital during the COVID pandemic. Increased utilization of CGM and rapid adoption of telemedicine may have ameliorated the impact of the pandemic on disease management.

Diabetic ketoacidosis drives COVID-19 related hospitalizations in children with type 1 diabetes.

BACKGROUND: Diabetes is a risk factor for poor COVID-19 outcomes, but pediatric patients with type 1 diabetes are poorly represented in current studies. METHODS: T1D Exchange coordinated a US type 1 diabetes COVID-19 registry. Forty-six diabetes centers submitted pediatric cases for patients with laboratory confirmed COVID-19. Associations between clinical factors and hospitalization were tested with Fisher's Exact Test. Logistic regression was used to calculate odds ratios for hospitalization. RESULTS: Data from 266 patients with previously established type 1 diabetes aged <19 years with COVID-19 were reported. Diabetic ketoacidosis (DKA) was the most common adverse outcome (n = 44, 72% of hospitalized patients). There were four hospitalizations for severe hypoglycemia, three hospitalizations requiring respiratory support (one of whom was intubated and mechanically ventilated), one case of multisystem inflammatory syndrome in children, and 10 patients who were hospitalized for reasons unrelated to COVID-19 or diabetes. Hospitalized patients (n = 61) were more likely than nonhospitalized patients (n = 205) to have minority race/ethnicity (67% vs 39%, P < 0.001), public insurance (64% vs 41%, P < 0.001), higher A1c (11% [97 mmol/mol] vs 8.2% [66 mmol/mol], P < 0.001), and lower insulin pump and lower continuous glucose monitoring use (26% vs 54%, P < 0.001; 39% vs 75%, P < 0.001). Age and gender were not associated with risk of hospitalization. Higher A1c was significantly associated with hospitalization, with an odds ratio of 1.56 (1.34-1.84) after adjusting for age, gender, insurance, and race/ethnicity. CONCLUSIONS: Higher A1c remained the only predictor for hospitalization with COVID-19. Diabetic ketoacidosis is the primary concern among this group.

Severe malnutrition causing superior mesenteric artery syndrome in an adolescent with Triple A syndrome.

Triple A syndrome, formerly known as Allgrove syndrome (AS), is characterized by achalasia, alacrima and adrenal insufficiency. Here we report an adolescent male with adrenal insufficiency who developed severe malnutrition secondary to a delayed diagnosis of achalasia. The severe malnutrition in our patient led to superior mesenteric artery (SMA) obstruction syndrome. Severe malnutrition to the point of SMA syndrome has not been previously described in the literature in Triple A syndrome.

Sick Day Management in Children and Adolescents with Type 1 Diabetes.

Diabetic Ketoacidosis (DKA) has high morbidity and mortality and can be prevented. It is extremely important to give clear guidance to patients and families on how to manage diabetes during intercurrent illnesses to avoid complications of ketoacidosis, dehydration,uncontrolled or symptomatic hyperglycemia and hypoglycemia. This descriptive review of clinical cases and management guidelines for sick days in children and adolescents with diabetes is provided as a resource for physicians who may take calls from parents of sick children with diabetes or manage these children in a clinic, emergency room or hospital setting.

Familial dysalbuminemic hyperthyroxinemia in a 4-year-old girl with hyperactivity, palpitations and advanced dental age: how gold standard assays may be misleading.

Here we report the case of a young girl who had vague signs and symptoms potentially attributable to hyperthyroidism and was found to have autoimmune thyroiditis and hyperthyroxinemia. The elevated serum free thyroxine levels were persistent when measured by both standard assays and equilibrium dialysis/high-pressure liquid chromatography-tandem mass spectrometry. The clinical symptoms, with discordant thyroid test results, created a diagnostic dilemma that led initially to unnecessary additional evaluations. She was ultimately found to have familial dysalbuminemic hyperthyroxinemia (FDH) and required no therapy. This case highlights the inherent difficulties in evaluating children, who typically have vague signs and symptoms of thyroid dysfunction, when, in addition, they have an unrelated acquired (autoimmune) as well as a genetic (FDH) defect. The benefit of including testing for immediate members of the family is emphasized.

Cushing's disease presenting as cholestatic hepatitis.

Here we report an adolescent male with Cushing's disease secondary to a pituitary adenoma who was admitted with cholestatic hepatitis. A detailed work-up for hepatitis was negative except for a novel heterozygous ABCB4 gene mutation encoding multidrug resistance type III (MDR3) protein. Upon resection of the pituitary adenoma, the hepatic biochemical abnormalities gradually improved. This case highlights that heterozygous ABCB4 defect may represent a genetic predisposition for nongenetic factors such as hormones or other metabolites to decrease normal MDR3 allele expression. It is known to act as a modifier gene and possibly played a role in the development of cholestatic hepatitis and cholelithiasis, in the presence of excess cortisol secondary to Cushing's disease in our patient.

Prevalence of vitamin D insufficiency in survivors of childhood cancer.

BACKGROUND: Data on 25-hydroxyvitamin D (25-OH D) status among survivors of childhood cancer are limited. Our aim was to determine the prevalence of and risk factors for 25-OH D insufficiency in a large, diverse population of cancer survivors being followed in a childhood cancer survivor clinic. PROCEDURE: Retrospective chart review in survivors seen for routine long-term follow-up, who underwent routine screening blood studies including 25-OH D levels. Vitamin D insufficiency was defined as 25-OH D <20 ng/ml. RESULTS: Four hundred eighty-four subjects (234 males) were evaluable for this analysis. Median age at 25-OH D testing was 12.3 years (2.05-36.4) and median age at cancer diagnosis was 3.9 years (0-18). Diagnoses included brain tumors (23.6%), neuroblastoma (21%), and leukemia (17.6%). Mean 25-OH D level was 25.2 ng/ml (SD = 10.37); 29% of subjects were 25-OH D insufficient. In univariate analysis, race, pubertal status, and age at cancer diagnosis were associated with 25-OH D insufficiency (P < 0.05). In multivariate analysis, a model including race and pubertal status provided a good fit for the data. CONCLUSIONS: The prevalence of 25-OH D insufficiency in these cancer survivors was high but similar to what has been described in the general population. No cancer specific variables were associated with 25-OH D insufficiency. Since cancer survivors are at a higher risk for subsequent malignancies, cardiovascular disease, and low bone mineral density, all of which may be affected by 25-OH D levels, interventions to improve 25-OH D status in this vulnerable population are needed.

TraR, a homolog of a RNAP secondary channel interactor, modulates transcription.

Recent structural and biochemical studies have identified a novel control mechanism of gene expression mediated through the secondary channel of RNA Polymerase (RNAP) during transcription initiation. Specifically, the small nucleotide ppGpp, along with DksA, a RNAP secondary channel interacting factor, modifies the kinetics of transcription initiation, resulting in, among other events, down-regulation of ribosomal RNA synthesis and up-regulation of several amino acid biosynthetic and transport genes during nutritional stress. Until now, this mode of regulation of RNAP was primarily associated with ppGpp. Here, we identify TraR, a DksA homolog that mimics ppGpp/DksA effects on RNAP. First, expression of TraR compensates for dksA transcriptional repression and activation activities in vivo. Second, mutagenesis of a conserved amino acid of TraR known to be critical for DksA function abolishes its activity, implying both structural and functional similarity to DksA. Third, unlike DksA, TraR does not require ppGpp for repression of the rrnB P1 promoter in vivo and in vitro or activation of amino acid biosynthesis/transport genes in vivo. Implications for DksA/ppGpp mechanism and roles of TraR in horizontal gene transfer and virulence are discussed.

Prevalence of anaemia among adolescent girls in the urban slums of Vellore, south India.

A community-based, cross-sectional study was conducted to determine the prevalence of anaemia among unmarried, adolescent south Indian girls in an urban slum setting. A total of 100 apparently healthy girls between the ages of 11 and 18 years were recruited. Their socioeconomic, dietary and anthropometric information was collected, and blood haemoglobin (Hb) was estimated. The prevalence of anaemia (Hb < 12 g%) was 29%. Most had mild anaemia; severe anaemia was not seen. Two-thirds of those with anaemia had low serum ferritin (<12 microg/L). Significant associations were observed between anaemia and low socioeconomic status, religion and reporting infrequent/non-consumption of meat (heme iron). Only meat consumption was related to haemoglobin by multiple regression analysis. Anaemia is a common problem among adolescent girls in this setting, though severe anaemia is rare. There is a need to improve their haemoglobin status through dietary modification along with preventive supplementation and nutrition education.