An "out of the box" approach for prevention of ketoacidosis in youth with poorly controlled type 1 diabetes: combined use of insulin pump and long-acting insulin.

BACKGROUND: Poorly controlled adolescents living with type 1 diabetes (T1D) and pump failure of insulin delivery leading to diabetic ketoacidosis (DKA) are still challenging in the western world. AIM: To investigate the effect of a combination modality of long-acting insulin for basal coverage and a pump for boluses, on the incidence of DKA and glycemic parameters in pediatric and young adults with poorly controlled T1D. METHODS: This multicenter, observational retrospective study included 55 patients (age range 3-25 years, 52.7% males) who were treated with the combination modality for a median of 18 months [(IQR)12,47], as part of their clinical care. Data were retrieved at initiation of the combined modality, after 6 months, and at last visit. RESULTS: Cohort's median age at combination modality initiation was 14.5 years [IQR12.4,17.3], and its median HbA1c level was 9.2% [IQR 8.2,10.2]. The main reasons for combination modality initiation were: (a) concern about sustained hyperglycemia on current management in 41.8%, (b) previous DKA episodes in 30.8%, and (c) refusal to wear a pump continuously in 14.6%. The percent of patients experiencing DKA who used the modality till end decreased from 25.4 to 8.8%. The frequency of DKA events per patient month decreased after 6 months from 0.073 (min 0, max 0.5) to 0.020 (min 0, max 0.5), p = 0.01, and at end to 0.016 (min 0, max 0.25), p = 0.007. CONCLUSIONS: The combination modality of once-daily long-acting insulin and pump for boluses is safe, feasible, and effective in preventing DKA among poorly controlled young people living with T1D, unable or un-willing to use advanced closed pumps.

Predictive factors for radiation-induced pituitary damage in pediatric patients with brain tumors.

BACKGROUND AND PURPOSE: Multiple studies demonstrated hypothalamic-pituitary dysfunction in survivors of pediatric brain tumors. However, few studies investigated the trajectories of pituitary height in these patients and their associations with pituitary function. We aimed to evaluate longitudinal changes of pituitary height in children and adolescents with brain tumors, and their association with endocrine deficiencies. MATERIALS AND METHODS: We conducted a retrospective analysis of 193 pediatric patients (54.9% male) diagnosed with brain tumors from 2002 to 2018, with a minimum of two years of radiological follow-up. Pituitary height was measured using MRI scans at diagnosis and at 2, 5, and 10 years post-diagnosis, with clinical data sourced from patient charts. RESULTS: Average age at diagnosis was 7.6 ± 4.5 years, with a follow-up of 6.1 ± 3.4 years. 52.8% underwent radiotherapy and 37.8% experienced pituitary hormone deficiency. Radiation treatment was a significant predictor of decreased pituitary height at all observed time points (p = 0.016, p < 0.001, p = 0.008, respectively). Additionally, chemotherapy (p = 0.004) or radiotherapy (p = 0.022) history and pituitary height at 10 years (p = 0.047) were predictors of endocrine deficiencies. ANOVA revealed an expected increase in pituitary height over time in pediatric patients, but this growth was significantly impacted by radiation treatment and gender (p for interaction = 0.005 and 0.025, respectively). CONCLUSION: Cranial irradiation in pediatric patients is associated with impairment of the physiologic increase in pituitary size; in turn, decreased pituitary height is associated with endocrine dysfunction. We suggest that pituitary gland should be evaluated on surveillance imaging of pediatric brain tumor survivors, and if small for age, clinical endocrine evaluation should be pursued.

Virtual reality's impact on children with type 1 diabetes: a proof-of-concept randomized cross-over trial on anxiety, pain, adherence, and glycemic control.

AIMS:  Assess the effectiveness of virtual reality (VR) technology, in reducing pain and anxiety, and improving adherence and glycemic control among children with type 1 diabetes (T1D). METHODS: Children with T1D, managed with continuous glucose monitoring and insulin pumps, were recruited for a randomized cross-over trial. Children were randomized to one of two interventions for diabetes management: group 1 used VR glasses first and group 2 listened to vocal-guided affective imagery first (audio). After 1 month, the interventions were crossed over. The outcome measures included pain and anxiety assessment, adherence, glycemic control, and patient-reported outcome measures (PROMs) of VR satisfaction and effectiveness. RESULTS:  Forty children, mean age 11.4 ± 1.8 years, were participated. During the VR part, the monthly mean pain score compared to the baseline improved in both groups by 30% (p = 0.03). A 14% reduction in the state anxiety score was observed from baseline to 1 month in both groups (p = 0.009). Glycemic control measures including time in range, time above range, and glucose management indicator improved in both groups during VR part (p < 0.004 for all), compared to audio part. After one month, the patient-reported outcome measure (PROM) of satisfaction and effectiveness was sixfold higher after 1 month in group 1 compared to group 2 (p = 0.002). Adherence improved for both groups. CONCLUSIONS: VR was shown to be effective in reducing pain and anxiety, improving adherence, PROM, and glycemic control among children with T1D. We suggest incorporating VR technology in pediatric diabetes clinics to facilitate and improve coping and management of diabetes. TRIAL REGISTRATION: Trial registration number and date of registration for prospectively registered trials:ClinicalTrials.gov Identifier: NCT05883267, May 10th, 2023.

Impact of COVID-19 on Lifestyle Habits and Emotional State of Childhood Cancer Survivors and Their Parents.

OBJECTIVE: The COVID-19 pandemic and associated social distancing measures affected the physical and emotional state of children and parents worldwide. Survivors of childhood cancer may be particularly vulnerable to these effects. We aimed to evaluate the lifestyle habits and emotional states of childhood cancer survivors and their parents during the COVID-19 outbreak. METHODS: Lifestyle habits and emotional distress were assessed in 43 childhood cancer survivors (aged 8-21 years) and their parents before and during the COVID-19 lockdown, using the PROMIS anxiety and depression modules and the "Mabat Youth" questionnaire. RESULTS: Most parents (80.5%) reported eating more family meals during home confinement compared to their usual routine. Patients' physical activity levels did not change significantly during confinement, leisure-related screen time nearly doubled (p < 0.001), and sleep duration increased (p = 0.006). Anxiety levels of children (p = 0.045) and parents (p = 0.02) increased during confinement compared to pre-pandemic levels, with no significant changes in depression levels. CONCLUSIONS: Contrary to concerns regarding lifestyle habits during the COVID-19 lockdown, eating behaviors of childhood cancer survivors improved, sleep duration increased, and physical activity remained unchanged. Still, screen time increased significantly. Parents of childhood cancer survivors reported higher anxiety levels for themselves and their children during home confinement. Our findings may assist medical and psycho-social teams in guiding parents of cancer survivors during similar circumstances in the future.

Hypothalamic-pituitary-gonadal function, pubertal development, and fertility outcomes in male and female medulloblastoma survivors: a single-center experience.

BACKGROUND: Endocrine deficiencies, including hypothalamic-pituitary-gonadal axis (HPGA) impairment, are common in survivors of childhood and adolescent medulloblastoma. Still, data regarding pubertal development and fecundity are limited, and few studies assessed HPGA function in males. We aimed to describe HPGA function in a large cohort of patients with medulloblastoma. METHODS: A retrospective study comprising all 62 medulloblastoma patients treated in our center between 1987 and 2021, who were at least 2 years from completion of therapy. HPGA function was assessed based on clinical data, biochemical markers, and questionnaires. RESULTS: Overall, 76% of female patients had clinical or biochemical evidence of HPGA dysfunction. Biochemical evidence of diminished ovarian reserve was seen in all prepubertal girls (n = 4). Among the males, 34% had clinical or biochemical evidence of gonadal dysfunction, 34% had normal function, and 29% were age-appropriately clinically and biochemically prepubertal. The difference between males and females was significant (P = .003). Cyclophosphamide-equivalent dose was significantly associated with HPGA function in females, but not in males. There was no association between HPGA dysfunction and other endocrine deficiencies, length of follow-up, weight status, and radiation treatment protocol. Two female and 2 male patients achieved successful pregnancies, resulting in 6 live births. CONCLUSIONS: HPGA dysfunction is common after treatment for childhood medulloblastoma. This is seen more in females, likely due to damage to the ovaries from spinal radiotherapy. Our findings may assist in counseling patients and their families regarding risk to future fertility and need for fertility preservation.

Dual diagnosis of type 1 diabetes mellitus and attention deficit hyperactivity disorder.

BACKGROUND: Data regarding glycemic control in children and adolescents with a dual diagnosis of type 1 diabetes mellitus (T1DM) and attention-deficit/hyperactivity disorder (ADHD) are limited. OBJECTIVE: To compare various aspects of diabetes control among youth with T1DM, between those with and without ADHD. METHODS: In this cross-sectional study of youth with T1DM, 39 had ADHD (mean age 14.1 ± 2.8 years) and 82 did not (control group, mean age 12.6 ± 3.3 years). Health-related quality of life was assessed by a Diabetes Quality of Life (DQOL) questionnaire submitted to their parents. Glycemic data were downloaded from glucometers, pumps, and continuous glucose monitoring systems. HbA1c levels, hospitalizations, and severe hypoglycemic and diabetes ketoacidosis events were retrieved from the medical files. RESULTS: Compared to the control group mean HbA1c level of the ADHD group was higher: 8.3 ± 1.1% versus 7.7 ± 1.0% (p = 0.005) and the percent of time that glucose level was in the target range (70-180 mg/dl) was lower: 48 ± 17% versus 59 ± 14% (p = 0.006). Mean glucose and glucose variability were higher in the ADHD group. Youth with ADHD who were not pharmacologically treated had worse HbA1c and more hospitalizations than those who were treated. DQOL did not differ between the control group, the treated ADHD group, and the untreated ADHD-Group. CONCLUSIONS: Dual diagnosis of T1DM and ADHD during childhood leads to worse diabetes control, which is more pronounced in the context of untreated ADHD. Healthcare providers should be aware of the difficulties facing youth with T1DM and ADHD in coping with the current intensive treatment of diabetes.

Adolescent Nonalcoholic Fatty Liver Disease and Type 2 Diabetes in Young Adulthood.

CONTEXT: The long-term risk of type 2 diabetes in adolescents with nonalcoholic fatty liver disease (NAFLD) is unclear. OBJECTIVE: To assess type 2 diabetes risk among adolescents with NAFLD. DESIGN AND SETTING: A nationwide, population-based study of Israeli adolescents who were examined before military service during 1997-2011 and were followed until December 31, 2016. PARTICIPANTS: A total of 1 025 796 normoglycemic adolescents were included. INTERVENTIONS: Biopsy or radiographic tests were prerequisite for NAFLD diagnosis. Data were linked to the Israeli National Diabetes Registry. MAIN OUTCOME MEASURES: Type 2 diabetes incidence. RESULTS: During a mean follow-up of 13.3 years, 12 of 633 adolescents with NAFLD (1.9%; all with high body mass index [BMI] at baseline) were diagnosed with type 2 diabetes compared with 2917 (0.3%) adolescents without NAFLD. The hazard ratio (HR) for type 2 diabetes was 2.59 (95% confidence interval [CI], 1.47-4.58) for the NAFLD vs. the non-NAFLD group after adjustment for BMI and sociodemographic confounders. The elevated risk persisted in several sensitivity analyses. These included an analysis of persons without other metabolic comorbidities (adjusted HR, 2.75 [95% CI, 1.48-5.14]) and of persons with high BMI; and an analysis whose outcome was type 2 diabetes by age 30 years (adjusted HR, 2.14 [95% CI, 1.02-4.52]). The results remained significant when a sex-, birth year-, and BMI-matched control group was the reference (adjusted HR, 2.98 [95% CI, 1.54-5.74]). CONCLUSIONS: Among normoglycemic adolescents, NAFLD was associated with an increased adjusted risk for type 2 diabetes, which may be apparent before age 30 years.

Primary Ovarian Insufficiency Nationwide Incidence Rate and Etiology Among Israeli Adolescents.

PURPOSE: The aim of the study was to estimate the current incidence and the distribution of etiologies of primary ovarian insufficiency (POI) in a nationwide study. The prevalence of POI in young adult women has recently increased, but the data cited for adolescents are more than three decades old. METHODS: Data regarding females aged <21 years diagnosed with POI during the years 2000-2016 were collected from all the pediatric endocrinology units in Israel. POI was defined by at least 4 months of amenorrhea in association with menopausal levels of follicle-stimulating hormone. Iatrogenic cases were excluded. RESULTS: For the 130 females aged <21 years included in the study, the distribution of POI etiologies was Turner syndrome/mosaicism in 56 (43%), idiopathic in 35 (27%), and other (developmental, genetic, metabolic, adrenal, and autoimmune) in 39 (30%) females. During the years 2009-2016, compared with 2000-2008, the incidence rate of new POI diagnoses per 100,000 person-years doubled (4.5 vs. 2.0; p value <.0001), and incidence rates of idiopathic and other etiologies increased by 2.6 (p value = .008) and 3.0 (p value = .002), respectively. In contrast, the incidence of Turner syndrome was constant (p value = .2). In the age group of 15-21 years, the current incidence of non-Turner POI in adolescents is one per 100,000 person-years. CONCLUSIONS: In this nationwide study, the incidence rate of POI in youth aged <21 years was one tenth of the rate that is commonly cited. A significant increase in the rate of POI in non-Turner females was observed over the last decade. Contributions of environmental and epigenetic factors should be studied.

High prevalence of attention-deficit/hyperactivity disorder in adolescents with severe obesity seeking bariatric surgery.

AIM: To examine the prevalence of attention-deficit/hyperactivity disorder (ADHD) and related post-surgical weight loss in adolescents with severe obesity seeking bariatric surgery. METHODS: The study population included 84 adolescents (age 13-19 years; 44 males, 40 females) with severe obesity who sought bariatric surgery at the Sheba Medical Centre in Israel during the years 2011-2017. Anthropometric and clinical data were collected from medical records. A subgroup of 20 participants filled questionnaires that evaluated ADHD-like symptoms, eating behaviours and quality of life. Data on adolescents that ultimately underwent surgery (n = 45) were also obtained. RESULTS: The prevalence of ADHD was 28.6% in adolescents seeking bariatric surgery, much higher than that of the general adolescent population of Israel (17.1%, P < .001). There were no significant differences in reductions of weight, body mass index, body mass index standard deviation scores and body fat percent between participants with or without ADHD. In the subgroup that filled questionnaires, higher scores on ADHD-Rating Scale at baseline were associated with greater excess weight loss. CONCLUSION: The prevalence of ADHD in adolescents seeking bariatric surgery was very high. Diagnosed ADHD was not related to post-surgical weight loss, whereas baseline ADHD-related behaviour was associated with higher post-surgical weight loss.

Klotho response to treatment with growth hormone and the role of IGF-I as a mediator.

CONTEXT: Klotho is an aging-modulating protein expressed mainly in the kidneys, which can be cleaved and shed to act as a circulating hormone. Several lines of evidence suggest a tight interaction between klotho and the GH-IGF-I axis. We showed previously that klotho levels are decreased in pediatric patients with growth hormone deficiency (GHD). Our aim now is to investigate the effect of GH therapy on klotho levels in these patients and to elucidate the role of IGF-1 in mediating secretion of klotho. BASIC PROCEDURES: Klotho levels were measured in 29 GHD pediatric patients (males=15, aged 12.2±3.3years), treated with GH for 2.5±2.8years; nineteen patients had samples obtained both before and during treatment. The effect of IGF-I and its downstream effectors on secretion of klotho to media was studied in COS-7 cells overexpressing klotho. MAIN FINDINGS: Klotho levels increased under GH treatment (from 1321±691pg/ml to 3380±2120pg/ml, p<0.001), and were higher compared to controls (1645±778pg/ml, p<0.001), resulting in supraphysiological levels. Fold-increase in klotho correlated with fold-increase in IGF-I (r=0.63, p=0.004). Studies in COS-7 cells overexpressing klotho revealed mTOR-dependent induction of klotho shedding by IGF-I. PRINCIPAL CONCLUSIONS: Klotho levels increased during GH treatment of pediatric GHD patients. This increase was associated with an increase in IGF-I levels. Furthermore, we showed, for the first time, a direct role of IGF-I in the regulation of klotho's shedding which depends on activation of the AKT-mTOR pathway. Our findings add further support for the close association between klotho and the GH/IGF-I axis.

Alpha-1 antitrypsin therapy is safe and well tolerated in children and adolescents with recent onset type 1 diabetes mellitus.

BACKGROUND AND OBJECTIVES: Alpha-1 antitrypsin (AAT) has been shown to reduce pro-inflammatory markers and protect pancreatic islets from autoimmune responses in recent studies. Our aim was to evaluate its safety and tolerability in three different doses, in a pediatric population with recent onset type 1 diabetes mellitus (T1DM). METHODS: A 37-wk prospective, open-label, phase I/II interventional trial, comprised of 24 recently diagnosed subjects (12 males; age 12.9 ± 2.4 yr), who received 18 infusions of 40, 60, or 80 mg/kg/dose high-purity, liquid, ready to use AAT over 28 wk (Glassia(®) ; Kamada Ltd., Ness Ziona, Israel). PRIMARY OUTCOMES: safety and tolerability; secondary outcomes: glycemic control, C-peptide reserve, and autoantibody levels. Possible responders were defined as individuals with peak C-peptide that declined less than 7.5% below baseline. RESULTS: No serious adverse events, diabetic ketoacidosis (DKA), or severe hypoglycemic episodes were reported. Adverse events were dose-independent and transient. Glycemic control parameters improved during the study in all groups, independent of dosage. Hemoglobin A1c (HbA1c) decreased from 8.43 to 7.09% (mean, p < 0.001). At the end of the study, 18 subjects (75%) had a peak C-peptide ≥0.2 pmol/mL. Eight subjects (33.3%) were considered possible responders and were characterized by shorter duration of T1DM at screening (54.5 ± 34.3 vs. 95.9 ± 45.7 d, p = 0.036) and greater decrease in their HbA1c during the study period (-2.94 ± 1.55 vs.-0.95 ± 1.83%, p = 0.016). CONCLUSIONS: AAT treatment was safe and well tolerated in pediatric subjects with recently diagnosed autoimmune diabetes. Placebo-controlled studies with larger cohorts and dose range are warranted in order to assess efficacy in maintaining pancreatic beta cell reserve and glycemic control.

Body composition changes in adolescents after laparoscopic sleeve gastrectomy.

BACKGROUND: Sleeve gastrectomy (SG) is a commonly used bariatric procedure in severely obese adolescents. Weight loss after SG is associated with marked changes in body composition, but factors associated with such changes have not yet been described in adolescents. OBJECTIVE: To identify factors associated with changes in body weight and composition in adolescents 1 year after SG. SETTING: University Hospital, Tel Hashomer, Israel. METHODS: Age, sex, weight, height, preoperative body mass index (BMI), and body fat percent measured by bioimpedance were collected in 25 adolescents (16 males, 9 females, age 16.6±1.5 yr) before and 1 year after SG. Obesity-related complications, preoperative weight loss, and physical activity after surgery were also recorded. Repeated-measures analyses of variance and linear mixed model analyses were performed. RESULTS: One year after SG, weight decreased by 32%, fat mass by 55%, and fat-free mass by 9% from baseline. Male participants lost significantly more weight than female participants, with larger decreases in fat mass (-65% versus -41%, P<.001) and body fat percent (-48% versus -21%, P<.001). The amount of physical activity at 1-year follow-up was also associated with larger reductions in body fat percent in both genders. Age or baseline BMI, fat mass, and fat-free mass were not associated with changes in BMI or body composition. CONCLUSION: Among obese adolescents 1 year after SG, the only modifiable factor associated with larger decreases in body fat percent was physical activity. Larger studies are needed to formally identify other possible predictors of body composition changes after SG.

Sun Exposure and Protection Habits in Pediatric Patients with a History of Malignancy.

BACKGROUND: Survivors of childhood cancer are at high risk for developing non-melanoma skin cancer and therefore are firmly advised to avoid or minimize sun exposure and adopt skin protection measures. We aimed to compare sun exposure and protection habits in a cohort of pediatric patients with a history of malignancy to those of healthy controls. METHODS: Case-control study of 143 pediatric patients with a history of malignancy (aged 11.2±4.6 y, Male = 68, mean interval from diagnosis 4.4±3.8 y) and 150 healthy controls (aged 10.4±4.8 y, Male = 67). Sun exposure and protection habits were assessed using validated questionnaires. RESULTS: Patients and controls reported similar sun exposure time during weekdays (94±82 minutes/day vs. 81±65 minutes/day; p = 0.83), while during weekends patients spent significantly less time outside compared to controls (103±85 minutes/day vs. 124±87 minutes/day; p = 0.02). Time elapsed from diagnosis positively correlated with time spent outside both during weekdays (r = 0.194, p = 0.02) and weekends (r = 0.217, p = 0.01), and there was a step-up in sun exposure starting three years after diagnosis. There was no significant difference regarding composite sun protection score between patients and controls. Age was positively correlated with number of sunburns per year and sun exposure for the purpose of tanning, and was negatively correlated with the use of sun protection measures. CONCLUSIONS: Although childhood cancer survivors are firmly instructed to adopt sun protection habits, the adherence to these instructions is incomplete, and more attention should be paid to improve these habits throughout their lives. Since sunlight avoidance may results in vitamin D deficiency, dietary supplementation will likely be needed.

Association between decreased klotho blood levels and organic growth hormone deficiency in children with growth impairment.

OBJECTIVE: Klotho is an aging-modulating protein expressed mainly in the kidneys and choroid plexus, which can also be shed, released into the circulation and act as a hormone. Klotho deficient mice are smaller compared to their wild-type counterparts and their somatotropes show marked atrophy and reduced number of secretory granules. Recent data also indicated an association between klotho levels and growth hormone (GH) levels in acromegaly. We aimed to study the association between klotho levels and GH deficiency (GHD) in children with growth impairment. DESIGN: Prospective study comprising 99 children and adolescents (aged 9.0 ± 3.7 years, 49 male) undergoing GH stimulation tests for short stature (height-SDS = -2.1 ± 0.6). Klotho serum levels were measured using an α-klotho ELISA kit. RESULTS: Klotho levels were significantly lower (p<0.001) among children with organic GHD (n = 11, 727 ± 273 pg/ml) compared to both GH sufficient participants (n = 59, 1497 ± 754 pg/ml) and those with idiopathic GHD (n = 29, 1645 ± 778 pg/ml). The difference between GHS children and children with idiopathic GHD was not significant. Klotho levels positively correlated with IGF-1- standard deviation scores (SDS) (R = 0.45, p<0.001), but were not associated with gender, pubertal status, age or anthropometric measurements. CONCLUSIONS: We have shown, for the first time, an association between low serum klotho levels and organic GHD. If validated by additional studies, serum klotho may serve as novel biomarker of organic GHD.

Advanced bone age and hyperinsulinemia in overweight and obese children.

OBJECTIVE: In obese children, bone age (BA) tends to significantly exceed chronological age (CA). In vitro studies in mice suggest that insulin may directly modulate skeletal growth. We investigated whether there is an association between fasting insulin and BA maturation in obese children. METHODS: The study cohort comprised 74 overweight and obese children ages 4 to 13 years. BA divided by CA was used as an index for bone advancement. Participants were classified into tertiles based on their BA:CA ratio. Advanced BA maturation was defined as the third tertile, with BA:CA > 1.21. Components of the metabolic syndrome, including fasting insulin, fasting glucose, triglycerides, and high-density lipoprotein (HDL) levels, were measured. RESULTS: Children with advanced BA were significantly younger, had a higher body mass index (BMI)-Z score (BMI-Z), and were taller than children with bone advancement in the lower tertiles. Females had a 4.7-fold increased risk for advanced BA compared with males (95% confidence interval [CI], 1.29-17.1; P = .02). Children with a BMI-Z ≥ 1.96 and fasting insulin ≤ 30 µU/L had a 3.6-fold increased risk of advanced BA (95% CI, 1.00-12.8; P = 0.05). Moreover, hyperinsulinemia (fasting insulin > 30 µU/L) was associated with a 6.8-fold increased risk for advanced BA, independent of the degree of obesity (95% CI, 1.45-32.1; P = .01). CONCLUSION: Marked hyperinsulinemia is associated with advanced BA in obese children. Insulin appears to modulate skeletal growth in humans.