Outcomes of BRCA pre-implantation genetic testing according to the parental mutation origin: a cohort study.

BACKGROUND: The process of gamete formation and early embryonic development involves rapid DNA replication, chromosome segregation and cell division. These processes may be affected by mutations in the BRCA1/2 genes. The aim of this study was to evaluate BRCA mutation inheritance and its effect on early embryonic development according to the parental origin of the mutation. The study question was approached by analyzing in vitro fertilization cycles (IVF) that included pre-implantation testing (PGT-M) for a BRCA gene mutation. METHODS: This retrospective cohort study compared cycles of pre-implantation genetic testing for mutations (PGT-M) between male and female patients diagnosed with BRCA 1/2 mutations (cases), to a control group of two other mutations with dominant inheritance (myotonic dystrophy (MD) and polycystic kidney disease (PKD)). Results were compared according to mutation type and through a generalized linear model analysis. RESULTS: The cohort included 88 PGT-M cycles (47 BRCA and 41 non-BRCA) among 50 patients. Maternal and paternal ages at oocyte retrieval were comparable between groups. When tested per cycle, FSH dose, maximum estradiol level, oocytes retrieved, number of zygotes, and number of embryos available for biopsy and affected embryos, were not significantly different among mutation types. All together 444 embryos were biopsied: the rate of affected embryos was comparable between groups. Among BRCA patients, the proportion of affected embryos was similar between maternal and paternal mutation origin (p = 0.24). In a generalized linear model analysis, the relative oocyte yield in maternal BRCA patients was significantly lower (0.7, as related to the non BRCA group)(p < 0.001). Zygote formation and blastulation were not affected by the BRCA gene among paternal cases (P = 0.176 and P = 0.293 respectively), nor by paternal versus maternal BRCA carriage (P = 0.904 and P = 0.149, respectively). CONCLUSIONS: BRCA PGT-M cycles performed similarly compared to non-BRCA cycles. Inheritance rate and cycle parameters were not affected by the parental origin of the mutation.

Youth-onset type 2 diabetes in Israel: A national cohort.

BACKGROUND: Prevalence of youth-onset type 2 diabetes (T2D) has increased worldwide, paralleling the rise in pediatric obesity. Occurrence and clinical manifestations vary regionally and demographically. OBJECTIVES: We assessed the incidence, and clinical and demographic manifestations of youth-onset T2D in Israel. METHODS: In a national observational study, demographic, clinical, and laboratory data were collected from the medical records of children and adolescents, aged 10-18 years, diagnosed with T2D between the years 2008 and 2019. RESULTS: The incidence of youth-onset T2D in Israel increased significantly from 0.63/100,000 in 2008 to 3.41/100,000 in 2019. The study cohort comprised 379 individuals (228 girls [59.7%], 221 Jews [58.3%], mean age 14.7 ± 1.9 years); 73.1% had a positive family history of T2D. Mean body mass index (BMI) z-score was 1.96 ± 0.7, higher in Jews than Arabs. High systolic (≥ 130 mmHg) and diastolic blood pressure (≥ 85 mmHg) were observed in 33.7% and 7.8% of patients, respectively; mean glycosylated hemoglobin (A1c) level at diagnosis was 8.8 ± 2.5%. Dyslipidemia, with high triglyceride (>150 mg/dl) and low HDL-c (<40 mg/dl) levels, was found in 45.6% and 56.5%, respectively. Microalbuminuria and retinopathy were documented at diagnosis, 15.2% and 1.9%, respectively) and increased (36.7% and 4.6%, respectively) at follow-up of 2.9 ± 2.1 years. Criteria of metabolic syndrome were met by 224 (62.2%) patients, and fatty liver documented in 65%, mainly Jews. Psychosocial comorbidity was found in 31%. Treatment with metformin (45.6%), insulin (20.6%), and lifestyle modification (18%) improved glycemic control. CONCLUSION: Youth-onset T2D in Israel has increased significantly and presents a unique profile.

Alarming increase in ketoacidosis in children and adolescents with newly diagnosed type 1 diabetes during the first wave of the COVID-19 pandemic in Israel.

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.

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.

The impact of a daily smartphone-based feedback system among women with gestational diabetes on compliance, glycemic control, satisfaction, and pregnancy outcome: a randomized controlled trial.

BACKGROUND: Patient compliance and tight glycemic control have been demonstrated to improve outcome in pregnancies complicated by gestational diabetes mellitus. The use of advanced technological tools, including smartphone-based platforms, to improve medical care and outcomes has been demonstrated in various fields of medicine, but only a few small studies were performed with gestational diabetes mellitus patients. OBJECTIVE: We aimed to study the impact of introducing a smartphone-based daily feedback and communication platform between gestational diabetes mellitus patients and their physicians, on patient compliance, glycemic control, pregnancy outcome, and patient satisfaction. STUDY DESIGN: This is a prospective, single-center, randomized controlled trial. Newly diagnosed gestational diabetes mellitus patients presenting to our multidisciplinary diabetes-in-pregnancy clinic were randomized to: (1) routine biweekly prenatal clinic care (control group); or (2) additional daily detailed feedback on their compliance and glycemic control from the clinic team via an application installed on their smartphone (smartphone group). The primary outcome was patient compliance defined as the actual blood glucose measurements/instructed measurements ×100. The secondary outcomes included diabetes-control parameters, pregnancy, and neonatal outcomes. The study was adequately powered to detect a 20% difference in patient compliance, based on a preliminary phase that demonstrated 70% baseline compliance to glucose measurements. RESULTS: A total of 120 newly diagnosed gestational diabetes mellitus patients were analyzed. The 2 groups did not differ in terms of age, parity, education, body mass index, family history, maternal comorbidities, oral glucose tolerance test values, and hemoglobin A1C at randomization. The smartphone group demonstrated higher level of compliance (84 ± 0.16% vs 66 ± 0.28%, P < .001); lower mean blood glucose (105.1 ± 8.6 mg/dL vs 112.6 ± 7.4 mg/dL, P < .001); lower rates of off-target measurements both fasting (4.7 ± 0.4% vs 8.4 ± 0.6%, P < .001) and 1-hour postprandial (7.7 ± 0.8% vs 14.3 ± 0.8%, P < .001); and a lower rate of pregnancies requiring insulin treatment (13.3% vs 30.0%, P = .044). The rates of macrosomia, neonatal hypoglycemia, shoulder dystocia, and other delivery and neonatal complications did not differ between the groups. Patients in the smartphone group reported excellent satisfaction from the use of the application and from their overall prenatal care. CONCLUSION: Introduction of a smartphone-based daily feedback and communication platform between gestational diabetes mellitus patients and the multidisciplinary diabetes-in-pregnancy clinic team improved patient compliance and glycemic control, and lowered the rate of insulin treatment.

A comparison of the usage of an open-source automated insulin delivery system and the MiniMed™ 780 G system in children and adolescents with type 1 diabetes in real-world settings: the AWeSoMe study group.

PURPOSE: In recent years there has been a noticeable increase in the use of advanced hybrid closed-loop systems (AHCLs) for managing type 1 diabetes (T1D) among youth. However, there is a lack of comparison between the open-source automated insulin delivery (AID) system and the MiniMed™ 780 G system (780 G). METHODS: In this multi-center study, we retrospectively compared selected glycemic ranges of 26 individuals who used open-source AID and 20 individuals who used 780 G (age 11.3 years [IQR 9.3, 12.9] and 13.4 years [IQR 10.9, 16.5], respectively, p = 0.069) from system initiation to the most recent visit. RESULTS: At baseline, the median HbA1c was significantly lower and the time below range (TBR)<54mg/dL was significantly higher in the open-source AID group compared to the 780 G group (6.8% [IQR 6.4, 7.1] vs. 7.4% [IQR 6.9, 8.6], p = 0.006 and (1.0% [IQR 0.5, 2.8] vs. 0.0% [0.0, 1.0], p = 0.014), respectively; the median time in range (TIR70-180mg/dL) was similar (p = 0.068). After a median duration of 10.9 months on AHCLs the reduction of HbA1c was similar ( ~ 0.3%). The time spent in the hypoglycemic ranges was longer among users of the open-source AID compared to 780 G (TBR54-70mg/dL 4.2% [IQR 2.6, 7.3] vs. 2.0% [1.0, 4.0], p = 0.005) and TBR<54mg/dL 1.1% [IQR 0.4, 2.3] vs. 0.0 [0.0, 1.0], p = 0.001). CONCLUSIONS: Both AHCLs similarly improved HbA1c and TIR70-180mg/dL. The open-source AID youth had better glycemic control but spent longer time in the hypoglycemic range. These findings must be considered when choosing the use of AHCL technologies.

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.

Real-Life Achievements of MiniMed 780G Advanced Closed-Loop System in Youth with Type 1 Diabetes: AWeSoMe Study Group Multicenter Prospective Trial.

Background: We assessed real-life glycemic outcomes and predictors of composite measures of optimal glycemic control in children and adolescents with type 1 diabetes (T1D) during their initial 12 months of the MiniMed™ 780G use. Methods: This prospective observational multicenter study collected demographic, clinical, and 2-week 780G system data at five time points. Optimal glycemic control was defined as a composite glycemic control (CGC) score requiring the attainment of four recommended continuous glucose monitoring (CGM) targets, as well as the glycemia risk index (GRI) of hypoglycemia and hyperglycemia and composite CGM index (COGI). Outcome measures included longitudinal changes in multiple glycemic parameters and CGC, GRI, and COGI scores, as well as predictors of these optimal measures. Results: The cohort included 93 children, 43% girls, with a median age of 15.1 years (interquartile range [IQR] 12.9,17.0). A longitudinal analysis adjusted for age and socioeconomic index yielded a significant improvement in glycemic control for the entire cohort (ptime < 0.001) after the transition to 780G. The mean hemoglobin A1c (HbA1c) (SE) was 8.65% (0.12) at baseline and dropped by >1% after 1 year to 7.54% (0.14) (ptime < 0.001). Optimal glycemic control measures improved at 12 months post 780G; CGC improved by 5.6-fold (P < 0.001) and was attained by 24% of the participants, the GRI score improved by 10-fold (P = 0.009) and was achieved by 10% of them, and the COGI improved by 7.6-fold (P < 0.001) and was attained by 20% of them. Lower baseline HbA1c levels and increased adherence to Advanced Hybrid Closed-Loop (AHCL) usage were predictors of achieving optimal glycemic control. Conclusions: The AHCL 780G system enhances glycemic control in children and adolescents with T1D, demonstrating improvements in HbA1c and CGM metrics, albeit most participants did not achieve optimal glycemic control. This highlights yet ongoing challenges in diabetes management, emphasizing the need for continued proactive efforts on the part of health care professionals, youth, and caregivers.

MiniMed 780G Advanced Hybrid Closed-Loop System Outcomes According to Pubertal Status: Awesome Study Group Real-Life Experience.

Background and Aims: Achieving good glycemic control is a major challenge for adolescents with type 1 diabetes (TID). The introduction of the MiniMed 780G system, an advanced hybrid closed-loop (AHCL) that enables an automatic correction of insulin, gave hope for improved glycemic outcomes in adolescents. We assessed specific characteristics associated with glycemic measures in youth with T1D switching to Minimed 780G. Methods: This retrospective observational real-life multicenter study from the AWeSoMe Group assessed continuous glucose monitoring (CGM) metrics of 22 patients (59% females, median age 13.9 interquartile range [IQR 11,18] years), from a high socioeconomic background. CGM metrics were recorded for 2-week periods before AHCL, after 1, 3, 6 months, and at the end of follow-up (median 10.9 [IQR 5.4, 17.4] months). Delta-variables (Δ) were calculated as the difference between the end of follow-up and baseline. Results: Time in range (TIR)70-180mg/dL increased from 65% [52, 72] to 75% [63, 80], P = 0.008, from baseline to end of follow-up. Time above range>180mg/dL decreased from 28% [20, 46] to 22% [14, 35], P = 0.047. Advanced pubertal stage was correlated with less improvement in ΔTAR>180mg/dL, r = 0.47, P = 0.05, and less CGM usage r = -0.57, P = 0.05. A longer disease duration was associated with less improvement in ΔTAR180-250mg/dL, r = 0.48, P = 0.05. Lower pump site change frequency was associated with higher glucose management indicator, r = 0.5, P = 0.03, and lower TIR70-180mg/dL r = -0.52, P = 0.08. Conclusion: The use of AHCL enabled improvements in TIR70-180mg/dL in youth with T1D. More advanced pubertal stages, longer disease duration, and less compliance were associated with less improvement, stressing the need for continuous support, and re-education in this age group.

Open-source automated insulin delivery systems (OS-AIDs) in a pediatric population with type 1 diabetes in a real-life setting: the AWeSoMe study group experience.

PURPOSE: The use of open-source automated insulin delivery systems (OS-AIDs), for the management of type 1 diabetes (T1D), has increased over recent years in all age groups. Real-life data has demonstrated the safety and efficacy of these systems, however, studies in the pediatric population remain limited. In this study, we aimed to examine the effect of transition to an OS-AIDs on glycemic parameters, and on several aspects related to quality of life. In addition, we aimed to characterize the socioeconomic position of families who chose this treatment modality, assess their motivations to do so, and evaluate treatment satisfaction. METHODS: In this multi-center observational real-life study from the AWeSoMe Group, we compared glycemic parameters of 52 individuals with T1D (56% males, mean diabetes duration 4.2 ± 3.9 years), from the last clinic visit prior to OS-AIDs initiation to the most recent clinic visit while using the system. Socioeconomic position (SEP) index was retrieved from the Israel Central Bureau of Statistics. Caregivers completed questionnaires assessing reasons for system initiation and treatment satisfaction. RESULTS: Mean age at OS-AIDs initiation was 11.2 ± 4 years, range 3.3-20.7 years with a median usage duration of 11.1 months (range 3-45.7). Mean SEP Index was 1.033 ± 0.956 (value range: -2.797 to 2.590). Time in range (TIR) of 70 to 180 mg/dl increased from 69.0 ± 11.9 to 75.5 ± 11.7%, (P < 0.001), and HbA1c decreased from 6.9 ± 0.7 to 6.4 ± 0.6%, (P < 0.001). Time in tight range (TITR) of 70 to 140 mg/dl increased from 49.7 ± 12.9 to 58.8 ± 10.8% (P < 0.001). No episodes of severe hypoglycemia or DKA were reported. Reduction in diabetes burden and sleep quality improvement were the main reasons for OS-AID initiation. CONCLUSIONS: In our cohort of youth with T1D, the transition to an OS-AID resulted in greater TIR and less severe hypoglycemia regardless of age, diabetes duration or SEP, which was found to be above average. The overall improvement in glycemic parameters in our study population with excellent baseline glycemic control, provides additional evidence of beneficence and efficacy of OS-AIDs in the pediatric population.

Real-World Treatment Patterns and Outcomes of Growth Hormone Treatment Among Children in Israel Over the Past Decade (2004-2015).

Objective: To assess a decade of growth hormone (GH) treatment patterns and outcomes in a real-world setting in Israel using a state-of-the-art computerized database. Methods: This large retrospective database study included 2,379 children initiating GH treatment in Maccabi Healthcare Services (between January 2004 and December 2014). Good adherence with therapy (proportion of days covered >80%) was assessed during follow-up. Results: At GH treatment initiation: 62.1% were boys; height standard deviation score (SDS) was -2.36 ± 0.65 (mean ± SD); age was 9.8 ± 3.1 years; and time from short stature diagnosis to first GH purchase was 4.8 ± 3.3 years. Mean treatment period was 3.5 ± 0.95 years; 79.4% of children were treated for more than 3 years. The two main indications for GH therapy were idiopathic short stature (ISS) (n = 1,615, 67.9%) and GH deficiency (GHD) (n = 611, 25.7%). Children in the highest socio-economic-status (SES) tertile comprised 61.3% of ISS and 59.7% of GHD. After 3 years, mean height gain SDS was 1.09 ± 0.91 for GHD and 0.96 ± 0.57 for ISS (p = 0.0004). Adult height (age 15 for girls and 17 for boys) was recorded for 624 patients (26.2%) with better outcomes for GHD than ISS (-1.0±0.82 vs. -1.28±0.93, respectively; p = 0.0002). Good adherence was achieved in 78.2% of the cohort during the first year and declined thereafter to 68.1% during the third year of the treatment. Conclusions: Children who initiate GH therapy are predominantly male, belong mainly to the upper SES, commence treatment a long period after initial recognition of short stature, and have suboptimal adherence. Appropriate referral, diagnosis, and follow-up care may result in better treatment outcomes with GH therapy.

Initiation of growth hormone therapy in idiopathic short stature: do gender differences exist?

BACKGROUND/AIMS: Growth hormone (GH) registries indicate that boys receive preferential GH treatment for idiopathic short stature (ISS). The aim was to determine whether age, auxological parameters, pubertal status, and target height differ between genders at GH initiation. METHODS: Review of the computerized files of the endocrine department of a tertiary pediatric medical center identified 184 patients who started GH therapy for ISS between 2003-2011. Data on auxologic parameters, predicted height, parental height, and pubertal status were collected and compared between boys and girls. RESULTS: Boys accounted for a significantly higher percentage of the study group (65.8%, p<0.001). At onset of GH therapy, there were no significant differences between boys and girls in age (10.2±3.1 vs. 9.9±2.4 years), height-standard deviation score (SDS) (-2.64±0.5 vs. -2.79±0.5), body mass index-SDS[(-0.65±1.01) vs. (-0.80±1.13)], or pubertal status (66% vs. 63.5% prepubertal). Predicted height-SDS was significantly higher in boys (-1.95±1.05 vs. -2.56±0.73, p<0.001). Midparental height-SDS was similar in the two groups, as were paternal and maternal height. CONCLUSIONS: The similar age, height deficit, and pubertal status at onset of GH treatment in boys and girls suggests that gender differences do not exist. Male predominance may stem from family preferences to treat boys. Future studies are warranted to assess the psychosocial aspects in the decision to initiate therapy.