Essential Role of BRCA2 in Ovarian Development and Function.

The causes of ovarian dysgenesis remain incompletely understood. Two sisters with XX ovarian dysgenesis carried compound heterozygous truncating mutations in the BRCA2 gene that led to reduced BRCA2 protein levels and an impaired response to DNA damage, which resulted in chromosomal breakage and the failure of RAD51 to be recruited to double-stranded DNA breaks. The sisters also had microcephaly, and one sister was in long-term remission from leukemia, which had been diagnosed when she was 5 years old. Drosophila mutants that were null for an orthologue of BRCA2 were sterile, and gonadal dysgenesis was present in both sexes. These results revealed a new role for BRCA2 and highlight the importance to ovarian development of genes that are critical for recombination during meiosis. (Funded by the Israel Science Foundation and others.).

Guidelines for urinary tract infections and antenatal hydronephrosis should be gender specific.

AIM: Febrile urinary tract infections (UTIs) may be associated with long-term renal damage. Our goal was to identify risk factors for future UTIs in children who had voiding cystourethrography (VCUG) as a part of an antenatal hydronephrosis (ANH) assessment or after a febrile UTI. METHODS: We conducted a cohort study based on the medical records of children aged 0-24 months who underwent a VCUG between January 2004 and December 2011 and had at least six months of follow-up. The incidence of future UTIs was assessed. RESULTS: We included 285 children: 176 had a primary UTI and 109 had ANH. We recorded 28 UTIs during the follow-up period, and the risk was 12.5% after a primary UTI and 5.5% after an ANH (p = 0.049). Multivariate analysis showed no risk difference was found between the groups. Females had a greater risk of febrile UTIs (hazard ratio 3.3, 95% confidence interval 1.03-9.2, p = 0.04), but the UTI risk did not differ between children with or without VURs. CONCLUSION: Female infants were at greater risk of febrile UTIs, regardless of the presence of VUR, VUR degree, ANH or a previous UTI. Clinical guidelines for UTI and ANH assessment should preferably be gender specific.

Evaluation of bone density in girls with precocious and early puberty during treatment with GnRH agonist.

BACKGROUND: Major changes in bone status occur during puberty. Most longitudinal studies have shown no impairment in bone mineral density (BMD) in girls with precocious (PP) and early puberty (EP) during and after GnRH agonist therapy. METHODS: In the present study we evaluated BMD, bone strength (BS) and bone metabolism in 26 girls with PP and with EP before and during treatment with GnRH agonist. BMD was measured by dual energy X-ray absorptiometry and BS was measured using the quantitative high frequency ultrasound technique at baseline, after 6 and 12 months from onset of therapy. Variables were compared with age- and sex-matched values of the same population. Biochemical markers of bone turnover were measured at the same intervals. RESULTS: Mean lumbar spine (LS) and femoral neck (FN) BMD were significantly lower at baseline (LS: p < 0.0001, FN: p < 0.0017) compared with age-matched reference values. Bone strength was significantly lower at the radius (p < 0.0001) and normal at the tibia. A non-significant increase in BMD and a significant increase in BS were observed throughout the first year of therapy with GnRH agonist. Serum bone specific alkaline phosphatase measurements were normal at baseline and remained stable. Urinary deoxypyridinoline\creatinine measurements were significantly higher (p < 0.0001) at baseline and decreased significantly (p < 0.001) during treatment. CONCLUSIONS: Girls with central idiopathic PP and EP have lower BMD and BS for chronological age and increased bone resorption markers. These parameters show a trend of normalization during the first year of therapy with GnRH agonist.

Combined Gestational Age- and Birth Weight-Adjusted Cutoffs for Newborn Screening of Congenital Adrenal Hyperplasia.

CONTEXT: Congenital adrenal hyperplasia (CAH) was among the first genetic disorders included in newborn screening (NBS) programs worldwide, based on 17α-hydroxyprogesterone (17-OHP) levels in dried blood spots. However, the success of NBS for CAH is hampered by high false positive (FP) rates, especially in preterm and low-birthweight infants. OBJECTIVE: To establish a set of cutoff values adjusting for both gestational age (GA) and birthweight (BW), with the aim of reducing FP rates. DESIGN: This cross-sectional, population-based study summarizes 10 years of experience of the Israeli NBS program for diagnosis of CAH. Multitiered 17-OHP cutoff values were stratified according to both BW and GA. PARTICIPANTS: A total of 1,378,132 newborns born between 2008 and 2017 were included in the NBS program. RESULTS: Eighty-eight newborns were ultimately diagnosed with CAH; in 84 of these, CAH was detected upon NBS. The combined parameters-adjusted approach significantly reduced the recall FP rate (0.03%) and increased the positive predictive value (PPV) (16.5%). Sensitivity among those referred for immediate attention increased significantly (94%). There were four false negative cases (sensitivity, 95.4%), all ultimately diagnosed as simple-virilizing. Sensitivity and specificity were 95.4% and 99.9%, respectively, and the percentage of true-positive cases from all newborns referred for evaluation following a positive NBS result was 96%. CONCLUSIONS: The use of cutoff values adjusted for both GA and BW significantly reduced FP rates (0.03%) and increased overall PPV (16.5%). Based on our 10 years of experience, we recommend the implementation of this two parameter-adjusted approach for NBS of classic CAH in NBS programs worldwide.

Correction to: Use of flash glucose-sensing technology (FreeStyle Libre) in youth with type 1 diabetes: AWeSoMe study group real-life observational experience.

Unfortunately, the co-author name was misspelled as "Avivit Brenner" instead of "Avivit Brener" in the original publication and the correct author name is updated here.

Use of flash glucose-sensing technology (FreeStyle Libre) in youth with type 1 diabetes: AWeSoMe study group real-life observational experience.

AIMS: Frequent glucose testing is required for optimal management of type 1 diabetes (T1D). Limited data are available regarding real-world experience of the novel technology for monitoring by continuous interstitial fluid glucose (IFG), using flash glucose-sensing technology (FSL-CGM). We aimed to assess the effect of FSL-CGM in a real-life clinical setting on glycemic control parameters, compliance, and adverse events among pediatric and young adult T1D patients. METHODS: This observational multi-center study assessed FSL-CGM use (6-12 months) in T1D patients (mean ± SD age 13.4 ± 4.9 years) who purchased the device out-of-pocket. Outcome measures included HbA1c, mean IFG levels, CGM metrics [time in hypoglycemia (< 54 mg/dL; < 3 mmol/L), in target range (70-180 mg/dL; 3.9-10 mmol/L), and in hyperglycemia > 240 mg/dL; > 13.3 mmol/L)], frequency of self-monitoring of blood glucose, acute complications, skin reactions, and reasons for initiation/discontinuation. RESULTS: Among patients with regular use of the FSL-CGM (n = 59), mean HbA1c decreased from 8.86 ± 0.23 to 8.05 ± 0.2% (73.3-64.5 mmol/mol) in 3 months (p = 0.0001) and plateaued thereafter. A clinically significant reduction in HbA1c (defined as a decrease of ≥ 0.5%) was associated with shorter diabetes duration. Of 71 patients who initiated use of the FSL-CGM, 12 (16.9%) discontinued during the study period. No statistically significant changes were found after FSL-CGM use, in mean and standard deviation IFG levels, and in time of glucose levels in target, hypoglycemia, and hyperglycemia ranges. One patient with hypoglycemia unawareness was found dead-in-bed while using FSL-CGM. CONCLUSIONS: Real-life observational data in a self-selected young T1D population demonstrated a significant and sustained reduction in HbA1c with FSL-CGM in one-third of the participants. Surveillance of glucose monitoring should be individualized, especially for patients with hypoglycemia unawareness.

Exercise and type 1 diabetes mellitus in youth; review and recommendations.

Regular physical activity has been one of the cornerstones of type 1 diabetes mellitus (T1DM) therapy for decades. The benefits attributed to regular physical activity include increased sense of well being, quality of life, improved body composition, improved blood pressure and more. The beneficial effect in individuals with T1DM includes decreased risk of diabetes-related complications and mortality. In view of the recent recommendations for physical activity in healthy youth, advocating daily participation in 60 minutes of moderate to vigorous physical activity, we review the recent literature regarding physical activity in the context of youth with T1DM. We discuss its physiological and metabolic effects in youth with T1DM, its health promoting benefits and challenges that exercise poses in these individuals.