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Purpose: Examine the acute hormonal and cytokine responses to free-weight resistance training in trained prepubertal and pubertal male children.

Methods: Prepubertal (n = 21; age 11.4 ± 1.1 years; Tanner I–II) and pubertal male children (n = 20; age 15.8 ± 0.7 years; Tanner III–V) conducted a moderate-intensity free-weight resistance training program to failure with venous blood sampling before (pre), immediately after (post) and during the recovery phase of the program (post-15,-30 min). Growth hormone (GH), insulin-like growth factor-I (IGF-I), cortisol, testosterone, IL-6, and TNF-α were analyzed in serum samples. Biological maturation was assessed according to the stages of the Tanner scale.

Results: There was a significant time-by-group interaction in IGF-I response (p = 0.044; η2 = 0.209) and testosterone (p < 0.001; η2 = 0.508), indicating a greater change in the pubertal group compared to the prepubertal group. Both groups significantly increased post-exercise GH levels (p < 0.05). Only the prepuberal group significantly increased levels of IL-6 at all post-exercise time points (p < 0.05). Both groups showed a significant (p < 0.05) increase in TNF-α levels compared to resting levels.

Conclusion: These data suggest that acute testosterone and IGF-I response following resistance training differ between trained prepubertal and pubertal male children. Moderate-intensity resistance training performed to failure may thus have different effects in trained prepubertal and pubertal male children, which should be considered when giving training advice. Trial registration: Clinical trials number: NCT05022992.

Background: Recombinant human growth hormone (rhGH, somatropin) therapy is approved in children with Prader–Willi syndrome (PWS).

Objectives: To report safety and effectiveness data for children with PWS treated with biosimilar rhGH (Omnitrope®, Sandoz) in the PAtients TReated with Omnitrope (PATRO) Children study.

Design: PATRO Children was a multicenter, non-interventional, postmarketing surveillance study.

Methods: Children with PWS received Omnitrope according to standard clinical practice. Adverse events (AEs) were monitored for the duration of Omnitrope treatment. Effectiveness outcomes were also assessed, including height standard deviation (SD) scores (HSDS).

Results: As of July 2020 (study completion), 235 patients with PWS had been enrolled. At baseline, 95.7% (n = 225) of patients were prepubertal and 86.4% (n = 203) were rhGH treatment-naïve. At analysis, the median (range) treatment duration in the study was 56.8 (2.9–155.8) months. AEs were reported in 192 patients (81.7%) and were suspected as treatment-related in 39 patients (16.6%). Serious AEs (SAEs) were reported in 96 patients (40.9%) and were suspected as treatment-related in 22 patients (9.4%). The most frequent treatment-related SAEs were sleep apnea syndrome (n = 11; 4.7%), tonsillar hypertrophy (n = 4; 1.7%), and adenoidal hypertrophy (n = 4; 1.7%). Development of scoliosis was considered treatment-related in two patients; development of impaired glucose tolerance in one patient and type 2 diabetes mellitus in another patient were considered treatment-related. Effectiveness outcomes were primarily assessed in 153 patients who completed 3 years of treatment. Among the 151 prepubertal patients (135 treatment-naïve), mean (SD) change from baseline in HSDS after 3 years was +1.50 (1.07) across all patients and +1.57 (1.07) for treatment-naïve patients.

Conclusion: These data suggest that biosimilar rhGH is well tolerated and effective in patients with PWS managed in real-life clinical practice. Patients with PWS should continue to be closely monitored for well-known safety issues (including respiratory, sleep, and glucose metabolism disorders, and scoliosis) during rhGH treatment.

Sotos syndrome belongs to the group of diseases characterised by features such as facial dysmorphism, intellectual disability, hypotonia and overgrowth. Usually, Sotos syndrome is caused by heterozygous mutations in the NSD1 gene at chromosome 5q35 or by large genomic deletions of the same region. Genotype-phenotype correlations have mainly been reported as an association of significant or major abnormalities and presence of 5q35 deletions rather than intragenic deletions or point mutations in NSD1. The congenital hyperinsulinaemic hypoglycaemia (CHI) has been described as an uncommon feature in the presentation of Sotos syndrome. Most of the patients with Sotos syndrome and transient CHI were carriers of 5q35 deletions while persistent CHI has been recently reported in individuals with point mutations or small NSD1 deletions. We report the clinical features and medical treatment in a new-born child with Sotos syndrome and CHI that was present for almost two years. Genetic cause of Sotos syndrome in this case was a novel, large genomic deletion encompassing 24 OMIM genes including the entire NSD1 gene and 6 other Morbid genes. Our report shows challenges in diagnostics and management of this rare genetic condition. We propose, that in neonatal diagnostics, the phenotypic spectrum of Sotos syndrome should include CHI as a characteristic feature and molecular genetic testing should be done by whole genome analysis.

Childhood-onset osteoporosis is a rare but clinically significant condition. Studies have shown pathogenic variants in more than 20 different genes as causative for childhood-onset primary osteoporosis. The X-chromosomal PLS3, encoding Plastin-3, is one of the more recently identified genes. In this study, we describe five new families from four different European countries with PLS3-related skeletal fragility. The index cases were all hemizygous males presenting with long bone and vertebral body compression fractures. All patients had low lumbar spine bone mineral density (BMD). The age at the first clinical fracture ranged from 1.5 to 13 years old. Three of the identified PLS3 variants were stop-gain variants and two were deletions involving either a part or all exons of the gene. In four families the variant was inherited from the mother. All heterozygous women reported here had normal BMD and no bone fractures. Four patients received bisphosphonate treatment with good results, showing a lumbar spine BMD increment and vertebral body reshaping after 10 months to 2 years of treatment. Our findings expand the genetic spectrum of PLS3-related osteoporosis. Our report also shows that early treatment with bisphosphonates may influence the disease course and reduce the progression of osteoporosis, highlighting the importance of early diagnosis for prompt intervention and appropriate genetic counseling.

Aim: To explore young adults' experiences of living with type 1 diabetes in the transition to adulthood, including experiences of the transfer from paediatric to adult care.

Design: A qualitative approach was used.

Method: Ten young adults, six women and four men, aged 19–29 years, participated. Participants were recruited at their regular diabetes clinic from spring 2021 to spring 2022. Semi-structured interviews were transcribed and analysed using qualitative content analysis.

Findings: Dreaming of being nurtured towards self-reliance was the overarching theme. Personal experiences of the transition to adulthood, including the transfer from paediatric to adult care, were described in terms of struggling to find balance in daily life, dealing with feelings of being different, being gradually supported to achieve independence, and wishing to be approached as a unique person in healthcare.

Conclusion: In healthcare, it is important to emphasize not only diabetes-related factors but also emotional and psychosocial aspects of life connected to the transition to adulthood, including the transfer to adult care. The young adults wished to be seen as unique persons in healthcare during their emerging adulthood and should therefore be supported to achieve self-reliance through personal preparations for new challenges and for the consequences of transitioning to adulthood. Specialist nurses can provide appropriate knowledge and leadership.

Implications for the Profession: These findings can guide nurse specialists in support for emerging adults to achieve self-reliance and indicate the importance of person-centred care when experiencing transition and transfer.

Reporting Method: The study adhered to EQUATOR guidelines, and the COREQ checklist for qualitative studies was used as the reporting method.

Background: No previous systematic review has quantitatively compared the effects of resistance training, endurance training, or concurrent training on hormonal adaptations in children and adolescents. Objective was to examine the effects of exercise training and training type on hormonal adaptations in children and adolescents.

Methods: A systematic literature search was conducted in the following databases: PubMed, Web of Science, and EBSCO. Eligibility criteria were: population: healthy youth population sample (mean age < 18 years); intervention: resistance training, endurance training, or concurrent training (> 4 weeks duration); comparison: control group; outcome: pre- and post-levels of hormones and cytokines; and study design: randomized and non-randomized controlled trials. We used a random-effect model for the meta-analysis. The raw mean difference in hormones from baseline to post-intervention was presented alongside 95% confidence intervals (CI). Further, the certainty of evidence quality and the risk of bias were assessed.

Results: A total of 3689 records were identified, of which 14 studies were eligible for inclusion. Most studies examined adolescents with fewer studies on children (age < 12 years, N = 5 studies) and females (N = 2 studies). Nine exercise training programs used endurance training, five studies used resistance training, and no eligible study used concurrent training. The meta-analysis showed no significant effect of exercise training on testosterone (MD = 0.84 nmol/L), cortisol (MD = − 17.4 nmol/L), or SHBG (MD = − 5.58 nmol/L). Subgroup analysis showed that resistance training significantly increased testosterone levels after training (MD = 3.42 nmol/L) which was not observed after endurance training (MD = − 0.01 nmol/L). No other outcome differed between training types. Exercise training resulted in small and non-significant changes in GH (MD = 0.48 ng/mL, p = 0.06) and IGF-I (MD = − 22.90 ng/mL, p = 0.07). GH response to endurance training may be age-dependent and evident in adolescents (MD = 0.59 ng/mL, p = 0.04) but not when children and adolescents are pooled (MD = 0.48 ng/mL, p = 0.06). Limited evidence exists to conclude on IL-6 and TNF-α effects of exercise training. Assessments of GRADE domains (risk of bias, consistency, directness, or precision of the findings) revealed serious weaknesses with most of the included outcomes (hormones and cytokines).

Conclusions: This systematic review suggests that exercise training has small effects on hormonal concentrations in children and adolescents. Changes in testosterone concentrations with training are evident after resistance training but not endurance training. GH's response to training may be affected by maturation and evident in adolescents but not children. Further high-quality, robust training studies on the effect of resistance training, endurance training, and concurrent training are warranted to compare their training-specific effects.

Aims: Residual beta cell function in type 1 diabetes (T1D) is associated with lower risk of complications. Autoantigen therapy with GAD-alum (Diamyd) given in 3 intralymphatic injections with oral vitamin D has shown promising results in persons with T1D carrying the human leukocyte antigen (HLA) DR3-DQ2 haplotype in the phase 2b trial DIAGNODE-2. We aimed to explore the efficacy of intralymphatic GAD-alum on blood glucose recorded by continuous glucose monitoring (CGM).

Methods: DIAGNODE-2 (NCT03345004) was a multicenter, randomized, placebo-controlled, double-blind trial of 109 recent-onset T1D patients aged 12 to 24 years with GAD65 antibodies and fasting C-peptide>0.12 nmol/L, which randomized patients to 3 intralymphatic injections of 4 μg GAD-alum and oral vitamin D, or placebo. We report results for exploratory endpoints assessed by 14-day CGM at months 0, 6, and 15. Treatment arms were compared by mixed-effects models for repeated measures adjusting for baseline values.

Results: We included 98 patients with CGM recordings of sufficient quality (DR3-DQ2-positive patients: 27 GAD-alum-treated and 15 placebo-treated). In DR3-DQ2-positive patients, percent of time in range (TIR, 3.9-10 mmol/L) declined less between baseline and month 15 in GAD-alum-treated compared with placebo-treated patients (-5.1% and-16.7%, respectively; P=0.0075), with reduced time>13.9 mmol/L (P=0.0036), and significant benefits on the glucose management indicator (P=0.0025). No differences were detected for hypoglycemia. GAD-alum compared to placebo lowered the increase in glycemic variability (standard deviation) observed in both groups (P=0.0219). Change in C-peptide was correlated with the change in TIR.

Conclusions: Intralymphatic GAD-alum improves glycemic control in recently diagnosed T1D patients carrying HLA DR3-DQ2.

Aim: Despite the enormous efforts to understand Congenital hyperinsulinism (CHI), up to 50% of the patients are genetically unexplained. We aimed to functionally characterize a novel candidate gene in CHI.

Patient: A 4-month-old boy presented severe hyperinsulinemic hypoglycemia. A routine CHI genetic panel was negative.

Methods: A trio-based whole-exome sequencing (WES) was performed. Gene knockout in the RIN-m cell line was established by CRISPR/Cas9. Gene expression was performed using real-time PCR.

Results: Hyperinsulinemic hypoglycemia with diffuse beta-cell involvement was demonstrated in the patient, who was diazoxide-responsive. By WES, compound heterozygous variants were identified in the adenylyl cyclase 7, ADCY7 gene p.(Asp439Glu) and p.(Gly1045Arg). ADCY7 is calcium-sensitive, expressed in beta-cells and converts ATP to cAMP. The variants located in the cytoplasmic domains C1 and C2 in a highly conserved and functional amino acid region. RIN-m(-/-Adcy7) cells showed a significant increase in insulin secretion reaching 54% at low, and 49% at high glucose concentrations, compared to wild-type. In genetic expression analysis Adcy7 loss of function led to a 34.1-fold to 362.8-fold increase in mRNA levels of the insulin regulator genes Ins1 and Ins2 (p ≤ 0.0002), as well as increased glucose uptake and sensing indicated by higher mRNA levels of Scl2a2 and Gck via upregulation of Pdx1, and Foxa2 leading to the activation of the glucose stimulated-insulin secretion (GSIS) pathway.

Conclusion: This study identified a novel candidate gene, ADCY7, to cause CHI via activation of the GSIS pathway.

OBJECTIVE: To evaluate the efficacy of aluminum-formulated intralymphatic glutamic acid decarboxylase (GAD-alum) therapy combined with vitamin D supplementation in preserving endogenous insulin secretion in all patients with type 1 diabetes (T1D) or in a genetically prespecified subgroup.

RESEARCH DESIGN AND METHODS: In a multicenter, randomized, placebo-controlled, double-blind trial, 109 patients aged 12–24 years (mean ± SD 16.4 ± 4.1) with a diabetes duration of 7–193 days (88.8 ± 51.4), elevated serum GAD65 autoantibodies, and a fasting serum C-peptide >0.12 nmol/L were recruited. Participants were randomized to receive either three intralymphatic injections (1 month apart) with 4 μg GAD-alum and oral vitamin D (2,000 IE daily for 120 days) or placebo. The primary outcome was the change in stimulated serum C-peptide (mean area under the curve [AUC] after a mixed-meal tolerance test) between baseline and 15 months.

RESULTS: Primary end point was not met in the full analysis set (treatment effect ratio 1.091 [CI 0.845–1.408]; P = 0.5009). However, GAD-alum–treated patients carrying HLA DR3-DQ2 (n = 29; defined as DRB1*03, DQB1*02:01) showed greater preservation of C-peptide AUC (treatment effect ratio 1.557 [CI 1.126–2.153]; P = 0.0078) after 15 months compared with individuals receiving placebo with the same genotype (n = 17). Several secondary end points showed supporting trends, and a positive effect was seen in partial remission (insulin dose–adjusted HbA1c ≤9; P = 0.0310). Minor transient injection site reactions were reported.

CONCLUSION: Intralymphatic administration of GAD-alum is a simple, well-tolerated treatment that together with vitamin D supplementation seems to preserve C-peptide in patients with recent-onset T1D carrying HLA DR3-DQ2. This constitutes a disease-modifying treatment for T1D with a precision medicine approach.

Introduction: PATRO Children is an international, observational, postmarketing surveillance study for a biosimilar recombinant human growth hormone (rhGH; somatropin, Omnitrope (R); Sandoz), approved by the European Medicines Agency in 2006. We report safety and effectiveness data for patients with Turner syndrome (TS).

Methods: The study population included infants, children, and adolescents with TS who received Omnitrope (R) treatment according to standard clinical practice. Adverse events (AEs) were monitored for safety evaluation, and height velocity (HV), height standard deviation score (HSDS), and HVSDS were calculated to evaluate treatment effectiveness.

Results: As of August 2019, 348 TS patients were enrolled from 130 centers. At baseline, 314 patients (90.2%) were prepubertal and 284 patients (81.6%) were rhGH treatment naive. The mean ( range) age at baseline was 9.0 (0.7-18.5) years, and mean (SD) treatment duration in the study was 38.5 (26.8) months. Overall, 170 patients (48.9%) reported AEs, which were considered treatment related in 25 patients (7.2%). One treatment-related serious AE was reported (intracranial hypertension). Mean.HSDS after 3 years of therapy was +1.17 in treatment-naive prepubertal patients and +0.1 in pretreated prepubertal patients. In total, 51 patients (31.1%) reached adult height (AH), 35 of whom were rhGH treatment naive; in these patients, mean (SD) HSDS was -2.97 (1.03) at the start of Omnitrope (R) treatment, and they achieved a mean (SD) AHSDS of -2.02 (0.9).

Conclusion: These data suggest that biosimilar rhGH is well tolerated and effective in TS patients managed in reallife clinical practice. Optimization of rhGH dose may contribute to a higher AH. (C) 2021 S. Karger AG, Basel