Once-Weekly Semaglutide in Adolescents with Obesity.

BACKGROUND: A once-weekly, 2.4-mg dose of subcutaneous semaglutide, a glucagon-like peptide-1 receptor agonist, is used to treat obesity in adults, but assessment of the drug in adolescents has been lacking. METHODS: In this double-blind, parallel-group, randomized, placebo-controlled trial, we enrolled adolescents (12 to <18 years of age) with obesity (a body-mass index [BMI] in the 95th percentile or higher) or with overweight (a BMI in the 85th percentile or higher) and at least one weight-related coexisting condition. Participants were randomly assigned in a 2:1 ratio to receive once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo for 68 weeks, plus lifestyle intervention. The primary end point was the percentage change in BMI from baseline to week 68; the secondary confirmatory end point was weight loss of at least 5% at week 68. RESULTS: A total of 201 participants underwent randomization, and 180 (90%) completed treatment. All but one of the participants had obesity. The mean change in BMI from baseline to week 68 was -16.1% with semaglutide and 0.6% with placebo (estimated difference, -16.7 percentage points; 95% confidence interval [CI], -20.3 to -13.2; P<0.001). At week 68, a total of 95 of 131 participants (73%) in the semaglutide group had weight loss of 5% or more, as compared with 11 of 62 participants (18%) in the placebo group (estimated odds ratio, 14.0; 95% CI, 6.3 to 31.0; P<0.001). Reductions in body weight and improvement with respect to cardiometabolic risk factors (waist circumference and levels of glycated hemoglobin, lipids [except high-density lipoprotein cholesterol], and alanine aminotransferase) were greater with semaglutide than with placebo. The incidence of gastrointestinal adverse events was greater with semaglutide than with placebo (62% vs. 42%). Five participants (4%) in the semaglutide group and no participants in the placebo group had cholelithiasis. Serious adverse events were reported in 15 of 133 participants (11%) in the semaglutide group and in 6 of 67 participants (9%) in the placebo group. CONCLUSIONS: Among adolescents with obesity, once-weekly treatment with a 2.4-mg dose of semaglutide plus lifestyle intervention resulted in a greater reduction in BMI than lifestyle intervention alone. (Funded by Novo Nordisk; STEP TEENS ClinicalTrials.gov number, NCT04102189.).

A Randomized, Controlled Trial of Liraglutide for Adolescents with Obesity.

BACKGROUND: Obesity is a chronic disease with limited treatment options in pediatric patients. Liraglutide may be useful for weight management in adolescents with obesity. METHODS: In this randomized, double-blind trial, which consisted of a 56-week treatment period and a 26-week follow-up period, we enrolled adolescents (12 to <18 years of age) with obesity and a poor response to lifestyle therapy alone. Participants were randomly assigned (1:1) to receive either liraglutide (3.0 mg) or placebo subcutaneously once daily, in addition to lifestyle therapy. The primary end point was the change from baseline in the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) standard-deviation score at week 56. RESULTS: A total of 125 participants were assigned to the liraglutide group and 126 to the placebo group. Liraglutide was superior to placebo with regard to the change from baseline in the BMI standard-deviation score at week 56 (estimated difference, -0.22; 95% confidence interval [CI], -0.37 to -0.08; P = 0.002). A reduction in BMI of at least 5% was observed in 51 of 113 participants in the liraglutide group and in 20 of 105 participants in the placebo group (estimated percentage, 43.3% vs. 18.7%), and a reduction in BMI of at least 10% was observed in 33 and 9, respectively (estimated percentage, 26.1% vs. 8.1%). A greater reduction was observed with liraglutide than with placebo for BMI (estimated difference, -4.64 percentage points) and for body weight (estimated difference, -4.50 kg [for absolute change] and -5.01 percentage points [for relative change]). After discontinuation, a greater increase in the BMI standard-deviation score was observed with liraglutide than with placebo (estimated difference, 0.15; 95% CI, 0.07 to 0.23). More participants in the liraglutide group than in the placebo group had gastrointestinal adverse events (81 of 125 [64.8%] vs. 46 of 126 [36.5%]) and adverse events that led to discontinuation of the trial treatment (13 [10.4%] vs. 0). Few participants in either group had serious adverse events (3 [2.4%] vs. 5 [4.0%]). One suicide, which occurred in the liraglutide group, was assessed by the investigator as unlikely to be related to the trial treatment. CONCLUSIONS: In adolescents with obesity, the use of liraglutide (3.0 mg) plus lifestyle therapy led to a significantly greater reduction in the BMI standard-deviation score than placebo plus lifestyle therapy. (Funded by Novo Nordisk; NN8022-4180 ClinicalTrials.gov number, NCT02918279.).

Gonadal development and function after immature testicular tissue banking as part of high-risk gonadotoxic treatment.

BACKGROUND: Experimental fertility preservation programs have been started to safeguard the future fertility of prepubertal and pubertal males requiring high-risk gonadotoxic treatment protocols. However, long-term follow-up studies evaluating the effects on their gonadal development and function related to the testicular biopsy procedure are rather limited. DESIGN: This two-center follow-up study (between 2002 and 2020) evaluated the gonadal development and function of a cohort of 59 prepubertal and pubertal males who have been offered immature testicular tissue banking (TTB) prior to conventional high-risk chemo- and/or radiotherapy (HR-C/R) or conditioning therapy before hematopoietic stem cell transplantation (CT-HSCT). The aim is to investigate the long-term impact of the testicular biopsy procedure and the high-risk gonadotoxic treatment. Testicular growth and the reproductive hormones luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), and inhibin B (INHB) were analyzed after treatment completion, and compared between males accepting TTB and those refusing TTB (control) as well as between HR-C/R and CT-HSCT treatment protocols. RESULTS: Of the 59 prepubertal and pubertal males included, 25 were treated by HR-C/R and 34 required CT-HSCT. TTB was accepted for 39 males and refused for 20 males. Most patients were prepubertal at diagnosis (85%), at TTB (79%), and at treatment completion (76%), and pubertal or postpubertal at their last follow-up visit (66%). After 5.0 (1.0-13.0) years post treatment, most patients show normal testicular volumes (83%) and normal LH (89%), FSH (87%), T (87%), and INHB (79%) serum levels. The testicular biopsy procedure did not have an effect on testicular growth, LH, FSH, T, and INHB. Significantly more small postpubertal testicular volumes (p = .0278) and low INHB serum levels (p = .0130) were recorded after CT-HSCT, especially after myeloablative conditioning. CONCLUSION: The clinical follow-up data demonstrate no effect related to the biopsy procedure, but a substantial risk for impaired gonadal development after high-risk gonadotoxic treatment, in particular myeloablative CT-HSCT. Longer follow-up studies with a larger study population are needed to confirm these preliminary findings.

Testicular biopsy for fertility preservation in early-diagnosed Klinefelter patients: patient characteristics and long-term follow-up.

RESEARCH QUESTION: Which early-diagnosed Klinefelter syndrome patients have been offered cryopreservation of testicular tissue as part of fertility preservation before spermatogonial stem cell (SSC) loss? Do these Klinefelter syndrome patients present with behavioural, cognitive and/or psychological problems? Does a testicular biopsy procedure have long-term effects on the gonadal development of Klinefelter syndrome patients? DESIGN: Early-diagnosed Klinefelter syndrome patients followed between 2009 and 2020 and offered testicular tissue banking in an experimental context at the Universitair Ziekenhuis Brussel were included. The prevalence of behavioural, cognitive and/or psychological problems was determined. Changes in testicular volume and in gonadal function (LH, FSH, testosterone and inhibin B [INHB]) were studied. RESULTS: Of the 48 Klinefelter syndrome patients included, 22 had testicular tissue removed (biopsy group) and 26 had no surgical intervention (control group). The need for specialized education was significantly higher in prenatally (P = 0.0159) and prepubertally (P = 0.0002) diagnosed Klinefelter syndrome patients. Psychological problems were significantly more prevalent in Klinefelter syndrome patients who did not opt for fertility preservation (P = 0.0447). In the first 4.2 (1.9-9.1) years after testicular biopsy, no difference in testicular volume was observed between the biopsied and the contralateral non-biopsied testes (P > 0.9999). After pubertal onset, no differences in LH, FSH, testosterone and INHB were found between the biopsy and the control groups (P = 0.1324 for LH, P > 0.9999 for FSH, P = 0.5433 for testosterone, P > 0.9999 for INHB). CONCLUSION: Early-diagnosed Klinefelter syndrome patients presented with behavioural, cognitive and/or psychological problems. Only psychological problems seemed to influence the decision towards fertility preservation. Follow-up data confirm that harvesting testicular tissue does not have a long-term impact on the gonadal development of Klinefelter syndrome patients.

Intratesticular xenografting of Klinefelter pre-pubertal testis tissue as potential model to study testicular fibrosis.

RESEARCH QUESTION: Is intratesticular xenotransplantation a potential ex-vivo model for studying testicular fibrosis related to Klinefelter syndrome? STUDY DESIGN: First, a feasibility study of an ex-vivo model to study testicular fibrosis in patients with Klinefelter syndrome was performed. Testis tissue from boys with pre-pubertal Klinefelter syndrome (n = 3) and controls (n = 2) (<18 years) was grafted to the mouse testis (n = 12) and recovered after 2, 4, 6 and 8 weeks. Part two of this study consisted of a validation of this model, evaluating the effects of the mast cell blocker ketotifen on the histology of the grafts of Klinefelter syndrome (n = 5) and controls (n = 3), transplanted to mice (n = 10), after 4 weeks of ketotifen or saline treatment. Immunohistochemistry determined the histology of the grafts and the presence of mast cells and spermatogonia. RESULTS: The feasibility study showed that 4 weeks after transplantation, all Klinefelter syndrome grafts could be recovered. Later, degeneration was observed. Most recovered grafts showed an intact histology, with 67 ± 12% intact tubules for the Klinefelter syndrome grafts and 65 ± 15% of intact tubules for the control grafts. In the few remaining Klinefelter syndrome grafts, treatment with ketotifen improved testicular histology compared with non-treated grafts. Graft survival was patient dependent. No germ cell loss was observed after transplantation. CONCLUSION: Xenografting could become a model for the longitudinal study of the fibrotic process related to Klinefelter syndrome; however, the current model has a limited survival period and patient-specific differences in histology.

Endothelial function and its determinants in children born after maternal bariatric surgery.

BACKGROUND: Children born from mothers who underwent bariatric surgery were found to have an improved lipid profile and lower CRP levels compared to siblings born before surgery. We hypothesized that surgery before pregnancy might also influence endothelial function in the offspring. METHODS: Blood sample analysis, blood pressure (BP) measurement, and peripheral arterial tonometry (PAT) were performed in 142 children (median age 10.5 years), either born from mothers who underwent bariatric surgery (BS) before pregnancy (n = 36) from mothers with overweight/obesity (OW/OB) (n = 71) or from normal weight (NW) mothers (n = 35), allowing the determination of the Reactive Hyperemia Index (RHI) in 111 children. RESULTS: Children of the BS group had a higher diastolic blood pressure SDS and a lower RHI compared to the children of the OW/OB and NW group (1.32 versus 1.37 in OW/OB and 1.70 in NW; p = 0.004). After log transformation and correction for age, weight SDS, BMI SDS, body fat percentage, and diastolic BP SDS, RHI was comparable between the groups. CONCLUSIONS: Children of mothers who underwent bariatric surgery before pregnancy do not have a disturbed endothelial function before puberty, when their increased diastolic BP and degree of adiposity is taken into account. IMPACT: Children born after maternal bariatric surgery have a higher diastolic blood pressure without impaired endothelial function. To our knowledge, this is the first study that investigates the vascular function of children based on maternal characteristics during pregnancy. Adult offspring of mothers with obesity during pregnancy have an increased cardiovascular mortality. Since we cannot demonstrate a childhood-onset primary vascular dysfunction, this cardiovascular vulnerability might be more related to the hypertension and body adiposity. Thus, more emphasis should be made on the prevention of obesity and hypertension in the offspring at risk for development of obesity.

Paediatric obesity: a systematic review and pathway mapping of metabolic alterations underlying early disease processes.

BACKGROUND: The alarming trend of paediatric obesity deserves our greatest awareness to hinder the early onset of metabolic complications impacting growth and functionality. Presently, insight into molecular mechanisms of childhood obesity and associated metabolic comorbidities is limited. This systematic review aimed at scrutinising what has been reported on putative metabolites distinctive for metabolic abnormalities manifesting at young age by searching three literature databases (Web of Science, Pubmed and EMBASE) during the last 6 years (January 2015-January 2021). Global metabolomic profiling of paediatric obesity was performed (multiple biological matrices: blood, urine, saliva and adipose tissue) to enable overarching pathway analysis and network mapping. Among 2792 screened Q1 articles, 40 met the eligibility criteria and were included to build a database on metabolite markers involved in the spectrum of childhood obesity. Differential alterations in multiple pathways linked to lipid, carbohydrate and amino acid metabolisms were observed. High levels of lactate, pyruvate, alanine and acetate marked a pronounced shift towards hypoxic conditions in children with obesity, and, together with distinct alterations in lipid metabolism, pointed towards dysbiosis and immunometabolism occurring early in life. Additionally, aberrant levels of several amino acids, most notably belonging to tryptophan metabolism including the kynurenine pathway and its relation to histidine, phenylalanine and purine metabolism were displayed. Moreover, branched-chain amino acids were linked to lipid, carbohydrate, amino acid and microbial metabolism, inferring a key role in obesity-associated insulin resistance. CONCLUSIONS: This systematic review revealed that the main metabolites at the crossroad of dysregulated metabolic pathways underlying childhood obesity could be tracked down to one central disturbance, i.e. impending insulin resistance for which reference values and standardised measures still are lacking. In essence, glycolytic metabolism was evinced as driving energy source, coupled to impaired Krebs cycle flux and ß-oxidation. Applying metabolomics enabled to retrieve distinct metabolite alterations in childhood obesity(-related insulin resistance) and associated pathways at early age and thus could provide a timely indication of risk by elucidating early-stage biomarkers as hallmarks of future metabolically unhealthy phenotypes.

Germ cell loss in Klinefelter syndrome: When and why?

Klinefelter syndrome (KS) is a quite common disorder with an incidence of 1-2 in 1,000 new-born males. Most patients are diagnosed in the light of a clinical checkup when consulting a fertility clinic with an unfulfilled child wish. Infertility in KS patients is caused by a massive germ cell loss, leading to azoospermia in more than 90% of the adult patients. Most seminiferous tubules in the adult KS testis are degenerated or hyalinized and testicular fibrosis can be observed, starting from puberty. However, focal spermatogenesis can be found in the testis of some patients. This offers the opportunity to extract spermatozoa from the testis by testicular sperm extraction (TESE). Nevertheless, TESE is only successful in about half of the KS adults seeking to father children. The reason for the germ cell loss remains unclear. To date, it is still debated whether the testicular tissue changes and the germ cell loss seen in KS is directly caused by an altered X-linked gene expression, the altered somatic environment, or a deficiency in the germ cells. In this review, we provide an overview of the current knowledge about the germ cell loss in KS patients.

Testicular immune cells and vasculature in Klinefelter syndrome from childhood up to adulthood.

STUDY QUESTION: Is the distribution of immune cells and the testicular vasculature altered in testicular biopsies from patients with Klinefelter syndrome (KS)? SUMMARY ANSWER: Increased numbers of macrophages and mast cells, an increased expression of decorin and an increased blood vessel density were found in KS samples compared to controls. WHAT IS KNOWN ALREADY: Most KS patients are infertile due to an early germ cell loss. From puberty onwards, testicular fibrosis can be detected. How this fibrotic process is initiated remains unknown. STUDY DESIGN, SIZE, DURATION: In this study, the number of macrophages, mast cells and their secretory products were evaluated in KS, Sertoli cell only (SCO) and control patient samples. The association between immune cell numbers and level of fibrosis in KS tissue was examined. In addition, the vascularization within these testicular tissue biopsies was studied. For immunohistochemical evaluation, KS patients at different stages of testicular development were included: prepubertal (aged 4-7 years; n = 4), peripubertal (aged 11-17 years; n = 21) and adult (aged >18 years; n = 37) patients. In addition, testicular tissue biopsies of adult SCO (n = 33) and control samples for the three KS age groups (prepubertal n = 9; peripubertal n = 5; adult n = 25) were analysed. Gene expression analysis was performed on adult testicular tissue from KS (n = 5), SCO (n = 5) and control (n = 5) patients. PARTICIPANTS/MATERIALS, SETTING, METHODS: Adult (>18 years) KS, SCO and control testicular tissue biopsies were obtained during a testicular sperm extraction procedure. KS peripubertal (11-18 years), prepubertal (<11 years) and age-matched control biopsies were obtained from the biobank of the university hospital. Immunohistochemistry was used to determine the tubular structure (H/PAS), the number of spermatogonia (MAGE-A4), macrophages (CD68) and mast cells (tryptase) and the blood vessel density (Von Willebrand factor). In addition, quantitative real-time polymerase chain reaction was used to determine the expression of secretory products of macrophages and mast cells (tryptase, tumour necrosis factor alpha and decorin). MAIN RESULTS AND THE ROLE OF CHANCE: A significant increase in the number of macrophages (P < 0.0001) and mast cells (P = 0.0008) was found in the peritubular compartment of testes of adult KS patients compared to control samples. However, no association between the number of immune cells and the degree of fibrosis was observed. In adult SCO samples, a significant increase was seen for peritubular macrophage (P < 0.0001) and mast cell (P < 0.0001) numbers compared to control samples. In the interstitial compartment, a significant increase in mast cell number was found in adult SCO samples compared to KS (P < 0.0001) and control (P < 0.0001) tissue. A significant difference (P = 0.0431) in decorin expression could be detected in adult KS compared to control patients. Decorin expression was mostly seen in the walls of the seminiferous tubules. When comparing the vascularization between KS patients and age-matched controls, a significant increase (P = 0.0081) in blood vessel density could be observed only in prepubertal KS testicular tissue. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: As controls for this study, testicular tissue biopsies of men who underwent a vasectomy reversal or orchiectomy were used, but these men may not represent fertile controls. In addition, a high variability in immune cell numbers, secretory products expression and number of blood vessels could be observed amongst all patient samples. WIDER IMPLICATIONS OF THE FINDINGS: Increased numbers of macrophages and mast cells have previously been described in non-KS infertile men. Our results show that these increased numbers can also be detected in KS testicular tissue. However, no association between the number of macrophages or mast cells and the degree of fibrosis in KS samples could be detected. Decorin has previously been described in relation to fibrosis, but it has not yet been associated with testicular fibrosis in KS. Our results suggest a role for this proteoglycan in the fibrotic process since an increased expression was observed in adult KS tissue compared to controls. Impaired vascularization in KS men was suggested to be responsible for the KS-related disturbed hormone levels. Our results show a significant difference in blood vessel density, especially for the smallest blood vessels, between prepubertal KS samples and age-matched controls. This is the first study to report differences between KS and control testicular tissue at prepubertal age. STUDY FUNDING/COMPETING INTEREST(S): The project was funded by grants from the Vrije Universiteit Brussel (E.G.) and the scientific Fund Willy Gepts from the UZ Brussel (D.V.S.). D.V.S. is a post-doctoral fellow of the Fonds voor Wetenschappelijk Onderzoek (FWO; 12M2819N). No conflict of interest is declared for this research project.

Early childhood obesity: a survey of knowledge and practices of physicians from the Middle East and North Africa.

BACKGROUND: Childhood obesity is one of the most serious public health issues of the twenty-first century affecting even low- and middle-income countries. Overweight and obese children are more likely to stay obese into adulthood. Due to the paucity of data on local practices, our study aimed to assess the knowledge and practices of physicians from the Middle East and North Africa region with respect to early-onset obesity. METHODS: A specific questionnaire investigating the perception and knowledge on early-onset obesity was circulated to healthcare providers (general physicians, pediatricians, pediatric gastroenterologist, neonatologists) practicing in 17 Middle East and North African countries. RESULTS: A total of 999/1051 completed forms (95% response) were evaluated. Of all respondents, 28.9% did not consistently use growth charts to monitor growth during every visit and only 25.2% and 46.6% of respondents were aware of the correct cut-off criterion for overweight and obesity, respectively. Of those surveyed, 22.3, 14.0, 36.1, 48.2, and 49.1% of respondents did not consider hypertension, type 2 diabetes, coronary heart disease, fatty liver disease, and decreased life span, respectively, to be a long-term complication of early childhood obesity. Furthermore, only 0.7% of respondents correctly answered all survey questions pertaining to knowledge of early childhood overweight and obesity. CONCLUSION: The survey highlights the low use of growth charts in the evaluation of early childhood growth in Middle East and North Africa region, and demonstrated poor knowledge of healthcare providers on the short- and long-term complications of early-onset obesity. This suggests a need for both continued professional education and development, and implementation of guidelines for the prevention and management of early childhood overweight and obesity.

Forearm bone mineralization in recently diagnosed female adolescents with a premenarchal onset of anorexia nervosa.

OBJECTIVE: Data available on bone mineralization by peripheral quantitative computed tomography (pQCT) in adolescents with an early onset anorexia nervosa (AN) is limited. We investigated whether a disturbed bone mineralization can be observed at the distal radius in recently diagnosed female adolescents with AN and a premenarchal onset of this disease. METHOD: Twenty-four premenarchal patients with AN and 22 healthy females which were age and height matched, were selected from our reference database; both groups underwent a pQCT bone assessment at the distal radius of the nondominant arm. RESULTS: The patients age ranged between 13.3 and 18.4 years. Their percent weight loss ranged between 5 and 36% (median 23%) and occurred within the preceding 3 to 44 months. Trabecular volumetric bone mineral density of the patient group was significantly lower than the comparison group (185.6 ± 30.2 vs.209.3 ± 34.0 mm(2) ; p = 0.02). Bone cross-sectional area, bone mineral content, total volumetric bone mineral density and periosteal circumference were also lower, albeit not significantly. The bone parameters were unrelated to the under nutrition severity and duration. DISCUSSION: In premenarchal patients with AN the trabecular bone mineralization of the forearm is significantly reduced, this might be an early indicator of altered bone mineral accrual. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2016; 49:809-812).

Attitudes of parents of Klinefelter boys and pediatricians towards neonatal screening and fertility preservation techniques in Klinefelter syndrome.

UNLABELLED: To evaluate the attitude of parents of Klinefelter syndrome (KS) boys and pediatricians with regard to early detection of KS and fertility preservation, a specific questionnaire investigating the acceptability towards neonatal screening for KS and the use of testicular biopsy and sperm collection was designed. The responses of 49 pediatricians and 18 parents were evaluated. All parents and 67% of the pediatricians consider neonatal screening for KS to be a good option. A total of 83.3% of the parents agree on performing a testicular biopsy in their pubertal KS boy, 72.2% are in favor of banking spermatozoa after masturbation while 77.7% agree on spermatozoa banking after penile vibro-stimulation or rectal electro-stimulation under general anesthesia. Sixty-nine percent of pediatricians would counsel parents and KS adolescents in favor of early detection and cryopreservation of spermatozoa after masturbation, and 71.2% agrees on testicular biopsy to detect spermatozoa or eventually spermatogonial stem cells (SSCs) for cryopreservation in minor KS patients. CONCLUSION: The majority of KS parents and pediatricians, completing a specific designed questionnaire on fertility preservation modalities, were in favor of neonatal screening of KS. Both sperm collection and SSC collection are highly appreciated by parents and pediatricians, despite the currently experimental character of these fertility preservation strategies.

Optimizing Childhood Obesity Management: The Role of Edmonton Obesity Staging System in Personalized Care Pathways.

Childhood obesity, affecting 29% of 7-9-year-olds across 33 European countries, is a significant public health challenge. Its persistence into adulthood poses grave health risks influenced by genetic, environmental, and socio-economic factors. Belgium introduced a new care pathway in December 2023, based on the Edmonton Obesity Staging System for Pediatrics (EOSS-P), addressing four health domains and staging obesity severity. This pathway operates across three levels: primary care physicians, Paediatric Multidisciplinary Obesity Management Centres (PMOCs), and Centers of Expertise for Paediatric Obesity Management (CEPOs). Each stage of EOSS-P demands tailored interventions. Early stages involve dietary interventions, physical activity promotion, and behavior modifications. As obesity severity progresses, treatments intensify, encompassing psychological support, anti-obesity medications, and, in some cases, bariatric surgery. Throughout these stages, the involvement of multidisciplinary teams is crucial, emphasizing family-based approaches and continuous monitoring. This article provides detailed guidelines for healthcare professionals, delineating interventions and recommendations tailored to each EOSS-P stage. It emphasizes a holistic approach that extends beyond BMI-based diagnosis, promoting personalized care and prompt escalations between care levels, thereby ensuring optimal management of childhood obesity. This comprehensive framework aims to address the complexities of childhood obesity, emphasizing the importance of timely and targeted interventions for better health outcomes.

Near adult height and BMI changes in growth hormone treated short children with Noonan syndrome: the Belgian experience.

Introduction A variable near adult height (NAH) outcome after growth hormone (GH) therapy in Noonan syndrome (NS) patients with short stature has been reported. The main objective of this study was to evaluate NAH and body mass index (BMI) evolution in a large Belgian cohort of NS patients treated for short stature. The secondary objectives were to investigate whether sex, genotype, the presence of a thoracic deformity and/or a heart anomaly might affect NAH and to validate the recently developed NAH prediction model by Ranke et al. Methods Clinical and auxological data of GH treated short NS patients born before 2001 were extracted from the national Belgrow registry. NAH was available in 54 (35 male) genotyped NS using a gene panel of 9 genes, showing pathogenic variants in PTPN11 in 32 and in SOS1 in 5 patients, while in 17 patients gene panel analysis was inconclusive (no mutation group). Results After a median (P10; P90) duration of 5.4 (2.2-10.3) years of GH therapy with a median dose of 0.05 mg/kg/day NS patients reached a median NAH of -1.7 (-3.4; -0.8) SDS. Median total height gain was 1.1 (0.1; 2.3) SDS. Sex, genotype and the presence of a thoracic or cardiac malformation did not correlate with NAH or total height gain. Linear regression modelling revealed that height SDS at start (beta=0.90, p<0.001), mid-parental height SDS (beta =0.27; p=0.005), birth weight SDS (beta=0.15; p=0.051), age at start (beta=0.07; p=0032) were independently associated with NAH SDS. Median BMI SDS increased significantly (p<0.001) from -1.0 (-2.5; 0.0) at start to -0.2 (-1.5; 0.9) at NAH. The observed NAH in a subgroup of 44 patients with more than 3 years of GH treatment was not statistically different from the predicted NAH by the Noonan NAH prediction model of Ranke. Conclusion Long-term GH therapy at a dose of 0.05 mg/kg/day in short NS patients is effective in improving adult height and BMI, irrespective of the genotype and presence or absence of cardiac and or thoracic anomalies.

Micro RNA in Semen/Urine from Non-Obstructive Azoospermia Patients as Biomarkers to Predict the Presence of Testicular Spermatozoa and Spermatogonia.

About half of testicular sperm extraction (TESE) procedures in men with non-obstructive azoospermia (NOA), including men with Klinefelter syndrome (KS), are unsuccessful. To avoid unnecessary invasive surgery, biomarkers for spermatozoa were studied. In addition, markers for spermatogonia in testis tissue were explored. This study aimed to find biomarkers in the semen and/or urine of NOA patients to predict the presence of spermatogonia in the testis. Differentially expressed miRNAs were identified (1) between samples from patients with and without a positive TESE procedure as well as (2) between TESE-negative patients with and without spermatogonia. A total of thirteen upregulated miRNAs (ten in seminal plasma and three in urine) were found in the TESE-negative/spermatogonia-positive group compared to the TESE-negative/spermatogonia-negative group. These miRNAs could be potential biomarkers for spermatogonia; however, more research is necessary to validate their predictive power.

Peripheral precocious puberty in Li-Fraumeni syndrome: a case report and literature review of pure androgen-secreting adrenocortical tumors.

INTRODUCTION: Pure androgen-secreting adrenocortical tumors are a rare but important cause of peripheral precocious puberty. CASE PRESENTATION: Here, we report a pure androgen-secreting adrenocortical tumor in a 2.5-year-old boy presenting with penile enlargement, pubic hair, frequent erections, and rapid linear growth. We confirmed the diagnosis through laboratory tests, medical imaging, and histology. Furthermore, genetic testing detected a pathogenic germline variant in the TP53 gene, molecularly confirming underlying Li-Fraumeni syndrome. DISCUSSION: Only 15 well-documented cases of pure androgen-secreting adrenocortical tumors have been reported so far. No clinical or imaging signs were identified to differentiate adenomas from carcinomas, and no other cases of Li-Fraumeni syndrome were diagnosed in the four patients that underwent genetic testing. However, diagnosing Li-Fraumeni syndrome is important as it implies a need for intensive tumor surveillance and avoidance of ionizing radiation. CONCLUSION: In this article, we emphasize the need to screen for TP53 gene variants in children with androgen-producing adrenal adenomas and report an association with arterial hypertension.

Point-of-care applicable metabotyping using biofluid-specific electrospun MetaSAMPs directly amenable to ambient LA-REIMS.

In recent years, ambient ionization mass spectrometry (AIMS) including laser ablation rapid evaporation IMS, has enabled direct biofluid metabolome analysis. AIMS procedures are, however, still hampered by both analytical, i.e., matrix effects, and practical, i.e., sample transport stability, drawbacks that impede metabolome coverage. In this study, we aimed at developing biofluid-specific metabolome sampling membranes (MetaSAMPs) that offer a directly applicable and stabilizing substrate for AIMS. Customized rectal, salivary, and urinary MetaSAMPs consisting of electrospun (nano)fibrous membranes of blended hydrophilic (polyvinylpyrrolidone and polyacrylonitrile) and lipophilic (polystyrene) polymers supported metabolite absorption, adsorption, and desorption. Moreover, MetaSAMP demonstrated superior metabolome coverage and transport stability compared to crude biofluid analysis and was successfully validated in two pediatric cohorts (MetaBEAse, n = 234 and OPERA, n = 101). By integrating anthropometric and (patho)physiological with MetaSAMP-AIMS metabolome data, we obtained substantial weight-driven predictions and clinical correlations. In conclusion, MetaSAMP holds great clinical application potential for on-the-spot metabolic health stratification.

Efficacy and safety of a 4-year combination therapy of growth hormone and gonadotropin-releasing hormone analogue in pubertal girls with short predicted adult height.

Objectives: To improve adult height in pubertal girls with a poor height prediction, treatment with growth hormone (GH) can be used in combination with a gonadotropin releasing hormone agonist (GnRHa), to delay closure of the growth plates. However, there are few studies to support this practice, and they show conflicting results. The objective of this trial is to assess the safety and efficacy of this combination treatment in early pubertal girls with a short predicted height, in comparison with matched controls. Design patients and methods: We designed an open-label, multicenter, interventional case-control study. Early pubertal girls with predicted adult height (PAH) below -2.5 SDS, were recruited in tertiary care centers in Belgium. They were treated for four years with GH and GnRHa. The girls were followed until adult height (AH) was reached. AH vs PAH, AH vs Height at start, and AH vs Target Height (TH) were evaluated, as well as safety parameters. Control data were assembled from historical patient files or from patients who preferred not to participate in the study. Results: Sixteen girls with mean age ( ± SD) at start of 11.0 years (± 1.3) completed the study protocol and follow-up. Their mean height ( ± SD) increased from 131.3 ± 4.1 cm (-2.3 ± 0.7 SDS) at start of treatment to 159.8 ± 4.7 cm (-1.1 ± 0.7 SDS) at AH. In matched controls, height increased from 132.3 ± 4.2 cm (-2.4 ± 0.5 SDS) to 153.2 ± 3.4 cm (-2.1 ± 0.6 SDS) (p<0.001). AH surpassed initial PAH by 12.0 ± 2.6 cm in treated girls; and by 4.2 ± 3.6 cm in the controls (p<0.001). Most treated girls reached normal adult height (>-2SD) (87.5%) and 68.7% reached or superseded the target height (TH), which was the case in only a minority of the controls (37.5% and 6.2%, respectively) (p= 0.003 and 0.001). A serious adverse event possibly related to the treatment, was a fracture of the metatarsals. Conclusion: A four-year GH/GnRHa treatment in early pubertal girls with a poor PAH seems safe and results in a clinically relevant and statistically significant increase in AH compared with matched historical controls. Clinical trial registration: ClinicalTrials.gov, identifier NCT00840944.

Virtual Reality for Distraction and Relaxation in a Pediatric Hospital Setting: An Interventional Study With a Mixed-Methods Design.

Accumulating evidence supports the use of virtual reality (VR) as an effective pain and anxiety management tool for pediatric patients during specific medical procedures in dedicated patient groups. However, VR is still not widely adopted in everyday clinical practice. Feasibility and acceptability measures of clinicians' experiences are often missing in studies, thereby omitting an important stakeholder in VR use in a clinical setting. Therefore, the aim of this mixed-methods study was to investigate the feasibility, acceptability, tolerability (primary outcomes), and preliminary effectiveness (secondary outcome) of Relaxation-VR in both pediatric patients aged 4-16 years and clinicians. Relaxation-VR is a VR application prototype aimed to provide distraction and relaxation for a variety of patient populations and procedures and is used to reduce anxiety, stress (tension) and pain for children in hospital. Multiple measures of acceptability, feasibility and tolerability, and pre-to-post changes in measures of pain, anxiety, stress and happiness were assessed in pediatric patients. At the end of the study, acceptability and feasibility of VR use was assessed in clinicians. Results indicate that VR use (in particular, the Relaxation-VR prototype) for both distraction and relaxation is acceptable, feasible and tolerable for a variety of pediatric patients aged 4-16 years, as assessed in both patients and clinicians, and can reduce anxiety, pain and tension (stress), and increase happiness in a hospital setting.

Intermittent Scanning Glucose Monitoring or Predicted Low Suspend Pump Treatment: Does It Impact Time in Glucose Target and Treatment Preference? The QUEST Randomized Crossover Study.

Objective: To compare glycemic control and treatment preference in children with type 1 diabetes (T1D) using sensor augmented pump (SAP) with predictive low glucose suspend (SmartGuard®) or pump with independent intermittent scanning continuous glucose monitoring (iscCGM, Freestyle libre ®). Methods: In this open label, cross-over study, children 6 to 14 years of age, treated with insulin pump for at least 6 months, were randomized to insulin pump and iscCGM (A) or SAP with SmartGuard® (B) for 5 weeks followed by 5 additional weeks. The difference in percentages of time in glucose target (TIT), (3.9 - 8.0 mmol/l), <3 mmol/l, > 8 and 10 mmol/l, were analyzed using linear mixed models during the final week of each arm and were measured by blinded CGM (IPro2®). Results: 31 children (15 girls) finished the study. With sensor compliance > 60%, no difference in TIT was found, TIT: A 37.86%; 95% CI [33.21; 42.51]; B 37.20%; 95% CI [32.59; 41.82]; < 3 mmol/l A 2.27% 95% CI [0.71; 3.84] B 1.42% 95% CI [-0.13; 2.97]; > 8 mmol/l A 0.60% 95% CI [0.56, 0.67]; B 0.63% [0.56; 0.70]. One year after the study all participants were on CGM compared to 80.7% prior to the study, with a shift of 13/25 participants from iscCGM to SAP. Conclusions: In this study, no significant difference in glycemic control was found whether treated with SAP (SmartGuard®) or pump with iscCGM. The decision of all families to continue with CGM after the study suggests a positive impact, with preference for SmartGuard®. Clinical Trial Registration: [clinicaltrials.gov], identifier NCT03103867.