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Central precocious puberty (CPP) is a developmental disorder caused by early activation of the hypothalamic-pituitary-gonadal axis. The incidence of CPP is rapidly increasing, but the underlying mechanisms are not fully understood. Previous studies have shown that gain-of-function mutations in the KISS1R and KISS1 genes and loss-of-function mutations in the MKRN3, LIN28, and DLK1 genes may lead to early initiation of pubertal development. Recent research has also revealed the significant role of epigenetic factors such as DNA methylation and microRNAs in the regulation of gonadotropin-releasing hormone neurons, as well as the modulating effect of gene networks involving multiple variant genes on pubertal initiation. This review summarizes the genetic etiology and pathogenic mechanisms underlying CPP.

Evaluating the effect of recombinant human growth hormone treatment on sleep-related breathing disorders in toddlers with Prader-Willi syndrome: a one-year retrospective cohort study.

BACKGROUND: Recombinant human growth hormone (rhGH) therapy is beneficial for children with Prader-Willi syndrome (PWS) in improving short stature and metabolism, but the effect of early rhGH treatment on respiratory and sleep parameters for PWS children under three years old remains elusive. Thus, this study aimed to investigate the impact of rhGH treatment on sleep-related breathing disorders (SRBDs) for toddlers with PWS. METHODS: A total of 17 age-matched PWS patients receiving rhGH treatment (rhGH group) and 17 control individuals not receiving rhGH treatment (non-rhGH group) were recruited for this study between October 2018 and January 2023. Data related to polysomnography-polygraphy (PSG) and serum levels of insulin-like growth factor (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) were collected. RESULTS: The mean age in the rhGH group was 20.76 ± 9.22 months, which was comparable to that of the non-rhGH group (25.23 ± 13.81 months). The demographic and anthropometric parameters were similar across the two groups after 52 weeks of treatment. Administration of rhGH to toddlers did not exert adverse effects on the obstructive apnea-hypopnea index (OAHI), central apnea index (CAI), oxygen desaturation index (ODI), mean percutaneous oxygen saturation (SpO2), lowest SpO2, duration when SpO2 is lower than 90%, or proportion of the patients with SpO2 lower than 90%. Furthermore, the increased IGF-1 z-score and IGFBP-3 level did not worsen SRBDs. CONCLUSION: Treatment with rhGH for 52 weeks on young toddlers with PWS showed no deleterious effects on SRBDs. This shed more light on the importance of initiating rhGH therapy early in PWS patients.

Early psychomotor development and growth hormone therapy in children with Prader-Willi syndrome: a review.

Prader-Willi syndrome (PWS) is a rare genetic disorder caused by the loss of imprinted gene expression on the paternal chromosome 15q11-q13. PWS is characterized by varying degrees of early psychomotor developmental deficits, primarily in cognition, language, and motor development. This review summarizes the early mental cognitive development, language development, and motor development in patients with PWS, compares the correlation of genotype with phenotype, and provides an update regarding the effects and concerns related to potential main side effects of treatment with recombinant human growth hormone on early psycho-cognitive and motor function development along with the linear growth and body composition of children with PWS.Conclusion: Early psychomotor development is strongly correlated with the prognosis of patients with PWS; moreover, current studies support that the initiation of interventions at an early age can exert significant beneficial effects on enhancing the cognitive and linguistic development of patients with PWS and allow them to "catch up" with motor development.  What is Known: • Prader-Willi syndrome is a rare genetic disorder characterized by multisystem damage, and children with Prader-Willi syndrome are typically characterized by early developmental delays, specifically in the areas of cognitive and motor development. • Recombinant human growth hormone therapy is the only medical treatment approved for Prader-Willi syndrome. What is New: • Extensive presentation of psycho-cognitive and motor development features and genotype-phenotype correlation in children with Prader-Willi syndrome.  • The effects of growth hormone on early psychomotor development in children with Prader-Willi syndrome were thoroughly reviewed, including their short- and long-term outcomes and any associated adverse effects.

OBMeta: a comprehensive web server to analyze and validate gut microbial features and biomarkers for obesity-associated metabolic diseases.

MOTIVATION: Gut dysbiosis is closely associated with obesity and related metabolic diseases including type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). The gut microbial features and biomarkers have been increasingly investigated in many studies, which require further validation due to the limited sample size and various confounding factors that may affect microbial compositions in a single study. So far, it lacks a comprehensive bioinformatics pipeline providing automated statistical analysis and integrating multiple independent studies for cross-validation simultaneously. RESULTS: OBMeta aims to streamline the standard metagenomics data analysis from diversity analysis, comparative analysis, and functional analysis to co-abundance network analysis. In addition, a curated database has been established with a total of 90 public research projects, covering three different phenotypes (Obesity, T2D, and NAFLD) and more than five different intervention strategies (exercise, diet, probiotics, medication, and surgery). With OBMeta, users can not only analyze their research projects but also search and match public datasets for cross-validation. Moreover, OBMeta provides cross-phenotype and cross-intervention-based advanced validation that maximally supports preliminary findings from an individual study. To summarize, OBMeta is a comprehensive web server to analyze and validate gut microbial features and biomarkers for obesity-associated metabolic diseases. AVAILABILITY AND IMPLEMENTATION: OBMeta is freely available at: http://obmeta.met-bioinformatics.cn/.

Current Pubertal Development in Chinese Children and the Impact of Overnutrition, Lifestyle, and Perinatal Factors.

CONTEXT: Age of pubertal onset has been decreasing in many countries but there have been no data on pubertal development in Chinese children over the last decade. OBJECTIVE: The primary objective of the study was to evaluate the current status of sexual maturation in Chinese children and adolescents. Secondary objectives were to examine socioeconomic, lifestyle, and auxological associations with pubertal onset. METHODS: In this national, cross-sectional, community-based health survey, a multistage, stratified cluster random sampling method was used to select a nationally representative sample, consisting of 231 575 children and adolescents (123 232 boys and 108 343 girls) between 2017 and 2019. Growth parameters and pubertal staging were assessed by physical examination. RESULTS: Compared to 10 years previously, the median age of Tanner 2 breast development and menarche were similar at 9.65 years and 12.39 years respectively. However, male puberty occurred earlier with a median age of testicular volume ≥4 mL of 10.65 years. Pubertal onset did occur earlier at the extremes, with 3.3% of the girls with breast development at 6.5-6.99 years old, increasing to 5.8% by 7.5-7.99 years old. Early pubertal onset was also noted in boys, with a testicular volume ≥ 4 mL noted in 1.5% at 7.5-7.99 years, increasing to 3.5% at 8.5-8.99 years old. Obesity and overweight increased risk of developing earlier puberty relative to normal weight in both boys and girls. CONCLUSION: Over the past decade, pubertal development is occurring earlier in Chinese children. While the cause is multifactorial, overweight and obesity are associated with earlier puberty onset. The currently used normative pubertal data of precocious puberty may not be applicable to diagnose precocious puberty.

Long-term Pegylated GH for Children With GH Deficiency: A Large, Prospective, Real-world Study.

CONTEXT: The evidence of long-term polyethylene glycol recombinant human GH (PEG-rhGH) in pediatric GH deficiency (GHD) is limited. OBJECTIVE: This study aimed to examine the effectiveness and safety of long-term PEG-rhGH in children with GHD in the real world, as well as to examine the effects of dose on patient outcomes. DESIGN: A prospective, observational, posttrial study (NCT03290235). SETTING, PARTICIPANTS AND INTERVENTION: Children with GHD were enrolled from 81 centers in China in 4 individual clinical trials and received weekly 0.2 mg/kg/wk (high-dose) or 0.1 to <0.2 mg/kg/wk (low-dose) PEG-rhGH for 30 months. MAIN OUTCOMES MEASURES: Height SD score (Ht SDS) at 12, 24, and 36 months. RESULTS: A total of 1170 children were enrolled in this posttrial study, with 642 patients in the high-dose subgroup and 528 in the low-dose subgroup. The Ht SDS improved significantly after treatment in the total population (P < 0.0001), with a mean change of 0.53 ± 0.30, 0.89 ± 0.48, 1.35 ± 0.63, 1.63 ± 0.75 at 6 months, 12 months, 24 months, and 36 months, respectively. In addition, the changes in Ht SDS from baseline were significantly improved in the high-dose subgroup compared with the low-dose subgroup at 6, 12, 24, and 36 months after treatment (all P < 0.05). A total of 12 (1.03%) patients developed serious adverse events. There was no serious adverse event related to the treatment, and no AEs leading to treatment discontinuation or death occurred. CONCLUSIONS: PEG-rhGH showed long-term effectiveness and safety in treating children with GHD. Both dose subgroups showed promising outcomes, whereas PEG-rhGH 0.2 mg/kg/wk might show additional benefit.

Age-related reference intervals for serum phytosterols in children by gas chromatography-mass spectrometry and its application in diagnosing sitosterolemia.

BACKGROUND AND AIMS: Serum phytosterol profiles are essential for the diagnosis and management of sitosterolemia. However, pediatric reference interval (RI) studies are scarce and various mass spectrometry (MS) approaches for phytosterol analysis still face multiple limitations. Therefore, an optimized gas chromatography (GC)-MS assay and age-related RIs in children are both required. MATERIALS AND METHODS: Cholesterol and phytosterols (sitosterol, campesterol, cholestanol, stigmasterol, and sitostanol) were simultaneously determined by optimized GC-MS and performance was verified by the lower limit of quantification (LLOQ), linearity, precision, recovery, matrix effects, and method comparison. Healthy children (247 males and 263 females) were recruited, sex and age dependence were assessed using quantile regression (2.5th percentile and 97.5th percentile), and RIs were established according to Clinical and Laboratory Standards Association guideline C28-A3. These RIs were validated in 19 patients with sitosterolemia and 23 patients with hypercholesterolemia. RESULTS: The optimized method shortened the sample processing time by approximately 60 min. Among the five phytosterols, all precision, recoveries (ranging from 89.97% to 104.94%), and relative matrix effects (%CV: ranging from 0.08% to 13.88%) met the specifications. GC-MS showed good agreement with lower cholesterol concentrations compared to conventional enzymatic methods. No significant differences between males and females were observed for all phytosterols, but age dependency was found and age-related RIs were established accordingly. Five phytosterols were significantly higher than RIs in patients with sitosterolemia. CONCLUSION: We established age-related RIs for five phytosterols in children based on an optimized GC-MS assay, providing a screening tool for the diagnosis of sitosterolemia in children.

The uncovered biases and errors in clinical determination of bone age by using deep learning models.

OBJECTIVES: To evaluate AI biases and errors in estimating bone age (BA) by comparing AI and radiologists' clinical determinations of BA. METHODS: We established three deep learning models from a Chinese private dataset (CHNm), an American public dataset (USAm), and a joint dataset combining the above two datasets (JOIm). The test data CHNt (n = 1246) were labeled by ten senior pediatric radiologists. The effects of data site differences, interpretation bias, and interobserver variability on BA assessment were evaluated. The differences between the AI models' and radiologists' clinical determinations of BA (normal, advanced, and delayed BA groups by using the Brush data) were evaluated by the chi-square test and Kappa values. The heatmaps of CHNm-CHNt were generated by using Grad-CAM. RESULTS: We obtained an MAD value of 0.42 years on CHNm-CHNt; this result indicated an appropriate accuracy for the whole group but did not indicate an accurate estimation of individual BA because with a kappa value of 0.714, the agreement between AI and human clinical determinations of BA was significantly different. The features of the heatmaps were not fully consistent with the human vision on the X-ray films. Variable performance in BA estimation by different AI models and the disagreement between AI and radiologists' clinical determinations of BA may be caused by data biases, including patients' sex and age, institutions, and radiologists. CONCLUSIONS: The deep learning models outperform external validation in predicting BA on both internal and joint datasets. However, the biases and errors in the models' clinical determinations of child development should be carefully considered. KEY POINTS: • With a kappa value of 0.714, clinical determinations of bone age by using AI did not accord well with clinical determinations by radiologists. • Several biases, including patients' sex and age, institutions, and radiologists, may cause variable performance by AI bone age models and disagreement between AI and radiologists' clinical determinations of bone age. • AI heatmaps of bone age were not fully consistent with human vision on X-ray films.

Early recombinant human growth hormone treatment improves mental development and alleviates deterioration of motor function in infants and young children with Prader-Willi syndrome.

BACKGROUND: Recombinant human growth hormone (rhGH) therapy has shown to improve height and body composition in children with Prader-Willi syndrome (PWS), the evidence of early rhGH treatment on motor and mental development is still accumulating. This study explored the time effect on psychomotor development, anthropometric indexes, and safety for infants and young children with PWS. METHODS: A phase 3, single-arm, multicenter, self-controlled study was conducted in six sites. Patients received rhGH at 0.5 mg/m2/day for first four weeks, and 1 mg/m2/day thereafter for up to 52 weeks. Motor development was measured using Peabody Developmental Motor Scales-second edition, mental development using Griffiths Development Scales-Chinese (GDS-C). Height standard deviation score (SDS), body weight SDS, and body mass index (BMI) SDS were also assessed. RESULTS: Thirty-five patients were enrolled totally. Significant improvements were observed in height, body weight, and BMI SDS at week 52; GDS-C score showed significant improvement in general quotient (GQ) and sub-quotients. In a linear regression analysis, total motor quotient (TMQ), gross motor quotient (GMQ), and fine motor quotient were negatively correlated with age; however, treatment may attenuate deterioration of TMQ and GMQ. Changes in GQ and locomotor sub-quotient in < 9-month group were significantly higher than ≥ 9-month group. Mild to moderate severity adverse drug reactions were reported in six patients. CONCLUSION: Fifty-two-week treatment with rhGH improved growth, BMI, mental development, and lessened the deterioration of motor function in infants and young children with PWS. Improved mental development was more pronounced when instituted in patients < 9 months old.

Construction of a new complete growth reference for urban Chinese children.

BACKGROUND: Growth chart is a valuable clinical tool to monitor the growth and nutritional status of children. A growth chart widely used in China is based on the merged data sets of national surveys in 2005. We aimed to establish an up-to-date, complete growth curve for urban Chinese children and adolescents with a full range of ages. METHODS: Using data collected in a large-scale, cross-sectional study (Prevalence and Risk factors for Obesity and Diabetes in Youth (PRODY), 2017-2019), we analyzed 201,098 urban children aged 3 to 18 years from 11 provinces, autonomous regions, and municipalities that are geographically representative of China. All participants underwent physical examinations. Sex-specific percentiles of height-for-age and weight-for-age were constructed by Generalized Additive Models for Location Scale and Shape (GAMLSS) model. We also compared the median values of height-for-age or weight-for-age between our growth chart and the established growth reference using Welch-Satterthwaite T-Test. RESULTS: Consistent with the established growth reference, we observed that the P50 percentile of height-for-age reached plateaus at the age of 15 years (172 cm) and 14 years (160 cm) for boys and girls, respectively. In addition, boys aged 10 ~ 14 years and girls aged 10 ~ 12 years exhibited the most dramatic weight difference compared to those of other age groups (19.5 kg and 10.3 kg, respectively). However, our growth chart had higher median values of weight-for-age and height-for-age than the established growth reference with mean increases in weight-for-age of 1.36 kg and 1.17 kg for boys and girls, respectively, and in height-for-age of 2.9 cm and 2.6 cm for boys and girls, respectively. CONCLUSIONS: Our updated growth chart can serve as a reliable reference to assess the growth and nutritional status in urban Chinese children throughout the entire childhood.

Population pharmacokinetic/pharmacodynamic analysis of PEG-rhGH enhances confidence in exploring dosing schemes with longer intervals.

BACKGROUND AND OBJECTIVES: PEG-rhGH (Jintrolong®, 0.2 mg/kg/week) is approved in China for the treatment of growth hormone deficiency (GHD) in children. Although 0.2 mg/kg/2 weeks PEG-rhGH failed the non-inferiority threshold of 20% compared with 0.2 mg/kg/week PEG-rhGH, it notably increases serum IGF-1 levels and height velocity in a phase IV trial. In the absence of investigation on the relationship between pharmacokinetics and pharmacodynamics, this analysis aimed to build a population pharmacokinetic/pharmacodynamic (PopPK/PD) model to characterize the relationship between serum PEG-rhGH concentration and serum insulin-like growth factor-1 (IGF-1) levels after subcutaneously administration of PEG-rhGH and to explore the possibility of flexible dosing schemes and improve the clinical monitor practice of IGF-1 levels. METHODS: A total of 41 subjects were included for the PopPK analysis, consisting of 30 healthy adults (single dose of 0.1-0.4 mg/kg) and 11 GHD children (multiple doses of 0.2 mg/kg/2 weeks for 26 consecutive weeks). Only GHD children were included for the PopPK/PD analysis. The time courses of serum PEG-rhGH concentrations in healthy adults and GHD children and those of serum IGF-1 levels stimulated by serum PEG-rhGH were well developed with non-linear mixed-effects modeling. RESULTS: Serum PEG-rhGH pharmacokinetics after subcutaneous administration were adequately described by a one-compartment model with a zero-order input into the absorption compartment followed by first-order absorption dictating absorption into the central compartment, with a dual elimination process consisting of a capacity limited process and a non-capacity limited process. Body weight was a significant covariate. The drug effects on IGF-1 levels were adequately described by a turnover model with saturable effect relationship. IGF-1 responses at the various dosing scheme scenarios were simulated, and illustrated that dosing schemes with intervals longer than the approved one week could be promising, which may provide comparable peaks and average IGF-1 levels and IGF-1 SDS to dosing schemes that have been clinically proven to be tolerated and effective. An accurate prediction of the time course of the effect of various dosing schemes may assist the clinical monitoring practice. CONCLUSIONS: This pharmacokinetic/pharmacodynamic analysis suggested that longer intervals or higher dosing strengths (e.g., 0.3 mg/kg/10 days) in children with GHD are promising compared with the approved dosing scheme (0.2 mg/kg/week). Our simulation may assist the clinical monitoring of the PEG-rhGH therapy.

Functional and metabolic alterations of gut microbiota in children with new-onset type 1 diabetes.

Gut dysbiosis has been linked to type 1 diabetes (T1D); however, microbial capacity in T1D remains unclear. Here, we integratively profiled gut microbial functional and metabolic alterations in children with new-onset T1D in independent cohorts and investigated the underlying mechanisms. In T1D, the microbiota was characterized by decreased butyrate production and bile acid metabolism and increased lipopolysaccharide biosynthesis at the species, gene, and metabolite levels. The combination of 18 bacterial species and fecal metabolites provided excellently discriminatory power for T1D. Gut microbiota from children with T1D induced elevated fasting glucose levels and declined insulin sensitivity in antibiotic-treated mice. In streptozotocin-induced T1D mice, butyrate and lipopolysaccharide exerted protective and destructive effects on islet structure and function, respectively. Lipopolysaccharide aggravated the pancreatic inflammatory response, while butyrate activated Insulin1 and Insulin2 gene expression. Our study revealed perturbed microbial functional and metabolic traits in T1D, providing potential avenues for microbiome-based prevention and intervention for T1D.

Long-acting PEGylated growth hormone in children with idiopathic short stature.

Objective: To evaluate the safety and efficacy of weekly PEGylated-recombinant human growth hormone (PEG-rhGH) in children with idiopathic short stature (ISS) in China. Design and methods: This was a multicenter, phase II study in which all subjects were randomized 1:1:1 to weekly s.c. injections of PEG-rhGH 0.1 (low-dose (LD) group) or 0.2 mg/kg/week (high-dose (HD) group) or control for 52 weeks. The primary end point was change (Δ) in height s.d. score (HT-SDS) from baseline to week 52. Secondary end points were height velocity (HV), bone maturity, insulin-like growth factor-1 (IGF-1) SDS, and IGF-1/insulin-like growth factor-binding protein-3 (IGFBP-3) molar ratio. Results: A total of 360 children with ISS were recruited in the study (n = 120 in each group). At week 52, ΔHT-SDS was 0.56 ± 0.26, 0.98 ± 0.35, and 0.20 ± 0.26 in the LD, HD, and control groups, respectively (within-group P < 0.0001; intergroup P < 0.0001). Statistically significant values of ΔHV, IGF-1, IGF-1/IGFBP-3 ratio, and IGF-1 SDS at week 52 from baseline were observed in both treatment groups (P < 0.0001). There were clear dose-dependent responses for all auxological variables. PEG-rhGH was well tolerated throughout the treatment period with treatment-emergent adverse events (TEAEs) reported in 86.5%, 84.6%, and 91.3% of children in the HD, LD, and control groups, respectively. The incidence of TEAEs was similar in all treatment groups despite the difference in doses. A total of 27 (8.7%) children experienced drug-related TEAEs. Conclusion: Fifty-two-week treatment with PEG-rhGH 0.1 or 0.2 mg/kg/week achieved significant improvement in HT-SDS and other growth-related variables, including HV, IGF-1 SDS, and IGF-1/IGFBP-3 ratio, in a dose-dependent manner. Both doses were well tolerated with similar safety profiles.

Risk factors for obesity and overweight in Chinese children: a nationwide survey.

OBJECTIVE: This study aimed to analyze a comprehensive set of potential risk factors for obesity and overweight among Chinese children with a full range of ages and with wide geographical coverage. METHODS: In the Prevalence and Risk Factors for Obesity and Diabetes in Youth (PRODY) study (2017-2019), the authors analyzed 193,997 children aged 3 to 18 years from 11 provinces, autonomous regions, and municipalities that are geographically representative of China. All participants underwent physical examinations, and their caregivers completed questionnaires including dietary, lifestyle, familial, and perinatal information of participants. A multilevel multinomial logistic regression model was used to evaluate the potential risk factors. RESULTS: Among the actionable risk factors that were measured, higher consumption frequencies of animal offal (odds ratios [OR] for an additional time/day = 0.91, 95% CI: 0.88-0.95, same unit for OR below unless specified otherwise), dairy products (0.91, 95% CI: 0.88-0.94), freshwater products (0.94, 95% CI: 0.91-0.96), staple foods (0.94, 95% CI: 0.92-0.96), and coarse food grain (OR for every day vs. rarely = 0.92, 95% CI: 0.86-0.98) were associated with lower relative risk of obesity. However, higher restaurant-eating frequency (OR for >4 times/month vs. rarely = 1.21, 95% CI: 1.15-1.29) and longer screen-viewing duration (OR for >2 hours vs. <30 minutes = 1.16, 95% CI: 1.10-1.22) were associated with higher relative risk of obesity. Increased exercise frequency was associated with the lowest relative risk of obesity (OR for every day vs. rarely = 0.72, 95% CI: 0.68-0.77). CONCLUSIONS: Changes in lifestyle and diet of Chinese children may help relieve their obesity burden.

Gonadal tumor risk in pediatric and adolescent phenotypic females with disorders of sex development and Y chromosomal constitution with different genetic etiologies.

Objectives: This retrospective study sought to investigate the risk and proportion of gonadal neoplasms in phenotypic female pediatric patients with DSD and the presence of the Y chromosome and different genetic backgrounds in a single Chinese center. Materials and Methods: From January 2012 to December 2020, pediatric and adolescent patients with DSD and the presence of the Y chromosome who had unambiguous female genitalia and underwent bilateral gonadectomy or gonadal biopsy were included in this study. Patients' demographics, karyotype, laboratory test results, gross pathology, and histology of gonadal tissue were all collected. The patients were divided into three groups based on their different genetic backgrounds, and the percentage of gonadal tumors was calculated to assess the risk of gonadal tumor and malignancy by etiology. Results: A total of 22 patients with DSD and an unambiguous female phenotype with a Y chromosome were recruited. The mean age was 10.91 ± 4.99 years (9 months to 19 years). Gonadal neoplasia was confirmed in six (27.3%) cases by pathological examination of surgical gonadal tissue samples. Among 44 gonadal samples from these 22 patients, the following were identified: five gonadoblastomas, three dysgerminomas, and two Leydig cell tumors. The youngest patient with a tumor was a 2-year-old girl with 46,XY complete gonadal dysgenesis (46,XY CGD or Swyer syndrome) and bilateral gonadoblastoma. Patients with 46,XY complete gonadal dysgenesis (4/6; 66.7%) had the highest tumor occurrence rate. Among 10 patients with Turner syndrome with the presence of the Y chromosome, only one patient was diagnosed with a gonadal tumor. Leydig cell tumor was diagnosed in only one of six patients with 46,XY androgen synthesis/action disorders. Conclusion: Pediatric patients with 46,XY complete gonadal dysgenesis had a significantly increased risk of developing gonadal tumors and underwent prophylactic gonadectomy as soon as the diagnosis was confirmed, whereas those with Turner syndrome with Y chromosome and 46,XY androgen synthesis/action disorders had a relatively low risk. In view of the limited number of patients, a large multicenter study with close follow-ups is needed to support these conclusions.

Association between new onset type 1 diabetes and real-world antibiotics and neonicotinoids' exposure-related gut microbiota perturbation.

BACKGROUND: The real-world exposure levels of non-therapeutic antibiotics and neonicotinoids in type 1 diabetes (T1D) children and their associations as environmental triggers through gut microbiota shifts remained unknown. We thus investigated the antibiotics and neonicotinoids' exposure levels and their associations with gut microbiota in pediatric T1D. METHODS: Fifty-one newly onset T1D children along with 67 age-matched healthy controls were recruited. Urine concentrations of 28 antibiotics and 12 neonicotinoids were measured by mass spectrometry. Children were grouped according to the kinds of antibiotics' and neonicotinoids' exposures, respectively. The 16S rRNA of fecal gut microbiota was sequenced, and the correlation with urine antibiotics and neonicotinoids' concentrations was analyzed. RESULTS: The overall detection rates of antibiotics were 72.5% and 61.2% among T1D and healthy children, whereas the neonicotinoids detection rates were 70.6% and 52.2% (P = 0.044). Children exposed to one kind of antibiotic or two or more kinds of neonicotinoids had higher risk of T1D, with the odd ratios of 2.579 and 3.911. Furthermore, co-exposure to antibiotics and neonicotinoids was associated with T1D, with the odd ratio of 4.924. Antibiotics or neonicotinoids exposure did not affect overall richness and diversity of gut microbiota. However, children who were exposed to neither antibiotics nor neonicotinoids had higher abundance of Lachnospiraceae than children who were exposed to antibiotics and neonicotinoids alone or together. CONCLUSION: High antibiotics and neonicotinoids exposures were found in T1D children, and they were associated with changes in gut microbiota featured with lower abundance of butyrate-producing genera, which might increase the risk of T1D.

Characterization of the oral microbiome of children with type 1 diabetes in the acute and chronic phases.

Background and Aim: The relationship between the oral microbiota and type 1 diabetes (T1D) remains unclear. We aimed to evaluate the variations in the oral microbiome in T1D and identify potentially associated bacterial factors. Methods: We performed high-throughput sequencing of the V3-V4 area of the 16S rRNA gene to profile the oral bacterial composition of 47 healthy children (CON group), 46 children with new-onset T1D in the acute phase (NT1D group), and 10 children with T1D in the chronic phase receiving insulin treatment (CT1D group). Multivariate statistical analysis of sequencing data was performed. Results: Compared to the CON group, the NT1D group was characterized by decreased diversity and increased abundance of genera harboring opportunistic pathogens, while this trend was partially reversed in the CT1D group. Differential genera between groups could distinguish the NT1D group from the CON group (AUC = 0.933) and CT1D group (AUC = 0.846), respectively. Moreover, T1D-enriched genera were closely correlated with HbA1c, FBG and WBCs levels. Conclusion: Our results showed that the acute phase of T1D was characterized by oral microbiota dysbiosis, which could be partially ameliorated via glycemic control. The possible role of oral microbiota dysbiosis on oral health and systemic metabolic status in T1D warrants further mechanistic investigation.

Clinical Incidence and Characteristics of Newly Diagnosed Type 1 Diabetes in Chinese Children and Adolescents: A Nationwide Registry Study of 34 Medical Centers.

Objective: To investigate the clinical incidence and characteristics of type 1 diabetes mellitus (T1DM) of children and adolescents at the time of initial diagnosis in China. Methods: Data on all pediatric patients with newly diagnosed T1DM were retrospectively collected from 34 medical centers in 25 major cities in China from January 2015 to January 2020. Patients were classified into three age groups: <5 years, 5 to <10 years, and ≥10 years of age. The same patient population was also categorized into diabetic ketoacidosis (DKA) and non-DKA groups based on clinical criteria. Results: The mean annual clinical incidence of T1DM was 3.16/100,000 from the years 2015 to 2019. A total of 6,544 patients with newly diagnosed T1DM aged 0-16 years (median 7.84 ± 3.8) were studied [ages <5 years (29.3%), 5 to <10 years (38.7%), and ≥10 years (32%)], 52.4% of them were women. In total, 90.5% of the cases were occurred in individuals without a family history. Patients had lower C-peptide (CP) and body mass index (BMI) z scores when compared with healthy children, 41.8% of them had measurable T1DM-related antibodies and 52.7% had DKA. Among all three age groups, the <5 years group had the lowest BMI z score, CP, and glycated hemoglobin (HbA1c) on average, while it had the highest incidence rate of DKA (56.9%). Compared to the non-DKA group, the DKA group was significantly younger, with a lower BMI z score and CP, higher antibody positive rate, HbA1c, and the rate of insulin pump therapy. Conclusion: The clinical incidence of T1DM in children and adolescents in China was 3.16/100,000. Patients with DKA at the first diagnosis of T1DM have a worse ß-cell function. Public health measures for the prevention and treatment of T1DM should focus on preschoolers (aged <5 years) in particular, considering the severity and the highest frequency of DKA in this age group. More efforts should be dedicated to early screening and diagnosis of the T1DM.

Nationwide Trends of Pediatric Obesity and BMI z-Score From 2017-2021 in China: Comparable Findings From Real-World Mobile- and Hospital-Based Data.

Introduction: Lifestyle changes including COVID-19 lockdown cause weight gain and may change obesity trends; however, timely changes are largely unknown and monitoring measures are usually lack. This first large-scale study aimed to analyze the real-world national trends of obesity prevalence of Chinese children in the past five years, and the impact of COVID-19 pandemic on pediatric obesity development through both mobile- and hospital-based data. Methods: This study included children aged 3 to 19 years old all over China from January 2017 to April 2021. Hospital-measured and parent-reported cases from XIGAO database were analyzed. Body mass index (BMI) z-score calculation and obesity status evaluation were made according to Chinese standards. We evaluated obesity/overweight prevalence over the past five years and the changes of BMI z-score during COVID-19 lockdown. Results: A total of 656396 children from 31 provinces were involved, including 447481 hospital-measured cases and 208915 parent-reported cases. The obesity and overweight prevalence were 8.05% (95%CI 7.76%-8.39%) and 10.06% (95%CI 10.79%-11.55%), comparable to those of China National Nutrition Surveys during 2015-2019. Northern China had the highest obesity prevalence. Parent-reported data had higher obesity/overweight prevalence than hospital-measured data (18.3% [95%CI 17.7%-18.9%] vs. 21.7% [95%CI 20.7%-23.0%]). The trend of obesity prevalence remained stable with slight decrease, but COVID-19 lockdown caused a significant increase of 1.86% in 2020. Both mobile- and hospital-based data showed weight gain in the first half of 2020. High BMI z-score increase were found among primary and junior middle school children, and children in northeast area during lockdown. Conclusion: Weight gain during COVID-19 among Chinese children had regional differences and mainly affect primary and junior middle school children, thus warrants targeted interventions. The mobile growth assessment based on parent-reported data was a feasible, efficient and timely way for obesity monitoring among Chinese children, especially during epidemic.

A Randomized Controlled Phase 3 Study on the Efficacy and Safety of Recombinant Human Growth Hormone in Children With Idiopathic Short Stature.

Background: To evaluate the safety and efficacy of daily somatropin (Jintropin®), a recombinant human growth hormone, in prepubertal children with ISS in China. Methods: This study was a multicenter, randomized, controlled, open-label, phase 3 study. All subjects were randomized 3:1 to daily somatropin 0.05 mg/kg/day or no treatment for 52 weeks. A total of 481 subjects with a mean baseline age of 5.8 years were enrolled in the study. The primary endpoint was change in (△) height standard deviation score (HT-SDS) for chronological age (CA). Secondary endpoints included △height from baseline; △bone age (BA)/CA; △height velocity (HV) and △insulin-like growth factor 1 (IGF-1 SDS). Results: △HT-SDS at week 52 was 1.04 ± 0.31 in the treatment group and 0.20 ± 0.33 in the control group (P < 0.001). At week 52, statistical significance was observed in the treatment group compared with control for △height (10.19 ± 1.47 cm vs. 5.85 ± 1.80 cm; P < 0.001), △BA/CA (0.04 ± 0.09 vs. 0.004 ± 0.01; P < 0.001), △HV (5.17 ± 3.70 cm/year vs. 0.75 ± 4.34 cm/year; P < 0.001), and △IGF-1 SDS (2.31 ± 1.20 vs. 0.22 ± 0.98; P < 0.001). The frequencies of treatment-emergent adverse events (TEAEs) were similar for the treatment and the control groups (89.8% vs. 82.4%); most TEAEs were mild to moderate in severity and 23 AEs were considered study-drug related. Conclusions: Daily subcutaneous administration of somatropin at 0.05 mg/kg/day for 52 weeks demonstrated improvement in growth outcomes and was well tolerated with a favorable safety profile. Trial Registration: ClinicalTrials.gov (identifier: NCT03635580). URL: https://clinicaltrials.gov/ct2/show/NCT03635580.