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Pubertal children with significant growth retardation represent a considerable therapeutic challenge. In growth hormone (GH) deficiency, and in those without identifiable pathologies (idiopathic short stature), the impact of using GH is significantly hindered by the relentless tempo of bone age acceleration caused by sex steroids, limiting time available for growth. Estrogen principally modulates epiphyseal fusion in females and males. GH production rates and growth velocity more than double during puberty, and high-dose GH use has shown dose-dependent increases in linear growth, but also can raise insulin-like growth factor I concentrations supraphysiologically, and increase treatment costs. Gonadotropin-releasing hormone analogs (GnRHas) suppress physiologic puberty, and when used in combination with GH can meaningfully increase height potential in males and females while rendering adolescents temporarily hypogonadal at a critical time in development. Aromatase inhibitors (AIs) block androgen to estrogen conversion, slowing down growth plate fusion, while allowing normal virilization in males and stimulating longitudinal bone growth via androgen receptor effects on the growth plate. Here, we review the physiology of pubertal growth, estrogen and androgen action on the epiphyses, and the therapeutic impact of GH, alone and in combination with GnRHa and with AIs. The pharmacology of potent oral AIs, and pivotal work on their efficacy and safety in children is also reviewed. Time-limited use of AIs is a viable alternative to promote growth in pubertal males, particularly combined with GH. Use of targeted growth-promoting therapies in adolescence must consider the impact of sex steroids on growth plate fusion, and treatment should be individualized.

Context Growth hormone (GH) therapy can increase linear growth in patients with growth hormone deficiency (GHD), Turner syndrome (TS), Noonan syndrome (NS), and Prader-Willi syndrome (PWS), although outcomes vary by disease state. Objective To assess growth and identify factors associated with growth response with long-term GH therapy. Methods Data from pediatric patients with GHD, TS, NS, and PWS obtained at GH treatment initiation (baseline) and annually for 5 years in the ANSWER Program and NordiNet® IOS were analyzed retrospectively. Height standard deviation score (HSDS) was assessed over time, and multivariate analyses determined variables with significant positive effects on growth outcomes in each patient cohort. Results Data from patients with GHD (n = 12 683), TS (n = 1307), NS (n = 203), and PWS (n = 102) were analyzed. HSDS increased over time during GH treatment in all cohorts. Factors with significant positive effects on ΔHSDS were younger age at GH initiation and lower HSDS at baseline (all cohorts) and higher GH dose (GHD and TS only); sex had no effect in any cohort. The modeling analysis showed that ΔHSDS was greatest in year 1 and attenuated over consecutive years through year 5. Estimated least-squares mean ΔHSDS values at year 5 by cohort were 1.702 (females) and 1.586 (males) in GHD, 1.033 in TS, 1.153 in NS, and 1.392 in PWS. Conclusion Long-term GH therapy results in large increases in HSDS in patients with GHD, TS, NS, and PWS. Greater gains in HSDS can be obtained with higher GH doses and earlier initiation of treatment.

Sex chromosome aneuploidies (SCAs), including 47,XXY, 47,XXX, 47,XYY, and supernumerary variants, occur collectively in approximately one of 500 live births. Clinical phenotypes are highly variable resulting in previous ascertainment rates estimated to be only 10%-25% during a lifetime. Historically, prenatal SCA diagnoses were incidental findings, accounting for ≤10% of cases, with the majority of diagnoses occurring postnatally during evaluations for neurodevelopmental, medical, or infertility concerns. The initiation of noninvasive prenatal screening (NIPS) in 2012 and adoption into standardized obstetric care provides a unique opportunity to significantly increase prenatal ascertainment of SCAs. However, the impact NIPS has had on ascertainment of SCAs is understudied, particularly for those who may defer diagnostic testing until after birth. This study evaluates the timing of diagnostic testing following positive NIPS in 152 infants with SCAs and potential factors influencing this decision. Eighty-seven (57%) elected to defer diagnostic testing after a positive NIPS until birth, and 8% (7/87) of those confirmed after birth were found to have discordant results on postnatal diagnostic testing, most of which would have influenced genetic counseling.

We characterize karyotypic and phenotypic features of a cohort of patients with Turner syndrome (TS) and lymphedema (LD). Medical records from two large TS specialized pediatric clinics were reviewed retrospectively. Seventy-one patients with TS and history of LD were identified, mean age 15.9 ± 7.71 years. Reported LD onset was in infancy in 72% of patients, with 56% (40/71) reporting LD present at birth. LD affected hands in 29% of patients, feet in 57%, and both hands and feet in 25%. 46% reported LD was a current problem, with 11% stating it was present but not a problem. 73% (52/71) of children in this cohort had the 45,X karyotype. The remainder had mosaic/complex karyotypes. 55% of children had congenital heart disease and 10% had renal anomalies. 76% were on growth hormone treatment, 52% had a history of estrogen replacement. Lymphedema is a frequently under-documented comorbidity in Turner syndrome, with limited data currently available. Analysis of a larger cohort comparing patients with TS with and without LD is underway including the role of growth hormone and estrogen replacement in LD. Given that new therapies are being developed for LD in other genetic conditions, a better understanding of LD in Turner syndrome is important for management considerations. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Context Daily growth hormone (GH) injections can be burdensome for patients and carers. Somapacitan is a long-acting, reversible albumin-binding GH derivative in development for once-weekly administration in patients with growth hormone deficiency (GHD). Objective The objective of this study is to evaluate the efficacy, safety, and tolerability of once-weekly somapacitan vs once-daily GH. Design REAL 3 is a multicenter, randomized, controlled, double-blind (somapacitan doses), phase 2 study with a 26-week main and 26-week extension phase (NCT02616562). Setting This study took place at 29 sites in 11 countries. Patients Fifty-nine GH treatment-naive prepubertal children with GHD were randomly assigned; 58 completed the trial. Interventions Interventions comprised 3 somapacitan doses (0.04 [n = 16], 0.08 [n = 15], or 0.16 mg/kg/wk [n = 14]) and daily GH (0.034 mg/kg/d [n = 14]), administered subcutaneously. Main Outcome Measures The primary end point was height velocity (HV) at week 26. Secondary efficacy end points included HV SD score (SDS) and insulin-like growth factor-I (IGF-I) SDS. Results At week 26, mean (SD) annualized HV for the somapacitan groups was 8.0 (2.0), 10.9 (1.9), and 12.9 (3.5) cm/year, respectively, vs 11.4 (3.3) cm/year for daily GH; estimated treatment difference (somapacitan 0.16 mg/kg/week—daily GH): 1.7 [95% CI –0.2 to 3.6] cm/year. HV was sustained at week 52, and significantly greater with somapacitan 0.16 mg/kg/week vs daily GH. Mean (SD) change from baseline in HV SDS at week 52 was 4.72 (2.79), 6.14 (3.36), and 8.60 (3.15) for the somapacitan groups, respectively, vs 7.41 (4.08) for daily GH. Model-derived mean (SD) IGF-I SDS for the somapacitan groups was −1.62 (0.86), −1.09 (0.78), and 0.31 (1.06), respectively, vs −0.40 (1.50) observed for daily GH. Safety and tolerability were consistent with the profile of daily GH. Conclusions In children with GHD, once-weekly somapacitan 0.16 mg/kg/week provided the closest efficacy match with similar safety and tolerability to daily GH after 26 and 52 weeks of treatment. A short visual summary of our work is available (1).

Objective To develop a multicenter, multistakeholder, prospective clinical registry of children and adolescents with migraine to support the collection of real-world data of sufficient quality to support regulatory submissions and provide site-based infrastructure support for future clinical trials. Background As new migraine treatments come to market, pediatric efficacy and safety trials of these agents are needed. A clinical registry is an ideal regulatory strategy to provide both real-world data and site infrastructure to execute these trials. Design Multicenter, multistakeholder, prospective real-world data clinical registry of children and adolescents, 4-17 years of age, diagnosed with migraine with or without aura. Participants will be followed for up to 12 months at 3-month intervals, with interval recording of clinical data at study sites and self-reported data via mobile health application, as well as biobanking. We developed electronic case report forms that incorporated routinely collected clinical data with National Institute of Neurological Disorders and Stroke Headache Common Data Elements (Version 2.0). All data are captured in a 21 CFR Part 11 - compliant electronic data capture system - augmented by a real-time, web-based, and customizable data visualization platform. We engaged vendors to provide ancillary biobanking, patient data entry, and data visualization services. Results We used an iterative and highly collaborative multistakeholder approach to design and implement a streamlined registry protocol with input from all participating US sites. At each design and implementation step, we received input from therapeutic area experts, the US Food and Drug Administration (FDA), the National Institutes of Health, patient and parent advocates, health technology partners, drug developers, and site-based clinical investigators. The registry is governed by a multistakeholder steering committee with representation from sites, industry partners, patient advocates, and a member from the FDA (non-voting with respect to steering committee matters). The multistakeholder and site-driven approach to registry design and execution was highly efficient and resulted in the first patient enrolled within 6 months of concept development. Conclusions By ensuring regulatory compliant implementation of the registry, we created both a source of real-world data and a multisite platform for the conduct of future clinical trials that can be submitted to regulatory authorities to support inclusion of pediatric data in approved drug labeling. A highly collaborative approach with broad stakeholder engagement at all stages of the registry development was a key to our operational success.

Growth hormone (GH) is used to treat short stature and growth failure associated with growth disorders. Birth size and GH status variably modulate response to GH therapy. The aim of this study was to determine the effect of birth size on response to GH therapy, and to determine the impact of GH status in patients born small for gestational age (SGA) on response to GH therapy. Data from the prospective, non-interventional American Norditropin® Studies: Web-Enabled Research (ANSWER) Program were analyzed for several growth outcomes in response to GH therapy over 3 years. GH-naïve children from the ANSWER Program were included in this analysis: SGA with peak GH ≥10 ng/mL (20 mIU/l), SGA with peak GH10 ng/mL (20 mIU/l), isolated growth hormone deficiency (IGHD) born SGA, IGHD not born SGA, and idiopathic short stature. For patients with IGHD, those who did not meet criteria for SGA at birth showed greater improvements in height SDS and BMI SDS than patients with IGHD who met criteria for SGA at birth. For patients born SGA, response to GH therapy varied with GH status. Therefore, unlike previous guidelines, we recommend that GH status be established in patients born SGA to optimize GH therapy.

To examine the independent contribution of risk factors developing during pregnancy to subsequent risk of obesity in young children.We conducted a historical cohort study using data from electronic medical records of mothers and their 3,302 singleton offspring born between 2004 and 2007 at a community-based obstetric facility who attended a 4-year well visit at a pediatric practice network. The child's body mass index (BMI) z score at age 4 years was studied in relation to the mother's gestational weight gain, gestational diabetes mellitus, gestational hypertension or preeclampsia, and prenatal tobacco use. Institute of Medicine categories defined excess and inadequate gestational weight gain at term. Analysis of variance and multiple linear regression were used to test their independent relation to BMI.Mothers were white (39%), African American (46%), and of Hispanic ethnicity (11%); 46% were privately insured. The association of net gestational weight gain with the child's BMI z score was significant after adjustment for prepregnancy maternal factors (P.001); gestational diabetes mellitus, gestational hypertension, and tobacco use were not significant in adjusted models. Children of mothers with excess gestational weight gain had a higher mean BMI z score (P.001) but a significant association was observed only for inadequate gestational weight gain after adjusting for prepregnancy BMI and other covariates. Prepregnancy BMI (P.001), Hispanic ethnicity (P.001), and being married (P.05) were independently associated with increasing BMI z score of the offspring.Preconception maternal factors had a greater influence on child obesity than prenatal factors. The gestational weight gain category was independently related to BMI z score of 4 year olds, but this association was significant only for mothers with inadequate gestational weight gain.II.

The overall health of the United States' (U.S.) population has been surveyed and reported for several decades in a quest by healthcare professionals to understand the etiology for healthcare disparities and seek to lessen its effects on individuals and, ultimately, eliminate them. Many of these surveys and reports have illuminated disparities, of access to healthcare by focusing on measures to address health literacy deficiencies. A plethora of information concerning patients' health literacy skills and printed information has been made available for dentists and their staff. The printed information is in the format of published patient- centered educational guidelines and readable dental and medical limited reach media (LRM), such as information sheets and prescription drug leaflets. LRM has great potential to enhance access to healthcare information for the reader of interest--your patient--at a readable and comprehensible level. Printed materials are an effective means to enhance health promotion and education for the lay populace. Tailored LRM protocol and the Patient Introduction Form (PIF) are excellent educational instruments for dentists and the dental/medical team (The Team). These instruments are valuable assets for The Team to assist its patients in monitoring and maintaining dental and medical adherence protocols in their daily lives.

Patients are provided limited-reach media materials, such as information sheets and pamphlets, as reinforcement of information when the oral healthcare professional is no longer face-to-face. Patients are more likely to use the printed information if text complexity and reader's ability match, or if their need to know the content provokes an urge to read. A number of researchers have developed readability tests. This study used the Fry Readability Graph to plot the results of three independent raters' averages of the number of sentences and the words (syllables) of continuous (prose) and non-continuous (matrix-style) pre-selected passages from several reputable sources. These limited-reach materials are frequently used in academic institutions' community engagement efforts. Several of the limited-reach materials we studied were ranked above the fifth-grade reading level, so consideration must be given to future distribution of these documents in communities where the average reading proficiency is lower. Several limitations, such as the quality of illustrations and measuring the reading level of individuals, were not investigated and must be considered as the authors continue to distribute literature in certain urban and suburban locales. This study is the genesis of an academic institution's community engagement efforts to provide information to clinicians and improve its outreach distribution of limited-reach media for patients who have varying levels of general and health literacy backgrounds.

The case study presented in this article is designed to provide an in-depth understanding of how a highly trained and experienced early childhood educator thinks about her interactions with children within the context of a setting identified as providing quality childcare for 3-, 4-, and 5-year-olds. Qualitative research methods are used, including interviews, participant observation, videotaping, and the teacher's reflections on interactions with children. Verbal and nonverbal patterns emerging from videotaped observations demonstrate how the teacher integrates information about specific children into these interactions. Although children's conceptions of time and space are consistently embedded in her thinking and reflected in her behavior, she never explicitly acknowledges these dimensions. The paper concludes with a discussion of the implications of the discrepancy between the teacher's implicit and explicit understanding of her interactions with children to childcare and the preparation and development of early childhood practitioners.

This essay reflects on the experience of mentoring undergraduate research on a Swedish practicum in childhood, family and social policy in Sweden from the perspective of the faculty advisor.

To assess global and regional brain matter variations associated with XYY syndrome by comparison with Klinefelter syndrome and typical development.We used two conceptually distinct voxel-based magnetic resonance imaging methods to examine brain structure in young males with XYY syndrome: (1) volumetric comparison to assess global grey and white matter volumes and (2) support vector machine-based multivariate pattern classification analysis to assess regional neuroanatomy. We assessed verbal, non-verbal, and spatial abilities with the Differential Ability Scales (DAS), and we measured autism diagnostic criteria in eight males with XYY syndrome using the Social Responsiveness Scale and the Autism Diagnostic Interview-Revised (ADI-R).A comparison of 36 typically developing males (mean age 11 y, SD 1 y 9 mo), 31 males with Klinefelter syndrome (mean age 9 y 8 mo, SD 1 y 8 mo), and eight males with XYY syndrome (mean age 11 y 6 mo, SD 1 y 11 mo) showed that total white and grey matter volumes were significantly, or nearly significantly, higher in males with XYY syndrome than in males belonging to the other two groups (grey matter: XYY males vs typically developing males, p0.006; XYY vs males with Klinefelter syndrome, p0.001; white matter: XYY males vs typically developing males, p=0.061; XYY males vs males with Klinefelter syndrome, p=0.004). Voxel-based multivariate pattern classification analysis indicates that, after controlling for global volumes, regional brain variations in XYY syndrome are more like those found in Klinefelter syndrome than those occurring in typical development. Further, visualization of classification parameters suggests that insular and frontotemporal grey matter and white matter, including known language areas, are reduced in males with XYY syndrome, similar to what is seen in Klinefelter syndrome. In males with XYY syndrome, DAS verbal and non-verbal scores were significantly lower than in typically developing participants (both p0.001). DAS scores were not significantly different between XYY and Klinefelter syndrome groups. In five of eight males with XYY syndrome, the Social Responsiveness Scale score exceeded the cut-off for a likely diagnosis of autism spectrum disorder (ASD). In three of eight males with XYY syndrome, the ADI-R score met the cut-off for ASD diagnosis; in another two, ADI-R scores within the social and communication domains met the cut-off values for a diagnosis of ASD.The results suggest that genetic variations associated with XYY syndrome result in increased brain matter volumes, a finding putatively related to the increased frequency of ASDs in individuals with this condition. In addition, frontotemporal grey and white matter reductions in XYY syndrome provide a likely neuroanatomical correlate for observed language impairments.

The therapeutic benefit of growth hormone (GH) therapy in improving height in short children is widely recognized; however, GH therapy is associated with other metabolic actions that may be of benefit in these children. Beneficial effects of GH on body composition have been documented in several different patient populations as well as improvements in lipid profile. Marked augmentation of bone mineral density also seems evident in many pediatric populations. Some of these benefits may require continued therapy past the acquisition of adult height. With long-term therapy of any kind, the adverse consequences of treatment should also be considered. Fortunately, long-term GH treatment seems to be safe and well-tolerated. This review describes the long-term metabolic effects of GH treatment in the pediatric population and considers how these may benefit children who are treated with GH.

This study determined whether surface roughness of the internal walls of a Class V resin composite preparation, using a carbide bur, a medium-grit diamond bur and a fine-grit diamond bur, affected the degree of microleakage of the restoration. The facial and lingual surfaces of 45 non-carious extracted human molars provided 90 samples for evaluation. The specimen surfaces were assigned randomly in equal numbers to one of three groups (n = 30). Conservative Class V composite preparations were made using one of three different burs: a 330-carbide bur, a 330 fine-grit diamond bur or a 330 medium-grit diamond bur (Brasseler USA). After acid etching, PQ1 (Ultradent Products Inc) primer/bonding resin and Vitalescence (Ultradent Products Inc) were applied and cured following the manufacturers' instructions. After minor finishing, the apices of all root surfaces were sealed with Vitrebond (3M), and the unprepared external surfaces were sealed with nail polish to within 1 mm of the restoration margins. The specimens were stored in distilled water at room temperature for 24 hours, then subjected to 1,200 thermocycles at 5 degrees C and 55 degrees C with a 30-second dwell time. After cycling, the teeth were immersed in a 5% solution of methylene blue dye for 12 hours. The molars were invested in clear acrylic casting resin, labeled, then sectioned once vertically approximately midway through the facial and lingual surfaces using a diamond coated saw blade. Microleakage was evaluated using a 10x microscope for the enamel and cementum surfaces and blindly scored by two independent examiners. In all cases, regardless of the examiner, at both the enamel and the dentin margins, the analysis revealed no statistically significant differences in microleakage across bur types. Further results show that dentin margins leaked significantly more than enamel margins for all bur types.