Clinical Practice Guidelines for the Care of Girls and Women with Turner Syndrome.

Turner syndrome affects 50 per 100,000 females, affects multiple organs through all stages of life, necessitating multidisciplinary care. This guideline extends previous ones and includes important new advances, within diagnostics and genetics, estrogen treatment, fertility, co-morbidities, and neurocognition and neuropsychology. Exploratory meetings were held in 2021 in Europe and US culminating with a consensus meeting in Aarhus, Denmark in June 2023. Prior to this, eight groups addressed important areas in TS care: 1) diagnosis and genetics, 2) growth, 3) puberty and estrogen treatment, 4) cardiovascular health, 5) transition, 6) fertility assessment, monitoring, and counselling, 7) health surveillance for comorbidities throughout the lifespan, and 8) neurocognition and its implications for mental health and well-being. Each group produced proposals for the present guidelines, which were meticulously discussed by the entire group. Four pertinent questions were submitted for formal GRADE (Grading of Recommendations, Assessment, Development and Evaluation) evaluation with systematic review of the literature. The guidelines project was initiated by the European Society for Endocrinology and the Pediatric Endocrine Society, in collaboration with members from the European Society for Pediatric Endocrinology, the European Society of Human Reproduction and Embryology, the European Reference Network on Rare Endocrine Conditions, the Society for Endocrinology, and the European Society of Cardiology, Japanese Society for Pediatric Endocrinology, Australia and New Zealand Society for Pediatric Endocrinology and Diabetes, Latin American Society for Pediatric Endocrinology, Arab Society for Pediatric Endocrinology and Diabetes, and the Asia Pacific Pediatric Endocrine Society. Advocacy groups appointed representatives for pre-meeting discussions and the consensus meeting.

Timing of onset of menses after GnRH agonist treatment for central precocious puberty.

OBJECTIVES: To understand possible predictors of the onset of menses after gonadotropin-releasing hormone agonist treatment cessation in girls with central precocious puberty (CPP). METHODS: This exploratory post hoc analysis of a phase 3 and 4 trial of girls with CPP treated with once-monthly intramuscular leuprolide acetate examined onset of menses after treatment completion using a time-to-event analysis. Pretreatment and end-of-treatment chronologic age (CA), bone age (BA)/CA ratio, and Tanner breast stage; pretreatment menses status; and end-of-treatment BA and body mass index (BMI) were studied as potential factors influencing the onset of menses. RESULTS: Median time to first menses after stopping treatment was 18.3 months among 35 girls (mean age at onset of treatment, 6.8 years) examined. Of 26 girls experiencing menses, 11 (42 %) menstruated at 16-21 months after stopping treatment. Most girls with pretreatment BA/CA≥1.4 started menstruating very close to 18 months after stopping treatment; those with less advanced BA/CA experienced menses at 9-18 months. End-of-treatment BA/CA≥1.2 was associated with a quicker onset of menses (14.5 vs. 18.5 months for BA/CA<1.2, p=0.006). End-of-treatment BA≥12 years predicted longer time to menses. No relationship with time to menses was observed for pretreatment menarche status, pretreatment or end-of-treatment Tanner breast stage (<3/≥3) or CA (<6/≥6 or ≤11/>11), or end-of-treatment BMI percentiles (<85.6/≥85.6 and <92.6/≥92.6). CONCLUSIONS: Pretreatment menarche status or CA do not appear to predict onset of menses, but pre- and end-of-treatment BA/CA may be helpful in anticipating time to first menses after stopping treatment.

Treatment of Central Precocious Puberty with a Focus on Girls.

The age of thelarche has declined in the past few decades but not the age of menarche. This is important when assessing girls who present with breast development between 6 and 8 years because not all of them will need treatment. The decision for treatment depends on age, bone age (BA), rate of pubertal progression, height velocity, psychosocial factors, and predicted adult height (PAH), with the caveat that height predictions are not precise and BA interpretation is variable.

Unstimulated Luteinizing Hormone for Assessment of Suppression During Treatment of Central Precocious Puberty with 6-Month Subcutaneous Leuprolide Acetate: Correlations with Clinical Response.

INTRODUCTION: Phase 3 trial of 6-month subcutaneous leuprolide acetate (SC-LA) in children with central precocious puberty (CPP) demonstrated efficacy and safety. Aims of this secondary analysis: evaluate unstimulated luteinizing hormone (LH) as efficacy measure; assess clinical suppression metrics; and present biochemical and clinical data for subgroups not achieving hormone suppression. METHODS: 62 children with treatment-naïve CPP received 2 doses of 45 mg SC-LA at 24-week intervals. Unstimulated and GnRH-stimulated LH, E2, and T concentrations were measured. Clinical measures included bone age (BA) and predicted adult height (PAH). RESULTS: 84% and 86% of children achieved unstimulated LH<1IU/L at weeks 24 and 48, respectively. Of 8 children not achieving unstimulated LH<1IU/L at week 24 that completed the study, all showed lack of pubertal stage progression and stable/decreased BA to chronological age ratio (BA/CA). Received operating characteristic (ROC) analyses suggested unstimulated LH is a good diagnostic predictor of GnRH-stimulated LH<4IU/L at week 24 and 48 (AUC=0.88). Across all children, mean BA/CA improved from 1.4 (screening) to 1.3 (week 48) and mean PAH increased by 3cm. Of 7 girls not achieving stimulated LH<4IU/L at week 24, all achieved E2<10pg/mL, showed lack of pubertal stage progression, and had stable or decreased BA/CA by week 48. Additionally, 6/7 had increased PAH by week 48 and 4 had unstimulated LH<1IU/L. CONCLUSION: Unstimulated LH has value as an efficacy measure and concentrations <1IU/L may be an adequate surrogate of treatment response in children with CPP. All children who completed the study had evidence of pubertal suppression.

Incidence of central precocious puberty declines to pre-pandemic levels post COVID-19 pandemic increase: single-center retrospective review in the United States.

Background and aim of the study: We previously published the increased frequency of new CPP cases during the Covid-19 pandemic in our pediatric endocrinology clinic at Rady Children's Hospital in San Diego, CA, US. We conducted this follow-up study to examine the incidence of new CPP cases requiring treatment with GnRH agonist (GnRHa) in our clinic during 2 years post-pandemic. Methods: We performed a retrospective comparison of the number of visits of children newly diagnosed with CPP treated with GnRHa during the 2 years following the first year of Covid-19 pandemic (5/2021-7/2023). We evaluated clinical and bone maturation data as well as differences in timing from diagnosis to onset of treatment. Results: We previously reported in the pre-Covid year, 28 children (1 boy, 27 girls) treated with GnRHa for CPP out of 2,340 new endocrinology visits (1.2% of patients seen). During Covid-19 year, 64 children (7 boys, 57 girls) were treated out of 2,261 new visits (2.8%). The incidence of new CPP cases requiring GnRHa during the pandemic more than doubled compared to pre-pandemic. In the first year post-year 1 of the pandemic (5/2021-4/2022), 46 children (3 boys, 40 girls) started treatment with GnRHa for CPP out of 2,595 new endocrinology visits (1.6% of patients seen). During the second follow-up year (5/2022-4/2023), 22 children (4 boys, 18 girls) started treatment with GnRHa for CPP out of 2,676 new endocrinology visits (0.8% of patients seen). Age at onset of treatment, degree of bone age (BA) advancement, time from diagnosis to onset of treatment, and changes in BMI during the pandemic were not different from pre-pandemic or post-pandemic. Conclusions: CPP cases requiring GnRHa treatment significantly increased during the first year of the Covid-19 pandemic and then decreased each year post-pandemic. This was not related to BMI, age at diagnosis, degree of bone age advancement, or time from diagnosis to onset of treatment as all these factors have been similar during pre-pandemic, pandemic, and post-pandemic years. It is reasonable that the postulated hypotheses published regarding the increase during the pandemic would resolve post-pandemic.

Inspiring New Science to Guide Healthcare in Turner Syndrome: Rationale, design, and methods for the InsighTS Registry.

Inspiring New Science to Guide Healthcare in Turner Syndrome (InsighTS) Registry is a national, multicenter registry for individuals with Turner syndrome (TS) designed to collect and store validated longitudinal clinical data from a diverse cohort of patients with TS. Herein, we describe the rationale, design, and approach used to develop the InsighTS registry, as well as the demographics of the initial participants to illustrate the registry's diversity and future utility. Multiple stakeholder groups have been involved from project conceptualization through dissemination, ensuring the registry serves the priorities of the TS community. Key features of InsighTS include recruitment strategies to facilitate enrollment of participants that appropriately reflect the population of individuals with TS receiving care in the US, clarity of data ownership and sharing, and sustainability of this resource. The registry gathers clinical data on diagnosis, treatment, comorbidities, health care utilization, clinical practices, and quality of life with the goal of improving health outcomes for this population. Future directions include multiple patient-centered clinical-translational research projects that will use the InsighTS platform. This thorough and thoughtful planning will ensure InsighTS is a valuable and sustainable resource for the TS community for decades to come.

Efficacy and Safety of Leuprolide Acetate 6-Month Depot for the Treatment of Central Precocious Puberty: A Phase 3 Study.

Context: Treatment options for central precocious puberty (CPP) are important for individualization of therapy. Objective: We evaluated the efficacy and safety of 6-month 45-mg leuprolide acetate (LA) depot with intramuscular administration. Methods: LA depot was administered at weeks 0 and 24 to treatment-naïve (n = 27) or previously treated (n = 18) children with CPP in a phase 3, multicenter, single-arm, open-label study (NCT03695237). Week 24 peak-stimulated luteinizing hormone (LH) suppression (<4 mIU/mL) was the primary outcome. Secondary/other outcomes included basal sex hormone suppression (girls, estradiol <20 pg/mL; boys, testosterone <30 ng/dL), suppression of physical signs, height velocity, bone age, patient/parent-reported outcomes, and adverse events. Results: All patients (age, 7.8 ± 1.27 years) received both scheduled study doses. At 24 weeks, 39/45 patients (86.7%) had LH suppressed. Six were counted as unsuppressed; 2 because of missing data, 3 with LH of 4.35-5.30 mIU/mL and 1 with LH of 21.07 mIU/mL. Through 48 weeks, LH, estradiol, and testosterone suppression was achieved in ≥86.7%, ≥97.4%, and 100%, respectively (as early as week 4 for LH and estradiol and week 12 for testosterone). Physical signs were suppressed at week 48 (girls, 90.2%; boys, 75.0%). Mean height velocity ranged 5.0 to 5.3 cm/year post-baseline in previously treated patients and declined from 10.1 to 6.5 cm/year at week 20 in treatment-naïve patients. Mean bone age advanced slower than chronological age. Patient/parent-reported outcomes remained stable. No new safety signals were identified. No adverse event led to treatment discontinuation. Conclusion: Six-month intramuscular LA depot demonstrated 48-week efficacy with a safety profile consistent with other GnRH agonist formulations.

Using change in predicted adult height during GnRH agonist treatment for individualized treatment decisions in girls with central precocious puberty.

OBJECTIVES: It is important to understand what variables influence change in predicted adult height (PAH) throughout GnRHa treatment for central precocious puberty (CPP) to individualize treatment decisions and optimize care. METHODS: Changes in PAH, chronological age (CA), bone age (BA), BA/CA, and height velocity (HV) were evaluated in girls with CPP throughout treatment with leuprolide acetate (n=77). A second analysis focused on changes in the 3 years preceding the first observed BA of ≥12 years. Relationships were characterized using plot inspection and linear mixed-effects analyses. Association between treatment duration and last assessed PAH was examined using multiple linear regression models. RESULTS: BA/CA and HV showed a nonlinear change during treatment, with the largest changes and improvement in PAH observed in the first 6-18 months. Rate of BA advancement tended to decrease more slowly in girls initiating treatment at a younger BA. On-treatment change in PAH was predicted by concurrent BA/CA change, HV, and BA, as well as CA at treatment initiation. Last assessed PAH was positively associated with longer treatment durations (primary/exploratory models cut-offs of ≥33/≥55 months). CONCLUSIONS: These findings support individualized monitoring during GnRHa treatment. Initial response should be interpreted with caution until 6-18 months after treatment initiation and failure should not be assumed based on continued bone maturation in girls starting therapy at a younger age. Treatment cessation should not be automatically based on a diminishing change in PAH or HV, as ongoing treatment may result in continued increase or maintenance of PAH.

Incidence of central precocious puberty more than doubled during COVID-19 pandemic: Single-center retrospective review in the United States.

Background and aim of the study: The frequency of new visits for precocious puberty increased during the Covid-19 pandemic in the pediatric endocrinology clinic at Rady Children's Hospital in San Diego, CA, US. A few recent studies have shown an increase in the frequency of Central Precocious Puberty (CPP) in other centers during this pandemic. This study evaluated the change in incidence of new CPP cases requiring treatment with GnRH agonist (GnRHa) at Rady Children's Hospital during the Covid-19 pandemic and compared it to pre-pandemic years. Methods: Data were reviewed retrospectively to compare the number of visits of children newly diagnosed with CPP treated with GnRHa during the Covid-19 pandemic (5/2020-4/2021) and before the pandemic (5/2018-4/2019). Clinical and bone maturation data were evaluated as well as differences in timing from diagnosis to onset of treatment. The incidence of CPP requiring treatment for 5 years prior to the pandemic was also reviewed to evaluate for trends over time. Results: A total of 92 subjects were included. During pre-Covid year, 28 children (1 boy, 27 girls) were treated with GnRHa for CPP out of 2,340 new endocrinology visits (1.2% of patients seen). During Covid-19 year, 64 children (7 boys, 57 girls) were treated out of 2,261 new visits (2.8%). The incidence of new CPP cases requiring GnRHa during the pandemic more than doubled compared to pre-pandemic. Age at onset of treatment, degree of bone age (BA) advancement, time from diagnosis to onset of treatment, and changes in BMI during the pandemic were not different from pre-pandemic. Conclusion: CPP cases requiring GnRHa treatment significantly increased during the first year of the Covid-19 pandemic. This was not related to increased BMI or delay in onset of treatment. Age at diagnosis, degree of bone age advancement, and time from diagnosis to onset of treatment were all similar during the first year of the pandemic compared to the prior year.

Design and feasibility of an implementation strategy to address Chagas guidelines engagement focused on attending women of childbearing age and children at the primary healthcare level in Argentina: a pilot study.

BACKGROUND: Chagas is a public health problem, especially in Latin America, exacerbated by migratory movements and increasing urbanization. Argentina is among the countries with the highest estimated prevalence in the region, with 1,500,000 people infected, with mother to child as the main mode of transmission. Vertical transmission has been significantly reduced by treating women of childbearing age; several guidelines in the region recommend treatment as a primary prevention strategy for the child and a secondary prevention strategy for women and their families. Despite recommendations, women of childbearing age are not always treated, and children do not receive timely diagnosis and treatment. The objective of this research was to design an implementation strategy to improve using Chagas guidelines focused on attending women of childbearing age and children at the primary healthcare level and pilot it in three primary health care centers in Argentina. METHODS: We conducted a pilot feasibility study using the Consolidated Framework for Implementation Research. A qualitative process evaluation was conducted using semi-structured interviews with health care providers and observations in primary health care centers. RESULTS: We developed a multifaceted implementation strategy including training, flowcharts and reminders, a register of suspected and confirmed cases, and the selection of a management facilitator. The pilot study took place between September 2019 and May 2020. The implementation level was heterogeneous and varied depending on the components, being the facilitating factors, the simplicity of the intervention, professionals' willingness to expand the indication of serologic tests, and staff commitment to the adoption of intervention components. The main barriers found were the change of authorities at the local level, some professionals´ reluctance to administer etiological treatment, staff shortages, lack of diagnostic supplies, and the health emergency caused by the COVID-19 pandemic. CONCLUSIONS: Behavioral change strategies should be applied to improve implementation to address some of the main barriers, including support actions offered by opinion leaders, medical experts, and local health authorities. Rapid diagnostic tests should be readily available to maintain behavior changes. We suggest further refinement of the strategy and its implementation in more centers to assess outcomes prospectively with a hybrid implementation research design.

Gonadotropin-releasing hormone analog therapies for children with central precocious puberty in the United States.

Gonadotropin-releasing hormone agonists (GnRHa's) are the standard treatment for children with central precocious puberty (CPP). We aim to present data on available GnRHa options with an easy-to-review table and discuss factors that influence treatment selection. Five GnRHa's are currently FDA-approved and prescribed in the US and published data suggest similar safety and efficacy profiles over the first year of treatment. One- and 3-month intramuscular (IM) leuprolide acetate (LA) have long-term safety and efficacy data and allow for flexible dosing. Six-month IM triptorelin pamoate offers a longer duration of treatment, but without long-term efficacy and outcome data. Six-month subcutaneous (SQ) LA combines a SQ route of injection and long duration of action but lacks long-term efficacy and outcome data. The 12-month SQ histrelin acetate implant avoids injections and offers the longest duration of action, but requires a minor surgical procedure with local or general anesthesia. Factors in treatment selection include route of administration, needle size, injection volume, duration of action, and cost. The current GnRHa landscape provides options with varying benefits and risks, allowing physicians and caregivers to select the most appropriate therapy based on the specific needs and concerns of the child and the caregiver. Agents have different advantages and disadvantages for use, with no one agent displaying superiority.

No pubertal growth spurt, rapid bone maturation, and menarche post GnRHa treatment in girls with precocious puberty.

OBJECTIVES: To study total growth, rate of bone maturation, and menarche after discontinuation of Gonadotropin releasing hormone agonist (GnRHa) treatment for central precocious puberty (CPP). METHODS: Twenty girls with CPP on treatment with GnRHa were followed from discontinuation of treatment to final height (FH). Height, height velocity (HV), and bone age were measured every 6 months. Age at menarche was collected. RESULTS: Once treatment is discontinued, rate of bone maturation (bone age [BA]/chronological [CA]) accelerated from 0.7 ± 0.3 at end of treatment to 1.2 ± 0.8 post treatment, similar to BA/CA prior to treatment. BA at treatment discontinuation ranged from 11-14 years. On average, treatment was stopped when CA was within 9 months of BA. All girls continued to grow from end of treatment to menarche averaging an increase of 4.7 ± 3.7 cm, with HV 3.2 ± 2.0 cm/year. Post-menarche they grew an additional 4.6 ± 2.1 cm, with HV 2.4 ± 1.9 cm/year. Acceleration of HV was not seen post treatment. The younger the BA at initiation or completion of treatment, the longer time to menarche. No one had menarche prior to a BA of 12.5 year. CONCLUSIONS: A pubertal growth spurt does not usually occur after treatment with GnRHa in girls with CPP. Rate of bone maturation accelerates post treatment. These factors are important in assessing optimal height outcome and decisions regarding cessation of treatment. This study will help clinicians give patients and families better estimates of growth and onset of menarche post treatment.

Observations and reports of incidents of how birthing persons are treated during childbirth in two public facilities in Argentina.

OBJECTIVE: This study sought to estimate the frequency and types of mistreatment during childbirth and explore health professionals' opinions on barriers/facilitators to providing respectful childbirth care. METHODS: This prospective mixed-methods investigation consisted of direct observations of childbirth (n = 250), at-home surveys with birthing individuals (n = 45), and qualitative in-depth health staff interviews (n = 6), conducted between January and July 2019, in two public facilities in Argentina. Frequencies of clinical practices and mistreatment and 5% confidence intervals were calculated. A logistic regression analysis was also conducted to examine associations between mistreatment and covariates of interest, with P < 0.05 considered statistically significant. RESULTS: Overall, 61/250 (24.4%, confidence interval 19.6%-30.6%) observations recorded instances of mistreatment; 20/45 surveyed participants (44.4%) reported at least one episode of mistreatment. The most frequent perpetrators were physicians (35.6%), birth companions (24.4%), midwives (22.2%), and nurses (13.3%). Participants with lower educational attainment and those racialized as non-white had higher odds of being mistreated. Health providers reported that respectful childbirth is currently widely implemented due to authorities' and communities' awareness on respectful birth´s rights. CONCLUSION: Almost a quarter of birthing people were observed to suffer mistreatment - primarily verbal abuse - and 44.4% of surveyed individuals reported mistreatment. Future research is needed to determine how to ensure the provision of respectful childbirth care for all. A quarter of participants experienced mistreatment; mostly those with lower educational attainment and/or racialized as non-white. Further research on implementation of respectful childbirth is warranted.

Importance of individualizing treatment decisions in girls with central precocious puberty when initiating treatment after age 7 years or continuing beyond a chronological age of 10 years or a bone age of 12 years.

OBJECTIVES: Gonadotropin-releasing hormone agonist treatment is important for optimal growth in girls with central precocious puberty (CPP). Data are lacking regarding benefit to height outcome when treatment is started after chronological age (CA) of 7 years, and if continued beyond CA of 10 years or bone age (BA) of 12 years. METHODS: Forty-eight girls with CPP were treated with monthly leuprolide depot. Change in predicted adult height (PAH) during treatment was assessed. Changes in PAH and growth velocity were compared between girls initiating treatment at CA <7 vs. ≥7 years, and BA ≥12 vs. BA <12 years. RESULTS: Mean baseline CA was 6.8 years, BA, 10.2 years; and PAH, 156.4 cm. BA/CA ratio decreased from pretreatment values, averaging 1.5 to 1.2 at the end of treatment. Proportion of girls with >5 cm PAH change during treatment was similar, and PAH increased throughout treatment in most girls, regardless of age at treatment initiation. PAH continued to increase in 16/19 girls who continued treatment after BA of 12 years, and also in 16/22 girls who continued treatment after CA of 10 years. CONCLUSIONS: PAH improved in most girls who initiated treatment after CA of 7 years. It continued to improve in most girls with longer treatment, even past BA of 12 years or CA of 10 years, which suggests that no absolute CA or BA limit should define initiation or end of treatment. Treatment plans need to be individualized, and neither treatment initiation nor cessation should be based on BA or CA alone.

Dexamethasone versus betamethasone for preterm birth: a systematic review and network meta-analysis.

OBJECTIVE: This study aimed to evaluate the comparative clinical effectiveness and safety of dexamethasone vs betamethasone for preterm birth. DATA SOURCES: The sources searched were MEDLINE, EMBASE, Cochrane Library, LILACS, ClinicalTrials.gov, and International Clinical Trials Registry Platform without language restrictions until October 2019 in addition to the reference lists of included studies. Field experts were also contacted. STUDY ELIGIBILITY CRITERIA: Randomized or quasi-randomized controlled trials comparing any corticosteroids against each other or against placebo at any dose for preterm birth were included in the study. METHODS: Three researchers independently selected and extracted data and assessed the risk of bias of the included studies by using Early Review Organizing Software and Covidence software. Random-effects pairwise meta-analysis and Bayesian network meta-analysis were performed. The primary outcomes were chorioamnionitis, endometritis or puerperal sepsis, neonatal death, respiratory distress syndrome, and neurodevelopmental disability. RESULTS: A total of 45 trials (11,227 women and 11,878 infants) were included in the study. No clinical or statistical difference was found between dexamethasone and betamethasone in neonatal death (odds ratio, 1.05; 95% confidence interval, 0.62-1.84; moderate-certainty evidence), neurodevelopmental disability (odds ratio, 1.03; 95% confidence interval, 0.80-1.33; moderate-certainty evidence), intraventricular hemorrhage (odds ratio, 1.04; 95% confidence interval, 0.56-1.78); low-certainty evidence), or birthweight (+5.29 g; 95% confidence interval, -49.79 to 58.97; high-certainty evidence). There was no statistically significant difference, but a potentially clinically important effect was found between dexamethasone and betamethasone in chorioamnionitis (odds ratio, 0.70; 95% confidence interval, 0.45-1.06; moderate-certainty evidence), fetal death (odds ratio, 0.81; 95% confidence interval, 0.24-2.41; low-certainty evidence), puerperal sepsis (odds ratio, 2.04; 95% confidence interval, 0.72-6.06; low-certainty evidence), and respiratory distress syndrome (odds ratio, 1.34; 95% confidence interval, 0.96-2.11; moderate-certainty evidence). Meta-regression, subgroup, and sensitivity analyses did not reveal important changes regarding the main analysis. CONCLUSION: Corticosteroids have proven effective for most neonatal and child-relevant outcomes compared with placebo or no treatment for women at risk of preterm birth. No important difference was found on neonatal death, neurodevelopmental disability, intraventricular hemorrhage, and birthweight between corticosteroids, and there was no statistically significant difference, but a potentially important difference was found in chorioamnionitis, fetal death, endometritis or puerperal sepsis, and respiratory distress syndrome. Further research is warranted to improve the certainty of evidence and inform health policies.

Community-engaged research in translational science: Innovations to improve health in Appalachia.

Health disparities between Appalachia and the rest of the country are widening. To address this, the Appalachian Translational Research Network (ATRN) organizes an annual ATRN Health Summit. The most recent Summit was held online September 22-23, 2020, and hosted by Wake Forest Clinical and Translational Science Institute in partnership with the Northwest Area Health Education Center. The Summit, titled "Community-Engaged Research in Translational Science: Innovations to Improve Health in Appalachia," brought together a diverse group of 141 stakeholders from communities, academic institutions, and the National Center for Advancing Translational Science (NCATS) to highlight current research, identify innovative approaches to translational science and community-engaged research, develop cross-regional research partnerships, and establish and disseminate priorities for future Appalachian-focused research. The Summit included three plenary presentations and 39 presentations within 12 concurrent breakout sessions. Here, we describe the Summit planning process and implementation, highlight some of the research presented, and outline nine emergent themes to guide future Appalachian-focused research.

Phase 3 Trial of a Small-volume Subcutaneous 6-Month Duration Leuprolide Acetate Treatment for Central Precocious Puberty.

CONTEXT: Gonadotropin-releasing hormone agonists (GnRHas) are standard of care for central precocious puberty (CPP). A 6-month subcutaneous injection has recently been approved by the Food and Drug Administration. OBJECTIVE: Determine efficacy, pharmacokinetics, and safety of 6-month 45-mg subcutaneous leuprolide acetate for CPP. DESIGN: Phase 3 multicenter, open-label, single-arm study. SETTING: 25 sites in 6 countries. SUBJECTS: 64 GnRHa-naïve children with CPP (age: 7.5 ± 0.1 years) received study drug: 59 completed the study. INTERVENTION(S): 2 doses of 45-mg subcutaneous leuprolide acetate (0.375 mL) at 0 and 24 weeks; children were followed for 48 weeks. MAIN OUTCOME MEASURE(S): Percentage of children with serum luteinizing hormone (LH) <4 IU/L 30 minutes following GnRHa stimulation at week 24. RESULTS: 54/62 (87%) children achieved poststimulation LH <4 IU/L at week 24; 49/56 (88%) girls and 1/2 boys maintained peak LH <4 IU/L at week 48. Mean growth velocity decreased from 8.9 cm/year at week 4 to 6.0 cm/year at week 48. Mean bone age was advanced 3.0 years beyond chronological age at screening and 2.7 years at week 48. Breast pubertal stage regressed or was stable in 97% of girls and external genitalia development regressed in both boys. Adverse events were mild and did not cause treatment discontinuation. CONCLUSIONS: A small volume of 45-mg subcutaneous leuprolide acetate administered at a 6-month interval effectively suppressed pubertal hormones and stopped or caused regression of pubertal progression. This long-acting GnRHa preparation of leuprolide acetate is a new, effective, and well-tolerated therapy for children with CPP.

Short-course Benznidazole treatment to reduce Trypanosoma cruzi parasitic load in women of reproductive age (BETTY): a non-inferiority randomized controlled trial study protocol.

BACKGROUND: Retrospective observational studies suggest that transmission of Trypanosoma cruzi does not occur in treated women when pregnant later in life. The level of parasitemia is a known risk factor for congenital transmission. Benznidazole (BZN) is the drug of choice for preconceptional treatment to reduce parasitic load. The fear of treatment-related side effects limits the implementation of the Argentine guideline recommending BZN 60d/300 mg (or equivalent) treatment of T. cruzi seropositive women during the postpartum period to prevent transmission in a future pregnancy. A short and low dose BZN treatment might reduce major side effects and increase compliance, but its efficacy to reduce T. cruzi parasitic load compared to the standard 60d/300 mg course is not yet established. Clinical trials testing alternative BZN courses among women of reproductive age are urgently needed. METHODS AND DESIGN: We are proposing to perform a double-blinded, non-inferiority randomized controlled trial comparing a short low dose 30-day treatment with BZN 150 mg/day (30d/150 mg) vs. BZN 60d/300 mg. We will recruit not previously treated T. cruzi seropositive women with a live birth during the postpartum period in Argentina, randomize them at 6 months postpartum, and follow them up with the following specific aims: Specific aim 1: to measure the effect of BZN 30d/150 mg compared to 60d/300 mg preconceptional treatment on parasitic load measured by the frequency of positive Polymerase Chain Reaction (PCR) (primary outcome) and by real-time quantitative PCR (qPCR), immediately and 10 months after treatment. Specific aim 2: to measure the frequency of serious adverse events and/or any adverse event leading to treatment interruption. TRIAL REGISTRATION: ClinicalTrials.gov . Identifier: NCT03672487 . Registered 14 September 2018.

A survey of care pathway and health-related quality of life impact for children with central precocious puberty.

Objective: To describe the timeline to diagnosis for children with central precocious puberty (CPP) and evaluate their psychosocial and health-related quality of life (HRQoL).Methods: A cross-sectional survey was used to prospectively collect data from caregivers, recruited via the MAGIC Foundation, of children with CPP. The control (non-CPP) group was recruited from a national panel of parents/caregivers. After completing a screening survey, respondents completed a burden of illness survey. Respondents in both groups completed the Pediatric Quality of Life Inventory (PedsQL) and Patient-Reported Outcomes Measurement Information System (PROMIS) peer relationship instruments.Results: Responses from 142 caregivers of children with and 300 without CPP were assessed. Mean time to treatment after a child's visit to the pediatric endocrinologist was 220 days and time from onset of symptoms to initiating treatment was approximately 2 years. Responses to HRQoL inventories were all lower in children with CPP versus non-CPP. Adjusted mean (± standard error) PedsQL total (65.3 ± 1.8 versus 75.7 ± 1.2), Psychosocial Health Summary (62.4 ± 1.8 versus 73.4 ± 1.2), and Physical Health Summary (70.7 ± 2.2 versus 79.9 ± 1.5) scores were significantly lower (p < .01) in CPP versus non-CPP group. PROMIS peer relationship T score (± standard error) was numerically lower for the CPP versus non-CPP group (45.4 ± 1.0 versus 47.4 ± 0.7, p = .11).Conclusions: In clinical practice, there is a longer than expected delay between CPP symptom onset and referral to an endocrinologist and ultimate treatment. Children with CPP experience a substantial disease burden with a significant impact on emotional, social, and physical functioning compared with children without CPP.

Treatment patterns, health resource utilization and costs among central precocious puberty patients treated with leuprolide or histrelin: an examination of the commercial and Medicaid populations.

Aims: To compare treatment duration, healthcare resource utilization (HRU), and direct healthcare costs between patients with central precocious puberty (CPP) treated with leuprolide or histrelin, and between patients with Medicaid or commercial insurance. This information is important as it affects treatment choice and outcomes.Materials and methods: This retrospective cohort study identified commercial and Medicaid-insured CPP patients ≤12-years-old who were diagnosed between 1 January 2010 and 30 September 2014 and had ≥1 prescription for leuprolide or histrelin (first prescription = index date). Treatment patterns were measured for the duration of available data; whereas, all-cause and disease-monitoring HRU and all-cause costs were compared between treatment groups for the year following treatment initiation. Multivariable analysis was used to adjust healthcare costs for differences in baseline patient characteristics.Results: A total of 1,177 commercially-insured (907 leuprolide and 270 histrelin) and 658 Medicaid-insured (613 leuprolide and 45 histrelin) patients were identified. Mean age at treatment initiation ranged from 7.5-8.5-years-old, 11.1-20.5% of patients were male, and the mean treatment duration was over one year. Commercially-insured patients treated with histrelin used more services in general than those treated with leuprolide but had fewer office visits. Healthcare service utilization was similar between Medicaid-insured treatment groups. In both payer populations, costs were similar.Limitations: The number of Medicaid-insured patients who received a histrelin implant was low, and this may make the findings more sensitive to influence by outliers.Conclusions: Mean overall healthcare costs were similar between CPP patients treated with leuprolide and those treated with histrelin. Medicaid patients generally received less testing and were less likely to receive specialist care. Patients treated with histrelin had fewer office visits but also had a shorter overall treatment.