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Item A Lecture to Teach an Approach and Improve Resident Comfort in Leading Resuscitation of Young Infants in the Emergency Department(University of California, 2022-01-15) Whitehead, Anne; Emergency Medicine, School of MedicineAudience: The intended audience of this lecture is emergency medicine residents at all levels of training. It is also appropriate for practicing emergency physicians interested in improving comfort in resuscitating sick young infants, ages 0-60 days. Introduction: The majority of sick and injured children in the United States are seen and treated in general emergency departments.1 This includes very young infants (0-60 days old) in need of immediate resuscitation. Resuscitation of children in this age group involves use of specific knowledge and skills that residents and emergency physicians in general have fewer opportunities to practice.2,3 Emergency medicine residents and practicing emergency physicians often report this as an area of particular discomfort in practice.4,5 It is important that the inconsistent and infrequent opportunities to resuscitate young infants during emergency medicine residency and beyond are supplemented by residency didactics that focus on improving comfort and skills with this population of sick children. This lecture focuses on a practical approach intended to improve the relevant knowledge, skills, and confidence required to stabilize a critically ill young infant in a general emergency department. Educational objectives: By the end of this lecture, participants should be able to:Apply a consistent approach to the initial resuscitation of a critically ill young infant in the emergency department.Select appropriate medications and equipment for use in resuscitation of critically ill young infants.Describe the components of the Pediatric Assessment Triangle,6 which can be used to identify critically ill infants and children.Improve comfort in resuscitating young infants in the emergency department. Educational methods: This is a live lecture format using PowerPoint slides. The lecture emphasizes a practical approach to improve the skills and knowledge required for successful young infant resuscitation. It utilizes a case-based approach, and encourages the audience to determine next steps in care to mimic the real time decision-making required for care of critically ill young infants in the ED. Research methods: Learners were asked to fill out anonymous pre- and post quizzes immediately prior to and directly after the lecture was given. These surveys included questions to assess resident knowledge as well as resident comfort as it pertained to resuscitation of critically ill young infants. Results: Resident comfort with resuscitation of young infants improved with a mean Standard Deviation (SD) pre-lecture rating of 23.1(14.9) on a 100-point visual analog scale and a mean (SD) post lecture rating of 46.7(14.6). Resident performance on all knowledge base questions improved on the post-lecture quiz for all four questions asked. Discussion: This lecture was effective in improving emergency medicine resident comfort and practical knowledge pertaining to resuscitation of young infants in the emergency department. The emphasis on a practical approach was well received by the resident audience, and they engaged well with audience participation portions of the lecture. The impact of the lecture can be enhanced by having the lecturer share their own real-world experience of resuscitation of young infants in the emergency department during the discussion portions of the lecture.Item Crinecerfont Lowers Elevated Hormone Markers in Adults With 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia(Endocrine Society, 2022) Auchus, Richard J.; Sarafoglou, Kyriakie; Fechner, Patricia Y.; Vogiatzi, Maria G.; Imel, Erik A.; Davis, Shanlee M.; Giri, Nagdeep; Sturgeon, Julia; Roberts, Eiry; Chan, Jean L.; Farber, Robert H.; Medicine, School of MedicineContext: Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is characterized by impaired cortisol synthesis and excess androgen production. Corticotropin-releasing factor type 1 receptor (CRF1R) antagonism may decrease adrenal androgen production. Objective: This work aimed to evaluate the safety, tolerability, and efficacy of crinecerfont (NBI-74788), a selective CRF1R antagonist, in 21OHD. Methods: This open-label, phase 2 study, with sequential cohort design (NCT03525886), took place in 6 centers in the United States. Participants included men and women, aged 18 to 50 years, with 21OHD. Interventions included 4 crinecerfont regimens, each administered orally for 14 consecutive days: 50 or 100 mg once daily at bedtime (cohorts 1 and 2, respectively); 100 mg once daily in the evening (cohort 3); and 100 mg twice daily (cohort 4). Participants could enroll in more than 1 cohort. Main outcomes included changes from baseline to day 14 in adrenocorticotropin (ACTH), 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone. Results: Eighteen participants (11 women, 7 men) were enrolled: cohort 1 (n = 8), cohort 2 (n = 7), cohort 3 (n = 8), cohort 4 (n = 8). Mean age was 31 years; 94% were White. Median percent reductions were more than 60% for ACTH (-66%), 17OHP (-64%), and androstenedione (-64%) with crinecerfont 100 mg twice a day. In female participants, 73% (8/11) had a 50% or greater reduction in testosterone levels; male participants had median 26% to 65% decreases in androstenedione/testosterone ratios. Conclusion: Crinecerfont treatment for 14 days lowered ACTH and afforded clinically meaningful reductions of elevated 17OHP, androstenedione, testosterone (women), or androstenedione/testosterone ratio (men) in adults with 21OHD. Longer-term studies are required to evaluate the effects of crinecerfont on clinical end points of disordered steroidogenesis and glucocorticoid exposure in patients with 21OHD.Item Differential effects of hydrocortisone, prednisone, and dexamethasone on hormonal and pharmacokinetic profiles: a pilot study in children with congenital adrenal hyperplasia(BioMed Central, 2016) Nebesio, Todd D.; Renbarger, Jamie L.; Nabhan, Zeina M.; Ross, Sydney E.; Slaven, James E.; Li, Lang; Walvoord, Emily C.; Eugster, Erica A.; Department of Pediatrics, IU School of MedicineBACKGROUND: Little is known about the comparative effects of different glucocorticoids on the adrenal and growth hormone (GH) axes in children with congenital adrenal hyperplasia (CAH). We sought to compare the effects of hydrocortisone (HC), prednisone (PDN), and dexamethasone (DEX) in children with classic CAH and to investigate a potential role of pharmacogenetics. METHODS: Subjects were randomly assigned to three sequential 6-week courses of HC, PDN, and DEX, each followed by evaluation of adrenal hormones, IGF-1, GH, and body mass index (BMI). Single nucleotide polymorphism (SNP) analysis of genes in the glucocorticoid pathway was also performed. RESULTS: Nine prepubertal subjects aged 8.1 ± 2.3 years completed the study. Mean ACTH, androstenedione, and 17-hydroxyprogesterone (17-OHP) values were lower following the DEX arm of the study than after subjects received HC (p ≤ 0.016) or PDN (p ≤ 0.002). 17-OHP was also lower after HC than PDN (p < 0.001). There was no difference in IGF-1, GH, or change in BMI. SNP analysis revealed significant associations between hormone concentrations, pharmacokinetic parameters, and variants in several glucocorticoid pathway genes (ABCB1, NR3C1, IP013, GLCCI1). CONCLUSIONS: DEX resulted in marked adrenal suppression suggesting that its potency relative to hydrocortisone and prednisone was underestimated. SNPs conferred significant differences in responses between subjects. Although preliminary, these pilot data suggest that incorporating pharmacogenetics has the potential to eventually lead to targeted therapy in children with CAH.Item Patient and Parent Perspectives on Testicular Adrenal Rest Tumors in Congenital Adrenal Hyperplasia(Karger, 2023-10) Nebesio, Todd D.; Kim, Mimi S.; Szymanski, Konrad M.; Kokorowski, Paul J.; Geffner, Mitchell E.; Eugster, Erica A.; on behalf of the Life with Congenital Adrenal Hyperplasia Study Group; Pediatrics, School of MedicineBackground: Testicular adrenal rest tumors (TARTs) increase the risk of infertility in males with classic congenital adrenal hyperplasia (CAH). There is no consensus regarding at what age screening testicular ultrasounds should begin and how often they should be repeated. Furthermore, it is unknown whether patients and parents are aware of the significance of TARTs. Objective: The objective of the study was to investigate awareness, concern, and screening rates for TARTs in males with classic CAH. Methods: Males with CAH and parents completed an online questionnaire from 2019 to 2020. Responses to questions about TARTs were analyzed. Fisher’s exact test was used to determine statistical significance. Results: Of 123 responders, 14 were males with CAH (range 16–54 years) and 109 were parents of males with CAH (son’s age range infancy to 37 years). Of all responders, 74% were concerned about the possibility of TARTs, 48% had discussions about TARTs with their endocrinologist, and 42% were aware of possible infertility in males with CAH. There was no difference between responses provided by affected males and parents for these topics (p ≥ 0.08). Among male responders with CAH, 93% had at least one testicular ultrasound, and 77% had undergone more than one. Among parent responders, 30% of their sons had at least one testicular ultrasound, and 61% had more than one. The frequency, total number, and age when the first testicular ultrasound was obtained were inconsistent in both groups. Fifty percent of male responders with CAH and 11% of sons were referred to a urologist for evaluation. Conclusions: Although most responders were concerned about TARTs, less than half recalled discussing this issue with their endocrinologist, and less than half were aware of the possibility of infertility. Although TARTs are most often treated medically, several responders were referred to a urologist. Standardized patient education and consensus guidelines are needed for the surveillance and management of TARTs in males with classic CAH.Item Tildacerfont in Adults With Classic Congenital Adrenal Hyperplasia: Results from Two Phase 2 Studies(Endocrine Society, 2021) Sarafoglou, Kyriakie; Barnes, Chris N.; Huang, Michael; Imel, Erik A.; Madu, Ivy-Joan; Merke, Deborah P.; Moriarty, David; Nakhle, Samer; Newfield, Ron S.; Vogiatzi, Maria G.; Auchus, Richard J.; Medicine, School of MedicineContext: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is typically treated with lifelong supraphysiologic doses of glucocorticoids (GCs). Tildacerfont, a corticotropin-releasing factor type-1 receptor antagonist, may reduce excess androgen production, allowing for GC dose reduction. Objective: Assess tildacerfont safety and efficacy. Design and setting: Two Phase 2 open-label studies. Patients: Adults with 21OHD. Intervention: Oral tildacerfont 200 to 1000 mg once daily (QD) (n = 10) or 100 to 200 mg twice daily (n = 9 and 7) for 2 weeks (Study 1), and 400 mg QD (n = 11) for 12 weeks (Study 2). Main outcome measure: Efficacy was evaluated by changes from baseline at 8 am in adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17-OHP), and androstenedione (A4) according to baseline A4 ≤ 2× upper limit of normal (ULN) or A4 > 2× ULN. Safety was evaluated using adverse events (AEs) and laboratory assessments. Results: In Study 1, evaluable participants with baseline A4 > 2× ULN (n = 11; 19-67 years, 55% female) had reductions from baseline in ACTH (-59.4% to -28.4%), 17-OHP (-38.3% to 0.3%), and A4 (-24.2% to -18.1%), with no clear dose response. In Study 2, participants with baseline A4 > 2× ULN (n = 5; 26-63 years, 40% female) had ~80% maximum mean reductions in biomarker levels. ACTH and A4 were normalized for 60% and 40%, respectively. In both studies, participants with baseline A4 ≤ 2× ULN maintained biomarker levels. AEs (in 53.6% of patients overall) included headache (7.1%) and upper respiratory tract infection (7.1%). Conclusions: For patients with 21OHD, up to 12 weeks of oral tildacerfont reduced or maintained key hormone biomarkers toward normal.