Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 Are Identified in Individuals with Congenital Hypogonadotropic Hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) and its anosmia-associated form (Kallmann syndrome [KS]) are genetically heterogeneous. Among the >15 genes implicated in these conditions, mutations in FGF8 and FGFR1 account for ∼12% of cases; notably, KAL1 and HS6ST1 are also involved in FGFR1 signaling and can be mutated in CHH. We therefore hypothesized that mutations in genes encoding a broader range of modulators of the FGFR1 pathway might contribute to the genetics of CHH as causal or modifier mutations. Thus, we aimed to (1) investigate whether CHH individuals harbor mutations in members of the so-called "FGF8 synexpression" group and (2) validate the ability of a bioinformatics algorithm on the basis of protein-protein interactome data (interactome-based affiliation scoring [IBAS]) to identify high-quality candidate genes. On the basis of sequence homology, expression, and structural and functional data, seven genes were selected and sequenced in 386 unrelated CHH individuals and 155 controls. Except for FGF18 and SPRY2, all other genes were found to be mutated in CHH individuals: FGF17 (n = 3 individuals), IL17RD (n = 8), DUSP6 (n = 5), SPRY4 (n = 14), and FLRT3 (n = 3). Independently, IBAS predicted FGF17 and IL17RD as the two top candidates in the entire proteome on the basis of a statistical test of their protein-protein interaction patterns to proteins known to be altered in CHH. Most of the FGF17 and IL17RD mutations altered protein function in vitro. IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (6/8 individuals). Mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH

A Framework for Inclusive Graduate Medical Education Recruitment Strategies: Meeting the ACGME Standard for a Diverse and Inclusive Workforce

© 2020 Lippincott Williams and Wilkins. All rights reserved. To help address health care disparities and promote higher-quality, culturally sensitive care in the United States, the Accreditation Council for Graduate Medical Education and other governing bodies propose cultivating a more diverse physician workforce. In addition, improved training and patient outcomes have been demonstrated for diverse care teams. However, prioritizing graduate medical education (GME) diversity and inclusion efforts can be challenging and unidimensional diversity initiatives typically result in failure. Little literature exists regarding actionable steps to promote diversity in GME. Building on existing literature and the authors\u27 experiences at different institutions, the authors propose a 5-point inclusive recruitment framework for diversifying GME training programs. This article details each of the 5 steps of the framework, which begins with strong institutional support by setting diversity as a priority. Forming a cycle, the other 4 steps are seeking out candidates, implementing inclusive recruitment practices, investing in trainee success, and building the pipeline. Practical strategies for each step and recommendations for measurable outcomes for continued support for this work are provided. The proposed framework may better equip colleagues and leaders in academic medicine to prioritize and effectively promote diversity and inclusion in GME at their respective institutions

Rapid vascular glucose uptake via enzyme-assisted subcutaneous infusion: enzyme-assisted subcutaneous infusion access study.

BACKGROUND: Enzyme-assisted subcutaneous infusion (EASI), with subcutaneous human recombinant hyaluronidase pretreatment, may offer an alternative to standard intravenous (IV) access. OBJECTIVES: This study's objectives were to assess paramedic (Emergency Medical Technician-Paramedic [EMTP])-placed EASI access in volunteers to determine (1) feasibility of EMTP EASI access placement; (2) subject/EMTP ratings of placement ease, discomfort, and overall EASI vs IV preference; and (3) speed of intravascular uptake of EASI infusate. METHODS: Twenty adults underwent 20-gauge IV placement by 4 EMTPs, receiving a 250-mL maximal-rate IV bolus of normal saline. Next, each subject received in the other arm a 20-gauge EASI access line (with 1-mL injection of 150 U of human recombinant hyaluronidase), through which was infused 250 mL D5NS (1 g glucose was labeled with stable tracer 13C). Blood draws enabled gas chromatography/mass spectrometry (GC/MS) assessment of 13C-glucose uptake. Intravenous access and EASI access were compared for time parameters and subject/EMTP ratings. Data were analyzed with median and interquartile range, Kruskal-Wallis testing, Fisher exact test, and regression (GC/MS data). RESULTS: Intravenous access and EASI access were successful in all 20 subjects. Compared with EASI access (all placed in <15 seconds), IV access took longer; but the 250-mL bolus was given more quickly via IV access. EMTPs rated EASI easier to place than IV; pain ratings were similar for IV and EASI. The GC/MS showed intravascular uptake at all time points. CONCLUSIONS: Enzyme-assisted subcutaneous infusion is faster and easier to initiate than IV access; intravascular absorption of EASI-administered fluids begins within minutes

Bridging the divide: Student grand rounds at the interface of basic science and clinical medicine

Problem: As biomedical research and clinical medicine become increasingly complex, physician-scientists and clinically oriented biomedical researchers play important roles in bridging the gap between disciplines. A lack of educational programming that addresses the unique needs of students preparing for careers at the interface of basic science and clinical medicine may contribute to trainee attrition. Approach: The MD-PhD/LHB Grand Rounds was introduced in 2008 as a trainee-driven collaborative effort of the Harvard/ Massachusetts Institute of Technology MD-PhD program at Harvard Medical School (HMS MD-PhD program), Harvard\u27s Leder Human Biology and Translational Medicine (LHB) program, and the Brigham and Women\u27s Hospital (BWH) Internal Medicine Department. Each of the program\u27s approximately 4 sessions per year begins with dinner, followed by a clinical case presentation led by a BWH MD-PhD resident with a master clinician faculty discussant, then a research presentation by an LHB PhD student or an MD-PhD student on a basic science topic related to the clinical case, and time for socialization. Outcomes: In a July 2017 survey of participating students and residents, respondents reported being highly satisfied with the program. Mean satisfaction ratings were 4.3 (SD 0.5) for 12 MD-PhD students, 4.2 (SD 0.7) for 31 LHB students, and 4.4 (SD 0.9) for 5 residents on a 5-point scale (5 = very satisfied). Free-text responses suggested MD-PhD students valued opportunities for active engagement with the resident presenter and faculty discussant. LHB students appreciated the absence of medical jargon in the clinical presentations. Residents\u27 reported reasons for participating included enjoyment of teaching and interaction with students. Next Steps: The Harvard MD-PhD/LHB Grand Rounds can serve as a template for developing similar programs at other institutions. Research is needed to determine whether such grand rounds programs can help fix the leaky pipeline in the training of future physician-scientists and clinically oriented biomedical researchers

Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 Are Identified in Individuals with Congenital Hypogonadotropic Hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) and its anosmia-associated form (Kallmann syndrome [KS]) are genetically heterogeneous. Among the &gt;15 genes implicated in these conditions, mutations in FGF8 and FGFR1 account for ~12% of cases; notably, KAL1 and HS6ST1 are also involved in FGFR1 signaling and can be mutated in CHH. We therefore hypothesized that mutations in genes encoding a broader range of modulators of the FGFR1 pathway might contribute to the genetics of CHH as causal or modifier mutations. Thus, we aimed to (1) investigate whether CHH individuals harbor mutations in members of the so-called "FGF8 synexpression" group and (2) validate the ability of a bioinformatics algorithm on the basis of protein-protein interactome data (interactome-based affiliation scoring [IBAS]) to identify high-quality candidate genes. On the basis of sequence homology, expression, and structural and functional data, seven genes were selected and sequenced in 386 unrelated CHH individuals and 155 controls. Except for FGF18 and SPRY2, all other genes were found to be mutated in CHH individuals: FGF17 (n = 3 individuals), IL17RD (n = 8), DUSP6 (n = 5), SPRY4 (n = 14), and FLRT3 (n = 3). Independently, IBAS predicted FGF17 and IL17RD as the two top candidates in the entire proteome on the basis of a statistical test of their protein-protein interaction patterns to proteins known to be altered in CHH. Most of the FGF17 and IL17RD mutations altered protein function in vitro. IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (6/8 individuals). Mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH