Prefrontal Cortex Dysfunction in Fragile X Mice Depends on the Continued Absence of Fragile X Mental Retardation Protein in the Adult Brain.

Fragile X Syndrome (FX) is generally considered a developmental disorder, arising from a mutation that disrupts the transcription of Fragile X Mental Retardation Protein (FMRP). However, FMRP regulates the transcription of other proteins and participates in an unknown number of protein-protein interactions throughout life. In addition to known developmental issues, it is thus likely that some dysfunction is also due to the ongoing absence of FMRP. Dissociating dysfunction due to developmental dysregulation from dysfunction due to the continued absence of FMRP is necessary to understand the different roles of FMRP and to treat patients effectively throughout life. We show here that FX model mice display substantial deficits in a PFC-dependent task. We then use conditional knock-out mice to eliminate FMRP only in the PFC alone of adult mice. We observe an increase in the proportion of nonlearners and a delay in the onset of learning in both FX and conditional knock-out mice. The results suggest that these deficits (1) are due to the absence of FMRP in the PFC alone and (2) are not the result of developmental dysregulation. Furthermore, PFC-associated deficits are rescued by initiating production of FMRP in adult conditional restoration mice, suggesting that PFC dysfunction may persist as long as FMRP is absent and therefore can be rescued after development. The data suggest that it is possible to dissociate the roles of FMRP in neural function from developmental dysregulation, and that PFC function can be restored in the adult FX brain.SIGNIFICANCE STATEMENT The absence of Fragile X Mental Retardation Protein (FMRP) from birth results in developmental disabilities and lifelong impairments. We show here that in mouse models PFC dysfunction in Fragile X Syndrome (FX) can be attributed to the continued absence of FMRP from the PFC, independent of FMRP status during development. Furthermore, initiation of FMRP production in the PFC of adult FX animals rescues PFC function. The results suggest that at least some FX-specific neurological defects can be rescued in the adult FX brain after development.

Assessing Baseline Knowledge and Usage Patterns of Sexual Orientation/Gender Identity Affirming Electronic Health Record Modules Within a Urology Division at a Single Tertiary Care Institution.

OBJECTIVE: To evaluate how sexual orientation and gender identity (SOGI)-affirming electronic health record (EHR) modules (which enable seamless location and documentation of patient SOGI data) are being used by providers/staff within a urology practice. MATERIALS AND METHODS: All 120 patient-facing providers/staff at a tertiary urology program were offered a 39-question Qualtrics-based survey, which assessed respondents' cultural competency, baseline knowledge of SOGI EHR modules, and SOGI module usage patterns. Cultural competency was assessed using the LGBT-Development of Clinical Skills Scale (LGBT-DOCCS). RESULTS: 96 qualified providers/staff completed the survey (response rate, 89%). Only 25% of respondents received training on finding/collecting SOGI data in the EHR. Respondents possessed high levels of LGBTQ attitudinal awareness (M=6.38/7) but low clinical preparedness (M=4.32/7), in large part due to perceived inadequate training to work with LGBT patients. Major drivers of clinical preparedness were respondent role and number of LGBT patients seen in the past year. While respondents uniformly report ease finding SOGI data, all providers/staff (particularly physicians) rarely use formal SOGI documentation tools. Few respondents partook in SOGI EHR training; those that did were significantly more likely to use formal SOGI documentation tools. CONCLUSION: This study revealed that providers/staff possess high general LGBTQ cultural competency and ability to find relevant SOGI data in the EHR, while also highlighting limited training in SOGI-affirming EHR tools and low usage of formal documentation tools. This framework could be a roadmap for evaluating SOGI-affirming EHR use by urology practices as such features increase in popularity.

Prognostic significance of sarcomatoid features in metastatic renal cell carcinoma treated with cytoreductive nephrectomy and targeted therapy.

INTRODUCTION: The presence of sarcomatoid features in localized renal cell carcinoma (RCC) is associated with worse outcomes. We sought to use a national database to evaluate the outcomes and prognosis of metastatic RCC (mRCC) with sarcomatoid features treated with cytoreductive nephrectomy (CN) and targeted therapy (TT). METHODS: The National Cancer Database (2010-2013) was used to identify patients with mRCC at diagnosis. Only patients who underwent CN followed by TT were included. Kaplan-Meier curves, log-rank test, and multivariate Cox regression analysis were used to compare overall survival (OS) between mRCC with and without sarcomatoid features. Subgroup analysis in patients with clear cell RCC (ccRCC) was performed. RESULTS: A total of 1,427 patients with mRCC treated with CN followed by TT were included of which 364 (26%) had mRCC with sarcomatoid features. mRCC with sarcomatoid features were more likely to have Fuhrman grade 4 cancer. mRCC with sarcomatoid features had worse OS than mRCC without sarcomatoid features (24.6 vs 12.0 months, P < 0.001). For the clear cell cohort, mRCC with sarcomatoid features had worse OS than mRCC without sarcomatoid features (26.2 vs 14.0 months, P < 0.001). Multivariate Cox regression showed sarcomatoid features was significantly associated with worse OS in the overall cohort (hazard ratio [HR] =1.63, 95% confidence interval [CI] =1.38-1.91, P < 0.001) and the ccRCC subcohort (HR=1.53, 95% CI=1.23-1.90, P < 0.001). DISCUSSION/CONCLUSION: mRCC with sarcomatoid features treated with CN and TT has a very poor and drastically different prognosis compared with mRCC without sarcomatoid features. With the expansion of systemic RCC therapies, investigation is needed to optimize treatment in this high-risk cohort.

A Model for Improving Health Care Quality for Transgender and Gender Nonconforming Patients.

PROBLEM DEFINITION: Transgender and gender nonconforming (TGNC) populations are disproportionately affected by limited health care access and poor health outcomes and commonly report discrimination and mistreatment in health care settings. Despite these disparities, comprehensive approaches to improve the quality of health care of TGNC patient populations are currently lacking. INITIAL APPROACH: The Vanderbilt Program for LGBTQ Health has developed a multifaceted, community-engaged approach to improve the quality of health care of TGNC patients, which includes the creation of a transgender patient advocacy program, a community advisory board, and a transgender health clinic. To support the continuous quality improvement of transgender health care, the program is currently piloting a novel multilevel monitoring and evaluation (M&E) system to collect information at the individual patient visit and health systems levels. NEXT STEPS: The next steps for Vanderbilt's community-engaged M&E system are to identify the clinics and health services most used by TGNC patients and assess the level of patient satisfaction in each area. This process will support the identification of high- and low-performing clinics and health services and allow for targeted delivery of trainings to improve the quality of culturally competent health care TGNC patients receive systemwide. CONCLUSION: In collaboration with TGNC patient populations and community stakeholders, Vanderbilt has created a model to improve the quality of both transition- and non-transition-related health care at the systems level that can be adopted by other health care systems nationally.