Browsing by Author "Walvoord, Emily C."
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Item An Animal Model of Combined Pituitary Hormone Deficiency Disease(2010-08) Colvin, Stephanie C.; Konieczny, Stephen F.; Rhodes, Simon J.; Walvoord, Emily C.; Belecky-Adams, Teri; Herring, B. Paul; Roper, RandallLHX3 is a LIM-homeodomain transcription factor that has essential roles in pituitary and nervous system development in mammals. Children who are homozygous for recessive mutations in the LHX3 gene present with combined pituitary hormone deficiency disease (CPHD) characterized by deficits of multiple anterior pituitary hormones. Most LHX3 patients also present with additional defects associated with the nervous system including a characteristic limited head rotation and sometimes deafness. However, of the 10 types of LHX3 mutation described to date, one mutation type (W224ter) does not result in the limited head rotation, defining a new form of the disease. W224ter patients have CPHD but do not have nervous system symptoms. Whereas other mutations in LHX3 cause loss of the entire protein or its activity, the W224ter mutation causes specific loss of the carboxyl terminal of the LHX3 protein—a region that we have shown to contain critical regulatory domains for pituitary gene activation. To better understand the molecular and cellular etiology of CPHD associated with LHX3 gene mutations, I have generated knock-in mice that model the human LHX3 W224ter disease. The resulting mice display marked dwarfism, thyroid disease, female infertility, and reduced male fertility. Immunohistochemistry, real-time quantitative polymerase chain reaction (PCR), and enzyme-linked immunosorbant assays (ELISA) were used to measure hormones and regulatory factor protein and RNA levels, an approach which is not feasible with human patients. We have generated a novel mouse model of human pediatric CPHD. Our findings are consistent with the hypothesis that the actions of the LHX3 factor are molecularly separable in the nervous system and pituitary gland.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 Engaging All Stakeholders to Create a Trusted, Data-Driven, Process Improvement Approach to Addressing Learner Mistreatment(Taylor & Francis, 2022-09-15) Walvoord, Emily C.; Howenstine, Michelle S.; Allen, Bradley L.; Ribera, Amy K.; Nabhan, Zeina M.; Tori, Alvaro J.; Eichholtz, Rebekah D.; Dankoski, Mary E.; Family Medicine, School of MedicineProblem: Learner mistreatment has remained an ongoing challenge in academic medicine despite accreditation requirements mandating that every program has systems in place to prevent and respond to mistreatment. While efforts vary across institutions, much remains unanswered in the literature about best practices. Additionally, for the foreseeable future, challenges in the learning environment will likely continue and potentially worsen, given the confluence of multiple external stressors including the COVID-19 pandemic, faculty burnout and general political divisiveness in the nation. It is essential, therefore, to focus on indicators of improvement via process metrics such as knowledge and awareness of mistreatment policies and procedures, willingness to report, reasons for not reporting, and satisfaction with having made a report, while simultaneously focusing on the more complex challenge of eliminating mistreatment occurrences. Intervention: We describe the aspects of our mistreatment prevention and response system first implemented in 2017 along with process and outcome measures. The interventions included expanding our policy outlining appropriate conduct in the teacher-learner relationship; a graduated response protocol to allegations of mistreatment with a clear escalation approach; an online reporting system; a graduate medical education exit survey which mirrors the AAMC Graduation Questionnaire on mistreatment; a robust communication and professional development campaign; a comprehensive data dashboard; and a comprehensive summary report dissemination plan. Context: The interventions were implemented at the largest allopathic medical school in the U.S., with nine campuses across the state. The system is available to all learners, including medical students, graduate students, residents, and fellows. Impact: Both institutional and national data sources have informed the continuous improvement strategies. Data from internal reporting systems, institutional surveys, and national data are presented from 2017 to 2021. Findings include an increasing number of incidents reported each year, including confidential reports from students who include their contact information rather than report anonymously, which we view as an indicator of learner trust in the system. Our data also show consistent improvements in learners’ awareness of the policy and procedures and satisfaction with having made a report. We also include other data such as the nature of complaints submitted and timeliness of our institutional response. Lessons Learned: We present several lessons learned that may guide other institutions looking to similarly improve their mistreatment systems, such as a close partnership between faculty affairs, diversity affairs, and educational affairs leadership; communication, professional development, and training through multiple venues and with all stakeholders; easily accessible reporting with anonymous and confidential options and the ability to report on behalf of others; policy development guidance; data transparency and dissemination; and trust-building activities and ongoing feedback from learners.Item In Vivo Analysis of Human LHX3 Gene Regulation(2011-02) Mullen, Rachel D.; Rhodes, Simon J.; Herring, B. Paul; Skalnik, David Gordon; Thurmond, Debbie C.; Walvoord, Emily C.LHX3 is a transcription factor important in pituitary and nervous system development. Patients with mutations in coding regions of the gene have combined pituitary hormone deficiency (CPHD) that causes growth, fertility, and metabolic problems. Promoter and intronic elements of LHX3 important for basal gene expression in vitro have been identified, but the key regulatory elements necessary for in vivo expression were unknown. With these studies, I sought to elucidate how LHX3 gene expression is regulated in vivo. Based on sequence conservation between species in non-coding regions, I identified a 7.9 kilobase (kb) region 3' of the human LHX3 gene as a potential regulatory element. In a beta galactosidase transgenic mouse model, this region directed spatial and temporal expression to the developing pituitary gland and spinal cord in a pattern consistent with endogenous LHX3 expression. Using a systematic series of deletions, I found that the conserved region contains multiple nervous system enhancers and a minimal 180 base pair (bp) enhancer that direct expression to both the pituitary and spinal cord in transgenic mice. Within this minimal enhancer, TAAT/ATTA sequences that are characteristic of homeodomain protein binding sites are required to direct expression. I performed DNA binding experiments and chromatin immunoprecipitation assays to reveal that the ISL1 and PITX1 proteins specifically recognize these elements in vitro and in vivo. Based on in vivo mutational analyses, two tandem ISL1 binding sites are required for enhancer activity in the pituitary and spine and a PITX1 binding site is required for spatial patterning of gene expression in the pituitary. Additional experiments demonstrated that these three elements cannot alone direct gene expression, suggesting a combination of factors is required for enhancer activity. This study reveals that the key regulatory elements guiding developmental regulation of the human LHX3 gene lie in this conserved downstream region. Further, this work implicates ISL1 as a new transcriptional regulator of LHX3 and describes a possible mechanism for the regulation of LHX3 by a known upstream factor, PITX1. Identification of important regulatory regions will also enable genetic screening in candidate CPHD patients and will thereby facilitate patient treatment and genetic counseling.Item Just Ask: Using Faculty Input to Inform Communication Strategies(Wiley, 2014) Hoffmann Longtin, Krista; Palmer, Megan M.; Welch, Julie L.; Walvoord, Emily C.; Dankoski, Mary E.Faculty members today are bombarded with information, yet limited in time and attention. Managing communication with faculty is an increasingly important function of faculty development offices. This study explored how communication frameworks can be paired with web design principles and attention economics to increase the effectiveness of communication with faculty members. We developed and tested communication approaches designed to enhance faculty members’ identification and involvement with our programs. The advantages, disadvantages, and effectiveness of each model are presented. Ultimately, the study reframed our understanding of communication strategies, not as static tools, but rather as opportunities to engage faculty.Item Optimism and Step 1(2020-03-06) Schleinkofer, Nathan; Kochhar, Komal; Walvoord, Emily C.Optimism is a personality trait that correlates with improved coping skills, physical health, and emotional wellbeing. Various interventions have been shown to increase optimistic thinking. To date, there have been few investigations into the effect of optimism on academic performance. For medical students, the USMLE Step 1 exam is a significant stressor that has a large impact on future career options. Beginning on February 27th 2019, one week after completing their foundational sciences curriculum, 2nd year medical students (n=112) at the Indiana University School of Medicine completed the Life Orientation Test-Revised (LOT-R), which assesses dispositional optimism. The LOT-R includes six questions scored on a 5-point Likert Scale from “I disagree a lot” to “I agree a lot”. Higher scores indicate a higher level of optimism. Students were instructed to complete the LOT-R before sitting for the Step 1 exam between February 23rd and April 6th. The correlation between Optimism scores and Step 1 exam scores were examined. The study received approval from Indiana University’s Institutional Review Board. The Optimism scores ranged from 6 to 30, mean = 22. The mean for adults ages 18-30 is 22.1. Step 1 exam scores ranged from 189 to 268, mean = 236.4. There was a small positive correlation (Pearson 0.257) between Optimism scores and Step 1 exam scores (p=0.006). There were no gender differences in Optimism or Step 1 exam scores. These results indicate that optimism may be a potentially significant factor associated with medical student performance, specifically on the USMLE Step 1 exam. Further research should investigate if a causal relationship exists between the two factors. If such a relationship is found, interventions specifically targeted to increase optimism may prove useful for improving student academic performance and possibly their overall wellbeing.Item Stepping Stones: A Leadership Development Program to Inspire and Promote Reflection Among Women Faculty and Staff(Wiley, 2017-06) Hoffmann-Longtin, Krista; Morgan, Zachary S.; Schmidt, Lauren Chism; Walvoord, Emily C.; Palmer, Megan M.; Dankoski, Mary E.; Communication Studies, School of Liberal ArtsWomen frequently benefit from focused faculty development opportunities not because they need to be “fixed,” but rather it is a means to demonstrate that success, even in chilly environments, is possible. The Stepping Stones program uses a unique design to provide participants with inspiration, time for reflection, and strategies for how to navigate one's career, through hearing about the journeys of successful women. In this article, we describe the program and evaluation results. Post‐event and longitudinal follow‐up surveys indicate that the program and its unique narrative format help to debunk the superwoman myth and leave participants with a sense of optimism about their future careers.Item Stepping Stones: Nine Lessons from Women Leaders in Academic Medicine(Texas A&M University, 2013) Palmer, Megan M.; Hoffmann-Longtin, Krista J.; Walvoord, Emily C.; Dankoski, Mary E.Women now make up half of all medical school matriculates; yet few women hold leadership positions in academic health centers. The reasons for this gender gap are complex and have been the subject of much discussion. However, the experiences of women who successfully ascend to positions of senior leadership are rarely examined. It is critical to develop a greater understanding of women's paths to leadership positions in order to inspire and enable more women to seek such opportunities. Using a semi-structured protocol, we interviewed 16 women leaders who were willing to share their career journeys in a public forum. These leaders were asked to share pivotal moments or milestones, referred to as "stepping stones," in their careers. The interviews were taped, transcribed and analysed for significant patterns and consistent themes. Nine themes were identified and included: hold fast to your values; be open to unexpected opportunities; surround yourself with people who believe in you and people you believe in; be assertive in your communication and actions; continually refine your leadership skills; don't take things personally; stay organized; build positive relationships and welcoming environments; and when and if necessary, prove them wrong. The women leaders had strikingly similar lessons to share. This study develops a deeper understanding of the career paths of women in leadership positions, setting the stage for future study as well as encouraging and empowering more women to climb the leadership ladder.Item Whole exome sequencing to identify genetic causes of short stature(S. Karger AG, 2014) Guo, Michael H.; Shen, Yiping; Walvoord, Emily C.; Miller, Timothy C.; Moon, Jennifer E.; Hirschhorn, Joel N.; Dauber, Andrew; Department of Pediatrics, IU School of MedicineBACKGROUND/AIMS: Short stature is a common reason for presentation to pediatric endocrinology clinics. However, for most patients, no cause for the short stature can be identified. As genetics plays a strong role in height, we sought to identify known and novel genetic causes of short stature. METHODS: We recruited 14 children with severe short stature of unknown etiology. We conducted whole exome sequencing of the patients and their family members. We used an analysis pipeline to identify rare non-synonymous genetic variants that cause the short stature. RESULTS: We identified a genetic cause of short stature in 5 of the 14 patients. This included cases of floating-harbor syndrome, Kenny-Caffey syndrome, the progeroid form of Ehlers-Danlos syndrome, as well as 2 cases of the 3-M syndrome. For the remaining patients, we have generated lists of candidate variants. CONCLUSIONS: Whole exome sequencing can help identify genetic causes of short stature in the context of defined genetic syndromes, but may be less effective in identifying novel genetic causes of short stature in individual families. Utilized in the clinic, whole exome sequencing can provide clinically relevant diagnoses for these patients. Rare syndromic causes of short stature may be underrecognized and underdiagnosed in pediatric endocrinology clinics.