• Acute Exercise Alters Promoter Methylation in Human Skeletal Muscle

      DeMenna, Jacob; The University of Arizona College of Medicine - Phoenix; Coletta, Dawn PhD (The University of Arizona., 2016-04)
      Background And Significance: Insulin resistance is an underlying disease of obesity and type 2 diabetes, which is a metabolic health crisis in the United States. Insulin resistance is caused by a combination of environmental and genetic factors. Understanding the epigenetic factors, specifically DNA methylation and how it influences the expression of genes linked to insulin resistance is of critical importance. Research Question: In this project, we set out to identify patterns of changes in DNA methylation in response to an acute exercise in healthy control subjects. Methods: Five lean (BMI = 23.6 ± 3.3 kg/m2) volunteers underwent a euglycemic hyperinsulinemic clamp with a baseline muscle biopsy and a single bout of aerobic exercise on a stationary bicycle for 48 minutes, rotating between 70 and 90% of VO2max, with a muscle biopsy taken 24 hours after completing the exercise. DNA was isolated from the baseline and 24 hours muscle biopsy, and next‐generation reduced representation bisulfite sequencing (RRBS) was performed, with analysis of the data using methylSig, and KEGG pathway analysis. Results: RRBS analysis captured 676,937 methylation sites, and of these 47,459 were differently methylated following acute exercise (P<0.05) with 4,574 sites occurring in promoter and untranslated (5’ and 3’) regions. The site with the greatest increase in methylation was within the gene NADP(+) ‐dependent malic enzyme cytosolic form (ME1) that demonstrated a significant methylation difference of +63.3%. A site in the gene for adenomatosis polyposis coli down‐regulated 1‐like (APCDD1L) was observed to have the most significant decrease in methylation by ‐65.3%. The gene with the highest incidence of differentially methylated sites was the gene for cardiomyopathy associated 5 (CMYA5) with 11 sites demonstrating a mean increase in methylation of 30.47%. The gene family with sequence similarity 176, member B protein (FAM176B) had the highest frequency of methylated sites (n=7) that were decreased in methylation with a mean decrease of ‐24.28%. KEGG pathway analysis was performed, which revealed significant (P<0.05) increases in methylation in the pathways of Wnt signaling, Heterotrimeric G‐protein signaling ‐Gi alpha and Gs alpha mediated, Cadherin signaling, Melanogenesis, Axon Guidance, and Neuroactive ligand‐receptor interaction. Significantly 4 enriched pathways with decreased methylation post exercise demonstrated one pathway, the Calcium signaling pathway. Conclusion: Our data demonstrates that a single bout of exercise can alter the DNA methylation pattern in skeletal muscle. Changes were observed in genes related to metabolic pathways, supporting previously published findings of changes in mRNA and proteins involved in metabolism following exercise. Future work is warranted with obese and type 2 diabetic participants to explore the differences in response to exercise between these groups.
    • Analysis of the Proposed Implementation of a Public Health District in Maricopa County

      Hoffman, Laura; The University of Arizona College of Medicine - Phoenix; England, Bob MD, MPH; Barraza, Leila JD, MPH (The University of Arizona., 2016-03-25)
      Background: Since the number and variety of services that a public health department is able to provide is related to its financial resources, it is important that each department have secure funding. The Public Health District model, in which the public health department is mostly funded by a dedicated public tax, rather than as a dependent on the county’s overall budget, has been proposed as an option for the Maricopa County Department of Public Health (MCDPH). This model was implemented in neighboring Pinal County in 2007 and is funded by a 0.1% sales tax. Specific aims: Our study aims are: (1) analyze the current MCDPH funding structure in comparison to other similarly sized county-managed public health departments, as well as review the development and structure of the Pinal County Public Health Services District as a local reference; (2) project the likely financial effects of the implementation of a tax-based Public Health District in Maricopa County; and (3) assess the potential effects on MCDPH management and public health outcomes in Maricopa County. We hypothesize that the implementation of a Public Health District in Maricopa County will secure a source of stable and increased funding and allow for improved public health services. Methods: Specific Aim 1: Budget data for FY 2011-2012 was analyzed for revenue types and percent contribution for each county department in the comparison. Budget data for FY 2003- 2014 for Pinal and Maricopa counties was analyzed in a similar manner. Phone interview with Pinal County Director, Mr. Thomas Schryer, was completed regarding the development of the Public Health District model in Pinal County; Specific Aim 2: Revenue data from the Maricopa County Jail Excise Tax was reviewed and utilized as a proxy to estimate potential income generated by a 0.1% sales tax; Specific Aim 3: The 2012 Maricopa County Community Health Assessment was evaluated to identify areas of need. Results: Specific Aim 1: Funding structures varied greatly between county public health departments, though heavy reliance on government funds was a common theme. Pinal County demonstrated increased funding stability with an increase in overall revenue budget upon implementation of Public Health District model. Specific Aim 2: Estimated revenue from a 0.1% sales tax was calculated to be $70 million in FY 2014-2015, with potential average revenue of $92 million over the next ten years. Specific Aim 3: Top areas for health improvement in Maricopa County include obesity, diabetes, lung cancer, cardiovascular disease and access to care. Conclusion: The current funding structure of the MCDPH follows the trend of other similarly sized county-managed public health departments with a heavy reliance on government funds. The potential revenue generated from a 0.1% sales tax in Maricopa County would be sufficient to significantly decrease the department’s dependence on general county funds and government grants. The result is increased overall funding and financial stability, thus helping the department to better target area needs and improve public health outcomes.
    • BDNF Knockdown in the VTA Blocks Social Stress‐Induced Deficits in Social Behavior and Nucleus Accumbens ΔFosB Expression

      Hakes, Emelia; The University of Arizona College of Medicine - Phoenix; Hammer, Jr., Ron PhD; Nikulina, Ella PhD (The University of Arizona., 2016-03-25)
      Social defeat stress, a salient stressor that translates readily from animal studies to humans, alters social approach behavior and induces brain‐derived neurotrophic factor (BDNF) in the ventral tegmental area (VTA), as well as the stable transcription factor, ΔFosB, in the nucleus accumbens (NAc) of rats. However, it is unknown whether VTA BDNF is required for these effects of stress. Rats underwent stereotaxic surgery to receive bilateral intra‐VTA infusions of adeno‐associated virus inducing green fluorescent protein (AAV‐GFP) or GFP and short hairpin RNA directed against BDNF (shRNA‐BDNF). Following recovery, rats were subjected to control handling or social defeat stress, consisting of a brief confrontation between an aggressive resident and an experimental intruder rat every third day for 10 days. Social interaction was assessed in a social approach assay two weeks later. Following perfusion, brains were removed and processed for immunohistochemical analysis of ΔFosB expression. VTA BDNF knockdown attenuated the effect of social stress on weight gain, and increased social approach behavior, which is normally reduced by social stress. Furthermore, social stress increased NAc ΔFosB labeling in AAV‐GFP rats, but this effect was blocked by prior shRNA‐BDNF treatment. This study further implicates VTA BDNF signaling in the effects of stress on social behavior. VTA BDNF appears to be required for the long‐lasting effects of social stress on ΔFosB expression in the NAc. Thus, activation of BDNF signaling in mesolimbic circuits may underlie the persistent deficits of social behavior induced by stress exposure in some individuals.
    • Building a Medical App: Approach, Infrastructure, and Challenges of Developing a Congenital Heart Defects App for Educational Purposes

      Stoker, Alexander; The University of Arizona College of Medicine - Phoenix; Richardson, Randy MD (The University of Arizona., 2016-03-25)
      Mobile software application (apps) have exploded in popularity since 2008, when Apple’s App Store opened and have become increasingly present in medical education and medical practice. As evidence of educators realizing the potential apps have for educating students, the University of Arizona has created a department called the Office of Instruction and Assessment (OIA), which has a programming team that is committed to assisting faculty in the design, development and implementation of apps for University of Arizona Students. Congenital heart defects are the most common type of birth defect in the United States, affecting nearly 1% of, or about 40,000, births per year. There are complex three‐dimensional relationships involved in many of the congenital heart defects that may be difficult for students to fully understand through the traditional method of reading and looking at two‐dimensional diagrams. The principle goal of this project was to participate in the design and development of an educational mobile app that allows the user to interactively rotate digital 3D models of hearts with congenital heart defects. Multiple approaches to developing an educational medical app were explored including utilizing basic app‐building programs that do not require computer coding or programming, paying a for‐profit company to develop an app, and collaborating with a larger educational institution that has the resources available for developing an app and has a potential use for the app. This thesis aims to describe the resources available to develop an educational app, the major factors that determine the best approach for app development and the challenges associated with each approach. Through the case example of developing “Heart Defects” with the Office of Instruction and Assessment at the University of Arizona and publishing the app on the Apple App Store it was determined that the major factors guiding the approach to app development are complexity of the app, computer programming experience of the individual planning to develop an app, and having access to a larger institution with the ability to develop apps and the institution having a perceived benefit from developing the app.
    • The Characteristics of Physicians Elected and Serving in State Legislatures and the United States Congress

      Petterson, Matthew; The University of Arizona College of Medicine - Phoenix; Derksen, Daniel MD (The University of Arizona., 2016-03-25)
      Physician participation in United States governance has a long and honorable history, dating to the nation’s inception. At a time of unprecedented change in health policy ‐ to control the growth of health care costs, to cover the uninsured through Affordable Care Act (ACA) provisions, to improve quality, to meet the demand for health services as the population grows and ages ‐ the need for physician leadership to guide policy interventions has never been greater. Yet physician‐legislator participation has declined. There is little data about physicians involved in shaping health policy in state or federal legislative branches. This study examines the characteristics of physician‐legislators at the federal and state levels, and compares them to U.S. physicians in general. Using rosters fixed on March 13, 2014, the study reviewed biographic and demographic information on physician‐legislators. The study’s four hypotheses were that physician‐legislators were more likely to be (1) men than women, (2) members of the Republican Party than the Democratic Party, (3) a non‐primary care physician than a primary care physician, and (4) elected in the states where they completed graduate medical education than where they attended college. Ninety‐five physician‐legislators were identified in 51 legislative bodies in 2014. Physician‐legislators were more likely to be male than female, to be Republican than Democrat, and to be practicing in a non‐primary care than in a primary care specialty. Physician‐legislators were less likely to be elected in the state where they completed graduate medical education training than where they attended college. No personal factor was identified that linked the majority of physician‐legislators to the state in which they were elected.
    • Chronic Pain in Noonan Syndrome: A Previously Unreported but Common Symptom

      Vegunta, Sravanthi; The University of Arizona College of Medicine - Phoenix; Grebe, Theresa A. MD (The University of Arizona., 2016-03-25)
      Background and Significance: Noonan syndrome (NS) is a multiple malformation syndrome characterized by pulmonic stenosis, cardiomyopathy, short stature, lymphatic dysplasia, craniofacial anomalies, cryptorchidism, clotting disorders, and learning disabilities. Eight genes in the RAS/MAPK signaling pathway are implicated in NS. Chronic pain is an uncommon feature. Research question and Methods: To investigate the prevalence of pain in NS, we distributed a two‐part questionnaire about pain among NS individuals at the Third International Meeting on Genetic Syndromes of the Ras/MAPK Pathway. The first part of the questionnaire queried demographic information among all NS participants. The second part was completed by individuals with chronic pain. Questions included musculoskeletal problems and clinical features of pain. Results: Forty‐five questionnaires were analyzed; 53% of subjects were female. Mean age was 17 (2–48) years; 47% had a PTPN11 mutation. Sixty‐two percent (28/45) of individuals with NS experienced chronic pain. There was a significant relationship between prevalence of pain and residing in a cold climate (P = 0.004). Pain occurred commonly in extremities/joints and head/trunk, but more commonly in extremities/joints (P = 0.066). Subjects with hypermobile joints were more likely to have pain (P = 0.052). Human growth hormone treatment was not statistically significant among subjects without chronic pain (P = 0.607). We conclude that pain is a frequent and under‐recognized clinical feature of NS. Conclusion: Chronic pain may be associated with joint hypermobility and aggravated by colder climate. Our study is a preliminary investigation that should raise awareness about pain as a common symptom in children and adults with NS.
    • Coccidioidomycosis as a Cause of Sarcoid in Arizona

      Yourison, Isaac; The University of Arizona College of Medicine - Phoenix; Kuberski, Tim MD (The University of Arizona., 2016-03-25)
      BACKGROUND AND SIGNIFICANCE: Sarcoidosis is a granulomatous disease of unknown etiology. Coccidioidomycosis is a granulomatous fungal infection due to Coccidioides immitis and Coccidioides Posadasii endemic to the Southwestern United States and the majority of the cases are reported from Arizona. The cause of sarcoidosis has been studied for over a hundred years without establishing an etiology. Establishing the cause of sarcoid would be a significant contribution to the understanding of an important multisystem disease. RESEARCH QUESTIONS: Based on clinical observations a group of patients with two granulomatous diseases – sarcoidosis and coccidioidomycosis led to the hypothesis for this Scholarly Project – can sarcoidosis be caused by the fungus Coccidioides? METHODS: A literature review was performed which resulted in 5 patient case reports, a medical record review was conducted of patients with sarcoidosis between 2004‐2014 at Maricopa Medical Center with a case‐control comparison to 68 matched patients, and PCR analysis of 34 sarcoid biopsy specimens from the 68 sarcoid patients identified from the medical record. Also, two main patients with sarcoidosis were studied, one prospectively and the other retrospectively, both patients had their diagnosis of sarcoidosis made in Arizona and both develop sarcoidosis. There was no evidence of an etiology for their sarcoidosis at the time of diagnosis, specifically no evidence of coccidioidomycosis. The prospective patient was followed for eight years before he developed coccidioidomycosis. Predicting correctly that a patient diagnosed with sarcoid in Arizona would eventually develop coccidioidomycosis provides strong evidence for an etiologic relationship between Coccidioides and sarcoidosis. INCOMPLETE STUDIES: There is one major study for this Project that has not been completed: 1. Genetic studies on patients with both sarcoidosis and coccidioidomycosis to determine if there is a genetic predisposition to disseminated coccidioidomycosis
    • Comparison of 64‐Slice EKG‐Gated Computed Tomographic Angiography, Transthoracic Echocardiography, and Transesophageal Echocardiography for Detection and Complete Characterization of Anomalous Coronary Arteries in Infants with Comorbid Congenital Cardiac Malformations

      Sridhar, Shravan; The University of Arizona College of Medicine - Phoenix; Richardson, Randy R. MD (The University of Arizona., 2016-03-25)
      Background and Objective: Computed tomographic angiography (CTA) offers several benefits over echocardiography in the detection of CAAs (coronary artery anomalies). These include higher spatial resolution, operator independency, non‐invasiveness, and the availability of reconstructive techniques to track the entire arterial course.1,4,9 Accordingly, standard clinical practice (per ACC/AHA guidelines for adults with CAAs) for adults with suspected CAAs includes use of CTA as a first‐line imaging modality.6 Currently, there is no evidence favoring either CTA, transthoracic echocardiography (TTE), or transesophageal echocardiography (TEE) for initial imaging of infants with suspected CAAs. Therefore, the aims of this retrospective study include investigating the efficacy of CTA, TTE, and TEE in the detection and complete characterization of CAAs. Methods: Imaging and surgical data for 27 patients who presented for evaluation of congenital heart disease between 2006 and 2011 were evaluated. Patients had a mean age of 2.2 ± 0.7 months at initial evaluation and had undergone EKG‐gated 64‐slice cardiac CTA with 3D reconstruction in addition to multiple TTE and TEE studies. Performance metrics (including sensitivity, specificity, positive predictive value, negative predictive value, and accuracy) of each modality in CAA detection were computed. Concordance between each modality and surgical/conventional angiographic diagnosis in the characterization of anatomy along the origin, course, and termination of anomalous coronary arteries was evaluated. The rate of limitations of each modality in the imaging and interpretation of coronary anatomy was also reported. Results: Using surgical/angiographic diagnosis as the gold standard, CTA produced a sensitivity, specificity, and accuracy of 80%, 50%, and 74%, respectively. TTE produced a sensitivity, specificity, and accuracy of 20%, 50%, and 26%, respectively. TEE produced a sensitivity, specificity, and accuracy of 27%, 100%, and 42%, respectively. CTA outperformed TTE and TEE at characterizing anatomy at the origin and course of an anomalous coronary artery. At characterizing anatomy at the termination of an anomalous coronary artery, CTA outperformed TEE but did not significantly outperform TTE. CTA had a higher rate of documented limitations to imaging/interpretation compared to TTE and TEE but a lower rate when compared to conventional angiography. Conclusion and Impact: CTA is a rapid, non‐invasive, operator‐independent imaging modality that offers high resolution, 3‐dimensional imaging of CAAs in infants. The results of this study indicate that CTA is the most sensitive and accurate modality for detection of CAAs in infants and is optimal for characterizing anatomy along the entire length of an anomalous coronary artery. As such, CTA may be the optimal modality for first‐line coronary artery imaging in infants with suspected anomalous coronary artery anatomy who have a high pretest probability for having a CAA.
    • Comparison of Alkaline and Acid Base Diet Profiles and its Correlation with Bone Mineral Density: A Cross Sectional Investigation

      Aguayo, Izayadeth; The University of Arizona College of Medicine - Phoenix; Johnston, Carol PhD (The University of Arizona., 2016-03-23)
      Previous studies suggest that dietary patterns that promote acidosis may have a negative effect on bone density, whereas a more alkaline‐based profile would be associated with better bone health. Thus, the aim of this study was to assess, in omnivores, vegetarians, and vegans bone mineral density using Dual‐energy X‐ray absorptiometry (DEXA) and compare it to their acid‐base status as indicated by urinary pH, Potential Renal Acid Load (PRAL) and serum anion gap. Our hypothesis was that plant‐based diets would be associated with a more alkaline acid‐base profile than omnivorous diets, and thus have a higher bone mineral density. Methods: We conducted a cross‐sectional study where we compared plant based vs. omnivorous diets. Eighty‐two subjects were enrolled in the study (27 omnivores, 27 vegetarians, and 28 vegans). Subjects were asked to fill out a medical history form and a 24‐ hour diet recall, and to complete a 24‐hour urine collection. After a few weeks, subjects returned to the test site to complete a DEXA scan. Acid base‐balance and bone health were determined using PRAL, urine pH, and anion gap as biomarkers for pH, and DEXA as an indicator of bone density. Our results showed that bone mineral density did not differ significantly between groups, although lacto‐ovo and vegan diets were more alkaline compared to meat based diets (6.5  0.4, 6.7  0.4, and 6.2  0.4 pH respectively, p = 0.003). Protein intake was found to be reduced by ~30% in individuals adhering to a lacto‐ovarian or vegan diet; yet protein was only associated with bone mineral density in those following vegan diets. Conversely, urinary pH was associated with bone mineral density only in those following a meat‐based diet. The significance of this study is that it provides knowledge in the area of osteoporosis prevention and perhaps specific recommendations based on diet groups: increased fruit and vegetable intake for those with high meat consumption, to improve the acid‐base homeostasis, and increased plant protein intake for individuals who follow a plant-based diet.
    • Comparison of Postoperative Respiratory Function in Neonates with Hypoplastic Left Heart Syndrome Following First Stage Palliation

      Pandurangi, Sindhu; The University of Arizona College of Medicine - Phoenix; Willis, Brigham MD (The University of Arizona., 2016-03-25)
      Purpose Available surgical procedures in the first stage of the palliation of hypoplastic left heart syndrome (HLHS) are currently the Norwood procedure with Blalock‐Taussing (BT) shunt, Norwood with a Sano shunt (5.0 mm right ventricular‐pulmonary artery conduit), or a hybrid procedure combining surgical pulmonary artery band placement and catheter‐based closure of the ductus arteriosus. Following any of the three procedures, it is necessary for patients to be mechanically ventilated for a period of time; however, little is known about the differences in pulmonary function and outcome among the three groups. Methods We conducted a retrospective chart review of 14 neonates who underwent stage 1 palliation for HLHS, by hybrid procedure or Norwood procedure with BT or Sano shunts, at Phoenix Children’s Hospital from September 2013‐December 2014. Demographic, hemodynamic, and outcome information was collected. Heart rate, respiratory rate, mean arterial pressure, end tidal carbon dioxide (ETCO2), cerebral and renal somatic oximetry, mean airway pressure, ratio of partial pressure of arterial oxygen to inspired oxygen (PaO2/FiO2), partial pressure of arterial carbon dioxide (PaCO2), dead space fraction (Vd/Vt), and dynamic compliance were measured preoperatively, postoperatively, and at multiple time points from 6 to 120 hours postoperatively. Respiratory data was collected using the NM3 monitor (Philips Respironics, Pittsburgh, PA). Outcome measures collected included maximum postoperative lactate, time to extubation, hospital length of stay, and mortality. Results Of the 14 patients, 7 received the Norwood with BT shunt, 5 received the Sano shunt, and 2 received the hybrid procedure. Through linear regression analysis of groups stratified by shunt size, we found that the Vd/Vt ratios of the Sano and 3.0 mm BT shunt groups were higher at earlier times points, but became indistinguishable by 48 hours postoperatively (p=0.02). Linear regression of the 3 surgical groups comparing Vd/Vt across all times points did not show any significant differences (p = 0.79). Linear regression of dynamic compliance among the three groups across all time points also was not significant (p = 0.72). No significant difference was observed in dynamic compliance across all time points when groups were stratified by shunt size (p = 0.33). Examining differences between BT and Sano groups at each time point from 0‐ 120 hours postoperatively using Mann Whitney U analysis did not reveal significance. Analysis of outcomes of length of mechanical ventilation (p=0.61), hospital length of stay (p =0.99), and mortality (p>0.99) also did not differ significantly among the 3 surgical groups. Conclusion Our study identified that the 3.0 mm BT and Sano shunt group had higher Vd/Vt ratios throughout the first 48 postoperative hours. No other differences were found in Vd/Vt or dynamic compliance when surgical groups or shunt sizes were compared. Despite the early differences noted, lack of differences in outcome measures suggests that these early differences have little influence on prognosis.
    • Complex Transcriptional Regulation of the Fibroblast Growth Factor‐23 Gene by 1,25‐Dihydroxyvitamin D3: Evidence for Primary and Secondary Mechanisms

      Saini, Rimpi; The University of Arizona College of Medicine - Phoenix; Haussler, Mark R. PhD (The University of Arizona., 2016-03-25)
      Fibroblast growth factor 23 (FGF23) is a circulating phosphaturic hormone synthesized in osteocytes and osteoblasts that corrects hyperphosphatemic states by inhibiting renal phosphate reabsorption via the fibroblast growth factor receptor‐1 and its klotho coreceptor. In a closed endocrine loop, 1,25‐dihydroxyvitamin D3 (1,25D) induces FGF23 expression in bone, with the phosphaturic peptide in turn acting at the kidney to feedback repress CYP27B1 to suppress production of 1,25D. FGF23‐null mice cannot correct the severe hyperphosphatemia and ectopic calcification that results from the 1,25D‐stimulated calcium and phosphate intestinal absorption and renal reabsorption. Furthermore, abnormal concentrations of FGF23 have been linked to several potentially fatal pathologies, including chronic kidney disease and cardiovascular events. FGF23 synthesis is induced by the 1,25D‐bound vitamin D receptor (VDR), resulting in FGF23‐signaled suppression of the phosphate transporters NaPi‐IIa and NaPi‐ IIc, decreasing renal phosphate reabsorption and resulting in urinary phosphate excretion. Previous reports document upregulation of FGF23 mRNA by 1,25D; however the exact molecular mechanism(s) for this phenomenon remain unknown. In preliminary research, we identified five functional vitamin D responsive elements (VDREs) in the human FGF23 gene region remote to the promoter that may directly control FGF23 gene transcription. However, these VDREs displayed only modest induction activity, implying that a secondary mechanism for transactivation by 1,25D must exist to explain the observed high magnitude induction of FGF23 mRNA and protein by vitamin D, in vivo, and in cultured osteoblasts. In the present study, we disprove our hypothesis that membrane and extracellular matrix proteins, namely klotho and/or osteopontin, induced by 1,25D‐liganded VDR, secondarily generate a signaling cascade to increase FGF23 production. Instead, by truncation and point mutagenesis, we characterized a novel cis‐regulatory module in the proximal promoter of mouse FGF23, located between ‐400 and ‐200 bp from the transcriptional start site. A ‐0.6 kb construct of the murine FGF23 promoter demonstrates a 4‐fold induction in response to 1,25D when transfected into human leukemia (K562) cells. Mutation of one of the ETS1 sites at ‐346 bp within this construct, or an adjacent VDRE/Nurr1 site, reduces the transcriptional response to 1,25D to that of a minimal ‐0.06 kb promoter construct. Thus, the composite ETS‐VDRE/Nurr1 cis‐element identified herein may function in 1,25D‐elicited induction of FGF23 in a primary mechanistic manner via a novel VDRE located at ‐334 bp in the murine FGF23 promoter, and/or in a secondary fashion through 1,25D‐primary transcriptional activation of ETS1 and Nurr1. Also, we demonstrate a significant 1.7‐ to 2.0‐fold increase in transcription of a ‐1.0 kb murine FGF23 promoter construct in response to high calcium exposure of MC3T3 mouse osteoblastic cells. Thus, the FGF23 proximal promoter harbors cis‐elements that drive responsiveness to 1,25D and calcium, agents that induce FGF23 to curtail the pathologic consequences of their excess. Our results contribute to the understanding of the complex transcriptional regulation of FGF23 by providing evidence for cis‐regulatory elements within the FGF23 proximal promoter that are responsive to primary and secondary actions of 1,25D and calcium. Such findings may influence future therapeutic modalities in the treatment of FGF23‐related pathologies.
    • CT Textural Analysis (CTTA) of Metastatic Treatment‐Resistant Pancreatic Adenocarcinoma (PDAC): Identifying Biomarkers for Genetic Instability and Overall Survival

      Campbell, David; The University of Arizona College of Medicine - Phoenix; Korn, Ronald MD, PhD (The University of Arizona., 2016-03-23)
      Metastatic, treatment‐resistant pancreatic ductal adenocarcinoma (PDAC) is a rapidly fatal disease that typically carries a bleak prognosis. Contrast‐enhanced CT is the current standard of care tool for imaging evaluation, and repeat imaging is routinely performed in clinical trials. The availability of these imaging data render them exploitable for further analysis. CT texural analysis (CTTA), a quantitative tool for examining a region of interest on CT and generating statistical parameters based on gray‐level pixel data, is powerful technique that has been studied in other cancers and shown to correlate with features such as tumor grade, stage, and prognosis. However, the application of CTTA to PDAC has not been studied. Given the paucity of diagnostic tests to guide therapy, validated CTTA biomarkers could be immensely useful. Identifying PDAC variants that have a relative deficit in DNA repair might allow these cancers to be treated with targeted cytotoxic regimens sooner. Additionally, identifying prognostic CTTA parameters would be useful in gauging the severity of disease. We sought to perform quantitative textural analysis on CT imaging from a clinical trial cohort of patients with metastatic, treatment‐resistant PDAC. We aimed to correlate CTTA features to molecular profiling results (copy number variations obtained by array CGH) and clinical features (overall survival). Metastatic tumor sites from patients with treatment‐resistant PDAC were biopsied and molecularly profiled. Intrachromosal copy number were assessed by CGH in tumor specimens, and patients were treated based on these individual molecular profiling results. Pre‐biopsy portal‐venous phase and non‐contrast CT scans were obtained for retrospective analysis (n=15). CTTA was performed by drawing regions of interest around the primary pancreas adenocarcinoma and the normal pancreas tissue. CTTA parameters including mean positive pixels, entropy, kurtosis, and skewness were derived using the TexRAD platform at texture filtering densities of 0, 2, 3, 4, 5, and 6 pixels. CTTA values were then compared to intrachromosomal copy number variation (CNV) per tumor and overall survival (OS) post treatment using a Spearman’s rank correlation coefficient. Additional linear regression analysis was performed for positive correlations, and a Kaplan‐Meier statistic was generated for OS using median CTTA entropy. Multivariate analyses for CNV and OS were also performed. CNV were negatively correlated with the kurtosis value of the primary tumor mass using medium texture filtering (p=0.034, n=15). Linear regression revealed a significant negative correlation between kurtosis and CNV (p=0.038). Secondary analysis of the normal pancreas using coarse texture filtering revealed that increasing entropy was associated with decreased OS (p=0.0014, n=12). Using median entropy as a cutoff value (median: 4.165), median OS was greater in the entropy < 4.165 group versus the entropy > 4.165 group (179 days v 43 days; 95% CI 73.137 – 166.87; p=0.004, n=12). This exploratory study with admittedly limited sample size raises interesting questions about the use of CTTA parameters as diagnostic tools and/or biopsy adjuncts in assessing PDAC susceptibility to commercially available cytotoxics. Secondarily, entropy, a potential marker of heterogeneity and inflammation in the normal pancreas, represents an intriguing possibility for gauging prognosis.
    • Diagnosing Ventilator‐Associated Pneumonia in Burn Patients: Endotracheal Aspirates Versus Bronchoalveolar Lavage

      Lish, James; The University of Arizona College of Medicine - Phoenix; Foster, Kevin N MD, MBA, FACS (The University of Arizona., 2016-03-25)
      Introduction: Ventilator‐associated pneumonia (VAP) is associated with increased mortality, ventilator days, intensive care unit days and length of stay, especially in the thermal burn patient. In addition to poorer patient outcomes it is estimated that VAP increases the cost of care, making the prevention of VAP a high priority within healthcare. While no “gold standard” diagnosis for VAP exists, criteria typically include clinical suspicion, radiography and microbiological testing. The purpose of this study was to correlate results of endotracheal tube swabs (ETT), endotracheal aspirates (TA) and broncheoalveolar lavage (BAL) in burn patients with suspected VAP. The goal of this study is to determine if TA sampling is a viable alternative to BAL in the diagnosis of VAP in burn patients. Methods: This was a non‐interventional prospective study of 42 adult burn patients with suspected VAP. Respiratory specimens via ETT, TA, and BAL were collected and cultured. Basic demographics, clinical signs and symptoms and culture results were collected and descriptive statistics were performed. Results: Concurrent cultures were performed on the 42 patients with suspected VAP. Correlations were done between TA, BAL and ETT. TA and BAL correlated 87% of the time while TA and ETT correlated 49% of the time. The correlation between ETT and BAL was 40%. Calculated sensitivities, specificities, positive predictive values (PPV) and negative predictive values (NPV) for TA and BAL were roughly equal, while the values for ETT were much lower. Conclusions: TA is nearly as reliable as BAL in identifying the causative organisms in VAP, and should be considered as an economical and easily obtained initial diagnostic test in burn patients suspected to have VAP.
    • Effectiveness and Student Perception of Simulated Case Based Learning in a Pre Clinical Medical Education

      Weed, Michael; The University of Arizona College of Medicine - Phoenix; Savi, Christine PhD (The University of Arizona., 2016-03-25)
      Over the past decade, patient simulation has become an important teaching tool in allopathic medical education. Initially, medical simulation was used exclusively in the clinical years of medical training, but implementation into pre‐clinical curriculum is becoming increasingly common. Because simulated teaching experiences are a relatively new practice in pre‐clinical medical education, little is known about their value in this setting. We hypothesize that high‐fidelity patient simulation is an effective method of teaching basic medical sciences during the pre‐clinical years and that it will be viewed favorably by students when compared to other established teaching modalities. The purpose of our study is to: (1) test for an effect of teaching method on test score performance by comparing the results of relevant test items given to two student groups: a simulation group and a traditional case‐based instruction group; (2) determine student perception of simulation as a learning method for basic medical sciences. Methods: A one tier, mixed methods design was used to sequence this study. Test item scores were obtained from the classes of 2015 and 2016 at the University of Arizona College of Medicine ‐ Phoenix and results were analyzed using descriptive statistics to compare means and item difficulty. A Fisher’s exact test was conducted to compare test item performance between students who did and did not use simulation in their case‐based instruction group. Presimulation and post‐simulation surveys were also administered and thematic extraction used to triangulate results to quantitative findings. Results: There was no significant difference between performance of the simulation (n=48) and non‐simulation (n=79) group on the three test items. Survey results from this particular study indicate that students do enjoy learning in the simulated case‐based environment and that they find it to be intellectually stimulating. They also believe simulation will be useful in their careers. They do not, however, believe that it is as effective at teaching basic medical sciences when compared to the traditional lecture hall setting. Students also find simulation learning to be more stressful than small group learning. Conclusion: Our findings suggest that students who learn material through simulated case instruction perform as well as their counterparts who learn the material in traditional small group non‐simulated settings. However, our survey data suggests that while student perception of simulation is positive overall, there are instances in which simulation is viewed less favorably than both small group and traditional lecture environments. When analyzed together, the test item performance and survey findings show that while simulation can be an effective teaching tool in pre‐clinical medical education, there was not a significant difference when compared to lecture hall and non‐ simulated small group learning settings.
    • Effectiveness of Using Texture Analysis in Evaluating Heterogeneity in Breast Tumor and in Predicting Tumor Aggressiveness in Breast Cancer Patients

      Hopp, Alix; The University of Arizona College of Medicine - Phoenix; Korn, Ronald MD, PhD (The University of Arizona., 2016-03-25)
      Objective and Hypothesis We hypothesize that tumor heterogeneity or tissue complexity, as measured by quantitative texture analysis (QTA) on mammogram, is a marker of tumor aggressiveness in breast cancer patients. Methods Tumor heterogeneity was assessed using QTA on digital mammograms of 64 patients with invasive ductal carcinoma (IDC). QTA generates six different values – Mean, standard deviation (SD), mean positive pixel value (MPPV), entropy, kurtosis, and skewness. Tumor aggressiveness was assessed using patients’ Oncotype DX® Recurrence Score (RS), a proven genomic assay score that correlates with the rate of remote breast cancer recurrence. RS and hormonal receptor status ‐ estrogen receptor (ER) and progesterone receptor (PR) ‐ were collected from pathology reports. Data were analyzed using statistical tools including Spearman rank correlation, linear regression, and logistic regression. Results Linear regression analysis showed that QTA parameter, SD, was a good predictor of RS (F=6.89, p=0.0108, R2=0.0870) at SSF=0.4. When PR status was included as a predictor, PR status and QTA parameter Skewness‐Diff, achieved linear model of greater fit (F=15.302, p<0.0001, R2=0.2988) at SSF=1. Among PR+ patients, Skewness‐Diff was a good linear predictor of RS (F=9.36, p=0.0034, R2=0.1320) at SSF=0.8. Logistic regression analysis showed that QTA parameters were good predictors of high risk RS probability, using different cutoffs of 30 and 25 for high risk RS; these QTA parameters were Entropy‐Diff for RS>30 (chi2=10.98, p=0.0009, AUC=0.8424, SE=0.0717) and Mean‐Total for RS>25 (chi2=9.98, p=0.0016, AUC=0.7437, SE=0.0612). When PR status was included, logistic models of higher log‐likelihood chi2 were found with SD‐Diff for RS>30 (chi2=18.69, p=0.0001, AUC=0.9409, SE=0.0322), and with Mean‐Total for RS>25 (chi2=25.56, p<0.0001, AUC=0.8443, SE=0.0591). For PR+ patients, good predictors were SD‐Diff for RS>30 (chi2=6.87, p=0.0087, AUC=0.9212, SE=0.0515), and MPP‐Diff and Skewness‐Diff for RS>25 (chi2=16.17, p=0.0003, AUC=0.9103, SE=0.0482). Significance Quantitative measurement of breast cancer tumor heterogeneity using QTA on digital mammograms may be used as predictors of RS and can potentially allow a non‐invasive and cost‐effective way to quickly assess the likelihood of RS and high risk RS.
    • The Effects of Stigma Toward Mental Illness on Family Physicians

      Sipe, Michelle; The University of Arizona College of Medicine - Phoenix; Goto, Kristine PhD (The University of Arizona., 2016-03-25)
      Many individuals utilize primary care as their main source of mental health care, as in many areas of the US access to specialized psychiatric care does not meet the demand. Prior research has showed that many healthcare practitioners, including those working in generalist fields, carry stigmatized views about individuals with mental illness. Such stigmatized views can result in misattribution of symptoms to mental illness and a decline in proper diagnosis and treatment. Our study aims to examine if stigmatized views about mental illness relate to family medicine physicians’ comfort levels with treating mental illness, patterns of referral to psychiatrists, or amount of continuing medical education on psychiatric issues. Our hypothesis is that family medicine physicians who carry less stigmatized views will be more comfortable and up to date with psychiatric care practices and less likely to refer mental health issues to specialized mental health services. Methods: We administered an email survey to family medicine physicians via the Arizona Academy of Family Physicians monthly electronic newsletter. The survey contained demographic questions, a short (5‐question) validated stigma questionnaire (Attitudes to Mental Illness Questionnaire or AMIQ), and questions regarding self‐stated comfort level with mental illness, amount of recent mental‐health CME, and likelihood of referral for various mental illnesses. Results: AMIQ stigma ratings and referral rates for anxiety were significantly related (p=.012), as were AMIQ stigma ratings and amount of mental health CME (p=.001). Other trends were discovered, but were not significant. Impact: These results further demonstrate the need for increased emphasis on psychosocial and psychiatric issues, particularly stigma reduction, in family medicine residency training and CME. If family medicine physicians with high levels of stigma are less likely to treat mentally ill patients or seek further education regarding psychiatric issues, it could disrupt their patients’ quality, cost, and continuity of care.
    • Evaluating CNS Lesions in HIV Patients: A Radiologic/Pathologic Review

      Hunter, Camille; The University of Arizona College of Medicine - Phoenix; Gridley, Daniel G MD; Van Tassel, Dane MD; Fairbourn, Phil MD (The University of Arizona., 2016-03-25)
      Background and Significance. HIV/AIDS is a commonly encountered disease process in many cities and medical centers throughout the world. Approximately 35 million people live with HIV/AIDS worldwide, many of whom develop pathology of the central nervous system (CNS). Many HIV/AIDS patients undergo substantial morbidity and mortality with the development of CNS abnormalities including toxoplasmosis encephalitis (TE), progressive multifocal leukoencephalopathy (PML), primary central nervous system lymphoma (PCNSL), and other opportunistic infections. Especially in these immunocompromised patients, early accurate diagnosis can affect patient management, which is vital to patient survival. Research Question. We hypothesized that fellowship‐trained neuroradiologists are more accurate than general radiologists in the diagnosis of HIV related CNS lesions. Methods. Following institutional IRB approval, we retrospectively analyzed patients with known HIV infection who underwent radiologic imaging and subsequent biopsy of an identified neuropathologic lesion(s) at Maricopa Medical Center between January 2007 and January 2015. Diagnostic scan reports were analyzed to determine whether or not the correct diagnosis was provided in the impression, and rates of correct diagnosis were compared between fellowship trained neuroradiologists and a general radiologists. Results. Thirty‐three patients received neurologic imaging with MRI for a pathologically proven HIV/AIDS related illness with 78 total lesions identified. The correct diagnosis was mentioned in 79% (15/19) of cases read by a neuroradiologist, but only 43% (6/14) of cases read by a general radiologist. Overall, the correct diagnosis was mentioned in the initial impression in 21 of 33 (64%) cases. Chi‐squared analysis showed a statistically significant relationship in the number of mentioned correct diagnoses by neuroradiologists versus general radiologists (p=0.033). Conclusions. Our study suggests that the availability and utilization of specialty fellowship trained staff in radiology is an essential part of accurate early diagnosis. Taking an active role in the work up and diagnosis of specialized disease processes is essential for successful and comprehensive care, especially in our local community where HIV/AIDS support and treatment is on the cutting‐edge.
    • Evaluation of Skin Cancer Screenings in Tucson, Arizona from 2006‐2013

      Romano, Gianna; The University of Arizona College of Medicine - Phoenix; Harris, Robin PhD (The University of Arizona., 2016-03-25)
      Background: One out of every three cancer diagnoses is a skin cancer, and the incidence of both melanoma and non‐melanoma type skin cancers is increasing. Skin cancers, including melanoma, are typically treatable if detected early. However, there is insufficient evidence to support recommendations to establish population based skin cancer screening programs. The specific aims of this study are 1) to evaluate characteristics of participants who attend a community skin cancer screening event and who are referred for follow up due to suspicious lesions, 2) to determine the proportion of participants with suspicious lesions identified at a community skin cancer screening event who complied with a request to visit a dermatologist or primary care physician, and 3) to evaluate attitudes toward sun protection practices, and perceived risk of developing skin cancer among participants who attend a community skin cancer screening and have a suspicious skin lesion. Methods: The Skin Cancer Institute sponsored a series of community skin cancer screening events in Tucson, Arizona from 2006 to 2013. Participants completed an American Academy of Dermatology screening form prior to a skin examination by a dermatologist. Participants with suspicious lesions identified at the examination who agreed to be contacted again received questionnaires 4 months after the initial screening to assess compliance with follow‐up recommendations, and their sun protection practices and risk perceptions. Results: 1979 community members attended the skin cancer screenings. The majority of the participants were Caucasian, females, had blue eyes and brown hair, were college educated, had no prior personal or family history of skin cancer, had health insurance but did not have a regular dermatologist, reported that they had never been to a skin cancer screening before, and stated that without this screening that they would not have their skin examined. 748 (37.8%) of community members were referred and instructed to see a dermatologist for further evaluation of a skin lesion. Of the 441 participants with a suspicious lesion who consented to participate in the follow‐up study, 120 returned a questionnaire; 90 (75%) reported that they followed up with a dermatologist or physician, and 30 (25%) did not. Of the 90 participants who followed up, 53% received a skin biopsy. The self reported diagnoses from the biopsies of the suspicious skin lesions were the following: 1% atypical or dysplastic nevus, 21% actinic keratosis, 16% basal cell carcinoma, 8% squamous cell carcinoma, 2% melanoma, and 38% did not have skin cancer. Conclusions/Impact: This study demonstrated that 38% of community skin cancer screening participants were referred for follow up due to a suspicious skin lesion being identified during a skin cancer screening event. It also appeared that 75% of those who responded to the follow‐up questionnaire complied with the request within four months, although the response rate for the follow‐up questionnaire was low. Therefore, implementing a formal reminder system following the skin cancer screenings may increase the percentage of participants who follow up with a primary care physician or dermatologist after the screening for further evaluation of their suspicious skin lesion.
    • Expedited Partner Therapy, Addressing Increased STD Infection Rates in Arizona

      Wade, Laura; The University of Arizona College of Medicine - Phoenix; Manriquez, Maria MD (The University of Arizona., 2016-03-25)
      Introduction: Chlamydia and gonorrhea are the two most reported sexually transmitted diseases (STDs) in Maricopa County.1 Effective treatment of the sex partner(s) of patients diagnosed with these STDs is an important step in preventing repeated infections. Expedited partner therapy (EPT) is the practice of prescribing antibiotics to the sex partner(s) of a patient diagnosed with a STD. EPT is recommended by the CDC in cases of uncomplicated chlamydia or gonorrhea infection.2 On September 26, 2008, Arizona statue was revised to allow for the use of EPT.3 Our study seeks to determine whether the use of EPT results in fewer repeat infections of chlamydia or gonorrhea within six months of initial diagnosis. Methods: We performed a retrospective chart review of 200 female patients diagnosed with chlamydia or gonorrhea between 2010 and 2013. We recorded how partner treatment was addressed, whether or not the patient had a repeat infection within six months, provider specialty and additional demographic information. Data was analyzed using One‐Way ANOVA or Wilcoxon Rank‐Sum for continuous variables and Chi‐Squared or Fisher’s Exact was used for categorical variables. Results: Overall documented percent repeat infection of 14.7% (n=20) out of 136 patients with follow up testing within 6 months. Loss to follow up of 32% (n=64). Percent repeat infection in EPT 0.0% (n=0), partner referral 16.1% (n=9), partner notification 20.9% (n=9) and not documented 16.7% (n=2). When comparing percent repeat infection in EPT (0.0%) to all other treatments combined (14.7%) the difference is statistically significant with p=0.025. Conclusions: The use of EPT results in fewer repeat infections in patients diagnosed with chlamydia. Limitations include loss to follow up and incomplete documentation in the electronic health record. Further investigation into the barriers to EPT is warranted to increase utilization of this strategy for partner treatment.
    • Factors Affecting Follow‐Up Care in Hodgkin’s Lymphoma Survivors

      Baker, Devon; The University of Arizona College of Medicine - Phoenix; Flood, Timothy MD (The University of Arizona., 2016-03-23)
      As research into the treatment of cancers improves patient’s chances for survival, the number of cancer survivors continues to increase. These patients are often treated with chemotherapy and radiation regimens that can increase their risk for cancers and other complications such as heart disease later on. Patients with Hodgkin’s lymphoma tend to be younger than patients with other cancers. Current treatment regimens lead to cures in many Hodgkin’s lymphoma patients with many long term survivors. However, these treatments place survivors at risk for numerous complications, most importantly other cancers and heart disease. Organizations such as the American Cancer Society recommend regular screening and surveillance by a patient’s doctor to detect these potential complications. To assess the factors that affect a patient’s follow‐up care we sent a survey to 365 Hodgkin’s Lymphoma survivors in Arizona and asked them about their specific follow‐up care. The survivors were identified using the Arizona Cancer registry, and 49 (13.4%) responded to our survey. However, of the 365 letter invitations that were sent out, 118 were returned undeliverable leading to a corrected response rate of 19.8%. Of the respondents 93% reported they were getting follow up care. We also looked at patient satisfaction with their care as a second outcome, 34 (72.3%) of the patients stated that they were strongly satisfied with their follow‐ up care. In order to assess physician‐patient communication, we asked patients if they had received a written follow‐up care plan. Of the respondents to this question, 14 (29.7%) noted that they had received a written follow up care plan. These two outcomes were stratified to various demographic factors (age, gender, education status, etc.) to determine if any of these caused a statistically significant difference in a patient’s satisfaction or whether or not they had received a written follow‐up plan. Due to the low number of responders, no statistically significant difference was found. Future studies are needed to further determine whether or not these sorts of demographic factors play a significant role but we believe studies like this are important as cancer survivorship continues to increase.