• Predicting Patient Response to Cancer Immunotherapy Using Quantitative Computed Tomography Based Texture Analysis

      Gordon, Joshua; The University of Arizona College of Medicine - Phoenix; Korn, Ronald (The University of Arizona., 2017-05-08)
      Cancer therapies have evolved continuously, with the newest class being immunotherapies targeting the PD‐L1/PD‐1 pathway. This pathway is often overexpressed in malignancies, which allow the aberrant cells to evade the body’s natural immune response that would normally eliminate them. The novel therapies currently being investigated are monoclonal antibodies that target either the PD‐L1 on the tumor cell or the PD‐1 on the lymphocyte. Considering there are significant toxicities with these therapies, namely gastrointestinal and endocrine adverse effects, a predictive tool that could allow physicians which patients are likely to respond to these immunotherapies could spare patients unnecessary therapy and potential economic harm. Since repetitive imaging of patients with cancer is necessary to monitor treatment response, advanced imaging analysis techniques on standard of care images, such as CT scans may provide insights into tumor patterns that could help to predict treatment response. Quantitative texture analysis (QTA) of computed tomography scans has been used in various settings to examine tissue heterogeneity as a predictive biomarker of response; we hypothesized that QTA may have potential value in predicting tumor response to immunotherapy. We performed a QTA on standard of care CT scans from patients to determine if a unique textural imaging signature could be identified that would serve as a predictive biomarker for response to PD‐L1/PD‐1 therapies in subjects with solid tumor malignancies in the lungs, liver, and lymph nodes. This study examined the diagnostic standard of care CT scans of the chest, abdomen, and pelvis (CT CAP) at baseline and follow‐up, which were acquired as part of routine clinical care for tumor staging and treatment response in 20 subjects whose personal health care information was removed prior to analysis. Regions of interest (ROI) were drawn around all identifiable tumor lesions on baseline CT scans provided that tumors were of reasonable size (>10 mm in diameter) and conspicuity. CT texture analysis was performed on these lesions to obtain a histogram readout of tumor texture based upon tissue densities on a per pixel bases. The output values from the QTA platform provided an estimate of tumor signal properties as expressed as the mean pixel density, standard deviation, entropy, kurtosis, skewness, and mean positive pixel values. Each subject was designated as achieving either a RECIST based treatment response or not. Statistical modeling was then conducted using regression techniques. There was no identifiable signature when examining all of the lesions together, but there were statistically significant correlations noted between QTA and RECIST responses for lung‐based lesions. The QTA derived mean pixel density parameter was a major component of separating out responders from non‐response. Of the 14 lung lesions (8 responder vs. 6 nonresponder) there was a significant difference in the mean density with a threshold cutoff of 11.91 (p < 0.0001). A Mann‐Whitney U‐test was performed on the total data set yielding a Z statistic of 2.6 (p=0.0092). Despite the relatively small number of patients in this initial study, there were promising findings regarding the mean density of lesions, suggesting that texture analysis can be used to predict if patients respond to PD‐L1/PD‐1 inhibitors. Further investigation is warranted in a larger population that can be differentiated by tumor type to validate these results.
    • Predictors of Primary Care Career Choice: A Review of AMCAS Applications of Four Graduating Classes at a New Medical School

      Korenstein, Alyssa; The University of Arizona College of Medicine - Phoenix; Cunningham, Tara K. (The University of Arizona., 2017-05-10)
      The United States (U.S.) is currently facing a shortage of primary care physicians, an issue particularly salient in Arizona. The purpose of this project is to investigate predictors of students entering primary care specialties that may be apparent from their American Medical College Application Service (AMCAS) applications, in order to best serve the needs of the physician workforce. We hypothesized that factors such as female gender, older age at application (“non‐traditional” students), and being raised in a rural/underserved community background may be predictors of students who choose primary care fields. AMCAS applications are completed by aspiring medical students and contain demographic information including gender, age, race, languages spoken, and family/community characteristics. Data provided also include academic factors such as college major, grade point average (GPA), and Medical College Admissions Test (MCAT) scores. Other subjective data reported by applicants include descriptions of extracurricular activities and a personal statement. The National Resident Matching Program (NRMP) is the system used by graduating students during the last semester of medical school to match students with their choice of specialty and the residency program wherein they will spend an additional three years, minimum, in training. Based on the Association of American Medical Colleges (AAMC) designations, we are considering primary care to be Family Medicine, Pediatrics, Internal Medicine, and Medicine‐Pediatrics. We examined data from AMCAS applications of all 149 students who graduated from the University of Arizona College of Medicine‐Phoenix between 2011‐2014, and compared to their NRMP match outcomes. Comparisons were made between non‐primary care versus primary care‐overall, as well as Family Medicine alone versus all other matches given the increasing rate of specialization within Internal Medicine and Pediatrics. Multiple logistic regression revealed two predictors of primary care career choice compared to non‐primary care: having more siblings (P=.003) and non‐physician parents (P=.017). Specific to Family Medicine, several predictors were identified compared to the non‐Family Medicine cohort: a slightly greater percentage of earned community college credits (P=.03), lower MCAT physical science (P=.009), higher MCAT verbal scores (P=.02), and lower paternal education (P=.003). Our analyses suggest having a greater number of siblings and non‐physician parents may predict primary care career choice. Specific to Family Medicine, academic factors including community college enrollment and MCAT scores may be of predictive value. Though the exact implications behind these findings are unclear, it is important to continually examine such data as medical schools can shape admissions selection criteria targeted at increasing the number of graduates seeking careers in primary care.
    • Primary Melanoma tumor immune contexture analysis: T regulatory cell to T effector cell ratio as related to MHC class II and GILT expression

      Cole, Lauren; The University of Arizona College of Medicine - Phoenix; Hastings, Karen (The University of Arizona., 2017-04-28)
      Histopathologic examination of the tumor microenvironment demonstrates the presence of a vast repertoire of infiltrating lymphocytes and antigen presenting cells (APC’s). Recent studies establish a strong correlation between the tumor microenvironment cell composition and prognostic value in terms of cell type, location and ratio, referred to as a tumor’s immunoscore. More specifically, the relationship between T regulatory (Treg) cell to T effector (Teff) cell percentage predominates as a mechanism of tumor immune evasion. Further investigation of the factors influencing the development of Treg and Teff cells is therefore warranted. Gammainterferon‐inducible lysosomal thiol reductase (GILT) acts to influence antigenic processing and presentation by MHC class II cells, ultimately impacting lymphocyte development. Evaluation of the role of GILT expression in MHC class II+ APC’s with respect to Treg and Teff cell development in primary melanoma lesions, to our knowledge, has not been reported. Therefore our investigation focuses on elucidating a plausible relationship between GILT presence and Treg to Teff cell ratio. The aim of our study is to examine a possible association between GILT expression in APC’s and Treg:Teff cell ratio. We hypothesized GILT expression in melanoma cells would result in a decreased Treg to Teff ratio or an enhanced T cell‐mediated response. Our study included 17 de‐identified primary melanoma specimens previously stained and scored for Treg, Teff, CD8, MHC class II and GILT. Scoring was performed through identification of four areas per specimen with highest Treg and Teff cell density. These four areas were then averaged with ± standard deviation (SD). With use of landmark association, these four areas were identified and scored for MHC class II and GILT in APC’s and tumor cells with consideration to presence/absence, intensity and frequency of staining. Statistical significance was not reached relative to our hypothesized relationship of a decreased Treg to Teff cell ratio in the presence of GILT+ MHC class II. Similarly, we did not reach statistical significance when comparing individual cell types to GILT, MHC class II and GILT + MHC class. In our study, we were unable reach statistical significance relative to our proposed correlation between MHC class II and GILT presence leading to a decreased Treg to Teff cell ratio or enhanced T‐cell mediated immune response. A major limitation of our study included the small sample size leading to a probable type II error, prompting the need for further investigation of the factors influencing the Treg to Teff cell ratio within the melanoma tumor microenvironment on a larger scale.
    • Prophylactic Anticholinergic Medications to Prevent Drug-Induced Extrapyramidal Symptoms: A Systematic Review

      Dare, Reese; The University of Arizona College of Medicine - Phoenix; Stapczynski, J. Stephan (The University of Arizona, 2017-04-28)
      Neuroleptic medications are commonly administered in the emergency department but are known to induce extrapyramidal symptoms (EPS) in some patients; typically dystonia and akathisia. This systematic review will examine if adjunctive medications are efficacious when given in conjunction with neuroleptic medications to prevent these extrapyramidal symptoms. The Central, DARE, LILACS, PubMed, CINAHL, and OVID databases were searched for relevant articles between January 2014 and February 2016. Inclusion criteria required the article to be a randomized controlled trial; administer an anticholinergic medication given concurrently or just prior to treatment with medications with known extrapyramidal side effects; and be published in English. The initial search strategy yielded 1222 prospective articles of which 1208 were excluded by title and/or abstract. Fourteen articles were retrieved in full text and independently reviewed by each author. Seven 7 RCTs representing 645 patients were determined to be appropriate for analysis. Meta‐analysis of 5 studies found a significant effect (OR 0.4 with 95% CI 0.23‐0.71) for utilizing anticholinergic adjunct medications in the prevention of EPS for 60 minutes after administration. No reduction was found (OR 1.14 with 95% CI 0.01‐164) in EPS after 60 minutes in meta‐analysis of 2 studies with opposing results. Adjunctive anticholinergic medication was effective in reducing symptoms of dystonia (OR 0.13 with 95% CI 0.04‐0.43) but not in reducing symptoms of akathisia (OR 0.74 with 95% CI 0.27‐1.98). This systematic review found that anticholinergic adjuvant anticholinergic treatment reduced EPS induced by antipsychotic medications during 60 minutes after administration, with the greatest reduction in dystonic symptoms.
    • Prospective Detection of Chemoradiation Resistance in Patients with Locally Advanced Esophageal Adenocarcinoma

      Veaco, Jennifer Mitchell; The University of Arizona College of Medicine - Phoenix; Stone, John F. (The University of Arizona., 2017)
      Approximately 25% of patients with locoregional esophageal adenocarcinoma (EC) are resistant (marked by minimal tumor regression; TRG 3) to preoperative chemoradiation, including 5FU‐based and CROSS regimens. Previously, an immunohistochemistry (IHC) test that accurately identifies patients as responders (TRG 0‐2) or non‐responders (TRG 3) to neoadjuvant CTRT was developed and validated. The current study was designed to identify gene expression profile (GEP) signatures able to predict response to preoperative treatment. Methods: Formalin‐fixed, paraffin‐embedded (FFPE) tumor tissue from 24 diagnostic biopsies (14 responders, 10 non‐responders) was collected. RNA was isolated, and RT‐PCR performed to assess the expression of 96 candidate genes chosen from in silicoanalysis. Genetic signatures incorporating genes with significant expression differences in pathologically determined responders versus non‐responders were identified, and linear and non‐linear predictive modeling methods were used to assess the accuracy of the signatures for predicting treatment response. Cross validation was performed to attain corrected accuracy values. Ten‐, 18‐, and 24‐gene signatures were identified with significantly different gene expression levels in responders compared to non‐responders (p < 0.05). Functional groups represented by the signatures included DNA damage repair, extracellular matrix remodeling, and 5FU metabolism. Partial Least Squares (PLS) prediction of treatment response was compared to pathologic TRG determined by blinded pathologic reading, and resulted in an area under the curve (AUC) of 0.99 and overall accuracy of 100% for the 24‐gene signature. Corrected AUC of 0.99 and accuracy of 95% resulted from five‐fold cross validation with 20 iterations. Heatmap analysis of the 24‐gene signature separated the EC cases into two distinct clusters, the first with 93% responders and the second with 90% non‐responders. The current study identifies novel gene signatures able to accurately predict EC patient response to preoperative treatment. The GEP may allow non‐responders to avoid unnecessary toxicities associated with chemoradiation therapy.
    • Qualitative Assessment of Activated Microglia and Astrocytes in Focal Cortical Dysplasia: Case Series of Pediatric Patients

      Yee, Nicole; The University of Arizona College of Medicine - Phoenix; Lifshitz, Jonathan; Adelson, P. David (The University of Arizona., 2017-05-22)
      Epilepsy is the most common neurologic condition seen in children. Focal cortical dysplasia (FCD), a seizure disorder characterized by abnormal cortical laminar development, comprises approximately 75% of medically intractable epilepsies in the pediatric population. A greater appreciation of the pathology and intrinsic properties of the epileptogenic zone may help in understanding why FCD lesions are drug‐resistant, and could potentially lead to more effective treatments in the pediatric population. Neuronal support cells such as microglia and astrocytes have shown to have a role in FCD pathology. These cells are also activated during aging and traumatic brain injury as evidence by morphological change. This study aims to characterize the spatial distribution of microglia and astrocytes using immunohistochemistry in dysplastic tissue of eight male pediatric patients diagnosed with FCD. Cortical specimens from patients who underwent surgical resection of focally dysplastic cortex at Phoenix Children’s Hospital between 2008 and 2014 were examined using immunohistochemistry. Primary antibodies against GFAP and Iba1, as well as structural staining using hematoxylin and eosin (H&E), were incubated on sections and further analyzed using bright‐field microscopy. A pattern of perivascular activated microglia was observed in five patients around at least one blood vessel, while a pattern of non‐localized ramified microglia was observed in the other three patients. No identifiable pattern of astrocytic distribution was found. Thus, distinct patterns of microglia, rather than astrocytes, suggest dual underlying mechanisms of epileptogenesis.
    • Quality of Life and Pain After Transobturator Mesh Placement

      Coyne, Catherine A.; The University of Arizona College of Medicine - Phoenix; Hibner, Michael (The University of Arizona, 2017-04-28)
      Extreme controversy surrounds the uncertainty of pelvic mesh and sling devices to essentially cure patients of stress urinary incontinence (SUI). A relatively new product that has taken the market by storm is the tension free Vaginal Tape‐ Obturator (TVT‐O) mesh by Ethicon, Gynecare. It has obtained Center for Disease Control approval and labeled a “clinically proven, safe product with a 90% cure rate for urinary incontinence,” according to the manufactures website (Ethicon, Gynecare)4, 8. One side effect that is known about this particular device is its ability to leave patients post surgery with unbearable, chronic pelvic pain2. Although the mesh is needed to prevent urinary incontinence, it is pivotal that the quality of life of our patients does not suffer appreciably with elective, non‐life threatening procedures. Another common mesh product is the pelvic sling by Monarc. One‐study reports more than 95 percent of patients who underwent elective surgery with the insertion of Monarc sling achieved complete dryness and did not require the use of pads following the procedure22. These are successful outcomes, but what occurs with the minority of patients that have unfavorable outcomes such as chronic pain12, 15, 16? A retrospective study was completed to deduce the onset of pain and severity of pain caused by the TVT‐O mesh and Monarc mesh‐utilizing data from Dr. Hibner’s patients. There were 19 chronic pelvic pain patients with an average age of 50, standard deviation of 11 years, seen by Dr. Hibner and his colleagues. These patients completed the International Pelvic Pain assessment form upon their first visit to the office and SF‐36 scores of physical and mental scores were obtained. Results found physical scores of 29.5 and mental scores of 36 in pelvic pain patients, which were higher than certain other chronic, medical diseases1. We were able to conclude that patients with pelvic pain from mesh have lower physical and mental SF‐36 scores than patients with other chronic diseases representing a decreased quality of life overall.
    • Quantitative Factors Correlated with Increased Length of Stay for Adult Patients Presenting to the Emergency Department with Abdominal and Pelvic Pain

      Spiro, Joshua; The University of Arizona College of Medicine - Phoenix; Yarmush, Joel (The University of Arizona., 2017-05-19)
      Abdominal/pelvic pain is one of the most common reasons that patients present to hospital emergency departments (ED). With 129.8 million emergency department visits per year nationally, efficient triage and admission of these patients from the ED is essential. At the New York Methodist Hospital (NYMH) ED, patients presenting with abdominal/pelvic pain are evaluated based on a series of factors such as pain scores, past medical history, physical exam, and laboratory tests. Depending on these factors, clinicians observe, evaluate, and treat their patients requiring varying lengths of stay in the emergency department before either being discharged or admitted to the hospital. Physicians must weigh the benefits and risks of each evaluation they perform knowing that their resources may be needed more urgently by other patients. Determine the quantitative factors correlated with an increased length of stay for adults presenting to the emergency department with abdominal or pelvic pain. Increases in factors such as age, pain, BMI, and vital signs will correlate with an increased length of stay in the emergency department as well as an increased rate of admission to the hospital. Data regarding the above factors were abstracted from a sample of adult patients (n=347) presenting to the New York Methodist hospital emergency department from June 1st, 2013 to May 31st, 2014. The review of patients presenting to the emergency department with abdominal/pelvic pain demonstrated that patients with lengths of stay greater than four hours had a significantly higher value for age, weight, BMI, and blood pressure compared to those with lengths of stay less than four hours. Additionally, patients that were admitted to the hospital had a statistically significantly higher value for age, pain scores, systolic blood pressure, and heart rate. The identification of factors associated with longer lengths of stay provides the first step in identifying how to improve patients’ access to care in a more time efficient manner. Understanding what factors account for delays in care and discharge will allow for more efficient allocation of time and resources to the patients that need it most.
    • Radiology Reporting Preferences of Non‐Radiologist Ordering Clinicians: Prose? Do you even list?

      Al‐Abbadi, Tabarik; The University of Arizona College of Medicine - Phoenix; Gridley, Daniel (The University of Arizona., 2017-04-20)
      The purpose of this survey was to expand the limited knowledge regarding non-radiologist physician preferences in radiology report styles and content.
    • Reproductive Life Planning in the Refugee Community: Focus on the Role of Men and Religion

      Hussain, Jawad; The University of Arizona College of Medicine - Phoenix; Johnson‐Agbakwu, Crista (The University of Arizona., 2017-05-09)
      Health literacy is the degree to which individuals have the capacity to understand basic health information and services needed to make appropriate health decisions. Women seen at Maricopa Integrated Health System (MIHS) Refugee Women’s Health Clinic (RWHC) are routinely offered education on developing a Reproductive Life Plan (RLP). In order to influence women’s reproductive health and medical decision‐making, there is a need to tailor RLP counseling to engage their male partners in the refugee community. We aimed to assess increased knowledge on preconception care related to the importance of developing a RLP, perspectives on birth spacing, and the influence of men as well as religion in medical decision‐making. We aimed to identify the refugee community’s receptivity to culturally and linguistically appropriate audiovisual modalities. Study participants comprised 120 refugees (39 men and 81 women) including couples, across the respective target languages with pre‐ and post‐Likert scale surveys assessing perspectives on RLP, birth spacing, the role of religion, and readiness for behavior change. Summary statistics examined changes in pre‐ and post‐Likert scale survey responses with responses dichotomized as Strongly agree/Agree compared against all other responses. A higher frequency of male respondents agreed about knowing what RLP means in the posttest relative to pretest (71.8% to 89.7%, P = 0.016) as well as 'Not having children…' (41% to 64.1%, P=0.035). Female respondents were more likely to agree to 'Know what RLP means' (76.5% to 86.4%, P =0.039) and 'Having a baby soon after…' (65.4% to 76.5%, P =0.035) after the training. They also were less likely to agree that 'RLP is about birth control' (71.6% to 59.3%, P =0.021). Amongst Muslim participants, we found improvement in knowing what RLP means (65.5% to 87.9%) and that it is important for men to have a RLP (67.2% to 84.5%). Cronbach’s alpha was used to measure internal inconsistency, with most values less than 0.5 and deemed unacceptable. Only one value, birth spacing, was > 0.6 and deemed questionable. There was the same degree of concordance, yet there also was discordance in the direction of opinions between women and men pre vs post‐test answers. When comparing couples pre and posttest, there was no significant differences observed across genders. This is the first reported U.S. initiative to provide a culturally and linguistically appropriate preconception health education. Project had demonstrated ability to mobilize several ethnic communities around the RLP. Respondents among both genders were more likely to agree about knowing what RLP means. The most challenging aspect of our community mobilization efforts was recruiting a larger sample size. Another limitation was the use of the Likert scale in a population with low literacy as there were some discrepancies in responses to negatively‐worded questions. Future studies could use a visual analog scale of smiley faces to assist those with limited literacy and incorporate a more global feel.
    • Retrospective Analysis of Injuries Sustained In Vehicle Front‐ and Back‐Overs in a Level I Pediatric Trauma Center

      Bendall, William Bryson; The University of Arizona College of Medicine - Phoenix; van Leeuwen, Kathleen (The University of Arizona., 2017-05-26)
      Motor vehicle accidents involving pedestrians are some of the most common and lethal forms of injury for children in the United States. Among younger children, a common mechanism of action for severe trauma is when a vehicle runs over the child in a forward or backward motion at low speed resulting in a blunt crush injury. This typically occurs in non‐traffic settings including driveways, sidewalks, and roadways. Such incidents have been referred to in many different ways in the literature but for the purposes of this paper will be referred to as low speed vehicle run‐overs. This is a retrospective chart review carried out at Phoenix Children’s Hospital in affiliation with the University of Arizona College of Medicine‐Phoenix that categorizes and examines the injuries sustained by patients involved in low speed vehicle runovers occurring between December 2007 and August 2013. Fifty‐five pediatric patients were included with a median age of 24 months and 6 of these patients were fatally injured. Internal injuries were common overall and significantly more common in children ≤24months. Over half of the cohort sustained fractures, with a 24% incidence of skull fractures. All fatalities were the result of traumatic brain injury. Twenty percent of victims required operative intervention. It was concluded that the severity of these types of incidents varies from minimal to life threatening and best care requires close and thorough evaluation by the trauma and emergency department teams.
    • The Role of Gilt in the Cross Presentation of the Melanoma Antigen gp100

      Johnson, Kenneth; The University of Arizona College of Medicine - Phoenix; Hastings, Karen Taraszka (The University of Arizona., 2017-05-10)
      In this study we examine the utility of using CD8+ T cell hybridomas to measure the ability of bone marrow dendritic cells (BMDCs) to internalize cancer proteins and display them to cytotoxic T cells, a process termed cross‐presentation. We test the ability of a newly generated T cell hybridoma called BUSA14 to detect cross‐presentation of the melanoma antigen gp100. BUSA14 produces a dose‐dependent response to human and mouse gp100 peptides. However, cross‐presentation of gp100 by BMDCs using SK‐MEL‐28 human melanoma cell lysates or direct MHC class I‐restricted presentation by B16 murine melanoma cells was not detected. Both SKMEL‐28 and B16 cells express gp100 protein by immunoblot, and gp100 as a membrane bound protein may be concentrated by cell fractionation techniques. We validated our crosspresentation assay with another T cell hybridoma B3Z to detect cross‐presentation of the model antigen ovalbumin. Lastly, we determined that although BUSA14 expresses the coreceptor CD8, BUSA14 lacks CD3 expression, which likely impairs the ability of this hybridoma to respond to engagement of the T cell receptor and contributes to the inability to detect presentation of native gp100 protein. To resolve these issues, we plan to use primary gp100‐specific T cells from pmel mice expressing the same T cell receptor as the BUSA14 hybridoma to detect presentation of gp100 protein. Ultimately, we plan to evaluate the requirements for cross‐presentation of gp100, including a role for gamma‐interferon‐inducible lysosomal thiol reductase (GILT), a disulfide bond reducing enzyme.
    • The Seasonality of Eosinophilic Esophagitis Flares in Children and Adolescents in Arizona

      Manley, Kelsi; The University of Arizona College of Medicine - Phoenix; Williams, Dana (The University of Arizona., 2017-05-11)
      Aeroallergens are implicated in the pathogenesis of eosinophilic esophagitis, which has a recurrent or relapsing nature. We aim to determine the incidence of seasonal disease recurrence, referred to as flares, of eosinophilic esophagitis in patients in Arizona with eosinophilic esophagitis in remission, and to characterize the presence of allergy and other disease co‐morbidities in patients that experience disease flare. A retrospective study was performed by analyzing data from visits of patients aged 5 to 18 years coded for eosinophilic esophagitis in remission seen by the Phoenix Children’s Hospital Pediatric Gastroenterology Department between June 2010 and June 2011. The data included 148 patients and 326 clinical visits. Data identified demographic information, allergy, and other disease co‐morbidities. Arizona seasons were defined as: spring from February 15 to June 15, and fall from September 1 to November 30, according to the typical pattern of allergen pollination. To analyze incidence and season of flares, statistical methods used included the Chi‐square tests and logistic regressions. Ninety‐four of 148 patients (63.5%) flared during the study period. An increased incidence of flares in the fall compared with other seasons was statistically significant (p = 0.041). Flares in the spring also had an increased incidence. Of the 94 patients that flared, 70 patients (74.5%) had environmental allergy, 83 (88.3%) had food allergy, and 66 (70.2%) had both environmental and food allergy. Our findings suggest a role for seasonal environmental allergens in the pathogenesis of eosinophilic esophagitis and disease flares in children in Arizona, particularly those with food allergy, environmental allergy, or both.
    • Study of an Early Wellness Program in Parkinson ’s Disease: Impact On Quality Of Life And Early Intervention Guidance

      Page, Brent Michael; The University of Arizona College of Medicine - Phoenix; Shill, Holly (The University of Arizona., 2017-05-26)
      Previous studies have shown that Parkinson’s disease (PD) patients are at an increased risk for a variety of complications impacting health related quality of life (HRQoL). Additionally, these various complications often lead to increased healthcare utilization. Wellness intervention in PD has shown to be effective in improving HRQoL and objective measures of disease burden such as motor functioning. What has not been demonstrated to date is whether patients who are given the opportunity to participate in regularly administered classes in these modalities will continue to attend and whether benefits will continue to be realized outside the strict confines of a controlled trial. This study examined whether intervening early in PD with a comprehensive Wellness Program is feasible and promotes lasting habits that will continue to provide sustained benefit. It was hypothesized that intervening early in PD with an intensive program involving structured exercise, socialization and PD specific education would serve to maintain or improve subject’s quality of life while decreasing healthcare utilization. Twenty‐one consenting ambulatory adult subjects diagnosed with PD within the last five years completed various screenings at baseline and following a required 6‐month Wellness Program intervention. Subjects were assessed at 12 and 18 months if they continued to participate. Patient demographics, disease specific quality of life, objective mobility, healthcare utilization and falls were assessed. Data were collected at Banner Sun Health Research Institute, located in Sun City, Arizona. All p‐values were 2‐tailed and P<0.05 was considered statistically significant. All data analyses were conducted using STATA‐14. Twenty of twenty‐one subjects completed the required 6‐month intervention. Continued participation was 70% at 12 months and 60% at 18 months. Overall HRQoL was stable at 18 months. Significant improvement was seen in patient reported mobility and emotion sub‐areas at 12 months. Communication specific HRQoL was significantly worsened at 12 months. Subjects demonstrated a stable level of physical activity while fatigue was significantly decreased. All objective measures were significantly improved from baseline. Healthcare utilization was decreased by 18 months. A total of 5 falls were reported by 3 subjects during the 6‐month interventional period. This pilot study demonstrates that comprehensive wellness intervention in early PD is feasible, effective, safe and valuable in establishing long‐term beneficial habits while potentially reducing healthcare utilization. The significant long‐term subject participation observed in this study establishes that wellness intervention may be practical for large scale implementation. The results also highlight the importance of addressing communication specific symptoms early in the course of the disease. Ultimately, this study will aid the design and implementation of future PD wellness interventions.
    • Systematic Review and Meta‐Analysis of Clinical Outcomes of Fractures Fixed with the Surgical Implant Generation Network (SIGN) Intramedullary Nail

      Sonenthal, Nechama; The University of Arizona College of Medicine - Phoenix; McLaren, Alex (The University of Arizona., 2017-05-18)
      The (Surgical Implant Generation Network) SIGN Intramedullary (IM) nail is designed to fix long bone fractures without using a costly C‐arm imaging device. It is distributed for free to countries in need, allowing for elevation of care from the standard, lengthy traction treatment in those countries to clinically superior IM nailing. This paper compares the clinical outcomes of the SIGN IM nail to those of the IM nails used in developed countries with use of a C‐arm. The terms “Surgical Implant Generation Network” and “union” were searched in four databases. Primary studies of SIGN IM nails were included and their outcomes, including union rate, time to union, and complications, were recorded and compared to historical data of IM nails used in developed countries. Overall, there is a similar union rate in bones fixed with SIGN IM nails (94.6%) versus bones fixed with IM nails in developed countries (92.3%) (p = 0.009, OR = 1.67), while some bone types (tibia and femur) demonstrated a lower union rate when individually stratified (p = 0.008, OR = 0.26 and p = 0.002 and OR = 0.15, respectively). Mean time to union for all bone types combined showed no significant difference between SIGN IM nails and IM nails used in developed countries (p = 0.26). Complications rates were similar between SIGN IM nails and IM nails used in developed countries. It is possible for the SIGN IM nail to be used to fix long bone fractures in developing countries with outcomes comparable to the IM nail used in developed countries.
    • A Systematic Review of Hyaluronidase‐Assisted Subcutaneous Fluid Administration in Pediatrics and Geriatrics and Its Potential Application in Low Resource Settings

      Wilhelm, Kelsey; The University of Arizona College of Medicine - Phoenix; Barcellona, Dawn (The University of Arizona., 2017-05-25)
      The role of enzyme‐assisted subcutaneous fluid administration (EASFA) in treating mild to moderate dehydration in pediatrics, geriatrics, and palliative care has been studied in developed countries. However, it has historically been underutilized due to widely available health care and alternative treatments, namely peripheral intravenous (IV) fluid administration. Fluid infusions in the subcutaneous tissue have a low risk of infection, are easy to administer, and have wide potential use. The use of EASFA in low resource settings to treat those with difficult IV access or where skilled healthcare workers are not as readily available could prove to be a live saving measure in many situations, including the care of patients in remote areas of the world, mass casualty events, or other disasters. Our objective was to determine if EASFA is a valid and appropriate technique to utilize in pediatric and elderly patients, and evaluate if it could be a safe and efficient way to provide fluid resuscitation in low resource settings. For this systematic review MEDLINE and Cochrane Library were searched from January 1950 to December 2015 to recover all available literature relevant to this topic. Studies that met the inclusion criteria were analyzed using Cohen’s D. This was calculated using the mean difference between intervention and control divided by the pooled standard deviation. For dichotomous outcome of the placement success rate the odds ratios were calculated with 95% confidence intervals. In reviewing 7 articles using Cohen’s D to compare mean differences to determine effect size, we found that catheter placement success rates and infusion rates were similar between EASFA and peripheral intravenous fluid administration. Additionally, it was found that the odds of correct initial needle placement was 7.19 times higher in EASFA versus intravenous administration. EASFA is a comparable alternative to intravenous fluid administration when delivering fluids to pediatric and elderly patients with mild to moderate dehydration. While infusion rates and total volume of fluids administered were similar, the high rate of success with placement of the subcutaneous catheter proves it to be more useful in some situations. Venous cannulation is difficult, even for a trained healthcare provider, and the ease of placement of subcutaneous catheters makes training lay people to administer subcutaneous fluids a possibility. Additionally, this type of fluid administration may lead to less psychological trauma to a child from multiple needle sticks, while still achieving a similar outcome of effective volume replacement. Based on the results of this study, further research is needed to evaluate the effectiveness of utilizing EASFA in low resource settings.
    • Targeting the Hippo Signaling Pathway in Atypical Teratoid Rhabdoid Tumor

      Norris, Gregory; The University of Arizona College of Medicine - Phoenix; Bhardwaj, Ratan (The University of Arizona., 2017-05-26)
      Atypical teratoid rhabdoid tumor (ATRT) is a highly malignant pediatric central nervous system tumor. The prognosis is often poor, with a 2‐year survival rate estimated at 15%. This dismal prognosis highlights the need to develop new treatment modalities for this devastating pediatric tumor. Recently, a tumor suppressing signaling pathway known as Hippo has emerged as a possible cancer treatment target. The Hippo signaling pathway is involved in organ growth and maintenance, and is dysregulated in many diverse cancers. We used quantitative real‐time PCR to evaluate the mRNA expression profile of Hippo pathway genes. We then used determined the protein expression of various Hippo components using Western blots. The results of this study suggest that Hippo plays a definite role in atypical teratoid rhabdoid tumor.
    • Training of Community Health Workers: Recognition of Maternal, Neonatal and Pediatric Illness

      McCabe, Chris; The University of Arizona College of Medicine - Phoenix; Yoblonski, Lara (The University of Arizona, 2017-05-11)
      This systematic review focuses on improving recognition and treatment of acute medical conditions in pregnant women, infants and children in low and middle income countries by Community Health Workers (CHWs). By examining critically selected articles from different electronic databases, this review seeks to organize and present the important characteristics of a training program aimed at reducing maternal, neonatal and childhood mortality. Data in the form of peer‐reviewed and published articles were collected using three public databases – PubMed, Ovid and EMBASE – using specific search terms. Greater than 300 articles where found using the specific search terms. Those articles were then processed through a series of inclusion and exclusion criteria resulting in a cohort of papers which were then individually analyzed for content. After critical analysis of all 15 publications included in the study, it becomes clear that training programs are incredibly diverse. These four aspects of training programs appear to be the most variable between the studies: size of the training program, length of the training program, training assessment and follow‐up refresher courses. Training programs that are shorter in duration or greater in class number do not seem to be any less effective than longer programs with fewer participants. Future studies should be performed in which one training program with identical training techniques, lengths, and focuses is taught in different regions. The impact that this study has on the literature is as follows: Training programs of shorter duration seem to be as effective as their longer counterparts. Finally, there is a clear need for more robust, standardized and geographically and culturally diverse training programs to more effectively study training methods.
    • Triage of Trauma Patients Injured By Large Animals: Do Urban Doctors Undertriage?

      Stevenson, Justin; The University of Arizona College of Medicine - Phoenix; Katz, Eric (The University of Arizona., 2017-05-19)
      In the United States the responsibility to develop criteria for trauma patient’s triage status rests upon individual hospitals rather than the American College of Surgeons. Traumatic injuries from large animals represent a potential need for expanded hospital resources. Urban emergency departments are less likely to regularly see patients with large‐animal related injuries and might be expected to underestimate the predicted injuries. There is scarce research on the topic of initial triage designation for large‐animal related injuries. The aim of this study is to investigate the adequacy of the initial triage designation given to patients presenting with injuries from animals larger than themselves at an urban, safety net, academic Emergency Department and Trauma Center (ACS Level 1 Adult, Level 2 Pediatric). A retrospective chart review was performed on patients presenting to the emergency department (ED) from Jan 2006 until September 2015 with injuries resulting from animals larger than the patient. A total of 213 patients met the inclusion criteria. Our study found that trauma patients injured by large animals who are triaged as low priority have dispositions that are not statistically different from those with higher initial prioritization.
    • Tumor Associated Antigens Harbor Readily Defined and Universally Immunogenic Regions Relevant For Cancer Immunotherapy

      McCurry, Dustin; The University of Arizona College of Medicine - Phoenix; Cohen, Peter; Gendler, Sandra (The University of Arizona., 2017-05-11)
      Recent advances in cancer immunology, highlighted by immune checkpoint inhibitors, have demonstrated that immunotherapy is a viable option in the oncologist’s armamentarium. Despite these advances, many patients are nonresponders. Preliminary studies have suggested that non-responders lack a de-novo anti-tumor antigen immune response that can be unmasked by checkpoint blockade; thus, strategies to induce anti-tumor immune responses are needed. We hypothesized that many tumor associated antigens (Ag) are readily susceptible to immune attack, but only in the context of identifying the tumor antigen epitopes that can reliably initiate an immune response, regardless of individual patient human leukocyte antigen (HLA) haplotype restrictions. We further hypothesized that epitope prediction strategies which seek to identify pan- or highly promiscuous-HLA binding epitopes would reduce the number of potential candidates and be more likely to accurately identify high-priority tumor Ag epitopes. Utilizing known HLA-serotype frequencies and setting a threshold of ninety percent of population coverage, regardless of race or ethnicity, twenty-nine different HLA-DRB1 haplotypes were chosen for antigen prediction utilizing the open source epitope prediction algorithm netMHCIIpan. Predictions were also performed for HLA-A serotypes utilizing the open source algorithm netMHCpan. Predicted epitopes were synthesized in the form of synthetic long peptides and tested in immune system sensitization assays involving unfractionated peripheral blood mononuclear cells (PBMC). Briefly, PBMC were subjected to a two-step culture, first synchronizing their exposure to the long peptides with aggressive surrogate activation of innate immunity, followed by IL-7-modulated T-cell hyperexpansion. Predictions resulted in identification of highly promiscuous-HLA binding epitopes. Unexpectedly, these epitopes clustered together forming high priority regions: unique “hot spots” with high densities of promiscuous HLA-binding epitopes from the widely expressed oncoproteins MUC1, HER2/neu and CMV-pp65 (p<0.0001, for predicted HLA-DRB1 binding affinities, compared to non-hot spot regions). Added synthetic long peptides (>20aa) derived from “hot spot” regions of MUC1, HER2/neu, and CMVpp65 reliably produced selective and sustained expansion of both CD4+ and CD8+ peptide-specific, interferon-γ (IFNγ)-producing Tcells when synchronized with step 2 exposure to exogenous IL-7 (p<0.0001 and p=0.0048, for CD4+ and CD8+ Ag-specific T-cells, respectively, compared to T-cells directed against peptides from non-hot spot regions). “Hot spot” peptide Ag-specific T-cells preferentially recognized endogenous tumor derived MUC1, either in MUC1 expressing tumor cell killing assays (p=0.038, compared to non-peptide Ag-specific T-cells) or as MUC1 tumor lysate when pulsed onto restimulatory PBMC (p=0.022 and 0.025, for CD4+ and CD8+ T-cells, respectively, compared to T-cells directed against peptides from non-hot spot regions). This mechanistically rational antigen selection sequence, effective even for unvaccinated donors, regardless of HLA-haplotype, enables rapid identification of tumor protein regions relevant for cancer immunology, including adoptive immunotherapy, vaccines, and even identification of tumor neo-antigens unique to each patient.