• Marijuana Smoking and the Risk of Developing COPD, Lung Cancer, And/or Chronic Respiratory Symptoms: A Systematic Review

      Byers, Chris; The University of Arizona College of Medicine - Phoenix; Campos‐Outcalt, Doug MD, MPH (The University of Arizona., 2017-06-01)
      The aim of this study is to conduct a systematic review of the existing evidence on marijuana use and its association, or the absence of an association, with an increased risk of developing chronic obstructive pulmonary disease (COPD), lung cancer, and/or chronic respiratory symptoms. We hypothesize that a systematic review will not demonstrate sufficient evidence to determine that marijuana use increases the risk of developing COPD, lung cancer, and/or chronic respiratory symptoms. The term “chronic respiratory symptoms” encompasses the following: cough, sputum production, wheeze, shortness of breath, acute bronchitis, and chest tightness. The following databases were searched for the topics of marijuana smoking, COPD, lung cancer, and chronic respiratory symptoms: MEDLINE (PubMed/OvidSP), the Cochrane Controlled Trials Register, the Cochrane Database of Systematic Reviews, PsycINFO, the Database of Abstracts of Reviews of Effects, and Google Scholar. The search ended September 7th, 2016. Studies were initially limited only by the requirement that they were based upon human research and published in English. Studies were included if they were systematic reviews, randomized controlled trials (RCTs), prospective or retrospective cohort studies, case control studies, or cross‐sectional studies. A total of 739 articles were screened for eligibility, 17 unique studies met the inclusion criteria and underwent qualitative analysis1‐17. The quality of systematic reviews was evaluated using the AMSTAR criteria18; cohort, case‐control, and cross sectional studies were evaluated based upon the Newcastle‐Ottawa Quality Assessment Scale (NOS) 19. No RCTs were identified. The overall quality of the evidence for each outcome was determined by utilizing the GRADE methodology20‐21. Studies were primarily assessed by a single reviewer, with random validation of assessments on a limited number of studies by a second reviewer. Overall, there is very low quality evidence that assesses for an association between marijuana smoking and an increased risk of developing lung cancer, COPD, and/or chronic respiratory symptoms. There was no conclusive finding for lung cancer and COPD. However, seven of eight studies concluded that there was an association between marijuana use and chronic respiratory symptoms. The totality of evidence describing any associations between marijuana smoking and the risk of developing lung cancer, COPD, and/or chronic respiratory symptoms is not strong enough to confidently state that marijuana use is associated with any of these chronic pulmonary conditions. Of all the evidence examined in this systematic review, the most convincing appears to be that relating to a potential positive association between marijuana smoking and the risk of developing chronic respiratory symptoms. Unfortunately, the overall quality of evidence was very low due to significant methodological weaknesses within the studies. Thus, there is insufficient evidence in the current literature to make a definitive statement regarding this possible association.
    • Healthcare Access among Adults with Frequent Mental Distress

      Khan, Khalid Salim; The University of Arizona College of Medicine - Phoenix; Hussaini, Khaleel PhD; Rahman, Shakaib MD; Shennib, Hani MD (The University of Arizona., 2016-05-04)
      Objective: Mental health plays a central role in the well‐being of individuals. Understanding the factors that influence mental wellness is critical in order to develop effective policy that addresses the burden of mental illness in society. The objective of this study is to identify a possible relationship between healthcare access and the presence of mental distress in individuals. Methods: Logistic regression was performed using cross sectional data from a CDC developed nationwide behavioral health surveillance program (BRFSS, 2013‐4). Odds ratios were estimated using frequent mental distress as the outcome of interest while adjusting for confounding variables such as smoking, binge drinking, obesity, etc. Six models were estimated utilizing our hypothesized variables of interest. Results: The calculated adjusted odds ratios (AOR) and confidence intervals (CI) demonstrated a positive correlation between certain variables measuring access to healthcare and the reporting of frequent mental distress, agreeing with the hypothesis. Those variables were financial cost preventing access to medical care (AOR [2], CI [1.9‐2.1]) as well as a span of more than 2 years having elapsed since a routine medical checkup by a healthcare provider (AOR [1.1], CI [1.1‐ 1.2]). The opposite effect was demonstrated in individuals who had no insurance coverage (AOR [.8], CI [.7‐.9]), which was contrary to the hypothesis. Conclusion: After adjusting for confounding variables, a strong relationship exists between individuals who are not able to see a physician due to cost, and the presence of frequent mental distress. Frequent mental distress is also increased in individuals who have not had a routine medical checkup with a physician in the last 2 years.
    • Safety and Visual Outcomes of Novel Abexterno Akreos® Single Pass Method of Transscleral Sutured Posterior Chamber IOL Implantation for Scleral Fixation of IOL

      Wallman, Andrew; The University of Arizona College of Medicine - Phoenix; Monson, Bryan MD (The University of Arizona., 2016-04-20)
      We present the safety and efficacy of a novel transscleral sutured posterior chamber intraocular lens (TSSPCIOL) implantation approach utilizing 25 gauge vitrectomy and a foldable posterior chamber intraocular lens implant (AKREOS AO60, Bausch & Lomb). 80 consecutive eyes that underwent single surgeon TSSPCIOL implantation between October 2008 and July 2012 at a referral‐based retina institution were analyzed for best spectacle‐corrected visual acuity (BCVA) and safety indicators. Postoperative complications included retinal detachment in 2 eyes (2.5%), Irvine‐Gass cystoid macular edema in 3 eyes (3.75%), with 2 of those cases occurring late, persistent postoperative corneal edema in 1 eye (1.25%), hyphema in 2 eyes (2.5%) and 1 case of postoperative vitreous hemorrhage with spontaneous clearing. The modified external approach with AKREOS® TSSPCIOL placement with 25 gauge vitrectomy has relatively few complications, improves visual acuity in patients requiring TSSPCIOL, and offers several advantages over traditional anterior chamber or conventional scleral sutured techniques.
    • Injections of Bone Marrow Aspirate Concentrate as Treatment for Discogenic Pain

      Shillington, Jon Mark; The University of Arizona College of Medicine - Phoenix; Wolff, Michael MD (The University of Arizona., 2016-04-20)
      Low back pain (LBP) is one of the most common musculoskeletal pain complaints, affecting up to 84% of the U.S. adult population. In the United States, the highest rate of incidence is between the ages of 45 and 64 years. The causes for LBP are complex and of multiple origins, but one of the primary causes is mechanical low back pain that is discogenic in etiology. This can be secondary to either internal disc disruption (IDD) and/or degeneration of the intervertebral disc (IVD), also known as degenerative disc disease (DDD) [10,11]. Combined physical and medical therapies are successful in relieving pain in approximately 90% of cases of low back pain. However, the remaining 10% become chronic and generate a serious public health problem, known as chronic low--‐back pain (CLBP). CLBP decreases both the quality of life and the labor capacity of the patient. As specific diagnostic procedures for LBP have improved, discogenic pain has been identified as the primary cause of CLBP amongst adults. Within the classification of discogenic pain, the most common specific cause of pain – up to 42% of LBP complaints – is internal disc disruption (IDD), with other distinguishable causes including disc herniation, degenerative disc disease (DDD), and instability of the lumbar segment [10]. Effective treatment for discogenic LBP – and therefore for CLBP – would provide significant relief for individuals as well as for the overall health care system and the employers affected by the patients’ condition. One promising treatment option involves the use of Mesenchymal Stem Cells (MSC), which may allow for regeneration of the disc itself. Treatment with MSCs via injections derived from autologous concentrated Bone Marrow Aspirate (cBMA) would capitalize on the regenerative potential of MSCs while reducing the risk of infection or rejection, both significant risks of treatment from a heterologous source. This project analyzed data collected from 33 patients with confirmed discogenic LBP, who were treated with intradiscal injections of autologous concentrated Bone Marrow Aspirate. After initial treatment, patients were monitored through follow up visits and questionnaires (VAS, Oswestry, SF--‐36) to determine the efficacy of treatment. The areas of interest for this study were intentionally narrow. This study sought to identify specifically the patients’ self--‐reported pain and functioning levels from 2 weeks post--‐treatment to 12 months post--‐treatment. Those reports were gathered using the aforementioned instruments and synthesized to show overall trends and statistically significant changes in the patients’ self--‐ assessment. The patients were also asked to give an overall impression of whether or not their back pain had improved post treatment. While admittedly limited in authority compared to a double--‐blind, randomized, controlled trial, the information was gathered from the patients with the hopes of augmenting ongoing research related to innovative treatments for discogenic LBP and of identifying new areas for further, future research.
    • The Interaction of β-catenin, Vitamin D, Resveratrol, and Two Common VDR Polymorphic Variants in Colorectal Carcinogenesis

      Van Pelt, Chad; The University of Arizona College of Medicine - Phoenix; Jurutka, Peter PhD (The University of Arizona., 2016-04-20)
      Vitamin D and resveratrol have been widely researched in recent years, especially their apparent abilities to impact a host of physiological processes. Resveratrol, a phytoalexin found in various berries, peanuts, and other vegetables, is purported to possess anti-aging, anti-inflammatory, antioxidant, anticancer, neuroprotective, and antiarthritic properties, while the classical endocrine functions of vitamin D are the control of calcium and phosphate homeostasis. The biologically active metabolite of vitamin D, 1,25-dihydroxyvitamin D (1,25D), is typically synthesized in the kidney, bound to vitamin D binding protein, and shuttled to cellular target sites. Mounting data on the effect of locally synthesized 1,25D in immune, epithelial, neural, and other tissues have led to an increased awareness of the myriad functions of vitamin D, including detoxification, cellular aging and its modulation, immune regulation, neurotransmitter activity, and metabolic control. Both endocrine and intracrine actions of vitamin D are mediated by the vitamin D receptor (VDR), a nuclear receptor that controls vitamin D-directed transcription of target genes. Importantly, the VDR has numerous polymorphisms, one of which results in two phenotypically distinct isoforms, designated M1 and M4. VDR M4 is postulated to be more active than M1 in vitamin D-dependent transactivation. Variable binding affinities between the two isoforms and VDR interacting proteins such as TFIIB and RXR have also been observed. Another protein known to interact with VDR is β-catenin, the mediator of the Wnt/β-catenin signaling pathway that can drive colorectal carcinogenesis. The goal of this study was to investigate the ability of vitamin D and resveratrol to regulate the Wnt/β-catenin system via stimulation of β-catenin-VDR (both M1 and M4) interaction and subsequent inhibition of β-catenin-mediated transcription. The current data reported herein support and extend previous work by demonstrating that VDR binds directly to β-catenin and that both vitamin D and resveratrol appear to enhance this interaction. We also present data that 1,25D-stimulated VDR is capable of inhibiting β-catenin transcriptional activity. Significantly, we have shown that the two common VDR polymorphisms M1 and M4, are functionally variable, both in their induction of vitamin D-dependent genes and in their inhibition of β-catenin-mediated transcription. VDR M4 exhibits both elevated transactivation and amplified capacity for β-catenin suppression compared to M1, and studies employing site-directed mutagenesis of VDR implicate the glutamic acid at position 2 as being responsible for the reduced activity of the M1 variant. Both polymorphic VDR variants display 1,25D-mediated enhancement of -catenin association, with the M1 SNP possessing a lower basal (-1,25D) binding to this protein partner but a higher fold stimulation in -catenin interaction in the presence of 1,25D. Taken together, these data support the notions that VDR influences pathways important for colorectal carcinoma (CRC) development, and that supplementation with vitamin D and resveratrol may reduce colon cancer risk in the general population, especially in individuals with the less active M1 VDR polymorphism. A comprehensive understanding of 1,25D and resveratrol action in VDR signaling may allow for a more personalized approach toward treating vitamin D–related disorders and evaluating risk for carcinogenesis.
    • The Use of Clinical Decision Rules to Reduce Unnecessary Head Ct Scans in Pediatric Populations

      Barrett, Jeffrey; The University of Arizona College of Medicine - Phoenix; Panchanathan, Sarada MD, MS (The University of Arizona., 2016-04-20)
      Background: Head computed tomography (CT) imaging is the gold standard study for rapidly identifying emergent traumatic brain injuries (TBIs). Exposure to the ionizing radiation utilized in CT increases lifetime risk for developing neoplasms. Currently there is little consensus on appropriate use of CT imaging for children with mild head injury. Clinical decision rules (CDRs) have been developed to identify children at very low risk of clinically significant brain injury. While these CDRs have been validated, their implementation has not been as well studied. Objective: To evaluate the efficacy of two CDRs in decreasing CT scan rate without missing clinically significant brain injuries. The two CDRs used in this study were the Children's Head Injury Algorithm for the Prediction of Important Clinical Events (CHALICE) and the Pediatric Emergency Care Applied Research Network (PECARN) algorithm. Both variations of the PECARN criteria for age 2 years and older and age <2 years were studied. Design/Methods: The medical records for patients with the diagnosis of head injury evaluated at the Maricopa Medical Center Pediatric Emergency Department for all of 2011 and 2012 were reviewed. A total of 331 charts were identified. The PECARN and CHALICE inclusion criteria and algorithms were applied to these charts to determine if the patients met criteria for CT scan. Patients with suspected non‐accidental injuries were excluded. Results: Of 331 patients, 238 met the inclusion criteria for CHALICE. 96 (40.3%) had CT scans performed. According to the algorithm, only 52 (21.8%) met criteria, which is an absolute rate reduction of 18.5%. One TBI was missed. 129 patients met the inclusion criteria for PECARN age 2 years and older. 73 (56.6%) had CT scans performed. 61 (47.2%) met criteria resulting in an absolute rate reduction of 9.4%. No TBIs were missed. 74 patients met inclusion criteria for PECARN age <2 years. Of these, 25 (33.7%) had CT scans performed and the same number met criteria resulting in no change in number of scans. One TBI was missed. Conclusions: Both the CHALICE and PECARN CDRs have the potential to reduce scan rates in our home institution. The CHALICE CDR would have resulted in a greater reduction in CT scans. PECARN also would have reduced the number of scans in children 2 years and older, but not in children <2 years old. The TBI that did not meet CDR criteria was also missed by clinical suspicion and a CT scan done on a later encounter was suspicious for a non‐accidental injury.
    • The Proportion of Adolescents Complaining of Anterior Knee Pain with Osteochondritis Dissecans and the Utility of Screening Radiographs in its Diagnosis.

      MacKenzie, James; The University of Arizona College of Medicine - Phoenix; Vaughn, Jeffrey M DO; Shrader, M Wade MD (The University of Arizona., 2016-04-01)
      Osteochondritis dissecans is a rare condition which can cause disabling knee pain in adolescents. Treatment and prognosis hinges upon the stage of the lesion and early detection is paramount 1‐3. Until recently, epidemiologic information regarding OCD in adolescents was unavailable. However in 2013 Kessler et al. demonstrated an incidence of 9.5/100,000 in the general adolescent population 4. Chief complains from patients with OCD usually localize pain to the knee joint line, but less commonly, patients may complain of anterior knee pain. This retrospective chart review looked at the amount of OCD diagnoses in adolescents specifically complaining of anterior knee pain without causative trauma in the years 2009 and 2010 at a major children’s hospital. It was noted that 7.5% of children with this presentation had a diagnosis of OCD. This number was over three orders of magnitude higher than the incidence seen in the general adolescent population as established by Kessler and may support the use of screening radiographs in this subset of patients to detect OCD in its early stages.
    • Inferior Vena Cava Filter Fracture and Migration to the Heart: A Review of the Literature and Case Report

      Bowles, Brad; The University of Arizona College of Medicine - Phoenix; Shennib, Hani MD (The University of Arizona., 2016-04-01)
      Background and Significance: The utilization of IVC filters for pulmonary embolism prevention has increased significantly over the past decade as the indications continue to expand. Although the risks associated with IVC filters are small, a well‐known complication is filter fracture and subsequent embolization of the fragment. Case reports have been published on the devastating effects of fragment migration to the heart, causing intense chest pain, pericardial effusion, cardiac tamponade and death. Research Question: There is a paucity of experience and guidelines for treating patients with a metallic foreign object lodged within the heart. Is there a consensus on the proper management of these cases? How do these patients present and what are the outcomes of treatment? Some clinicians have chosen to observe and monitor, while others have gone to the operating room for open‐heart surgery and retrieval of the fragment. Methods: In an attempt to answer these questions, a systematic review of the published literature was conducted between 1985 and 2015. Only articles related to IVC filter fracture and subsequent fragment migration to the heart were included. The clinical presentation, workup, management, treatment and outcomes were collected as available. Results: A total of 23 articles were published consisting of a prospective study, retrospective series and case reports. There were 37 migrated fragment to the heart reported in 29 patients. The most common clinical presentations were chest pain (69.0%) and no symptoms (27.6%). Regarding treatment, ten patients underwent observation, three had successful endovascular retrieval, 12 went to the operating room for open‐heart surgery and four cases were unreported. Of the 12 patients with reported pericardial effusion, 11 (91.7%) underwent open surgical repair. Of the eight asymptomatic patients, seven (87.5%) were ultimately in observation and the management of the other was unreported. Conclusions: There appears to be a consensus in the literature that observation and close follow up are appropriate options for asymptomatic patients. Symptomatic patients with pericardial effusion may benefit from open‐heart surgery. Cardiovascular compromise such as cardiac tamponade should be managed with open surgery. Based upon these findings and other details in the cases, we have proposed a management algorithm.
    • Management of Rhinosinusitis During Pregnancy: Systematic Review and Expert Panel Recommendations

      Jategaonkar, Ameya; The University of Arizona College of Medicine - Phoenix; Lal, Devyani MD (The University of Arizona., 2016-04)
      Background: Rhinosinusitis, both acute and chronic, represents a common disease. Approximately 29.6 million adults in the United States suffer from sinusitis with 11 million suffering from CRS1. The multicenter GA2LEN study showed that amongst lifetime nonsmokers, women were at a greater risk of being affected by chronic rhinosinusitis than men2. Various other rhinologic manifestations of pregnancy have also been described. Nevertheless, management of rhinosinusitis during pregnancy is poorly described in the literature. Objectives: 1. Conduct a systematic review of the literature for the management of acute and chronic rhinosinusitis (CRS) during pregnancy. 2. Make evidence based recommendations on the management of acute and chronic rhinosinusitis during pregnancy. Methods: A systematic review of the literature was conducted using MEDLINE and EMBASE databases. Search terms included “rhinitis” OR “sinusitis” OR “rhinosinusitis” AND “pregnant” OR “women” OR “gender”. Title, abstract, and full manuscript review was conducted. Full manuscripts including citations and references were reviewed if the abstract noted any gender specific outcomes. A multispecialty panel of experts in the fields of rhinology, allergyimmunology, and obstetrics‐gynecology was invited to review the systematic review. Recommendations were sought on the use of the following for the management of CRS during pregnancy: oral corticosteroids, antibiotics, leukotriene antagonists, topical corticosteroid sprays/irrigations/drops, aspirin desensitization, elective surgery for CRS, and vaginal birth vs. planned cesarean delivery for patients with history of skull base erosions or CSF rhinorrhea. Results: 3052 abstracts were screened, and 88 manuscripts were reviewed. No relevant level 1, 2 or 3 studies were found. Expert panel recommendations were synthesized. Conclusions: Several recommendations were made. These include continuing all modern topical corticosteroids for CRS maintenance, using pregnancy safe antibiotics for acute rhinosinusitis and CRS exacerbations, and discontinuing aspiring therapy for desensitization in patients with aspirin exacerbated respiratory disease.
    • The Role of Injection Laryngoplasty (IL) in Treating Deep Interarytenoid Notch (DIN) Associated Dysphagia in Young Children

      Frantz, Garrett; The University of Arizona College of Medicine - Phoenix; Williams, Dana MD (The University of Arizona., 2016-04)
      BACKGROUND Deep Interarytenoid Notch (DIN) is the mildest form of laryngotracheoesophageal cleft defect and is frequently found in young children with dysphagia and aspiration. Treatment guidelines are not defined. Injection laryngoplasty (IL) is a surgical procedure injecting polymer gel into the issue around the defect. Our objective was to evaluate the efficacy of IL in pediatric populations with severe dysphagia and aspiration. METHODS We conducted a pilot retrospective chart review of DIN patients under 36 months who underwent IL at PCH. Severity of dysphagia before and after IL was measured using modified barium swallows (MBS) (scale 0‐10) and documented symptoms. Statistical analysis was done using paired two sample t‐test with a p value of 5 percent. RESULTS Patients with initial MBS above double honey (7) improved an average of 2.6 ±1.38 points while those with initial scores below 7 did not see a statistical change in MBS. At the end of the study period, the final MBS scores for both groups were statistically similar.CONCLUSIONS IL treatment for DIN associated dysphagia results in improvement of MBS scores and symptoms in toddlers with severe aspiration. Careful timing of IL impacts morbidity. Future prospective controlled studies are necessary to evaluate the role of IL and medical interventions in thickener wean and clinical improvement.
    • Implementation of a Pediatric Stroke Team: Outcomes and Resource Utilization

      Esque, Jacquelin; The University of Arizona College of Medicine - Phoenix; Buttram, Sandra MD (The University of Arizona., 2016-04)
      Background and Significance: Pediatric stroke is associated with significant morbidity and mortality. In an effort to improve diagnosis and patient management, we established a Pediatric Stroke Team (PST) available 24/7 in January 2012. Outcomes of patients before and after PST implementation are reported. Methods: Retrospective review of pediatric stroke patients (Jan 2009 ‐Dec 2012) at Phoenix Children’s Hospital in Phoenix, Arizona. Primary outcomes assessed were Glasgow Outcome Scale‐Extended Pediatric Revision (GOS‐E Peds) and discharge disposition. Hospital length of stay, time to neuroimaging, stroke therapies, and adherence to neuroprotective strategies (sodium, glucose, temperature) were also evaluated. Data were analyzed by Wilcoxon rank sum, Fisher’s exact, and chi‐square. Results: There were 64 patients pre‐PST and 30 post‐PST. Overall, GOS‐E Peds was improved post‐PST 2 [1, 3] vs. pre‐PST 3 [2, 6] (p = 0.004) with no change if deaths were excluded (post‐PST (2 [1, 2]) vs. pre‐PST (2 [1, 6]) (p = 0.030)). Discharge to home was more common in the post‐PST group (p = 0.018). Definitive neuroimaging tended to occur more quickly post‐PST 2h [1, 2.6] compared to pre‐PST 4.7h [1.3, 16.5] (p =0.16). Post‐PST patients appropriately received heparin (23%) more often than pre‐PST (6%) (p = 0.034) and had fewer episodes of hyperglycemia (3%) compared to pre‐PST (20%) (p = 0.033). There were no differences in episodes of fever, hyponatremia or hypoglycemia. Conclusions: Availability of a PST improved patient care and outcomes. Time to definitive neuroimaging was decreased, appropriate therapies were administered and adverse events (hyperglycemia) were decreased with PST management. We continue to strive for improved care of pediatric stroke patients.
    • “It’s About Heart”: A Qualitative Study of Rural Family Physician Training Needs.

      Varner, Samantha; The University of Arizona College of Medicine - Phoenix; Brown, Steven MD (The University of Arizona., 2016-04)
      Efforts to reduce a chronic physician shortage and meet the needs of rural communities face long standing challenges such as physician recruitment and retention. While these topics have been researched at length, issues surrounding the contribution of training specifically geared toward the needs of the Southwest’s rural communities are not well understood. The goal of this investigation is to discuss with rural family physicians the realities of rural practice and to determine what, if any, skills and competencies are specific to rural family practice and that, if addressed in training, would increase the number of students and residents pursuing rural family medicine and increase the number of physicians in rural areas. Methods: Physicians throughout rural areas in the Southwest meeting the role of thought leader were interviewed. Chain sampling was used to generate diversity of ideas. Interviews were conducted in person or by phone using a semi‐structured format and a topic guide. Participants were asked to discuss what skills they feel are important to a successful practice in a rural community, the degree to which the competencies were covered in their residency training, and how having or not having these skills might affect job satisfaction and retention. Interviews were recorded and transcribed. Transcripts were analyzed by a two person committee for repeating themes. Results: Seven major repeating themes were evident in the data. Of these residency training type, individual resilience, comfort with lack of resources, community were some of the most common and important to participants. Conclusion: This study has shown that the challenges to recruitment and retention of family physicians in rural areas are many and complex. These results combined with the extensive literature studying successful recruitment and retention programs demonstrates the enormous potential that exists in a multifactorial approach to rural recruitment and retention to meet the tremendous need for more family physicians in rural areas.
    • 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.
    • Label‐free Microscopic Assessment of Glioblastoma Biopsy Specimens Prior to Biobanking

      Zehri, Aqib; The University of Arizona College of Medicine - Phoenix; Preul, Mark MD (The University of Arizona., 2016-04)
      Introduction: Glioblastoma is the most common primary brain tumor with a median 12‐ to 15‐ month patient survival. Improving patient survival involves better understanding the biological mechanisms of glioblastoma tumorigenesis and seeking targeted molecular therapies. Central to furthering these advances is the collection and storage of surgical biopsies (biobanking) for research. We addressed an imaging modality, confocal reflectance microscopy (CRM), for safely screening glioblastoma biopsy samples prior to biobanking to increase the quality of tissue provided for research and clinical trials. We hypothesize that CRM is a safe and effective method for screening specimens prior to biobanking. Methods: Intracranial implantation of human glioma cells was performed to create glioblastoma xenografts. Rodents xenografts were anesthetized to collect whole brain specimens, which were sectioned into tumor containing slices. One set of slices were incubated with DAPI and imaged. A coefficient of determination analysis was then used to compare cells identified with CRM to cells labeled with DAPI. The other set of slices were imaged using CRM at various time points and subsequently frozen for later analysis of DNA, RNA, and protein integrity. We subsequently imaged human glioma biopsies with CRM to determine cellularity and necrosis. Results: CRM provides definitive contrast between cell nuclei, cytoplasm, and extracellular tissue to help identify tumor regions, margins, and acellular regions of animal glioblastoma specimens without altering DNA, RNA, or protein expression of imaged tissue. When imaging fresh human biopsy samples, CRM can differentiate a cellular glioblastoma biopsy from a necrotic biopsy. Conclusion: These data illustrate CRM’s potential for rapidly and safely screening clinical biopsy samples prior to biobanking, which demonstrates its potential as an effective screening technique that can improve the quality of tissue biobanked for patients with glioblastoma.
    • Marijuana Use and the Risk of Depression: A Systematic Review and Meta‐Analysis

      Gentry, James; The University of Arizona College of Medicine - Phoenix; Campos‐Outcalt, Doug MD, MPA (The University of Arizona., 2016-03-25)
      Objective: To conduct a systematic review of the evidence pertinent to the relationship between marijuana use and depression and perform a meta‐analysis on the data in order to inform evidenced‐based practice. The question of interest is: Is marijuana use associated with increased risk of developing depression? Methods: The databases MEDLINE (PubMed), The Cochrane Library, CINAHL (EBSCO), psycINFO, and Google Scholar were searched for the topics of marijuana use and depression through October of 2013. Studies were included if they were systematic reviews, randomized controlled trials, prospective or retrospective cohort studies, or case‐control studies. No randomized controlled trials were discovered. Quality of cohort and case‐control studies was evaluated using the Newcastle‐Ottawa Quality Assessment Scale 1. Overall quality of evidence was determined using the GRADE methodology 2,3. The Bradford‐Hill criteria 4 were used to assess for causation. Studies were assessed by two reviewers. 173 articles were screened for eligibility. Of these fourteen articles were considered to fit the inclusion criteria. Nine homogeneous studies were included in the meta‐analysis. Results: The quality of the evidence reviewed is low to very low. It does not meet Bradford‐Hill criteria for causation. There is a slight positive correlation between marijuana use and onset of depression. However, those studies included in the meta‐analysis demonstrated a low overall pooled odds ratio (OR = 1.17; 95% CI = 1.06—1.29). Conclusion: The evidence suggests a slight positive correlation between marijuana use and depression but is not sufficient to draw a conclusion. This evidence is generally of very low quality. It does not demonstrate a dose response, and is without a significant magnitude of effect.
    • 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.
    • 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.
    • 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.
    • Identifying an Oxygenation Index Threshold for Increased Mortality in Acute Respiratory Failure

      Hammond, Brandon; The University of Arizona College of Medicine - Phoenix; Dalton, Heidi MD; Willis, Brigham MD (The University of Arizona., 2016-03-25)
      Objectives: To examine current oxygenation index (OI) data and outcomes using EMR data to identify a specific OI values associated with outcome. Methods: Retrospective review of electronic medical record (EMR) data for patients age 1 month ‐ 20 years mechanically ventilated for >24 hours in the PICU. Serial, average and maximum OI values were calculated. Length of mechanical ventilation, hospital stay and outcome were assessed. Results: OI was calculated on 65 patients from EMR data, of which 6 died (9.2%). The median maximum OI was 10 for all patients, 17 for non‐survivors (NS), and 8 for survivors (S), (p=0.14 via Wilcoxon rank‐sum test). Odds ratios (OR) indicated 2.1 times increase odds of death (p=.08), 95% confidence interval (0.89–5.03) for each one‐percent increase in maximum OI. Average OI OR also revealed 2.1 times increase in odds of death (p=.14), 95% confidence interval (0.77–5.48). ROC analysis indicated a higher discriminate ability for max OI (AUC = 0.68) than average OI (AUC = .58). OI cut points for mortality were established. Mortality was unchanged until max OI >17, for which mortality nearly tripled at a value of 18% versus 6‐7% for range 0‐17. Conclusions: Serial assessment of OI values may allow creation of alert values for increased mortality risk and aid in development of clinical decision rules. Consideration for escalation of therapies for respiratory failure such as high frequency ventilation or ECMO at lower levels of OI than historically reported may be warranted. This study also helps to validate prior reports that OI is useful as a severity score for clinical research and outcome prediction.
    • A Survey to Assess Parent Perspective of the Impact of a Gluten‐Free, Casein‐Free Diet on Their Child’s Symptoms of Autism Spectrum Disorder

      Wendt, Rebecca; The University of Arizona College of Medicine - Phoenix; Melmed, Raun MD; Savi, Christine PhD (The University of Arizona., 2016-03-25)
      With the prevalence of Autism Spectrum Disorder (ASD) rising (approximately 1 in 45)1 treatment for the disorder becomes even more important. Families turn to both traditional and alternative medicinal sources for help. The Gluten‐Free, Casein‐Free (GFCF) diet is an example of an alternative therapeutic approach. Study Aims: Our aims were to design and begin initial validation of a survey to evaluate the use and efficacy of the GFCF diet in children with ASD with concurrent gastrointestinal (GI) symptomatology. We also aimed to assess feasibility of the survey in the target population through piloting the survey. This is the first step in determining association of the GFCF diet in children with ASD. Methods: A survey was developed with expert review, meant for completion by parents and primary caregivers of children with ASD. The survey content included demographics, treatments used, GI symptoms (as measured by a modified Rome III parent report form), food allergies and intolerances, and frequency of aberrant behaviors (as measured by the Aberrant Behavior Checklist). Questions regarding diet use (specifically gluten‐free diet, casein‐free diet, or GFCF) were included in the treatment modalities and as well as questions regarding compliance and length of time used. The survey was advertised to our target population and 38 completed responses were obtained for a pilot study. Results: The pilot study revealed questions which were not clear to the target population and required modifications. Data from the responses revealed 14/38 participants who attempted the GFCF diet or its variants with their child, 11 for 3 months or greater. Number of food intolerances was heightened among those who used the diet or its variants. Heightened ABC irritability subscores were noted among those with GI symptoms. Conclusions: The pilot survey developed for this project suggests that the use of the GFCF diet in children with ASD is not only common but also might be a useful therapeutic agent. The need for further validation of the tool is paramount.