2014 CNMSRS Compendium by Kimberley Ormiston

Table of Contents

WELCOME

CHAIRS, DISCUSSION LEADERS AND ORGANIZING COMMITTEE

SCIENTIFIC PROGRAM (Complete Scheduling of Poster and Oral Presentations)

SESSION 1 of 2: LIGHTNING ORAL PRESENTATIONS

James Pius, Dalhousie University

Kyle Phipps, Dalhousie University

Gabrielle Chartier, University of Montreal

Camille Vallée-Gravel, McGill University

Thiviya Selvanathan, McMaster University

Alexandra Ladouceur, University of Montreal

Yin Hui, University of Western Ontario

Robert Vanner, University of Toronto

SESSION 1 of 2: POSTER DISCUSSION

Christopher Aiken, University of Manitoba

Oliver Ayling, University of Toronto

Jason Bau, University of Calgary

Matthew Benesch, University of Alberta

Marc Nicolas Bienz, Université de Montréal

Megan Blades, University of Calgary

David Bulir, McMaster University

Andrea Cervi, University of Ottawa

Daljeet Chahal, Université de Montréal

Gabrielle Chartier, Université de Montréal

Zachary Corso, University of Manitoba

35 2

Erin Degelman, University of Calgary

Octavian Dobrescu, McGill University

Ariane Drouin, Université de Montréal

Matt Eagles, Memorial University of Newfoundland

Amanda Eslinger, University of Calgary

Jamie Fleet, McMaster University

Carlen (Kay) Fung, University of British Columbia

Hart Goldhar, University of Toronto

Stefan Hamilton, Memorial University of Newfoundland

Aurélie Houle, Université de Montréal

Tina Hu, University of Toronto

Yin Hui, University of Western Ontario

Patrick Jung, University of Manitoba

Cara Katz, University of Manitoba

Divjot Kumar, University of British Columbia

Alexandra Ladouceur, Université de Montréal

Mathieu Laflamme, Université Laval

Lawrence Lau, University of Manitoba

Andre Le, Memorial University of Newfoundland

SESSION 2 of 2: POSTER DISCUSSION

Aldrich Leung, University of Alberta

Ran (Richard) Liu, University of British Columbia

Branavan Manoranjan, McMaster University

Kathryn Menzies, University of Manitoba

Nima Moghaddam, University of British Columbia

Jennifer Ortynski, University of Alberta

Richa Parihar, Memorial University of Newfoundland

Bhavika Patel, University of Calgary

64 3

Michael Peplowski, University of Calgary

Amit Persad, University of Alberta

Kyle Phipps, Dalhousie University

James Pius, Dalhousie University

Tara Riddell, Dalhousie University

Thiviya Selvanathan, McMaster University

Patrick Steadman, University of Toronto

Charlie Tan, McMaster University

Christina Thornton, University of Calgary

Ethan Toumishey, Dalhousie University

Camille VallĂŠe-Gravel, McGill University

Luke Vanderhooft, University of Manitoba

Robert Vanner, University of Toronto

Zhanni Weber, University of Manitoba

James Yan, University of Western Ontario

Vanessa Zannella, University of Toronto

Kevin Zuo, University of Alberta

Austin Zygmunt, Dalhousie University

SESSION 2 of 2: LIGHTNING ORAL PRESENTATIONS

Vanessa Zanella, University of Toronto

Christopher Aiken, University of Manitoba

Amanda Eslinger, University of Calgary

Christina Thornton, University of Calgary

Matthew Benesch, University of Alberta

Ran (Richard) Liu, University of British Columbia

Austin Zygmunt, Dalhousie University

PARTICIPATING SCHOOLS

PARTICIPANT CONTACT INFORMATION

SPONSORING AGENCIES

Welcome to the 6th Canadian National Medical Student Research

Symposium! The opportunity to indulge your curiosity, make a discovery and thereby make a change in the world is an incredible privilege that few have. Researchers are one group that is very fortunate to do so. At the same time, there is no doubt that learning how to conduct and interpret research, how to develop it into a substantial portion of your career, and how to maintain a successful program is hard work that is fraught with uncertainly, insecurity and the occasional burst of excitement. Over the next several days you have the opportunity to share your experiences, your emerging research projects and your own experimental findings with others. This is an excellent way of helping you determine if research truly is a passion for you. For those individuals who can combine the superb breadth of biological understanding that a medical degree provides with the ability to ask well focused, targeted questions that develops in a graduate degree program, there are a great many professional opportunities. Future options range from leading large multicentre research groups, to running your own laboratory, to being a key collaborator with a sophisticated understanding of the benefits (and limitations) of biomedical research. The trainees this year represent medical schools, and research disciplines, from across Canada. About one third of our 65 attendees are in their first year of hands-on research, one third have intermediate experience and another third are engaged in joint MD PhD programs. As the abstracts demonstrate, your work ranges from studies of individual gene polymorphisms or molecules through to population and health systems research. Because so much ground breaking research is highly multidisciplinary, we have designed the program to increase academic and social interactions between trainees such as yourselves with those enrolled in non-clinical graduate training programs. Make the most of the opportunity! I want to personally thank the individuals and organizations that have enabled us to offer you this special opportunity. Money is never is excess supply and they have gone to great effort to support this initiative. Contributors are listed at the back of the Symposium program. We welcome you and hope you enjoy the novel science, the professional development activities and the pleasures of meeting others with similar interests during your three days here.

Kent T. HayGlass PhD Canada Research Chair in Immune Regulation Director, Advanced Degrees in Medicine University of Manitoba

POSTER DISCUSSIONS POSTER DISCUSSION LEADERS Gabrielle Chartier - Université de Montréal Matthew Benesch - University of Alberta Bhavika Patel – University of Ottawa

ORAL PRESENTATIONS Session Chairs: Session 1 – Mathiew Laflamme – Laval Université Stefan Hamilton – Memorial University of Newfoundland Session 2 - Divjot Kumar – University of British Columbia Erin Degelman – University of Calgary

ORGANIZING COMMITTEE Dr. Kent HayGlass – Director, Advanced Degrees in Medicine, CNMSRS Coordinator Kimberley Ormiston – Undergraduate and Graduate Research Programs Coordinator Alexandra Kuzyk – Committee Member and MD/PhD student Cameron Kaye – Committee Member and MD/PhD student Christopher Aiken – Committee Member and MD/PhD student

Canadian National Medical Student Research Symposium University of Manitoba Scientific Program Canadian National Medical Student Research Symposium DAY 1: Tuesday, June 10th, 2014 12:00 – 23:00 14:00 – 16:00 14:00 - 17:30 12:00 – 17:30 18:00 18:30 18:40 19:50 20:00

Students check-in at Canad Inns Destination Centre throughout the day. Early bird Tours; Trolley Tour of Winnipeg or National Microbiology Lab Reserve the tour of your choice HERE. There is no charge for the tours. Registration Desk opens in Brodie Centre. Please note there are two registration desks for two separate events. Please ensure you register for the CNMSRS (not the CSHRF). Trainees should mount their posters prior to 17:30. Poster number/position assigned at registration Opening reception – Mixer and Welcome Banquet Canad Inns Ambassador Ballroom Welcome by Dr. Kent HayGlass, Advanced Degrees in Medicine, CNMSRS Coordinator Dinner Clinical Investigator Trainee Association of Canada (CITAC) information overview. Alexandra Kuzyk MD PhD trainee, CITAC Executive Committee Keynote Speaker Dr. Tobias Kollmann, MD/PhD. University of British Columbia “Why was obtaining MD PhD training the right decision for me?”

DAY 2: Wednesday, June 11th, 2014 *Remember to bring your electronic device for real time evaluation of the oral presentations.

7:30 – 8:45 7:45 – 8:35 8:40 9:00 – 10:30 10:40 – 11:40

Late arrivals registration available on 2nd floor Atrium Apotex Centre Continental Breakfast Atrium Apotex Centre 2nd floor Welcome by Dr. Kent HayGlass Apotex Building ‐ Procurity Lecture Theatre, Main Floor Lightening Oral Presentations – Session 1 of 2 (6 minute oral presentation, 4 minutes for questions) Procurity Lecture Theatre, Main floor Poster Discussion Session 1 of 2(Coffee available 10:30-11:00) Brodie Centre 2nd level (Mezzanine) Trainee groups A1, B1 & C1 presenting. 8

(Presentation timing - 3 minutes presentation, 3 minutes discussion) 11:45 – 12:30 12:30 – 13:30

13:30 – 14:30

14:40 – 15:30

Luncheon Joe Doupe Concourse– Shared with CSHRF participants Keynote Speaker: Dr. Tobias Kollmann – Senior Clinician Scientist, Child and Family Research Institute, Associate Professor, Department of Pediatrics, University of British Columbia “Neonatal Development of Human Immunity: Implications for Health and Disease” Frederic Gaspard Theatre (theatre A) Professional Development ‘Strategies to Obtain—and Keep — a Position as a Clinician Scientist’ Moderator: Dr Kent HayGlass, University of Manitoba. Panel Members: Dr. Tobias Kollmann, Senior Clinician Scientist, Child and Family Research Institute, Associate Professor, Department of Pediatrics, UBC. Dr Cheryl Greenberg, Clinician Scientist and Chair, Department of Pediatrics, Univ. of Manitoba. Manitoba Institute for Child Health. Dr Richard Keijzer, Clinician Scientist, Thorlakson Chair in Surgical Research Assistant Professor, Department of Pediatrics and Child Health. Manitoba Institute for Child Health. Poster Discussion Session 2 of 2 (Brodie Centre 2nd level, main corridor) Trainee groups A2, B2 & C2 presenting. (Presentation timing - 3 minutes presentation, 3 minutes discussion)

*Remember to bring your electronic device for real time evaluation of the oral presentations.

15:40 – 16:50 16:50 17:30 23:00

Lightning Oral Presentations Session 2 of 2 Procurity Lecture Theatre (Apotex Center, Main floor) 6 minute oral, 4 minute questions Welcome by Dr. Don Miller, CSHRF Coordinator, “ International Diabetes Symposium” the following day CSHRF and CNMSRS dinner and mixer at Lower Fort Garry. Busses departs from front of Brodie Centre for social evening. Participants return via bus to Canad Inns Destination Centre. Busses start returning at 22:30, 23:30 and 23:59.

DAY 3: Thursday, June 12th, 2014 8:00 8:30 11:00 12:00

Continental Breakfast (Cinnamon Buns and Coffee) J. Hildes Concourse (2nd floor adjacent to Frederic Gaspard Theatre A) Canadian Student Health Research Forum (CSHRF) Frederic Gaspard Theatre (A) Symposium Theme ‘Diabetes – Nature over Nurture’ Students to check out of Hotel prior to end of conference. Hotel will provide a secure area for luggage. Luncheon Brodie Centre (joint CNMSRS and CSHRF participants) 9

13:00 17:00 18:00

CSHRF ongoing Lectures Reception Joe Doupe Concourse (joint CNMSRS and CSHRF) Students depart for airport. Students keep your taxi receipt for reimbursement by your home institution (if applicable).

Detailed Oral Presentation Schedule Session 1 of 2 0900 – 1030

Session I – Lightning Oral Presentations Each presentation will be 6 minutes for presentation and 4 minutes for questions; 10 minutes in total. Procurity Lecture Theatre Main Floor – Apotex Centre Chairs: Mathieu Laflamme – University of Laval Stefan Hamilton – Memorial University of Newfoundland Student

School

Abstract Title

James Pius

Dalhousie University

Modulation of the Immune Response After Stroke By Manipulation of the Endocannabinoid System Could Improve Outcomes

Kyle Phipps

Dalhousie University

Alternatively Activated Macrophages Improve Fat Graft Survival through Induction of Angiogenesis in a Mouse Model

Gabrielle Chartier

University of Montreal

Cognitive Vulnerability to Depression: A Study on Depressive Adolescents and their Siblings

Camille Vallée-Gravel

McGill University

Can Sildenafil Treat Retinopathy of Prematurity?

Thiviya Selvanathan

McMaster University

Neuroinflammation in Schizophrenia: A PET study with [18F]-FEPPA

Alexandra Ladouceur

University of Montreal

Cerebral Processes Related to Analgesia Induced by Distraction and Heterotopic Noxious Counterstimulation

Yin Hui

University of Western Ontario

Are We Preparing our Trainees to Prescribe for Older Patients?

Robert Vanner

University of Toronto

Sox2-Expressing Cells Drive Hierarchical Growth and Relapse in SHH-Subgroup Medulloblastoma

1040 – 1140

Session I – Poster Discussion Each presentation will be 3 minutes for presentation and 3 minutes for questions; 6 minutes in total. Brodie Centre Mezzanine Poster Discussion Leaders: Bhavika Patel – University of Ottawa Matthew Benesch – University of Alberta Gabrielle Chartier - Université de Montréal Poster # Student Christopher 500 Aiken

School University of Manitoba

501

Oliver Ayling

University of Toronto

502

Jason Bau

503 504

Matthew Benesch Marc Nicolas Bienz

505

Megan Blades

506

David Bulir

507

Andrea Cervi

508

Daljeet Chahal

509 510

511 512

Gabrielle Chartier Zachary Corso Erin Degelman Octavian Dobrescu

University of Calgary University of Alberta Université de Montréal University of Calgary McMaster University University of Ottawa University of British Columbia Université de Montréal University of Manitoba University of Calgary McGill University Université de Montréal Memorial University of Newfoundland University of Calgary McMaster University University of British Columbia University of Toronto Memorial University of Newfoundland

513

Ariane Drouin

514

Matt Eagles

515

Amanda Eslinger

516

Jamie Fleet

517

Carlen (Kay) Fung

518

Hart Goldhar

519

Stefan Hamilton

520

Aurélie Houle

521

Tina Hu

522

Yin Hui

523

Patrick Jung

524

Cara Katz

University of Manitoba

525

Divjot Kumar

526

Alexandra Ladouceur

University of British Columbia

Université de Montréal University of Toronto University of Western Ontario University of Manitoba

Université de Montréal

Project Title Uncoupling the in vivo tumorigenic properties of tumor propagating cells from their in vitro properties Perioperative Complications Explain Differences in Outcomes Between Clipping and Coiling Following Aneurysmal Subarachnoid Hemorrhage Structural Determinants for the Catalytic Inhibition of Human Topoisomerase IIα by Salicylate-related Compounds Inhibition of Autotaxin from Mammary Adipose Tissue Delays Breast Tumor Growth and Metastasis in Mice Expression of Prognostic Marker IL-6 in Prostate Cancer Tissue and Blood Plasma Developing Three-colour Fluorescence Cross-correlation Spectroscopy Targeting a Chaperone-translocator Interaction with a Peptide Mimetic Inhibits Chlamydia Pneumoniae Infection The Role of Innate Immunity in the Oncolytic Properties of Vesicular Stomatitis Virus (VSV) Recurrence Analysis of Brain Metastases After Surgical Resection With or Without Adjuvant Whole Brain Radiation

~Time

Group

N/A

10:40 START

~ 10:46

N/A

~10:52

~10:58

~11:04

~11:10

~11:16

Cognitive Vulnerability to Depression: A Study on Depressive Adolescents and their Siblings Managing Uncertainty in Clinical Decision-making: A Qualitative Evaluation

N/A

~11:22

Influence of Telomere Dynamics on Disease Progression and Therapeutic Response in Bone Marrow Failure Syndromes

10:40 START

Neonatal Hypoxic-Ischemic Encephalopathy and the Cerebellum

~ 10:46

Coronary Artery Bypass Grafting Strategies for the Anterolateral Territory: A Prospective Randomized Clinical Trial

~10:52

Examining Angiogenesis in Neurodegenerative Disease

~10:58

Treating donor site pain in burn victims that have undergone autologous split-thickness skin grafting: A review of the literature Population Based Outcomes of initiating oral atenolol in patients with and without chronic kidney disease

N/A

~11:04

Non-pharmacological Management of Orthostatic Hypotension: A Systematic Review

~11:10

Long-term Risk of Heart Failure Associated with Adjuvant Trastuzumab in Breast Cancer Patients

~11:16

Real-life Drug Survival of Tumour Necrosis Factor-α Inhibitors in Inflammatory Arthritis

~11:22

10:40 START

~ 10:46

N/A

~10:52

~10:58

~11:04

N/A

Optimizing the Doctor-patient Encounter Concerning Asthma in Children Lower Dose of a Highly Beta-1 Selective Antagonist Preserves Cerebral Perfusion in Hemodiluted Rats Are We Preparing our Trainees to Prescribe for Older Patients? The Impact of Frailty on Post-operative Delirium in Cardiac Surgery Patients Risk factors for Incident Nonmedical Prescription Opioid Use and Abuse/Dependence: Results from a Longitudinal Nationally Representative Sample Reliability of Clinical Tonsil Size Grading in Children Cerebral Processes Related to Analgesia Induced by Distraction and Heterotopic Noxious Counter-stimulation

527

Mathieu Laflamme

Université Laval

528

Lawrence Lau

University of Manitoba

529

Andre Le

Memorial University of Newfoundland

Red Blood Cell Transfusion in Acute Cerebral Injuries: A Systematic Review of Preclinical Studies The Utility of Pocket-Sized Echocardiography to Assess Left Ventricular Systolic Function Prior to Permanent Pacemaker Implantation Thyroid Fine Needle Aspiration Biopsy: an Evaluation of its Utility in a Community Setting

~11:10

~11:16

~11:22

1440 - 1530

Session 2 of 2 – Poster Discussion Each presentation will be 3 minutes for presentation and 3 minutes for questions; 6 minutes in total. Brodie Centre Mezzanine Poster Discussion Leaders: Bhavika Patel – University of Ottawa Matthew Bensch – University of Alberta Gabrielle Chartier - Université de Montréal 531

Aldrich Leung

532

Ran (Richard) Liu

533 534

Branavan Manoranjan Kathryn Menzies

535

Nima Moghaddam

536

Jennifer Ortynski

537

Richa Parihar

538

Bhavika Patel

539

Michael Peplowski

540

Amit Persad

541

Kyle Phipps

542

James Pius

543

Tara Riddell

544 545 546 547 548 549 550

Thiviya Selvanathan Patrick Steadman Charlie Tan Christina Thornton Ethan Toumishey Camille Vallée-Gravel Luke Vanderhooft

551

Robert Vanner

552

Zhanni Weber

553

James Yan

14:40 START

N/A

Activated Wnt Signaling targets Sox2+ Treatment-refractory Medulloblastoma Stem Cells

~14:46

Cystic Fibrosis in Canadian Hutterites

~14:52

A Qualitative Overview of the Surgical Safety Checklist Compliance and its Pitfalls in Providence Healthcare

~14:58

14:40 START

~14:46

~14:52

~14:58

~15:04

N/A

~15:10

N/A

Autism-associated genes alter the morphology of the mouse cerebellum

14:40 START

Following Celebrities’ Medical Advice: A Meta-narrative Analysis

~ 14:46

N/A

~14:52

N/A

~14:58

~15:04

University of Alberta University of British Columbia McMaster University University of Manitoba University of British Columbia

Intestinal and Gastric Permeability in Children with Eosinophilic Esophagitis and Reflux Esophagitis

University of Alberta Memorial University of Newfoundland University of Ottawa

FIFE S.T.A.R.S (Students Taking Academic Review Sessions): The Development of a Novel Peer-to-Peer Learning Platform Diabetes Complications and Comorbidities in Patients Newly Diagnosed with Diabetes in Newfoundland and Labrador (NL): Gender Differences

University of Calgary University of Alberta Dalhousie University Dalhousie University Dalhousie University McMaster University University of Toronto McMaster University University of Calgary Dalhousie University McGill University University of Manitoba University of Toronto University of Manitoba University of Western Ontario

Voice Discrimination and Recognition in Acquired Prosopagnosia

Examining Psychosocial Distress in Pediatric Cardiology Patients Tumour Necrosis Factor (TNF) Alpha and Interferon (IFN) Gamma Induce Transcriptional Downregulation of Aquaporin 3 RNA Expression through Distinct Mechanisms AP-2delta Regulates Polysialylation of NCAM Via Transcriptional Regulation of ST8SIA Alternatively Activated Macrophages Improve Fat Graft Survival through Induction of Angiogenesis in a Mouse Model Modulation of the Immune Response After Stroke By Manipulation of the Endocannabinoid System Could Improve Outcomes Predictors of influenza Vaccine Failure and the Impact of Influenza immunization Among Hospitalized Canadian Adults Neuroinflammation in Schizophrenia: A PET study with [18F]-FEPPA

Harmless Commensal Microbial Neighbors Synergistically Trigger Pseudomonas aeruginosa Virulence Genes in Cystic Fibrosis Evaluation of a novel molecular therapeutic target in non-small cell lung cancer Can Sildenafil Treat Retinopathy of Prematurity? Variables Affecting Whole-blood Cobalt Levels in Patients Implanted with the DePuy ULTAMET® Metal-on-Metal Articulation Sox2-Expressing Cells Drive Hierarchical Growth and Relapse in SHH-Subgroup Medulloblastoma Analyzing and Optimizing the Treatment of Patients with Staphylococcus aureus Bloodstream Infections Digital Atlas of Ultrasound-Guided Trunk and Lower Limb Nerve Blocks

554

Vanessa Zannella

555

Kevin Zuo

556

Austin Zygmunt

University of Toronto University of Alberta Dalhousie University

Reprogramming Metabolism with Metformin Improves Tumor Oxygenation and Radiotherapy Response A Novel Electrophysiological Method for Quantifying the Severity and Extent of Length-Dependent Polyneuropathy Inter-provincial Variation and Determinants of Access to Team-based Primary Care in Canada

N/A

~15:10

N/A

1540 – 1650

Session 2 of 2 – Lightning Oral Presentations Each presentation will be 6 minute for presentation and 4 minutes for questions. Procurity Lecture Theatre Main Floor – Apotex Centre Chairs: Divjot Kumar – University of British Columbia Erin Degelman – University of Calgary Vanessa Zanella

University of Toronto

Reprogramming Metabolism with Metformin Improves Tumor Oxygenation and Radiotherapy Response

Christopher Aiken

University of Manitoba

Uncoupling the in vivo tumorigenic properties of tumor propagating cells from their in vitro properties

Amanda Eslinger

University of Calgary

Treating donor site pain in burn victims that have undergone autologous split-thickness skin grafting: A review of the literature

Christina Thornton

University of Calgary

Harmless Commensal Microbial Neighbors Synergistically Trigger Pseudomonas aeruginosa Virulence Genes in Cystic Fibrosis

Matthew Benesch

University of Alberta

Inhibition of Autotaxin from Mammary Adipose Tissue Delays Breast Tumor Growth and Metastasis in Mice

Ran (Richard) Liu

University of British Columbia

Voice Discrimination and Recognition in Acquired Prosopagnosia

Austin Zygmunt

Dalhousie University

Inter-provincial Variation and Determinants of Access to Team-based Primary Care in Canada

Lightning Oral Abstracts SESSION 1 of 2 Procurity Lecture Theatre, Apotex Building Main Floor, Room 164 9:00 â&#x20AC;&#x201C; 10:30 a.m. Wednesday, June 11th, 2014

Modulation of the Immune Response After Stroke By Manipulation of the Endocannabinoid System Could Improve Outcomes. James Pius1, Ian Burkovskiy3, Lizeth Orozco, Juan Zhou2,4, Melanie Kelly3, Christian Lehmann2,3,4 Faculty of Medicine1, Department of Anesthesia2, Pharmacology3, Microbiology & Immunology4, Dalhousie University, Halifax, Nova Scotia. Rationale: Stroke is the third-leading cause of death in Canada. The prognosis of patients after stroke is influenced by medical complications suffered during stroke. The immune system is involved in the brain damage produced by stroke and the damaged brain, in turn, promotes immune suppression. Alterations in the bodyâ&#x20AC;&#x2122;s endocannabinoid system (ECS) are one of the pathways involved in the above process. Activation of ECS has been reported to decrease neuroinflammation, preventing cell death. However, its simultaneous action in peripheral tissue contributes to CNS injury-induced immunodepression syndrome (CIDS), leading to fatal infections. There are two potential therapeutic approaches to CIDS; one involves reduction of neuroinflammation and the other involves immune activation. Reduction of neuroinflammation can be achieved by activating the ECS with agonists early in the pathology of stroke, thus mitigating CIDS. Immune activation can be achieved with ECS antagonists administered later on in the pathology of stroke once CIDS has been established. Objectives: Establish a mouse model of stroke that can be used to test the above two potential therapies for CIDS. Characterize a novel activator of the ECS which selects for the cannabinoid receptor CB2R. Methods: Immunosuppression by CNS injury was induced via occlusion of the left common carotid artery followed by controlled hypoxia. Following immunosuppression, endotoxemia was induced with lipopolysaccharide (LPS) injected intraperitoneally. The extent of immune activation was assessed with intravital microscopy (IVM). This quantifies the extent of leukocyte activation (adhesion) by imaging the microcirculation of the small intestine. Results: In the absence of CNS injury and following LPS challenge, there was a significant increase in the number of adhering leukocytes in the intestinal microvasculature. However, following induced CNS injury, immunodepression was observed as decreased leukocyte adhesion in the microcirculation and was proportional to the severity of the CNS injury. A similar effect is also seen in mice without CNS injury and treated with the novel CB2R agonists after endotoxemia. Conclusions: The novel CB2R agonist has strong anti-inflammatory effects on the immune system. A mouse model of CIDS was successfully established and could be used to test potential therapeutic approaches in the future.

Funding: Faculty of Medicine Gladys Osman Summer Studentship JamesPius@Dal.Ca 16

Alternatively Activated Macrophages Improve Fat Graft Survival through Induction of Angiogenesis in a Mouse Model Kyle D. Phipps, PhDa, Simon Gebremeskel, BScb, Joshua Gillis, MDc, Paul Hong, MD, FRCSCd, Brent Johnson, PhDb,e, Michael Bezuhly, MD, FRCSCb,c a

Faculty of Medicine, Dalhousie University, Halifax, Canada Department of Immunology and Microbiology, Dalhousie University, Halifax, Canada c Division of Plastic and Reconstructive Surgery, Dalhousie University, Halifax, Canada d Division of Otolaryngology, Dalhousie University, Halifax, Canada e Department of Pathology, Dalhousie University, Halifax, Canada b

Rationale: Autologous fat grafting is a common technique used to correct soft tissue defects. The technique has a variety of applications including the treatment of congenital craniofacial anomalies, hemifacial atrophy and breast reconstruction. A major drawback of the technique is unpredictable graft volume retention, resulting in under-correction necessitating repeated procedures. The authors’ evaluated whether graft retention in a mouse model could be improved via graft supplementation with alternatively activated M2 macrophages, a cell type known to play a critical role in tissue repair. Objective: Develop a clinically feasible technique to improve autologous fat graft volume retention. Methods: Fat grafts of C57BL/6 mouse inguinal fat pads were supplemented with M2 macrophages, generated by in vitro culture of macrophages harvested by intraperitoneal injection of Brewer’s thioglycollate. Grafts supplemented with saline or M2 macrophages were injected under recipient mouse scalps and assessed by serial volumetric microCT analysis. Explanted grafts underwent immunohistochemical and flow cytometric analyses for vascular density and retained macrophage numbers, respectively. M2 culture supernatants were added to stromal vascular fractions (SVF) containing adipose-derived stem cells (ASC) to assess their ability to induce adipogenic gene expression. Results: One month following graft injection, no significant difference was noted between M2supplemented (105±7.0 mm3) and control graft volumes (72±22 mm3). By three months postinjection, M2-supplemented grafts remained stable while controls experienced further volume loss (103±8 mm3 vs. 39.4±15 mm3, p=0.015). Overall, control and M2 macrophage-supplemented grafts retained on average 26.8% and 70%, respectively, of their baseline volumes. Presence of M2 macrophages in the supplemented grafts was confirmed by flow cytometry. M2-supplemented grafts demonstrated a 157% increase in vascular density compared to controls (p<0.05). Induction of adipogenic C/EBPα gene expression was observed when M2 supernatants were added to SVF containing ASC. Conclusion: M2 macrophages improve autologous fat graft volume retention by stimulating angiogenesis. These findings provide proof-of-principle for the development of fat grafting techniques that harness reparative properties of M2 macrophages.

Funding: IWK Health Centre Establishment Grant, Capital District Health Authority Research Fund and the Dalhousie Medical Research Foundation W. Alan Curry Studentship. kphipps@dal.ca 17

Cognitive Vulnerability to Depression: A Study on Depressive Adolescents and their Siblings. Gabrielle Chartiera,b, Catherine Herbab,c, Patricia Garela,b and Linda Booija,b,d Faculté de médecine, Université de Montréal, bMaladies du cerveau, CHU Ste-Justine, Département de psychologie, Université du Québec à Montréal, dDepartment of Psychiatry, McGill University. a c

Rationale: Major depression affects more than 15% of the Canadian population. At least half of first depressive episode appear before adulthood. A negative cognitive bias is present among individuals who suffer from major depression. This bias is also reported among individuals at high risk of major depression (e.g. child of depressed mother). No study to date aimed to evaluate cognitive vulnerability of siblings of depressed individuals. Objectives: the present study aim to verify if siblings of depressed adolescents present a cognitive vulnerability that would predispose them to develop a major depression. Methods: We recruited 49 adolescents (18 adolescents treated for depression, 16 siblings and 15 controls), aged between 12 and 20 years old. The cognitive vulnerability of every participant has been assessed using an auto-report questionnaire of symptoms (LEIDS-R) that evaluates cognitive reactivity and a task of facial recognition. Social cognition of participants is measured using the Movie for Assessment of Social Cognition (MASC) that we translated from german to french. Results: Preliminary analyses tend to show that the group of depressed adolescents request more time to recognize facial emotions like happiness compared to the two other groups (p=0,055). The siblings present the same tendency compared to controls (p=0,090). Depressed adolescents present more hypermentalisation in their interpretation of social interactions (p=0,046), a tendency that is also present in siblings compared to controls (p=0,090). Conclusions: Some results of our preliminary analyses tend to confirm the presence of a cognitive vulnerability to depression among siblings of depressed adolescents. Those results need to be confirmed by bigger samples and longitudinal studies.

Funding : Fondation du CHU Ste-Justine. Gabriell.bchartier@gmail.com 18

Can Sildenafil Treat Retinopathy of Prematurity? Camille Vallée-Gravelab, Suna Jungab, Xiaojuan Yangb, Zehra Khojaa, Anna Polosab, Pierre Lachapelleb, and Pia Wintermarka Division of Newborn Medicine, Department of Pediatrics, Montreal Children's Hospital, McGill University, Montreal, Canadaa and Ophtalmology Department, Montreal Children's Hospital, McGill University, Montreal, Canadab Rationale: Sildenafil is a potent vasodilatator that is used in newborns for persistent pulmonary hypertension. In adults, sildenafil was found to be pro-angiogenic. In newborns, the effect of sildenafil on eyes has never been tested. This is of concern especially in premature newborns, as they are at risk to develop retinopathy of prematurity (ROP) secondary to supplemental oxygen therapy, a serious ocular disorder associated with excessive neovascularization. The goal of the research was to determine whether sildenafil was beneficial or harmful on the retina of premature newborns suffering from ROP. Methods: The oxygen induced retinopathy (OIR) model in rat pups was used. Rat pups were exposed to hyperoxia (i.e., 80% oxygen) from postnatal day (P) 4 to P14 for 22.5 hours daily, interrupted by three 30-minute intervals of normoxia (i.e., 21% O2). Half of the exposed animals (n=8) were treated with sildenafil 50 mg/kg twice a day from P5 (i.e., 24 hours after the beginning of hyperoxia) to P17 ("sildenafil group"); the other half (n=8) were given the vehicle solution from P5 to P17 ("vehicle group"). Control age-matched animals (n=16) were raised simultaneously in normoxic conditions (21% O2) (“control group”). Electroretinograms (ERGs) were recorded at P29. Animals were euthanized at P30, and their eyes were extracted at that time. Retinas were analyzed by histology. Results: Hyperoxic animals gained weight more slowly than control animals; the rat pups from the sildenafil group gained weight even more slowly than the ones from the vehicle group. Some exposed rats in the sildenafil group had repetitive rhythmic movement suggestive of seizures during the normoxic breaks. ERGs recording of the hyperoxic animals demonstrated a somewhat preserved a-wave amplitude, but a significant reduction in the scotopic and photopic b-wave amplitudes, suggesting that the function of the photoreceptors (where the a-wave is generated) was relatively preserved, whereas that of inner retinal neurons (where the b-wave is generated) was severely impaired. The impairment of the b-wave (inner retina) was worst in the sildenafil group compared to the vehicle group. Conclusion: The use of sildenafil may be more harmful than beneficial at the level of the retina in premature newborns; this is of concern as sildenafil is already in use in these newborns. Further experimentations, including detailed retinal histology, are needed to confirm these preliminary results.

Funding: CIHR camille.vallee-gravel@mail.mcgill.ca 19

Neuroinflammation in Schizophrenia: A PET study with [18F]-FEPPA Thiviya Selvanathana,b, Miran Kenkb,c, Naren Raob,c, Ivonne Suridjanb,c, Pablo M Rusjanb,c, Jeffrey Meyerb,c, Alan A Wilsonb,c, Sylvain Houleb,c, Romina Mizrahib,c a Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON b PET Group, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON c University of Toronto, Department of Psychiatry, Toronto, ON Rationale: Neuroinflammation has been implicated in schizophrenia (SCZ). Microglial activation, a key component of brain inflammatory processes, is associated with increased expression of mitochondrial translocator protein 18 kDa (TSPO), which has been a target for in vivo imaging using positron emission tomography (PET). Early imaging studies in SCZ used the radioligand [11C]-PK11195 with various properties that hinder its quantification and interpretation, which led to the development of second-generation TSPO radioligands. In second generation TSPO radioligands tissue uptake is dependent on rs6971 polymorphism in the TSPO gene. The present study is the first to use the novel PET radioligand [18F]-FEPPA and high-resolution HRRT tomograph to determine whether there is increased neuroinflammation in patients with SCZ, while taking into account the rs6971 polymorphism. Methods: Fourteen patients with SCZ and 26 healthy volunteers (HV) underwent [18F]-FEPPA PET imaging and MRI. We obtained [18F]-FEPPA total volumes of distribution (VT) for multiple regions of interest (ROI). Severity of psychopathology was assessed and rs6971 polymorphism was genotyped to classify participants as high or mixed affinity binders (HAB and MAB, respectively). Low affinity binders were excluded from the analysis due their instability in fitting. Results: Statistically significant differences in [18F]-FEPPA VTs were observed between the genetic groups (HAB vs MAB; F=20.366 p<0.001) but not between the SCZ and HV (F=1.276 p=0.266). Correcting for genotype, significant correlations were observed between the Positive and Negative Symptom Scale (PANSS) general psychopathology score and the VT in the medial prefrontal cortex (r=0.853 p=0.002). Length of illness correlated inversely with VTs in hippocampus (r=-0.621 p=0.031) and dorsolateral prefrontal cortex(r=-0.621 p=0.024). No other significant correlations were observed. Conclusions: No significant difference in neuroinflammation, as measured by [18F]-FEPPA binding to TSPO, was observed between SCZ and HV. Correlations between [18F]-FEPPA TSPO binding and length of illness and the PANSS general psychopathology score suggest that further studies exploring the relationship between regional neuroinflammation and symptoms of SCZ are warranted.

Funding: Brain and Behaviour Foundation (formerly known as NARSAD) thiviya.selvanathan@medportal.ca 20

Cerebral Processes Related to Analgesia Induced by Distraction and Heterotopic Noxious Counter-stimulation. Alexandra Ladouceura, Pierre Rainvillec and Mathieu Pichéb a

Département de psychologie, Université du Québec à Trois-Rivières; b Département de chiropratique, Université du Québec à Trois-Rivières, Trois-Rivières, Qc, Canada G9A 5H7; c Département de stomatologie, Faculté de Médecine dentaire, Université de Montréal, Montréal, Qc, Canada H3T 1J4 Rationale: Heterotopic noxious counter-stimulation (HNCS) by the application of a sustained noxious stimulus has been shown to inhibit nociceptive processes and decrease pain perception induced by a competing noxious stimulus. However, it is still not clear how attentional processes may contribute to these effects. Objectives: Examine brain processes associated with analgesia induced by distraction and HNCS. Methods: Sixteen healthy volunteers participated in this fMRI study, approved by the ethics board of “Centre de Recherche de l’Institut Universitaire de Gériatrie de Montréal”. Acute pain was evoked by transcutaneous electrical stimulations of the right sural nerve. A total of 48 stimuli were distributed in 4 conditions: baseline, heterotopic innocuous counter-stimulation (HICS), HNCS and recovery. Counter-stimulation was applied on the left upper limb using a thermode (HICS) or an ice pack (HNCS). Attention was manipulated between two counterbalanced sessions by instructing participants to focus their attention on shock pain or on counter-stimulation. Results: Shock-pain was decreased during HICS compared to baseline, and this effect was significantly greater during the attention to counter-stimulation session compared to the attention to shock-pain session (p<0.001). This indicates that distraction produced robust analgesic effects. As for counter-stimulation, shock-pain was significantly decreased during HNCS compared to HICS, even when attention was focussed on shock-pain (p<0.01). Moreover, shock-evoked activity in the primary somatosensory cortex (SI) was specifically decreased by distraction whereas shock-evoked activity in the precentral gyrus (PrCG) was specifically decreased by HNCS. Conclusions: These results indicate that analgesia induced by distraction and HNCS involves partly distinct cerebral mechanisms.

Funding: This project was funded by the Natural Science and engineering council (NSERC), the chair in pain neurophysiology (Université du Québec à Trois-Rivières (UQTR) and the Canadian Institutes of Health Research (CIHR). Alexandra Ladouceur was supported by the « Fondation de recherche en chiropratique du Québec », the « Groupe de Recherche sur les Affections Neuromusculosquelettiques from UQTR» and the CIHR. Alexandra.ladouceur @umontreal.ca 21

Are We Preparing our Trainees to Prescribe for Older Patients? Yin Hui, BScPhm RPh, MD Candidate1,2 Lorelei Lingard, PhD1,2 Laura Diachun, MEd MD FRCP(C)1,2,3,4 1

Department of Medicine, Schulich School of Medicine and Dentistry, Western University; 2Centre for Education Research & Innovation, Schulich School of Medicine and Dentistry, Western University; 3Division of Geriatric Medicine, Parkwood Hospital, St. Joseph’s Health Care (SJHC); 4 Division of Geriatric Medicine & Geriatric Psychiatry, Western University Rationale: Medication-related adverse events are a significant cause of morbidity and mortality in the geriatric population. Given the aging population, educating medical trainees about appropriate prescribing of medications for geriatric patients is becoming increasingly important. This study explored the teaching discussions that occur with respect to prescribing and the use of potentially inappropriate medications (PIMs) on the internal medicine clinical teaching unit (CTU). Methods: Using case study methodology, morning case review simulation involved the presentation of 1-3 scripted admission histories to each of 25 CTU attendings (13 geriatricians and 12 internists) who were instructed to respond authentically. All cases contained opportunities to discuss PIMs and geriatric prescribing. Semi-structured interviews explored attending’s perceptions of their teaching decisions. Inductive analysis of 68 case review discussions was conducted. Results: Geriatrician and internist attendings varied in terms of their degree of uptake of the geriatric prescribing teaching and learning opportunities built into the cases. Emergent themes included the type of PIMs, nature of the medication teaching emphasis (e.g., sliding scale or anticoagulation), and age-based contextualization. Conclusions: Teaching about geriatric prescribing and PIMs can play a crucial role for the care of geriatric patients. Further research in other settings (e.g. outpatient) and with other attending groups is needed to fully explore where and how this teaching could optimally occur.

Funding: AMOSO, St. Joseph’s Health Care Foundation, Program of Experimental Medicine, SRTP yhui2015@meds.uwo.ca 22

Sox2-Expressing Cells Drive Hierarchical Growth and Relapse in SHH-Subgroup Medulloblastoma Vanner, Robert1; Remke, Marc1, Gallo, Marco1; Lee, Lilian1; Head, Renee1; Kushida, Michelle1; Hochedlinger, Konrad2; Korshunov, Andrey3; Pfister, Stephan3; Taylor, Michael D1; Dirks, Peter B1 1 Brain Tumour Research Centre, Developmental and Stem Cell Biology, Toronto Hospital for Sick Children 2 Massachusetts General Hospital, Boston, USA 3 Division of Pediatric Neurooncology, DKFZ, Heidelberg, Germany Introduction: Intratumoural heterogeneity creates a significant therapeutic challenge. In medulloblastoma, the most common malignant pediatric brain tumour, how the tumourâ&#x20AC;&#x2122;s phenotypically diverse cell types contribute to growth and relapse are unknown. Methods: Patched1 heterozygous mice were used as a preclinical model for the 30% of medulloblastomas exhibiting dysregulated Sonic hedgehog (SHH) signaling. Gene expression profiling was performed on 82 human medulloblastomas and a non-overlapping cohort of 305 medulloblastoma samples was analyzed by immunohistochemistry. Results: Ptc medulloblastomas were found to contain rare cells expressing the neural stem cell marker Sox2 (<5%), common progenitor-like doublecortin (DCX)-expressing cells (60%) and frequent neuron-like cells positive for NeuN (30%). Thymidine analogue pulse-chase experiments showed that Sox2+ cells are quiescent and slowly cycling compared to rapidly cycling DCX+ cells. DCX+ cells that exited the cell cycle began to express NeuN. Sox2+ cells isolated from Ptc;Sox2eGFP tumours showed significantly greater self-renewal in both in vitro and in vivo limiting dilution analyses. Fate mapping in Ptc; Sox2creER mouse tumours confirmed that Sox2+ cells drive tumour growth in situ. Critically, lineage traces contained labelled DCX+ and NeuN+ cells, demonstrating that Sox2+ cells drive growth by self-renewing and differentiating to generate tumour bulk. Anti-mitotic and SHH-targeted therapy ablated dividing cells but enriched for Sox2+ cells which provide a reservoir for relapse. Indeed, lineage traces from treated mice were significantly greater versus control. Sox2+ Ptc cells expressed a distinct gene expression profile that was correlated with worse outcome in human SHH-medulloblastoma patients. Similarly, patients whose tumours contained higher frequencies of Sox2+ cells suffered greater mortality. A drug screen of 5 primary medulloblastoma cultures revealed nanomolar sensitivity to the transcriptional inhibitor Mithramycin. In vivo treatment of Ptc allografts with Mithramycin delayed tumour growth. Discussion: We have discovered a new paradigm of hierarchical tumour expansion and recurrence driven by quiescent, therapy resistant Sox2+ cells. Sox2+ cells divide slowly to produce the fast-dividing DCX+ cells that eventually differentiate to become NeuN+. While conventional therapies spare Sox2+ cells that drive tumour relapse, Mithramyicn attenuates their self-renewal, slowing tumour growth. We predict that targeting the Sox2+ population is necessary to achieve medulloblastoma cure.

rob.vanner@mail.utoronto.ca

Poster Discussion Abstracts Session 1 of 2 Groups A1, B1, C1 presenting

Brodie Centre Mezzanine 10:40 â&#x20AC;&#x201C; 11:40 a.m. Wednesday, June 11th, 2014

Uncoupling the in vivo tumorigenic properties of tumor propagating cells from their in vitro properties acf

Christopher Aiken, bcfLudivine Morrison, cfMelissa Bridges, defMarc Del Bigio, abcefTamra Werbowetski-Ogilvie a

Department of Physiology, bDepartment of Biochemistry and Medical Genetics, cRegenerative Medicine Program, dDepartment of Pathology, eManitoba Institute of Child Health, fUniversity of Manitoba, Winnipeg, MB

Introduction In the field of cancer stem cell research, there is a generally accepted principle that cells demonstrating a higher self-renewal capacity in vitro exhibit larger and faster tumor growth, increased tumor penetrance and decreased survival in vivo. However, a handful of papers have revealed an inverse correlation between these characteristics in genetic mouse models of the adult brain cancer glioblastoma (GBM). Despite these findings, this relationship has not been directly evaluated using xenograft models of human brain tumors. We have set out to investigate this relationship using multiple human brain tumor cell lines. Methods We have isolated two sub-clones from a medulloblastoma cell line, a childhood form of brain cancer, which demonstrate higher and lower self-renewal in vitro. We have evaluated the tumor initiating capacity, self-renewal, survival and tumor aggressiveness in vivo using an intracerebral xenograft model in non-obese diabetic severe combined immunodeficient (NOD SCID) mice. Results Our results demonstrate that cells with a lower self-renewal capacity in vitro, when injected into the frontal cortex of NOD SCID mice, result in a shorter survival and increased tumor grade, when compared to cells displaying a higher self-renewal capacity. MRI imaging and histological analysis has revealed these two cellular populations form very distinct tumor phenotypes with distinguishing clinical presentations. To strengthen these findings, we are working to recapitulate them in additional brain tumor cell lines both in vitro and in vivo as an added proof of principle. Conclusion We have established that cells exhibiting increased self-renewal in vitro do not always translate to an increased tumorigenic potential and decreased survival in vivo. This translation of in vitro findings to in vivo is a vital step in the process of drug discovery and the design of new targetedtreatment strategies. One must therefore keep in mind that the properties of a targeted population in vitro can change when going from the controlled environment of a dish to the complex milieu of the mouse.

umaiken@cc.umanitoba.ca 25

Perioperative Complications Explain Differences in Outcomes Between Clipping and Coiling Following Aneurysmal Subarachnoid Hemorrhage Oliver G.S. Ayling, George M. Ibrahim, MD, R. Loch Macdonald, MD, PhD Objective: Aneurysmal subarachnoid hemorrhage (aSAH) after rupture of an intracranial aneurysm is associated with significant morbidity and mortality, with better outcomes reported following endovascular coiling compared to microsurgical clipping of the aneurysm. However, there is much debate clinically and in the literature as to which method is best for patients. Previous studies have examined the long-term outcome differences between endovascular coiling and microsurgical clipping but the contribution of perioperative complications to outcome is unknown. Here, we sought to evaluate the contribution of perioperative complications associated with both aneurysm-securing procedures to patient outcomes. Methods: An analysis of perioperative complications from the double-blind, randomized control trial, CONCIOUS-1 trial was performed. Neurological scores for patients who underwent microsurgical clipping and endovascular coiling were analyzed pre-operatively and each day following the procedure. Complications associated with post-operative decline in neurological status were identified for both cohorts. Using a multivariate logistic regression, we evaluated whether peri-operative neurological decline was associated with long-term outcomes on the Extended Glasgow Outcome Scale. Results: Patients who underwent clipping had a significantly greater decline in their neurological scores post-operatively than patients who underwent coiling (p=0.0024). Multivariate analysis revealed that intra-operative hypertension (p=0.0044) and intra-operative induction of hypotension (p=0.011) were associated with a decline in neurological status for patients undergoing clipping. Peri-operative thromboembolism was associated with post-operative decline in neurological status for patients undergoing coiling (p=0.03). On multivariate logistic regression, post-operative neurological deterioration was strongly associated with a poor GOSE score at 3 months (OR 0.86, 95% CI 0.78-0.95, p=0.0032). Conclusion: Microsurgical clipping following aSAH is associated with a worse perioperative neurological decline than endovascular coiling, which may explain poorer long-term outcomes in this cohort. This study highlights the importance of peri-operative factors when comparing outcomes between clipping and coiling and underlines the need to mitigate the morbidity of surgical strategies following aSAH.

Clinical Trial Registration Information: URL: www.clinicaltrials.gov Identifier: NCT00111085 oliver.ayling@mail.utoronto.ca

Structural Determinants for the Catalytic Inhibition of Human Topoisomerase IIα by Salicylate-related Compounds Jason T Baua, Ebba U Kurza a

Southern Alberta Cancer Research Institute and Dept. of Physiology and Pharmacology, University of Calgary, Calgary, Canada Rationale: Topoisomerase II (topo II) is a ubiquitous enzyme essential for cell survival through its role in regulating DNA topology. Topo II is also the intracellular target of several common chemotherapeutics (topo II poisons); treatment with these agents results in the accumulation of cytotoxic enzyme-linked DNA double-stranded breaks. In contrast, non-break inducing topo II catalytic inhibitors have also been described and evaluated for the use in clinical settings. We previously identified salicylate, the primary metabolite of aspirin, as a novel catalytic inhibitor of topo II. In this work, we demonstrated that co-administration of salicylate attenuates the cytotoxic effects of topo II poisons. As many compounds bear structural similarities to salicylate, including clinically used salicylate-based non-steroidal anti-inflammatory drugs (NSAIDs), we sought to examine whether topo II inhibition could be extended to a larger class of compounds, including those in clinical use. Objective: As catalytic inhibitors may negatively impact the efficacy of chemotherapy regimens incorporating topo II poisons, we sought to determine if other salicylate-based compounds can function as topo II inhibitors Methods: Using multiple biochemical approaches (both in cyto and in vitro), we selectively screened structural analogs of salicylate and salicylate- and non-salicylate-based NSAIDs to examine their capacity to inhibit topo II. Results: Many of the compounds tested attenuated doxorubicin-induced DNA double-strand break signaling, and behaved as topo II catalytic inhibitors in vitro. Substitutions at the 2’ and 5’ positions of the benzene ring of salicylate elicited the greatest effects, increasing the potency of topo II inhibition. Examination of a number of salicylate- and non-salicylate-based NSAIDs revealed that several clinically used salicylate-based therapeutics, including sulfasalazine and diflunisal, are inhibitors of topo II at clinically relevant concentrations, while non-salicylate-based NSAIDs had no such effect. Conclusions: Our findings indicate that derivatives of salicylate can inhibit topo II with varying efficacy and attenuate doxorubicin-induced DNA break signaling. The potency of these compounds is determined by the placement of substituents at discrete positions around the benzene ring. Current in vivo studies are underway investigating whether salicylate coadministration can negatively impact chemotherapeutic regimens incorporating topo II poisons.

Funding: Canadian Breast Cancer Foundation – Prairies jtbau@ucalgary.ca 27

Inhibition of Autotaxin from Mammary Adipose Tissue Delays Breast Tumor Growth and Metastasis in Mice Matthew G.K. Benesch, Xiaoyun Tang, Jay Dewald, Ganesh Venkatraman, Todd P.W. McMullen, and David N. Brindley Department of Biochemistry, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada Introduction: Breast cancer is the most common malignancy among women and one-third of patients die once their cancers become resistant to therapy. We propose that the lipid growth factor lysophosphatidate (LPA) contributes to this. LPA is produced by the secreted enzyme autotaxin (ATX) from lysophosphatidylcholine (LPC). ATX is important physiologically in tissue remodeling and wound repair processes but is overproduced in many cancers, promoting cancer progression and treatment resistance. Some cancers like melanoma secrete ATX. However adipose tissue both subcutaneous and mammary also secretes ATX but its influence on breast cancer is unknown. No therapies currently target LPA signaling. Methods: Female BALB/c mice were injected in breast adipose tissue with 20,000 4T1 BALB/c breast cancer cells and tumor growth was monitored with caliper measurements. Upon sacrifice tumors were weighed. ATX mRNA was quantified by RT-PCR and activity by choline release from LPC. We also evaluated the efficacy of ONO-8430506, a novel oral ATX inhibitor (Ono Pharmaceuticals, Japan). Mice were gavaged with vehicle or ONO-8430506. Some mice were also treated intraperitoneally with doxorubicin. LPA species were measured by mass spectrometry. Results: 1) Breast adipose tissue expresses significantly more ATX than breast cancer cells, and is further induced 3-fold by the adjacent tumor compared to the contralateral breast. 2) ONO8430506 decreases plasma ATX activity by >50%, and decreases unsaturated LPA concentrations in plasma and tumors. 3) Initial tumor growth and subsequent lung metastasis was 2-3-fold lower in ONO-8430506-treated mice and this effect was synergistic with doxorubicin. 4) ATX inhibition decreased tumor and systemic pro-inflammatory cytokine levels. Conclusions: This study demonstrates for the first time that ATX from breast tissue promotes cancer progression and an ATX inhibitor can slow cancer development despite the cancer cells producing negligible ATX. ATX inhibition also improves the effectiveness of conventional chemotherapy by interrupting cross-talk between cancer cells and stromal elements. We hope ATX inhibitors will soon enter clinical trials.

Funding: CIHR, Vanier CGS, Alberta-Innovates Health Solutions, Canadian Breast Cancer Foundation, Alberta Cancer Foundation, Ono Pharmaceuticals Ltd. benesch@ualberta.ca 28

Expression of Prognostic Marker IL-6 in Prostate Cancer Tissue and Blood Plasma Marc Bienz1, 2, Benjamin Péant2, Guergana Tchakarska2, Anne-Marie Mes-Masson2, Fred Saad2, 3 1 University of Montreal, Montreal, Qc (M.D.-M.Sc. program student); 2 Montreal Cancer Institute, CRCHUM; 3Montreal University Hospital Center, Division of Urology Rationale: In prostate cancer (PCa) patients, it is established that high serum levels of IL-6 correlate with disease progression, and that IL-6 expressed by PCa cells could reactivate the androgen receptor and stimulate proliferative and anti-apoptotic pathways. Similarly, the expression of the cytoplasmic protein kinase IKKe has been correlated with PCa progression, and associated in vitro with an increase in the secretion of IL-6. Objectives: To further our understanding of IL6’s role in PCa, we aim to evaluate the relationship between IL-6 tissue expression and serum levels in advanced disease. As a secondary endpoint, we aim to correlate in tissu expression of IKKe and IL-6. Methods: Immunofluorescent co-staining of IKKe and IL-6 was performed using large-scale PCa tissue microarrays (TMA), composed of samples of various tumor grades (n= 230). Signal quantification was performed using the VisiomorphTM image analysis platform. Cytokine serum levels were measured by ELISA assay. Patients were grouped according to the Gleason score of the radical prostatectomy specimen (≤3+3, 3+4, 4+3, ≥4+4). Results: ELISA assay analysis indicated that patients had respectively lower IL-6 serum levels as tumor grade increased. In the low grade disease group (≤3+3), patients with IL-6 serum levels above 8.5 pg/ml tended to have a higher risk of biochemical recurrence (BCR) than their respective counterparts (p=0.088). Furthermore, every 1 pg/ml increase in IL-6 serum levels was associated with a 2.4% increased risk of BCR (CI 95%: 1.009-1.038, p= 0.001) in patients with Gleason scores ≤3+3. Immunofluorescent co-staining of IL-6 and IKKe has been optimized on TMA test samples. An additional staining targeting epithelium-specific protein (PSA, cytokeratin 18 and 19) has been developed to quantify IL-6 and IKKe in tissu levels to the epithelium restrictively. Conclusions: Preliminary results demonstrate that high IL-6 serum levels in patients with low grade PCa could help identify patients with a higher risk of BCR. To validate these results on a larger cohort, this analysis will be extended on serum samples of 600 patients. Further analysis will give additional insight on the relation between IL-6 serum and in tissu levels and help evaluate whether IKKe expression could be combined to IL-6 serum levels as a prognostic tool for PCa.

Funding: Terry Fox Research Institute, Canadian Urologic Oncology Group (CUOG) marc.bienz@gmail.com 29

Developing Three-colour Fluorescence Cross-correlation Spectroscopy Megan L Bladesa, Ekaterina Grekovaa, Holly M Wobmaa, Kun Chenb, Warren CW Chanb and David T Cramba a

Department of Chemistry, University of Calgary Institute of Biomaterials and Biomedical Engineering, Donnelly Centre for Cellular and Biomolecular Research, Chemistry, Materials Science and Engineering, and Chemical Engineering, University of Toronto b

Rationale: As the field of proteomics expands, so must the techniques used to study the biomolecular reactions involved in physiological activity. Currently, binding events at the picomolar (10-12) level can be monitored with dual-colour fluorescence cross-correlation spectroscopy (FCCS). FCCS temporally correlates fluctuations in fluorescence intensities resulting from the diffusion of two molecules with spectrally distinct fluorescent labels through a small interrogation volume. Species that are physically bound to one another produce a cross-correlation, which provides information about the association. However, many biological reactions and pathways are complex, involving more than two interacting species. In order to follow the kinetics of complex macromolecular assembly/disassembly using three-colour FCCS, the technique must be able to confidently measure the concentration of components with multiple labels in a solution with high concentrations of free species. Methods: In this study, a novel FCCS technique was developed to track fluctuations in fluorescence intensities of three distinct fluorophores. A triple cross correlation can be calculated if all three species are physically linked. The decay of this correlation can be used to find the concentration and size of triply labeled species. Three-colour quantum dot barcoded nanobeads were used to develop and optimize the technique. Results: Proof-of-principle experiments were carried out which validate the mathematical model used to analyze three-colour FCCS data. Three-colour FCCS is capable of detecting barcoded nanobeads at picomolar concentrations in solution containing background quantum dots at greater than 800:1 concentration. Conclusions: 3C-FCCS can be used to determine the concentrations of singly and triply labeled species in complex nanoparticle solutions. This study is the first example of direct three-colour FCCS and the technique can now be used in a wide variety of applications to investigate complex assembly/disassembly kinetics in real time.

Funding: NSERC, Alberta Innovates â&#x20AC;&#x201C; Technology Futures mblades@ucalgary.ca

Targeting a Chaperone-translocator Interaction with a Peptide Mimetic Inhibits Chlamydia Pneumoniae Infection David C. Bulir1, Daniel A. Waltho3, Christopher B. Stone2, Kenneth A. Mwawasi2, James B. Mahony2 1

MD/PhD Program, McMaster University, Hamilton, ON M. G. DeGroote Institute for Infectious Disease Research, Faculty of Health Sciences and the Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON 3 Faculty of Medicine, University of Ottawa, Ottawa, ON, CAN 2

Background: The translocator proteins of the T3SS, Chlamydia outer protein (Cop) B and D, of Chlamydia pneumoniae are essential for T3S and infection of host cells. Despite our knowledge on the T3SS of C. pneumoniae, little is known about the function of the translocator proteins and their interaction with their cognate chaperone LcrH_1 in the chlamydial life cycle. The objective of the study was to elucidate the role of CopB and CopD and their interaction with the cognate chaperone, LcrH_1. Methods: Fragments of CopB and CopD, excluding the transmembrane domains, were cloned using the Gateway expression system. Alanine substitutions were generated in the conserved chaperone binding (CBD) motif, PxLxxP, of both CopB and CopD using overlapping PCR. Glutathione-S-transferase (GST) pull downs were performed between LcrH_1 and various CopB and CopD constructs to assess interactions. Peptides containing various chaperone binding motif sequences together with a cell penetrating peptide (CPP) were chemically synthesized and tested for their ability to inhibit chlamydial infections in vitro. Results: We have previously shown that LcrH_1 interacts within the N-terminal region of CopB and CopD. We show here that the conserved CBD sequence of PxLxxP is an essential component for interactions between the translocators and LcrH_1 since mutations of the conserved residues completely abolished the interactions. Pre-treatment of C. pneumoniae with the CBD/CPP peptide reduced infection by nearly 80% compared to control peptide, and the inhibition was dose dependent. Conclusions: Alanine substitutions for three key resides of the CopD PxLxxP motif (P120A, L122A, P125A) completely abolished the interaction between LcrH_1 and CopD. This is the first demonstration of the essential role of conserved amino acids within the predicted CBD motif of a chlamydial translocator protein. The CBD/CPP peptide blocked chlamydial infection of cells and when stabilized with a carrier protein could represent a novel class of therapeutics to prevent and treat ascending chlamydial infections.

David.bulir@medportal.ca 31

The Role of Innate Immunity in the Oncolytic Properties of Vesicular Stomatitis Virus (VSV) Andrea Cerviac, Naomi DeSilvaa, John Bellab, Harold Atkinsacd a Center for Cancer Therapeutics, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada; bDepartment of Biochemistry, Immunology and Microbiology, University of Ottawa, Ottawa, Ontario, Canada; cDepartment of Medicine, University of Ottawa, Ottawa, Ontario, Canada; dBlood and Marrow Transplant Program, The Ottawa Hospital, Ottawa, Ontario, Canada Rationale: The use of viruses engineered to selectively infect tumor cells while sparing normal tissues (oncolytic viruses, OVs) represents a novel approach to anti-cancer therapy. The mechanism of action of these agents includes direct cytolysis of infected tumor cells, intra-tumor vascular thrombosis, targeted gene therapy, and anti-cancer immune responses. OVs influence on anti-tumor immunity is complex but is influenced by cells of the innate immune response within infected tumors. The current project aimed to characterize both the spatial and temporal distribution of innate immune cells in a murine model of colon adenocarcinoma at various time points following intravenous OV infection with vesicular stomatitis virus (VSV), to gain further insight into immunity-related oncolytic effector mechanisms. Methods: Bilateral tumors were established by injecting CT26 cells (3 x 105) into the flanks of female Balb/C mice. Once tumors achieved a palpable size, mice were treated with VSV (5 x 108 particles) by tail vein injection, and tumors were harvested 0 hours, 6 hours, 9 hours, and 24 hours later. Immunohistochemistry was used to visualize markers of VSV infection, neutrophils, macrophages, cellular apoptosis, and endothelial cells within isolated tumors. Results: VSV protein was evident throughout the tumors 6 hours after intravenous injection and was followed by caspase 3-dependent apoptosis in the center of the tumor that was not limited to regions where viral proteins were expressed. The distribution of neutrophils was largely unchanged following VSV infection; however, macrophages were actively recruited to areas of central tumor necrosis, especially at the 24 hour timepoint. These changes were accompanied by a down-regulation of tumor endothelial marker expression. Conclusions: Innate immune cells, particularly macrophages, are mobilized throughout VSV infection and preferentially recruited to areas of active tumor cell death, which may impact on tumor vasculature. Further experiments using liposomal clodronate to deplete macrophages prior to VSV infection will determine if these cells are important mediators of VSV oncolytic efficacy.

acerv011@uottawa.ca

Recurrence Analysis of Brain Metastases After Surgical Resection With or Without Adjuvant Whole Brain Radiation Daljeet Chahala, Derrick G. Leeb, Brian Toyotac a

Northern Medical Program, University of British Columbia, Prince George, BC School of Population and Public Health, University of British Columbia, Vancouver, BC c Division of Neurosurgery, University of British Columbia and BC Cancer Agency, Vancouver, BC b

Rationale: Tumors that metastasize to the brain are associated with poor survival, and tend to recur at the original site after treatment. Analysis of different treatment modalities are necessary to determine risk factors associated with tumor recurrence. Objectives: To investigate tumor recurrence rates, survival, and prognostic factors in patients treated with surgery with or without adjuvant brain radiation. Methods: 98 patients who underwent surgical resection for metastatic brain tumors between 2006 and 2013 were identified by retrospective chart review. Data regarding demographics, tumor characteristics, type of radiation therapy received, and patient status were collected. Multivariate analysis was done for recurrence and survival. Results: Patients comprised of 62 females and 36 males, and mean age was 61 years. Median overall patient survival was 175 days. 78 of these patients received adjuvant whole brain radiation, and 20 received no post-surgical radiation. There was tumor recurrence in 17 cases (17.3%); median time to recurrence was 148.5 days. Multivariate analysis using a 4 year postsurgery cut-off revealed that use of adjuvant whole brain radiation was significantly associated with decreased tumor recurrence compared to patients receiving no radiation (p=0.01, relative risk = 0.18). Delay in adjuvant radiation (p<0.01, RR = 7.11) and tumors within occipital lobes (p=0.03, RR = 4.19) were significantly associated with higher risk of recurrence. Administering radiation therapy as initial therapy rather than performing surgery immediately increased tumor recurrence (p=0.09, RR = 4.20). Multivariate analysis of patient survival using a 5 year cut-off revealed that receiving adjuvant whole brain radiation compared to no adjuvant radiation (p = 0.04, RR = 0.51), and Karnofsky performance scales of greater or equal to 70 (p < 0.01, RR = 0.97) were significantly associated with longer survival. Tumors in temporal lobes (p < 0.01, RR = 5.06) and presence of extra-cranial metastases (p = 0.04, RR = 1.76) were significantly associated with decreased survival. Conclusion: Adjuvant whole brain radiation is associated with decreased tumor recurrence and longer survival. Delaying adjuvant radiation may increase recurrence. Location of the metastasis influences recurrence and survival.

Funding: Mach-Gaensslen Foundation of Canada daljeetc@alumni.ubc.ca 33

Funding : Fondation du CHU Ste-Justine. Gabriell.bchartier@gmail.com 34

Managing Uncertainty in Clinical Decision-making: A Qualitative Evaluation Corso, Za; Sisler, Jb; Driedger, SMc; a

BSc. University of Manitoba, Faculty of Medicine, Winnipeg, Canada MD MClSc CCFP FCFP. University of Manitoba, Faculty of Medicine, Winnipeg, Canada c PhD. University of Manitoba, Department of Community Health Sciences, Winnipeg, Canada b

Background: Though clinical uncertainty is pervasive throughout all fields of medicine, there is currently a lack of detailed understanding when it comes to the manner in which physicians manage this uncertainty in order to make clinical recommendations to their patients. The purpose of this project was to explore the presence of clinical uncertainty, its impact on the decision making process, and the ways in which physicians adapt their decision making process in order to cope with this uncertainty. Methods: Family physicians (n = 6) and oncologists (n = 8) were interviewed using a series of qualitative semi-structured interviews. Convergent interviewing was used to aid in exploring these topics and increase scientific rigour. NVivo9TM was used to aid in coding the responses and findings were based on analysing convergences and divergences between participants. Results and discussion: When there was a low degree of clinical uncertainty, physicians would consult external sources to attempt to fill in gaps in their own knowledge or experience (i.e. literature, guidelines, colleagues…). When there was a high degree of uncertainty, physicians attempted to decrease this uncertainty using less reliable practices (i.e. less applicable literature, less rigorous literature, intuition, anecdotal experiences, and consulting colleagues). In high uncertainty situations, patient preferences generally played a much more significant role in determining the clinical recommendation. Conclusions: The degree of uncertainty present dictated the methods by which physicians attempted to cope with the lack of clinical evidence. It was the interplay of weighing the clinical risks and benefits in light of the patient’s preferences which led to the final decision, with patient involvement being critical in the process. Keywords: Qualitative, Convergent interviewing, Uncertainty, Decision making process, Physicians, Cancer.

Funding: Canadian Cancer Society Research Institute, Canadian Foundation for Innovation, Manitoba Research and Innovation Fund, the Government of Canada’s Canada Research Chairs program, and the University of Manitoba’s B.Sc in Medicine program. zcorso@gmail.com

Influence of Telomere Dynamics on Disease Progression and Therapeutic Response in Bone Marrow Failure Syndromes Erin S. Degelmana, and Tara L. Beattieb a Department of Medical Science, bDepartment of Biochemistry and Molecular Biology, University of Calgary and Southern Alberta Cancer Research Institute. Calgary, Canada Rationale: Aplastic Anemia (AA) is a bone marrow failure disease where insufficient levels of hematopoietic cells are produced. In approximately 10-15% of patients, the AA evolves into a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Studies have demonstrated an association between shortened chromosome ends, advanced AA and increased risk of developing blood cancers. Heterozygous mutations in the gene encoding the telomerase protein component hTERT, are seen in approximately 10% of patients with AA, resulting in shortened telomeres. Objectives: Determine how these telomerase mutations and shortened telomeres impact disease progression and response to therapeutics. Methods: To understand the biochemical properties and cellular consequences of mutant hTERT expression we have generated expression constructs that correspond to four specific hTERT mutations found in patients with familial AA and progression to MDS or AML. Constructs were expressed in a leukemic cell line (THP-1), catalytic activity was measured using the telomeric repeat amplification protocol (TRAP) and cell cycle analysis was performed using a double thymidine block, followed by flow cytometry to measure DNA content. Cells were cultured for 72 hours in the presence of therapeutics and viability was measured by Alamar Blue. Results: We have demonstrated that all four hTERT mutants retain telomerase activity in vitro and we are investigating the consequences of their expression in leukemic cells lines. Preliminary data suggests that expression of certain mutant hTERT proteins in THP-1 cells, results in a delay of the G1/S transition, which may have profound implications during hematopoiesis, negatively impacting the development and differentiation of mature blood cells. In addition, THP-1 cells expressing mutant hTERT proteins are more resistant to treatment with specific chemotherapeutic agents that are commonly used to treat patients with AML. Additional assays will be performed to characterize the biochemical properties of the mutations, and to examine the function in hematopoiesis. Conclusion: Resistance to therapeutics suggests that protocols used in the treatment of leukemia might have differential efficacies depending on whether cells express wild-type or mutant hTERT. By defining the role of telomeres in hematological disorders, it may be possible to alter treatment strategies based on predicted outcomes from our investigations.

Funding: CIHR, ACF emstebne@ucalgary.ca 36

Neonatal Hypoxic-Ischemic Encephalopathy and the Cerebellum Octavian Dobrescu, Ă&#x2030;lodie Boudes, Pia Wintermark, MD Department of Newborn Medicine, Montreal Childrenâ&#x20AC;&#x2122;s Hospital, McGill University Health Center, Quebec, Canada. Rationale: Some newborns are asphyxiated around the time of birth, i.e. they lacked oxygen and blood causing hypoxic-ischemic encephalopathy (HIE) and in some cases brain hypoxic-ischemic injury. These lesions can have devastating consequences on the infant's development, affecting motor functions as well as cognitive capacities. The only therapeutic intervention to date is induced hypothermia, which has shown to limit the extent of injury in certain cases. Clinically, brain hypoxic-ischemic injury is evaluated using magnetic resonance imaging (MRI) to observe abnormalities in the cerebrum, more specifically in the watershed areas, the basal ganglia and the cortical areas. The cerebellum, which is involved in many developmental aspects, has not been studied in the context of HIE. Objectives: To evaluate the cerebellum and the tracts connecting it to the cerebrum in a cohort of asphyxiated newborns treated with hypothermia using diffusion-tensor imaging (DTI), an MRI technique based on water diffusion in biological tissues. Methods: Asphyxiated term newborns who met the criteria for induced hypothermia treatment underwent two early MRI scans on day of life (DOL) 1 and DOL 2-3 as well as one or two late scans around day 10 of life and around 1 month of age. A control group of healthy infants underwent the same MRI scanning sequence. Diffusion values were measured in different regions of interest in the cerebellum (i.e. the dentate nucleus, the superior, middle and inferior cerebellar peduncles and the cerebellar white matter) and compared between the two groups. Results: Asphyxiated newborns showed significant cerebellar water diffusion differences compared to normal infants, suggesting abnormalities in neural tracts in the cerebellum. These differences were most significant in the dentate nucleus (p<0.0001), the superior cerebellar peduncle (p<0.0001) and the middle cerebellar peduncle (p<0.001). There were no significant differences in diffusion for the inferior cerebellar peduncle and the cerebellar white matter. Conclusion: The cerebellum is also at risk during HIE and lesions seem to occur predominantly in the peduncles that connect it to the cerebrum. Further investigations are required to better understand the pathological mechanisms at play as well as the clinical relevance of these cerebellar abnormalities.

Funding: CIHR, Clarke McLeod Scholarship octavian.dobrescu@mail.mcgill.ca

Coronary Artery Bypass Grafting Strategies for the Anterolateral Territory: A Prospective Randomized Clinical Trial Ariane Drouina, Nicolas Noiseuxab, Carl Chartrand-Lefebvrebc, Gilles Soulezbc, Samer Mansourbd, Jan-Alexis Tremblaya, Fadi Basilea, Ignacio Prietoa and Louis-Mathieu Stevensab a

Division of cardiac surgery, bResearch center, cDepartment of radiology, dDivision of cardiology, Centre hospitalier de l’Université de Montréal (CHUM). Montreal, Canada. Rationale: In severe coronary artery disease, coronary artery bypass grafting (CABG) surgery is indicated to re-establish an adequate blood supply to the myocardium. As bypass using a left internal mammary artery (LIMA)-to-left anterior descending coronary artery (LAD) anastomosis allows the best graft patency results, we developed a surgical strategy using a saphenous vein graft (SVG) as a venous bridge to distribute the LIMA blood flow to the anterolateral cardiac territory. This novel strategy could extend the patency benefits associated to the LIMA. Other potential benefits include easier anastomoses, possibility to use the SVG as a vein patch angioplasty, shorter SVG requirement and reduced manipulations of the ascendant aorta. Objectives: The primary objective is to assess whether the venous bridge strategy allows noninferior anterolateral graft patency index (proportion of non-occluded CABGs out of the total number of CABGs) compared to the conventional CABG technique. Secondary objectives include clinical outcomes assessing (death, myocardial infarction and need for revascularization) at thirty days, one, five and ten years postoperative.

Methods: Between July 2012 and 2016, 200 patients undergoing a primary isolated CABG surgery using cardiopulmonary bypass with a LAD bypass graft and at least another target on the anterolateral territory will be randomized (1:1) according to 1) the venous bridge strategy and 2) the conventional strategy with a LIMA-to-LAD anastomosis and revascularization of the other anterolateral target(s) with a separated aorto-coronary SVG. The primary outcome is the anterolateral graft patency index, evaluated at one year by 256-slice computed tomography angiography. Ten years of clinical follow-up is planned to assess clinical outcomes. We present short- and mid-terms preliminary security data for patients randomized until now. Results: Between July 2012 and December 2013, 51 patients were randomized (63±8 years old, 88% men). Thirty days after surgery, two postoperative deaths (4%) and two myocardial infarctions (4%) occurred, including one with revascularization of the anterolateral territory by percutaneous coronary intervention (PCI) (2%). Of the seventeen patients with one year followup, one patient presented a myocardial infarction requiring PCI and not involving the anterolateral territory. Conclusion: Preliminary results of this on-going trial suggest short-term safety of the two strategies.

Funding: Canadian Institutes of Health Research (CIHR). Registration: www.clinicaltrials.gov; NCT01585285. Ariane.drouin@umontreal.ca 38

Examining Angiogenesis in Neurodegenerative Disease Matt Eagles a, Jordan Warford b, and Alexander Easton b a

Memorial University of Newfoundland Faculty of Medicine, bDepartment of Pathology, Dalhousie University Faculty of Medicine Rationale: Previous studies have indicated that angiogenesis takes place in neurodegenerative conditions such as Multiple Sclerosis (MS) and Alzheimer’s disease (AD). Specifically, increased vessel counts were observed in experimental autoimmune encephalomyelitis (EAE), an animal model of MS; and in the hippocampus of rats injected with β-Amyloid (an animal model of AD). Furthermore, EAE mice treated with bevacizumab have shown decreased clinical and pathological scores. Objectives: Determine whether there is evidence for angiogenesis in human histological sections of brains afflicted with MS or AD pathology. Methods: Post-mortem brain tissue was obtained from both control and diseased (MS & AD) brains, and slides were stained for vessel counting with a CD31 antibody. After staining, the counter was blinded and selected 3 fields (using the 20x objective lens) with good staining for vessel counts. Afterword’s, atrophy measurement was performed using an Aperio Slide Scanner and software. Lastly, correlation analysis was performed on AD brains to determine if the extent of pathology in specific areas increased vessel counts. Results: Statistically significant increases in vessel counts were seen in both MS and AD brains (p<0.05). After atrophy correction, AD brains still had increased mean vessel counts, but the result was no longer statistically significant. There was also a positive correlation between areas of increased β-amyloid density, and vessel counts; however, a negative correlation was seen between tau pathology, and vessel counts. Conclusions: The results support the hypothesis that angiogenesis plays a role in neurodegenerative diseases. The mediators of this increase in vasculature remain under study.

Funding: endMS Research and Training Network Email:meagles@mun.ca 39

Treating donor site pain in burn victims that have undergone autologous split-thickness skin grafting: A review of the literature Amanda Eslinger1, Duncan Nickerson MD, FRCSC, FACS2 1

Leaders in Medicine, Undergraduate Medical Education; 2Division of Plastic Surgery, Department of Surgery, University of Calgary Introduction: Current standard of treatment for deep burn injuries is split-thickness skin grafting(STSG). STSGs are harvested from a remote area of healthy skin creating a new wound referred to as the donor site. Pain, caused by harvest, is reported to be one of the most distressing symptoms following STSG. Resultant pain can affect early mobilization, sleep and the need for analgesics post-operatively. Although donor site pain presents a significant problem, there are no evidence-based guidelines concerning its treatment. The purpose of this literature review was to synthesize information on current practices for managing donor site pain and to determine whether further investigation of donor site pain management is warranted. Methods: Ovid MEDLINE was searched using the terms ‘burn’, ‘donor site’, ‘pain’, and ‘splitthickness skin graft’ from 2003–2013. Only human studies were included in the review. NonEnglish language articles were excluded from the review. Results: The literature review identified five techniques used in minimizing donor site pain. One technique initiated treatment prior to STSG harvest by infiltrating the pre-harvest site with a combined anesthetic/tumescent solution. Four techniques initiated treatment immediately following STSG harvest: 1) continuous subcutaneous local anesthetic infusion (CSLA); 2) subcutaneous injection of anesthetic; 3) application of topical anesthetic gels; and 4) the use of ice packs. All studies measured pain using a visual analog scale(VAS). In a majority of studies subjects gave anecdotal reports of decreased pain at the donor site regardless of the technique used to treat pain. Few studies showed that a particular technique significantly decreased VAS scores. Conclusions: Although donor site pain is of chief concern for both the patient and the physician its treatment is scantily addressed. This review highlights the need to design and carry out more rigorous and effective studies in order to work towards standardizing care and improving the patients’ pain experience following STSG harvest.

ajesling@ucalgary.ca 40

Population Based Outcomes of Initiating Oral Atenolol in Patients With and Without Chronic Kidney Disease Jamie L. Fleet1,2, Matthew A. Weir3, Eric McArthur2, Sundus Ozair4, Philip J. Devereaux5, Matthew A. Roberts6, Arsh K. Jain2,3, and Amit X. Garg2,3,7. 1. 2. 3. 4. 5. 6. 7.

Michael G. DeGroote School of Medicine, McMaster University, Waterloo, Canada Institute for Clinical Evaluative Sciences, Ontario, Canada Division of Nephrology, Department of Medicine, Western University, London, Canada Schulich School of Medicine and Dentistry, Western University, London, Canada Division of Cardiology, Department of Medicine, McMaster University, Hamilton, Canada Department of Nephrology, Austin Health, Australia Department of Epidemiology & Biostatistics, Western University, London, Canada

Rationale: Atenolol and metoprolol are commonly prescribed beta-blockers. Atenolol elimination depends on kidney function while metoprolol does not. We hypothesized that compared to metoprolol tartrate, initiating oral atenolol in the outpatient setting would be associated with more adverse events in older patients, especially those with chronic kidney disease. Methods: We conducted a population-based matched retrospective cohort study comparing new atenolol and metoprolol tartrate users in Ontario. Patients were 1:1 matched on seven variables, including a propensity score in order to take into account probability of receiving an atenolol prescription over metoprolol. Patients with end stage renal disease were excluded, as were those under the age of 65 for lack of complete provincial drug coverage. The outcomes were all-cause mortality and a composite of hospitalization with bradycardia or hypotension. Relative risks were found for the entire cohort as well as an interaction with presence of chronic kidney disease. Results: Compared to metoprolol tartrate, initiating atenolol was not associated with a higher risk of hospitalization with bradycardia or hypotension (incidence 0.71% vs. 0.79%, relative risk 0.90; 95% confidence interval [CI]; 0.80 to 1.01), and the presence of chronic kidney disease did not modify this association (p-value for interaction 0.5). Atenolol initiation was associated with a lower 90-day risk of mortality than metoprolol (incidence 0.97% vs. 1.44%, relative risk 0.68 (95% CI 0.61 to 0.74), and the presence of chronic kidney disease did not modify this association (p-value for interaction 0.6). Conclusions: Contrary to our expectation, we found atenolol versus metoprolol was associated with a lower 90-day risk of mortality in patients with and without moderate chronic kidney disease, with no difference in the risk of hospitalization with bradycardia or hypotension.

Jamie.fleet@medportal.ca 41

Non-pharmacological Management of Orthostatic Hypotension: A Systematic Review. Carlen Ka-Yin Fung, BSN1, Andrei Krassioukov, MD, PhD, FRCPC,1,2,3,4, Angie Travlos, and Patricia Mills, MD, MHSc, FRCPC.1,2,3,4 1

Faculty of Medicine; 2Div of Physical Medicine and Rehabilitation; 3ICORD (International Collaboration on Repair Discoveries) Department of Medicine, University of British Columbia; 4GF Strong Rehabilitation Center, Vancouver Coastal Health, Vancouver, BC;

Rationale: Orthostatic hypotension (OH), an excessive and prolonged drop in blood pressure (BP), can be characterized by debilitating symptoms such as dizziness, nausea, visual disturbances, cognitive slowing, and loss of consciousness. OH management guidelines recommend starting with non-pharmacological strategies before proceeding to pharmacological measures. We therefore conducted a systematic review to assess the efficacy of various nonpharmacological methods in managing OH. Methods: A systematic review was performed through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and SPORTDiscus from January 1980 to April 2013. Reference lists of relevant studies and reviews were retrieved and scanned for citations to expand the data set. Prospective experimental studies assessing non-pharmacological interventions for management of orthostatic BP drop in various patient populations were included. All studies identified through the literature search were reviewed independently in duplicate with discrepancies resolved by consensus or by a third author. Two reviewers independently extracted data for analysis, including systolic and diastolic BP and orthostatic symptoms in response to postural challenge before and after the intervention. Included studies were also assessed in duplicate for methodological quality (Physiotherapy Evidence Database scale for randomized trials, Downs and Black tool for non-randomized trials). Results: Twenty-five of 642 studies screened met selection criteria. Ten non-pharmacological interventions for management of orthostatic hypotension were identified under two general categories: 1) physical modalities (exercise, functional electrical stimulation, compression, physical countermaneuvers, compression with physical countermaneuvers, and sleeping with head up); 2) dietary measures and medication withdrawal (oral potassium, water ingestion, meals, and medication withdrawal). Strong levels of evidence were found for five of the ten interventions: functional electrical simulation in spinal cord injury, compression of the legs and/or abdomen and physical countermaneuvers in various patient populations, eating smaller and more frequent meals in chronic autonomic failure, and oral potassium in the elderly. Conclusions: There are strong levels of evidence to suggest that certain non-pharmacological measures are effective in counteracting the symptoms experienced and the drop in BP seen in patients with OH within particular population groups. However, this was based on a limited number of studies with small sample sizes. Further research into all interventions is warranted.

Funding: UBC Summer Student Research Program kfung@alumni.ubc.ca 42

Long-term Risk of Heart Failure Associated with Adjuvant Trastuzumab in Breast Cancer Patients Hart Goldhar1, Andrew Yan2, Dennis Ko1,3,4, Craig Earle1,3,4,5, George A. Tomlinson6, Maureen E. Trudeau1,4, Murray Krahn1,7, Monika Krzyzanowska1,3,6, Raveen Pal8, Christine B. Brezden2, Scott Garuva9, Kelvin Chan1,4 1

University of Toronto, Toronto, ON; 2St. Michaelâ&#x20AC;&#x2122;s Hospital, Toronto, ON; 3Institute for Clinical Evaluative Sciences, Toronto, ON; 4Sunnybrook Odette Cancer Centre, Toronto, ON; 5Ontario Institute for Cancer Research, Toronto, ON; 6University Health Network, Toronto, ON; 7Toronto Health Economics and Health Assessment, Toronto, ON; 8Kingston General Hospital, Kingston, ON; 9Cancer Care Ontario, Toronto, ON Background: The late cardiac effect of adjuvant trastuzumab (T) and its potential interaction with anthracycline in the general population have not been well studied. The purpose of this retrospective population-based cohort study was to determine the long-term risk of heart failure (HF) associated with adjuvant T and chemotherapy, compared to chemotherapy alone. Methods: Female breast cancer patients in Ontario, diagnosed between 2003 and 2009 were identified by the Ontario Cancer Registry and linked to administrative databases to ascertain demographics, cardiac risk factors, comorbidities, and use of adjuvant T and other chemotherapy. Patients with pre-existing HF were excluded. The main endpoint was new diagnosis of HF, obtained using an algorithm of admissions and physician claims data. Group differences were assessed by the Kaplan-Meier (KM) method and multivariable piecewise Cox regression. Competing risk analysis using the Fine and Gray method and propensity score matching analysis were performed. Results: 19 074 women with breast cancer treated with adjuvant chemotherapy were identified, of whom 3 371 (17.7%) also received adjuvant T. Anthracycline use was 84.9% overall. The groups did not differ significantly in demographics, comorbidities, or cardiac risk factors. After a median follow-up of 5.9 years, patients treated with T and chemotherapy were more likely to develop HF than patients on chemotherapy alone (5-year KM estimates of 5.3% vs. 2.6%; p<0.0001 (log-rank)). After adjusting for confounders, adjuvant T remained independently associated with incident HF in the first 1.5 years (HR=5.77, 95% CI 4.38-7.62, p=0.0004), but not thereafter (HR=0.87, 95% CI 0.57-1.33, p=0.53). Anthracycline did not increase the risk of HF with T synergistically (interaction p=0.23). Competing risk and propensity score analyses revealed similar results. Conclusion: In this large population-based cohort study of breast cancer patients with long-term follow-up, adjuvant T was associated with increased risk of HF in breast cancer survivors, within the first 1.5 years of initiating treatment, but not thereafter. This provides reassurance about the long-term cardiac safety of adjuvant T in the general population.

hart.goldhar@mail.utoronto.ca 43

Real-life Drug Survival of Tumour Necrosis Factor-α Inhibitors in Inflammatory Arthritis Stefan Hamiltona and Proton Rahmanb a

Memorial University, bDepartment of Rheumatology, Memorial University, St. Clare's Mercy Hospital, St. John's, Newfoundland, Canada Rationale: Inflammatory arthritis is a spectrum of diseases arising from immune dysregulation in the body causing pain, stiffness, swelling, and tenderness in the joints. Due to incomplete understanding of its pathogenesis, management has classically been directed at relieving symptoms in the short term, with no treatment capable of stemming the long-term progression of joint damage. Recently, tumour necrosis factor-α inhibitors (TNFi’s) have revolutionized inflammatory arthritis treatment because of their ability to act on targets driving inflammation. As a result, most patients treated with TNFi’s have significant reductions in disease activity and joint damage. Although randomized controlled trials (RCTs) have been instrumental in demonstrating this effect, observational studies on the effectiveness and sustainability of TNFi’s have been lacking. Such studies add value by ascertaining the long-term effects of an intervention in a highly generalizable population.

Objectives: To compare the efficacy of a first course of TNFi therapy in three forms of inflammatory arthritis (rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS)), and to compare the first-course efficacy of three widely used TNFi’s (infliximab, etanercept, and adalimumab) within each of RA, PsA, and AS. Methods: A retrospective cohort study design was used. Efficacy was measured using the proven surrogate marker of drug survival. Crude TNFi survival was compared using Kaplan-Meier curves with log rank testing, and TNFi survival adjusted for potential confounders was compared using Cox regression with hazard ratios (HRs) for treatment termination. Results: 332 patients were eligible for the analysis (114 RA, 58 PsA, and 160 AS patients). Crude TNFi survival was significantly greater in AS patients compared to RA (p = 0.028) or PsA (p = 0.045) patients. Both crude and adjusted TNFi survival was greater in RA patients taking adalimumab vs. etanercept (p = 0.010 and HR = 0.34 (95% confidence interval (CI) 0.14-0.80)). Male AS patients had superior TNFi survival than did female AS patients (HR = 0.51 (95% CI 0.27-0.95)). Conclusions: This study helps to validate two key findings observed in previous studies: superior TNFi survival in AS vs. PsA and RA patients and superior TNFi survival in male vs. female AS patients.

sshamilton@mun.ca 44

Optimizing the Doctor-patient Encounter Concerning Asthma in Children Aurélie Houlea, Francine M Ducharme MD, MSca,b,c a

Research Center, Sainte-Justine University Hospital Center, University of Montreal, Montreal, Canada; bDepartment of Pediatrics, University of Montreal, Montreal, Canada; cDepartment of Social and Preventive Medicine, University of Montreal, Montreal, Canada; Rationale: Long term use of inhaled corticosteroids (ICS) is the cornerstone of the management of persistent asthma in children. However, treatment adherence is less than 50 %. The intention to follow or not the prescribed treatment usually begins when the treatment is discussed during the medical interview. Objectives: To identify key elements of medical visit that influenced the families’ intention to adhere to long-term ICS use. Methods: We conducted a qualitative and semi-quantitative case study in which children with asthma and their parents were approached before their medical visit at the asthma and the pulmonary clinics of Sainte-Justine University Hospital Center and invited to participate separately in a semi-structured interview and complete a self-administered questionnaire. Results: Seven parents of children aged between 2 to 15 years old and two children with asthma aged ≥ 8 years old were approached and agreed to participate in the study. All parents had the intention to adhere to long-term ICS use. Trust in the doctor, satisfaction with the medical interview, obtaining sufficient information regarding the benefits and side effects of the drug, explanation of lung function test results, and use of images to explain the pathophysiology of asthma were the main motivators to adhere to long-term ICS use reported by parents. Only 29% of parents reported being worried about the drug side effects. The explanation of the expected benefits and side effects of the drug, the medicine’s positive impact on their health and confidence in the doctor were key elements motivating children to have the intention to adhere to long-term ICS use. Forgetfulness to take the medicines, to believe that asthma is not serious, and being unsure of the usefulness of the drugs were the main deterring factors in children. Conclusions: Despite the small sample size and the uniform parental’s intention to adhere, some elements motivating and decreasing the intention to adhere to long-term ICS were identified. In 2014, we will approach more participants to explore with more power the determinants of parental and patient’s intention to adhere to long-term ICS use.

Funding: Department of Social and Preventive Medicine of the University of Montreal, Dr. Francine M Ducharme lab Aurelie.houle@umontreal.ca 45

Lower Dose of a Highly Beta-1 Selective Antagonist Preserves Cerebral Perfusion in Hemodiluted Rats Tina Hua, W. Scott Beattieb, C. David Mazera, Howard Leong-Poia, Hiroko Fujiia, David F. Wilsonc, Albert K.Y. Tsuia, Gregory M.T. Harea a

Department of Anesthesia, Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, bDepartment of Anesthesia, Toronto General Hospital, University of Toronto, cDepartments of Biochemistry and Biophysics, University of Pennsylvania. Rationale: Perioperative β-adrenergic antagonists reduce the risk of myocardial ischemia, but at the potential cost of increased stroke and mortality, particularly in the setting of acute blood loss and fluid resuscitation (hemodilution). β-antagonism has been shown to limit cerebral oxygen delivery during hemodilution by attenuating both cardiac output (β1-effect) and cerebral vasodilatory responses (β2-effect). We hypothesized that low dose treatment with a highly β1specific antagonist (nebivolol) would control heart rate while maintaining cerebral perfusion during hemodilution. Methods: Anesthetised rats (2% isoflurane) were treated with vehicle (control) or nebivolol at doses consistent with β1-selective or β1+β2 (non-selective) pharmacokinetics (1.25 and 2.5 mg/kg intravenously, respectively). We assessed the impact of nebivolol on heart rate (HR), mean arterial pressure (MAP), regional cerebral blood flow (rCBF, laser Doppler), cardiac output (CO, echocardiography), brain tissue PO2 (G2 oxyphor), and hypoxic proteins (HIF-1α and nNOS, Western blot) before and after hemodilution to a hemoglobin concentration near 60 g/L by exchanging 50% of the total blood volume with 10% pentastarch (1:1 volume exchange). Arterial blood gases were measured before and after hemodilution. Data are presented as the mean ± SD and statistical significance is determined by two-way ANOVA with significance assigned at p<0.05. Results: In vehicle controls, hemodilution increased HR, CO, and rCBF while MAP was maintained and brain PO2 decreased. Both doses of nebivolol comparably reduced HR and attenuated the CO response to hemodilution. Low dose nebivolol did not attenuate the increase in rCBF following hemodilution and brain PO2 was maintained relative to control levels. High dose nebivolol attenuated the rCBF and caused a further reduction in brain PO2 after hemodilution. Brain HIF-1α and nNOS protein levels were increased after hemodilution in rats treated with high dose nebivolol. Conclusions: Treatment with both doses of nebivolol caused a comparable reduction in HR and MAP and attenuated the CO response to hemodilution. However, only the high dose of nebivolol further attenuated cerebral oxygen delivery after hemodilution. Our data support the hypothesis that lower dose nebivolol can confer myocardial protection while reducing the risk of cerebral hypoxia during hemodilution.

Tina.hu@mail.utoronto.ca 46

Are We Preparing our Trainees to Prescribe for Older Patients? Yin Hui, BScPhm RPh, MD Candidate1,2 Lorelei Lingard, PhD1,2 Laura Diachun, MEd MD FRCP(C)1,2,3,4 1

Funding: AMOSO, St. Joseph’s Health Care Foundation, Program of Experimental Medicine, SRTP yhui2015@meds.uwo.ca 47

The Impact of Frailty on Post-operative Delirium in Cardiac Surgery Patients Patrick Jung,a Michael A. Pereira,a Brett M. Hiebert,b Dr. Navdeep Tangri,c Dr. Rakesh C. Arorad a UGME, University of Manitoba; bCardiac Sciences Program, St. Boniface Hospital; cDepartment of Internal Medicine, University of Manitoba; dDepartment of Surgery, University of Manitoba

Rationale: Frailty is a geriatric syndrome of decreased physiologic reserves, which leaves individuals in a state of increased vulnerability. Post-operative delirium is an acute disorder of attention and cognition that is associated with important negative outcomes. The link between frailty and post-operative delirium has not been elucidated in the cardiac surgery population. Thus, the objectives of this study were: i) to determine if frailty in cardiac surgery patients is associated with an increased occurrence of post-operative delirium, and ii) to identify which elements within the definition of frailty are most predictive of delirium. Methods: A prospective cohort study was conducted at St. Boniface Hospital. Patients over age 18 and undergoing elective CABG and/or valve procedures were eligible to participate. Excluded were patients in whom post-operative delirium could not be reliably assessed. 133 patients consented to participate and completed all study requirements. The primary exposure variable was frailty, as defined by the Modified Fried criteria. The primary outcome variable was postoperative delirium, as assessed by the Confusion Assessment Method (CAM) and the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Linear regression modeling was performed. Results: Seventy-two patients (54.1%) met the definition of frailty. Twenty-four of the 133 (18.0%) experienced post-operative delirium. Frail patients had a greater than five-fold increased risk of post-operative delirium (OR 5.05, 95% CI 1.58-16.13, P-value 0.0015). Within the Modified Fried criteria, weight loss and weak grip strength were the two components most predictive of postoperative delirium. Conclusions: Frailty in cardiac surgery patients was seen to increase the risk of post-operative delirium by five-fold. Weight loss and weak grip strength were the elements of frailty most predictive of delirium. External validation of our findings is required.

Funding: Department of Surgery, University of Manitoba; Cardiac Sciences Program, WRHA; MHRC; MMSF; CIHR. jungp@myumanitoba.ca

Risk factors for Incident Nonmedical Prescription Opioid Use and Abuse/Dependence: Results from a Longitudinal Nationally Representative Sample Cara Katz1, RenĂŠe El-Gabalawy2, Katherine Keyes3, Silvia S. Martins3 & Jitender Sareen1 (1) Department of Psychiatry, University of Manitoba; (2) Department of Psychology, University of Manitoba; (3) Department of Epidemiology, Columbia University Background: There has been a significant increase in opioid prescriptions and the prevalence of opioid nonmedical use. Nonmedical use may lead to opioid abuse/dependence, a serious public health concern. The aim of this paper was to determine the mental and physical health predictors of incident nonmedical prescription opioid use (NMPOU) and abuse/dependence, and the impact of comorbidity in a longitudinal, nationally representative sample. Methods: Data come from Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (N=34,653; â&#x2030;Ľ20 years old). Mental disorders were assessed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV edition. Physical conditions were based on self-reports of physician-diagnoses. Multiple logistic regression models examined the associations between mental and physical health predictors at Wave 1 and their association to incident NMPOU and abuse/dependence disorders at Wave 2. Results: After adjusting for sociodemographics, Axis I and II mental disorders and physical conditions, the presence of mental disorders (i.e., mood, personality disorders and substance use disorders), physical conditions (i.e., increasing number of physical conditions, any physical condition, arteriosclerosis or hypertension, cardiovascular disease and arthritis) and sociodemographic factors (i.e., sex and marital status) at Wave 1 positively predicted incident abuse/dependence at Wave 2. Comorbid disorders increased the risk of NMPOU and abuse/dependence. Conclusion: These results suggest the importance of mental and physical comorbidity as a risk for NMPOU and abuse/dependence, emphasizing the need for careful screening practices when prescribing opioids.

Funding: Manitoba Health Research Chair Award (Sareen), NIDA-NIH Grant (Martins), Vanier Canada Graduate Scholarship and Manitoba Graduate Scholarship (El-Gabalawy) katzc@cc.umanitoba.ca 49

Reliability of Clinical Tonsil Size Grading in Children Divjot Kumara, Dianne Valenzuelaa, Frederick K Kozakab, Jeffrey P Ludemannab, J Paul Moxhamab, Jane Leaab, Neil K Chadhaab a

University of British Columbia, bDivision of Pediatric Otolaryngology, British Columbia Children’s Hospital. Vancouver, Canada Rationale: Tonsillar enlargement may be associated with detrimental health effects in the pediatric population. Tonsil grading systems (or scales) allow clinicians and researchers to precisely record and communicate changes in tonsil size. Currently, however, there exists significant variability in the choice of tonsil grading scales both in clinical practice and research. Furthermore, the reliability of the available scales has not been previously studied and compared in a ‘real-life’ clinical setting. Objectives: The objectives of this study were to assess the interobserver and intra-observer reliabilities of the Brodsky Scale, Friedman Scale, and Modified 3grade scale (latter designed at our institution). Methods: We recruited 116 children aged 3-18, attending the Pediatric Otolaryngology outpatient clinic at BC Children’s Hospital. For each child, 2 separate tonsil assessments (with a 5 minute interval in between) were conducted by 4 independent observers, including: 2 Pediatric Otolaryngologists, 1 Fellow/Resident, and 1 Medical Student. Inter-observer and intra-observer reliabilities were derived using Intra-Class Correlation Coefficients (ICCs) and Pearson Correlation Coefficients (PCCs), respectively. To discount for asymmetric scores, data analysis was conducted on the left tonsil only. Results: Mean inter-observer reliability was highest for the Brodsky Scale (0.721), followed by the Friedman Scale (0.647), and Modified 3-Grade Scale (0.599). The mean intra-observer reliability for the Brodsky, Friedman, and Modified 3-grade scales were 0.954, 0.932, and 0.927, respectively. Conclusions: The Brodsky grading scale demonstrated the highest inter-observer and intraobserver reliability. Our study supports the employment of this tonsil grading system for future clinical care and clinical research in children.

Funding: Child and Family Research Institute, Office of Pediatric Surgical Evaluation and Innovation kumardivjot@gmail.com

Cerebral Processes Related to Analgesia Induced by Distraction and Heterotopic Noxious Counter-stimulation. Alexandra Ladouceura, Pierre Rainvillec and Mathieu Pichéb a

Red Blood Cell Transfusion in Acute Cerebral Injuries: A Systematic Review of Preclinical Studies Mathieu Laflamme1, Amélie Boutin MSc1, Hourmazd Haghbayan1, Michèle Shemilt BSc1, François Lauzier MD MSc FRCPC1,3,4, Lynne Moore PhD1,2, Ryan Zarychanski MD MSc FRCPC5, Jacques Lacroix MD FRCPC6, François Lamontagne MD MSc FRCPC7, Dean A Fergusson PhD8, Philippe Desjardins MD1, Alexis F Turgeon MD MSc FRCPC1,3 1. CHU de Québec Research Center (Hôpital de l’Enfant-Jésus), Population Health and Optimal Health Practices Research Unit (Trauma - Emergency - Critical Care Medicine), Université Laval, Québec, QC Canada; 2. Department of Social and Preventive Medicine, Université Laval, Québec, QC Canada; 3. Division of Critical Care Medicine, Department of Anesthesiology, Université Laval, Québec, QC Canada; 4. Department of Medicine, Université Laval, Québec, QC Canada; 5. Department of Internal Medicine, Sections of Critical Care Medicine, of Haematology and of Medical Oncology, Faculty of Medicine, University of Manitoba, MB Canada; 6. Department of Pediatrics, Critical Care Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC Canada; 7. Department of Medicine, Université de Sherbrooke, Sherbrooke, QC Canada; 8. Clinical Epidemiology Unit, Ottawa Hospital Research Institute, Ottawa, ON Canada;

Abstract withheld at Author’s request

mathieu.laflamme.2@ulaval.ca

The Utility of Pocket-Sized Echocardiography to Assess Left Ventricular Systolic Function Prior to Permanent Pacemaker Implantation Lawrence Laua, Robin Ducasa, Jacques Rizkallaha, Davinder S Jassala, Colette M Seifera a

Section of Cardiology, Department of Internal Medicine, Faculty of Medicine, University of Manitoba, Winnipeg, Canada Background: A subset of patients receiving first-time permanent pacemakers (PPM) may also benefit from an implantable cardioverter defibrillator (ICD) based on the presence of left ventricular systolic dysfunction (LVSD). Routine screening using pocket-sized echocardiography (PSE) may be useful in identifying such patients. Objective: To determine whether PSE can be used by a sonographic trainee to adequately screen for LVSD in a patient population receiving a first-time PPM. Methods: A sonographic trainee (medical student) acquired images using PSE, which were then evaluated by an experienced echocardiologist for both image quality and presence of LVSD. The sensitivity and specificity of assessment by the inexperienced sonographer was determined in comparison the echocardiologist. Results: The patient population included 71 individuals (66% male, mean age 77Âą12 years). Interpretable images where left ventricular ejection fraction (LVEF) could be adequately assessed were obtained in 93% of the patient population. As compared with the echocardiologist, the sonographic trainee had a sensitivity of 60% and a specificity of 98% in detecting LVSD. Conclusions: For patients receiving first-time PPM, the use of PSE by a sonographic trainee combined with interpretation by an experienced imaging cardiologist can triage for the need to perform standard transthoracic echocardiography (sTTE) by determining the presence of LVSD.

Funding: CancerCare Manitoba, H. T. Thorlakson Foundation, Manitoba Medical Service Foundation, Dean of the Faculty of Medicine, Associate Dean (Research) of the Faculty of Medicine, Manitoba Health Research Council, Manitoba Institute of Child Health, Heart and Stroke Foundation, Kidney Foundation of Manitoba, Health Sciences Centre Research Foundation, and Leukemia and Lymphoma Society of Canada, as part of the Bachelor of Science in Medicine program. umlau23@mymanitoba.ca 53

Thyroid Fine Needle Aspiration Biopsy: an Evaluation of its Utility in a Community Setting Andre Le MS3a, Greg Thompson PhD MDb, Yanqing Yi PhDc, Benjamin Hoyt MDb a:

Memorial University of Newfoundland Faculty of Medicine Dalhousie Department of Otolaryngology: Head and Neck Surgery c: Memorial University of Newfoundland Faculty of Medicine: Department of Health and Humanities b:

Background: Thyroid cancer rates are on the rise worldwide with over 5000 new cases estimated in 2012 in Canada. The American Thyroid Association recommends the use of fine-needle aspiration (FNA) in the workup of thyroid nodules to allow triaging. Studies show that thyroid FNA accuracy may vary based on cytopathologists in academic versus community centers. To date, there has been no literature available regarding the accuracy of preoperative FNA results with regards to final pathology in a Canadian community center. Our goals were to demonstrate how accurate thyroid FNA was at our center, comparing these results to other community-based and academic centers. Methods: Medical records for patients who underwent thyroidectomy performed by two otolaryngologists in Fredericton, NB, between September 2008-February 2013 were retrieved. 125 patients with 197 FNA biopsies were analyzed. Statistical analysis with Fisher’s exact test allowed comparison of malignancy rates per FNA category between centers, and chi-square tests were used for FNA distribution comparison. FNAs were compared using each preoperative FNA sample as a separate data point as well as using the “most malignant” FNA per thyroidectomy. Results: Distribution of FNA diagnoses at our center was: 38(19%) benign, 100(51%) inconclusive, 8(4%) suspicious for malignancy, 2(1%) malignant, and 49(25%) unsatisfactory. FNA distribution was significantly different between our center and comparison centers (ChiSquare p<0.05). Malignancy rates for each category were 26.3%, 29.0%, 75%, 100% and 12.2% respectively. Comparison to other community studies showed significantly higher malignancy rates for FNA benign (Fisher’s exact p= <0.05). Comparison to a geographically close academicbased center reveals a similar concerning trend for the malignancies per FNA benign (26.3% vs 16.0%). Conclusion: The high rates of malignancy for each FNAB category in comparison to other studies brings to question whether a high volume, expert cytopathologist would be an asset in interpreting our FNAB samples. Physicians should always use clinical judgment when evaluating thyroid nodules, and in the case of our center, should not always be reassured by a benign FNAB. This study also shows the need to interpret FNAB on a center specific basis and not to base results on those available through the literature.

k55arl@mun.ca 54

Poster Discussion Session 2 Groups A2, B2, C2 presenting Brodie Centre Mezzanine 14:40 â&#x20AC;&#x201C; 15:40 p.m. Wednesday, June 11th, 2014

Intestinal and Gastric Permeability in Children with Eosinophilic Esophagitis and Reflux Esophagitis Aldrich J Leunga, Mordechai A Slaea, Amr Abdelradia, Cheryl Kluthea, Leanne Shirtona, Ronda Danchukb, Sujata Persadc, Rabin Persada, Jon Meddingsd, Hien Q Huynha aUniversity of Alberta Division of Pediatric GI Nutrition, bWomen and Children’s Health Research Institute, cUniversity of Alberta Division of Pediatrics, dUniversity of Calgary Faculty of Medicine Rationale: Eosinophilic esophagitis (EoE) is an allergic and immune-mediated entity that is characterized by eosinophilic infiltration of the esophageal mucosa. It shares a similar clinical presentation to reflux esophagitis (RE), which is due to prolonged and/or excessive exposure to pepsin and stomach acids. As many as 80% of EoE patients may also have a history of atopy and/or allergies, which have previously been shown to be associated with increased intestinal permeability. Objectives: This study was designed to assess gastrointestinal permeability in EoE patients, and to see if it differed from RE, normal scopes, and healthy controls. Methods: Gastrointestinal permeability was measured using multiple sugar probes – lactulose (L), mannitol (M), and sucrose – administered through a sugar drink. Overnight urines were collected and analyzed using high performance liquid chromatography. The different sugar concentrations were used as measures of GI permeability: L/M ratio was a measure of small bowel permeability, and total sucrose was a measure of gastric permeability. Results: We analyzed samples from 23 EoE patients, 13 RE, 14 normal scopes with GI symptoms, and 26 healthy controls. All four groups had lactulose-to-mannitol ratios less than the upper limit of normal (<0.025) and total sucrose values less than 100mg. There was no statistically significant difference in gastrointestinal permeability between the four groups (L/M p=0.26, sucrose p=0.46). Conclusions: Our data suggests that an alteration in GI permeability does not play a role in EoE or RE pathophysiology.

Funding: University of Alberta FoMD, WCHRI, Stollery Children’s Hospital Foundation ajleung@ualberta.ca 57

Voice Discrimination and Recognition in Acquired Prosopagnosia Ran R Liua, Raika Pancaroglua, Charlotte S Hillsa, Brad Duchaineb and Jason JS Bartona a

Departments of Medicine (Neurology) and Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, Canada, bDepartment of Psychology, Dartmouth University, Dartmouth, USA. Rationale: Right or bilateral anterior temporal damage can impair face recognition with relatively preserved perception and discrimination of faces. However, it has been questioned whether this represents an associative variant of prosopagnosia or a multi-modal disorder of person recognition, because recognition via other sensory modalities has seldom been evaluated in these subjects. Objective: Our goal was to determine if voice discrimination or voice recognition was impaired in subjects with impaired face recognition. Methods: We developed two novel tests for voice discrimination and voice recognition. Subjects performed a match-to-sample test of voice discrimination and a test of short-term recognition of recently heard voices, as well as a questionnaire about face and voice identification in daily life. In 73 control subjects, we found that performance had good testing characteristics, with results that were not at ceiling and which had low variance. Using these tests, we tested 10 subjects with apperceptive or associative defects in face recognition after various cerebral lesions. Brain lesions were previously characterized using structural MRI imaging. Results: All four subjects with apperceptive prosopagnosia due to lesions limited to fusiform cortex had intact voice discrimination and recognition. One subject with bilateral fusiform and anterior temporal lesions had impaired discrimination for both faces and voices, which we believe is the first described case of combined apperceptive prosopagnosia and apperceptive phonagnosia. The two subjects with bilateral anterior temporal lesions had impaired face and voice recognition but intact face and voice discrimination. All three subjects with right anterior temporal lesions, two with an associative form of prosopagnosia, had normal voice perception and recognition. Conclusions: Deficits indicating a multi-modal syndrome of person recognition were found in two subjects with bilateral anterior temporal lesions. A modality-specific associative prosopagnosia does exist and can be caused by unilateral right anterior temporal lesions.

Funding: American Academy of Neurology, Fight for Sight Foundation r.liu@alumni.ubc.ca 58

Activated Wnt Signaling targets Sox2+ Treatment-refractory Medulloblastoma Stem Cells. Branavan Manoranjana,b,c, Sujeivan Mahendramc, Chitra Venugopalc, Robin M. Hallettd, Nicole McFarlanec, John A. Hassellb,d, Bradley W. Dobleb,c, Sheila K. Singhb,c,e a

Michael G. DeGroote School of Medicine, bDepartment of Biochemistry & Biomedical Sciences, McMaster Stem Cell & Cancer Research Institute, dMcMaster Centre for Functional Genomics, e Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada c

Rationale: Brain tumours represent the leading cause of childhood cancer mortality, of which medulloblastoma (MB) is the most frequent malignant pediatric brain tumour. The molecular classification of MB has identified activated Wnt and Shh signaling to represent subgroups with good and intermediate outcomes, respectively. While Shh-driven MB has been of particular therapeutic interest, treatment resistance has posed a significant challenge. Given the role of brain tumour-initiating cells (BTICs), in promoting radio- and chemoresistance, we investigated the mechanistic profile of treatment-refractory Shh-dependent MB BTICs. Methods: We investigated the differential stem cell gene expression profile in 325 primary human MBs. Using a subsequent series of knockdown, overexpression, chromatin immunoprecipitation (ChIP), in vitro and in vivo stem cell assays we then assessed the role of Sox2 as a novel downstream target of the Shh effector proteins, Gli1 and Gli2. The in vivo clinical utility of this mechanism was established by treating MB BTICs with conventional radio- and chemotherapy. In order to convert aggressive MBs into an ostensibly benign tumour, treatment-refractory Sox2+ BTICs were then selectively targeted by small molecule Wnt agonists. Results: Changes in Sox2 expression in response to Shh pathway regulators were restricted to a distinct subset of tumour cells, CD15+ BTICs. ChIP experiments further demonstrated the presence of a differential signaling mechanism as Gli proteins showed Sox2 promoter binding only in CD15+ BTICs. The functional relevance of this cell-intrinsic mechanism was characterized by an in vitro and in vivo increase in treatment-resistant Sox2+ BTICs. Treatment of therapyresistant BTICs with Wnt agonists resulted in a survival advantage in human-mouse xenografts along with a decrease in tumour size and frequency of Sox2+ BTICs. Conclusion: Our work demonstrates for the first time that Sox2 is regulated by the Shh pathway in MB and Sox2+ BTICs represent the treatment-resistant clone in Shh-dependent MB. We further provide evidence for a novel therapeutic approach in converting aggressive subgroups into a clinically-treatable Wnt-driven MB. We have also characterized the importance of studying cancer at a cellular level as distinct differences in subsets of tumour cells may not otherwise be appreciated in todayâ&#x20AC;&#x2122;s era of bulk tumour genomic analyses.

Funding: CIHR, CRS, BTFC, ABTF, ALSF, OICR branavan.manoranjan@medportal.ca

Cystic Fibrosis in Canadian Hutterites Menzies, K.J.,a Strobel, S.,a Mayo, J.,b and Hans Pasterkamp,ab a University of Manitoba, Faculty of Medicine, bChildren’s Hospital, Winnipeg, Mb RATIONALE: Hutterites are a communal branch of Anabaptists. They constitute a significant proportion of patients with Cystic Fibrosis (CF) at Western Canadian CF Clinics (WCCFC). While over 1,900 mutations of the CFTR-gene are known today, only three predominant genotypes have been identified in Hutterites. Our study examined the genotype-phenotype correlation in this selected population. METHODS: We used data extracted from the Canadian Patient Data Registry (CPDR), based on Hutterite-specific surnames, and we collected information about Hutterite patients directly from the WCCFC. Since Hutterites may carry the common dF508 mutation and/or the Hutterite-specific M1101K mutation of CFTR, we compared their genotypes to non-Hutterite dF508 homozygous Controls. RESULTS: 82 Hutterites with CF, incl. 16 deceased, were identified from the CPDR. WCCFC data confirmed that 64 of 1,197 patients currently being followed are Hutterite. There were 2,494 CPDR-identified Controls (46.3% female). 34 of Hutterites (41.5%) were homozygous M1101K, 17 (20.7%) heterozygous M1101K/dF508, 15 (18.3%) homozygous dF508 and 4 (4.9%) dF508/unknown. Based on pancreatic enzyme use, Hutterites carrying one or two copies of M1101K were significantly more likely to be pancreatic sufficient: 12/34 (35%) M1101K homozygous and 7/17 (41%) M1101K/dF508 heterozygous vs. 0/15 dF508 homozygous and 44/2,494 (2%) Controls: On average, Hutterites had a better nutritional status, based on their BMI (adults) or BMI% (children): 22.6 ± 4.3 vs. 21.3 ± 3.4 in 39 vs. 1,547 Controls, and 43.5 ± 28.8% vs 38.1 ± 27.0% in 71 vs 2,211 Controls. However, this was statistically significant only for M1101K homozygous patients. That group (32/34) also had significantly better lung function than Controls (2,229/2,494) at last measurement, with FEV1 73 ± 5.0 % predicted vs. 62.2 ± 0.6 %. While the average age at diagnosis was not different, the age at death was younger in Hutterites (n=16) vs. Controls (n=484): 16.7 ± 11.3 y vs. 27.2 ± 10.2 y (p<0.05, t-test). CONCLUSION: Further studies should clarify why Hutterites, considering their apparent genotypic advantage, their life in socially stable communities that are free of environmental tobacco smoke, and their typically calorie-rich diet, may nevertheless have a shorter life expectancy than dF508 homozygous patients with CF.

Funding: MICH, Children’s Hospital, Winnipeg, MB; Cystic Fibrosis Canada; Nakielny Fund menzieskj@gmail.com 60

A Qualitative Overview of the Surgical Safety Checklist Compliance and its Pitfalls in Providence Healthcare Nima Moghaddama, Trina Montemurrob

MD, FRCP(C)

Faculty of Medicine, University of British Columbia, bDepartment of Anesthesia, Providence Healthcare. Vancouver, Canada Rationale: Surgical safety checklists employed during perioperative period have shown to provide a platform for better communication amongst team members and reduce the incidence of postoperative complications. At Providence Healthcare, a customized checklist comprising of three phases â&#x20AC;&#x201C; briefing, timeout, and debriefing- has been developed that incorporates the relevant safety items encountered in our surgical suites. To date, compliance with the surgical checklist has been promising; however, like most facilities, cultural barriers have prevented full adoption of the checklist on some surgical services. Objective: In this study, we set out to determine the enablers and barriers to proper completion of the checklist in a variety of operating rooms. Methods: During an eight-week period, we audited 150 surgeries for completion of the safety checklist at the Providence Healthcare operating rooms. Moreover, through a series of interviews with different surgical staff, we asked for feedback and recommendations on how to improve the checklist. Results: The briefing phase showed the lowest compliance amongst the three phases of the checklist. In almost 10% of cases with completed checklists, the surgical staff did not address some relevant items in the checklist. The timeout phase was routinely done in all surgical suites, showing a near perfect compliance rate. We also noted many instances in which some surgical staff were absent during the checklist completion. In our hospital, cardiac surgery showed the lowest compliance with checklist completion. Despite some resistance to checklist adoption, a â&#x20AC;&#x153;good catchâ&#x20AC;? was noted in 4-8% of the cases audited. Conclusion: The results of this audit have showed that the checklist is an important part of OR safety culture. With the help of the cardiac surgeons, Providence Healthcare has developed a novel, more relevant, cardiac-specific checklist in hopes that adoption and compliance will improve in the future. Other modifications have been made to the checklist for patients receiving nerve blocks etc in hopes of improving compliance and patient safety. We have learned that for a checklist to fully be adopted, it needs to be relevant and valued by all members of the surgical team.

nimamogh@gmail.com

FIFE S.T.A.R.S (Students Taking Academic Review Sessions): The Development of a Novel Peer-to-Peer Learning Platform Jennifer Ortynski, Jesse Basnak, Meghan Chow, Emeka Nzeku and Laurie Mereua aDepartment of Endocrinology, Faculty of Medicine and Dentistry, University of Alberta Rationale: Taking a comprehensive, yet focused, history and physical is a vital aspect of a physicianâ&#x20AC;&#x2122;s repertoire. Despite this, there are numerous time and resource constraints for students to practice these abilities within the current medical curriculum. The University of Alberta is in its fourth year of developing the FIFE S.T.A.R.S program, a novel peer-to-peer clinical learning exercise, offering students extracurricular opportunities to practice their patient interview and physical examination skills. Objectives: To enhance pre-clinical student's history taking and physical exam skills through the implementation of a student-run tailored learning platform. Methods: Student volunteers write case scenarios - based upon physician shadowing opportunities or lecture notes and materials - to supplement learning within the curriculum. These cases are physician reviewed before being used by our student participants during a FIFE S.T.A.R session. A session is comprised of students acting the part of the patients portrayed in the case scenarios, with their peers playing the role of the physician taking their history and/or physical. The student participants evaluate one another as they switch roles, ensuring an educational experience for every participant. These sessions have been streamlined to improve the efficiency of peer-to-peer learning. Through development of electronic assessments, peer evaluation is received automatically by the student to supplement immediate oral feedback after each session. Results: In a survey of first-year medical students, 97% of respondents felt that FIFE S.T.A.R.S filled a gap in the medical curriculum. 82% of students agreed that FIFE S.T.A.R.S. is just as effective as their mandatory clinical skills sessions, and even more effective than their shadowing experiences. Furthermore, nearly all students supported the use of peer-to-peer feedback, and attested to the quality of case scenarios created by their colleagues. Conclusions: By the completion of pre-clerkship training, all students must reach a minimum level of competence. FIFE S.T.A.R.S. has the potential to become a tailored learning platform that aspires to provide participants with case scenarios addressing specific weaknesses identified through our evaluation process. With the feedback received from previous years, future work will focus on improving each session, developing a website, and implementing a tailored learning platform.

Funding: Emerging Leaders in Health Promotion ortynski@ualberta.ca

Diabetes Complications and Comorbidities in Patients Newly Diagnosed with Diabetes in Newfoundland and Labrador (NL): Gender Differences Richa Parihar and Shabnam Asghari Faculty of Medicine, Memorial University of Newfoundland and Labrador Introduction: Diabetic patients are known to develop complications and co-morbidities as a result of the disease. Determining gender susceptibility to diabetic complications can lead to improved patient-centered care for patients. Objectives: To examine the gender differences on complications and comorbidities in patients newly diagnosed with diabetes in NL. Methods: A retrospective cohort study, patients were followed for 5 years from the date of diagnosis, between 1998 to 2003, till their deaths or end of study (2008), whichever came first. The study included individuals who were newly diagnosed with diabetes aged 20 years and older that were identified using provincial medico-administrative data. Gestational diabetes was excluded. Diabetes complications and comorbidities were defined as any record for cardiovascular disease, renal failure, end stage renal disease and lower-extremity amputation during the study period. Late diagnosis was identified as any record for complications at the time of diagnosis. Other variables included healthcare utilization and place of residence. Healthcare utilization was defined as number of visits with family physicians, specialists as well as number of hospitalizations per year. Descriptive analyses as well as multiple logistic regressions were performed. Results: There were 20,292 patients, mean age 60(Âą15); 50% were women. Majority of the patients (63%) belonged to urban areas. Approximately, 17% of the men and 13% of the women had a late diagnosis (p<0.000). Five year after diagnosis, 27% and 18% of men and women respectively had at least one complication, while 18% of men and 16% of women had died during the study period. Men were more likely to develop diabetic complications than women (OR = 1.63, CI 1.51-1.75) after being accounted for age, late diagnosis, place of residence and healthcare utilization. Conclusion: Men are prone to late diagnosis and developing more diabetic co-morbidities than women in NL. The differences in the healthcare utilization and the susceptibility to late diagnose in males can account for the differences observed between gender. Therefore, the gender differences in health and healthcare should be taken into account in diabetes management. Further research is required to determine the biological and healthcare factors.

rp4440@mun.ca 63

Examining Psychosocial Distress in Pediatric Cardiology Patients Bhavika Patel1, Lillian Lai2, Renee Sananes3, Gary Goldfield1, Pat Longmuir1 1

Healthy Active Living and Obesity Research Group, Children’s Hospital of Eastern Ontario Research Institute 2 Division of Cardiology, Children’s Hospital of Eastern Ontario 3 Labatt Family Heart Centre, The Hospital for Sick Children Objective: Examine the emotional health of pediatric cardiology patients and evaluate potential mental health screening tools for cardiac clinic use. Methods: Cross-sectional, observational study with convenience sampling of children attending clinic for routine appointments. Data collection at The Children’s Hospital of Eastern Ontario (2013) and The Hospital for Sick Children (2011). Patients 6 to 14 years of age were approached with responsible cardiologist’s permission. Patient’s emotional health assessed through standardized instruments (PedsQL Core, MASC, BASC-2) administered to parent and child. Five families withdrawn and referred for clinical psychology support due to BASC-2 responses. Results: Fifty patients and their parents were enrolled in the study (24 male, mean age 10.13±2.43yrs). Participants had structural (n=38), rhythm (n=5), heart function (n=4) or infectious (n=3) cardiac diagnoses. Parent and child PedsQL scores demonstrated significantly lower (p<.01) ratings of the child’s emotional functioning compared to ratings of physical (parent mean difference 10.7 (95% CI: 5.2, 16.3); child 11.5 (95% CI: 7.1, 15.8)) and social functioning (parent mean difference 8.8 (95% CI: 3.2, 14.4); child 8.1 (95% CI: 2.7, 13.6)). Lower parent reported quality of life for the child (PedsQL) was associated (R=-0.63, p<.001) with increased anxiety behaviours (BASC). Lower child reported quality of life (PedsQL) was associated with higher multidimensional anxiety symptoms (MASC; R=-0.63, p=0.003) and anxiety-related behaviours (BASC; R=-0.46, p=0.001). Parent (BASC) and child reports of child’s mental health were not correlated (MASC: (r<0.20, p>0.32; BASC, r<0.17, p>0.56), except for attention (r=0.60, p=.03) and hyperactivity (r=0.55, p=.04) problems. Parent and child PedsQL scores were correlated for physical (r=0.33), social (r=0.36), and school (r=0.43) functioning but not emotional functioning (p>0.10). Conclusions Among pediatric cardiology patients, emotional function makes more significant contributions to diminished quality of life than physical function. The PedsQL correlates with extensive mental health assessments (MASC and BASC), and may thus be an appropriate clinical screening tool for patients too young (age < 8 years) for more detailed assessments. Parent and child perceptions are similar for quality of life and attention or hyperactivity problems but differ for most measures of child emotional health. Cardiologists must strive to understand both patient and parent perspectives.

bpate020@uottawa.ca 64

Tumour Necrosis Factor (TNF) Alpha and Interferon (IFN) Gamma Induce Transcriptional Downregulation of Aquaporin 3 RNA Expression through Distinct Mechanisms Michael A. Peplowski, Andrew J. Vegso, Wallace K. MacNaughton Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada Rationale: Although aquaporins (AQP) are known to be involved in water movement and inhibition of AQP3 is associated with the development of diarrhea, the role of AQP3 in the barrier dysfunction that characterizes inflammatory bowel diseases remains unknown. We hypothesized that TNFα and IFNγ were involved in the transcriptional inhibition of AQP3 RNA expression in intestinal inflammation. Methods: AQP3 expression was assessed in C57Bl/6 mice administered dextran sodium sulfate (DSS) to induce colonic inflammation. In vitro, the human adenocarcinoma cell line HT29 was treated with either TNFα or IFNγ and AQP3 pre-mRNA and mRNA expression were assessed by real-time RT-PCR. Cytokine-responsive transcriptional elements were elucidated using AQP3 promoter driven firefly luciferase expression. Results: AQP3 was decreased early in DSS colitis, with diminished basolateral membrane staining in epithelial cells lining colonic crypts. Similarly, TNFα or IFNγ-treated HT29 cells had decreased AQP3 pre-mRNA expression at 2 hr, followed by decreased mRNA expression at 6-12 hr. Assessment of AQP3 protein expression was not possible since all commercially available antibodies tested were unable to detect human AQP3. IFNγ-induced transcriptional inhibition of AQP3 expression was reversed using a broad-spectrum JAK inhibitor (JAK Inhibitor I, 10 µM), but not a JAK2 specific inhibitor (JAK2 Inhibitor II, 10 µM). Truncated AQP3 promoter constructs revealed an IFNγ-responsive transcriptional element in the 251bp region upstream of the TATA box. In contrast, TNFα-induced transcriptional inhibition of AQP3 expression was not reversed by inhibitors of the PI3K, AKT, NF-κB, ERK/MAPK and p38 MAPK pathways (LY294002, 10 µM; Triciribine, 1 µM; BAY11-7082, 30 µM; U0126, 10 µM and SB203580, 10 µM respectively), however, a TNFα-responsive transcriptional element was also found to be localized in the 251bp region upstream of the TATA box. In addition, promoter truncation constructs revealed a constitutive transcriptional suppressor localized to the 251 – 666bp region upstream of the TATA box. Conclusions: AQP3 expression is downregulated early in colitis and this downregulation may be driven by two key mediators of inflammation, namely TNFα and IFNγ, through distinct cell signaling cascades.

Funding: CIHR, CCFC, AIHS mapeplow@ucalgary.ca 65

AP-2delta Regulates Polysialylation of NCAM Via Transcriptional Regulation of ST8SIA Amit Persad1, Xiaodong Li1, Elizabeth Monckton1, Roseline 1 Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta T6G 1Z2, Canada. Introduction: Activating Protein 2 (AP-2) is a family of transcription factors that play critical roles in developmental processes. It is composed of five proteins containing a well-conserved Cterminal domain and a divergent N-terminal domain. Of all five AP-2 proteins, AP-2delta contains the least conserved N-terminal domain. A recent study of AP-2delta knockout mice has identified certain abnormalities in brain development, particularly in the structures of the midbrain. Our lab has previously characterized AP-2delta expression in the developing chick retina as being restricted to a subset of retinal ganglion cells. Aim: To characterize the changes induced by AP-2delta misexpression in chick and by AP2delta knockout in mice by: (i) misexpressing AP-2delta in embryonic chick retina and studying phenotypic and molecular changes, and (ii) studying structural and molecular changes in the AP2delta knockout mice. Methods: We used RT-PCR, in situ hybridization, western blotting and tissue immunostaining to examine ST8SIA mRNA and protein distribution in developing chick retina and knockout mouse tissue. Analysis of ST8SIA promoters was done by chromatin immunoprecipitation (ChIP) followed by PCR amplification. Results: We have observed an abnormal ganglion fibre phenotype in AP-2delta misexpressing chick retina. Furthermore, AP-2delta expression was correlated with elevated levels of polysialic acid (PSA), a modification involved in the attenuation of the adhesive function of neural cell adhesion molecule (NCAM). In particular, we have linked a highly polysialylated variant of NCAM to AP-2delta expression. We also observe increased levels of certain ST8SIA sialyltransferases, such as ST8SIA2, which modulates polysialylation, and ST8SIA5, which is involved in ganglioside synthesis. PCR of DNA retrieved by ChIP identified the ST8SIA2 and ST8SIA5 promoter regions as being occupied by AP-2delta. Moreover, in the AP-2delta knockout mice we observe a reduction in retinal and neural levels of ST8SIA2 and ST8SIA5 RNA. Conclusions: Taken together, these data indicate that AP-2delta plays a role in retinal axon routing and fasciculation through regulation of ST8SIA family proteins, especially ST8SIA2 and PSA-NCAM. In addition, we suggest that ST8SIA5 is also related to AP-2delta associated phenotypic changes.

Funding: CIHR apersad@ualberta.ca

kphipps@dal.ca 67

Funding: Faculty of Medicine Gladys Osman Summer Studentship JamesPius@Dal.ca 68

Predictors of influenza Vaccine Failure and the Impact of Influenza immunization Among Hospitalized Canadian Adults Tara Riddella, Lingyun Yeb, and Shelly McNeilbc, on behalf of the Public Health Agency of Canada/Canadian Institutes of Health Research Influenza Research Network (PCIRN) Serious Outcomes Surveillance (SOS) Networkd aDalhousie University, Halifax, NSb Canadian Center for Vaccinology, IWK Health Centre, Halifax, NSc Division of Infectious Diseases, Department of Medicine, Dalhousie University, Halifax, NSd. The investigators of this network include A. Ambrose, M. Andrew, G. Boivin, W. Bowie, A. Chit, M. Elsherif, K. Green, F. Haguinet, S. Halperin, T. Hatchette, B. Ibarguchi, K. Katz, J. Johnstone, J. Langley, J. Leblanc, M. Loeb, D. MacKinnon-Cameron, A. McCarthy, A. McGeer, S. McNeil, J.Powis, D. Richardson, M. Semret, V Shinde, G. Stiver, S. Trottier, L. Valiquette, H. Wang, D. Webster, L. Ye.

Rationale: Seasonal influenza vaccination is the best form of protection against influenza despite suboptimal vaccine effectiveness (VE). Many Canadians become hospitalized with influenza despite vaccination, however there is no data on whether vaccination may attenuate disease severity, and little evidence of host factors that may be predictive of vaccine failure and severe disease exists. Finally, assessment of the impact of prior season vaccination on VE is critical given concerns raised by some experts that VE may be impaired in patients receiving repeated annual vaccination. Methods: The PCIRN Serious Outcomes Surveillance Network conducted active surveillance for influenza in 40 adult hospitals, in 7 provinces, during the 2011/12 influenza season and estimated influenza VE using a test-negative case-control design. Vaccinated cases and controls were compared to identify risk factors for vaccine failure, and cases with each form of severe disease (developed complications, required mechanical ventilation, died or admitted to ICU) were also compared. In all analyses, logistic regression was performed to determine statistical significance, which was set at P<0.05. Results: A total of 1363 patients, 528 cases and 835 controls, were enrolled. Of the participants, the mean age was 68 years (18 to 104y), 606 (44.5%) were male, and 791 (58%) had the current season influenza vaccine. Among adults aged 16-64y, only male gender predicted severe disease while amongst those aged â&#x2030;Ľ65y, baseline Frailty Index but not age, predicted severe disease. Influenza vaccination was not associated with decreased severity of disease in either group. Obesity and current or past smoking history were predictors of vaccine failure. Receipt of influenza vaccine in the prior season did not impair the effectiveness of the current season vaccine. Conclusions: While influenza vaccine did not appear to attenuate disease severity in those with vaccine failure, predictors of vaccine failure and severe outcomes were identified. This may allow improved targeting of education and suggests that alternate prevention and treatment strategies may be required in the frail elderly.

Funding: CIHR, Canadian Foundation of Infectious Disease Undergraduate Summer Research Award, and the Dalhousie University Faculty of Medicine George Mattar Summer Studentship. tr803383@dal.ca 69

Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON PET Group, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON c University of Toronto, Department of Psychiatry, Toronto, ON b

Rationale: Neuroinflammation has been implicated in schizophrenia (SCZ). Microglial activation, a key component of brain inflammatory processes, is associated with increased expression of mitochondrial translocator protein 18 kDa (TSPO), which has been a target for in vivo imaging using positron emission tomography (PET). Early imaging studies in SCZ used the radioligand [11C]-PK11195 with various properties that hinder its quantification and interpretation, which led to the development of second-generation TSPO radioligands. In second generation TSPO radioligands tissue uptake is dependent on rs6971 polymorphism in the TSPO gene. The present study is the first to use the novel PET radioligand [18F]-FEPPA and high-resolution HRRT tomograph to determine whether there is increased neuroinflammation in patients with SCZ, while taking into account the rs6971 polymorphism. Methods: Fourteen patients with SCZ and 26 healthy volunteers (HV) underwent [18F]-FEPPA PET imaging and MRI. We obtained [18F]-FEPPA total volumes of distribution (VT) for multiple regions of interest (ROI). Severity of psychopathology was assessed and rs6971 polymorphism was genotyped to classify participants as high or mixed affinity binders (HAB and MAB, respectively). Low affinity binders were excluded from the analysis due their instability in fitting. Results: Statistically significant differences in [18F]-FEPPA VTs were observed between the genetic groups (HAB vs MAB; F=20.366 p<0.001) but not between the SCZ and HV (F=1.276 p=0.266). Correcting for genotype, significant correlations were observed between the Positive and Negative Symptom Scale (PANSS) general psychopathology score and the VT in the medial prefrontal cortex (r=0.853 p=0.002). Length of illness correlated inversely with VTs in hippocampus (r=-0.621 p=0.031) and dorsolateral prefrontal cortex(r=-0.621 p=0.024). No other significant correlations were observed. Conclusions: No significant difference in neuroinflammation, as measured by [18F]-FEPPA binding to TSPO, was observed between SCZ and HV. Correlations between [18F]-FEPPA TSPO binding and length of illness and the PANSS general psychopathology score suggest that further studies exploring the relationship between regional neuroinflammation and symptoms of SCZ are warranted.

Funding: Brain and Behaviour Foundation (formerly known as NARSAD) thiviya.selvanathan@medportal.ca 70

Autism-Associated Genes Alter the Morphology of the Mouse Cerebellum P. Steadman1,2, J. Ellegood1, K. U. Szulc 3,4, D. H. Turnbull 3,4, R. M. Henkelman 1,2, J. P. Lerch 1,2; 1 Mouse Imaging Ctr., Toronto, ON, Canada; 2Dept. of Med. Biophysics, Univ. of Toronto, Toronto, ON, Canada; 3Kimmel Ctr. for Biol. and Med. at the Skirball Inst. of Biomolecular Med.; 4 Dept. of Radiology, New York Univ. Sch. of Med., New York, NY Background: In human populations, magnetic resonance imaging (MRI) of autism populations helps assess the neuroanatomical phenotype of the disorder. Over 250 genes have been associated with Autism Spectrum Disorders (ASD) and when performing a human study the population will carry various underlying genetic factors. Further, imaging genetic animal models that recapitulate an autism-associated mutation can quantify the impact of genetics on brain morphology and mitigate the confounding factors in human studies. Methods: We used MRI to image three genetic mouse models with single mutations implicated in autism: Neuroligin-3 R451C knock-in (16 male mice total, 8 wild type (WT)), Methyl-CpG binding protein-2 (MECP2) 308-truncation (54 mice total, 20 WT) and integrin Î˛3 homozygous knockout (24 male mice, 12 WT). Genotypes were compared to WT using ttests; multiple comparisons were controlled using the False Discovery Rate (FDR). Results: We identified the morphological differences specific to the cerebellum, a structure repeatedly linked to autism in human neuroimaging and postmortem studies. To accomplish a comparative analysis, a segmented cerebellum template was created and used to segment each study image. Thirty-nine different cerebellar structures were delineated with our template. For Neuroligin-3 R451C male mutants, the gray (effect size (ES) = 1.94, FDR q = 0.03) and white (ES = 1.84, q = 0.037) matter of crus II lobule and the gray matter of the paraflocculus (ES = 1.45, q = 0.045) were larger in volume. The MECP2 mutant mice had cerebellar volume changes that increased in scope depending on the genotype: hemizygous males to homozygous females. The integrin Î˛3 mutant mouse had a drastically smaller cerebellum than controls with 28 out of 39 cerebellar structures smaller. Further, we report differences in the cerebellum vermis in mouse models with known repetitive behaviours, a common trait of individuals with ASD. Conclusion: Using a novel 3dimensional atlas of the cerebellum, an improvement from 2 to 39 structure definitions, we show specific differences in neuroanatomy across several genetic ASD mouse models. Our imaging results start to characterize genetic influences on neuroanatomy and suggest a link to ASD behaviours. This work further illuminates the cerebellumâ&#x20AC;&#x2122;s role in autism.

pesteadman@gmail.com 71

Following Celebrities’ Medical Advice: A Meta-narrative Analysis Charlie Tana, Steven J Hoffmanbc a

Michael G. DeGroote School of Medicine, bDepartment of Clinical Epidemiology & Biostatistics, McMaster University; Hamilton, Ontario, Canada c Department of Global Health & Population, Harvard School of Public Health; Boston, Massachusetts, USA Rationale: Celebrities can have substantial influence as medical advisors. However, their impact on public health is equivocal: depending on the advice’s validity, celebrity engagements can benefit or hinder efforts to educate patients on evidence-based behaviours and improve their health literacy. Objective: To synthesize multiple disciplinary insights explaining the influence celebrities have on people’s health-related behaviours. Methods: A meta-narrative analysis of economics, marketing, neuroscience, psychology, and sociology literatures was conducted. This involved systematic searches of electronic databases: BusinessSource Complete (1886-), Communication & Mass Media Complete (1915-), Humanities Abstracts (1984-), ProQuest Political Science (1985-), PsycINFO (1806-), PubMed (1966-), and Sociology Abstracts (1952-). Empirical evidence and established theories from each discipline were prioritized in crafting each narrative. Results: According to the economics literature, celebrities distinguish endorsed items from competitors and can catalyze herd behaviour. Marketing studies tell us that celebrities’ characteristics are transferred to endorsed products, and that the most successful celebrity advisors are those viewed as credible, a perception they can create with their success. Neuroscience research supports these explanations, finding that celebrity endorsements activate brain regions involved in making positive associations, building trust and encoding memories. The psychology literature tells us that celebrity advice conditions people to react positively toward it. People are also inclined to follow celebrities if the advice matches their self-conceptions or not following it creates cognitive dissonance. Sociology explains how celebrities’ advice spreads through social networks and how their influence is a manifestation of people’s desire to acquire celebrities’ social capital. Conclusion: The influence of celebrity status is a deeply rooted process that can be harnessed for good or abused for harm. A better understanding of celebrity can empower health professionals to take this phenomenon seriously and use patient encounters to educate the public about sources of health information and their trustworthiness. Public health authorities can use these insights to implement regulations and restrictions on celebrity endorsements and design counter marketing initiatives—perhaps even partnering with celebrities—to discredit bogus medical advice while promoting evidence based practices.

charlie.tan@medportal.ca 72

Harmless Commensal Microbial Neighbors Synergistically Trigger Pseudomonas aeruginosa Virulence Genes in Cystic Fibrosis Christina S. Thorntonac, Matthew L. Workentinee, Christopher D. Sibleyac, Harvey R. Rabinab Douglas G. Storeyd and Michael G. Suretteae. a

Department of Microbiology, Immunology and Infectious Diseases, bAdult Cystic Fibrosis Clinic, Leaders in Medicine Program, Faculty of Medicine, dDepartment of Biological Sciences, University of Calgary, Calgary, Alberta, Canada. eDepartments of Medicine and Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada. c

Rationale: Cystic fibrosis (CF) is the most common lethal genetic disease among Caucasians. 90% of CF patients succumb to pulmonary failure from chronic respiratory infections. Traditionally, research has focused on a narrow spectrum of microorganisms as principal pathogens such as Pseudomonas aeruginosa (PA). The oropharyngeal flora (OF) have been implicated in enhancing pathogenesis of PA while acting as benign commensals, otherwise known as “synergens”. These interactions may skew the balance between clinical stability and acute pulmonary exacerbation, leading to hospitalization. The objectives here were to evaluate these interactions and construct synergen mutants to identify the pathway(s) involved. Methods: Seven oropharyngeal-derived microbes were isolated from sputum of adult CF patients (Streptococcus. sp, Rothia. sp and Actinomyces. sp) and screened in vitro for affecting PA virulence gene expression in co-cultures. The ability of these ‘benign’ microbe ‘synergens’ to stimulate PA virulence genes was evaluated using transformed PA reporters harboring luciferase constructs for known virulence gene promoters. The luciferase light production caused by the coculture vs. monoculture of PA was monitored to quantify 'synergen' activity by measuring changes in light production. Transposon libraries in the synergens were constructed with 8000 mutants screened. Results: Up-regulation of PA virulence gene expression was seen for all 7 synergens tested. The virulence pathways affected were for quorum sensing or bacterial communication. The highest upregulation was by Streptococcus. sp, with 1800-fold increased virulence gene expression in coculture as compared to PA alone. From 8000 synergen mutants, 526 were isolated as hits involved in co-culture. 61 of these mutants were conserved in all PA reporters, suggesting common interaction pathway(s) triggered by the synergens. 35 mutants displayed 10-fold or greater activation in co-culture as compared to the wild-type, demonstrating a gain-of-function mutation. Conclusions: We have found that seemingly harmless non-pathogenic oropharyngeal ‘synergen’ microbes can trigger virulence genes in PA found in CF patients. The production of secondary signaling molecules have been shown to influence pathogen virulence profiles by modulating bacterial cell-cell communication pathways. Understanding the way in which commensal microbes synergistically trigger virulence will lead to better treatment and management of CF. Funding: Canadian Institutes of Health Research (CIHR) Doctoral Studentship, Alberta Innovates Health Solutions (AIHS) MD/PhD Studentship, Cystic Fibrosis Canada (CFC) Studentship.

ceshaghu@ucalgary.ca 73

Evaluation of a novel molecular therapeutic target in non-small cell lung cancer Ethan Toumisheya, Jonathan Moorea, Dr. Cenk Acarb, Jane Agarb, Dr. Brian Johnstonb, Dr. Tony Reimana,b,c a

Department of Medicine, Dalhousie Medicine bSaint John Regional Hospital, Horizon Health Network cUniversity of New Brunswick

Rationale Lung cancer is the second most common cancer among Canadian men and women and the leading cause of cancer mortality. Currently there has been a development of targeted therapies that have improved outcomes for a select group of patients. New and better therapies need to be developed for patients suffering from lung cancer. We are working with a biotech company on the evaluation of a proprietary novel compound which could be a novel therapy for lung cancer. Here we investigated the expression of the molecular target of this novel compound in resected nonsmall cell lung cancer (NSCLC). Materials and Methods The study used a NSCLC clinical-pathological database consisting of a clinical information database along with corresponding tumour tissue microarrays. These samples were stained using an immunohistochemical protocol for the target protein of interest and then two investigators evaluated the expression level using a semi-quantitative method (H-score). This method produced a potential range of protein expression from 0-200, 0 being no expression and 200 being high expression. Protein expression was analyzed with respect to demographic data, clinical parameters, and survival outcomes. Results There was sufficient tumor sample and clinical information to include 170 patients out of 202. The patientsâ&#x20AC;&#x2122; protein expression is normally distributed. Median overall survival in this cohort was 4.33 years (95% CI=(3.69,5.51) and one year survival was 83.4% (95% CI=77.9, 89.3). Using cut-off analysis, patients were separated in to a low expression group (n= 131, 81.5%) and a high expression group (n=31, 18.5%). High protein expression is associated with reduced overall survival (p=0.005) and reduced time to relapse (p=0.0456). Conclusion Expression of the novel molecular therapeutic target is found in NSCLC, and high expression of this protein is indicative of poor prognosis both in terms of overall survival and time to relapse. This result provides evidence that the protein is a potential therapeutic target for NSCLC chemotherapy. Furthermore, targeting this protein could provide novel therapy for those patients who face worse prognoses.

Funding: DMRF Katherine Robarts Studentship toumishey@gmail.com 74

Funding: CIHR Camille.vallee-gravel@mail.mcgill.ca 75

Variables Affecting Whole-blood Cobalt Levels in Patients Implanted with the DePuy ULTAMET® Metal-on-Metal Articulation Luke Vanderhooft, Colin Burnell, Lynda Loucks, Eric Bohm Section of Orthopaedic Surgery, University of Manitoba Concordia Joint Replacement Group Purpose: Metal on metal (MoM) total hip replacements (THA) have been implanted in large numbers, however, recent concerns about elevated metal ions has resulted in markedly decreased use of this bearing surface. The purpose of this study is to evaluate whether there is a variation in whole blood cobalt (Co) levels based on gender, unilateral vs bilateral device, age, body mass index (BMI), years implanted and acetabular cup inclination. Methods: A random sample of 114 patients (130 THA) implanted with the DePuy Ultamet® MoM THA was selected from a prospective academic arthroplasty database. All patients were a minimum of six months from surgery, and underwent whole blood cobalt levels and radiographic assessment of cup angle. Co levels were compared by unilateral / bilateral status and gender. Correlation analysis was used to assess the relationship between age, body mass index (BMI), years implanted and cup inclincation. Results: Thirty-two women and 82 men had 98 unilateral and 16 bilateral MoM THA. At time of follow up, the mean age was 56.6 years, BMI was 30.6, length of time implanted was 4.6 years, cup inclination was 45.6 degrees, and Co level was 2.7 ug/l. Intra and inter-rater reliability of the inclination angle measurements was established with an ICC of 0.96 and 0.91, respectively. Seven of 114 patients (6.1%) had Co levels ≥7.0 ug/l. Median Co levels in bilat patients was 2.5 versus 1.4 ug/l in unilateral patients, p =0.03. Co levels in males was 2.8 versus 2.4 ug/l in females, p=0.45. The correlation between Co level and cup inclination: -0.09 (p=0.442); BMI: 0.01 (p=0.903), age: 0.05 (p=0.595) and years implanted: 0.30 (p=0.002). Conclusion: Elevated Co levels remain a concern with MoM THA designs. With our sample, we were unable to detect a relationship between Co levels and age, gender, BMI or cup inclination. The number of years implanted had a weak (r=0.3) but statistically significant positive correlation with Co level. Patients with bilateral devices also had statistically higher median levels than those with unilateral THA. These findings appear to suggest that Co levels should be followed in most patients, and particularly those with bilateral THAs, as levels may tend to rise with increased length of follow up.

lvanderhooft@gmail.com 76

rob.vanner@mail.utoronto.ca

Analyzing and Optimizing the Treatment of Patients with Staphylococcus aureus Bloodstream Infections Zhanni Webera, Sheryl Zelenitskyab a

Faculty of Pharmacy, University of Manitoba, bDepartment of Pharmacy, St. Boniface General Hospital (SBGH), Winnipeg, Canada. Rationale: S.aureus bloodstream infection (BSI) is one of the most common and recognized BSIs. Despite treatment with antimicrobials with in vitro susceptibility, all-cause mortality rates range from 20% to 50%. The treatment of S.aureus BSI remains a major challenge. Objectives: To describe cases of S.aureus BSI in the clinical setting and provide strategies to optimize antimicrobial treatment practices. Methods: A retrospective study of adult patients at SBGH with laboratory confirmed and clinically significant S.aureus BSI from 2009 to 2013. Patient medical records were reviewed by using electronic database and medical charts. Cases of polymicrobial BSI, dialysis, early mortality and relapsing episodes were excluded. Descriptive statistics were used to characterize the study population, treatment practices and clinical outcomes. Results: 108 cases were included. The mean age was 66 + 19 years, 34.3% were female, 71.3% were complicated and 14.9% were methicillin-resistant (MRSA) infections. The selection of optimal antimicrobial therapy (broad or targeted) increased from 42.6% to 51.9% to 62.0% in each consecutive 24 hour timeframe, post index blood culture. Broad therapy was initiated at 7.1 + 10.5 hours (median 4 hours) compared with 64.0 + 44.9 hours (median 63.8 hours) for optimal targeted therapy. Early therapy for methicillin-sensitive S.aureus (MSSA) included cloxacillin in 60.9% and cefazolin in 18.5% of cases. Maximum doses of cloxacillin and cefazolin were used in 87.5% and 76.5% of cases, respectively. In patients receiving vancomycin, 37% achieved therapeutic troughs >15mg/L within the first 3 days of therapy. Full clinical response was observed by day 3 in 31.5% of cases, day 5 in 45.4% and day 7 in 55.6%. The lack of clinical response observed in 28.7% of cases by day 7 was consistent with the end-of-treatment failure rate of 29.6%. The in-hospital, infection-related mortality was 20.4%. Conclusions: At 72 hours, 38% of cases had still not received optimal antimicrobial therapy. The mean time to optimal targeted therapy was 64.0 hours. Furthermore, clinical response within the first 7 days was indicative of end-treatment-response and survival. In conclusion, opportunities exist to improve the outcomes of S.aureus BSI by hastening the diagnosis and optimizing antimicrobial treatment strategies.

Funding: Leslie F. Buggey Graduate Scholarship. umweber@myumanitoba.ca. 78

Digital Atlas of Ultrasound-Guided Trunk and Lower Limb Nerve Blocks James Yan*, Marjorie Johnson†BSc, PhD, Rakesh V Sondekoppam‡ MD, Sugantha Ganapathy‡ MD FRCPC *Schulich School of Medicine & Dentistry, †Department of Anatomy and Cell Biology, ‡Department of Anesthesia and Perioperative Medicine, Western University, London, Ontario, Canada Introduction: Anatomy is integral to the training of anesthesia procedures. Models based on ultrasound scanning of cadavers with or without block performance and their subsequent dissection are developed with the intent to incorporate anatomical basis of sonoanatomy and procedure performance. These models can be a significant burden to training costs and are limited in number. An interactive platform which demonstrates the relevant gross anatomy and sonoanatomy may have a place in assessing and improving the cognitive skills important for resident and fellowship training in ultrasound-guided regional anesthesia procedures. We aim to develop a digital atlas regional anesthesia procedures under ultrasound to enhance sonoanatomy training. Methods: The atlas uses cadaver dissections, cross-sectional Visible Human Project images, and surface anatomy to link ultrasound images with corresponding surface and internal anatomy. Significant anatomical structures are identified and labeled. Narrated video of relevant ultrasoundguided nerve blocks is provided with written descriptions of the blocks and their indications. The truncal blocks demonstrated include both neuraxial blocks and non-neuraxial blocks. The lower limb includes femoral, obturator, popliteal, sub gluteal sciatic, and the adductor canal nerve blocks. A custom web platform houses the atlas online for trainee use. Results and discussion: The resulting digital atlas training module is expected for use by medical students, anesthesiology residents, and regional anesthesia fellows as an educational resource. Currently, our anatomy lab holds monthly ultrasound-guided nerve block training sessions wherein gross anatomy is taught using cadaveric dissections and on live human volunteers. The digital atlas may be incorporated in training to provide real-time feedback of block knowledge. The project aims to create a widely accessible digital atlas that will enhance the training of safe and effective nerve blocks. When completed, we hope to test the efficacy of the atlas on novice and experienced learning behaviour with aims to improve the teaching methods of ultrasound-guided regional anesthesia.

Funding: SROP (Schulich Research Opportunities program) Personal Conflict of Interest: None Jan.jry@gmail.com 79

Reprogramming Metabolism with Metformin Improves Tumor Oxygenation and Radiotherapy Response Vanessa E. Zannella1,2,5,짜, Alan Dal Pra1,3,4,짜, Hala Muaddi1,5,짜, Trevor D. McKee1, Shawn Stapleton1,6, Jenna Sykes1, Rachel Glicksman3,4, Selim Chaib1,7, Paul Zamiara1,2, Michael Milosevic1,2,3,4, Bradly G. Wouters1,4,6,7,8, Robert G. Bristow1,2,3,4,$, Marianne Koritzinsky1,2,4,$* 1 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. 2 Institute of Medical Science, University of Toronto, Canada. 3 Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada 4 Department of Radiation Oncology, University of Toronto, Canada. 5 Faculty of Medicine, University of Toronto, Canada. 6 Department of Medical Biophysics, University of Toronto, Canada. 7 Department of Radiation Oncology (Maastro Lab), GROW School for Oncology & Developmental Biology, Maastricht University, Maastricht, The Netherlands. 8 Selective Therapies Program, Ontario Institute for Cancer Research, Toronto, ON, Canada. 짜 These first authors contributed equally $ These senior authors contributed equally Purpose: Tumor hypoxia is a negative prognostic factor in multiple cancers, due in part to its role in causing resistance to radiotherapy. Hypoxia arises in tumor regions distal to blood vessels as oxygen is consumed by more proximal tumor cells. Reducing the rate of oxygen consumption is therefore a potential strategy to reduce tumor hypoxia. We hypothesized that the anti-diabetic drug metformin, which reduces oxygen consumption through inhibition of mitochondrial complex I, would improve radiation response by increasing tumor oxygenation. Experimental Design: Tumor hypoxia was measured in xenografts before and after metformin treatment using 2-nitroimidazole hypoxia markers quantified by immunohistochemistry (IHC), flow cytometry and positron emission tomography (PET)-imaging. Radiation response was determined by tumor growth delay and clonogenic survival in xenografts with and without administration of metformin. The impact of metformin use on outcome was assessed in 504 localized prostate cancer patients treated with curative-intent, image-guided radiotherapy (IGRT) from 1996 to 2012. Three-year biochemical relapse-free rates were assessed using the Kaplan-Meier method. Results: Metformin treatment significantly improved tumor oxygenation in two xenograft models as measured by IHC, flow cytometry and PET imaging. Metformin also led to improved radiotherapy responses when mice were administered metformin immediately prior to irradiation. Clinically, metformin use was associated with an independent and significant decrease in early biochemical relapse rates (p=0.0106). Conclusion: Our data demonstrate that metformin can improve tumor oxygenation and response to radiotherapy. Our study suggests that metformin may represent an effective and inexpensive means to improve radiotherapy outcome with an optimal therapeutic ratio.

vanessa.e.zannella@gmail.com 80

A Novel Electrophysiological Method for Quantifying the Severity and Extent of LengthDependent Polyneuropathy Kevin J. Zuoa, Robyn Leea, Nicole Clarkeb, and K. Ming Chanc aFaculty of Medicine & Dentistry, b Centre for Neuroscience, cDivision of Physical Medicine & Rehabilitation, University of Alberta, Edmonton, AB, Canada Rationale: Length-dependent polyneuropathy is a complication of various common disorders, including diabetes, where 50% of patients are affected. Sensory symptoms can be highly debilitating and manifest initially in the distal foot before progressing proximally in a symmetrical “glove and stocking” distribution. Current electrophysiological methods cannot assess nerve function proximal to the ankle, which greatly limits the clinician’s ability to monitor disease progression and evaluate treatment response. Methods: We developed a novel, non-invasive electrophysiological technique capable of measuring the most proximal segment of the sural nerve at the popliteal fossa. We performed nerve conduction studies on 10 cm segments of the sural nerve from forefoot to ankle, ankle to lower leg, and proximal calf to popliteal fossa, as well as the superficial radial nerve at the wrist. Sensory nerve action potential (SNAP) amplitude and conduction velocity (CV) were calculated. Normative values were established from 63 healthy controls spread into young (20-40 years), middle (41-60 years) and old (>60 years) age ranges. Results were compared with those from 60 age-matched Type I and II diabetic patients. Clinical symptom severity was scored using Michigan Neuropathy Screening Instrument (MNSI). Results: Excellent intraobserver (r=0.87, p<0.01) and interobserver (r=0.87, p<0.01) reliability of electrophysiological measures were obtained. In healthy controls, SNAP amplitudes were greatest at the wrist, then the ankle, proximal calf, and forefoot. Differences in electrophysiological measures were insignificant between age groups except at the forefoot and ankle, where SNAP amplitudes were smaller in the old age group compared to the young (p<0.05). In diabetic patients, SNAP amplitudes and CV were significantly lower at all sites than in age-matched controls (p<0.05), particularly at the most distal nerve segment (forefoot): 4.5 ± 2.6 µV, 41 ± 6 m/s in controls vs. 1.3 ± 1.9 µV, 19 ± 20 m/s in diabetics (p<0.05). Proximal nerve segments, including the proximal calf, were also affected in diabetic subjects. Symptom severity in diabetic patients scored by MNSI was significantly correlated with electrophysiological measures at the ankle (p<0.05). Diabetes duration and age at diagnosis were not correlated with electrophysiological values. Conclusions: Compared to control subjects, significantly lower electrophysiological values were recorded in diabetic patients, even in the most proximal segment of the sural nerve at the proximal calf. Electrophysiological measures are significantly correlated with symptom severity. This novel, reliable technique improves longitudinal monitoring of length-dependent polyneuropathy and evaluation of response to treatment.

Funding: Alberta Innovates Health Solutions Summer Studentship kzuo@ualberta.ca

Inter-provincial Variation and Determinants of Access to Team-based Primary Care in Canada Austin Zygmunta, Dr. Fred Burgea aDepartment of Family Medicine, Dalhousie University. Halifax, Canada. Rationale: Efforts to reform health care in Canada have resulted in structural changes to primary care delivery over the past ten years. One such effort has been the introduction of team-based primary care models in all provinces. These models involve general practitioners working collaboratively with other health providers to deliver care to patients. As health care delivery is the responsibility of provincial governments and not the federal government, the adoption of these new models varies widely across the country. In addition, minimal research is available on how the composition of team-based care may vary amongst provinces and what may predict patientâ&#x20AC;&#x2122;s access. Objectives: This study examines variations in the composition of team-based primary care amongst Canadians provinces and identifies patient characteristics that may predict access. Methods: This study uses data from a cross sectional population survey, the 2008 Canadian Survey of Experiences with Primary Health Care, the most recent and only national survey of primary healthcare in Canada. The total sample size available for analysis was 11,521 (70.8% response rate), however, respondents with no regular primary care physician were excluded (n=1,618). Team-based care comprised general practitioner (GP) plus nurse-only teams; GP plus other health provider-only teams; and GP plus both nurse and other health provider teams. Logistic regression was used to examine determinants of access to team-based care, adjusting for age, sex, health status, total number of chronic conditions, income, education, and province of residence. Results: The composition of team-based care varies widely amongst the provinces, with GP plus nurse-only teams the most common models except in Quebec and Manitoba where GP plus other health provider-only teams were more common. The only statistically significant predictor of access to team-based care was a patientâ&#x20AC;&#x2122;s province of residence. Conclusion: Future assessments should aim to increase accuracy in the definition of team-based care through improvements in survey question design and patient education. With continuity of primary care reform in Canada, a new national survey is needed.

Funding: This work was supported by Dalhousie Universityâ&#x20AC;&#x2122;s Faculty of Medicine through their Dr. F. Murray Fraser Summer Studentship. austin.zygmunt@dal.ca 82

Lightning Oral Presentations SESSION 2

Procurity Lecture Theatre, Apotex Building Main Floor, Room 164 15:40 â&#x20AC;&#x201C; 16:50 Wednesday, June 11th, 2014

vanessa.e.zannella@gmail.com 85

Uncoupling the in vivo tumorigenic properties of tumor propagating cells from their in vitro properties acf

Christopher Aiken, bcfLudivine Morrison, cfMelissa Bridges, defMarc Del Bigio, abcefTamra Werbowetski-Ogilvie a

umaiken@cc.umanitoba.ca 86

Treating donor site pain in burn victims that have undergone autologous split-thickness skin grafting: A review of the literature Amanda Eslinger1, Duncan Nickerson MD, FRCSC, FACS2 1

Leaders in Medicine, Undergraduate Medical Education; 2Division of Plastic Surgery, Department of Surgery, University of Calgary

Introduction: Current standard of treatment for deep burn injuries is split-thickness skin grafting(STSG). STSGs are harvested from a remote area of healthy skin creating a new wound referred to as the donor site. Pain, caused by harvest, is reported to be one of the most distressing symptoms following STSG. Resultant pain can affect early mobilization, sleep and the need for analgesics post-operatively. Although donor site pain presents a significant problem, there are no evidence-based guidelines concerning its treatment. The purpose of this literature review was to synthesize information on current practices for managing donor site pain and to determine whether further investigation of donor site pain management is warranted. Methods: Ovid MEDLINE was searched using the terms ‘burn’, ‘donor site’, ‘pain’, and ‘splitthickness skin graft’ from 2003–2013. Only human studies were included in the review. NonEnglish language articles were excluded from the review. Results: The literature review identified five techniques used in minimizing donor site pain. One technique initiated treatment prior to STSG harvest by infiltrating the pre-harvest site with a combined anesthetic/tumescent solution. Four techniques initiated treatment immediately following STSG harvest: 1) continuous subcutaneous local anesthetic infusion (CSLA); 2) subcutaneous injection of anesthetic; 3) application of topical anesthetic gels; and 4) the use of ice packs. All studies measured pain using a visual analog scale(VAS). In a majority of studies subjects gave anecdotal reports of decreased pain at the donor site regardless of the technique used to treat pain. Few studies showed that a particular technique significantly decreased VAS scores. Conclusions: Although donor site pain is of chief concern for both the patient and the physician its treatment is scantily addressed. This review highlights the need to design and carry out more rigorous and effective studies in order to work towards standardizing care and improving the patients’ pain experience following STSG harvest.

ajesling@ucalgary.ca 87

ceshaghu@ucalgary.ca 88

Funding: CIHR, Vanier CGS, Alberta-Innovates Health Solutions, Canadian Breast Cancer Foundation, Alberta Cancer Foundation, Ono Pharmaceuticals Ltd. benesch@ualberta.ca 89

Voice Discrimination and Recognition in Acquired Prosopagnosia Ran R Liua, Raika Pancaroglua, Charlotte S Hillsa, Brad Duchaineb and Jason JS Bartona a

Funding: American Academy of Neurology, Fight for Sight Foundation r.liu@alumni.ubc.ca 90

Funding: This work was supported by Dalhousie Universityâ&#x20AC;&#x2122;s Faculty of Medicine through their Dr. F. Murray Fraser Summer Studentship. austin.zygmunt@dal.ca 91

Participating Medical Schools

Symposium Contact Information CNMSRS On-Site Contact Info Kimberley Ormiston

204-789-3558 204-333-7426 cell Office: S212 Medical Services Bldg. 750 Bannatyne Avenue University of Manitoba Winnipeg, MB R3E 0T6 Email: kim.ormiston@med.umanitoba.ca

Canad Inns HSC

Canad Inns Destination Centre Health Sciences Centre 720 William Avenue Winnipeg, MB Local phone 204-269-9090 Toll-Free 1-888-332-2623 (CANAD)

Lower Fort Garry National Historic Site of Canada Tel: 204-785-6050 Toll Free: 1-888-773-8888 5925 Highway 9 St. Andrews, MB R1A 4A8

Sponsoring Agencies

Dr. Paul H.T. Thorlakson Foundation