2015 CNMSRS Compendium by Kimberley Ormiston

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Table of Contents

WELCOME

CHAIRS, DISCUSSION LEADERS AND ORGANIZING COMMITTEE

SCIENTIFIC PROGRAM (Complete Scheduling of Poster and Oral Presentations)

DETAILED ORAL PRESENTATION SCHEDULE SESSION 1 OF 2 (A.M. SESSION)

POSTER GROUPS A,B,C – POSTER DISCUSSION

POSTER GROUPS D,E – POSTER DISCUSSION

DETAILED ORAL PRESENTATION SCHEDULE SESSION 2 OF 2 (P.M. SESSION)

LIGHTNING ORAL ABSTRACTS A.M. SESSION

GREG HOSIER, DALHOUSIE UNIVERSITY

GABRIEL DEVLIN, MCGILL UNIVERSITY

DAVID BERGERON, UNIVERSITÉ de LAVAL

PAULA SLANEY, UNIVERSITY OF NEWFOUNDLAND AND LABRADOR

ELIZABETH SIMMS, MCMASTER UNIVERSITY

ANDREW DHAWAN, QUEEN’S UNIVERSITY

CRISTINA BOSTAN, UNIVERSITÉ de MONTRÉAL

CAMERON KAYE, UNIVERSITY OF MANITOBA

POSTER DISCUSSION SESSION 1 OF 2 GROUPS A, B, C

DEREK CHAN, MCMASTER UNIVERSITY

BING YU CHEN, MCGILL UNIVERSITY

KYLIE GOODYEAR, MEMORIAL UNIVERSITY OF NEWFOUNDLAND AND LABRADOR

ALEXANDRA PRIOR, UNIVERSITY OF MANITOBA

CHRIS AIKEN, UNIVERSITY OF MANITOBA

JORDAN CROSINA, UNIVERSITY OF MANITOBA

SONAM MAGHERA, UNIVERSITY OF OTTAWA

JEFFREY LE, DALHOUSE UNIVERSITY

ALEXANDER OBERC, MCMASTER UNIVERSITY

HILARY PRICE, MEMORIAL UNIVERSAL OF NEWFOUNDLAND AND LABRADOR

LAURA GOODLIFFE, QUEEN’S UNIVERSITY

MARGOT ROSENTHAL, UNIVERSITY OF MANITOBA

JESSICA KAPRALIK, UNIVESITY OF OTTAWA

RICHARD WU, UNIVERSITY OF TORONTO

NICHOLAS HOLZAPFEL, MCMASTER UNIVERSITY

JOY HOLLAHAN, MEMORIAL UNIVERSITY OF NEWFOUNDLAND AND LABRADOR

SHANNON CHUN, QUEEN’S UNIVERSITY

JEONGA GIM, UNIVERSITY OF MANITOBA

REBECCA LANG, UNIVERSITY OF MANITOBA

JAMES WU, UNIVERSITÉ de MONTRÉAL

CAITLIN CHRYSTOJA, UNIVERSITY OF TORONTO

ASHISH DESHWAR, UNIVERSITY OF TORONTO

Poster Groups D, E: POSTER DISCUSSION

VICTOR TANG, QUEEN’S UNIVERSITY

MEAGAN LYSZCZYK, UNIVERSITY OF ALBERTA

THOMAS FUDGE, UNIVERSITY OF MANITOBA

JARED WILCOX, UNIVERSITY OF TORONTO

DAN COJOCARU, UNIVERSITY OF BRITISH COLUMBIA

MARK GRANT, QUEEN’S UNIVERSITY

EPSITA SHOME, UNIVERSITY OF ALBERTA

NOREN KHAMIS, UNIVERSITY OF BRITISH COLUMBIA

NOREEN SINGH, UNIVERSITY OF CALGARY

EUGEN LUNGU, UNIVERSITÉ de MONTRÉAL

P.M. SESSION: LIGHTNING ORAL PRESENTATIONS

ROSS PRAGER, UNIVERSITY OF BRITISH COLUMBIA

JESSICA LUC, UNIVERSITY OF ALBERTA

SABIN BOZSO, UNIVERSITY OF ALBERTA

CHRIS NEWELL, UNIVERSITY OF CALGARY

JAMES STONE, UNIVERSITY OF MANITOBA

SARAH MAXIMOS, UNIVERSITY OF MONTREAL

ROBYN ELPHINSTONE, UNIVERSITY OF TORONTO

PARTICIPATING SCHOOLS

PARTICIPANT CONTACT INFORMATION

SPONSORING AGENCIES

Welcome to the 7th Annual 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 53 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 FACILITATOR Paula Slaney – Memorial University of Newfoundland and Labrador - Facilitator Group A Christina Bostan – Université de Montréal – Facilitator Group B Cameron Kaye - University of Manitoba – Facilitator Group C Ross Prager – University of British Columbia – Facilitator Group D Greg Hosier – Dalhousie University – Facilitator Group E

ORAL PRESENTATIONS Session Chairs: Session 1 – Derek Chan – McMaster University Penny Toliopoulos - Université de Montréal

Session 2 - Robert Schmidt – University of Manitoba Connie Lee – University of Alberta

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

Tuesday, June 2nd, 2015 12:00 – 11:00 p.m. 4:00 – 5:30 p.m. 4:00 – 5:30 p.m

Students check in at Canad Inns Destination Centre throughout the day Registration desk opens in Brodie Atrium. Please note there are two registration desks for 2 concurrent student research conferences. Please ensure you register at the CNMSRS desk (not CSHRF) Trainees should mount their posters prior to 5:30 p.m. Poster number/position assignments given at registration desk

6:00 p.m.

Opening reception – Mixer and Welcome Banquet Canad Inns Ambassador Room A (second floor). Business casual dress.

6:45 p.m.

Welcome by Dr. Kent HayGlass, Director Advanced Degrees in Medicine, CNMSRS Coordinator

7:00 p.m.

Dinner

7:50 p.m.

8:00 p.m.

CITAC (Clinical Investigator Trainee Association of Canada) presentation. CITAC representative Chris Aiken, Executive Council Keynote speaker Anthony Jevnikar, MD/MSc, FRCPC Western University ‘Why was Obtaining Research Training the Right Decision for Me? Dr. Jevnikar is Director of Transplantation Nephrology at London Health Sciences Centre and a scientist at the Robarts Research Institute and Lawson Health Research Institute. Fellows in his lab study autoimmune diseases, including diabetes and lupus kidney disease, and the prevention of kidney transplant rejection

Wednesday, June 3rd, 2015 7:30 a.m. to 8:45 a.m.

Late registration table on the 2nd floor Atrium, Apotex Atrium

7:45 a.m. to 8:20 a.m.

Continental Breakfast 2nd floor Atrium, Apotex Centre

8:40 a.m.

Welcome by Dr. Kent HayGlass Procurity Lecture Theatre, Room 164, main floor Apotex Centre

8:45 a.m. to 10:30 a.m.

Lightning Oral Presentations (6 minute oral presentation, 4 minutes for questions: 10 minutes total). Procurity Lecture Theatre, main floor Apotex

10:40 a.m. to 11:40 p.m.

Poster Discussion Session 1. Trainee groups A1, B1 and C1 presenting. Coffee available. Brodie Mezzanine

11:45 a.m. to 12:30 p.m.

12:30 p.m. to 1:30 p.m.

1:30 p.m. – 2:30 p.m.

2:40 p.m. – 3:30 p.m. 3:40 p.m. – 4:50p.m.

4:50 p.m.

Free Social Time

Luncheon Joe Doupe Concourse (CNMSRS and CSHRF). Lunch ticket required (included in your name badge holder) Keynote Speaker Dr. Anthony Jevnikar MD/MSc, FRCPC Dr. Jevnikar is Director of Transplantation Nephrology at London Health Sciences Centre and a scientist at the Robarts Research Institute and Lawson Health Research Institute. Fellows in his lab study autoimmune diseases, including diabetes and lupus kidney disease, and the prevention of kidney transplant rejection. ‘Regulating Cell Death: Translation to Clinical Transplant Survival’ Frederic Gaspard Theatre (Theatre A) Professional Development Workshop: ‘Making the most of your experience as an MD PhD or MD MSc student: Tips, Pitfalls and Successful Strategies’ Moderator; Dr. Kent HayGlass Panelist: Dr. Anthony Jevnikar Panelist: Dr. Greg Costain, MD/PhD Graduate 2015, University of Toronto Attendees are encouraged to briefly review the document found on the electronic version of schedule (website). Frederic Gaspard Theatre (Theatre A) Poster Discussion Session 2. Trainee groups A2, B2 and C2 presenting. Brodie Mezzanine. Lightning Oral Presentations Session 2. Procurity Lecture Theatre, Main Floor Apotex. 6 minute oral presentation, 4 minutes for questions (10 minutes in total). Overview by Dr. Xi Yang, CSHRF Coordinator, June 4th event ‘International Symposium on Immune Balance and Health’ Procurity Lecture Theatre, Apotex Centre Options you may wish to consider; Meeting new friends for dinner (diverse restaurant choices in the Exchange District), Polo Bear Exhibit at Assiniboine Park, The Canadian Human Rights Museum, The Forks, or the Winnipeg Art Gallery (known as the WAG)

CNMSRS participants are registered to attend all CHSRF events this day. Please wear your CNMSRS name badge for food venues.(no need to register for the Symposium) Continental Breakfast (Cinnamon Buns, Coffee and Juice), J. Hildes 8:00 a.m. to 9:00 Concourse adjacent to 2nd floor entrance Frederic Gaspard Theatre. Canadian Student Health Research Forum CSHRF) International Symposium on Immune Balance and Health 9:00 a.m. to 12:00

   

Wanjun Chen, MD National Institutes of Health, Bethesda, Maryland Peter Lipsky, MD AMPEL BioSolutions, Charlottesville, Virginia Dr. Yong-Jun Liu, MD, PhD MedImmune, Gaithersburg, Maryland Luanne Metz, MD University of Calgary, Alberta 8

11:00 a.m.

CSMSRS students to check out of hotel. Please advise front desk that you will require a secure, luggage storage area until your shuttle to the airport.

12:00 p.m. – 1:30

Luncheon and CSHRF Awards Ceremony – Brodie Atrium

1:30 p.m. – 4:30

CSHRF ongoing lectures, Frederic Gaspard Theatre (Theatre A)

5:15 p.m.

Awards Ceremony for CSHRF CIHR Competition – Brodie Atrium

Canadian Student Health Research Forum Symposium Thursday, June 4th, 2015

Detailed Oral Presentation Schedule Session 1 of 2 0845 – 1030

A.M. Session – 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: Derek Chan – McMaster University Penny Toliopoulos - Université de Montréal Student and Poster #

School

Abstract Title

Greg Hosier, 301

Dalhousie University

Overactive bladder symptoms following radical prostatectomy

Gabriel Devlin, 302

McGill University

Injury Epidemiology and Surgical Care in Haiti

David Bergeron, 303

Université Laval

Clinical impact of a second FDG-PET in atypical/unclear dementia syndromes

Paula Slaney, 304

Memorial University of Newfoundland

Staphylococcus aureus Bacteremia in Children at Eastern Health: How are we doing?

Elizabeth Simms, 305

McMaster University

Ara h 1 Peptide Immunotherapy Ameliorates PeanutInduced Anaphylaxis

Andrew Dhawan, 306

Queen’s University

A computational modelling approach for deriving biomarkers to predict cancer risk in premalignant disease

Greg Costain (no poster)

University of Toronto

Predicting schizophrenia in a high risk genetic subtype

Cristina Bostan, 309

Université de Montréal

In Vivo Functionality of a Corneal Endothelium Grafted by Cell-Injection Therapy in a Feline Model

Cameron Kaye, 310

University of Manitoba

Contrast-Enhanced Microwave Biomedical Imaging using Contrast Source Inversion (CSI) Algorithms

1040 – 1140

Poster Groups A,B,C – Poster Discussion Each presentation will be 3 minutes for presentation and 3 minutes for questions; 6 minutes in total. Brodie Centre Mezzanine Poster Discussion Facilitators: Group A - Paula Slaney, Memorial University of Newfoundland and Labrador Group B - Cameron Kaye, University of Manitoba Group C - Cristina Bostan, Université de Montréal Student

School

Project Title

Derek Chan

McMaster University

Lfc Regulates Hematopoietic Stem Cell Differentiation

Bing Yu Chen

McGill University

Kylie Goodyear

Memorial University Newfoundland

Poster # Group

321

Comparison of the Focal Electroretinogram Composition Between Central and Peripheral Retinal Areas in Healthy Subjects

322

Status of High-Sensitivity C-Reactive Protein (hs-CRP) as a Biomarker for Cardiac Health in Laparoscopic Sleeve Gastrectomy Patients

323

Alexandra Prior

University Manitoba

"Microvascular decompression for hemifacial spasm: patients and outcomes favor surgery"

324

Chris Aiken

University Manitoba

Functional characterization of novel biomarkers in selecting for subtype specific medulloblastoma phenotypes

325

Jordan Crosina

University Manitoba

Developing a Model for the Intraoperative Prediction of Cardiac Surgery-Associated Acute Kidney Injury

326

Sonam Maghera

University of Ottawa

Identifying Patients at Higher Risk of Prolonged Air Leak After Lung Resection

327

Jeff Le

Dalhousie University

Severity of Burn injury and the relationship socioeconomic status in Nova Scotia, Canada

328

Robert Schmidt

University Manitoba

Telomere length and cyclin-dependent kinase 1 levels in patients with chronic lymphocytic leukemia

335A

Penny Toliopoulos

Université Montréal

Kinematic versus mechanically aligned total knee arthroplasty for unicompartmental knee arthroplasty

336A

revision

Alexander Oberc

McMaster University

Investigating the relationship between Crohn’s disease risk factors and adherentinvasive E. coli

329

Hilary Price

Memorial University of

Laparoscopic sleeve gastrectomy (LSG) as a therapeutic strategy for the management of polycystic ovarian syndrome (PCOS) in obese patients

330

Clinical Features and Outcomes of Influenza Infection in Community Dwelling Older Adults Presenting to Emergency Departments

331

Newfoundland

Laura Goodliffe

Queen's University

Margot Rosenthal

University Manitoba

Molecular characterization of multi-drug resistant (MDR) and extremely drug resistant (XDR) Streptococcus pneumoniae isolates from Canadian hospitals between 2007-2013"

Jessica Kapralik

University of Ottawa

Richard (You) Wu

332

Aortic Valve Repair Improves Mid-term Outcomes Versus Replacement for Aortic Insufficiency: A Propensity Matched Study

333

University Toronto

Prebiotics promote intestinal epithelial barrier function by activating protein kinase C

334

Shannon Chun

Queen's University

Prevention of proteasomal degradation of mitofusin 2 decreases cell proliferation and restores mitochondrial dynamics

337

Jeonga Gim

University Manitoba

The Oncofetal Protein HMGA2 Promotes Telomere Stability in Cancer Cells

338

Rebecca Lang

University Manitoba

Modulating Glycogen Synthase Kinase-3 in Chronic Lymphocytic Leukemia

339

James Wu

Université Montréal

Towards a new 3D classification for Adolescent Idiopathic Scoliosis (AIS): 3D subgroups derived from a fuzzy clustering algorithm

340

Caitlin Chrystoja

University Toronto

Pneumatic dilation versus laparoscopic Heller myotomy to improve disease-specific quality-of-life in patients with primary achalasia

341

Ashish Deshwar

University Toronto

The Apelin Receptor (Aplnr) enhances Nodal signaling for proper cardiac progenitor development

342

Nicholas Holzapfel

McMaster University

Investigating the role of MSI2 in the Pathogenesis of Acute Myelogenous Leukemia

335

Joy Hollahan

Memorial University

Do parents’ sodium intakes affect the offspring? A transcriptomic study of rat heart tissue 336

Newfoundland

1440 - 1530

Poster Groups D,E – Poster Discussion Each presentation will be 3 minutes for presentation and 3 minutes for questions; 6 minutes in total. Brodie Centre Mezzanine Poster Discussion Facilitators: Group D – Ross Prager, University of British Columbia Group E - Greg Hosier, Dalhousie University Student

School

Project Title

Poster # Group

Victor Tang

Queen's University

Effects of HIV and stimulant drug abuse on microstructural white matter integrity and cognitive impairment

343

Meagan Lyszczyk

University of Alberta

Systematic review of the safety of mind-body interventions in children

344

Thomas Fudge

University Manitoba

Reflux of CT Contrast Into The IVC: Defining Boundaries Between Pathologic and Iatrogenic Reflux

345

Jared Wilcox

University Toronto

Neural stem cells promote recovery in cervical spinal cord injury through myelination without synaptic connectivity

346

Dan Cojocaru

UBC

The Impact of Small Kidneys

347

Connie Le

University of Alberta

Transfection of oligonucleotides labeled with quantum dots and organic dyes for fluorescence sensing of target

348

350

DNA/RNA in cells

Mark Grant

Queen's University

A novel quantitative approach to the measurement of abdominal aortic calcification as applied to the Canadian Multicenter Osteoporosis Study (CaMOS)

Epsita Shome

University of Alberta

An Evaluation of Potential Novel Biomarkers BNIP3, AIF, DR5, Mcl-1 and FABP7 in Glioblastoma Tumors

351

Allen Fu

University of Alberta

Characterizing pathobionts and their interaction with the intestinal epithelial lining: contributions to inflammatory bowel disease

352

Noren Khamis

UBC

Preventing opioid overdoses: tracking urine fentanyl concentrations among illicit drug users across British Columbia

353

Noreen Singh

University of Calgary

Identification of Catalytic Residues in ATP-Citrate Lyase

354

Eugen Lungu

Université Montréal

Identification of patients with poor outcomes after hip arthroplasty: development of a preliminary prediction algorithm

355

Andrew Denisuik

University Manitoba

The Continued Rise of Extended-Spectrum β-LactamaseProducing Escherichia coli in Canadian Hospitals: CANWARD 2007-2013

356

1540 – 1650

P.M. Session – Lightning Oral Presentations Each presentation will be 6 minute for presentation and 4 minutes for questions. Procurity Lecture Theatre Main Floor – Apotex Centre Chairs: Student and Poster #

School

Abstract Title

Ross Prager, 311

UBC

Mass Gatherings Health: improving the quality and operationalization of field-collected data

Jessica Luc, 312

University of Alberta

2-Methoxyestradiol: A Hormonal Immunomodulatory Agent That Promotes Pulmonary Endothelial Integrity for Ex-Vivo Lung Perfusion

Sabin Bozso, 313

University of Alberta

Comparing Lung Function in Non-DCD and DCD Lungs: Is There a Potential Role for Adjunct Pharmaceuticals?

Chris Newell, 314

University of Calgary

Jump power reflects the degree of disability in neuromuscular disease

James Stone, 315

University Manitoba

Outcomes in Adult Survivors of Childhood Burn Injury as Compared to Matched Controls

Sarah Maximos, 316

Université Montréal

Impact of Type 2 Diabetes on CYP450 Activities of the Kidney

Robyn Elphinstone, 317

University Toronto

Deletion of S-nitrosoglutathione reductase (GSNOR) improves outcomes in an experimental model of cerebral malaria

Lightning Oral Abstracts A.M. Session Procurity Lecture Theatre, Apotex Building Main Floor, Room 164 8:45 â&#x20AC;&#x201C; 10:30 a.m. Wednesday, June 3rd, 2015

Overactive bladder symptoms following radical prostatectomy. Gregory W Hosiera, Jeffrey G Himmelmanb, Karthik K Tennankorec, and Ashley R Coxb a Faculty of Medicine, bDepartment of Urology, cDepartment of Nephrology, Dalhousie University and Nova Scotia Health District. Halifax, Canada. Rationale: Treatment of prostate cancer is associated with a number of genitourinary adverse effects. The rate of overactive bladder symptoms has yet to be investigated in a large cohort of patients treated with radical prostatectomy for clinically localized prostate cancer. In addition, the impact of radiation therapy on development of overactive bladder symptoms post-radical prostatectomy is not well known. Objectives: Describe the proportion of men who developed overactive bladder symptoms after radical prostatectomy and determine if subsequent radiation therapy increases the risk of overactive bladder post-radical prostatectomy. Methods: We performed a retrospective cohort study of patients who underwent radical prostatectomy for localized prostate cancer at our institution between January 2006 and June 2011. We excluded patients with pre-operative overactive bladder symptoms. We followed health records of all identified patients. Overactive bladder symptoms included urinary urgency, frequency, urge incontinence, and nocturia. Descriptive statistics were used to analyze baseline characteristics. A Cox regression analysis treating radiation as a time varying covariable was used to assess the impact of radiation on the outcome of overactive bladder. For all statistical methods, a two-sided p-value of <0.05 was considered significant. Results: Of the 875 patients who met study criteria, 29% developed de novo overactive bladder symptoms. The most common overactive bladder symptom was nocturia (22%) followed by frequency (21%) and urgency (18%). Of those with de novo overactive bladder symptoms, 21% were treated with anticholinergic therapy, 4% with conservative therapy, 1% with beta-3 agonist therapy, and 74% had no documented treatment. After adjusting for age, body-mass-index, presence of post-operative stress urinary incontinence, smoking status, stage of cancer, and use of nerve sparing surgery, radiation therapy was associated with an increased risk of overactive bladder symptoms (Adjusted Hazard 8.11, 95% CI 5.89-11.17, p <0.001). Conclusions: Symptoms of overactive bladder are prevalent in men who undergo radical prostatectomy. The risk of developing overactive bladder symptoms post-radical prostatectomy is increased approximately 8-fold by subsequent radiation therapy. Our results suggest that overactive bladder symptoms may be under treated in men following prostate cancer treatment. Funding: Dalhousie University, Department of Urology, Ralph Pickard Bell Endowment Studentship Award Email: gregory.hosier@dal.ca

Injury Epidemiology and Surgical Care in Haiti Gabriel Devlina, Camille Turgeon-Provosta, Gabrielle Pierreb, Tarek Razeka, Dan Deckelbauma, Sosthene Pierreb aCentre

for Global Surgery, Department of General Surgery, Faculty of Medicine, McGill University, Montreal, QC, Canada and bDepartment of Surgery, HĂ´pital de l'UniversitĂŠ d'Etat d'Haiti, Port-au-Prince, Haiti Rationale: Trauma is a leading cause of global morbidity and mortality, especially in low-income countries, where rates of death and disability due to injury are respectively two and three times higher compared to high-income countries. However, the ability of healthcare systems in developing areas to address the burden of trauma is limited by the lack of information about the types of injuries that occur in these areas. Trauma registries are databases that document care delivered to patients hospitalized with injuries, and they are integral components of trauma care systems in North American and Europe. Several published studies suggest that information collected by trauma registries can help decrease rates of injury-related death. However, despite their benefits, trauma registries remain scarce in most low-income countries. Objectives: Establish and develop a trauma registry of patients hospitalized for injuries at a large academic hospital in Port-au-Prince, Haiti. Methods: For each trauma patient arriving at the hospital, trained on-site staff systematically collected data for each trauma patient that arrived at the hospital. Staff collected data using a standardized form, which existed in paper and electronic formats. The form asked for information such as patient demographics, how the injury occurred, the type of injury sustained, the injury severity, and what happened to the patient after they were hospitalized. After data collection, we inputted and integrated the data into an electronic database for investigation and analysis. Using this database, we calculated summary statistics in order to describe the typical trauma patient profile, characterize the major types of injuries that occur, and identify some preliminary targets for future quality improvement and health policy initiatives. Results: The data registry collected data from 183 trauma patients over a 10 month period. Overall, 85% of total entries in the database were complete. Most patients were young and male. The most common causes of trauma were motor vehicle collisions (50% of all cases) and person-to-person violence (25%). Among motor vehicle collision patients, seatbelt and helmet use was very low. Patients often required several hours to arrive at the hospital, with only 60% of patients arriving at the hospital within 2 hours of the trauma. 42% of trauma patients presented with severe injuries. The most common types of severe injuries were fractures (35% of all patients) and cerebral injuries (16%). We noted that only 12.5% patients with severe injuries received an urgent operation request. Conclusions: Inadequate pre-hospital care and the low number of urgent operation requests could be preliminary targets for trauma care quality improvement, while injury prevention initiatives should focus on seat belt and helmet use. Future development and expansion of this registry will require increasing data capture and making data collection more independent. Funding: Sir Edward W. Beatty Memorial Scholarship Email: gabriel.devlin@mail.mcgill.ca

Clinical impact of a second FDG-PET in atypical/unclear dementia syndromes David Bergeron1, Jean-Mathieu Beauregard2, Jean Guimond3, Marie-Pierre Fortin1, Michèle Houde1, Stéphane Poulin1, Louis Verret1,4, Rémi W. Bouchard1,4, Robert Laforce Jr1,4 1

Clinique Interdisciplinaire de Mémoire (CIME), CHU de Québec, Québec, Canada; 2Département

d'imagerie médicale, CHU de Québec 3

Service de médecine nucléaire, Institut de Cardiologie et de Pneumologie de Québec (IUCPQ)

Département des Sciences Neurologiques, Université Laval, Québec, Canada.

Rationale: Diagnosis of atypical/unclear dementia is often difficult and this delays treatment initiation. Several authors have shown that beyond standard dementia workup, 18Ffluorodeoxyglucose positron emission tomography (FDG-PET) reduces the number of unclear diagnoses, leads to earlier treatment, and has a beneficial impact on families. However, it is not uncommon that the FDG-PET findings are equivocal in this setting. For those cases, a repeat FDG-PET may clarify the diagnosis and prevent treatment delay. Objective: Evaluate the clinical impact of a second FDG-PET on the diagnostic process of atypical dementias in tertiary care memory clinics. Methods: We retrospectively assessed the clinical impact of a repeat FDG-PET in 59 patients with atypical/unclear dementia syndromes and inconclusive initial FDG-PET. Changes in primary diagnosis, diagnostic confidence, and management following the second FDG-PET were examined. Results: Conducting a second FDG-PET reduced the number of unclear diagnoses from 80% to 34%, led to diagnostic change in 24% of cases, and treatment modification in 22% of patients. Overall, the clinical impact was higher when initial diagnostic confidence was low and the second FDG-PET repeated ≥12 months after the first one. Conclusion: In tertiary care memory clinic settings, when diagnostic incertitude persists despite extensive evaluation and an equivocal FDG-PET, repeating the FDG-PET 12 months later can clarify the diagnosis and improve the care management. Funding: Société Alzheimer de Québec, Vanier scholarship Email: david.bergeron.5@ulaval.ca

Staphylococcus aureus Bacteremia in Children at Eastern Health: How are we doing? Paula Slaneya, and Dr. Natalie Bridgera,b of Medicine, bDepartment of Pediatrics, Memorial University and Janeway Children’s Health and Rehabilitation Centre. St. John’s, Canada. aDepartment

Rationale: Staphylococcus aureus is a major cause of bloodstream infections worldwide. These infections are associated with a high level of morbidity and mortality if not treated promptly and appropriately. Objectives: To assess current adherence to quality-of-care indicators in the management of Staphylococcus aureus bacteremia (SAB) and to assess outcomes of SAB treatment in children at Eastern Health in St. John’s, Newfoundland. Methods: A retrospective chart audit of children with cultured SAB from January 2000 to July 2014 was performed evaluating five quality-of-care indicators: whether a formal infectious diseases consultation was requested, the type and duration of antibiotic, whether follow-up blood cultures and echocardiography were performed, and whether a focal source was present. If a focus was present, removal was noted. The sensitivity profile of the organism (i.e. Methicillin sensitive vs. Methicillin resistant) along with patient outcomes was also assessed. If a central line was in place and no other focal source of the bacteremia was found we described these cases as catheter-related infections. Results: A total of 43 patients with SAB were identified; 4 were not included due to lack of available information; all of the 39 remaining were Methicillin sensitive. Nine of the 39 cases (23%) had a formal infectious diseases consultation and 10 (26%) had undergone an echocardiography procedure. Twentynine (74%) patients had follow-up blood cultures. Twenty-seven patients (69%) had a focal source identified, of those fifteen patients (38%) were determined to likely have a catheter-related infection. Of the catheter-related infection cases four (27%) had the central line removed. The type and duration of antibiotics administered varied with each case. There were only 6 (15%) cases that assessed each of the five quality-of-care indicators. The mortality rate was four (10%) patients. Conclusions: With respect to the treatment of Staphylococcus aureus bacteremia in children at Eastern Health there are several areas that require improvement including: formal infectious disease consultation and prompt removal of central lines when they are the suspected focus. The implementation of a protocol for the treatment of SAB could improve adherence to these quality-of-care indicators at Eastern Health. Funding: SURA Email: g45pas@mun.ca

Ara h 1 Peptide Immunotherapy Ameliorates Peanut-Induced Anaphylaxis

E. Simms, C. Rudulier, J. Wattie, W.W. Kwok, E. James, M. Jordana, M. Larché

Rationale: Peptide immunotherapy, a treatment that makes use of short peptides representing major allergen T cell epitopes, has been shown to be efficacious in reducing symptoms of allergic rhinoconjunctivitis in ongoing clinical trials. In the current study we evaluated whether this approach could prevent anaphylaxis in a murine model of peanut allergy.

Methods: Mice transgenic for the human leukocyte antigen DRB1*0401 were sensitized to peanut epicutaneously and then treated with 100 ug or 30 ug of Ara h 1 peptides. Mice were subsequently challenged intraperitoneally with peanut and clinical anaphylaxis was evaluated. Mice were sacrificed and samples of spleen, inguinal lymph node, mesenteric lymph node, bone marrow, and peritoneal lavage were collected. HLA DRB1*0401 tetramers specific for the treatment peptides were used to identify peanut-specific T cells.

Results: Peanut-sensitized mice treated with Ara h 1 peptides demonstrated significantly decreased anaphylaxis following peanut challenge. Control mice treated with saline experienced a mean maximum temperature drop of 5°C, while mice receiving 100 ug of peptide experienced a drop of 2.4°C (p=0.0065), and mice receiving 30 ug of peptide experienced a drop of 1.8°C (p=0.0226). Mean hematocrit values for control mice were 49.9%, while values for the 100 ug group were 43.2% (p=0.0747) and the 30 ug group were 41.0% (p=0.0113). Numbers of Ara h 1specific T cells were reduced in treatment group tissue samples.

Conclusions: The ability of peptide immunotherapy to ameliorate signs and symptoms of anaphylaxis in an experimental, murine model supports the further evaluation of this form of therapy in clinical peanut allergy.

A computational modelling approach for deriving biomarkers to predict cancer risk in premalignant disease Andrew Dhawan1, Trevor A. Graham2, Alexander G. Fletcher3 1

School of Medicine, Queen's University, Kingston, Ontario, Canada

Barts Cancer Institute, Queen Mary University of London, London, UK

Mathematical Institute, University of Oxford, Oxford, UK

Rationale: The lack of effective biomarkers for predicting cancer risk in premalignant disease is a major clinical problem. There are a near-limitless number of potential measurements of premalignant disease that could be made: there is a choice of both the molecule or morphological feature to be measured, and also a choice of how the tissue should be sampled (biopsied). Practical constraints mean that only a few candidate biomarkers can be evaluated empirically. However, there is no framework to determine which of the plethora of putative biomarker strategies is the most promising. Objectives: Here we have sought to solve this problem by developing a framework for in silico biomarker development. Methods: We construct a simple computational model of carcinogenesis in premalignant disease and use the model to evaluate a extensive list of tissue sampling strategies in space and time, and choice of molecular analysis of these samples. Results: Our model predicts that: (i) (ii) (iii) (iv)

taking more biopsies improves prognostication, but with diminishing returns for each additional biopsy; longitudinally-collected biopsies provide only marginally more prognostic information than a single biopsy collected at the latest possible time-point; measurements of clonal diversity are more prognostic than measurements of the presence or absence of a particular abnormality; and the spatial pattern of clonal expansions is a particularly prognostic measure.

Conclusions: This study demonstrates how computational modelling provides a mechanistic framework for understanding how and when a lesion should best be measured to derive optimal prognostic biomarkers, and thereby diminish empirical constraints. Funding: Queenâ&#x20AC;&#x2122;s University (AD), 2020 Science (AGF)

Email: adhawan@qmed.ca

In Vivo Functionality of a Corneal Endothelium Grafted by Cell-Injection Therapy in a Feline Model Cristina Bostan,1, 2 Mathieu Thériault,3 Karolyn Forget,1 John D. Cameron,5 Stéphanie Proulx,3, 4 Isabelle Brunette1, 2 1

Maisonneuve-Rosemont Hospital Research Center, Montreal, QC; 2Department of Ophthalmology, University of Montreal, Montreal, QC; 3LOEX, CHU Québec Research Centre, Quebec, QC; 5Department of Ophthalmology, Laval University, Quebec, QC; 5Ophthalmology & Visual Neurosciences and Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, MN. Rationale: The only currently available treatment for irreversible corneal endothelial failure is allotransplantation, which is overshadowed by donor tissue shortage, postoperative donor corneal endothelial cell (CEC) attrition and risk of rejection. The transplantation of CEC amplified in culture has the potential to overcome these limitations. Objective: To evaluate the functionality of a corneal endothelium grafted by injection of cultured CEC in the anterior chamber of a living feline endothelial deficiency model. Methods: We operated the right eyes of 10 animals. Seven were scraped off their central corneal endothelium and injected with 2 x 105 (n=2), 1 x 106 (n=4) or no (n=1) feline CEC suspended in 0.2 mL and supplemented with ROCK inhibitor. The entire corneal endothelium was removed in the other three eyes, which were injected with 1 x 106 (n=1) or no (n=2) CEC. Subjects were then positioned eyes-down for three hours to allow deposition of injected CEC on the denuded Descemet’s membrane by gravity. Animals were followed for one month after surgery. Outcome parameters included graft transparency (0, opaque to 4, clear), pachymetry, CEC vital staining and morphometry, scanning and transmission electron microscopy, histology, function and wound healing-related protein immunostaining. Results: At one month postoperatively, the mean transparency score was 3.75 ± 0 and pachymetry 789 ± 9 μm in eyes injected with 2 x 105 CEC, 2.7 ± 1 and 968 ± 272 μm, respectively, in eyes grafted with 1 x 106 CEC, and 0.8 ± 0.4 and 3,071 ± 235 μm in entirely scraped controls. Histopathology revealed grafted regions non-uniformly repopulated by a double- or multi-layer of cells, with poorly defined intercellular junctions and abundant collagenous matrix in the extracellular space, expressing K8/18, α-SMA, COL1 and FN, but only weakly positive for Na+/K+-ATPase and ZO-1. Conclusion: Cell-injection therapy for corneal endothelial transplantation in the feline model reconstituted an incompletely functional corneal endothelium and potentiated a fibrotic healing reaction. Further efforts for optimization of this therapy in species with non-replicating CEC are required before testing in clinical trials. Funding: Fonds de Recherche du Quebec – Santé (FRQS), Vision Health Research Network (VHRN), Canadian Institutes of Health Research (CIHR) E-mail: cristina.bostan@umontreal.ca

Contrast-Enhanced Microwave Biomedical Imaging using Contrast Source Inversion (CSI) Algorithms Cameron Kayea, Ian Jeffreya, and Joe LoVetria a Department of Electrical and Computer Engineering, University of Manitoba, Winnipeg, MB, Canada Rationale: Microwave imaging (MWI) continues to steadily progress towards clinical application as a low-cost complementary imaging tool for breast cancer detection and treatment monitoring. Contrast-enhanced MWI is a relatively new extension to the research field which employs exogenous agents to improve resulting reconstructions by artificially accentuating the complex dielectric or magnetic property variation between healthy and cancerous tissues. Although a handful of microwave contrast agent studies have been carried out focusing primarily on modifying the permittivity of the targeted tissue, recent investigations of magnetic nanoparticles (MNP) have been of particular interest, since they augment the magnetic permeability of the region in which they accumulate. Methods: A previously described finite element contrast source inversion (FEM-CSI) algorithm was recently extended to both high-order and magnetic materials using a time-harmonic, discontinuous Galerkin formulation of Maxwellâ&#x20AC;&#x2122;s equations (DG-CSI). It is based on an earlier dielectric and magnetic, low-order, integral equation CSI formulation, and supports unstructured discretizations of dielectric, magnetic, and perfectly conducting media, which is ideal for MNP-enhanced targets in open boundary or conductive enclosures. Results: Inversions of synthetic data from simple 2D targets and breast models containing localized collections of MNPs at various simulated concentrations, as well as arbitrary inclusions of high dielectric or conductive material, were performed with FEM-CSI and DG-CSI to test both algorithmsâ&#x20AC;&#x2122; detection thresholds. Experimental data collected from polyethylene 2D targets containing actual dilutions of magnetite MNPs or high dielectric ceramics were also investigated, using antenna arrays successfully employed in the past for phantom imaging and human forearm imaging trials. Conclusions: We have shown that contrast-enhanced MWI can be performed with both the FEMCSI and DG-CSI algorithms, with the latter allowing the detection of targeted induced magnetic anomalies within otherwise purely dielectric targets, including highly inhomogeneous and lossy biological tissues, using the electromagnetic response produced by clusters of retained MNPs.

Funding: CIHR, NSERC, Vanier CGS.

Poster Discussion Session 1 of 2 Groups A, B, C Presenting Brodie Centre Mezzanine 10:40 â&#x20AC;&#x201C; 11:40 a.m. Wednesday, June 3rd, 2015

Lfc regulates hematopoietic stem cell differentiation Derek Chanabc, Maria S. Josed, Robert Rottapeld and Kristin J. Hopebc aMichael

G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada Stem Cell & Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada cDepartment of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada dPrincess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada bMcMaster

Rationale: Mammalian hematopoiesis is a tightly regulated process sustained by hematopoietic stem cells (HSCs) that generate all types of blood cells. Understanding how HSCs produce progenitor cells to maintain blood production can potentially shed light on mechanisms involved in various types of bone marrow failures. Lfc/Arhgef2, a RhoA-specific guanine nucleotide exchange factor (GEF), has recently been implicated in cortical precursor-mediated neurogenesis by means of proper orientation of the mitotic spindle during cell division. Here, we studied whether Lfc has a similar function in HSCs. Methods: We investigated Lfc expression in primary human and mouse HSCs and progenitor populations. After confirming expression, isolated bone marrow from a generated Lfc knockout (Lfc-/-) mouse model was used to perform a series of in vitro (colony forming unit (CFU) assays) and in vivo functional assays (non-competitive and competitive serial reconstitution experiments) to assess the hematopoietic consequences of embryonic Lfc loss. Results: Lfc expression profiling data in human and mouse HSC populations showed a corresponding 6.2- and 7.9-fold elevated expression over progenitor populations. Myeloid CFU assays showed fewer Lfc-/- generated colonies compared to control (Lfcfl/fl) bone marrow. Hematopoietic reconstitution was generally maintained in serial non-competitive transplants. However, defects were evident in serial competitive transplants where Lfc-/- bone marrow reconstituted poorly compared to wild type bone marrow and Lfc-/- HSCs accumulated with few that were able to differentiate into multipotent progenitors. Conclusions: Our work demonstrates for the first time that Lfc/Arhgef2 regulates mouse HSC differentiation into multipotent progenitors and that the loss of Lfc impairs the degree of in vivo hematopoietic reconstitution. Future work will look at whether this phenotype is due to a GEFindependent role of Lfc and whether or not mitotic spindle orientation is altered between normal and knockout contexts.

Funding: OGS derek.chan@medportal.ca 26

Comparison of the Focal Electroretinogram Composition Between Central and Peripheral Retinal Areas in Healthy Subjects. Bing Yu Chena, Mathieu Gauvinb, Antoine Brassard Simardc, Pierre Lachapelleb a

Faculty of Medicine, McGill University, Montreal, Quebec, Canada; bDepartment of Ophthalmology & Neurology-Neurosurgery, Montreal Children’s Hospital Research Institute, McGill University, Montreal, Quebec, Canada; cDepartment of Electrical Engineering, École de Technologie Supérieure, Montreal, Quebec, Canada. Rationale: The electroretinogram (ERG) is the recording of retinal bioelectrical activities upon homogenous light stimulus. Unlike the ERG which measures the sum of bioelectrical activities, the focal ERG (fERG) is recorded upon stimulation of a localized retinal area and could assess local retinal functions. fERGs in healthy subjects have been rarely investigated. Objectives: Evoke fERGs from macular and peripheral retinal areas in normal subjects and compare them using time and time-frequency domains. Methods: Photopic fERGs were recorded using our fERG apparatus, built upon a hemisphere of a table tennis ball and three straws horizontally positioned respectively at the nasal, central and temporal positions. Three visual fields of 10° radius were measured on one subject using a perimetry test to localize the stimulated retinal areas (nasal: 40°; central: 0°; temporal: 35°). A baseline ERG was recorded with all the three straws plugged by earplugs. Then, the nasal, central or temporal straw was unplugged one at the time and an ERG was recorded. The baseline ERG was subtracted from each ERG to obtain the corresponding fERG. The percentage of oscillatory potentials (%OPs) was calculated from the ratio of the sum of Discrete Wavelet Transform (DWT) descriptors between 80-160Hz on the sum of DWT descriptors between 20-160Hz. The amplitudes and implicit times of the a- and b-waves and %OPs were compared among the three assessed retinal areas. Results: The amplitudes of the a- and b-waves were higher in the central compared to the nasal and temporal fERGs, although only the b-wave amplitude difference between nasal and central fERGs was significant (p<0.05). All peak times were found similar. %OPs in the central fERG (48.1%±5.3) was significantly higher compared to the nasal (37.9%±3.2) and temporal fERG (37.0%±3.5) (p<0.0001). Conclusion: In normal subjects, OPs were more preponderant in the macula compared to the periphery, possibly because OP-generating bipolar cells could be more predominant in the macula than the periphery. This OP preponderance was also found in patients with end-stage retinitis pigmentosa, characterized by peripheral retinal degeneration and narrow central visual fields. This clinical correlation should be further investigated. Funding: CIHR, FRQ-S, RRSV.

Email: bingyuchen1994@gmail.com

Status of High-Sensitivity C-Reactive Protein (hs-CRP) as a Biomarker for Cardiac Health in Laparoscopic Sleeve Gastrectomy Patients Authors: K.L. Goodyear, D.M. Gregory, L.K. Twells, and E. Randell Faculty of Medicine, Memorial University of Newfoundland Rationale: Adipose tissue plays a role in development of the low-grade inflammatory state associated with obesity. Inflammation may play a key role in the formation and progression of atherosclerotic plaques, which accumulate on blood vessel walls leading to cardiovascular pathologies. C-reactive protein (CRP) is an acute phase inflammatory protein endorsed by the American Heart Association as a biomarker for the assessment of cardiovascular risk (i.e., > 3mg/L-high risk) and a positive correlate with obesity. Methods: This study examined changes in circulating hs-CRP levels with respect to cardiovascular health and adiposity in a baseline cohort of patients (n=67) who have undergone laparoscopic sleeve gastrectomy for the treatment of morbid obesity. hs-CRP, fasting lipid panel, and liver function test as well as anthropometric measures were collected at baseline, 3 and 6 months. Results: The sampling population at baseline (n=67) was 83.6% female and displayed the following characteristics in terms of mean (SD): age 44.6 (9.8), weight of 133.7kg (22.5), waist circumference (WC) 141.7cm (16.7), and BMI of 43.3kg/m2 (6.7). Patients reported: hypertension (53.6%), T2DM (42%), sleep apnea (60.6%), coronary artery disease (5.8%), and dyslipidemia (57.4%). Pre-operative hs-CRP level: 13.0mg/L (10.4). At 6 months post surgery (n=48) weight, WC, BMI, and hs-CRP were 101.3kg (16.1), 112.4cm (11.6), 36.7kg/m2 (5.2) and, 6.3mg/L (6.4) respectively. All changes significant at p<0.05. Conclusions: All eligible surgical patients were assigned an elevated risk category for CVD pre-surgery. Post-surgery, improvements in hs-CRP demonstrate a decreased level of risk for the development of CVD. Email: k.goodyear@mun.ca

Microvascular decompression for hemifacial spasm: patients and outcomes favor surgery Alexandra Prior, Anthony M Kaufmann, M.D., B.Sc. (Med), M.Sc., FRCSC University of Manitoba, Section of Neurosurgery, Winnipeg, Canada Rationale: Hemifacial spasm (HFS) causes considerable physical disability and emotional distress. Currently, patients have the option to undergo serial botox injections (SBI) to paralyze affected muscles or undergo potentially curative Microvascular Decompression Surgery (MVD). Despite its safety record and potential for a cure, MVD is not a widely used option in North America, with less than 10% of patients electing MVD. In Manitoba, however, our experience is unique in that we have a subspecialized centre that performs a high volume of MVDs. Objective: Our aim was to conduct a long-term population based study of the perioperative SBI trends, as well as the utilization and outcomes for MVD surgery, for Manitoba HFS patients to observe if access to a high volume centre affects treatment preference. Methods: All MVD for HFS in the Canadian province of Manitoba were identified over a 13.5-year consecutive period, January 2001 to June 2014. Patient demographics, clinical details and surgical outcomes were determined from medical records. Long-term outcomes were further assessed by telephone interview. Results: 104 Manitobans underwent MVD for HFS. Age at HFS onset was 48.9 ±10.4 (17-72), duration at MVD was 6.6±5.7 (1-31) and age at MVD was 55.8±10.8 (20.8-76.8) years. SBI utilization prior to MVD surgery was none for 30%, <1 year for 35% and long-term use in 35% averaging 4.5±3.0 (1.25 -15) years. There were no serious surgical complications or severe permanent deficits. Long-term spasm relief was complete and persisting in 84%, partial spasm relief in 9% and no improvement in seen in 7%. Surgical outcome was not related to age, HFS duration, gender, or prior SBI. The utilization of MVD for HFS was 0.64/100,000/year, calculated from 8±3 (2-13) cases per year and a provincial population of 1.2 million. Based upon the reported disease incidence of 0.8/100,000 people/year the proportion of HFS patients electing MVD was 80%. Perioperative botox trends showed that 1/3 of patients did not use botox prior to surgery, while 1/3 of patients used botox for 1 year or less and 1/3 of patients used botox for more prior to electing surgery. Conclusions: The potential safety and success of MVD for HFS was again confirmed in our study. Our MVD utilization rate was 80%, 8-fold higher than what has been reported in previous literature. Additionally, patients’ preference for perioperative SBI was variable, with the majority of patients never utilizing SBI or undergoing SBI for less than 1 year prior to electing surgery. These trends suggest that most HFS sufferers elected MVD over long-term use of SBI when MVD is available at a local, high volume center. Funding: BSc Med Committee Email: priora@cc.umanitoba.ca

Functional characterization of novel biomarkers in selecting for subtype specific medulloblastoma phenotypes Christopher Aiken1, Lisa Liang1, Robyn McClelland1, Ludivine CoudiĂ¨re Morrison1, Marc Remke2, Vijay Ramaswamy2, Marc R. Del Bigio3, Michael D. Taylor2, Tamra E. Werbowetski-Ogilvie1 1. Regenerative Medicine Program, Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada 2. Arthur and Sonia Labatt Brain Tumour Research Centre and Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada 3. Department of Pathology, University of Manitoba and Manitoba Institute of Child Health, Winnipeg, Manitoba, Canada Major research efforts have focused on the isolation and characterization of brain tumor stem cells, or propagating cells (BTPC) in a variety of brain cancers. Elucidating cell surface marker profiles that can be used to selectively isolate this cellular population is an imperative first step in the development of targeted therapies. Medulloblastoma (MB) is the most common form of pediatric brain cancer. MB is divided into 4 molecular subgroups; Wnt, Sonic Hedgehog (SHH), Group 3 and Group 4. Given the variable results obtained for currently utilized markers, as well as the cellular heterogeneity within and between MB sub-groups, it is likely there are additional surface marker profiles capable of selecting for sub-type specific MB BTPCs. We set out to identify novel surface marker combinations capable of selecting for TPCs in SHH MB. We employed the new BD Bioscience Lyoplate screening platform to compare 242 human cell surface marker levels across high and low self-renewing SHH MB sub-clones. The top 25 markers were refined by evaluating expression levels in Shh vs Group 3,4 and Wnt variants in transcriptome datasets representing 548 patient samples. Four markers, CD271, CD106/VCAM1, EGFR and CD171/NCAM-L1 showed consistent differential expression in the SHH subtype relative to the other variants. Flow cytometry validation in additional cell lines confirmed these findings. As a proof of principle, functional characterization of CD271 in SHH MB in vitro and in vivo was performed. Using fluorescence activated cell sorting and gain/loss of function studies, our results suggest that CD271 selects for a progenitor like cell in SHH MB. This work highlights a new approach to screening for differentially expressed surface markers across matched samples. We delineated a cell surface fingerprint for BTPC populations from MB molecular variants, however the utility can be seen in normal stem cell biology and across all forms of cancer.

Developing a Model for the Intraoperative Prediction of Cardiac Surgery-Associated Acute Kidney Injury Jordan Crosinaa, Brett Hiebertb, Nora Choic, Julie Hoac, Rakesh Arorabd, Claudio Rigattoa a

Department of Internal Medicine, Faculty of Health Sciences, University of Manitoba, bCardiac Sciences Program, St. Boniface Hospital Research Centre, cDepartment of Immunology, Faculty of Health Sciences, University of Manitoba, dDepartment of Surgery, Faculty of Health Sciences, University of Manitoba. Winnipeg, Canada. Rationale Acute kidney injury (AKI) is an important complication of cardiac surgery, greatly increasing risk of mortality. Its pathogenesis is incompletely understood, and no specific treatments are presently available. Current models for prediction of cardiac surgery-associated AKI (CSA-AKI) are insufficient, and perform particularly poorly in patients without kidney dysfunction at baseline. The inability to predict which patients will develop CSA-AKI is a major barrier to prevention and early treatment. Objective We sought to identify which intraoperative variables can improve discrimination of the Thakar risk score for CSA-AKI. Methods A prospective, observational cohort (n=324) of adult cardiac surgery patients was recruited from a tertiary care centre for this analysis. Acute kidney injury (AKI) was defined using the 2012 KDIGO guidelines. The Thakar risk score was calculated for each patient. Utilizing logistic regression models, the area under the Receiver Operating Characteristic (AUROC) curve was calculated for the Thakar risk model on its own, and for the Thakar risk model plus different intraoperative variables to identify improvements in model discrimination. Models were compared for the entire study cohort, and for a subgroup of patients who did not have documented pre-existing kidney dysfunction (Baseline creatinine <106 Îźmol/L & eGFR â&#x2030;Ľ60 ml/min). Results The Thakar score alone gave an AUROC of 0.721 (95%CI=0.619-0.824) in the entire cohort and 0.596 (95%CI=0.433-0.759) in the subset without baseline kidney dysfunction. Hematocrit at initiation of cardio-pulmonary bypass (CPB) statistically improved model discrimination for postoperative AKI in the subgroup of patients without pre-existing kidney dysfunction (AUROC=0.730, 95%CI=0.603-0.857, p=0.035), as well as in the overall cohort (AUROC=0.770, 95%CI=0.6820.857, p=0.031). Measures of mean arterial blood pressure dynamics, time on CPB, and blood transfusion did not improve model discrimination. Conclusions Measuring hematocrit during CPB may help predict the development of CSA-AKI. The link between hematocrit and the pathogenesis of CSA-AKI requires further investigation, and may provide a target for early intervention. Funding MHRC Establishment grant (JH). MMSF, MHRC, Department of Surgery, and CIHR (RA). Satellite Health, Kidney Foundation, and CIHR (CR). Email: crosinaj@myumanitoba.ca

Identifying Patients at Higher Risk of Prolonged Air Leak After Lung Resection Sonam Maghera1 BSc, Andrew J Seely2,3 MD PhD, Donna E Maziak2 MD MSc, Farid M Shamji2 MD, Sudhir R Sundaresan2 MD, P James Villeneuve2,3 MD PhD and Sebastien Gilbert2,3 MD.

Faculty of Medicine, University of Ottawa, Ottawa Ontario, Canada, 2Division of Thoracic Surgery, University of Ottawa, Ottawa, Ontario, Canada, 3The Ottawa Hospital Research Institute.

Rational: Prolonged air leak after lung resection is an affliction that increases the burden of care for the patient and for the health care system in general. Predictive models of prolonged air leak have relied on information that is not always available preoperatively (e.g: extent of resection, pleural adhesions).

Objective: Our objective was to construct a model to identify patients at increased risk of prolonged air leak using preoperative factors exclusively.

Methods: From 2012 to 2014, data on consecutive patients undergoing pulmonary resection was collected prospectively. Prolonged air leak was defined as lasting > 7 days and requiring hospitalization. Factors associated with the primary outcome (p<0.2) were included in a multivariate model. Regression coefficients were used to develop a weighted risk score for prolonged postoperative air leak.

Results: Of 225 patients, 8% (18/225) developed a prolonged air leak. Male gender (p=0.08), smoking history (p=0.03), BMI <= 25 (p<0.01), MRC dyspnea score > 1 (p=0.06), and DLCO% < 80% (p=0.01) were selected for inclusion in the final model. Weighted scores were: male gender (1 point), BMI <=25 (0.5 point), smoker (2 points), DLCO < 80% (2 points), MRC Dyspnea > 1 (1 point). The area under the receiver operating characteristic curve was 0.8 [95% CI=0.7-0.9]. An air leak score > 4 points offered the best combination of sensitivity (83% [95% CI=58-96]) and specificity (65% [95% CI=58-71]).

Conclusion: A subgroup of lung resection patients at higher risk for a prolonged air leak can be effectively identified using widely available, preoperative factors. The proposed scoring system is simple, clinically relevant to the informed consent, and allows preoperative patient selection for interventions to reduce the risk of prolonged air leak.

Email: smagh074@uottawa.ca

Severity of Burn injury and the relationship socio-economic status in Nova Scotia, Canada. Jeffrey Le

ab c b b b , Lihui Liu , Sarah Alyouha , Jason Williams , Micheal Bezhuly

a Dalhousie Medical School , Dalhousie Department of Surgery, Division of Plastics and Reconstructive b c Surgery , Dalhousie Department of Mathematics and Statistics . Halifax, Canada. Rationale: To date few Canadian studies have examined the relationship between socioeconomic status (SES) and incidence of burn injury. Using varying measurements of SES, previous studies have demonstrated a relationship between lower SES populations and increased risk of severity of burn injury. Objective: Given the unique geographic and socioeconomic environment of Nova Scotia, Canada, we seek to evaluate whether this relationship holds true using median income as a measure of SES. Methods: All Nova Scotia residents admitted to the Queen Elizabeth II burn unit in Halifax, Nova Scotia from 19952012 were included in the study. Patients were excluded if they did not possess a Nova Scotia postal code. Socioeconomic status was estimated by linking the subjectâ&#x20AC;&#x2122;s postal code to median family household income via Canadian population census data at the level of dissemination areas (A dissemination area (DA) is a small, relatively stable geographic unit composed of one or more adjacent dissemination blocks. It is the smallest standard geographic area for which all census data are disseminated) from 1995-2012. For each of the four equal income groups ranging from lowest to highest income quartile were compared (average total burn percentage). Beta regression analysis was performed to evaluate the effect of median family income on likelihood of having a burn injury in each income quartile. Results: 302 patients were included in the analysis. Average percent total burn surface area was 19%, 15%, 15% and 14 % (p = 0.18) per income quartile (Q1:lowest â&#x20AC;&#x201C; Q4: highest), respectively. Likelihood ratios for income quartile Q1- Q4 were 1.3(0.8-1.6), 1.2 (0.6 1.4), 0.7 (0.6-1.2) respectively. Conclusion: Contrary to findings in other geographic regions of the world, severity or incidence of burn injury in Nova Scotia, Canada does not change in relation to SES when using family median income as a surrogate.

Funding: Department of Medical Research Foundation Harold Cook Endowment Email: HTJLE@dal.ca

Investigating the relationship between Crohn’s disease risk factors and adherent-invasive E. coli Alexander Oberc, Cherrie Small, Brian K Coombes. Department of Biochemistry and Biomedical Sciences, McMaster University. Hamilton, Canada. Rationale: Crohn’s disease (CD) is an immune-mediated intestinal illness that is a significant health concern in many developed countries. Several environmental and genetic risk factors have been implicated in CD pathogenesis, along with increased abundance of adherent-invasive Escherichia coli (AIEC). AIEC are commonly found in the intestine of patients with CD and we recently discovered that chronic colonization with AIEC leads to intestinal inflammation and fibrosis in conventional mice. This new model allows us to examine how environmental and genetic risk factors in CD impact upon AIEC phenotypes in the gut. Objectives: To investigate whether genetic and environmental risk factors influence AIEC colonisation and pathology in a mouse model. Methods: We are investigating how certain antibiotics, which are paradoxically both risk factors and treatments for CD, impact AIEC in the colonized gut. We are also investigating the behaviour and pathogenesis of AIEC in mice carrying mutations associated with susceptibility to CD in humans (ie NOD2). AIEC colonisation will be scored by quantitative culturing from feces, cecum, and colon. Pathology will be scored using standard histological methods from the cecum, colon, and ileum as well as by measuring inflammatory cytokines. Results: Preliminary data indicate an expansion of AIEC following the treatment of mice with some classes of antibiotics used in the treatment of CD. Whether these changes in bacterial load are accompanied by an attendant increase in intestinal pathology is underway. Conclusions: Our preliminary data indicates that CD risk factors can augment AIEC colonization. We anticipate that these results will provide a mechanistic understanding of AIEC in the pathophysiology of Crohn’s disease. Funding: CIHR Email: alexander.oberc@medportal.ca

Laparoscopic sleeve gastrectomy (LSG) as a therapeutic strategy for the management of polycystic ovarian syndrome (PCOS) in obese patients Hilary I. Price1, Kendra Lester1, Laurie K. Twells1,2, Christopher S. Kovacs 1, & Deborah M. Gregory1,3 1. Faculty of Medicine, Memorial University, Health Sciences Centre, 300 Prince Philip Drive, St. John's, NL, A1B 3V6, Canada 2. School of Pharmacy, Memorial University, Health Sciences Centre, 300 Prince Philip Drive, St. John's, NL, A1B 3V6, Canada 3. Eastern Health, Health Sciences Centre, 300 Prince Philip Drive, St. John's, NL, A1B 3V6, Canada

Background: PCOS is the most common endocrine disorder in women of reproductive age with a prevalence of 6-10% and is often underreported. This syndrome negatively impacts reproductive (infertility, menstrual dysfunction, hirsutism, hyperandrogenism) and metabolic (insulin sensitivity, metabolic syndrome, Type 2 Diabetes mellitus (T2DM), dyslipidemia) health. PCOS confers increased risk of endometrial cancer, and also increased mortality due to the T2DM, cancer, and cardiovascular disease. It has been noted to affect 28% of obese women. Emerging evidence suggests that bariatric surgery may be an effective therapeutic strategy for the management of PCOS. Objective: To determine the prevalence of PCOS and related symptoms in women eligible for bariatric surgery. Methods: We evaluated the prevalence of PCOS in 164 females in a cohort study who underwent LSG between 2011 to 2014. Questionnaires were administered to all consenting research participants before surgery. The focus of this analysis is on 33 women who self-reported the presence of PCOS. Results: The average age was 41Âą9 years and average preoperative weight was 128Âą19 kg. Irregular menstrual cycle, problems with facial hair, and trouble conceiving were reported by 42%, 64% and 42%, respectively. High prevalences of T2DM (67%), dyslipidemia (61%), and hypertension (48%) were reported. 30% reported all three conditions. Conclusions: One in five women in our study self-reported PCOS diagnosed by a health professional as well as other metabolic disorders. Bariatric care teams need to be aware of the high prevalence of PCOS in this population. Follow-up surveys will assess post-surgery improvements in symptoms, reproductive health and fertility. Email: hilary.price@mun.ca

Clinical Features and Outcomes of Influenza Infection in Community Dwelling Older Adults Presenting to Emergency Departments Authors: Laura Goodliffe, MPHa, Po-Po Lam, MScb, Brenda L. Coleman PhDa, Karen Green, MScc, Jeff Powis, MD, MScd, David Richardson, MDe, Kevin Katz, MD CM, MScf, Bjug Borgundvaag, MDg, Allison McGeer, MDh. Affiliations: a. Infectious Disease Epidemiology Research Unit, Mount Sinai Hospital, Toronto, ON, Canada; b. Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada; c. Microbiology, Mount Sinai Hospital, Toronto, ON, Canada; d. Infectious Disease, Toronto East General Hospital, Toronto, ON, Canada; e. William Osler Health System, Brampton, ON, Canada; f. Infection Prevention & Control, North York General Hospital, Toronto, ON, Canada; g. Schwartz/Reisman Emergency Medicine Institute, Mount Sinai Hospital, Toronto, ON, Canada; h. Infection Control, Mount Sinai Hospital, Toronto, ON, Canada. Objectives. To describe the clinical features, outcomes of influenza infection and health care utilization for individuals 60 years and older with laboratory-confirmed influenza presenting to emergency departments (ED) in Ontario. Methods. We identified community-dwelling older adults presenting to six EDs with influenzacompatible symptoms during the 2011/12 and 2012/13 influenza seasons. Clinical characteristics were collected from patient interviews and chart review. Influenza vaccination history was collected; nasopharyngeal swabs were tested for influenza. Follow-up was conducted with cases up to 30 days after symptom onset. Results. Of 1337 participants, 147 (11%) had flu (94 AH3N2, 12 AH1N1, 4 A (not subtyped), 37 B). The most commonly reported symptoms were cough (93%), fatigue (92%), (84%) and weakness; 44% of patients had a measured temperature â&#x2030;Ľ37.5oC at time of triage. CDC and PHAC influenza-like illness (ILI) definitions captured 32% and 23% of all cases, respectively. Among cases, 83 (55%) were hospitalized with a median length of stay of 5 days (IQR: 3-7 days); four patients (3%) died. Of the 101 patients at home on day 30 from symptom onset, 28 (28%) were not well enough to return to regular activities. Median time to return to regular activities was 18 days (n=134; range 2 to > 30 days). Conclusions. Older adults commonly present with influenza with non-specific symptoms (such as cough, weakness & fatigue) and the standardized definitions fail to capture the majority these individuals. The majority of older adults with influenza who present to the ED are hospitalized, and recovery is prolonged. Email: lgoodliffe@qmed.ca

Molecular characterization of multi-drug resistant (MDR) and extremely drug resistant (XDR) Streptococcus pneumoniae isolates from Canadian hospitals between 2007-2013. Margot Rosenthal, George G Zhanel and Kim Nichol Department of Medical Microbiology, College of Medicine, Faculty of Health Sciences, University of Manitoba. Winnipeg, Canada.

Rationale : Streptococcus pneumoniae (S.pn) is a major pathogen causing pneumonia, otitis media, bacteremia, and meningitis across all age groups in Canada. Multi-drug resistant (MDR) S.pn represent approximately 2.8% of all S.pn isolates and are of increasing concern due to limited treatment options. Objectives : To assess antibiotic resistance patterns among MDR S.pn collected from Canadian hospitals, as well as to assess the genotypic and phenotypic relatedness of these isolates, their mechanisms of penicillin and macrolide resistance, and their virulence, based on pilus-encoding islets. Methods : Isolates for this study were obtained from the CANWARD surveillance study between 2007-13 and chosen based on their MDR phenotype. Antimicrobial susceptibility testing was performed according to CLSI methods. Phenotypic and genotypic relatedness were assessed by serotyping and pulsed-field gel electrophoresis (PFGE) respectively. Mechanisms of macrolide resistance mef(E) and erm(B) were detected by PCR analysis and mechanisms of penicillin resistance were assessed by PCR amplification followed by DNA sequencing of penicillin binding protein (PBP) genes 1A, 2B and 2X. Detection of pilus type 1 (P1) and type 2 (P2) pathogenicity islets were assessed by PCR. Results : MDR S.pn obtained from Canadian hospitals are genetically related and primarily composed of serotypes 19A and 19F. Within MDR isolates, resistance rates of >75% were associated with clarithromycin, clindamycin, doxycycline, penicillin and trimethoprim/sulfamethoxazole, with 72.4% of isolates displaying simultaneous resistance to all five antimicrobials. Isolates commonly carried resistance to penicillin + 4 other chemically unrelated classes of antibiotics, a level of resistance we termed extremely drug-resistant (XDR). All isolates tested positive for either macrolide resistance genes mef(E) (88.5%) or erm(B) (82.0%), with many of the isolates (70.5%) testing positive for both genes. Penicillin resistance was associated with highly similar amino acid substitutions in PBP1A, 2B and 2X. The majority of isolates carried P1(80.3%) or P2 (73.8%), with 73.8% of isolates carrying both pili. PFGE revealed 4 clusters that were genetically related and associated with known clones Taiwan19F-14, England14-9, Spain9V-3, Spain23F-1 and Sweden15A-25. The 13-valent conjugate pneumococcal vaccine provides coverage against 93.4% of the MDR isolates. Conclusions: MDR S.pneumoniae are present across Canada with 80% of strains displaying resistance to â&#x2030;Ľ 5 classes of antimicrobials. The MDR strains show genetic relatedness, primarily possess the dual mef(E) and erm(B) genotype and show changes in key PBP motifs. As well, they increasingly possess both P1 and P2 virulence pili. The vast majority of these MDR isolates are serotypes that are covered by PCV-13 and PPSV-23 vaccines. Email : umrose32@cc.umanitoba.ca, ggzhanel@pcs.mb.ca

Aortic Valve Repair Improves Mid-term Outcomes Versus Replacement for Aortic Insufficiency: A Propensity Matched Study Jessica Kapralika, Kathryn McLeana, Vincent Chana, Benjamin Sohmerb, Marc Ruela, Thierry Mesanaa, Munir Boodhwania a

Department of Cardiac Surgery, bDepartment of Cardiac Anesthesiology, University of Ottawa Heart Institute. Ottawa, Canada Objectives: Aortic valve (AV) repair has emerged as a feasible and attractive alternative to AV replacement in patients with aortic insufficiency (AI) with or without aortic root pathology. However, little data exists comparing outcomes following repair versus replacement. We performed a single-center comparative study in patients undergoing AV repair or replacement for AI. Methods: Patients undergoing AV replacement (n=263) or repair (n=153) for AI between 2000 and 2014, with or without aortopathy, were included. Patients with acute aortic dissection, active endocarditis, concomitant aortic stenosis, or previous AV intervention were excluded (n=155). To adjust for baseline differences, non-parsimonious logistic regression models were used to generate propensity scores. A 1:1 greedy matching algorithm was used to create 70 propensity matched pairs. Peri-operative and long-term clinical and echocardiographic outcomes were assessed, focusing on survival and valve-related events, and analyzed using Kaplan-Meier techniques. Primary endpoints included late mortality, myocardial infarction (MI), stroke, and AV reoperation. Total follow-up exceeded 1100 patient-years in the entire cohort and 800 patientyears in the matched cohort. Results: The matched replacement and repair patients were similar in age (57±14 vs. 56 ±15, p=0.75), sex (Female: 17% vs. 25%, p=0.22), incidence of LV dysfunction (27% vs. 24%, p=0.38), severe AI (67% vs. 74% p=0.42), presence of coronary disease (11% vs. 10%, p=0.78) and LV End-diastolic Diameter (6.2±0.9 vs. 6.1±0.9, p=0.63). Replacements consisted of 53% mechanical, 41% bioprosthetic, and 6% homograft valves. Repair consisted of 61% valve-sparing root replacements, 70% cusp repairs with 43% bicuspid AVs. In-hospital mortality (1% vs. 4%, repair vs. replacement, p=0.62) and perioperative outcomes were similar between groups. Fouryear survival was 97±2% and 87±4% in repair vs. replacement groups (p=0.11). A total of 6 valverelated events occurred in the repair group compared to 18 in the replacement group. Freedom from primary endpoints at 4 years was 97±2% and 82±8% in the repair vs. replacement groups (p=0.03). Conclusions: In a propensity matched cohort, AV repair for AI was associated with a mid-term reduction in death and serious valve related complications compared to AV replacement. AV repair should be considered, when technically feasible, as the preferred treatment of AI. Funding: Faculty of Medicine, University of Ottawa Email: jkapr060@uottawa.ca

Prebiotics promote intestinal epithelial barrier function by activating protein kinase C Richard Y Wu1,2, Pekka Määttänen1, Kathene Johnson-Henry1, Philip M Sherman1,2. 1. Cell Biology Program, Research Institute, Hospital for Sick Children; 2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. Rationale: There is growing interest in using selective nutrients as dietary supplements to deliver long-term health benefits to the host. Prebiotics are non-digestible oligosaccharides that promote the growth of select gut microbes, but may have other effects on the mucosal barrier. Objective: The aim of this study is to determine the effects of prebiotics on intestinal epithelial barrier function and to characterize their mechanisms of action. Methods: Caco2-Bbe cells were seeded onto Transwell filters. Polarized monolayers were subsequently exposed to inulin or short-chain fructo-oligosaccharide (scFOS), and then challenged with enterohemorrhagic Escherichia coli strain CL56, serotype O157:H7 (EHEC). Transepithelial electrical resistance (TER), translocation of dextran and zona-occludens-1 (ZO-1) mRNA, protein expression and immunofluorescence labelling were used to measure barrier integrity. Activation of protein kinase C (PKC) was assessed by immunoblotting. Results: Pathogen challenge of epithelial monolayers abrogated TER (13.3±1.6 % of baseline, n=5) and increased dextran flux (847.4±108.4 ng) – two markers of epithelial permeability. However, pre-treatment with either prebiotic protected against EHEC-induced barrier permeability (n=6) and prevented ZO-1 redistribution (n=3). Both inulin and scFOS increased ZO-1 mRNA expressions (1.5±0.2 & 1.4±0.1 folds for inulin and scFOS; n=4) and protein levels (2.0±0.6 and 1.9±0.4 folds, n=4). Mechanistically, both prebiotics induced a dose- and time-dependent activation of PKC. Inhibition of PKC activity with pharmacological inhibitors and siRNA abolished the prebiotics-induced effects. Discussion: These results indicate that prebiotics can enhance epithelial barrier integrity. Such protection is mediated through the activation of specific PKC isoforms in host epithelial cells. Future aims are to characterize the specific upstream and downstream PKC signaling cascades that mediate these effects. Acknowledgements: RYW is supported by Vanier CGS, CIHR MD/PhD Studentship, and a NASPGHAN Medical Student Scholarship. PMS is the recipient of a CRC in Gastrointestinal Disease. The work was funded by an operating grant from CIHR and a research contract from Lallemand Health Solutions (Montreal, Quebec).

Investigating the role of MSI2 in the Pathogenesis of Acute Myelogenous Leukemia Nicholas Holzapfel1,2, Stefan Rentas1, Muluken Belew1, Gabriel Pratt3, Gene Yeo3, Kristin Hope1 1 McMaster University, Department of Biochemistry 2 McMaster University, Faculty of Medicine 3 University of California, San Diego Introduction: Musashi-2 (MSI2) is an RNA binding protein that is thought to alter the expression of target mRNAs in the cytoplasm and prevent the maturation of microRNAs (miRNAs) in the nucleus. Multiple studies indicate that MSI2 plays an important role in the maintenance of hematopoietic stem cell populations and recent studies identify MSI2 as an independent prognostic factor for overall survival in patients with Acute Myelogenous Leukemia (AML). The RNA-targets of MSI2 are believed to be potent regulators of stemness and deregulation of these targets could very well contribute to neoplastic transformation. Methods: MSI2 was extensively profiled across human AML samples and functional assays were performed. Lentiviral particles were used to transduce human AML samples with shRNA targeting MSI2; these samples were then transplanted into immunocompromised mice. The human leukemic graft was analyzed 3 months post transplantation and compared to control mice. To identify the RNA targets to which MSI2 binds, cross-linking immunoprecipitation followed by next generation sequencing (CLIP-Seq), was performed. MSI2 RNA targets were validated by RNAImmunoprecipitations (RIPs) and select targets have been further characterized via western blotting and immunofluorescence. Results: Functional assays demonstrate that a loss of MSI2 impairs the function of human AML samples when transplanted into immunocompromised mice. CLIP-Seq analysis demonstrated extensive binding of MSI2 to the (U/G)UAGUU sequence motif with predominant localization to the 3' UTR of processed mRNAs. CLIP-Seq revealed an unbiased list of MSI2 RNA targets that were ranked according to P-value and further analyzed via RIP, western blotting, and immunofluorescence. Conclusion: MSI2 is a critical RNA binding protein whose down-regulation severely impairs the function of human AML cells. MSI2 binds predominantly to the 3'UTR of numerous mRNAs harbouring a specific consensus sequence and ultimately controls the expression of these targets. Further elucidation of these targets is likely to reveal novel mechanisms that are critical for the maintenance of AML cells

Do parentsâ&#x20AC;&#x2122; sodium intakes affect the offspring? A transcriptomic study of rat heart tissue. Joy Hollahan, Raniru Randunu, Linda Chafe, Dr Nic Fairbridge, Dr Lourdes Pena-Castillo, Dr Sherri L Christian & Dr Bruce Van Vliet Division of Biomedical Sciences, Faculty of Medicine; Department of Biochemistry, Department of Computer Sciences, Faculty of Science; Memorial University of Newfoundland. St Johnâ&#x20AC;&#x2122;s, NL. Background: The North American diet typically contains high amounts of sodium, often well above recommended levels of intake. Previous animal studies have indicated the possibility that a high maternal sodium intake during gestation and lactation may later affect the cardiovascular and renal systems of the grown offspring. Such effects need to be explored in detail in order to understand whether a similar phenomenon may occur in humans. Objective: The purpose of this study was to test the hypothesis that an increased parental sodium intake during gestation and lactation will cause transcriptomic gene changes in adult offspring heart tissue, detectable as differential expression of genes using an RNA-Seq approach. Methods: Sprague-Dawley rats were provided with a control (0.49% NaCl) or high sodium (8% NaCl) diet through pregnancy and lactation. Weaned offspring were fed an intermediate (1.25% NaCl) sodium diet. Tissue was collected from the left ventricle of the heart in 14 week old offspring. Extracted RNA was sequenced (RNA-Seq) using an IonTorrent Personal Genome Machine. Sequence data from 4 male and 4 female rats per treatment group was analyzed using bioinformatics tools to generate candidate lists of differentially expressed genes between the offspring of parents fed a control vs high sodium diet. Results: Bioinformatics analysis identified a number of differentially expressed gene candidates. In males, no genes were significantly differentially expressed between the high and low salt offspring groups. Subsequent analysis focused on female offspring and the identification of gene candidates that may be up- or downregulated due to the parental salt intake. Gene candidates with altered expression levels included natriuretic peptides (NppA and NppB), myosins, and calcium channel subunit proteins. Additionally, several genes associated with involved in fibrosis were significantly differentially expressed suggesting a possible fibrotic response in female offspring hearts. Discussion and Conclusions: RNA-Seq is a method that enables a comprehensive description of transcriptomic gene changes. This approach led to the identification of a number of gene candidates that appear to be differentially expressed in the heart of female offspring of parent rats exposed to a high salt diet during breeding, pregnancy, and lactation. These initial results suggest that parental sodium intake may have a programming effect on female offspring, affecting genes related to cardiac function. However, the results of the RNA-Seq will have to be confirmed in a larger number of samples using an independent method (quantitative PCR) before conclusions may be firmly made. Acknowledgements: Supported by the Canadian Institutes of Health Research (#OSO120289).

Prevention of proteasomal degradation of mitofusin 2 decreases cell proliferation and restores mitochondrial dynamics Shannon Chun1, Kuang-Hueih Chen1, Asish Das Gupta1, and Stephen L. Archer1 Department of Medicine, Queenâ&#x20AC;&#x2122;s University, Kingston, Ontario, Canada.

Rationale: Unrestricted cell proliferation and apoptosis resistance are hallmarks of cancer. This proliferative diathesis is due in part to downregulation of mitochondrial fusion mediator, mitofusin 2 (MFN2). It is hypothesized that proteasomal degradation is promoted via protein kinase A (PKA) by phosphorylation of MFN2 at serine 442. Therefore, decreasing serine 442 phosphorylation of MFN2 may restore protein levels, augment its antiproliferative property, and improve mitochondrial dynamics. Objective: To evaluate the potential utility of a phosphorylation resistant MFN2 mutant in cancer gene therapy through examination of cell proliferation and mitochondrial fragmentation. Methods: This hypothesis was investigated by comparing wild type MFN2 (MFN2-WT) to MFN2 mutants: one which was phosphoresistant due to a S-442-A substitution (MFN2-PD) and the other which was constitutively phosphorylated from a S-442-D substitution (MFN2-CP). These genetic constructs were delivered in A549 non-small cell lung cancer cells via adenoviral vectors. The effects on cell proliferation and apoptosis were measured by Click-iT EdU proliferation assays and TUNEL assays, respectively. Immunoblot analyses were performed to determine protein expression of MFN2 constructs and also to determine the effect of pharamacological inhibitors of PKA and proteasome on MFN2 protein levels. Finally, mitochondrial dynamics was studied by confocal microscopy following staining of the mitochondria by potentiometric dye TMRM. Results: MFN2-PD caused greater MFN2 protein expression, suppression of proliferation, and increased apoptosis compared to MFN2-WT. In contrast, MFN2-CP not only failed to increase expression of MFN2 but also did not inhibit cell proliferation, restore mitochondrial morphology, or induce apoptosis. Pharmacological inhibition of PKA or proteasome blockade was found to increase MFN2 protein expression and decrease mitochondrial fragmentation. Conclusion: Inhibiting phosphorylation of MFN2 at serine 442 increases MFN2 expression, enhances its antiproliferative effects, improves apoptotic responses, and restores mitochondrial morphology in A549 cells. This strategy may have future therapeutic implications in lung cancer management and potentially other cancers.

Email: schun@qmed.ca

The Oncofetal Protein HMGA2 Promotes Telomere Stability in Cancer Cells Jeonga (Jenna) Gim, BSc Med; Suchitra Natarajan, PhD-candidate; Farhana Begum, MSc; Thomas Klonisch, MD, PhD; Sabine Hombach-Klonisch, MD, PhD. Department of Human Anatomy and Cell Science, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. Introduction HMGA2 is a non-histone chromatin binding protein that is expressed in fetal tissues, and reexpressed frequently in cancer cells. HMGA2 has various functions that lead to poor prognosis for cancer patients, including DNA repair capabilities. Telomeres are the nucleotide repeats at the end of a chromosome protected from being recognized as DNA damage sites by the shelterin complex of six proteins. Our research has shown that HMGA2 interacts with a key protein of the shelterin complex called TRF2 (Telomere Repeat-binding Factor 2) and that HMGA2 has a protective and TRF2 stabilizing role on telomeres. Methods Cell lines included the undifferentiated thyroid cancer UTC8505, lung cancer A549 without and with expression of exogenous HMGA2; rhabdomyosarcoma RD and fibrosarcoma HT1080 (C1) with endogenous expression of HMGA2 and a doxycycline-induced shRNA-mediated downregulation of HMGA2. DNA damage was induced by methyl-methanesulfonate (MMS). Immunoprecipitation (IP) of nuclear protein extracts was done to detect TRF2 and HMGA2 protein interaction. Immunoblot analysis was completed to detect TRF2, HMGA2 and Î˛-actin. Fluorescence microscopy and quantitative analysis of DAPI stained nuclei were done to determine the number of anaphase bridges and micronuclei. Combined immunofluorescence for the detection of 53BP1 (p53-binding protein 1) or HMGA2 and fluorescence in situ hybridization (FISH) using a Cy3-Telomere PNA Probe was performed to detect colocalization of HMGA2 with telomere repeats and to quantify telomere dysfunction-induced foci (TIF). Results Immunoprecipitation of endogenous HMGA2 in C1 cells and exogenous HMGA2 in UTC8505 cells from nuclear protein extracts was performed. TRF2 protein was detected in the pull-downs of both cell lines. Co-IP of TRF2 in RD and C1 cells demonstrated the interaction with endogenous HMGA2 protein. Combined immuno-FISH showed co-localization of telomeric TTAGGG repeats and HMGA2 foci in C1 cells. Presence of HMGA2 significantly decreased the number of anaphase bridges and micronuclei in C1, UTC8505 and A549 cell lines, and there was no difference upon MMS-treatment. Furthermore, knockdown of HMGA2 resulted in an increase in the number of telomere dysfunction-induced foci detected by combined immunofluorescence for 53BP1 and in situ hybridization for telomere repeats. Conclusion HMGA2 interacts with TRF2, a key component of the shelterin complex, and increases telomere stability.

umgim@myumanitoba.ca

Modulating Glycogen Synthase Kinase-3 in Chronic Lymphocytic Leukemia Rebecca Lang1, Armando Peoppl2, Cheryl Peltier2, Versha Banerji1, 2, 3, 4 1 University of Manitoba, 2CancerCare Manitoba, Department of Medical Genetics and Biochemistry, 4Department of Internal Medicine, Introduction: Chronic lymphocytic leukemia (CLL) is the most common hematological malignancy in North America and Europe with a median age of onset of 72. Due to the advanced age of most patients with CLL, many are unable to tolerate standard treatments and receive sub-optimal care. Despite the availability of various treatment options, CLL remains incurable. Glycogen synthase kinase-3 (GSK-3) is a metabolic enzyme dysregulated in CLL. It has two isoforms: GSK-3α and β. Our hypothesis is that GSK-3 is a critical enzyme for CLL cell survival and therefore a target that can be exploited for therapeutic benefit. Methods: The effect of chemical pan-GSK-3 inhibition on β-catenin stabilization was observed in lymphoid cell lines after 24 hour of treatment with 15 μM SB. Cell viability was assessed by observing the levels of ATP as measured by luminescence after 48 and 72 hours of treatment with LiCl and SB. Cell viability was also observed by AnnexinV/PI staining using flow cytometry. Nine shRNAs were validated by sequencing. Knockdown of GSK-3α and GSK-3β was confirmed by western blot in U937 cells, a myeloid cell line in which this technique has already been confirmed. ShRNAs that resulted in the most consistent knockdown were selected for subsequent experiments. JVM3 cells treated with 15 μM SB served as a positive control for βcatenin stabilization. Results: We observed β-catenin stabilization with SB compared to DMSO control following treatment with SB. I-83 cells demonstrated a time and dose dependent loss of ATP as measured by luminescence at 48 and 72 hours compared to untreated and vehicle controls. Loss of cell viability was also observed by Annexin V/PI staining. Isoform-specific loss of both GSK-3α and GSK-3β were validated in I-83, Nalm-6, JVM3 and BJAB cell lines without stabilization of βcatenin. Conclusion: The phenotypic effects of isoform-specific loss of GSK-3 have not yet been characterized in CLL. Characterizing these effects may aid in the understanding and development of isoform-specific inhibitor of GSK-3.

Towards a new 3D classification for Adolescent Idiopathic Scoliosis (AIS): 3D subgroups derived from a fuzzy clustering algorithm WU, Jamesac; PARENT, Stefanac; AUBIN, Carl-Éricbc; KADOURY, Samuelb; NEWTON, Peterd; LENKE, Lawrencee; LAFAGE, Virginief; LABELLE, Hubertac a

Faculty of Medicine-University of Montreal, bÉcole Polytechnique de Montréal, cCHU SainteJustine, dChildren's Hospital and Health Center San Diego, eWashington University Orthopedics, f NYU Hospital for Joint Diseases Rationale: Better understanding of the 3D deformity present in AIS should provide a more comprehensive approach to help guide surgical treatment. The SRS 3D taskforce’s mandate is to develop a 3D surgical classification of AIS and surgical approaches using 3D criteria. Objectives: Demonstrate the existence of clinically distinct 3D groups to describe AIS and that they are different from those outlined in the Lenke classification and should be treated with a specific surgical plan. Design: A total of 952 3D spine reconstructions of pre-operative patients with AIS were analyzed using a fuzzy clustering algorithm. Consensus was then established among four experienced spine deformity surgeons for the 3D subgroups based on 1) if the subgroups were different and 2) if the curve pattern presented would be treated differently or not. Methods: Ten 3D parameters were used to define the groups: Cobb angles, apical axial rotations and planes of maximal curvature (PMC) of three spinal levels (proximal thoracic, mid-thoracic and thoracolumbar/ lumbar), maximal kyphosis and lordosis. A fuzzy c-means clustering algorithm was used, with 5-15 possible clusters allowed. Consensus was established based on representative cases selected among the 3D subgroups that were presented to a panel of four surgeons. Results: The algorithm optimized the number of clusters to 11. The population of the clusters varies between 11(1.16%) and 230(24.2%). To simplify visual representation and comparison, a Da Vinci (top) view was created for each cluster, illustrating 8 of the parameters used. A one-way ANOVA showed a significant difference between groups for at least the 8 parameters included in the Da Vinci view. Complete agreement was reached that all subgroups differed significantly and that the surgical plan would differ between different clusters. Conclusion: We have found 11 groups with distinct 3D spinal deformities and treatment approaches. Complete agreement among the four surgeons indicates that these subgroups are clinically relevant and will serve as the basis for a new 3D classification. Funding: COPSE, MENTOR, CIHR Email: james.wu@umontreal.ca

Pneumatic dilation versus laparoscopic Heller myotomy to improve disease-specific quality-of-life in patients with primary achalasia Caitlin C Chrystoja1,2, Julie Takata2, Gail E Darling3, Nicholas E Diamant4, Paul P Kortan5, George A Tomlinson6,7, Wayne Deitel8, Audrey Laporte1, David R Urbach1,2,9 1

Institute of Health Policy, Management and Evaluation, University of Toronto, 2Division of Support, Systems and Outcomes, University Healthy Network, 3Division of Thoracic Surgery, Toronto General Hospital, University of Toronto, 4Division of Gastroenterology, Department of Medicine, University Health Network, 5Division of Gastroenterology, Department of Medicine, St Michael’s Hospital, 6Dalla Lana School of Public Health, University of Toronto, 7Department of Medicine, University Health Network and Mount Sinai Hospital, 8Department of Medical Imaging, St Michael’s Hospital and University of Toronto, 9Department of Surgery, University Health Network and University of Toronto. Toronto, Ontario, Canada. Importance: Achalasia is a chronic, progressive, and incurable esophageal motility disease. There is clinical uncertainty about which treatment should be recommended as first-line therapy. Objective: To evaluate the effectiveness of pneumatic dilation (PD) compared to laparoscopic Heller myotomy with partial fundoplication (LHM) in improving achalasia-specific quality-of-life. Design, Setting, and Participants: A prospective, multicenter, 2-arm parallel-group randomized trial with balanced allocation at 6 academic hospitals in Canada. Functional and imaging studies were performed blinded and all outcome assessors were blinded. Fifty treatment naïve adults with a clinical diagnosis of primary achalasia, confirmed by manometric tests, were enrolled between November 2005 and March 2010 and followed for 5 years after treatment. Interventions: Treatment of achalasia by PD or LHM. Main Outcomes and Measures: The primary outcome was the difference between the treatments in the mean improvement of the achalasia severity questionnaire (ASQ) score at 1 year from baseline. Prespecified secondary outcomes included general and gastrointestinal quality-of-life, symptoms, esophageal physiology measures, complications, and incidence of retreatment. Results: No significant differences between treatments in the improvement of ASQ score at 1 year from baseline (27.5 points in LHM arm vs 20.2 points in PD arm; difference 7.3 points [95% CI -4.7, 19.3]; P=0.23). No differences between treatments in improvement of symptoms, general and gastrointestinal quality-of-life or measures of esophageal physiology (lower esophageal sphincter relaxation and pressure, esophageal emptying, abnormal esophageal acid exposure). Improvements in ASQ score diminished over time for both interventions. At 5 years, there were no differences between treatments in improvement of ASQ score, symptoms, and general or gastrointestinal quality-of-life. There were no serious adverse events. No patient who received LHM required retreatment, while 20% of patients treated with PD received subsequent LHM and occasionally, further dilations. Conclusion and Relevance: Treatment with PD or LHM similarly improved achalasia-quality-oflife at 1 year. These findings support the recommendation of either intervention as a first-line therapy for patients with primary achalasia. Trial Registration: clinicaltrials.gov Identifier: NCT00188344. International Standard Randomised Controlled Trial Number Register: ISRCTN05714772. CIHR grant number: MCT-76449. Funding: CIHR. Email: caitlin.chrystoja@mail.utoronto.ca. 46

The Apelin Receptor (Aplnr) enhances Nodal signaling for proper cardiac progenitor development. Ashish R. Deshwarab and Ian C. Scottab a

Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada; b Department of Molecular Genetics, University of Toronto Rationale: Heart disease is the second leading cause of death in Canada and in order to develop novel therapies it is crucial that we understand the molecular mechanisms that underlie the proper formation of the heart. There is a significant knowledge gap with regards to the earliest steps in this process. How cardiac progenitors migrate during gastrulation to reach the proper location for subsequent organogenesis during embryonic development remains unclear. The Apelin receptor (Aplnr) is one gene that has been implicated in this process. Loss of the Aplnr results in a delay in the ingression of cardiac progenitors and the complete absence of the heart and early cardiac gene expression. Objectives: Determine at a molecular level how the Aplnr is required for proper cardiac development. Methods: The zebrafish was used a model system. Results: We present evidence to suggest that the Aplnr enhances Nodal signaling to initiate the migration program at the correct time in development. Apelin receptor loss of function embryos exhibit a reduction in a wide range of Nodal target genes while activation of the receptor is capable of boosting their expression. Furthermore, loss of Aplnr results in a delay in the expression of the cardiogenic transcription factors mespaa/ab. By elevating Nodal levels in aplnrb mutant embryos we are able to fully restore cardiac differentiation. We also find that loss of Aplnr attenuates the activity of a point source of the Nodal ligands Squint and Cyclops. Finally, we find that the Aplnr acts non-cell autonomously to regulate the nodal signaling pathway. Conclusions: We propose that in the absence of the Aplnr the appropriate Nodal threshold required to initiate the downstream cardiac progenitor â&#x20AC;&#x153;specification/migrationâ&#x20AC;? program requires a longer length of time to be attained. This translates into a delay in migration and consequently cardiac progenitors are not capable of reaching their final destination. In this study we demonstrate how the fine tuning of a key signaling pathway is critical for the proper development of the early embryo. Funding: CIHR E-mail: ashish.deshwar@mail.utoronto.ca

Poster Discussion Session P.M. Groups D, E presenting Brodie Centre Mezzanine 14:40 â&#x20AC;&#x201C; 15:30 p.m. Wednesday, June 3rd, 2015

Effects of HIV and stimulant drug abuse on microstructural white matter integrity and cognitive impairment Victor M Tanga,c, Donna J Langb, c, Chantelle J Giesbrechtd, William J Panenkaa,c, Taylor Willia,c, Ric M Procyshyna,c, Fidel Vila-Rodrigueza, Willough Jenkinsa, Tania Lecomtee, Heidi N Boydac,f, G William MacEwana, William G Honera,c, Alasdair M Barrc,f a) Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, Canada V6T2A1 b) Department of Radiology, University of British Columbia, 3350-950 W 10th Avenue, Vancouver, Canada V5Z1M9 c) British Columbia Mental Health & Addictions Research Institute, 938 W 28th Avenue, Vancouver, Canada V5Z4H4 d) Department of Psychology, Simon Fraser University, 8888 University Drive, Burnaby, Canada V5A1S6 e) Département de Psychologie, Université de Montréal, Montréal, Quebec, Canada f) Department of Pharmacology, University of British Columbia, 2176 Health Sciences Mall, Vancouver, British Columbia, Canada V6T1Z3 Background: Illicit stimulant drug abuse (including cocaine, methamphetamine, and amphetamine) is a pervasive public health problem, thought to be associated with decreased neurological white matter integrity and declining cognitive function. Importantly, those dependent on stimulants are often part of a complex, multi-morbid population. Vancouver’s downtown east side is a major epicenter of illicit drug use and HIV epidemics, and in the present study, we take a cohort of stimulant users also with HIV to study their neurological and cognitive deficits. Methods: We measured fronto-temporal microstructural white matter integrity through diffusion tensor imaging in the genu of the corpus callosum, the anterior commissure (AC), and the anterior limb of the internal capsule (ALIC). A comprehensive neurocognitive test battery was performed to measure fine motor speed/dexterity, verbal memory/learning, processing/visual scanning, cognitive and attentional set shifting, and sustained attention. Results: Participants HIV+ and using stimulants were found to have decreased white matter integrity on all tracts examined, and showed some level of cognitive deficit in each of the cognitive domains explored. Correlational analyses showed significant relationships between attentional set shifting tests and white matter integrity in the genu and right ALIC, fine motor speed/dexterity related to all tracts, verbal learning/memory to right and left ALIC, sustained attention to the AC, left ALIC, and genu, and cognitive set shifting to left ALIC and AC. Conclusions: These findings on white matter and cognitive abnormalities are important in characterizing populations of complex comorbidity. More research and clinical efforts should be made to target the co-occurrence of these serious health conditions. Contact: vtang@qmed.ca

Systematic review of the safety of mind-body interventions in children. Meagan Lyszczyk, Denise Adams and Sunita Vohra CARE Program, Department of Pediatrics, University of Alberta. Edmonton, Canada. Rationale: Mind-body interventions are a diverse range of techniques designed to enhance the mindâ&#x20AC;&#x2122;s positive impact on bodily functions and symptoms and includes therapies such as meditation, biofeedback, and hypnosis. A 2007 US survey reported that mind-body interventions were used by 19.2% of adults and 4.3% of children each year. While these therapies are commonly used by children, there is a limited understanding of the safety of such use. Objectives: To systematically review adverse events associated with mind-body interventions in children and to assess the quality of harms reporting in relevant studies. Methods: A search strategy was developed and applied in five databases from inception to May 2013, irrespective of language. Inclusion criteria were that the study (1) was a primary investigation/report, (2) most or all of the study population was less than 21 years of age, (3) the study investigated a mind-body intervention, and (4) adverse events were assessed. Data was extracted from all included studies and summarized descriptively. Results: Of 8670 unique references identified by the search, 53 were included (184 are pending review). Data extraction of the included studies has identified 31 adverse events. Examples of reported harms include dizziness, increased anxiety, tibia fracture, blue-tinted vision, and worsening of depression and self-concept. Many papers that list harms do not report on seriousness or duration of adverse events or patient outcome. Conclusions: Mind-body interventions are frequently used by children, making the assessment of their safety a priority. Preliminary analysis has shown that adverse events may be associated with these interventions. A way to improve the quality and quantity of information would be for all current and future research to assess and report harms. This review will allow mind-body intervention instructors, healthcare practitioners and the public to better assess the risks associated with these practices. Funding: AIHS Email: mlyszczy@ualberta.ca

Reflux of CT Contrast Into The IVC: Defining Boundaries Between Pathologic and Iatrogenic Reflux Thomas Fudge a, Brett Memauri ab and Davinder Jassal abc a Faculty of Medicine University of Manitoba, b Department of Radiology St Boniface Hospital, c Institute of Cardiovascular Sciences. Rational: Reflux of intravenous contrast into the inferior vena cava (IVC) or hepatic veins seen on contrast enhanced computed tomography (CT) studies has been linked to right-sided heart disease including tricuspid regurgitation (TR), pulmonary hypertension, and right ventricular systolic dysfunction (RVSD). Current CT protocols call for increasingly faster contrast injection rates, which have led to relatively frequent visualization of the reflux sign. Objective: Assess the clinical role of reflux at high contrast injection rates while correcting for right ventricular function obtained by pocket-sized echocardiography (PSE). Methods: Patients having undergone contrast enhanced CT examination at rates of 3-6 ml/sec were recruited to undergo a limited PSE examination. Presence and severity of IVC reflux on CT, was compared to right ventricular fractional area change (< 35% = RVSD), TR, IVC diameter and IVC collapse during sniff test. Results: 86 patients underwent PSE. IVC reflux incidence was 79% (68/86), with 38 patients exhibiting reflux to the suprahepatic level, and 30 having significant reflux (hepatic level). There were no statistically significant differences between varying injection rates and RVSD. There was a significant difference favoring greater reflux with RVSD when injection rates were combined (P = 0.0393). In those with significant reflux, higher injection rates were linked to higher Hounsfield units within the hepatic veins for both normal and RVD, but the population size was too small to draw significance. Conclusion: Although population numbers were too low for statistical significance, we believe that faster injection rates play a major role in the incidence and severity of IVC reflux. Further research is needed to understand the clinical significance of this sign. Funding: BSc.Med Funding Affiliates. Email: umfudget@myumanitoba.ca

Neural stem cells promote recovery in cervical spinal cord injury through myelination without synaptic connectivity JT Wilcox1,2, K Satkunendrarajah2, JA Zuccato2, Chio JC2, MG Fehlings1,2,3 1 Institute of Medical Science, University of Toronto; 2Division of Genetics and Development, Toronto Western Research Institute, University Health Network; 3Division of Neurosurgery, Krembil Neuroscience Center, Toronto, Canada. Purpose: Preclinical studies of cell transplantation applied to cervical models of SCI are limited. We sought to determine the efficacy and mechanism of neural precursor cell (NPC) transplantation in a translational rodent model of cervical contusion-compression injury. Methods: A bilateral contusion-compression injury was generated at C6 in adult wistar rats. Two weeks post-injury, animals received: i) adult brain-derived (a)NPCs (4x10^5 cells/animal), ii) embryonic stem cell-derived (ES-)NPCs, iii) vehicle control, or iv) sham operation. Neurobehavioural testing was conducted for up to 16 weeks post-injury for forelimb strength, locomotion, and nerve conduction study. Direct trans-synaptic tracing was achieved using pseudorabies viral vectors injected into the forelimb. Histology and immunohistochemistry quantitatively assessed host tissue and exogenous grafts. Results: Long-term survival of cell grafts was observed with cells localized rostrocaudally surrounding the lesion, throughout grey and white matter. NPCs were found to efficiently deposit myelin in white matter, but did not form functional synapses with endogenous circuitry. White and grey matter volumes were significantly improved as early as 2 weeks post-transplant in aNPC and ES-NPC treated animals (p<0.05), with concomitant reduction in GFAP+/CSPG+ glial scar volumes. Forelimb function and grip strength improved following NPC engraftment up to 16 weeks, including: i) two-fold increase in grip strength (p<0.01); increased swing speed, duty cycle, and print width, length and area (p<0.05), and; peak forelimb conduction amplitude and latency (p<0.05). Conclusions: Transplantation of neural stem/precursor cells in the injured cervical spinal cord result in significantly improved spinal tissue and forelimb function, warranting further study to enhance and exploit efficacy to inform clinical translation. Funding: CIHR. Email: jared.wilcox@mail.utoronto.ca

The Impact of Small Kidneys Dan Cojocarua, Eli W Matsella, Allison A Eddyab, and Douglas G Matsellabc Department of Pediatrics, British Columbia Children’s Hospital, bChild and Family Research Institue, cBritish Columbia Provincial Renal Agency. Vancouver, Canada. a

Purpose of Study: Up to 60-70% of children with chronic kidney disease (CKD) have congenital anomalies of the kidney and urinary tract (CAKUT). CAKUT is a group of heterogeneous diseases, with different causes, natural histories, and rates of progression. Children with small and/or dysplastic kidneys have a form of CAKUT, collectively referred to as renal hypodysplasia (RHD). Most children with CKD experience a progressive decline in kidney function over time. The different forms of CKD progress at different rates, with CKD due to glomerulonephritis progressing more rapidly than that caused by congenital anomalies of the kidney. The rate of decline of kidney function among patients with RHD is highly variable and the factors that determine outcome are still poorly understood. Objectives: To identify clinical variables that determine renal long-term renal outcome in children with RHD and to define the role of kidney size as a predictor of developing end-stage renal disease (ESRD). Methods: This was a single-center retrospective cohort analysis. The primary outcome was the development of ESRD. We identified 202 RHD cases, with 25 cases (12%) reaching ESRD at a mean age of 8.9 (±6.6) years. Results: Children with RHD with a known genetic syndrome had the smallest kidneys while those with posterior urethral valves (PUV) had the largest kidneys at diagnosis. Cases with bilateral RHD were most likely to develop ESRD. Younger gestational age (OR 0.8, CI 0.69–0.99, p=0.05), smaller kidney size at diagnosis (OR 0.13, CI 0.03–0.47 p=0.002), lower best-estimated glomerular filtration rate (eGFR) (OR 0.74, CI 0.58–0.93), proteinuria (OR 1.03, CI 1.01–1.05, p<.001), and high blood pressure (OR 1.02, CI 1.01–1.04, p=0.01) were associated with the development of ESRD, while kidney size at diagnosis was independently associated with ESRD (HR 0.03, CI 0.01–0.72, p=.043). Conclusions: In children with RHD, kidney size at diagnosis predicts the likelihood of developing ESRD. Funding: BC Provincial Renal Agency Email: dancojo4@gmail.com

A novel quantitative approach to the measurement of abdominal aortic calcification as applied to the Canadian Multicenter Osteoporosis Study (CaMOS) Mark Grant1, Jeremy Guenther1, Tassos Anastassiades2, Wilma M. Hopman3, Stephen Adams1, Robert Nolan4, Michael A Adams1 and Rachel M. Holden 2,1 1. Department of Biomedical and Molecular Science, Queen’s University, Kingston, ON, Canada 2. Department of Medicine, Queen’s University, Kingston, ON, Canada 3. Clinical Research Centre, Kingston General Hospital, and Department of Public Health Sciences 4. Department of Radiology, Queen’s University, Kingston, ON, Canada Abstract: Rationale: Lateral spine radiographs provide a widely available and inexpensive resource for characterizing abdominal aortic calcification (AAC). The most widely accepted measurement of AAC is a semi-quantitative technique generated by the Framingham Heart Study (F-AAC-24). Methods: We developed an analytical method to quantify ACC (QAAC) on lateral spine radiographs and determined the association between bone mineral density (BMD) measured by dual energy X-ray absorptiometry (DXA) and AAC measured by QAAC and a modified Framingham score (F-AAC-12) in 110 participants of the CaMOS Study. Severity of AAC was quantified by measuring pixel intensities using a line profile tool that exported all data points across a userdefined region of the aorta with internal standardization to the vertebral endplates and noise calibration to the density of the vertebral body. Pixel intensities were distributed according to their fraction of regional standard values so as to make them comparable within and between images of different quality. The inter-observer reliability for the QAAC was higher than with the visual and semi-quantitative Framingham method and the pseudo-colored images illustrate the potential to meaningfully resolve severity of calcification. Results: There were significant and negative associations between the QAAC and BMD measures of the hip and spine in the study cohort as a whole and in males and females separately that were not observed with the modified Framingham score. This association remained significant after adjustment for age, sex, estimated glomerular filtration rate, phosphate and hypertension. Conclusion: The QAAC is a highly reproducible approach to measuring AAC but whether it is capable of monitoring subtle calcific changes over time requires further study. We propose that the QAAC could be applied to observational studies and randomized controlled trials that seek to determine the impact of interventions that modify bone density and structure as a treatment for vascular calcification and cardiovascular disease in the general population.

An Evaluation of Potential Novel Biomarkers BNIP3, AIF, DR5, Mcl-1 and FABP7 in Glioblastoma Tumors Epsita Shome1, Anthony C. Lott1, Mark E. Lipson2, Marshall W. Pitz2,3, Spencer B. Gibson2,3,4, and David D. Eisenstat 1,2,3,4,5 1. Faculty of Medicine and Dentistry, University of Alberta 2. Faculty of Medicine, University of Manitoba 3. CancerCare Manitoba 4. Manitoba Institute of Cell Biology, Winnipeg, MB 5. Departments of Pediatrics, Medical Genetics, and Oncology, University of Alberta Introduction: Glioblastoma (GBM) is the deadliest cancer of the central nervous system. Currently, epigenetic silencing by MGMT promoter methylation is the only confirmed prognostic biomarker for GBM. Previous studies have identified proteins whose level of expression may be associated with GBM patient prognosis or response to treatments. The purpose of this project is to determine if any of these proteins can be used as novel accurate prognostic biomarkers in GBM patients. Our proteins of interest include BNIP3 (Bcl-2 Nineteen kDa Interacting Factor), AIF (Apoptosis Inducing Factor), DR5 (Death Receptor 5), Mcl-1 (Myeloid Cell Leukemia Sequence 1) and FABP7 (Fatty Acid Binding Protein 7). Previous studies from our research group have shown that the mislocalization of cytoplasmic BNIP3 to the nucleus confers resistance to temozolomide and also represses AIF and DR5 expression, both of which promote apoptosis at high levels. Mcl-1 is an anti-apoptotic protein found in high levels in malignant GBM tumours. FABP7 is associated with increasing tumour infiltration and migration. Our hypotheses are that GBM patients whose tumours show decreased FABP7 expression, decreased Mcl-1 expression, increased AIF and DR5 expression, and/or cytoplasmic BNIP3 expression rather than nuclear expression will have longer overall survival or better treatment response. Methods: Immunohistochemistry was performed on paraffin-embedded slides of GBM tumours from a patient cohort in Manitoba using antibodies against the four proteins. BNIP3 subcellular localization was also determined through dual immunofluorescence using the nuclear marker DAPI. The tumour samples were scored semi-quantitatively for AIF and DR5 protein expression and BNIP3 localization; immunostaining and grading analysis are still ongoing for FABP7. Results: There was a non-significant trend of BNIP3 nuclear localization with patient outcomes and no correlation with Mcl-1 expression; other data will be compared to the clinical variables of progression free survival and overall survival. Conclusions: Depending on the results, one or more of these proteins will be evaluated as a potential biomarker using a different GBM patient cohort to confirm its effectiveness in predicting patient outcomes. Supervisor: David D. Eisenstat, Departments of Pediatrics, Medical Genetics, and Oncology Funding: Alberta Cancer Foundation Email: epsita@ualberta.ca

Preventing opioid overdoses: tracking urine fentanyl concentrations among illicit drug users across British Columbia Noren Khamisa, Ashraf Amlanib, Geetha Raghukumara, Erica Tsanga, Jane Buxtona,b a

University of British Columbia, bBC Centre for Disease Control

Rationale: Fentanyl is a dangerous opioid that is 100 times more potent than morphine. There has been a recent rise in the mixing of fentanyl into other illicit drugs in British Columbia (BC); however, illicit drug users are not informed of the fentanyl content of these drugs. The powerful nature of the drug combined with the lack of knowledge about fentanyl among illicit drug users has resulted in a 5x increase in fentanyl-related opioid overdoses across BC from 2012 to 2014. Objectives: This study attempts to track the geographical distribution of fentanyl-contaminated illicit drugs in BC, including which drugs are being mixed with fentanyl, where these drugs are being sold, and where these drugs are being consumed. Methods: Recruitment posters were placed across 20 harm reduction clinics throughout BC in order to recruit 400 visitors of harm reduction clinics as our study participants. Participants were asked to complete a brief anonymous questionnaire outlining their demographic characteristics and indicating which illicit drugs they had taken over the past 3 days. Participants then provided a urine sample which was tested for the presence of fentanyl using a rapid fentanyl test strip by the individual harm reduction sites. Questionnaires and urine test results were returned to the BC Centre for Disease Control for analysis. Study participants were provided with $5 cash or a $5 food voucher upon completion of the study. Results: The results of the study will be compiled in order to determine the geographical distribution of fentanyl and to elucidate which drugs are being mixed with fentanyl. Conclusions: Once data analysis is complete, appropriate public health measures will be taken to circulate harm reduction messages regarding the mixing of fentanyl into illicit drugs. The goal of the public health response is to curb the incidence of unnecessary opioid overdose-related deaths. Email: nkhamis@alumni.ubc.ca

Identification of Catalytic Residues in ATP-Citrate Lyase Noreen Singh, Kelsey Holoweckyj, Marie Fraser Department of Biological Sciences, University of Calgary, Calgary, Canada. Introduction: An enzyme in the human body that regulates lipogenesis and cholesterolgenesis is ATP-citrate lyase (ACLY). ACLY synthesizes acetyl-CoA and oxaloacetate from citrate, CoA and ATP, with citryl-CoA as an intermediate. The product, acetyl-CoA, is involved in embryonic and brain development. Mouse studies suggest that ACLY is important during brain development as homozygous Acly knockout mouse embryos died early in development. ACLY has been suggested to be a target for cancer therapy because tumour cells have an accelerated rate of fatty acid synthesis and ACLY is a key enzyme in this synthesis. Results from this research will increase our overall understanding of ACLY reaction mechanism; which will eventually aid treating metabolic disorders and cancers. Hypothesis: Knowledge of the reaction mechanism is limited and will be of use in understanding the energy flow in cells. Our current insight into the mechanism by which citryl-CoA is cleaved to form acetyl-CoA and oxaloacetate is based on sequence similarity of ACLY to citrate synthase. Both enzymes have histidine and aspartic acid residues at similar positions in their sequences. We hypothesize that citryl-CoA binds at this site in ACLY and is cleaved into acetyl-CoA and oxaloacetate using these residues. Method and Results: To test this hypothesis, we mutated these residues to alanine of ACLY in the bacterial model organism, Chlorobium limicola, and subsequently purified each respective protein. Kinetic assays of both the histidine and aspartic acid mutants indicated that they had a reduced specific activity (0.70 ± 0.006 U/mg and 0.13 ± 0.002 U/mg, respectively) when compared to the wildtype (1.2 ± 0.007 U/mg). Following kinetic assays, biophysical analyses were done to determine whether the predicted residues were catalytic. Mutated catalytic residues should not alter the protein conformation or change the binding capacity of the protein to its substrates. Differential Scanning Fluorimetry revealed that by comparing the melting temperature (Tm) between wildtype and mutated ACLY were not statistically significant. Therefore, suggesting no conformational change of mutant ACLY caused the reduction of catalytic activity. Conclusion: This work identifies the catalytic residues of ACLY and complements previous structure determination, increasing our currently limited knowledge about this enzyme. Funding: NSERC Email: singn@ucalgary.ca

Identification of patients with poor outcomes after hip arthroplasty: development of a preliminary prediction algorithm Eugen Lungu1, 2; Pascal-André Vendittoli2, 3 ; François Desmeules2, 4 1

Department of Biomedical Sciences, Faculty of Medicine, University of Montreal, Montreal, QC, Canada; 2Orthopaedic Clinical Research Unit - Maisonneuve-Rosemont Hospital University of Montreal affiliated Research Center, Montreal, QC, Canada; 3Department of Surgery, Faculty of Medicine, University of Montreal, Montreal, QC, Canada; 4School of Rehabilitation, Faculty of Medicine, University of Montréal, Montreal, QC, Canada Rationale: Hip arthroplasty is considered a definitive treatment for patients with hip osteoarthritis that is non-responsive to more conservative approaches. However, up to 23% of patients undergoing total hip (THA) or resurfacing arthroplasty (HR) experience unfavourable pain outcomes 3 months to 5 years after the procedure and up to 15% report dissatisfaction with surgery. Identification of patients at risk of poor outcomes following THA or HR could enable appropriate education, intensive rehabilitation and targeting of modifiable risk factors. Objective: To develop a prediction algorithm (PA) aimed at identifying patients at risk of poor outcomes following THA or HR. Methods: Retrospective data on 265 subjects having undergone primary unilateral hip arthroplasty (188 classical THAs and 77 HRs) were collected from the database of the Maisonneuve-Rosemont Hospital, Montreal, Canada. Hip pain, stiffness and function, as measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were recorded preoperatively and at a mean postsurgical follow-up (± SD): 446 ± 171 days. Demographic and clinical variables recorded just before the surgery as well as answers to individual WOMAC items were considered as potential predictors. Patients were considered as having a poor outcome if they had a postoperative total WOMAC score in the worst tertile of the sample and if they perceived their operated hip ’’Like an artificial joint with minimal restriction’’ or ’’Like an artificial joint with major restriction’’. The PA was developed using recursive partitioning. Results: A PA consisting of the following variables achieved the most acceptable level of prediction: gender, age at the time of surgery, body mass index and three items of the preoperative WOMAC (degree of pain with walking on a flat surface and during night as well as degree of difficulty with putting socks or stockings). The rule had a sensitivity of 75.0% (95% CI 59.8-85.8), a specificity of 77.8% (95% CI 71.9-82.7), and a positive likelihood ratio of 3.38 (95% CI 2.49-4.57). Conclusions: The preliminary PA shows promising results at identifying patients at risk of poor outcome after hip arthroplasty, and could assist in their management. Funding: FRSQ

Email: eugen.lungu@umontreal.ca

Lightning Oral Presentations SESSION 2

Procurity Lecture Theatre, Apotex Building Main Floor, Room 164 15:40 â&#x20AC;&#x201C; 16:50 Wednesday, June 3rd, 2015

Mass Gatherings Health: improving the quality and operationalization of field-collected data Ross Pragera,b, Andrew Guya,b, Sheila Turrisb,c,d, and Adam Lunda,b,c,d aFaculty

of Medicine, University of British Columbia, bMass Gathering Medicine Interest Group, University of British Columbia, cDepartment of Emergency Medicine, University of British Columbia, dJustice Institute of British Columbia Mass Gatherings Health (MGH) is a growing specialty dedicated to providing quality medical care at large public gatherings. Worldwide, mass gatherings can place substantial burden on local healthcare infrastructure. These events create dynamic and challenging environments in which to plan for and provide health and emergency medical services (HEMS). Also, the patterns of injury and illness differ from those typically encountered in the community. As such, MGH research is necessary to grow the evidence base for optimizing HEMS at mass gatherings. Ensuring quality data is a significant problem for MGH, and has important implications for patient care, provider liability, and the advancement of MGH research. The broader MGH issues of poor research methodology and lack of standardized terminology have been explored in the literature; however, little emphasis has been placed on correcting the ubiquitous operational issue of poor data quality. Without legible, accurate and complete data, further attempts to generate theories and models for MGH will fail. This analysis draws on experience providing care at mass gathering events, as well as our experience with a web-based Event and Patient Registry containing more than 20,000 patient encounters. The development and management of the Registry database has highlighted issues surrounding poor front-line data quality and completeness, and from this we propose specific suggestions for improving data quality at mass gatherings. Problems in the ability to capture and analyse data arise primarily from poor documentation. We have identified several themes that lead to poor documentation including human, environmental, and logistical factors. Common documentation issues include missing patient encounter forms, missing data fields, illegibility, and missing time stamps. Use of electronic records, additional volunteer training, and pre- and post-event briefings may improve documentation. Before higher order questions surrounding MGH can be addressed, we must first ensure the data is high quality and adequately representative of the complex phenomena that occur during mass gatherings. Funding: Unfunded Email: rprager@alumni.ubc.ca

2-Methoxyestradiol: A Hormonal Immunomodulatory Agent That Promotes Pulmonary Endothelial Integrity for Ex-Vivo Lung Perfusion Jessica G.Y. Luc 1,2, Roxane Paulin 3, Joanne Y Zhao 1,2, Darren H Freed 1,2,4,5, Evangelos D Michelakis 3, Jayan Nagendran 1,2,4,5 1

Division of Cardiac Surgery, Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta. 2 Mazankowski Alberta Heart Institute. 3 Division of Cardiology, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta. 4 Alberta Transplant Institute. 5 Canadian National Transplant Research Program. Introduction: Lung transplantation is the mainstay therapy for patients with end-stage lung disease refractory to medical management. However, the number of patients listed for lung transplantation exceeds the number of donors available. Normothermic Ex-Vivo Lung Perfusion (EVLP) has emerged as a platform for assessment, evaluation and targeted therapies where lungs are perfused with a bloodless solution containing nutrients, proteins and oxygen outside of the body before transplantation. Donor lungs are frequently injured and exhibit high levels of inflammation and lung edema. Thus, inhibition of the inflammation and edema in the donor lungs by EVLP may result in improved donor organ quality and higher rates of successful transplantation. Aim: As pregnancy has been shown to prolong transplant allograft survival in rat models, we investigated the use of 2-Methoxyestradiol (2ME2), an anti-cancer metabolite of estrogen that is upregulated significantly during pregnancy in an in-vitro model of rejection and pulmonary microvascular endothelial dysfunction. Methods: Human peripheral blood mononuclear cells (PBMCs) were cultured and pre-treated with 2ME2 before activation. Cultured medium and cells were collected for protein analysis. Proliferation and apoptosis assays were performed and analyzed by flow-cytometry. The permeability of human pulmonary microvascular endothelial cells (EC) was assessed using the Transwell culture assay. Results: TNF-α cytokine production in 2ME2 treated activated PBMCs were modestly reduced relative to controls. T-cell proliferation was significantly blunted upon treatment with 2ME2 and a decrease in apoptosis correlated with a decrease in caspase-9 activity. 2ME2 was able to block the induction of stressinduced senescence caused by activation of T-cells and was beneficial in reducing TNF-α induced EC permeability. Conclusions: Our results show that 2ME2 has an immunomodulatory effect that could be exploited in the setting of cellular rejection by blunting activated T-cell proliferation, without causing apoptosis or stress induced senescence. Additionally, 2ME2 is able to block TNF-α induced EC permeability. Taken together, 2ME2 is a promising anti-inflammatory and endothelial targeted therapeutic that may be added to the EVLP circuit to reduce pulmonary edema and inhibit the immune response in donor lungs. Funding: AIHS Email: jgluc@ualberta.ca

Comparing Lung Function in Non-DCD and DCD Lungs: Is There a Potential Role for Adjunct Pharmaceuticals? Sabin J. Bozsoa, BSc, Darren H. Freedab, MD, PhD, FRCSC and Jayan Nagendranab, MD, PhD, FRCSC a

Faculty of Medicine and Dentistry, bDepartment of Surgery, Division of Cardiac Surgery, University of Alberta and Mazankowski Alberta Heart Institute, Edmonton, Canada Introduction: Ex-vivo lung perfusion (EVLP) is a technique that perfuses and ventilates lungs at normothermia, thus replicating physiologic conditions outside the human body. Donation after circulatory death (DCD) is a strategy that has the potential to significantly increase the number of lung transplants being performed. By utilizing EVLP we are able to continuously monitor lung function and perform organ-enhancing therapies, leading to a more informed clinical decision making process. This is especially useful when dealing with DCD lungs, which may have suffered some damage due to warm ischemic time. Methods: In order to test pharmacotherapies such as resveratrol treatment, we must first establish the characteristics of non-DCD and DCD lungs on EVLP. To do so we designed and built our own unique EVLP device using a variety of components readily available in a hospital as well as custom-made parts using a 3D-printer. We randomized 5 sets of lungs from 40kg pigs to either a DCD or non-DCD procurement strategy. The lungs were all perfused with commercially available STEEN solution, a low potassium dextran perfusate. Results: On the device we measured pulmonary vascular resistance, pulmonary artery pressure and peak airway pressure as indicators of lung function. We were also able to analyze the perfusate for TNFa levels to gauge the level of immune activation in the lungs and also assessed the oxygenation capacity of the lungs by measuring a PaO2/FIO2 (PF) ratio. We were able to demonstrate that the DCD lungs were damaged as evidenced by poorer lung function, lower PF ratios and higher TNFa levels than the non-DCD lungs. Additionally we found a correlation between TNFa levels and lung function, specifically PVR, with worse function in those lungs with the higher TNFa levels. Conclusions: This is significant because it implies that there is the potential to improve the function of lungs acquired from DCD donors. Our next goal is to demonstrate that improved lung function in DCD lungs is possible after treating with pharmacotherapies, such as resveratrol. Funding: Canadian Institutes of Health Research, University Hospital Foundation, Alberta Transplant Institute, Canadian National Transplant Research Program

Contact: bozso@ualberta.ca

Jump power reflects the degree of disability in neuromuscular disease. Christopher Newell1, Barbara Ramage6, Alberto Nettel-Aguirre4, 5, Ion Robu6, Fariha Ahmed2 and Aneal Khan3, 4 Department of Medical Science1, Medical Genetics3, Pediatrics4, Community Health Sciences5 and Neurosciences6, Bachelor of Health Sciences2, Faculty of Medicine, University of Calgary and Alberta Children’s Hospital, Calgary, Canada. Rationale: Mitochondrial diseases can impair muscle function and restrict mobility. Motor disability can affect the ability to work, ambulate and quality of life. Clinical measures of functional ability currently exist (timed chair up-and-go, 6-minute walk test, grip strength, etc.) although tests which apply functional measures in patients with mitochondrial disease are scarce. Whether to measure degenerative changes in mobility or response to therapy, a reproducible, and easy to perform functional measure is needed. We therefore developed a novel application of peak jumping power (PJP) as a quantitative index of functional mobility in mitochondrial disease patients. Objectives: Determine if PJP can measure the functional ability in patients with mitochondrial disease. Methods: Adult and pediatric patients were recruited from the metabolic diseases clinic, healthy controls through a recruitment poster. Subjects performed 5 successive jumps from a squat position, without countermovement, while standing on a force plate. Mass and instantaneous force were used to compute velocity from which instantaneous power (watts) and the best result was divided by the mass (kg) to give the PJP (watts/kg). Ambulatory ability was recorded as: healthy controls (HC), patients with no reported functional weakness (ambulatory competent; AC), patients with self-reported functional weakness (ambulatory weakness; AW), patients dependent on walking aids (ambulatory assistance; AA), and patients dependent on a wheelchair (WC). Results: A total of 88 healthy controls and 110 patients with neuromuscular disease were recruited. Most patients were diagnosed with mitochondrial disease (n=61). The PJP in HC (19.1 W/kg ± 0.7) was not different compared to AC (17.2 W/kg ± 1.1, p<0.275). However, AW (9.9 W/kg ± 0.7), AA (5.7 W/kg ± 1.1) and WC (2.3 W/kg ± 0.6) followed a stepwise decline in PJP as ambulatory capacity decreased (p<0.01). This trend persisted across the age range of our subjects (controls; 3 - 65 years, patients; 4 – 83 years of age), demonstrating that PJP and ambulatory capacity are related. Conclusions: PJP is an easy to perform, quantitative measure of ambulatory ability in patients with neuromuscular diseases including mitochondrial disease. PJP scores clearly distinguish patients who require different types of ambulatory assistance. Funding: ACHRF, ACHRI, MitoCanada. Email: cnewell@ucalgary.ca

Outcomes in Adult Survivors of Childhood Burn Injury as Compared to Matched Controls

Stone J1, Gawaziuk JP2,3, Khan S3, Chateau D3, Bolton JM4, Sareen J4, Enns J1, Doupe M3, Brownell M3, and Logsetty S2,5 1

Faculty of Medicine, MD Candidate, University of Manitoba, Winnipeg, Manitoba, Canada

Manitoba Firefighters Burn Unit, Winnipeg, Manitoba, Canada

Manitoba Center for Health Policy, University of Manitoba, Winnipeg, Manitoba, Canada

Department of Psychiatry, University of Manitoba, Winnipeg, Manitoba, Canada

Department of Surgery, Sections of General and Plastic Surgery, University of Manitoba, Winnipeg, Manitoba, Canada

Objective: Limited research exists examining long-term mental and physical health outcomes in adult survivors of pediatric burns. We examine the post-injury lifetime prevalence of common mental and physical disorders in a large pediatric burn cohort and compare the results with matched controls. Methods: 745 survivors of childhood burns identified in the Burn Registry (<18 yr of age and Total Body Surface Area >1% between April 1, 1988 and March 31, 2010) were matched 1:5 to the general population based on age at time of injury (index date), sex and geographic residence. Post-injury rate ratio (RR) was used to compare burn (cases) and control cohorts for common mental and physical illnesses through physician billings, and hospital claims. Risk Ratios were adjusted for sex, rural residence and income. Results: Compared to matched controls, post burn cases had significantly higher Rate Ratios of all mental disorders, which remained significant (p < 0.05) after adjustment (major depression RR=1.54 (confidence interval 1.22-1.95), anxiety disorder RR=1.50 (CI 1.25-1.80), substance abuse RR=2.35 (CI 1.71-3.24), suicide attempt RR=4.33 (CI 1.55-12.1) or any mental disorder RR=1.54 (CI 1.32-1.82). Physical illnesses were also increased in burn survivors: arthritis RR=1.24 (CI 1.08-1.4), fractures RR=1.37 (1.18-1.59), total respiratory morbidity RR=1.13 (CI 1.02-1.25) and any physical illness RR=1.15 (CI 1.05-1.26). Conclusion: Adult survivors of childhood burn injury have significantly increased risk of post-burn mental and physical illnesses. Screening and appropriate management of these illnesses is essential when caring for this population.

IMPACT OF TYPE 2 DIABETES ON CYP450 ACTIVITIES IN THE KIDNEY Sarah Maximos1,3, Yat Hei Leung1,2, Sophie Gravel1,2, François Bélanger1, Fleur Gaudette1, Véronique Michaud1,2,3 1 Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), 2Faculty of Pharmacy of University of Montréal, 3Faculty of Medicine of University of Montréal, Montreal, Qc, Canada. Rationale: CYP450s play a central role in the overall metabolism of drugs and endogenous substrates. In addition to the liver, the CYP450s are expressed in the kidneys. Some CYP450 (e.g. CYP1A, 2C, 2J and 4A) are involved in cardiovascular homeostasis as well as renal function. Evidence indicates that the kidneys possess a significant CYP450s metabolic activity. Many data suggest that pathological conditions such as type 2 diabetes (T2D) could influence the expression and functional activity of CYP450. Objectives: The aim was to evaluate the effects of T2D on the activities of CYP450 isoenzymes found in the kidneys from diet-induced obesity (DIO) mice. Methods: C57BL/6 mice fed a high-fat diet (HFD) were used as a T2D model and were stratified according to their phenotype; 1) mice with a low response to the HFD (LR) (n=12), 2) with a high response to HFD (HR) (n=16) and 3) mice fed a normal diet (ND) (n=12). The kidneys were excised and microsomes were prepared using the ultracentrifugation method. In vitro incubations were performed with renal microsomes and different CYP450 probe markers. Metabolites were analyzed by LC-MS/MS. Results: Cyp2e1 showed the highest metabolic activity in the 3 groups of mice. Renal metabolic activities of cyp3a and cyp4a were decreased in both HFD groups (LR and HR), whereas cyp2b and cyp2j activities were reduced only in HFD-HR group compared to ND. In contrast, renal cyp2d activity was higher in HFD groups.

CYP450s probes Bupropion Ebastine Midazolam Lauric acid Bufuralol Chlorzoxazone

cyp cyp2b cyp2j cyp3a cyp4a cyp2d cyp2e

Cyp Activity (fmol metabolite/min/mg prot) ND LR HR 12.7 ± 0.7 13.1 ± 0.2 8.8 ± 0.7* 15.8 ± 0.2 16.6 ± 0.5 10 ± 1* 0.67 ± 0.24 0.09 ± 0.01* 0.069 ± 0.001* 34.8 ± 0.3 30.0 ± 0.5* 22.0 ± 0.6* 3.5 ± 0.03 7.6 ± 0.3* 7.0 ± 0.2* 141 ± 3 154 ± 3 110 ± 2

*p- value <0.005 (vs ND) Conclusion: Our results suggest that T2D affects CYP450 activity in the kidneys and this modulation is isoenzyme-dependent. Modulation of renal CYP450s by T2D could influence local drug disposition as well as the kidney function. Funding: CIHR and FRQS sarah.maximos@umontreal.ca 65

Deletion of S-nitrosoglutathione reductase (GSNOR) improves outcomes in an experimental model of cerebral malaria Robyn E. Elphinstone1, Jonathan S. Stamler2, and Kevin C. Kain1 1

Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Tropical Disease Unit, Department of Medicine, University of Toronto; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; 2Institute of Transformative Molecular Medicine, Case Western Reserve University, Cleveland, OH, United States Rationale: Malaria continues to cause morbidity and mortality worldwide. Decreased nitric oxide (NO) bioavailability is associated with disease severity and worse clinical outcomes in malaria infection. NO bioactivity can be mediated through a post-translational modification, S-nitrosylation, which regulates a wide variety of cellular signaling processes. Objectives: To determine if increased levels of S-nitrosylation would improve outcomes in experimental cerebral malaria (ECM). Methods: ECM was induced by infecting mice with a mouse specific malaria strain, Plasmodium berghei ANKA (PbA). Wild type mice were compared to S-nitrosoglutathione reductase (GSNOR) knockout (KO) mice. The deletion of GSNOR results in mice with increased levels of S-nitrosylation. The mice were followed for survival, parasitemia, weightloss, and a modified Rapid Murine Coma and Behavioural Score (RMCBS). Throughout the course of infection, plasma levels of endothelial activation markers and cytokines were measured by ELISA. On day six post infection, an Evanâ&#x20AC;&#x2122;s blue assay was used to measure the integrity of the blood brain barrier. Results: In susceptible (wild type C57BL/6) mice, ECM leads to 80-100% fatality within 5-10 days post infection. When GSNOR knockout (KO) mice are used in this model, they have significantly improved survival compared to wild type mice (p<0.0001). Of interest, despite having an increased parasite burden (p<0.0001), GSNOR deficient mice displayed improved RMCBS (p<0.001 D6 and D7 post infection) and improved maintenance of blood brain barrier integrity (p<0.01). Plasma levels of endothelial activation markers (VWF, Ang-2, sICAM-1, and sVCAM-1) were not significantly different at any of the time points measured. However, there were significantly higher levels of IFN-Ď&#x2019; on D4, and D5 post infection in the GSNOR KO mice compared to wild type controls (p<0.001) suggesting that the GSNOR KO mice have altered immune responses to PbA. This is currently being explored using bone marrow transplants to further elucidate the role of the hematopoietic compartment in mediating protection in the GSNOR null mice. Conclusions: Increased S-nitrosylation, due to loss of GSNOR, improves outcomes in ECM and provides a novel target for potential adjunctive therapies in severe malaria. Funding: CIHR, Vanier CGS Email: robyn.elphinstone@mail.utoronto.ca

Participating Medical Schools

Symposium Contact Information CNMSRS On-Site Contact Info Kimberley Ormiston 204-789-3558 S210 Medical Services Bldg. 750 Bannatyne Avenue University of Manitoba Winnipeg, MB R3E 0T6 Email: kim.ormiston@umanitoba.ca

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