Issue 30 by The Meducator

WINTER 2017 | ISSUE 30

Interview with Dr. Matthew miller d e v e lo p m e n t o f t h e u n i v e r s a l f l u va c c i n e

hereditary breast and ovarian cancer p r e v e n tat i v e s u r g e ry u p ta k e a n d b r ca1/2

the virtual reality of our healthcare system A c r i t i ca l r e v i e w

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table of

table of contents

CONTENTS

Winter 2017 | ISSUE 30 02 INTRODUCTION 03 MEDPULSE 05 MEDBULLETINS 07 FORUMSPACE 09 ABSTRACTS 10 INFOGRAPHIC 11 PATHOPROFILE OPINION 13 Over-the-Counter Statins: A Gateway to Misuse RESEARCH INSIGHT 15 Relationship Between Neural Crest Cell and Anterior Segment Dysgenesis

CRITICAL REVIEW 19 Allergic Asthma: The Emerging Relationship

Between the Gut Microbiome and Regulatory B Cells

23 Hereditary Breast and Ovarian Cancer: Factors

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Influencing the Uptake of Preventative Surgeries Among BRCA1 and BRCA2 Mutation Carriers

27 The Virtual Reality of Our Healthcare System 31 INTERVIEW SPOTLIGHT 34 CONTRIBUTORS Cover Artist Candy Niu

ToC Artist

Matilda Kim

The Birth of Venus is one of the world’s most celebrated paintings. Painted by Sandro Botticelli in the mid-1480s, this masterpiece has inspired many generations. Artist Candy Niu reinterpreted this classic work from an anatomical perspective to showcase how underneath it all, Venus, the goddess of love and beauty, is the same as the rest of us. Even when reduced to her basic biology, Venus retains her grace. This cover is a testament to the profound beauty often found in the sciences. We are very proud to present more pieces highlighting the inherent creativity of the health sciences in the 30th issue of The Meducator. In this issue, contemporary health sciences issues are explored from an international perspective. Staff editor Devin Roshan reports international health sciences news across the globe an innovative Medpulse piece with graphic artist Kelsie Ou. Delving deeper into recent breakthroughs, Devin Roshan, Eva Liu, Angela Dong, and Jim Xie discuss superbugs, Zika virus, gene technology, and multiple sclerosis in Medbulletin articles. Continuing our tradition of collaboration with McMaster Health Forum, Steven Cho, Malcom Hartman, Ahmad Firas Khalid, Janice Mok, and Padmaja Sreeram highlight the recent healthcare disparities faced by female Syrian refugees through a Forumspace review. Furthering our longstanding focus on original undergraduate research, Caberry (Weiyang) Yu, Owais Mian, and Annie Wu share Research Abstracts of their work investigating cancer prognostication, knee arthroplasty, and macrophage response, respectively. Staff editor Ashley Lam and graphic artist Tony Chen collaborate to create an Infographic on the risks of sugar overconsumption. In our Opinion feature, Ahmed Abdelaal and Kelvin Ng challenge current perceptions on over-thecounter statin approval. This issue’s Research Insight investigates the relationship between neural crest cell specification and anterior segment dysgenesis by featuring the work of Jeong Won Park, Vanessa Martino, and Judith West-Mays.

introduction

INTRODUCTION ISSUE 30

dear reader,

A series of critical reviews analyzes novel developments and controversial topics within the health sciences. Shawn Khan analyzes the role of the gut microbiome and regulatory B cells in allergic asthma. The factors that influence patient decisions to undergo preventative mastectomy are elucidated by David Bobrowski in his analysis of BRCA1/2 genetic testing. The Meducator dives into the world of novel technology as iSci’s Aakash Shaw describes potential applications of virtual reality in our healthcare system.

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As our 30th publication cycle draws to a close, we wish to thank our phenomenal team for their invaluable contributions throughout the year, particularly Creative Directors Maine Bing and Michael Sun, Managing Editors Ishan Aditya and Arshia Javidan, and Video Manager Faizan Bhatia. The immense creativity and dedication demonstrated by contributors and our Editorial, Graphics & Design, and Video teams are testaments to our staff ’s passion for the health sciences, as well as all that can be explored through the vibrancy of writing, multimedia, and art.

Abirami kirubarajan

W I N T E R 2017

Matthew Yau

Bachelor of Health Sciences (Honours) Class of 2018

Cyclospora Outbreak Oct 2016 - Ontario, Canada

Jul 2016 - Massachusetts, USA

The slow production of conventional vaccines hinders responses to emerging epidemics. Earlier this year, Daniel Anderson and colleagues at MIT synthesized a new, multi-purpose vaccine by encasing antigen RNA in a modified polymer nanoparticle that protects the RNA from degradation. After a single dose, the vaccine protected mice against lethal exposure to a myriad of deadly pathogens, including Ebola virus, H1N1 influenza, and parasitic Toxoplasma gondii. The researchers hope that their work will pave the way for the testing of synthetic vaccines on humans.

Cyclospora is a microscopic, single-celled parasite commonly found in tropical countries that causes intestinal illness when ingested. Following an outbreak in Canada, a total of 81 cases were reported. As of October 6th, the Public Health Agency of Canada reports that the outbreak is over and that the Canadian Food Agency suspects imported fresh produce to be the culprit.

Rapid-Response Vaccines

Synthetic Bones Oct 2016 - Illinois, USA

Dr. Ramille Shah and colleagues from Northwestern University recently developed a ‘hyperelastic bone’ using a 3D printer. The hyperelastic bone is comprised of hydroxyapatite, a calcium-based mineral that is similar to those found in animal bones. After implanting grafts into mice, rats, and a macaque, researchers found that the material fused with tissue and triggered bone regeneration. Upon testing its strength and elasticity, Shah’s team found that the synthetic bone was able to withstand loads of similar weight to their natural counterparts.

Zika Virus and Guillain-Barré Syndrome

Oct 2016 - Bogotá, Colombia

Since the outbreak of Zika Virus (ZIKV), the number of GuillainBarré Syndrome (GBS) cases in Colombia has increased. GBS is a demyelinating disease that causes muscle weakness and paralysis. Researchers tested GBS patients for ZIKV using RT-PCR assays on blood, cerebrospinal fluid, and urine. The results revealed virologic evidence of ZIKV in GBS patients, thus establishing a link between the two diseases. Research on the etiology of ZIKVrelated GBS is currently underway.

MED

PULSE

Polio Reemerges

Aug 2016 - Borno, Nigeria

Following two years of latency, three cases of wild polio type one were reported by the government of Nigeria in Borno. Symptoms of polio include fever, fatigue, vomiting, leg pain, and neck stiffness. The government has declared the outbreak a public health emergency. In response, the World Health Organization is presently organizing large-scale immunization.

Hormonal Contraceptives and Depression Sept 2016 - Copenhagen, Denmark

Hormonal contraceptives have been clinically proven to influence mood, but their association with depression has been largely unaddressed until now. Danish researchers sought to determine if hormonal contraceptives are positively linked to the use of antidepressants. In a prospective case-cohort study, researchers discovered that hormonal contraceptives were associated with the subsequent use of antidepressants and first diagnoses of depression, especially among adolescents.

Nobel Prize in Medicine Oct 2016 - Tokyo, Japan

The 2016 Nobel Prize in Physiology or Medicine was awarded to molecular biologist Yoshinori Ohsumi for his research in the field of autophagy, the process by which cells digest and recycle their components. At the Tokyo Institute of Technology, Ohsumi used microscopy images of yeast cells to determine the mechanism of autophagy.

Sepsis and Antimicrobial Resistance Oct 2016 - Delhi, India

Sepsis, a systemic infection, is one of the leading global causes of neonatal deaths. Researchers followed sepsis-vulnerable neonates born in tertiary care centres in Delhi, India and tested them for antimicrobial susceptibility. They found an alarmingly high incidence of sepsis and antimicrobial resistance in neonates born in tertiary hospitals. These findings highlight the importance of designing global strategies to reduce sepsis-related neonatal deaths in developing nations.

Deadly and Undetectable Sept 2016 - Taif, Saudi Arabia

From late August to early September, a concerning number of Middle East Respiratory Syndrome (MERS) cases were reported in Taif and surrounding cities in Saudi Arabia. MERS is a viral respiratory disease caused by a coronavirus. Initial symptoms include fever, cough, and shortness of breath, but what makes MERS deadly are its nonspecific symptoms. Following five particularly severe cases, the World Health Organization issued an urgent recommendation to implement control measures to prevent the spread of MERS.

Rising Obesity in Australia Sept 2016 - Sydney, Australia

A study conducted by the University of Sweden hypothesizes that the obesity rate among Australian adults will increase from 28 to 35 percent by the year 2025. Researchers suggest that approximately 13 percent of the population in 2025 will fall under the â&#x20AC;&#x2DC;severely obeseâ&#x20AC;&#x2122; category. In other words, one in eight individuals will have a BMI of over 35.

Author | Devin Roshan

Artist | Kelsie Ou

Citations can be found on meducator.org

MEDBULLETIN SUPERBUGS

ZIKA VIRUS

EVA L IU

ANG ELA D ONG

Antibacterial resistance poses an enormous threat to the ability to treat common diseases. It occurs when bacteria develop genetic mutations that render antibiotic drugs ineffective, resulting in prolonged hospital stays and high mortality rates. 1 Multi-drug resistant (MDR) bacteria, also known as superbugs, are urgent threats to global health due to a lack of effective treatment. 2 Thus, many research labs are tasked with finding novel drugs that can combat MDR bacteria.

Heavily featured in recent news for its rapid spread through South America, Zika is a mosquito-borne virus with no established vaccine or prevention methods. Although Zika contraction is often characterized by little to no symptoms, pregnant women may pass the virus onto their fetuses, resulting in birth defects such as microcephaly. 1 Previously, it was believed that mosquitoes could only contract the virus by biting an infected host. However, new research shows that female mosquitoes carrying the Zika virus can pass the infection onto their offspring via vertical transmission. 1

medbulletin

Star-shaped Peptide Polymers Kill Superbugs

A recent study conducted at the University of Melbourne has led to the development of Structurally Nanoengineered Antimicrobial Peptide Polymers (SNAPPs), which exhibit antibacterial properties while being non-toxic to the body. 3 The polymers are shown to be highly effective against all tested gram-negative pathogens, including those that demonstrate resistance to other antibiotics. SNAPPs are capable of killing gram-negative bacteria both in vivo and in vitro . 3 Analyses using microscopy and bioassay techniques have shown that the polymer works through multiple pathways, including destruction of bacterial cell membranes, dysregulation of ion movement across cytoplasmic membranes, and induction of cell death. 3 The various bactericidal mechanisms of the polymer makes it more difficult for bacteria to develop resistance to it. Furthermore, experiments on red-blood cells show that the dosage needs to be increased 100 times relative to the standard for the substance to be toxic, making it safe for use.

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SNAPPs have yet to be incorporated into a commercially viable drug as they have not been tested on humans and currently lack specificity towards certain types of bacteria. However, SNAPPs’ pre-clinical success presents new possibilities for targeting MDR bacteria.

1. 2. 3. 4.

Slama T. Gram-negative antibiotic resistance: there is a price to pay. Critical Care. 2008;12(Suppl 4):S4. Antimicrobial resistance [Internet]. World Health Organization. 2016 [cited 20 September 2016]. Available from: http://www.who.int/mediacentre/factsheets/fs194/en/ Lam S, O’Brien-Simpson N, Pantarat N, Sulistio A, Wong E, Chen Y et al. Combating multidrug-resistant Gram-negative bacteria with structurally nanoengineered antimicrobial peptide polymers. Nature Microbiology. 2016;1:16162. Superbugs Banner [Image on the Internet]. 2016 [cited 2016 Nov 9]. Available from: https://www. herpes-coldsores.com/std/wp-content/uploads/2014/07/Ecoli1.jpg

Study finds new ROUTE OF ZIKA VIRUS transmission

The study, published in the Journal of Tropical Medicine and Hygiene , elucidated that infected eggs of the Aedes aegypti can survive for months on dry surfaces, ensuring the virus’ survival in cold or dry conditions even without a vertebrate host. Thus, the Zika virus will persist even if all adult mosquitoes were eliminated because the mosquito’s offspring can carry the virus into the next generation. This further complicates current measures to combat Zika transmission. 1 Luckily, not all species of mosquito can transmit the Zika virus through vertical transmission. 2 It should also be noted that the study observed mosquitoes in a laboratory setting as opposed to the wilderness, which could impact the generalizability of the results. 2 The conclusions from the study can be used to improve the current methods for combatting Zika transmission. Recommended interventions include the use of insecticides, the elimination of standing water, and the release of genetically-modified mosquitoes that sterilize the mosquito populace or hinder vertical viral transmission. 2

1. 2. 3.

Milius S. Mosquito moms can pass Zika to offspring [Internet]. Science News. 2016 [cited 19 September 2016]. Available from: https://www.sciencenews.org/blog/science-ticker/mosquito-moms-can-passzika-offspring?mode=topic&context=69 Thangamani S, Huang J, Hart C, Guzman H, Tesh R. Vertical Transmission of Zika Virus in Aedes aegypti Mosquitoes. American Journal of Tropical Medicine and Hygiene [Internet]. 2016 [cited 19 September 2016];. Available from: http://www.ajtmh.org/content/early/2016/08/23/ajtmh.16-0448 Zika Virus Banner [Image on the Internet]. 2016 [cited 2016 Nov 9]. Available from: https://hhpblog. s3.amazonaws.com/blog/wordpress/wp-content/uploads/2016/04/Zika-update-042016-image.jpg

CRISPR

CRISPR Goes Viral

multiple sclerosis

S1PR1 Modulator and Multiple Sclerosis

JIM XIE

D EVIN ROSHAN

In the 1980s, scientists discovered that bacterial genomes held arrays of repeating DNA sequences with unique intermittent strings of viral DNA. They named this configuration Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and later found to it to work in combination with CRISPR-associated (Cas) enzymes to edit viral genetic information.

Multiple sclerosis (MS) is an autoimmune disorder that destroys the myelin sheath, a critical insulator surrounding axons, in the central nervous system. 1,2 While MS affects more than 2.3 million individuals globally, current therapeutic options are limited. 2,3

CRISPR has already been proven to prevent HIV infection in human cells. 2 Now it is entering clinical trials as a form of immunotherapy for cancer patients. 3 Although CRISPR is currently a mere firstgeneration tool, it will undoubtedly continue to transform the fields of biology and medicine.

Discovery of the G-protein coupled receptor sphingosine 1-phosphate receptor 1 (S1PR1) evoked interest in the scientific community as a possible therapeutic target for MS and other autoimmune disorders. 4,5 S1PR1 activation has been linked to myelin production, astrocyte migration, neurite outgrowth, and neurogenesis. 4,5 The link between S1PR1 and myelin-producing oligodendrocytes is of particular interest because new oligodendrocytes could potentially reverse early demyelination. 2 A study recently published in Lancet Neurology discusses amiselimod, a novel oral selective modulator of the S1PR1 receptor. 4 In the double-blind phase II clinical trial, patients from Europe and Canada with relapsing MS were randomly assigned to a range of daily doses of amiselimod or placebo for 24 weeks. 4 From weeks 8-24, researchers monitored axonal damage and used advanced magnetic resonance to locate lesions. 4

3. 4.

1. 2. 3. 4. 5. 6.

Noseworthy J, Lucchinetti C, Rodriguez M, Weinshenker B. Multiple Sclerosis. N Engl J Med. 2000;343(13):938-952. Chang A, Tourtellotte W, Rudick R, Trapp B. Premyelinating Oligodendrocytes in Chronic Lesions of Multiple Sclerosis. N Engl J Med. 2002;346(3):165-173. Haussleiter I, Brune M, Juckel G. Review: Psychopathology in multiple sclerosis: diagnosis, prevalence and treatment. Ther Adv Neurol Disord. 2009;2(1):13-29. Kappos L, Arnold D, Bar-Or A, Camm J, Derfuss T, Kieseier B et al. Safety and efficacy of amiselimod in relapsing multiple sclerosis (MOMENTUM): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2016;15(11):1148-1159. Oâ&#x20AC;&#x2122;Sullivan C, Dev K. The structure and function of the S1P1 receptor. Trends Pharmacol Sci. 2013;34(7):401-412. Multiple Sclerosis Banner. [Image on the Internet]. 2016. [cited 2016 Nov 9]. Available from: http:// celebnhealth247.com/wp-content/uploads/2016/11/Multiple-Sclerosis-1-1200x801.jpg

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Ledford H. Riding the CRISPR Wave. Nature [Internet]. 2016 [cited 2016 Sep 15];531(7593):156159. Available from: http://www.nature.com/polopoly_fs/1.19510!/menu/ DOI: 10.1038/531156a5. Zhu W, Lei R, Duff YL, Li J, Guo F, Wainberg MA, et al. The CRISPR/Cas9 systme inactivates latent HIV-1 proviral DNA. Retrovirology [Internet]. 2015 [cited 2016 Sep 15];12:22. Available from http:// retrovirology.biomedcentral.com/articles/10.1186/s12977-015-0150-z/ The Scientist. CRISPR Therapy to Enter Trials [Internet]. The Scientist; 2016 [updated 2016 Jul 25, cited 2016 Sep 15]. Available from: http://www.the-scientist.com/?articles.view/articleNo/46625/ title/CRISPR-Therapy-to-Enter-Trials/Gizmodo. CRISPR Banner [Image on the Internet]. 2014. [cited 2016 Nov 9]. Available from: http://www.brasil247.com/images/cms-image-000350395.jpg

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Doses of 0.2 mg and 0.4 mg of amiselimod were found to significantly reduce the number of lesions. 3 Amiselimod was safe, well-tolerated, and efficacious, reducing disease activity in a dose-dependent manner. 4 The selective S1PR1 modulator is the first to be investigated for treatment of MS in phase II studies without adverse cardiac events. 4 However, amiselimod warrants further investigation to determine if it is a feasible long-term treatment for MS and other autoimmune-mediated diseases. 4

medbulletin

Since then, scientists have adapted Cas9 enzymes from bacteria to cut and edit the genome of virtually any organism. What makes the CRISPR-Cas9 pair unique is its unrivaled precision, efficiency, and flexibility. Researchers now have an extremely accurate means of targeting and studying particular DNA sequences in vast genomes. Experiments using genetically-engineered organisms that traditionally take a year or more to complete can now be accomplished in just a few months with CRISPR. Furthermore, modifications to CRISPR, such as the disruption of Cas9 enzymes, have opened up expansive paths of study in various subfields such as epigenetics. 1

FORUMSPACE

Syrian Refugee Women: A Vulnerable Population Struggles to Find Care Steven Cho 1 , Malcolm Hartman 2 , Ahmad Firas Khalid 3 , Janice Mok 2 , & Padmaja Sreeram 1 Bachelor of Health Sciences (Honours), Class of 2018, McMaster University, 2Bachelor of Health Sciences (Honours), Class of 2017, McMaster University, 3Health Policy PhD Candidate, McMaster University

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forumspace

Introduction

The McMaster Health Forum strives to be a leading hub for improving health outcomes at the regional and provincial levels in Canada. Through problemsolving and discussion, the Forum harness information, convene stakeholders, and prepare action-oriented leaders to meet pressing health issues creatively.

repeatedly reported rape or fear of rape as the chief motivation to flee the country.6 Moving forward, it Canadians pride themselves for having a health system will be important to monitor the mental well-being of founded on the principles of universality and accessibility. women refugees in Canada and offer programs that Over the next few years, the system must address the will support their health. As the healthcare of refugees health-related needs of Syrian refugees in Canada. has been primarily coordinated at a provincial level, it is Between November 2015 and September 2016, Canada critical for each province to organize and support mental welcomed 31,444 refugees from Syria and is currently health services for refugees, rather than relying on processing another 20,261 applications.1 Compared to direction from the federal government. For example, in the previous intake of 1,306 Syrian refugees in 2013, this Ontario, the Central Local Health Integration Network represents a large influx of citizens that will undoubtedly funds an organization called Across Boundaries, which strain the health system.2 To manage this increased provides ethno-culturally specific and gender-sensitive resettlement commitment, the government has adopted mental health services.5 Existing programs such as a targeted approach to resettlement by prioritizing the Across Boundaries can act as models for policymakers needs of women, a particularly vulnerable group among when they are planning for the services needed to address refugees due to their possible history with sex and the mental health challenges of Syrian refugee women. gender-based violence.3,4 In order for the health system to truly match the values it was founded upon, there is Primary Care a need to address the specific health challenges faced by refugees and, in particular, the challenges faced by While access to primary care is a concern for the general refugee women once they arrive in Canada. immigrant population, this challenge is magnified with refugees given their turbulent past. Refugees are nearly Mental Health Services twice as likely to report poor health within four years of their arrival as compared to the general immigrant It would come as no surprise that refugees may be population, thus it is important that they engage with the exposed to many stressors, which place them at a primary care system.7 A barrier to accessing primary care higher risk for mental illness. This is especially critical is the lack of information regarding system navigation, for women refugees, as gender is a critical determinant a phenomenon that is especially pronounced among of mental health. Studies have shown that depression, women refugees, as they are less likely to gain language anxiety, and sexual domestic violence affect women to proficiency compared to male refugees.8 Community a much greater extent than men across most countries navigators are trained healthcare workers who link and settings.5 In fact, female refugees from Syria have patients to healthcare providers and support patients to

reduce healthcare disparities. They can provide guidance to vulnerable populations in order to overcome access barriers. This guidance, however, has not yet been widely adopted for Canadian refugee populations.9 In the United States, community navigators have been successfully employed to decrease health disparities among female refugees. Similar programs could likewise be implemented in Canada.10

to bear the expense. While the IFHP does cover translation services, there are restrictions placed on the length and type of medical visit for which a translator will be reimbursed.13 Given that communication between the patient and provider is fundamental for care delivery, there is a need to reduce restrictions to accessing this benefit.

Culturally-Appropriate Healthcare Services

Conclusion

More discussions on current healthcare topics are available at http://www.mcmasterhealthforum.org/ 1.

Government of Canada C and IC. #WelcomeRefugees: Key figures [Internet]. 2015 [cited 2016 Oct 4]. Available from: http://www.cic.gc.ca/ english/refugees/welcome/milestones.asp 2. Canada finally fills 2013 Syrian refugee promise,

says work under way on next one [Internet]. The Globe and Mail. [cited 2016 Oct 4]. Available from: http://www.theglobeandmail.com/news/ politics/canada-finally-fills-2013-syrian-refugeepromise-says-work-underway-on-next-one/ article23628469/

3. Library of Parliament Research Publications. Resettling Refugees: Canada’s Humanitarian Commitments [Internet]. 2015 [cited 2016 Oct 6]. Available from: http://www.lop.parl.gc.ca/ content/lop/ResearchPublications/2015-11-e. html#txt23

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Reviewed by Dr. Michael Wilson

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As Canada accepts more Syrian refugees, it will be pertinent to address the health challenges of An underlying issue that Syrian refugee women women, who constitute a particularly vulnerable face is their inexperience with Canadian culture population.Currently,Syrian women refugees face and languages. Family caregivers, who are typically a myriad of health-related challenges, including women, have reported significant challenges in a lack of mental health services, difficulties accessing healthcare and social services due to in accessing primary care, and struggles with language barriers.12 Health outcomes in refugee obtaining culturally-sensitive services. Increasing populations are directly tied to English proficiency. access to culturally-appropriate mental health Specifically, language barriers interfere with services and primary care will be an important all aspects of their experience, from the initial first step to ensuring that our healthcare system consultation to follow-up care instructions.15 The is truly universal and accessible. This will allow all current lack of funding for interpreters inevitably Canadians their rightful access to care. ■ forces the individual or community health center

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Moreover, cultural competence needs to be interwoven into all aspects of care that are Additional barriers to primary care access provided to Syrian refugees. Physicians should may result from primary care providers. The be cognizant of the religious and culturallyInterim Federal Health Program (IFHP) specific values held by Syrian refugee women provides healthcare coverage to refugees, but when discussing illness and treatment. For general practitioners may not accept a refugee’s example, diagnosing mental illness and imposing coverage due to unfamiliarity with the program. a treatment schedule based on models of Even if a physician knows of the program, the Western medicine may alienate some patients.6 reimbursement process is complex as the To overcome this barrier, culturally-competent healthcare practioner must first submit an training can be provided at various levels application to become a registered provider under within the healthcare system. This training IFHP.11 Given the aforementioned barriers may be situated at the level of the institution or for refugees to access care, the extra paperwork practitioner. Implementing such an approach required from physicians further disincentivizes at the practitioner level would initially help to the process. Action is needed to revise the IFHP, facilitate trust between the refugee population such that physicians can better accommodate the and healthcare providers.14 health needs of refugees.

4. Gagnon AJ, Merry L, Robinson C. A Systematic Review of Refugee Women’s Reproductive Health. Refuge Can J Refug [Internet]. 2002 Aug 1 [cited 2016 Oct 18];21(1). Available from: http://refuge.journals.yorku. ca/index.php/refuge/article/view/21279 5. Government of Canada PW and GSC. Mental health and well-being of recent immigrants in Canada :: Ci4-105/1-2013EPDF - Government of Canada Publications [Internet]. 2002 [cited 2016 Oct 6]. Available from: http://publications.gc.ca/ site/eng/441787/publication.html 6. Hassan G, Kirmayer LJ, Mekki-Berrada A, Quosh C, el Chammary R. Culture, context and the mental health and psychosocial wellbeing of Syrians: a review for mental health and psychosocial support staff working with Syrians affected by armed conflict. Geneva: UNHCR. 2015. 7. Newbold B. The short-term health of Canada’s new immigrant arrivals: evidence from LSIC. Ethn Health. 2009 Jun 1;14(3):315–36. 8. Pottie K, Ng E, Spitzer D, Mohammed A, Glazier R. Language Proficiency, Gender and Self-reported Health: An Analysis of the First Two Waves of the Longitudinal Survey of Immigrants to Canada. Canadian Journal of Public Health / Revue Canadienne de Sante’e Publique. 2008;99(6):505–10. 9. Shommu NS, Ahmed S, Rumana N, Barron GRS, McBrien KA, Turin TC. What is the scope of improving immigrant and ethnic minority healthcare using community navigators: A systematic scoping review. Int J Equity Health [Internet]. 2016 Jan 15 [cited 2016 Oct 5];15. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4714538/ 10. Percac-lima S, Ashburner JM, Bond B, Oo SA, Atlas SJ. Decreasing Disparities in Breast Cancer Screening in Refugee Women Using Culturally Tailored Patient Navigation. J Gen Intern Med. 2013 Nov;28(11):1463–8. 11. Miedema B, Hamilton R, Easley J. Climbing the walls. Can Fam Physician. 2008 Mar;54(3):335–6. 12. Stewart MJ, Neufeld A, Harrison MJ, Spitzer D, Hughes K, Makwarimba E. Immigrant women family caregivers in Canada: implications for policies and programmes in health and social sectors. Health Soc Care Community. 2006 Jul 1;14(4):329–40. 13. Government of Canada C and IC. Interim Federal Health Program – Information for health-care professionals [Internet]. 2014 [cited 2016 Oct 5]. Available from: http:// www.cic.gc.ca/english/refugees/outside/ arriving-healthcare/practitioners.asp 14. Horvat L, Horey D, Romios P, Kis-Rigo J. Cultural competence education for health professionals. In: The Cochrane Collaboration, editor. Cochrane Database of Systematic Reviews [Internet]. Chichester, UK: John Wiley & Sons, Ltd; 2014 [cited 2016 Oct 18]. Available from: http://doi.wiley. com/10.1002/14651858.CD009405. pub2 15. McKeary M, Newbold B. Barriers to Care: The Challenges for Canadian Refugees and their Health Care Providers. Journal of Refugee Studies. 2010 Dec 1;23(4):523– 45. 16. Forumspace Banner 1 [Image on the Internet]. 2016 [cited 2016 Nov 6]. Available from: http://gdb.voanews. com/886AEBFF-CF91-4AC1-ABD60B963F879FBE_w987_s_s.jpg 17. Forumspace Banner 2 [Image on the Internet]. 2016. [cited 2016 Nov 6]. Available from: https://vid.alarabiya.net/ images/2016/02/10/3f17e2e1-d05e40b3-9b57-9e88b8e3ecfc/3f17e2e1d05e-40b3-9b579e88b8e3ecfc_16x9_788x442.JPG 18. Forumspace Banner 3 [Image on the Internet. 2015. [cited 2016 Nov 7]. Available from: https://d.ibtimes.co.uk/en/ full/1447930/syria-refugees.jpg 19. Forumspace Banner 4 [Image on the Internet].

ABSTRACTS Circulating Tumour DNA for Cancer PrognosticatioN Caberry (WeiYang) Yu1 Bachelor of Health Sciences (Honours), Class of 2018, McMaster University Princess Margaret Cancer Centre, University Health Network

Nasopharyngeal carcinoma (NPC) is a squamous cancer of the head and neck which affects the nasopharyngeal epithelium. Since NPC cells express Epstein-Barr Viral (EBV) genes, a double-stranded DNA herpes virus, its tumours release circulating tumour DNA (ctDNA) containing EBV into circulation. Despite having uses for detection, staging, and screening, plasma EBV DNA analysis is particularly useful for post-treatment prognostication, or assessment of disease course. Due to the positive relationship between plasma EBV DNA concentration and tumour volume, EBV DNA clearance after radiotherapy is predictive of treatment outcome. Detecting small amounts of DNA is vital. The purpose of this project is to assess the current practice of using quantitative polymerase chain reaction (qPCR) or droplet

digital PCR (ddPCR) to interrogate a specific gene associated with EBV, as this has a false positive rate of 7%. ddPCR, which measures absolute nucleic acid quantity by counting molecules encapsulated in discrete, volumetrically defined partitions, is hypothesized to have a similar detection limit as qPCR. First, genomic DNA (gDNA) from an EBV+ cell line and EBVcell line are isolated, purified, and sheared. Then, variable amounts of EBV DNA are detected using either qPCR or ddPCR. The results show that the size-selected EBV+ and EBV- gDNA are approximately 200 base pairs, and that qPCR and ddPCR have similar detection limits for the EBV genome. In conclusion, more sensitive DNA quantification techniques than qPCR and ddPCR are needed for clinical use.

Time Duration of Intraoperative Tourniquet Application is a Risk Factor for Postoperative Venous Thromboembolism in Knee Replacement Patients Owais mian1 Bachelor of Health Sciences (Honours), Class of 2017, McMaster University

tableabstracts of contents

within 14 days of TKA were identified. Each index patient was matched to two controls who were receiving rivaroxaban but had no VTE complication. Patients’ demographics and medical histories and the duration of tourniquet application were extracted. Results: Seven postoperative VTEs were identified from a total of 234 patients. During the surgery, the index cases had a significantly longer tourniquet application time than the controls (65±3.3 min and 49±2.4 min, respectively). There were no intraoperative complications and no noticeable differences in blood loss. Objective: The aim of this study was to evaluate the intraoperative factors that were associated with VTE following TKA despite rivaroxaban Conclusion: This study illustrates that intraoperative factors such as prolonged tourniquet application are associated with postoperative VTE, administration. explaining the failure of rivaroxaban. We suggest a reduction in tourniquet Methods: We conducted a retrospective case-control study in Hamilton application time as well as more emphasis on pre-surgical anticoagulation (2013-2015). Patients who received rivaroxaban but developed VTE treatment.

Background: A common complication following total knee arthroplasty (TKA) is the formation of blood clots (venous thromboembolism or VTE). Clotting begins in the leg and can travel to the lungs, leading to respiratory distress and even death. Rivaroxaban is a common blood thinner used to prevent postoperative VTE. Despite this practice, some patients still develop VTE, with clinical features seemingly preceding rivaroxaban administration. As rivaroxaban can only prevent new clots from forming after administration, clot formation may be attributed to factors during the surgery, before the drug is given.

Effect of nano-structured glassy film topography on macrophage function Annie Wu1 Bachelor of Health Sciences (Honours), Class of 2019, McMaster University Project Investigator: Dr.Jose Moran-Mirabal

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The host immune response against foreign materials, also known as the foreign body response, poses a significant challenge for implanted biomaterials and medical devices. Macrophages and dendritic cells play a crucial role in the immune response. Thus current efforts are being made to modulate their activity and behaviour in vivo. We hypothesize that surface topography in the biological scale (nanometer to micrometer range) can modulate macrophage function, specifically phagocytosis, without necessitating the use of bioactive agents. In our study, we investigate the effect of topography using a novel, nanostructured glassy film, synthesized through the deposition of 2-50 nm of silicon dioxide on pre-stressed polystyrene. The glassy film is further subjected to high heat,

inducing substrate shrinkage. The compressive stress of the shrinking substrate induces the formation of complex structures on the material surface. Murine bone marrow-derived macrophages were subsequently seeded onto the surfaces and incubated with Streptococcus pneumoniae bacteria to evaluate the effect of topography on macrophage phagocytosis. Fluorescent images showed increased phagocytic ability of macrophages cultured on the structured surfaces in comparison to flat surfaces. Both the extent and homogeneity of bacterial uptake improved in macrophages cultured on the glassy films. It was concluded that surface topography can passively modulate macrophage behaviour in vitro and serves as a promising avenue of study for the future development of novel biomaterials.

Author: Writing:Ashley AshleyLam Lam Art: Tony Chen Artist: Tony Chen

On Our

verconsumption of Suga r

The American Heart Association recommends a daily added sugar limit of:

6 tsp 3 tsp 9 tsp

women

children

men

Soft drinks and sweetened beverages are the

primary source of added sugars 3

tsp 1 1 soda

Beverages are often sweetened with

fructose

extracted and concentrated from:

beets corn

of packaged foods in supermarkets contain added

sugarcane 3

sugar ...a process that removes fiber and nutrients

Fructose may lead to leptin resistance, causing increased hunger 4

there is a

rapid increase

Glucose stimulates the pancreas to release and more energy is stored as

fat

insulin

6 7

Diabetes Dental caries Atherosclerosis

after drinking sweetened beverages, which lack fiber to slow down metabolism

Possible health risks of high sugar intake include:

Weight gain

glucose & fructose

1. Johnson, R.K., Appel, L., Brands, M., Howard, B., Lefevre, M., Lustig, R., Sacks, F., Steffen, L., & Wyllie-Rosett, J. (2009, September 15). Dietary sugars intake and cardiovascular health: a scientific statement from the American Heart Association.Circulation , 120(11), 1011-20. 2. Soft drinks: sugar content. Retrieved from http://www.floridahealth.gov/chdcollier/Documents/ToothFairy/sugarinsodas.pdf

3. Ng, S.W., Slining, M.M., & Popkin, B.M. (2012). Use of caloric and noncaloric sweeteners in US consumer packaged foods, 2005-2009. Journal of the Academy of Nutrition and Dietetics , 112(11), 1828-1834.e1821-1826. 4. Shapiro, A., Mu, W., Roncal, C., Cheng, K.-Y., Johnson, R.J., & Scarpace, P.J. (2008). Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding.American Journal of Physiology. Regulatory, Integrative and Comparative Physiology , 295(5), R1370–1375.

5. Bray, G.A. ,How bad is fructose? Am J Clin Nutr. American Society for Nutrition; 86(4):895–6. 6. Stanhope KL, Havel PJ. Endocrine and metabolic effects of consuming beverages sweetened with fructose, glucose, sucrose, or high-fructose corn syrup. Am J Clin Nutr [Internet]. American Society for Nutrition; 2008 Dec; 88(6):1733S–1737S. 7. Howard B V., Wylie-Rosett J. Sugar and Cardiovascular Disease. Circulation. 2002;106(4).

Authors: Jessica Chee, Valerie Kim Artist: Bob Yang

Pathoproﬁle

ALZHEIMER’S

Alzheimer’s disease is an age-related neurodegenerative disorder characterized by gradual cognitive decline. With 44 million people affected worldwide, it is one society’s most prevalent degenerative diseases1 The number of Canadians suffering from Alzheimer’s or a related form of dementia is estimated to double to around 1.3 million people within the next generation.2-4 This could be due to the repercussions of chronic stress over longer life expectancies.

γ-secretase

table of contents

There are two types of Alzheimer’s: early-onset (familial) Alzheimer’s and late-onset (sporadic) Alzheimer’s. Despite its enigmatic etiology, a growing body of research has noted several hallmark symptoms of familial Alzheimer’s including loss of neurons, general atrophy of the brain, such as amyloid-β plaques and neuroﬁbrillary tangles (NFTs).5 Two of the most prominent pathological features of the disease, Aβ42 peptide plaques and hyperphosphorylated tau tangles, are integral to understanding the progressive cognitive decline associated with familial Alzheimer’s.3,5

Nicas tri

Presenilin

Pe n - 2

h-1 Ap

NEUROLOGICAL FEATURES

α-secretase β-secretase

Amyloid Precursor Protein

β-stub

α-stub

APP CLEAVAGE The APP gene encodes an amyloid precursor protein (APP), an inactive protein that must undergo modiﬁcations before its conversion to an activated form. While the function of APP remains elusive, growing research suggests that it may play a role in neuronal growth and repair.5 Normally, APP is initially cleaved by the enzymes, α-secretase and β-secretase, forming an α-stub and a β-stub, respectively.4 These cleavage products are further cleaved by γ-secretase, an enzyme complex comprised of four proteins - Nicastrin, Aph1, Pen-2, and the catalytic core presenilin.6 Following cleavage, the α-stub generates a p3 peptide, and the β-stub produces an extracellular C-terminal fragment, an intracellular domain fragment, and a variable amyloid-β (Aβ) peptide.6,7 This peptide can exist in different forms with lengths ranging from 39 to 49 residues; in particular, the peptide most commonly exists as Aβ40 or Aβ42.7,8 Accumulation of the more toxic Aβ42 isoform instigates the aggregation of amyloid plaques.7,8

Aβ42

Aβ40 β-amyloid plaque

Recent studies have demonstrated that certain presenilin (Ps) mutations can alter the site of APP cleavage and subsequently increase the Aβ42/Aβ40 ratio.6 These mutations additionally reduce the catalytic efﬁciency of γ-secretase, favouring the production of peptides of longer lengths, such as Aβ42.6 Because of their key role in APP cleavage, γ-secretase and its catalytic core, presenilin, have become attractive therapeutic targets for Alzheimer’s disease.6,8

TAU TANGLES

Microtubule

introduction

Tau Proteins

Growing evidence suggests that APP and Ps mutations are associated not only with amyloid plaques, but also with neurofibrillary tangles (NFTs).9 NFTs are aggregates of hyperphosphorylated tau proteins that accumulate in brain regions critical to cognitive function.9,10 Responsible for stabilizing microtubules, tau supports the neuronal cytoskeleton and facilitates axonal transport.7 However, following aberrant modifications, tau triggers the synaptic loss and neuronal death characteristic of Alzheimer’s. According to recent research, the Aβ peptides comprising amyloid plaques may also contribute to Caspase the formation of NFTs.9,10 In particular, Aβ activates Activation caspases involved in programmed cell death, or apoptosis.9,10 Caspase activation induces cleavage of tau at its carboxy-terminus, and the resulting tau Carboxyl-terminus Cleavage fragments assemble more rapidly into filaments.9,10 + Further conformational changes initiate and accelHyperphosphorylation erate tau phosphorylation and aggregation.9,10 Tangled and twisted, the filaments impede axonal transport and impair neuronal function, ultimately leading to the potentiation of caspase-mediated apoptotis.10 Given the significant role of NFTs in neurodegeneration, studies continue to investigate the therapeutic potential of inhibiting abnormal hyperphosphorylation and disassembling filament aggregates.11

Neuroﬁbrillary Tangles

REFERENCES

| A p r i l 2015

Sep;1(1):a006189. 6. Selkoe DJ, Wolfe MS. Presenilin: running with scissors in the membrane. Cell. 2007 Oct 19;131(2):215-21. 7. Bonner JM, Boulianne GL. Drosophila as a model to study age-related neurodegenerative disorders: Alzheimer’s disease. Experimental gerontology. 2011 May 31;46(5):335-9. 8. De Strooper B. Loss‐of‐function presenilin mutations in Alzheimer disease. EMBO reports. 2007 Feb 1;8(2):141-6. 9. Cotman CW, Poon WW, Rissman RA, Blurton-Jones M. The role of caspase cleavage of tau in Alzheimer disease neuropathology. Journal of neuropathology & experimental neurology. 2005 Feb 1;64(2):104-112. 10. Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwar S, Guillozet AL, et al. Caspase cleavage of tau: Linking amyloid and neuroﬁbrillary tangles in Alzheimer’s disease. Proceedings of the national academy of sciences. 2003 Aug 19;100(17):10032-37. 11. Medeiros R, Baglietto-Vargas D, LaFerla FM. The role of tau in Alzheimer’s disease and related disorders. CNS neuroscience & therapeutics. 2011 Oct;17(5): 514-24.

m e d u cato r

1. Alzheimer’s Statistics [Internet]. Alzheimers.net. 2016 [cited 2016Oct10]. Available from: http://www.alzheimers.net/resources/alzheimers-statistics/ 2. 15 per cent of people with dementia under 65: Alzheimer society - Technology & Science - CBC News [Internet]. CBC News. CBC/Radio Canada; 2009 [cited 2016Oct10]. Available from: http://www.cbc.ca/news/ technology/15-per-cent-of-people-with-dementia-under-65-alzheimer-society-1.779540 3. Jeong YH, Park CH, Yoo J, Shin KY, Ahn SM, Kim HS, Lee SH, Emson PC, Suh YH. Chronic stress accelerates learning and memory impairments and increases amyloid deposition in APPV717I-CT100 transgenic mice, an Alzheimer’s disease model. The FASEB journal. 2006 Apr 1;20(6):729-31. 4. Naghavi M, Wang H, Lozano R, Davis A, Liang X, Zhou M, Vollset SE, Ozgoren AA, Abdalla S, Abd-Allah F, Aziz MI. Global, regional, and national age-sex speciﬁc all-cause and cause-speciﬁc mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385(9963):117-71. 5. Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT. Neuropathological alterations in Alzherimer disease. Cold Spring Harbor Perspectives in Medicine. 2011

ARTIST Kelsie Ou

Over-the-Counter Statins A GATEWAY TO MISUSE

AHMED ABDELAAL and Kelvin Ng Bachelor of Health Sciences (Honours), Class of 2019 McMaster University Correspondence: abdelaa@mcmaster.ca, ngk@mcmaster.ca

opinion

ABSTRACT

One in four Canadians over the age of 20 are at a significant risk of developing cardiovascular disease.1 Despite their proven efficacy as a lipid-lowering therapy for patients at risk, statins continue to be under-prescribed and underused. Proponents of over-the-counter statins argue that increased accessibility will improve usage and lighten the economic burden of cardiovascular diseases.2 Furthermore, statins have proven to be clinically effective at low doses. Despite these potential benefits, statins should not be approved as over-thecounter drugs as they are accompanied by greater risks of misuse compared to prescription statins. Over-the-counter approval of statins would set precedence as the first approval of a drug made specifically for treating chronic diseases. This opens up the possibility for future prescriptions to be approved as over-the-counter drugs that will be accompanied with their unique benefits and inevitable risks.

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INTRODUCTION

Improvement of statin use in Canadians has been lackluster, increasing by only five percent in patients from 1992 to 2009.10 This poses a significant problem since statins are the primary method used by the healthcare industry to reduce CVD.3 Approval of over-the-counter (OTC) low-dose statins, which would not require prescriptions, presents a potential solution to narrowing the treatment gap. Through easier accessibility, OTC statins may effectively combat barriers to treatment, including long physician wait times and expensive physician visit costs. Benefits of Bridging the Treatment Gap A ten-year cost-effectiveness model of the United States drug market was used to predict the effects of a switch to OTC statins on usage, disease burden, and health care costs. The model found the introduction of OTC statins would result in a 27% increase in usage. Such a change would lead to 293,492 fewer major vascular events and 135,299 fewer revascularization procedures, a treatment to bypass blocked arteries, in the next decade.8 This would ultimately save 10.8 billion dollars in health care costs.8 The reduction in physician office visits would further save nine billion dollars.8

Cardiovascular disease (CVD) is a class of heart diseases primarily caused by the narrowing of blood vessels. Elevated cholesterol, high blood pressure, and smoking status are some significant risk factors of CVD.3 The Framingham risk score, an assessment tool that estimates a patient’s risk of developing CVD over the next ten years, is computed using these risk factors.4 This score is then used by clinicians to determine whether a Given these benefits, Merck & Co requested to have their OTC patient is at high, intermediate, or low risk of CVD. Usually, statin, Lovastatin, approved by the FDA. If Merck & Co received patients at intermediate and high risk are prescribed statins as a approval, it would have set precedence as the first pharmaceutical preventative therapy.3 Statins are prescription drugs that decrease company to sell an OTC drug intended for treating chronic the synthesis of cholesterol and can lower one’s risk of CVD diseases, which could vastly affect future OTC drug approval.9 by 20-25%.5 The clinical efficacy of statins has been shown in However, the FDA rejected this request due to a number of numerous studies and validated by the United States Food and risks associated with unregulated statin use, sparking controversy Drug Administration (FDA).5-8 While 18 million Canadians are around OTC statins.11 We believe that the FDA should not currently at intermediate risk of CVD, only four million receive approve OTC statins due to the increased potential for misuse, cholesterol-lowering therapy.8 Those left untreated constitute low adherence, and adverse drug interactions involving statins. one-third of Canada’s coronary artery disease cases.8 Herein lies the treatment gap.

Risks of Unregulated Accessibility

10.

11.

12.

Edited by TAKHLIQ AMIR

Dr. Eva Lonn is Senior Scientist at the Population Health Research Institute, as well as Primary Panelist and Co-author of the Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult. Her research interests include clinical trials in the primary and secondary prevention of cardiovascular diseases, the study of cardiovascular risk factors, and cardiovascular epidemiology. She is also a Professor in the Division of Cardiology in the Department of Medicine at McMaster University.

13.

Hennessy D, Tanuseputro P, Tuna M, Bennett C, Perez R, Shields M et al. Population health impact of statin treatment in Canada. Health Reports [Internet]. 2016 [cited 23 October 2016];27(1):20-28. Available from: http://www.statcan.gc.ca/pub/82003-x/2016001/article/14305-eng.pdf D’Agostino R, Vasan R, Pencina M, Wolf P, Cobain M, Massaro J et al. General Cardiovascular Risk Profile for Use in Primary Care: The Framingham Heart Study. Circulation [Internet]. 2008 [cited 29 October 2016];117(6):743-753. Available from: http://circ.ahajournals.org/content/117/6/743.full Osende J, Ruiz-Ortega M, Blanco-Colio L, Egido J. Statins to prevent cardiovascular events in hypertensive patients. The ASCOT-LLA study. Nephrology Dialysis Transplantation [Internet]. 2004 [cited 4 October 2016];19(3):528-531. Available from: http://ndt.oxfordjournals.org/content/19/3/528.full Shepherd J, Cobbe S, Ford I, Isles C, Lorimer A, Macfarlane P et al. Prevention of Coronary Heart Disease with Pravastatin in Men with Hypercholesterolemia. New England Journal of Medicine [Internet]. 1995 [cited 4 October 2016];333(20):1301-1308. Available from: https://www.ncbi.nlm.nih.gov/ pubmed/7566020 Gersh B. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet [Internet]. 2011[cited 4 October 2016];2011:359-360. Available from: https://www.ncbi.nlm.nih.gov/ pubmed/21067804 Stomberg C, Albaugh M, Shiffman S, Sood N. A Cost-Effectiveness Analysis of Over-theCounter Statins. Am J Manag Care [Internet]. 2016 [cited 4 October 2016];22(5):175184. Available from: https://www.ncbi.nlm. nih.gov/pubmed/27266585 Rashid S. Should cholesterol-lowering medications be available in Canada without a prescription?. Canadian Journal of Cardiology [Internet]. 2007 [cited 4 October 2016];23(3):189-193. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC2647865/ Joffres M, Shields M, Tremblay M, Gorber S. Dyslipidemia Prevalence, Treatment, Control, and Awareness in the Canadian Health Measures Survey. Can J Public Health [Internet]. 2013 [cited 23 October 2016];104(3):252257. Available from: http://journal.cpha.ca/ index.php/cjph/article/viewFile/3783/2794 Minhas R. Statins in primary care: bridging the treatment gap. Br J Cardiol [Internet]. 2004 [cited 4 October 2016];11:487-91. Available from: https://bjcardio.co.uk/2004/11/ statins-in-primary-care-bridging-the-treatment-gap/ Gotto A. Over-The-Counter Statins Are Worth Considering in Primary Prevention of Cardiovascular Disease. Circulation [Internet]. 2006 [cited 4 October 2016];114(12):13101314. Available from: http://circ.ahajournals. org/content/114/12/1310 Melin J, Struble W, Tipping R, Reynolds J, Vassil T, Levy S et al. A Consumer Use Study of Over-the-Counter Lovastatin (CUSTOM). The American Journal of Cardiology [Internet]. 2004 [cited 4 October 2016];94(10):12431248. Available from: https://www.ncbi.nlm. nih.gov/pubmed/15541238 Barter P. The Argument Against the Appropriateness of Over-the-Counter Statins. Circulation [Internet]. 2006 [cited 4 October 2016];114(12):1315-1320. Available from: http://circ.ahajournals.org/content/114/12/1315 Zhelyazkova-Savova M, Gancheva S, Sirakova V. Potential statin-drug interactions: prevalence and clinical significance. SpringerPlus [Internet]. 2014 [cited 28 October 2016];3(1):174-187. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4000599/

| winter 2 0 1 7

Reviewed by Dr. EVA LONN

m e d u cato r

While they have wide safety margins, OTC statins also make it harder for physicians to track the medications their patients take and thus increases

FIGURE 1: Change in Price, Sales and Utilization of Simvastatin in the UK compared to control countries from 1997-2007. The control countries used were the US, Canada and New Zealand. BTC Simvastatins were introduced in 2004. Following BTC approval of Simvastatin in the UK, statin use increased ten-fold from 1997 while its price and sales dropped.14

opinion

Clinicians play a key role in assessing a patient’s need for statins by considering blood test results in an overall risk assessment. They also educate patients on managing other risk factors such as physical inactivity and blood pressure. Without this intervention, individuals may misinterpret blood test results or forego cholesterol testing prior to their drug purchase. Hence, the use of statins by individuals at low risk of CVD might unnecessarily elevate the risk of side effects. A multi-centre study conducted in the United States in 2004 simulated the possibility of adverse drug interactions. The an OTC setting to investigate potential consumer risk of statin-induced rhabdomyolysis, a syndrome activity following the introduction of OTC statins. characterized by muscle necrosis, may increase The results revealed that 20% of people purchasing significantly if statins are taken along with statins were low-risk, while 25% did not undergo fibrates, another class of medication that reduces cholesterol testing.12 the risk of CVD.13 Patients may be incentivized to take OTC statins along with fibrates for a High-risk patients are equally susceptible to potential additive effect if they deem fibrates to be statin misuse. Since low-dose OTC statins can inadequate for treatment. The possibility of adverse only effectively treat intermediate-risk patients, drug interactions is already high with physician high-risk patients should continue using their involvement. In fact, a study of statin prescriptions prescription statins and avoid using low-dose OTC in hospitals found that 26. 1% of patients received statins. The aforementioned study showed 23% of co-prescriptions of statins with other medications low-dose statin consumers were either high-risk known to cause dangerous interactions.13 Without or had too high cholesterol levels to be effectively physician involvement, the risk of adverse drug treated by low-dose statins.12 High-risk patients interactions may be even higher. The risks of may substitute prescription statins for their OTC misuse, low adherence, and additional adverse drug counterparts because they are cheaper and more interactions may be potentially reduced through accessible to the public. Since OTC statins’ dosages physician involvement in a patient’s statin therapy. are too low to effectively reduce their risk of CVD, they may actually cause more harm than good due CONCLUSION to side effects and ineffective treatment.3 Secondary prevention measures are also often required The prevention and management of CVD risk alongside prescription statins to manage the risk requires bridging the marked treatment gap in of CVD, indicating the need for direct physician- the Canadian population. Although OTC statins patient interaction. present a valid solution, the ability of patients to manage their own preventative care remains Since OTC statins are used as a preventative therapy, a predominant concern. It is crucial for statin they also raise the concern of low adherence. Current consumers to understand the importance of OTC drugs are intended for acute care, in which clinician intervention so as to avoid possible misuse. symptom relief is easily recognizable, encouraging There are safer alternatives to narrowing the gap, people to use the drugs effectively to become which include an introduction of patient education healthy. Conversely, the benefit of OTC statins can programs and stricter adherence to guidelines for only be tracked through regular blood tests. This physician prescription, both subject matters for inconvenience, combined with the lack of incentive future consideration. to treat a potentially life-long asymptomatic disease, predicts low adherence to OTC statins.9

RESEARCH Insight

ARTIST BOB YANG

Relationship Between Neural Crest Cell Specification and Anterior Segment Dysgenesis

Jeong Won Park 1 , Vanessa Martino 2 Bachelor of Health Sciences Class of 2017, McMaster University

Department of Pathology and Molecular Medicine, McMaster University

ABSTRACT

Development of the anterior segment of the eye is closely associated with neural crest cell migration and specification. Its development is complex as it requires the functioning of a combination of local factors, receptors, inductors, and signalling between tissues such as the optic cup and periocular mesenchyme (POM). POM is comprised of neural crest-derived mesenchymal progenitor cells that give rise to numerous important anterior segment structures such as the cornea, and trabecular meshwork. Several genes involved in the migration and specification of the POM have been identified, including PITX2, FOXC1, and Tfap2b. The author, with the help of Judith West-Mays and Vanessa Martino, has conducted an extensive literature search on recently published articles surrounding anterior segment dysgenesis and its associated genes and transcription factors in order to construct this review paper.

Introduction

NCC originate at the neural plate border where the neural folds join to form the neural tube.4-6 An array of neuroectoderm-derived cranial NCC, otherwise known as POM, migrates distinctively from the prosencephalon and mesencephalon into the eye in three waves.4 The first wave of cells moves and settles in the space between the anterior surface of the lens and surface ectoderm to form the corneal endothelium.4,6 The second wave of cells migrates into either the space between the surface ectoderm or the corneal epithelium and the endothelium to form portions of the corneal stroma.4,6 Lastly, the third wave moves in between the corneal endothelium and the anterior rim of the optic cup, giving rise to the ciliary body stroma, iris stroma, and trabecular meshwork.4,6 Interruption in any of these three waves of NCC migration could potentially contribute to defective anterior segment tissues and development of ASD.

PITX2, not italicized and in capital letters, represents a transcription factor. PITX2, italicized and in capital letters, represents a human gene. Pitx2, in lower case, represents an animal gene.

FIGURE 1: NCC migration/ specification. Here, NCC give rise to all the structures labelled in blue.

m e d u cato r | W inter 2 0 1 7

Neural crest cells (NCC) are multipotent, migratory stem cells that emerge from the dorsal neural tube and serve critical functions in embryonic development.4-6 They migrate to different regions of the body and form diverse cell lineages and structures, including the peripheral nervous system, craniofacial skeleton, as well as numerous ocular and periocular structures.4,6 Improper development of the neural crest can cause craniofacial and ASD genes ocular defects such as Axenfeld-Rieger syn7-10 drome (ARS). ARS is a disorder that af- PITX2 and FOXC1 fects anterior segment structures derived from There are two ASD genes, the periocular mesenchyme (POM) and has PITX2* and FOXC1, that have been found to cause glaucoma in up to 75% of been extensively researched patients after early childhood diagnosis.13-16 in the past decade. NumerNCC, with respect to ocular development, are ous studies have demonstrated generally derived from the forebrain (pros- their close relation to the emencephalon) and midbrain (mesencephalon). bryonic development of the They give rise to corneal endothelium and anterior segment of the eye stroma, iris stroma, ciliary body stroma, and and their extensive role in

research insight

Anterior segment dysgenesis (ASD) is a developmental abnormality in which the anterior segment of the eye is affected, in particular the cornea, iris, lens, and structures of the iridocorneal angle. Approximately 50% of ASD patients are at risk for developing glaucoma, a leading cause of vision loss nationwide.1-3 Proper development of anterior segment tissues is crucial in maintaining the healthy, normal-functioning eye as these tissues serve important functions ranging from visual acuity, and light transmission and refraction, to maintaining an optimal intraocular pressure (IOP). Differentiation and specification of the neural crest-derived mesenchymal progenitor cells into their prospective anterior segment tissues mark one aspect of proper development of the anterior segment of the eye.

trabecular meshwork, all of which are important anterior structures of a normal, healthy eye.4,5,11,12 Many clinical entities of ASD exist with distinct manifestations, contributing to the complexity of the disorder. This paper aims to focus on differentiation and specification of NCC in relation to the onset of ASD, an area that necessitates further research.

m e d u cato r

W I N T E R 2017

research insight

specification of mesenchymal progenitor cells, primarily of neural crest origin.17-22 Pitx2, expressed in the POM, is required for specification of NCC into the aforementioned structures (shown in Figure 1) through the three waves of cell movement.4

ly associated with ASD, particularly corneal defects.17 It has been found that AP-2β is required for the establishment of angiogenic privilege (corneal avascularity) in the developing cornea, formation of the anterior angle, as well as the specification of the three corneal layers: corneal epithelium, stroma, and endoPitx2 is also a downstream effector that is ac- thelium.17 The loss of this transcription factor tivated in response to tissue-to-tissue signal- led to the development of synechia (adhesion ling from the lens in the embryonic stage.23-25 between iris and cornea) and anterior subcapLens ablation experiments, wherein the lens sular cataracts (loss of lens transparency).17 is removed in an animal model, have shown that lens formation plays a critical role in the AP-2β is largely implicated in the develdevelopment of the cornea and anterior seg- opment of primary closed angle glaucoma. ment.23,26-28 This is because the lens acts as Closed angle in the anterior eye contributes a transforming growth factor beta (TGF-β) to increased IOP as it disrupts the circulation signaling centre that controls the develop- of aqueous humor within the eye. Consement of NCC-derived ocular structures, dem- quently, this results in loss of retinal ganglion onstrated by the failure of the NCC to form cells and a damaged optic nerve. AP-2β NCC the corneal endothelium and stroma in the knockout (KO) mutants have also exhibited a absence of the lens.23,29 This finding illustrates variety of corneal phenotypes, which affect all the complexity involved in the formation of three corneal layers, leading to complete abanterior segment tissues via inductive signal- sence of the endothelial layer.17 ling between the lens and POM. Overall, the AP-2β NCC KO model used in FOXC1 is another class of transcription fac- the study demonstrates that this transcriptors closely related to ASD, though FOXC1 tion factor follows a similar regulatory netmutations have relatively milder prognoses for work for anterior segment development as glaucoma development when compared to the Pitx2 and Foxc1.17 Mutant mice with condicombination of PITX2 and FOXC1 defects.7 tional deletion of Pitx2 in the POM or its deTight control of the two genes is necessary rivatives exhibit a lack of angiogenic privilege for normal development, as 40% of patients and develop neovascularization (formation of with ARS have shown mutations of either new blood vessels) of the cornea.18 Also, the FOXC1 or PITX2.7 Notably, recent findings mice present with similar anterior segment as have shown co-localization of PITX2A and the AP-2β NCC KO phenotypes since they FOXC1 within a common nuclear subcom- show failure in the formation of the corneal partment, with PITX2A shown to negatively endothelium, disorganization of the corneal regulate FOXC1 activity.7 Expression of the stroma, and defects of the corneal epithelitwo proteins in the POM and the physical um.17 Furthermore, Chen et al. demonstrated complex they form with one another has also that AP-2β levels are significantly reduced in been shown.7 In mice, PITX2A and FOXC1 the absence of Pitx2 in the POM.18 transcription factors are co-expressed in cells Treatment of the presumptive anterior segment that later becomes corneal endothelium or stroma. This finding successfully demonstrates the pres- With consistent patterns of corneal defects ence of both transcription factors during an- present in ASD, regenerative medicine can terior segment development and a possible be further explored in order to mitigate problems associated with corneal abnormalities. bidirectional relationship between them.7 Regenerative medicine involving the use of a patient’s own stem cells to repair dysfuncActivating Protein-2 Beta (AP-2β) A more recent finding pertaining to the AP- tional tissues is a growing area of research. 2β transcription factor and its role in neural Recent findings indicate that dental stem crest cell specification is gaining attention cells (DSCs) may be a potential alternative and providing further insight into genes as- treatment for 30corneal opacities and endothesociated with the onset of ASD. The gene lial disorders. Corneal transplantation, the Tfap2b has been shown to encode the tran- current standard of care, is highly invasive scription factor AP-2β, which is largely impli- and limited by the number of available donor therapy cated in the development of the corneal layers tissues. Embryonic stem cell (ESC) 30,31 has also been used in the eye. One study and the formation of the iridocorneal angle.17 showed that patients exhibited improved viAP-2β, like PITX2 and FOXC1, is also high-

sual acuity with no particular adverse cell proliferation or rejection when ESC-derived retinal pigment epithelial cells were transplanted into the subretinal space to treat age-related macular degeneration.30 However, ESC therapy is limited by concerns regarding long-term safety and graft survival. As an alternative, investigators have employed adult stem cell therapy (ASCT).30 ASCT requires ex vivo manipulations that involve isolating, enriching, identifying, and growing adult stem cells before they can be used to replace any cells of the dysfunctional organs via transplantation and cell injection.30 ASCT aims to allow normal, healthy cells to differentiate into functional cells in the target diseased tissues.30,32

Acknowledgements Special thanks to Judith West-Mays and Vanessa Martino, a graduate student in WestMays’ lab performing all experiments on AP2β NCC mutants. These two inviduals have provided guidance towards finding relevant literature that helps with knowledge-building in the field of ophthalmology, specifically with regards to anterior segment dysgenesis and AP-2β. ■

Judith-West Mays is a Professor of Pathology and Molecular Medicine at McMaster University, as well as the Assistant Dean of the Medical Sciences Graduate Program. Her research interests include the molecular and genetic mechanisms regulating eye development and disease.

Strungaru M, Dinu I, Walter M. Genotype-Phenotype Correlations in Axenfeld-Rieger Malformation and Glaucoma Patients with FOXC1 and PITX2 Mutations. Investigative Opthalmology & Visual Science. 2007;48(1):228. Gould DB, John SW. Anterior segment dysgenesis and the developmental glaucomas are complex traits. Human molecular genetics. 2002 May 15;11(10):1185-93. Reneker LW, Silversides DW, Xu L, Overbeek PA. Formation of corneal endothelium is essential for anterior segment development-a transgenic mouse model of anterior segment dysgenesis. Development. 2000 Feb 1;127(3):533-42.

6. 7.

Williams Bohnsack B. Neural crest derivatives in ocular development: Discerning the eye of the storm. Birth Defects Research Part C: Embryo Today: Reviews. 2015;105(2):87-95 Beebe DC, Coats JM. The lens organizes the anterior segment: specification of neural crest cell differentiation in the avian eye. Developmental biology. 2000 Apr 15;220(2):424-31. Creuzet S, Vincent C, Couly G. Neural crest derivatives in ocular and periocular structures. Int J Dev Biol. 2005 Jan 1;49(2-3):161-71. Berry F. Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene does in Axenfeld-Rieger syndrome and anterior segment

dysgenesis. Human Molecular Genetics. 2006; 15(6): 905-919 8. Lines MA, Kozlowski K, Walter MA. Molecular genetics of Axenfeld–Rieger malformations. Human molecular genetics. 2002 May 15;11(10):1177-87. 9. Hjalt TA, Semina EV. Current molecular understanding of Axenfeld–Rieger syndrome. Expert reviews in molecular medicine. 2005 Nov 8;7(25):1-7. 10. Doucette L, Green J, Fernandez B Johnson G, Parfrey P, Young T. A novel, non-stop mutation in FOXE3 causes an autosomal dominant form of variable anterior segment dysgenesis including Peters anomaly. Eur J Hum Genet. 2010;19(3):293-299

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Continued research on ASD has allowed for identification of multiple genes associated with the condition, several of which include Pitx2, Foxc1, Tfap2b. It has been found that these genes do not work independently of one another. Rather, they regulate or affect one another in the process of POM specification into anterior segment tissues such as the components of the corneal layers and structures of the iridocorneal angle. Research has also suggested the possibility of sequential formation of anterior segment tissues. This was clearly demonstrated in the lens ablation experiment, in which the lens allowed for subsequent specification of the POM into the anterior structures through inductive signalling. This review paper aimed to emphasize the importance of proper embryonic development of the anterior structures and the possible complications that can arise as a result of its improper development. These complications include ARS, subcapsular cataracts, and glaucoma. Finally, a potential treatment using adult stem cells, specifically dental stem cells, has highlighted the possibility of regenerating the damaged cornea frequently resulting from ASD. Future steps include further investigation of the AP-2β NCC KO mouse mutants and determination of whether knockouts at different time points during embryonic development yield different clinical manifestations. Regenerative medicine, such as the use of DSCs, should be further validated and advanced to human trials in order to treat the millions affected by ASD.

11. Chavarria-Soley G, Michels-Rautenstrauss K, Caliebe A, Kautza M, Mardin C, Rautenstrauss B. Novel CYP1B1 and known PAX6 mutations in anterior segment dysgenesis (ASD). Journal of glaucoma. 2006 Dec 1;15(6):499-504. 12. Liu P, Johnson RL. Lmx1b is required for murine trabecular meshwork formation and for maintenance of corneal transparency. Developmental Dynamics. 2010 Aug 1;239(8):2161-71. 13. Pressman CL, Chen H, Johnson RL. LMX1B, a LIM homeodomain class transcription factor, is necessary for normal development of multiple tissues in the anterior segment of the murine eye. Genesis. 2000 Jan 1;26(1):15-25. 14. Qiu Q, Chen H, Johnson RL. Lmx1b‐ expressing cells in the mouse limb bud define a dorsal mesenchymal lineage compartment. genesis. 2009 Apr 1;47(4):224-33. 15. Weng J, Luo J, Cheng X, Jin C, Zhou X, Qu J, Tu L, Ai D, Li D, Wang J, Martin JF. Deletion of G protein-coupled receptor 48 leads to ocular anterior segment dysgenesis (ASD) through down-regulation of Pitx2. Proceedings of the National Academy of Sciences. 2008 Apr 22;105(16):6081-6. 16. Luo J, Zhou W, Zhou X, Li D, Weng J, Yi Z, Cho SG, Li C, Yi T, Wu X, Li XY. Regulation of bone formation and remodeling by G-proteincoupled receptor 48. Development. 2009 Aug 15;136(16):2747-56. 17. Martino VB, Sabljic T, Deschamps P, Green RM, Akula M, Peacock E, Ball A, Williams T, West-Mays JA. Conditional deletion of AP-2β in mouse cranial neural crest results in anterior segment dysgenesis and early-onset glaucoma. Disease Models & Mechanisms. 2016 Aug 1;9(8):849-61. 18. Chen L, Martino V, Dombkowski A, Williams T, West-Mays J, Gage P. AP-2β Is a Downstream Effector of PITX2 Required to Specify Endothelium and Establish Angiogenic Privilege During Corneal Development. Investigative Opthalmology & Visual Science. 2016;57(3):1072. 19. Evans AL, Gage PJ. Expression of the homeobox gene Pitx2 in neural crest is required for optic stalk and ocular anterior segment development. Human molecular genetics. 2005 Nov 15;14(22):3347-59. 20. Cox CJ, Espinoza HM, McWilliams B, Chappell K, Morton L, Hjalt TA, Semina EV, Amendt BA. Differential regulation of gene expression by PITX2 isoforms. Journal of Biological Chemistry. 2002 Jul 12;277(28):25001-10. 21. Amendt BA, Sutherland LB, Semina EV, Russo AF. The Molecular Basis of Rieger Syndrome ANALYSIS OF PITX2 HOMEODOMAIN PROTEIN ACTIVITIES. Journal of Biological Chemistry. 1998 Aug 7;273(32):20066-72. 22. Suh H, Gage PJ, Drouin J, Camper SA. Pitx2 is required at multiple stages of pituitary organogenesis: pituitary primordium formation and cell specification. Development. 2002 Jan 15;129(2):329-37. 23. Priston M, Kozlowski K, Gill D, Letwin K, Buys Y, Levin AV, Walter MA, Héon E. Functional analyses of two newly identified PITX2 mutants reveal a novel molecular mechanism for Axenfeld–Rieger syndrome. Human molecular genetics. 2001 Aug 1;10(16):1631-8. 24. Sowden JC. Molecular and developmental mechanisms of anterior segment dysgenesis. Eye. 2007 Oct 1;21(10):1310-8. 25. Cvekl A, Wang WL. Retinoic acid signaling in mammalian eye development. Experimental eye research. 2009 Sep 30;89(3):280-91. Balkan W, Klintworth GK, Bock CB, Linney E. Transgenic mice expressing a constitutively active retinoic acid receptor in the lens exhibit ocular defects. Developmental biology. 1992 Jun 1;151(2):622-5. 26. Balkan W, Klintworth GK, Bock CB, Linny E. Transgenic mice expressing a constitutively active retinoic acid receptor in the lens exhibit ocular defects. Developmental biology. 1992 Jun 1;151(2):622-5. 27. Enwright JF, Grainger RM. Altered retinoid signaling in the heads of small eye mouse embryos. Developmental biology. 2000 May 1;221(1):10-22. 28. Trainor P, editor. Neural crest cells: Evolution, development and disease. Academic Press; 2013 Nov 23. 29. Kumar S, Duester G. Retinoic acid signaling in perioptic mesenchyme represses Wnt signaling via induction of Pitx2 and Dkk2. Developmental biology. 2010 Apr 1;340(1):67-74. 30. Yam GH, Peh GS, Singhal S, Goh BT, Mehta JS. Dental stem cells: a future asset of ocular cell therapy. Expert reviews in molecular medicine. 2015;17:e20. 31. Perry BC, Zhou D, Wu X, Yang FC, Byers MA, Chu TM, Hockema JJ, Woods EJ, Goebel WS. Collection, cryopreservation, and characterization of human dental pulp-derived mesenchymal stem cells for banking and clinical use. Tissue Engineering Part C: Methods. 2008 Jun 1;14(2):149-56. 32. Syed-Picard FN, Du Y, Lathrop KL, Mann MM, Funderburgh ML, Funderburgh JL. Dental pulp stem cells: a new cellular resource for corneal stromal regeneration. Stem cells translational medicine. 2015 Mar;4(3):276-85.

research insight

Specifically, DSCs can be integrated into ASCT to regenerate and restore ocular tissues. This is because DSCs are derived from cranial NCC and may possess similar properties to neural crest progenitor cells that give rise to many structures of the anterior segment of the eye.30,32 In fact, the study showed that when undifferentiated, immature human dental pulp stem cells (DPSCs) were transplanted into an animal model of limbal stem cell deficiency, it resulted in a reconstructed corneal epithelium, reduction in neovascularization, and clear cornea. This animal model involves extensive corneal damage and permanent visual impairment, and is often used to study the effects of stem cells in healing damaged tissues. This particular model and its limbal stem cell deficiency manifests as the lack of repopulation of corneal epithelium and is viable for testing the healing capacity of the DSCs. These results clearly demonstrate their capacity to replace limbal stem cells and restore the cornea.30-32 Furthermore, the study showed that DPSCs may serve as an abundant source of retinal-like stem cells with the ability to differentiate into retinal neurons and photoreceptors.30

Conclusion

ARTIST MICHAEL SUN

ARTIST CANDY NIU

CRITICALREVIEW REVIEW CRITICAL

Allergic Asthma: THE EMERGING RELATIONSHIP BETWEEN THE GUT MICROBIOME AND REGULATORY B CELLS

Shawn Khan1 Bachelor of Health Sciences (Honours) Program, Class of 2018 McMaster University

Correspondence: khans53@mcmaster.ca

ABSTRACT

As the global prevalence of allergic asthma continues to rise, there is growing interest in exploring the relationship between the gut microbiome of the host and the ability to regulate allergic inflammation. This was prompted by several studies that commonly demonstrated a correlation between the presence of microbial-rich environments and lower levels of childhood allergic asthma. With constant antigen exposure, the mucosal immune system of the gut must regulate environmental stimuli, such as bacteria and food antigens, to sustain immune homeostasis. This is achieved by maintaining immune tolerance to support the gut mucosaâ&#x20AC;&#x2122;s commensal microbiota and mounting a simultaneous, controlled immune response to eliminate pathogenic species. The immune patterns of the gut microbiome are thought to shape allergic asthma progression through its shared immunomodulatory role with the airway microbiome. Currently, studies are examining the role regulatory B cells play in allergic asthma through immune regulation. This review will discuss the relationship between regulatory B cells and the gut microbiome in maintaining immune homeostasis within the allergic disease framework. Introduction

The gut microbiota

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Allergic Inflammation General Function In patients with allergic asthma, inhalation Currently, it is thought the microbiome of the of seemingly harmless allergens can trigger gut influences the host immune response, parIgE-mediated inflammatory processes, resulting ticularly the mediators involved in adaptive in an aberrant expansion of Cluster of Differen- immunity. As the gut is constantly exposed to tiation (CD) 4+ T cells and eosinophilia. This antigens, the gastrointestinal tract is considered allergic inflammatory reto be the largest immune sponse is facilitated by the interface to the environrelease of type-2 (Th2) ment. With such a high imbalances in cytokines, such as Interantigen load, the mucogut microbiome leukin (IL)-4 and IL-13, composition have been sal immune system of which further induces the the gut must coordinate proposed to cause maturation of IgE-proan elaborate balance benumerous human ducing B cells. Currenttween intestinal inflammahealth conditions ly, studies are exploring tory responses to harmful the effect of gut dysbiosis, pathogens and tolerogenic the imbalance of the gut responses to commensal microbiota, on the homeostatic capacity of al- flora.6 As the first line of defense against the lergic asthmatics.1,2 invasion of resident microbiota, the intestinal epithelium forms a physical barrier consisting Microbial Exposure & Health of mucus, antimicrobial proteins, and immunoThe concurrent evolution of the host and the globulin A (IgA), and tight-junction complex. commensal microbiota has resulted in a dynam- With bacterial stimulation, intestinal epithelic symbiotic relationship.3 However, individuals ial cells can provide a non-specific immune are reducing their exposure to microbial-rich response to foreign invaders by secreting varienvironments, which can be attributed to life- ous pro-inflammatory and anti-inflammatory style changes in the areas of increased hygiene, cytokines.7 As the gastrointestinal tract plays a industrialized food supply, and excessive anti- large role in immune function, imbalances in gut biotic use. These factors, along with the shift microbiome composition have been proposed to towards smaller families in which there is de- cause numerous human health conditions, rancreased exposure to infections, have accompan- ging from obesity to Crohnâ&#x20AC;&#x2122;s disease.8 ied an increase in allergic disease prevalence.4,5

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fecal burden of Clostridium difficile and a higher Microbiome Diversity C. difficile to Bifiobacteria ratio.10 Another study The pathogenesis of allergic diseases, including demonstrated these findings with a diversity of asthma, is in part attributable to the composition bacteria. In both experimental cases, early-life of microbial colonies in the gastrointestinal tract. bacterial colonization produced significantly deA collaborative relationship has been identified creased circulating IgE concentrations in adultbetween the development of allergic diseases in hood. However, the administration of these bacchildhood and factors such as early-life antiterial strains in adult animicrobial exposure, Caesmal models did not lead to arian delivery, and formuprotection, suggesting the la feeding. The capacity for the development of importance of early life microbial composition to childhood allergic environmental exposure to shape the immune system 9,11 asthma may be in part diverse microbes. From has been demonstrated in due to microbiome an immunological standstudies of antimicrobial perturbations in early 9,10 point, the altered inflamadministration. life. matory response from the lack of microbial diversity Given that the identified in the gut microbiota may early risks occur immedibe due to compromised functional capacity of ately before and after birth, the development of regulatory cells. Studies have already shown childhood allergic asthma may be in part due a relationship between the gut microbiome, to microbiome perturbations in early life. In regulatory T cells (Tregs), and allergic diseases. support of this hypothesis, studies have shown However, given that regulatory B cells (Bregs) that neonates have a higher likelihood of allerhave been shown to act earlier and facilitate the gic disease development, or atopy, with a higher

IgE+ plasma B cells

Naive B cells

Regulatory B cells

IL-4, IL-13

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Basophils

IL-10, TGF-Î˛ ?

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Isotype switching

IgG4 antibodies FIGURE 1: Hypothesized loci of interference of regulatory B cells.

IgE antibodies

Th2 cells

IL-5

? Allergens

Differentiation and clonal expansion

Eosinophils

TCR

CD40

Naive CD4+ T cells

Antigen-presenting cells B cells T cells Granulocytes

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recruitment of Tregs to sites of immune inflam- develop more severe forms of arthritis compared mation, the relationship between Bregs and the to controls. Interestingly, Rosser et al. showed that the disruption of the gut microbiome gut microbiome requires further investigation. through antibiotic treatment or changes in the Regulatory B cells sterility of housing condiBreg cells can dampen tions reduces the number inflammation by regulatand activity of Breg cells.14 ing the differentiation of While these findings have methods by which T cells into Tregs. Bregs been replicated in models one can achieve more can attenuate inflamma- tolerogenic conditions of autoimmunity, further tion through the secre- in early life to prevent research still needs to be tion of IL-10 (Br1) and conducted in the context allergic disease will TGF-α (Br3). IL-10 has of allergic diseases.15 be vital in alleviating been shown to have an economic burdens immunosuppressive effect DISCUSSION on health systems through the dampening worldwide. of Th2 inflammatory proGiven the increase in the cesses by binding to T cell prevalence of asthma over receptors and blocking co-stimulatory signalling. the past several decades, it is predicted that by Meanwhile, TGF-α binds T cell receptors to en- 2025 the number of individuals affected worldcourage the maturation of Tregs, which have the wide will increase to 400 million people.16 While capacity to inhibit the activation of effector T it is thought that allergic asthma is the consecells. The disruption of TGF-α receptor signal- quence of inappropriate immune activation in ling has been shown to increase susceptibility to response to innocuous allergens, further investiallergic asthma development in mice, while IL- gation may reveal these immune responses to be 10 has been implicated in humans. In addition, appropriated by pathogenic microbiome comit is thought that the inhibitory immunoglobu- positions. Consequently, methods by which one lin, IgG4, secreted by Bregs, protects against the can achieve more tolerogenic conditions in early inflammatory action of IgE by interfering with life to prevent allergic disease will be vital in alallergen-IgE interactions and binding to excess leviating economic burdens on health systems allergen, as shown in Figure 1.11,12,13 worldwide. Finally, manipulating the early life environment to optimize the regulatory pathUsing mouse models of arthritis, Rosser et al. ways of B cells provides a promising and necessuggest that the gut microbiota may increase sary avenue for primary prevention strategies. ■ IL-1α and IL-6 production to encourage the differentiation of IL-10-producing Bregs in the spleen and mesenteric lymph nodes.14 While only produced in conventionally housed mice, IL-1α and IL-6 directly promote Breg cell differentiation and IL-10 production. It has been observed that mice that do not have the IL-6 receptor (IL-6R) or IL-1 receptor 1 (IL-1R1) on B cells show lower levels of IL-10-producing B cells. Moreover, mice lacking these receptors

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John-Paul Oliveria is an Associate Faculty Member at McMaster University. His research interests at McMaster’s Cardiorespiratory Laboratory include the mechanism of allergic airway inflammation, as well as novel therapeutics for asthma and B cell biology.

2. 3.

Soyer, O. U. et al. Mechanisms of peripheral tolerance to allergens. Allergy Eur. J. Allergy Clin. Immunol. 68, 161–170 (2013). Licona-Limón, P., Kim, L. K., Palm, N. W. & Flavell, R. A. TH2, allergy and group 2 innate lymphoid cells. Nat. Immunol. 14, 536–42 (2013). Liu, Z., Cao, A. T. & Cong, Y. Microbiota regulation of inflammatory bowel disease and colorectal

cancer. Semin. Cancer Biol. 23, 543–52 (2013). 4. Strachan, D. P. Hay fever, hygiene, and household size. BMJ 299, 1259–60 (1989). 5. Campbell, D. E., Boyle, R. J., Thornton, C. a & Prescott, S. L. Mechanisms of Allergic Disease Environmental and genetic determinants for the development of allergy. Clin. Exp. Allergy n/a–n/a (2015). doi:10.1111/cea.12531

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Edited by Anna goshua and arlinda deng 1.

12.

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Roediger, W. E. Role of anaerobic bacteria in the metabolic welfare of the colonic mucosa in man. Gut 21, 793–8 (1980). Yatsunenko, T. et al. Human gut microbiome viewed across age and geography. Nature 486, 222–7 (2012). Hwang, J.-S., Im, C.-R. & Im, S.-H. Immune disorders and its correlation with gut microbiome. Immune Netw. 12, 129–38 (2012).

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Reviewed by john paul oliveria

Penders, J. et al. Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics 118, 511–21 (2006). Kalliomäki, M. et al. Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. J. Allergy Clin. Immunol. 107, 129–34 (2001). van Nimwegen, F. A. et al. Mode and place of delivery, gastrointestinal microbiota, and their influence on asthma and atopy. J. Allergy Clin. Immunol. 128, 948–55. e1–3 (2011). Braza, F., Chesne, J., Castagnet, S., Magnan, a & Brouard, S. Regulatory functions of B cells in allergic diseases. Allergy 69, 1454–1463 (2014). Khan S., Oliveria JP. Regulatory B Cells: The New Cells on the Block to Modulate Allergic Asthma. Journal of Health Science Inquiry.7, 21–22 (2016) Rosser, E. C. et al. Regulatory B cells are induced by gut microbiota–driven interleukin-1B and interleukin-6 production. Nat. Med. 20, 1334–1339 (2014). Sattler, S. et al. IL-10-producing regulatory B cells induced by IL-33 (Breg(IL-33)) effectively attenuate mucosal inflammatory responses in the gut. J. Autoimmun. 50, 107–22 (2014). Asthma Statistics | AAAAI. at <http:// www.aaaai.org/about-aaaai/newsroom/ asthma-statistics>

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ARTIST DAVID HU

CRITICAL REVIEW

Hereditary Breast and Ovarian Cancer:

Factors Influencing the Uptake of Preventive Surgeries Among BRCA1 AND brca2 Mutation Carriers

david bobrowski1

Bachelor of Health Sciences (Honours) Program, Class of 2018, McMaster University Correspondence: bobrowd@mcmaster.ca

Genetic testing for breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) mutations in clinical oncology is becoming more widely employed around the world.1,2,3 Testing allows clinicians to determine if unaffected highrisk women carry a BRCA mutation, and if preventive care in the form of prophylactic procedures and/or increased surveillance is advisable. As well, identifying carrier status can aid physicians in tailoring the best treatment for affected women with breast or ovarian cancer. However, studies have shown that the uptake of preventive strategies, particularly risk-reducing surgeries, among unaffected women found to carry a BRCA mutation is influenced by a number of factors. These include cost of genetic testing, cancer-related distress, patient consultation, perceived benefits and risks of invasive surgery, and level of education. To alleviate these emotional and cognitive barriers, clinicians should ensure women carrying a BRCA mutation are well-informed about available treatments and potentially fatal outcomes associated with breast and ovarian cancer.

INTRODUCTION

COST-UTiLITY OF GENETIC TESTING

Genetic testing can be an expensive process.3,4,5 As a result, many countries and institutions ration this service based on eligibility criteria and riskassessments. Genetic counselling without testing has been reported to cost approximately $200, while counselling, testing, and disclosure of carrier status collectively can exceed $2000.3,4,5 However, advances in genetic sequencing have gradually decreased the cost of testing. The factors normally considered in determining if a patient is eligible for testing involve the probability of a woman carrying a BRCA mutation and the cost of the test.3 The probability of a positive test outcome is a function of age, gender, disease status, ethnicity, and family history of relevant conditions. Robinson et al. emphasized the utility of genetic testing and the associated uptake of prophylactic procedures in underserved and underrepresented populations.6 In this way, recognizing factors

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BRCA1 and BRCA2 are human caretaker genes encoding for proteins that function to repair damaged DNA. Mutations in either of these genes therefore threaten the stability of genetic material and increase cancer susceptibility.1,2,3 Specifically, hereditary breast cancer has been estimated to account for 5–10% of all breast cancers, and carriers of BRCA1 or BRCA2 genetic mutations have a 40–80% lifetime risk of developing breast cancer.1,2 The frequency of these mutations may vary significantly between populations depending on geographic origin and ethnically defined genetic combinations. For example, approximately 23% of unselected cases of breast cancer in the Bahamian population are attributable to a mutation in the BRCA1 gene.1,2 In Canada, a country with a more ethnically diverse population, the population attributable risk is approximately 1%.

detection and prophylactic surgeries. As well, the standard of treatment for women with breast or ovarian cancer carrying a BRCA mutation may vary compared to that of non-carriers.

“ Genetic testing can be an expensive process. As a result, many countries and institutions ration this service based on eligibility criteria and risk-assessments.”

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Genetic testing for mutations in the BRCA1 and BRCA2 cancer susceptibility genes in clinical practice is an accessible service in North that influence the decision-making process America and Europe for high-risk individuals and barriers to the uptake of prophylactic and patients diagnosed with breast cancer.2 surgeries by individuals who are found to carry a A study on Canadian women with a BRCA BRCA mutation has been identified as a subject 3,6 mutation reported an uptake of preventive for further research. bilateral mastectomy at 36% and preventive oophorectomy at 61%.13 By detecting BRCA1 The National Comprehensive Cancer Network and BRCA2 mutations prior to cancer diagnosis, has advised that BRCA1 and BRCA2 patients can be offered preventive interventions, mutation carriers be offered prophylactic including increased surveillance for early bilateral mastectomy, the surgical removal

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of both breasts.7 Risk-reducing prophylactic bilateral salpingo-oophorectomy, the surgical removal of both ovaries and Fallopian tubes, is generally recommended to women ages 35 to 40 with a BRCA1 and BRCA2 mutation.7,8

fully covered by health insurance policies. As an example of a similar disparity in outcomes, Skytte et al. reported a 10 year uptake of 50% for preventive bilateral mastectomy in healthy BRCA mutation carriers with no personal history of breast or ovarian cancer, while JulianSalpingo-oophorectomy has been cited as the Reynier et al. reported an uptake rate of only cornerstone of this genetic clinical program, 8%.14,17 and Finch et al. have shown that preventive salpingo-oophorectomy in BRCA mutation CANCER-RELATED DISTRESS carriers is associated with a 70% reduction in all-cause mortality until age 70.9 Preventive Given the high probability of mutation bilateral mastectomy has been documented to carriers developing potentially fatal cancers, it reduce breast cancer risk by approximately 95% is important to understand the factors that in women with prior or concurrent preventive influence risk-reducing behaviour, particularly salpingo-oophorectomy and by approximately preventive surgery. Metcalfe et al. conducted a 90% in women with intact ovaries.10 A two-year follow-up of Jewish women identified prospective multi-institutional study involving to carry a BRCA mutation who participated 2400 women positive for a BRCA mutation in population genetic testing.13 It was reported reported no cases of breast cancer following that 90% of this population of women accepted mastectomy (0/247) and a 7% (98/1372) preventive oophorectomy, but only 11% incidence of breast cancer in those not treated opted for preventive bilateral mastectomy as a with prophylactic bilateral mastectomy.11 therapeutic option. These rates of uptake were It is therefore notable that the uptake of these interpreted to reflect cancer-related distress. It preventive surgical strategies by mutation was suggested that the greater the psychological carriers is lower in some countries.12 The cost impact of a positive test result, the sooner the associated with these preventions is a likely patient proceeded to a surgical solution; distress factor influencing patient uptake and may levels may decrease for those who undergo vary significantly by country. Madalinska et al. prophylactic interventions. It is not clear if documented that approximately three quarters elevated cancer-related distress is a transient phenomenon or if it persists over the long-term.

“Salpingo-oophorectomy has been cited as the cornerstone of this genetic clinical program, and Finch et al. have shown that preventive salpingo-oophorectomy in BRCA mutation carriers is associated with a 70% reduction in all-cause mortality until age 70.” of BRCA mutation carriers in the Netherlands who met eligibility criteria for preventive surgery had undergone preventive oophorectomy after the first gynaecologic consultation. The study acknowledged that this percentage of uptake was higher than that reported in studies in the United States, United Kingdom, and Australia (ranging from 23%-60%), with variability of patient insurance coverage as a possible limiting factor in these countries.16 All patients enrolled in the study in the Netherlands were

FAMILY-RELATED FACTORS Time to risk reducing prophylactic oophorectomy was also related to age and the completion of childbearing at the time of BRCA mutation testing.14 Evans et al. documented that younger women are more prone to delay preventive oophorectomy and the authors suggested that to more accurately measure the uptake of preventive surgery, longer-term follow-up is required.15 The highest rate of prophylactic oophorectomy occurred in post-menopausal women who were least likely to experience the possible adverse effects of surgically induced menopausal symptoms.14 In premenopausal women, outcomes of oophorectomy include infertility and onset of menopause.16 In contrast to natural menopause onset, surgical menopause may cause more unfavourable symptoms and decrease the patient’s quality of life. An association between the uptake of prophylactic surgery and a history of cancer in first-degree relatives has also been noted.14 It was established that having first-degree relatives with breast and/or ovarian cancer significantly influence the course of treatment and increase the acceptance of prophylactic bilateral mastectomy or prophylactic oophorectomy.

PATIENT CONSULTATION A physician’s counsel may be a key determinant in a patient’s decision to proceed to preventative surgery. Julian-Reynier et al. have correlated the effects of pre-test intentions with the speed and rate of uptake of preventive bilateral mastectomy and preventive oophorectomy following the disclosure of genetic testing.14,16 Women who had already made their decision proceeded to prophylactic surgery at a faster rate and were likely the recipients of sufficient information and counselling to ensure an informed decision-making process. Conversely, it has been suggested that the failure of physicians to discuss and endorse surgical interventions might be perceived by women as an indirect recommendation against this therapeutic option.16

have been shown to not meaningfully be associated with education level. On the other hand, more highly educated women have been shown to consider a wider range of issues when opting for preventive surgery. Supplementary investigations are necessary to gain a more comprehensive understanding of the connection between education, taking into consideration a patient’s understanding of hereditary cancer, and uptake of prophylactic interventions.16,18

Conclusion

may be a key determinant in a patient’s decision to proceed to preventative surgery.”

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Reviewed by Dr. kevin zbuk Dr. Zbuk is an Associate Professor in the Department of Oncology at McMaster University. His areas of interest include cancer genetics and the molecular classification of gastrointestinal polyposis syndromes. Dr. Zbuk’s oncology practice focuses on gastrointestinal malignancies. Edited by Joella Ho and angela dong 1.

Fackenthal J, Olopade O. Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations. Nature Reviews Cancer. 2007;7(12):937948. Narod S, Salmena L. BRCA1 and BRCA2

Mutations and Breast Cancer. Discovery Medicine [Internet]. 2011 [cited 1 October 2016];12(66):445-453. Available from: http:// w w w.discover ymedicine.com/Steven-ANarod/2011/11/25/brca1-and-brca2-mutations-

and-breast-cancer/ Narod S. BRCA mutations in the management of breast cancer: the state of the art. Nature Reviews Clinical Oncology. 2010;7(12):702-707.

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the stigma of a cancer diagnosis specific to country and/or culture, preferences of a partner or other family members, personal circumstances (e.g. employment, finances, family responsibilities), the perceived risk and benefit of invasive surgery, and importantly, the perceived incurability of ovarian or breast cancer.16,18 It has been suggested that emotional rather than cognitive factors may fuel opinions about the effectiveness of ovarian and breast cancer treatment as perceptions about the curability of these cancers

Lawrence W, Peshkin B, Liang W, Isaacs C, Lerman C, Mandelblatt J. Cost of Genetic Counseling and Testing for BRCA1 and BRCA2 Breast Cancer Susceptibility Mutations. Cancer Epidemiology and Prevention Biomarkers [Internet]. 2001 [cited 1 October 2016];10(5):475-481. Available from: http://cebp.aacrjournals. org/content/10/5/475.short Walsh T, Lee M, Casadei S, Thornton A, Stray S, Pennil C et al. Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. Proceedings of the National Academy of Sciences. 2010;107(28):12629-12633. Lynce F, Graves K. Differences in Uptake of Risk Reduction Strategies Among Underserved Populations. EBioMedicine. 2015;2(11):1598-1599. NCCN Clinical Practice Guidelines in Oncology [Internet]. Nccn.org. 2016 [cited 23 August 2016]. Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp Bradbury A, Ibe C, Dignam J, Cummings S, Verp M, White M et al. Uptake and timing of bilateral prophylactic salpingo-oophorectomy among BRCA1 and BRCA2 mutation carriers. Genetics in Medicine. 2008;10(3):161-166. Finch A, Lubinski J, Moller P, Singer C, Karlan B, Senter L et al. Impact of Oophorectomy on Cancer Incidence and Mortality in Women With a BRCA1 or BRCA2 Mutation. Journal of Clinical Oncology. 2014;32(15):1547-1553. Rebbeck T. Bilateral Prophylactic Mastectomy Reduces Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers: The PROSE Study Group. Journal of Clinical Oncology. 2004;22(6):10551062. Domchek S. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA. 2010;304(9):967. Metcalfe K, Birenbaum-Carmeli D, Lubinski J, Gronwald J, Lynch H, Moller P et al. International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers. International Journal of Cancer. 2008;122(9):2017-2022. Metcalfe K, Mian N, Enmore M, Poll A, Llacuachaqui M, Nanda S et al. Long-term follow-up of Jewish women with a BRCA1 and BRCA2 mutation who underwent population genetic screening. Breast Cancer Res Treat. 2012;133(2):735-740. ulian-Reynier C, Bouhnik A, MouretFourme E, Gauthier-Villars M, Berthet P, Lasset C et al. Time to prophylactic surgery in BRCA1/2 carriers depends on psychological and other characteristics. Genetics in Medicine. 2010;12(12):801807. Evans D, Lalloo F, Ashcroft L, Shenton A, Clancy T, Baildam A et al. Uptake of Risk-Reducing Surgery in Unaffected Women at High Risk of Breast and Ovarian Cancer Is Risk, Age, and Time Dependent. Cancer Epidemiology Biomarkers & Prevention. 2009;18(8):23182324. Madalinska J, van Beurden M, Bleiker E, Valdimarsdottir H, Lubsen-Brandsma L, Massuger L et al. Predictors of Prophylactic Bilateral Salpingo-Oophorectomy Compared With Gynecologic Screening Use in BRCA1/2 Mutation Carriers. Journal of Clinical Oncology. 2007;25(3):301-307. Skytte A, Gerdes A, Andersen M, Sunde L, Brøndum-Nielsen K, Waldstrøm M et al. Risk-reducing mastectomy and salpingo-oophorectomy in unaffected BRCA mutation carriers: uptake and timing. Clinical Genetics. 2010;77(4):342-349. Gregg G. Psychosocial Issues Facing African and African American Women Diagnosed With Breast Cancer. Social Work in Public Health. 2009;24(12):100-116.

critical review

It is clear that a myriad of factors may influence patient uptake of risk-reducing surgeries. It is likely that gaps in the knowledge base of patients have adversely impacted the adoption of life saving strategies that might benefit BRCA1/2 carriers. Additional educational efforts should be directed towards FrenchCanadian, Bahamian, Ashkenazi Jewish, and other ethnic groups known to have a high risk At A Multivariate Level of carrying a BRCA mutation.2,3,16 Physicians Treatment decisions based on positive genetic should involve BRCA1/2 mutation positive testing for BRCA1/2 mutation are multifactorial. patients in the psychologically-sensitive and Additional variables impacting these results patient centered decision-making process include level of education, socioeconomic status, intended to inform carriers of the pros and cons of cancer risk-reduction options, including prophylactic oophorectomy and prophylactic “ a physician’s counsel bilateral mastectomy. ■

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ARTIST CATHY REN

CRITICAL REVIEW

The Virtual Reality of Our Healthcare System

Aakash Shaw Integrated Science, Class of 2016, McMaster University Correspondence: shawa6@mcmaster.ca

Healthcare is an ever-advancing field that adapts new technologies and techniques to provide the most efficient and appropriate care for patients. Today, virtual reality (VR) may be the start of a paradigm shift for a multitude of healthcare services. VR is being studied as a safe and early intervention for rehabilitation and as a non-pharmacological analgesic option for patients recovering from accidents or motor neuron diseases. VR devices can prepare patients for physiotherapy or occupational therapy, which could significantly enhance therapeutic efficiency. As an analgesic, VR could prove to be an excellent alternative to overused medications. VR is also being employed for medical training to provide more immersive opportunities for students to practice their medical skills. This article examines how VR can contribute to these sectors of healthcare, highlights its impeding factors, and evaluates its potential.

Rehabilitation and Therapeutic Uses of VR

Rehabilitation aims to help patients recover from injury or illness, and prepare them to return to their daily routine. The predicament lies in creating a rehabilitation setup which accurately portrays daily obstacles, as they tend to be costly and challenging for patients to overcome in early stages of recovery. VR can provide a safe means of delivering a realistic environment which can bolster confidence and better prepare patients for real-world obstacles.3,4 In fact, therapeutic uses are the most documented medical application of VR over the last decade.1

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Imagine leaving behind your anxiety and doubts to enter into a stunning fantasy world where your steps are guided by ethereal trails. The three major factors of rehabilitation are Now imagine these being the first steps you’ve early intervention, specific task training, and taken since a major accident or a motor neurepetition, all of which can be addressed ron disease diagnosis. Though this concept through VR.3,5 Documented observations sugmay seem outlandish, it is quickly becoming gest that prolonged inactivity in patients prior feasible for patients around the globe through to rehabilitation results in greater dystrophy of virtual reality (VR) systems. Though previously muscles and nerve connections, whereas earlimited by lack of technological innovation and lier interventions promote the maintenance high costs, the VR industry is now growing of undamaged areas and the repair of partially thanks to investment from companies such as damaged nerves.3,4 As VR requires little human Oculus VR and HTC, making VR more feaassistance compared to physiotherapy or occusible. Beyond consumer use, this revolution has pational therapy, it can be implemented imrevealed a unique opportunity for VR to be mediately as an early intervention.3 Developused in healthcare, where it can improve paers can design objectives in multidimensional tient rehabilitation, offer a new mode of treatenvironments to promote ample repetition of ment, and assist in education. realistic task motions. VR’s effectiveness is exemplified in a 2011 study which observed that A Whole New World – How later stage Parkinson’s Disease (PD) patients it Works often lose control of their step regulation patterns (gait), making locomotion rather diffiVR is a computer-based technology that atcult.3,4 Mirelman and his colleagues discovered tempts to reproduce elements of reality, inthat with active VR training, the patients had cluding visual fields, audio output, and haptic enhanced control over their steps, took longer sensations. Head-mounted displays (HMD) and more confident strides, and more often provide full immersion in a virtual environremembered to place their foot farther away ment (VE) and are at the forefront of the VR from an obstacle to avoid falls.4,6 Furthermore, industry. They enclose users’ full range of vision VR showed promising clinical effectiveness as within a screen and are used in conjunction

critical review

INTRODUCTION

with noise-cancelling headphones and vibrating controllers to simulate reality.1 Alternatively, multiple screens known as a tri-screen display are also common. Although many VR systems are being tested in a clinical setting, research has yet to determine their effectiveness in other situations.2

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critical review

compared to conventional therapies. In a 2015 study, 10 chronic stroke patients were exposed to 30-minute VR training sessions in addition to conventional therapy, while the control group only received conventional therapy.7 According to the Berg Balance Scale and 10m Walking Test, statistically significant improvements were found in balance and gait as compared to control participants.7 Therefore, the trial asserted VR as an effective resource for rehabilitation. Overall, these studies suggest that VR can be a beneficial adjunct to conventional rehabilitation.

Another major aspect of rehabilitation is motivation. These simulations provide exciting incentives for patients to repeat limb movements in contrast to the traditional goal of reaching a target number of repetitions.8,9 Rand et al. found that stroke patients using VR reported higher frequency of arm movements during therapy and reached greater intensities throughout their recovery period.9 It is suggested that the purposeful goals designed in realistic VEs encourage patients to continue these repeated motions, unlike in comparatively dull therapy rooms.3,9

pain requires attention to the location of stimulus in order for the brain to process the incoming signals. VR may impede this process by introducing a flood of new sensory information to divert the brainâ&#x20AC;&#x2122;s attention.2,10,12 To explore this hypothesis, a 2011 clinical trial measured reductions in pain, time spent thinking about pain, and general unpleasantness in 54 pediatric burn patients undergoing occupational therapy with and without VR. Their data showed significant reductions in physical pain and time spent thinking about their pain in the presence of VR, which led to the conclusion that VR enhanced analgesic effects.14 In light of this evidence, research has been extended to other forms of pain, including chronic pain and headaches, and stress management. Further studies should elucidate how these virtual effects translate to the outside world, and whether VR will be a viable replacement for pharmacological agents.12,15,16

WHAT ELSE CAN WE LEARN FROM VR?

Although VR demonstrates the potential to directly benefit patients, it can also indirectly imVR has led to significant improvements in both pact them. Education of medical doctors places children and adult patients suffering from vari- heavy emphasis on competency, proficiency, ous motor diseases such as PD, spinal cord in- and resource usage efficiency. The implementajury, and limb immobilization due to strokes.4,5,8 tion of VR has increasingly been a new focus of This research suggests that VR training can be schools and hopsitals in an effort to continua valuable tool in supporting patient recovery ously improve their teaching methods.17,18 by simulating various aspects of their regular lifestyle. Currently, surgical students who require supervision and guidance during their first surgeries VR as a Nonpharmacofrequently extend the total surgical time and consequently increase surgical complications.19 logical Analgesic It is suggested that these consequences can be The research into VR rehabilitation eventually avoided through the use of VR-based educaled to another application for medical care. Pa- tion. Simulations may allow trainees to refine tients with burn injuries undergo occupational techniques through visualization and motion and skin stretching therapy, and large amounts practice in a controlled teaching environment, of pharmacological analgesics are required to thereby reducing the likelihood of error during suppress the excruciating pain.2,10,11 With a fo- live surgery. Studies demonstrate that teachcus on finding nonpharmacological solutions ing laparoscopic and gastrointestinal surgeries due to severe side effects and tolerance buildup, through VR is both cost-effective and results VR is proving to be a promising solution.12 in faster operative times, fewer errors, and more A study by Hoffman et al. determined that VR competent and independent trainees.18,19 generates greater compliance for occupational and skin stretching therapy, as participants re- However, though these are encouraging preported pain reduction when immersed in the liminary observations, there is no conclusive VR world.2,10 These results were followed up evidence that VR should replace supervised with functional magnetic resonance imaging practice. Snyder et al. compared performance (fMRI) scans which demonstrated impres- of students trained with a pre-recorded VR sive reductions in the pain-sensing areas of simulation against those with human supervithe brain during VR use.2 A larger study of 88 sion and discovered that while VR reduced baparticipants found similar reports of decreased sic errors similar to human supervision, human pain.10,13 It is stipulated that the sensation of supervision provided more detailed feedback

in complex cases.20 Thus, while VR could reduce early operational costs and complications, evaluation by human supervisors would still be a necessity.

no green light yet on vr Despite the apparent benefits of VR for patient care and medical training, further research is required to ascertain whether these applications are efficient. As VR has only become accessible in the last decade, past studies were limited by the financial burden of technological obselescence, due to the rapid progress of the VR field. Furthermore, previous studies were often underpowererd as a result of low participant compliance.5,21 New clinical trials with greater sample populations are needed to compare the recent advances in VR with current therapy models, treatment regiments, and teaching methods in order to support widespread VR applications.6,12

THE FUTURE IS VIRTUAL As the world progresses towards a digital age with ever-advancing technologies, VR emerges not only as an entertainment medium, but also as an impactful tool in healthcare. Its potential in rehabilitation and treatment allows for the implementation of enriching and individualized options for patient care. Additionally, VR presents a promising opportunity for education of medical professionals by providing a superior alternative to textbooks and instructional videos. Trainees will be able to virtually experience techniques and procedures to better prepare them for live patient care. Future research must focus on the cost-efficiency of this technology and consolidate its effectiveness relative to conventional therapies. Finally, it is important to evaluate the magnitude of VR exposure required for patients and trainees to experience significant benefits. The investment in VR can profoundly enhance the face of healthcare in terms of how and when the appropriate care is delivered to patients. ■

10.

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Finally, it has not yet been determined how much VR training is required to produce meaningful outcomes.12,16 Ideally, VR training should be effective within a similar time frame

20.

Dr. Gurmit Singh is a professor in the department of Pathology and Molecular Medicine at McMaster University, and head of the Singh lab which focuses on breast and prostate cancers. He has considerable expertise in the field of cancer-induced pain and teaches a course regarding mechanisms of pain as a well-respected instructor in the Health Sciences program. Edited by ELLEN HE AND KEVIN REN 1.

2. 3.

Small C, Stone R, Pilsbury J, Bowden M, Bion J. Virtual restorative environment therapy as an adjunct to pain control during burn dressing changes: study protocol for a randomised controlled trial. Trials [Internet]. Trials; 2015;16:329. Available from: http://dx.doi.org/10.1186/s13063015-0878-8 Sveistrup H. Motor rehabilitation using virtual reality. J Neuroeng Rehabil. 2004;1:10. Carlozzi NE, Gade V, Rizzo A ”Skip”, Tulsky DS.

Using virtual reality driving simulators in persons with spinal cord injury: three screen display versus head mounted display. Disabil Rehabil Assist Technol [Internet]. 2013;8(2):176–80. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/22775982 4. Levin MF. Can virtual reality offer enriched environments for rehabilitation? Expert Rev Neurother. 2011;11(2):153–5. 5. Mirelman A, Maidan I, Herman T, Deutsch JE, Gila-

di N, Hausdorff JM. Virtual reality for gait training: Can it induce motor learning to enhance complex walking and reduce fall risk in patients with Parkinson’s disease? Journals Gerontol - Ser A Biol Sci Med Sci. 2011;66 A(2):234–40. Lloréns R, Gil-Gómez J-A, Alcañiz M, Colomer C, Noé E. Improvement in balance using a virtual reality-based stepping exercise: a randomized controlled trial involving individuals with chronic stroke. Clin Rehabil. 2015;29(293):261–8.

21. 22.

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Reviewed by Dr. Gurmit Singh

Just MA, Stapley PJ, Ros M, Naghdy F, Stirling D. A comparison of upper limb movement profiles when reaching to virtual and real targets using the Oculus Rift : implications for virtual-reality enhanced stroke rehabilitation. Proc 10th Intl Conf Disabil Virtual Real Assoc Technol. 2014;2–4. Rand D, Givon N, Zeilig G, Nota A, Weingarden H. Counting repetitions of upper extremity movements while playing video games compared to traditional therapy : implications for stroke rehabilitation. Proc 9th Intl Conf Disabil Virtual Real Assoc Technol [Internet]. 2012;10–2. Available from: www.icdvrat.org Sharar SR, Miller W, Teeley A, Soltani M, Hoffman HG, Jensen MP, et al. Applications of virtual reality for pain management in burn-injured patients. Expert Rev Neurother. 2008;8(11):1667–74. Hoffman HG, Meyer III WJ, Ramirez M, Roberts L, Seibel EJ, Atzori B, et al. Feasibility of Articulated Arm Mounted Oculus Rift Virtual Reality Goggles for Adjunctive Pain Control During Occupational Therapy in Pediatric Burn Patients. Cyberpsychology, Behav Soc Netw. 2014;17(6):397–401. Hoffman HG, Doctor JN, Patterson DR, Carrougher GJ, Furness T a. Virtual reality as an adjunctive pain control during burn wound care in adolescent patients. Pain. 2000;85(1-2):305–9. Gromala D, Tong X, Choo A, Karamnejad M, Shaw CD. The Virtual Meditative Walk : Virtual Reality Therapy for Chronic Pain Management. Proc 33rd Annu ACM Conf Hum Factors Comput Syst. 2015;521–4. Sharar SR, Carrougher GJ, Nakamura D, Hoffman HG, Blough DK, Patterson DR. Factors Influencing the Efficacy of Virtual Reality Distraction Analgesia During Postburn Physical Therapy: Preliminary Results from 3 Ongoing Studies. Arch Phys Med Rehabil. 2007;88(12 SUPPL. 2):43–9. Schmitt YS, Hoffman HG, Blough DK, Patterson DR, Jensen MP, Soltani M, et al. A randomized, controlled trial of immersive virtual reality analgesia, during physical therapy for pediatric burns. Burns [Internet]. Elsevier Ltd and International Society of Burns Injuries; 2011;37(1):61– 8. Available from: http://dx.doi. org/10.1016/j.burns.2010.07.007 Shiri S, Feintuch U, Weiss N, Pustilnik A, Geffen T, Kay B, et al. A Virtual Reality System Combined with Biofeedback for Treating Pediatric Chronic Headache — A Pilot Study. Pain Med. 2013;14:621–7. Hudlicka E. Virtual training and coaching of health behavior: Example from mindfulness meditation training. Patient Educ Couns [Internet]. Elsevier Ireland Ltd; 2013;92(2):160–6. Available from: http://dx.doi.org/10.1016/j. pec.2013.05.007 Nagendran M, Gurusamy K, Aggarwal R, Loizidou M, Davidson B. Virtual reality training for surgical trainees in laparoscopic surgery. Cochrane Database Syst Rev. 2013;(8). Walsh C, Sherlock M, Ling S, Carnahan H. Virtual reality simulation training for health professions trainees in gastrointestinal endoscopy. Cochrane Database Syst Rev. 2012;(6). Larsen CR, Soerensen JL, Grantcharov TP, Dalsgaard T, Schouenborg L, Ottosen C, et al. Effect of virtual reality training on laparoscopic surgery: randomised controlled trial. BMJ [Internet]. 2009;338:b1802. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/19443914\nhttp://www. pubmedcentral.nih.gov/articlerender. fcgi?artid=PMC3273782 Snyder CW, Vandromme MJ, Tyra SL, Porterfield JR, Clements RH, Hawn MT. Effects of virtual reality simulator training method and observational learning on surgical performance. World J Surg. 2011;35(2):245–52. Mathur AS. Low Cost Virtual Reality for Medical Training. IEEE Virtual Real Conf 2015. 2015;345–6. Sigrist R, Rauter G, Riener R, Wolf P. Augmented visual, auditory, haptic, and multimodal feedback in motor learning: A review. Psychon Bull Rev [Internet]. 2013;20:21–53. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/23132605\nhttp://link. springer.com/10.3758/s13423-0120333-8

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In addition, for therapeutic purposes, VR technology does not yet provide highly accurate haptic feedback aside from vibrations.8 Some research argues that greater tangible senses are required to help patients relearn motions such as feeling the weight of an object, while contrasting research suggests visualization alone is adequately beneficial to practice and boost patient confidence.2,4,8 Other studies interject by noting that most forms of haptic feedback are not necessary at all for motor skill relearning after childhood, and that positional control alone is sufficient.22 It is unclear whether the benefits of movement practice combined with visualization outweigh the lack of physical pressure during this training.2,8,22 However, studies have yet to assess the effectiveness of vibrations in terms of haptic feedback.

to most physiotherapy sessions in order to be a sufficient replacement. Extending beyond regular therapy periods may reduce compliance or produce negative effects.5 These concerns must be addressed before VR is standardized into the healthcare system.

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INTERVIEW SPOTLIGHT

DR.MATTHEW MILLER STAR in VACCINE DEVELOPMENT ARLINDA DENG1, AVRILYNN DING1, OWEN LUO2

Bachelor of Health Sciences (Honours), Class of 2017, McMaster University Bachelor of Health Sciences (Honours), Class of 2019, McMaster University

 DR. MATTHEW MILLER IS AN ASSISTANT PROFESSOR IN THE

DEPARTMENT OF BIOCHEMISTRY AND BIOMEDICAL SCIENCES AT MCMASTER UNIVERSITY, AND PRINCIPAL INVESTIGATOR IN THE INSTITUTE FOR INFECTIOUS DISEASES RESEARCH AND THE MCMASTER IMMUNOLOGY RESEARCH CENTRE. AS A SUCCESSFUL YOUNG SCIENTIST IN THE FIELD OF IMMUNOLOGY, HE IS PUSHING THE FRONTIERS OF BIOMEDICAL DISCOVERY AND HAS BEEN RECENTLY AWARDED WITH THE 2015-2016 CIHR NEW INVESTIGATOR AWARD. DR. MILLER’S CURRENT RESEARCH FOCUSES ON THE INTERACTION BETWEEN VIRUSES AND THE IMMUNE SYSTEM AS IMPLICATED IN NEURODEGENERATIVE DISEASE AND VACCINE DEVELOPMENT.



Thank you for taking the time to speak with us Dr. Miller. What inspired you to pursue an academic career in the field of immunology and what made you join McMaster’s Immunology Research Centre?

Good question. I became interested in immunology as a Bachelor of Medical Sciences student at Western University, which was a brand new program when I started there. During the later years of my studies, I quickly fell in love with microbiology while taking an introductory course on it in second year and saw that it was unlike anything I had done before. I ultimately began a concentrated specialization in microbiology and immunology. Like many students at that stage of their education, I hadn’t decided on my future career path, having toyed with the idea of medical school, but never being sold by it. However, during my fourth year, I did an honours thesis project in immunology, which granted me significant access to a lab. This flipped the switch for me and I ultimately did not apply to medical school. I instead continued studying at Western, due to continued interest in my thesis project, until the completion of my PhD. The interest

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In your opinion, what are the highlights of your research?

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sparked during my undergraduate degree has persisted and compounded until today.

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Most pathogens fortunately don’t change much over time in structurally. The flu does. Flus evolve very rapidly to evade the preexisting immunity that is generated by either natural infection or vaccine. The protein on the outside of a flu agent that attaches to and infects our cells resembles a lollipop. It has a big, round, globular head and a skinny stalk. Like lollipops, for every flu, the head is either a different shape, colour, or flavour. Our immune system only recognizes one shape or colour typically, and preferentially generates antibodies against the head portion. But, the virus can change the head whenever it wants and the protein remains functional— it’s a really unique property of the flu. Like a lollipop, the stem is conserved across all flus and never changes. That’s partially because the virus requires the stem protein in order to infect the cell. The virus wants to mutate so that antibodies for the stalk can’t bind either. However, it can’t do that because then it becomes non-functional. So, by teaching the immune system to preferentially make antibodies to this unchanging portion,

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After completing my PhD at Western, I began my postdoctoral fellowship at the Icahn School of Medicine at the Mount Sinai Hospital in New York City. I had the opportunity to work with Dr. Peter Palese, a world-acclaimed virologist and leading expert in the influenza virus. Upon completing my postdoctoral studies, the decision to remain in the U.S. or return to Canada was presented to me when looking for faculty positions. Even though there were a series of advantages to becoming a member of the vast and productive U.S. international research institutions, the Canadian research scene was more supportive to new investigators. McMaster University was the best fit in terms of resources, location, and faculty. What was important to me was to go to a place with excellent faculty and students. As faculty members, it is largely students that drive our research since we physically can’t be in the lab at all times. My colleagues are also excellent researchers— they’re all doing amazing work. I wanted to be in a place where everyone around you is great and where it isn’t easy to be great. It was very motivating to come here, as it is easy to become complacent if you go somewhere and are immediately heads and tails above everyone else. McMaster is an institution where doing great things is the norm, pushing you to become really great.

Recently, a significant number of media publications have broadcasted your collaborative research in characterizing a novel universal flu vaccine. Can you explain what a universal vaccine is capable of in the context of the flu and the immunological mechanisms that make your proposed strategy possible?

interview spotlight

A major highlight of my research began during the 2009 swine flu epidemic. At the time, scientists were investigating the antibody immune responses of those infected with swine flu versus those vaccinated against swine flu. They noticed that both populations were producing an antibody that recognizes a conserved component of the flu virus and as a result, could elicit a protective effect against a multitude of different flu strains. Thus, I investigated if this broad-spectrum antibody phenomenon was unique to swine flu or ubiquitous to all flus. My lab knew that induced systemic production of the swine flu antibody could become a viable universal flu vaccination strategy and therefore alleviate the need for revaccination each year. Ultimately, we discovered that this is a general phenomenon that can be exploited to “trick” the immune system into producing broad-spectrum flu antibodies. The resulting vaccine is now licensed and ready for clinical trial. Another major highlight relates to our research on neurodegenerative diseases, which is necessitated by the aging population and the fact that most of these diseases have few treatments and certainly no cures. We stumbled upon the observation that viral infections and their subsequent immune responses may trigger these neurodegenerative diseases. This is an exciting new frontier with a series of interesting findings that would make a big difference in a field that really needs it in the future.

we can protect against different flus, even when they mutate.

 Your

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interview spotlight table of contents

recent publications often address Fc- dependant mechanisms. What biological characteristics of the Fc receptor make it a potential target for vaccine development?

I’d love to talk about that. Antibodies can be divided into two sections: a section that is specific to a pathogen, or the variable region, and a constant region that basically never changes, or the Fc region. The variable region is what we’ve always considered important because upon binding to the virus, it can prevent it from infecting the host cell. But, it turns out the constant region can also protect you. When viruses replicate, they put viral proteins onto the surfaces of the cells that they’ve infected. Antibodies that are specific to the virus will bind to the pieces of the virus on the surface of the cell, and the Fc region is then sitting out waving like a flag. That flag will get recognized by receptors of an immune cell, which will kill that infected cell before the infection can spread. These mechanisms don’t protect you from initially getting infected, but they protect you from what matters, which is clinical symptoms. This has taught us that we can also make antibodies that are really good at flagging the immune system to eliminate infected cells before the virus replicates. The antibodies our bodies prefer to make against flu and current seasonal flu vaccines are very good at neutralizing the virus, but the types of antibodies that a universal vaccine generates are really good at flagging immune cells to come and kill virally infected cells. This is a new and exciting field for universal flu vaccine development.

 We know you have won numerous

awards even in the early stages of your career, but what do you feel is your proudest achievement?

You know, I think that as a scientist who is also a professor at a university, what really makes you the proudest is your ability to impact students. I mean, maybe other people will say my Nature paper or this big award, but to me, at the end of the day, those things tend to be very passing. They have their little moment of glory when you’re at a ceremony or when you publish, but it’s not lasting. Graduating a PhD student or seeing my fourth year thesis students convocate— that makes me really proud. Because here is someone who hopefully you’ve had a really life changing influence on, whose experience with you is something that is going to be meaningful and hopefully play a role in their future, even if they’re not going into the field you are in. Even if those people do not go on to become flu experts, hopefully what they learned about thinking critically and logically and the importance of using the scientific method to evaluate the validity of anything they encounter in life causes them to be a much better person in society. Awards are nice when they happen, but they are pretty acute, have short half-lives, and are passing in nature. Maybe it looks great on paper, but at the end of

the day what is it really, beyond a plaque on the wall or letters after your name? The impact we have on trainees and seeing them succeed is what makes me most proud. Here is an actual life that I’ve been able to make a difference in as opposed to an award I can stick in a trophy case or on a wall as inanimate objects.

 That’s

very inspiring — there are many nerve - wracking experiences where you are not sure whether the effort you put in today will ever come to fruition. What advice do you have for students interested in research?

There is one enlightening piece of advice that I did not appreciate until I figured it out myself. When you are following your tracks, you tend to be a highly motivated person who measures your success by achieving goals. But, eventually you reach a stage where all of a sudden, it hits you: do I also want to have a life outside of academic goals? Until the end of my postdoc, my identity revolved around doing well academically and professionally. I do not believe in reincarnation so around the time I was looking for jobs, I realized that I only get to live life once. Like wow, I better make sure I don’t miss out on all the things I want to do just because I’m so singularly focused on these academic goals. It was the first time in my life where I started to make decisions that weren’t simply based on external or superficial expectations of what success looks like. It’s still important to work hard and be focused, but also remember that life exists beyond these goal-driven ideals. The biggest piece of advice I would give specifically to undergraduate students in their later years is to really endeavour not to define your own success by the external expectations society has set. I am a scientist so I care about data-driven evidence. There is unequivocal data out there that if you make $70,000 a year, then no amount of money beyond that changes your self-identified level of happiness. Obviously $70,000 depends on where you live, but it’s basically an average, comfortable, middle-class salary. A lot of times, people want a job that will make them a lot of money or want a job that is associated with a title that people really revere. But, what I tell people is: at the end of the day, you work the vast majority of your life and there is no amount of money that can buy you happiness in your job. If you work every day at some soulless job that pays you $250,000 a year, and you’re working twelve hour days and you hate every minute of it, then what good is all of that? Other people are like, “That’s so great, you have a sweet Mercedes in the garage” and you’re like, “Yeah I drive it to my soulless job every day, sitting in traffic on the Don Valley, it’s really great”. That is something I have always been introspective about in a way that has been good for me. As the few people who have the privilege or benefit of a good university education, we can largely make decisions about our career that are in line with what makes us happy. ■

GRAPHICS & DESIGN Creative Directors Maine Bi Michael Sun

EDITORS-IN-CHIEF Abirami Kirubarajan Matthew Yau EDITORIAL BOARD Managing Editors Ishan Aditya Arshia Pedram Javidan Editors Takhliq Amir Sama Anvari Jessica Chee Kevin Chen Arlinda Deng Avrilynn Ding Angela Dong Sarah Ge Anna Goshua Ellen He Joella Ho

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MEDUCATOR | D e c 2 0 1 4 m e d u c a t o r | winter 2 0 1 7

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Missing: Avrilynn Ding, Anna Goshua, David Hu, Marcel Jansen, Owen Luo, Adrian Marcuzzi, Kevin Ren, Bob Yang

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