Issue 31 by The Meducator

SPRING 2017 | ISSUE 31

Newborn Screening and Whole Genome Sequencing A Perfect Match or an Emerging Ethical Crisis?

Understanding Shock and Kill A Potential HIV Cure

Interview with Anne McKeage former History of Health and Medicine Librarian

WWW.MEDUCATOR.ORG

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table of contents

CONTENTS

SPRING 2017 | ISSUE 31 02 INTRODUCTION 03 MEDPULSE 05 MEDBULLETIN 07 FORUMSPACE 09 ABSTRACTS 10 INFOGRAPHIC 11 PATHOPROFILE OPINION 13 Newborn Screening and Whole Genome Sequencing: A Perfect Match or an Emerging Ethical Crisis? 15 Lifting the Price on Human Life: How Nonfinancial Donor Compensation Could Eradicate the Organ Trade CRITICAL REVIEW 17 Regulatory T cells in Allergic Asthma 21 Understanding Shock and Kill: A Potential HIV Cure 25 INTERVIEW SPOTLIGHT 29 BIOMEDICAL GRAPHICS CONTEST 30 CONTRIBUTORS Cover Artist Bob Yang ToC Artist Matilda Kim

On behalf of the team, it is our pleasure to introduce the 31st issue of The Meducator. We are incredibly proud of our staff members and all they have accomplished this year. From holding scientific literacy workshops in collaboration with the Hamilton-Wentworth District School Board, to on-campus partnerships with NeuroXChange, Descipher, and the McMaster Undergraduate Research Association, to our first-ever issue launch event, our team’s enthusiasm has allowed The Meducator’s impact to grow even further beyond our print journal. Our final issue this year serves as a reminder of all that undergraduate research is able to achieve. This issue begins with a beautiful cover by Bob Yang that highlights the symmetry and mathematical beauty that can be found in the sciences. We then explore global breakthroughs within the health sciences through our Medpulse piece by staff members Jessica Chee and Tony Chen. Editors Sabrina Lin, Anna Goshua, Sama Anvari, and Kevin Ren take a critical look at news in our Medbulletin piece to explore stem cells, the opioid crisis, ketamine, and novel surgical treatments, respectively. Exploring the effects of poverty on health, the McMaster Health Forum continues our longstanding collaboration through our Forumspace piece with Malcolm Hartman, Alena Lukich, Janice Mok, and Padmaja Sreeram. Next, we feature four abstracts by Omar Shawaf, Aaron Edward, Daiana Pogacean, and Elsie Amoako to highlight original undergraduate research. Through our arts-based Pathoprofile piece, we elucidate the FKBP5-mediated pathway of stress with collaboration between staff members Takhliq Amir, Owen Luo, and Cathy Lu. Our two Opinion pieces then evaluate the ethical implications of newborn screening as well as nonfinancial organ donor compensation, through articles from Adam Wade-Vallance and Edward Li, respectively. Two critical reviews have been selected for this issue of the Meducator. Mobeen Mubasher details the role of regulatory T cells in allergic asthma, while documenting current and future immunotherapies for the condition. Sarah Ge, Parsa Mehraban Far, and Devin Roshan writes about an emerging HIV treatment that employs latency reversing agents to “shock and kill” the virus.

introduction

INTRODUCTION ISSUE 31

dear reader,

In addition, we have had the privilege of hosting former history of health and medicine librarian, Anne McKeage. Ashley Lam and Kevin Chen’s interview with Anne spans a range of topics including McMaster’s Rare Book Room, undergraduate involvement in the history of medicine, and her personal experiences as an archivist. The Meducator also hosted its inaugural Biomedical Graphics Contest, in which the winning submission from a McMaster wide contest has been published.

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The Meducator’s 31st publication would not have been possible without each and every one of the 40 members of our editorial, graphics, and video teams. Special thanks to Creative Directors Maine Bing and Michael Sun, Managing Editors Ishan Aditya and Arshia Javidan, and Video Manager Faizan Bhatia for their amazing work. We look forward to welcoming incoming Editors-in-Chiefs, Sarah Ge and Sabrina Lin. We are confident that they will do a superb job of maintaining The Meducator’s mission of sharing undergraduate research to the McMaster community.

Abirami kirubarajan

Sp r i n g 2 0 1 7

Matthew Yau

Bachelor of Health Sciences (Honours) Class of 2018

M No More Addiction?

Irradiated Gro und Beef

Feb 2017

Ottawa, Cana In response da to a massive r e call of beef Alberta in 20 products in 12 due to an E. coli infect Canada has ion, Health approved th e sale of irra beef. 1 Irradi diated ground ation is the process by blasted with which food ionizing radi is ation salmonella, E. Coli, and othe in an effort to reduce r harmful ba policy harbou cteria. 2 This rs promise of a safer food industry. Feb 2017 nada British Columbia, Ca

Columbia may iversity of British Scientists at the Un ce that makes mi in netic construct ge a ed rat ne ge ve ha e mice had an caine addictions. Th them immune to co n, an adhesive the protein cadheri overexpression of d strengthens an ds cells together bin ich wh n tei pro in synapses of 6 tion of cadherin synapses. Stabiliza cocaine-induced urons prevents dopaminergic ne ted with the so ate receptors as cia changes to the glutam ce lose the mi the , ch su the brain. As reward circuitry of w is ne research ry of cocaine. Th pleasurable memo n may very well ptibility to addictio suggests that susce mined solely by ter de and is not have a genetic basis judgment.

Rejuvenating Blood

Feb 2017 Lund, Sweden

to a increased predisposition Aging is associated with ing lud inc es eas related dis wide array of bloodand , cer can od blo of es typ anemia, leukemia, certain to h, efforts have been made suc As ty. uni imm d ere low has n ede Sw in ls. A group rejuvenate blood stem cel d haematopoietic stem age ng lati iso in succeeded coding and reprogrambar cells (HSCs) using genetic in d pluripotent stem cells ming them into induce for ty aci cap the w t to sho mice. This group is the ďŹ rs reversed to a younger ng bei Cs HS old ly nal functio state.4

Feb 2017 , USA if Cal ornia

tive Contracep le a M torically w e AN have his s rt o ff ons e only op5ti e elopment h tly, the tive dev

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Moths T hreaten Crops in Africa The Spo d

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Chatty V iruses

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6 Dec 201 China

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REFERENCES 1. Kohut, T. Irradiated Ground Beef Approv ed by Health Canada [Internet]. Global News: Consu mer. 2017 Feb 22. Available from: http://globalnews.ca/news/3265782/irradiated-ground-be ef-approved-health-canada/ 2. Morrison RM, Buzby JC, Lin CT. Irradia ting ground beef to enhance food safety. Food Review : The Magazine of Food Economics. 1997;20(1). 3. Erez Z, Steinberger-Levy I, Shamir M, Doron S, Stokar-Avihail A, Peleg Y et al. Communicati on between viruses guides lysis–lysogeny decisions. Nature. 2017 Jan 18;541(7638):488-493. 4. Wahlestedt M, Erlandsson E, Kristia nsen T, Lu R, Brakebusch C, Weissman I.L et al. Clonal reversal of ageing-associated stem cell lineage bias via a pluripotent intermediate. Nat. Commun. 2017 Feb 22;8:14533 5. Colagross-Schouten A, Lemoy MJ, Keesle r RI, Lissner

MEDPULSE

injection of Vasalgel™ for adult male rhesus monkeys. Basic Clin. Androl. 2017 Feb 7;27(1):4. 6. Mills F, Globa AK, Liu S, Cowan CM, Mobasser M, Phillips AG et al. Cadherins mediate cocain e-induced synaptic plasticity and behavioral conditi oning. Nat. Neurosci. 2017 Feb 13. 7. Gunther, M. New Pest Threatens Crops in West Africa[Internet]. Norwegian Institute of Bioeconomy Research. 2017 Jan 13. Available from: http://www.nibio.no/en/news/new-pest-threatens-crops-in-west-africa 8. European Centre for Disease Contro l and Prevention. Recent upsurge of A(H7N9) cases in China, updated rapid risk assessment [Internet]. 2017 Jan 30. Available from: http://ecdc.europa.eu/en/press/ news/_layouts/forms/News_DispForm.aspx?ID=1539&List=8db7286c-fe 2d-476c-913 ages/home.aspx 9. Lau C, Aubry M, Musso D, Teissier A, Paulous S, Desprès P et al. New evidence for endem ic circulation of Ross River virus in the Pacific Islands and the potential for emergence. Int. J. Infect. Dis 2017 Feb 8;57:73-76.

Feb 2016 stralia Adelaide, Au

irus: Ross River V ? nd the bal Epidemic The Next Glo RV) has been circulating arouchers in ar iver virus (R ding to rese

Ross R -80. Accor d be c since 1979 s that it coul al South Paciﬁ demonstrate pi su ce ar en M id . ev w epidemic Australia, ne the rne global e ar bo , oit es bi qu la os s and wal oo the next m it ar l, ng ta ka fa y iﬁcall V is not animals, spec lthough RR li A bi s. de ru vi be n is th ts, and ca in jo re reservoirs of so d , fevers, an causes rashes s.9 th on m tating for

MEDBULLETIN STEM CELLS

OPIOIDS

SABRINA LIN

ANN A GOSHUA

Researchers at the University of Cambridge have recently succeeded in creating the world’s first mouse embryo-like structure using embryonic stem cells (ESCs) and trophoblast stem cells (TSCs). 1 Led by Professor Magdalena Zernicka-Goetz, the research team combined genetically modified mouse ESCs and TSCs in a three-dimensional extracellular matrix to create a selfassembling structure with properties similar to a natural embryo. 1

Since the patent of the highly addictive narcotic Oxycontin in 1996, rates of opioid addiction, overdose, and death have been skyrocketing in Canada. 1 In British Columbia, over 900 deaths have been recorded due to overdose from fentanyl, a synthetic opiate. In 2016, the opiate epidemic in British Columbia led the province to declare a state of emergency. 2 The root of the epidemic has been attributed to careless prescribing by physicians. Will the emergence of a potentially non-addictive opioid change the landscape of pain treatment?

medbulletin

Artificial Mouse Embryo Developed in Lab

Mammalian embryogenesis requires intricate interactions between embryonic and extra-embryonic tissues to orchestrate morphogenesis with changes in developmental potential. 2 By using genetically modified stem cells and specific inhibitors, the team showed that embryogenesis of ESC- and TSC-derived embryos, ETS-embryos, depends on the crosstalk involving Nodal signaling. 3 According to Zernicka-Goetz, embryonic and extra-embryonic cells communicate with one another to form a structure that resembles an embryo, sharing anatomically identical regions with similar rates of development. 3 A striking revelation elucidated by the study is that communication between cells is bidirectional in nature, in which cells guide each other in the biological development of the organ. 4 Previous attempts to grow embryo-like structures using only ESCs have been met with limited success precisely because different cell types lack this critical coordination. 3

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In Zernicka-Goetz’ model, cultured stem cells organised themselves, with ESCs and TSCs on opposing ends. A cavity then opened up within each cluster before joining together, eventually becoming the large, pro-amniotic cavity in which the embryo developed. 3

Scientists at Tulane University and Southeast Louisiana Veterans Health Care System have developed and tested a pain reliever in rats that is as potent as morphine, but has fewer side effects, including a minimal risk of addiction. 3 They engineered four novel analogs of endomorphin, an endogenous peptide that acts at the same mu opioid receptor as other narcotics. At equianalgesic or higher doses, all of the analogs demonstrated a lower incidence of respiratory depression, motor impairment, tolerance, and addictive potential relative to morphine. The analogs also reduce glial activation, which has been implicated in causing side effects, such as opioid hyperalgesia and dependence, suggesting a differential mechanism of action compared to traditional opioids. 4 Within the next two years, the research team hopes to trial endomorphin analogs in humans within the next two years, which will be necessary to ascertain if these analgesics will truly enable clinicians to offer patients impressive pain relief with minimal side effects.

The creation of this artificial embryo-like structure is critical in facilitating insights into the developmental process of a natural human embryo. 5 Similar approaches could one day be used to explore fetal growth shedding light on the role of the maternal environment in birth defects and health. 5 1. 2. 3. 4. 5. 6.

Non-addictive opioids: a game-changer in time of crisis?

Harrison S, Sozen B, Christodoulou N, Kyprianou C, Zernicka-Goetz M. Assembly of embryonic and extraembryonic stem cells to mimic embryogenesis in vitro. Science. 2017. Scientists create artificial mouse ‘embryo’ from stem cells for first time. ScienceDaily. 2017. Bedzhov I, Graham S, Leung C, Zernicka-Goetz M. Developmental plasticity, cell fate specification and morphogenesis in the early mouse embryo. Philosophical Transactions of the Royal Society B: Biological Sciences. 2014;369(1657):20130538-20130538. Scientists create artificial mouse ‘embryo’ from stem cells for first time [Internet]. Phys.org. 2017 [cited 8 March 2017]. Available from: https://phys.org/news/2017-03-scientists-artificial-mouse-embryostem.html Mayer K. Genetic Engineering & Biotechnology News [Internet]. Genengnews.com. 2017 [cited 8 March 2017]. Available from: http://www.genengnews.com/print/44255 Stem Cell Banner. [Image on the Internet]. 2016 Apr 9 [cited 2017 Mar 25]. Available from: https://3. bp.blogspot.com/-iRb69VI92Fc/VwlNlxl3DQI/AAAAAAAACvI/jwUhqQ3OL-svKz3bYHoEAGH2xnP8qXOEA/s320/stem-cell-therapy.jpg

1. 2.

4. 5.

Meldrum M. A Capsule History of Pain Management. JAMA. 2003;290(18):2470. Mail V. B.C. declares public health emergency as overdoses surge again [Internet]. The Globe and Mail. 2017 [cited 7 March 2017]. Available from: http://www.theglobeandmail.com/news/british-columbia/ overdoses-prompt-bc-to-declare-public-health-emergency/article29631552/ [Retrieved 20th March 2017]. Zadina J, Nilges M, Morgenweck J, Zhang X, Hackler L, Fasold M. Endomorphin analog analgesics with reduced abuse liability, respiratory depression, motor impairment, tolerance, and glial activation relative to morphine. Neuropharmacology. 2016;105:215-227. Available from: http://dx.doi.org/10.1016/j.neuropharm.2015.12.024 [Retrieved 20th March 2017] Watkins L, Hutchinson M, Rice K, Maier S. The “Toll” of Opioid-Induced Glial Activation: Improving the Clinical Efficacy of Opioids by Targeting Glia. Trends in Pharmacological Sciences. 2009;30(11):581-591. Available from: doi: 10.1016/j.tips.2009.08.002 [Retrieved 20th March 2017]. Neurotransmitter Banner. [Image on the Internet]. 2016 Apr 6 [cited 2017 Mar 25]. Available from: http:// supplementsinreview.com/wp-content/uploads/2016/04/Firing-Neurons.jpg

DEPRESSION

Ketamine: club drug turned antidepressant?

ACL injury

A Novel Surgical Treatment for Anterior Cruciate Ligament Injury KEVIN REN

Major depressive disorder, colloquially known as depression, is defined as a depressive state lasting for two weeks or more. 1 Depression affects about 3.2 million Canadians; however, onethird of these individuals fail current treatments, highlighting a need for novel therapies to treat patients with treatmentrefractory depression (TRD). 2 A recent article published in JAMA by Sanacora et al. highlighted the potential of intravenous ketamine hydrochloride, otherwise known as ketamine, for treatment of TRD. 3

One of the four major ligaments in the knee, the anterior cruciate ligament (ACL), prevents excessive forward movement and rotation of the tibia relative to the femur. Injuries to the ligament typically occur due to rapid deceleration, twisting, or landing during athletic competition. 1 Currently, the standard surgical treatment is a procedure known as ACL reconstruction. This involves the removal and replacement of the torn ACL with a graft harvested from the patient ’s own tendons. 2 However, a novel surgical technique developed at the Sports Medicine Research Laboratory may prove to be a better alternative.

Ketamine is used clinically as an anaesthetic, and has gained popularity as a “club drug” due to its ability to induce hallucinations. Remarkably, data from double-blind randomized clinical trials comparing ketamine to placebo have demonstrated it to have rapid and robust antidepressant effects. 3 Ketamine, an uncompetitive antagonist of N-methyl D-aspartate glutamate receptors, was found to produce antidepressant effects in murine models by enhancing transmission through a differential class of glutamate receptors. 4 However, a recent study published in Nature suggests that ketamine’s antidepressant properties may be due to alternative mechanisms. 5 Overall, divergent literature demonstrates how poorly researchers understand how ketamine elicits its effects.

Bridge-enhanced ACL repair (BEAR) uses a bioactive scaffold to complement standard suturing techniques. Unlike ACL reconstruction, BEAR seeks to preserve rather than remove the remaining ACL tissue. 3 Post-injury, the ACL cannot heal by itself due to the premature dissipation of the scaffold that naturally forms when blood fills up damaged tissue. However, BEAR surgically implants a substitute collagen-based scaffold that forms a “bridge” between the two torn ACL ends. The patient ’s own blood is then injected into this scaffold, providing proteins and growth factors while promoting clot formation. 4,5 Within six to eight weeks, the torn ends of the ACL grow back into the scaffold, ultimately replacing it with new tissue. 3 BEAR presents several benefits over traditional ACL reconstruction. Most notably, it decreases rates of posttraumatic joint pain and stiffness. Moreover, preserving the torn ends of the ACL also offers potential advantages, as the preserved ligament may retain proprioceptive function. During the healing process, small stresses on the ligament tissue can activate proprioceptive fibers, triggering microcorrections that restore normal knee dynamics and kinematics. However, extraneous factors such as sex can influence the effectiveness of BEAR, highlighting that further research and assessment is still required before BEAR can transition into a surgical standard. 4,5

3. 4. 5. 6.

2. 3. 4. 5. 6.

Anterior Cruciate Ligament Injury (ACL) | Department of Orthopaedic Surgery [Internet]. Department of Orthopaedic Surgery. [cited 2016Sep10]. Available from: http://orthosurg.ucsf.edu/patient-care/ divisions/sports-medicine/conditions/knee/anterior-cruciate-ligament-injury-acl/ Zarins B. Anterior Cruciate Ligament (ACL) Reconstruction Animation [Internet]. YouTube. YouTube; 2007 [cited 2016Sep11]. Available from: https://www.youtube.com/watch?v=q96m0jrqn7k Bridge-Enhanced (TM) ACL Repair Clinical Trial Overview [Internet]. Anterior Cruciate Ligament (ACL) Program. Boston Children’s Hospital; [cited 2016Sep11]. Available from: http://www.childrenshospital.org/centers-and-services/anterior-cruciate-ligament-program/bridge-enhanced-acl-repair-trial Proffen BL, Perrone GS, Roberts G, Murray MM. Bridge-Enhanced ACL Repair: A Review of the Science and the Pathway Through FDA Investigational Device Approval. Annals of Biomedical Engineering Ann Biomed Eng. 2015;43(3):805–18. Kiapour AM, Fleming BC, Murray MM. Biomechanical Outcomes of Bridge-enhanced Anterior Cruciate Ligament Repair Are Influenced by Sex in a Preclinical Model. Clinical Orthopaedics and Related Research® Clin Orthop Relat Res. 2015Jun;473(8):2599–608. Knee Banner. [Image on the Internet]. 2015 [cited 2017 Mar 25]. http://www.utahorthopediccenters.com/wp-content/uploads/2015/07/Xray-knee-17383024XXXLg-624x832.jpg

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Statistics Canada. Mental and substance use disorders in Canada. Ottawa: Minister of Industry; 2013. Available from: http://www.statcan.gc.ca/pub/82-624-x/2013001/article/11855-eng.htm [Accessed 11 March 2017]. Conway C, George M, Sackeim H. Toward an Evidence-Based, Operational Definition of TreatmentResistant Depression. JAMA Psychiatry. 2017;74(1):9. Available from: doi:10.1001/jamapsychiatry.2016.2586 [Accessed 11th March 2017]. Sanacora G, Frye M, McDonald W, Mathew S, Turner M, Schatzberg A et al. A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. JAMA Psychiatry. 2017. Available from: doi:10.1001/jamapsychiatry.2017.0080 [Accessed 11th March 2017]. Zorumski C, Izumi Y, Mennerick S. Ketamine: NMDA Receptors and Beyond. Journal of Neuroscience. 2016;36(44):11158-11164. Available from: https://doi.org/10.1523/JNEUROSCI.1547-16.2016 [Accessed 11th March 2017]. Zanos P, Moaddel R, Morris P, Georgiou P, Fischell J, Elmer G et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533(7604):481-486. Available from: doi: 10.1038/nature17998 [Accessed 11th March 2017]. Depression Banner. [Image on the Internet]. 2016 Dec 6 [cited 2017 Mar 25]. Available from: http:// www.aspergersmichigan.com/wp-content/uploads/2016/11/depression.jpg

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Ketamine as a novel treatment for TRD has generated a great interest in the field of psychiatry. However, Sanacora et al. caution against administration of ketamine without medical supervision, since to date, few studies have investigated ketamine’s long-term efficacy and safety. 3 Furthermore, long-term ketamine abuse has been associated with cognitive impairment, which raises concerns about its safety as a treatment. 5 Despite ketamine’s promise as a therapeutic agent for TRD, further investigation is required to evaluate its short and long term effects and to elucidate its mechanism of action.

medbulletin

SAMA A NVARI

FORUMSPACE Insufficient funds: Poverty’s effect on health MALColm hartman1 , alena lukich 2 , janice mok 1 , padmaja sreeram1 Bachelor of Health Sciences (Honours), McMaster University, Master of Business Administrations, Specialization in Health Services, McMaster University

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forumspace

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

Context

both seasonal and part-time workers.5 Though these rates may help to characterize the gender wage gap in The World Health Organization states that “poverty Ontario, they do not tell the entire story. It is critical to is the single largest determinant of health”.1 Indeed, note that these rates vary significantly among different the relationship between poverty and health has been age groups, as well as among traditionally disadvantaged accepted for many decades, with the League of Nations demographics, such as visible minorities.5 For example, Health Organization noting in 1933 that economic Indigenous women earn 18% less than Indigenous men despair had created “the gravest dangers for health and and 36% less than non-Indigenous men in hourly wages.5 the very existence of millions of people”.2 Although Racialized women and women with disability earn 34% poverty is often thought of as an issue exclusive to and 48% less than non-racialized men and men without developing countries, its impact is also felt in developed disability, respectively, in hourly wages.5 Women who nations such as Canada. In the past decade, 9% of the identify with more than one marginalized identity are Canadian population have been considered low-income more severely affected by the gender wage gap, and thus citizens, translating to about 3 million Canadians living deserve special consideration in the development and in relative poverty.3 Low-income Canadians have a consideration of poverty reduction and health promotion shorter life expectancy and suffer from more illnesses policies.6 than Canadians with higher incomes regardless of age, sex, race, and place of residence.4 To address the issue Structural reasons beyond the issue of equal pay for equal of poverty, the Canadian Government is currently work contribute to women being disproportionately conducting national case studies to inform a new federal represented among Canada’s low-income population. poverty reduction strategy.3 Throughout this process, For example, no gender wage gap was reported between it will be important to consider the unique challenges men and women who earn minimum wage per hour; faced by specific groups. This article will highlight however, more women than men hold minimum wage key challenges faced by low-income women - a group jobs.5 Normative gender stereotypes and practices play a disproportionately affected by poverty - as well as policy role in sustaining gendered workforce participation, and options that could be considered within efforts to reduce it is often the case that professions dominated by women poverty among low-income women. offer less earning potential.6

Gender wage gap

Differences in the gender wage gap and overall income are important to address for many reasons, the most The gender wage gap in Ontario is 14% in average compelling being that the effects of these differences hourly wages, 25% in average annual earnings for full- accumulate over time. Women earning less in time workers, and 29% in average annual earnings for employment incomes contribute to a gender pension gap

later in life, increasing the risk of older women falling below the poverty line after retirement.5

Caregiving

Reviewed by Dr. Michael Wilson

Edited by sama anvari

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

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In Ontario, life expectancy at the age of 65 is 21.7 years for females, compared to 18.7 years for males.12 Male partners in Canada are also on average slightly older than females. When combined, these realities contribute to women

Older single women, particularly those whose identities intersect with other marginalized populations, are overwhelmingly represented among Canada’s low-income population. As Canada and the province of Ontario set their strategic priorities, it is imperative that future initiatives should engage with and support populations most burdened by poverty. In addition, poverty-reduction initiatives should reflect a nuanced understanding of heterogeneity among low-income populations. ■

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Women live longer and alone

Conclusion

forumspace

Caregivers are individuals who provide unpaid and ongoing care or social support to a family member, neighbour, or friend who is in need due to physical, cognitive, or mental health conditions.7 Women have historically performed this service, and, as of 2012, the majority (53%) of caregivers in Ontario are female, with women spending more time providing weekly unpaid care than men.8 Since Canadian Pension Plan (CPP) benefits are accrued through workforce participation, lower income compounded with time spent away from work has a larger effect on female caregivers. Unsurprisingly, many female caregivers report financial hardship as a result of their responsibilities.9 At present, some financial support is provided to caregivers in Ontario through a federal tax credit or insurance benefits. However, these programs have limited public awareness, the application process can be cumbersome, and the benefits offered are not always sufficient.10 In addition to increasing public awareness about existing financial programs supporting caregivers, another option to consider would be offering a means-tested income support (i.e., caregiver allowance) for caregivers who face financial burden. For example, Nova Scotia’s Caregiver Benefit Program targets lower-income caregivers with a high-level of disability. Eligible caregivers receive $400 per month through the program.11 However, little to no evidence has been published on this financial strategy, so its effects are unclear.7

over 65 being almost twice as likely to live alone compared to men (31.5% vs. 16.0%). Living alone negatively impacts health outcomes in both men and women.13 For example, a study following 44,573 participants over four years found that living alone was associated with significantly higher mortality between the ages of 45 to 80 years.14 Moreover, single older women were found to be more likely to experience financial challenges, with data indicating that 17% of women over 65 were low-income compared to 12% for men in the same age group.15 Addressing the financial stability of single older women could involve a re-evaluation of the Guaranteed Income Supplement program payments (i.e., non-taxable benefit), which provide an allowance to low-income seniors. Alternatively, the Ontario health system and its sub-regions could consider policies or programs that target other negative consequences of living alone. For example, a medium-quality systematic review identified that social activities and groups where older adults were active participants are effective for decreasing the negative aspects of social isolation.16 This may be a viable option, given that the Ontario government has emphasized the importance of civic engagement for older adults.17

1. Poverty and social determinants [Internet]. 2017 [cited 2017 Jan 19]. Available from: http://www.euro.who.int/en/health-topics/ environment-and-health/urban-health/activities/poverty-and-social-determinants 2. Walker K. Historical perspectives on economic crises and health. Hist J. 2010;53(02):477–94. 3. Employment and Social Development Canada. Canada News Centre - The Government of Canada announces the Tackling Poverty Together Project [Internet]. 09:19:00.0 [cited 2017 Jan 19]. Available from: http://news. gc.ca/web/article-en.do?nid=1119579 4. Public Health Agency of Canada Government of Canada. What Makes Canadians Healthy or Unhealthy? - Population Health Approach - Public Health Agency of Canada [Internet]. 2001 [cited 2017 Feb 3]. Available from: http://www.phac-aspc.gc.ca/ph-sp/determinants/determinants-eng.php 5. Gender Wage Gap Strategy Steering Committee. Final Report and Recommendations of the Gender Wage Gap Strategy Steering Committee [Internet]. 2016 Jun [cited 2017 Feb 3]. (Prepared for Minister of Labour and the Minister Responsible for Women’s Issues). Available from: https://files. ontario.ca/7198_mol_gwg_finalreport_eng_ wa_08f_v2_1.pdf 6. Shimmin C. Backgrounder: The impact of poverty on health | Evidence Network [Internet]. 2015 [cited 2017 Feb 3]. Available from: http://evidencenetwork.ca/archives/24642 7. Wilson M, Gauvin F, Plog J. Citizen Brief: Improving Care and Support for Unpaid Caregivers in Ontario. [Internet]. Hamilton, Ontario: McMaster Health Forum; 2014 Nov [cited 2017 Jan 8]. Available from: https:// www.mcmasterhealthforum.org/docs/defaultsource/Product-Documents/citizen-briefs/ support-for-unpaid-caregivers-in-ontario-cb. pdf?sfvrsn=2 8. The Change Foundation. A Profile of Family Caregivers in Ontario [Internet]. Toronto: The Change Foundation; 2016 [cited 2017 Jan 7]. Available from: http://www.changefoundation.ca/profile-of-family-caregiversontario/ 9. Service Canada. Canada Pension Plan - Overview [Internet]. 2015 [cited 2017 Jan 8]. Available from: https://www.canada.ca/en/ services/benefits/publicpensions/cpp.html 10. Williams A, Crooks V, Giesbrecht M, Dykeman S. Evaluating Canada’s Compassionate Care Benefit: from the perspective of family caregivers [Internet]. Hamilton, Ontario: McMaster University; 2010 [cited 2017 Jan 8]. Available from: http://www.mcmaster.ca/ mihe/documents/CCB/CCB_Final_Report. pdf 11. Caregiver Benefit | novascotia.ca [Internet]. [cited 2017 Jan 8]. Available from: http:// novascotia.ca/dhw/ccs/caregiver-benefit.asp 12. Government of Canada SC. Life expectancy, at birth and at age 65, by sex and by province and territory [Internet]. 2012 [cited 2017 Jan 8]. Available from: http://www.statcan. gc.ca/tables-tableaux/sum-som/l01/cst01/ health72a-eng.htm 13. Statistics Canada. Living arrangements of seniors [Internet]. [cited 2016 Dec 10]. Available from: https://www12.statcan.gc.ca/ census-recensement/2011/as-sa/98-312x/98-312-x2011003_4-eng.cfm 14. Udell JA, Steg PG, Scirica BM, Smith SC, Ohman EM, Eagle KA, et al. Living Alone and Cardiovascular Risk in Outpatients at Risk of or With Atherothrombosis. Arch Intern Med. 2012 Jul 23;172(14):1086–95. 15. Statistics Canada. Senior Women [Internet]. [cited 2017 Jan 8]. Available from: http://www.statcan.gc.ca/pub/89503-x/2010001/article/11441-eng. htm#a11 16. Dickens AP, Richards SH, Greaves CJ, Campbell JL. Interventions targeting social isolation in older people: a systematic review. BMC Public Health. 2011;11:647. 17. The Ontario Seniors’ Secretariat. Ontario’s Action Plan for Seniors [Internet]. Toronto: Queen’s Printer for Ontario; 2013 [cited 2016 Dec 10]. Available from: http://www. oacao.org/images/ontarioseniorsactionplanen.pdf

ABSTRACTS investigating paopa, a new potential antipsychotic for the treatment of schizophrenia: an in vivo microdialysis study OMAR SHAWAF1 McMaster Integrative Neuroscience Discovery & Study (MiNDS) Program

tableabstracts of contents

Schizophrenia is a mental disorder that affects approximately 1% of the global population. The disorder is largely characterized into three main symptom groups: positive, negative, and cognitive. Conventional antipsychotic drugs (APDs) act as dopamine D2 receptor antagonists that compete with endogenous dopamine at the orthosteric binding site, thereby attempting to attenuate psychotic symptoms marked by striatal hyperdopaminergic signaling. Unfortunately, APDs are associated with adverse motor and metabolic side effects. In order to circumvent the challenges posed by the evolutionarily conserved nature of orthosteric sites when creating highly selective D2 receptor ligands, selective positive allosteric modulators (PAMs) are used. PAOPA, in addition to attenuating behavioural abnormalities in preclinical amphetamineinduced animal models of schizophrenia, has proven to be the most potent positive allosteric modulator of the dopamine D2 receptor. However, the

mechanism through which PAOPA mediates its effects remains unclear. Three groups (n=14; n=3-5/group) of male Sprague Dawley rats received subcutaneous injections of d-amphetamine (1 mg/kg) following a 0.9% saline (1 mL/kg) or PAOPA (1 mg/kg) pre-treatment. Following treatment, in vivo striatal dialysate samples were collected using microdialysis to assess whether the behavioural changes measured in the locomotor test were associated with changes in dopamine levels. Interestingly, PAOPA pretreatment attenuated the amphetamine-induced locomotor hyperactivity, confirming previous results which suggest D2 receptor internalization. PAOPA also reduced striatal dopamine dialysate levels overall, but not at the 20 or 40 minute interval. PAOPA treatment alone had no effect. This study presents further avenues of exploration for the potential development of PAOPA as a novel APD.

LPS-Induced Blood-Brain Barrier Disruption: Assessing Lithium’s Molecular and Therapeutic Effects Aaron Edward1; Jay Patel2; Ritesh Daya2; Benicio Frey2,3,4; Ram Mishra2,3 Molecular Biology and Genetics Co-op Program, McMaster University; 2McMaster Integrative Neuroscience Discovery & Study (MiNDS) Program; 3Department of Psychiatry & Behavioural Neurosciences, McMaster University; 4Mood Disorders Program and Women’s Health Concerns Clinic, St. Joseph’s Hospital Hamilton

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Bipolar disorder (BD) is a chronic and severely debilitating psychiatric illness that affects approximately 2% of the world population. While lithium compounds remain the hallmark mood-stabilizing agent for the treatment of BD, their exact mechanism of action is unknown. There is growing evidence suggesting that the inflammation of the blood-brain barrier (BBB), combined with the passage of pro-inflammatory cytokines into the central nervous system, is a contributing factor to the pathophysiology of a number of neuropsychiatric diseases, including BD. However, in the case of BD, the role of inflammation remains understudied. We tested lithium’s ability to prevent inflammatory disruption in the BBB, implicating the role of inflammation in the pathophysiology of BD. In our study, we assessed if chronic pre-treatment with lithium was able to prevent BBB disruption in the Sprague Dawley rat. Lipopolysaccharide (LPS) was administered to induce an inflammatory response and subsequently disrupt the BBB 24

hours before sacrifice. Intravenous administration of sodium fluorescein (NF) was used to quantify the degree of BBB disruption. The results were compared to a group of sham-injected rats. Western blot analysis will also be completed on the tight junction proteins occludin and claudin-V to assess changes in BBB integrity. Through the NF assays, we were able to demonstrate that lithium partially prevents BBB disruption in several brain regions – including the prefrontal cortex, cortex, and striatum – and whole brain samples, as compared to LPS-only negative controls. The results suggest that lithium may have a therapeutic action in an animal model of BBB disruption. Our novel approach to studying BD through inflammation of the BBB will open new avenues for understanding BD’s pathophysiology and will advance our understanding of lithium’s therapeutic moodstabilizing properties.

spatiotemporal expression of autism-related and fmrp target genes in the fmr1 knock out mouse model Daiana Pogacean1; katerina liaconis1; jonathan lai1; jane A. foster1 Department of Psychiatry and Behavioural Neuroscience, St. Joseph’s Healthcare

Syndrome as this serves as a gateway into understanding the complexity and heterogeneity of ASD. Using in situ hybridization, three genes are examined for their spatiotemporal expression across the hippocampus and somatosensory cortex (S1) brain regions. All samples were collected from wild type (WT) and fragile X mice during postnatal development. Target genes were selected to meet the following two criteria: 1) identified gene variants in ASD individuals and 2) known FMR1 protein targets. Significant differences were observed in PTEN mRNA between WT and fragile X mice at postnatal day 21 in both the S1 and dentate gyrus brain regions. No significant differences were found between WT and fragile X mice for CHD8 and SYNGAP1 mRNA. This approach will further the ongoing analysis of the underlying biological basis of ASD, which is necessary for optimizing therapeutics in the future.

introduction abstracts

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by impaired social communication and repetitive behaviours. The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) defines ASD as an umbrella term for the following four separate disorders: autistic disorder, Asperger disorder, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified. Currently, there is no empirical biological method to diagnose ASD patients. While advances have been made in understanding ASD, development of new treatments is limited. Fragile X Syndrome (FXS) has become pertinent to elucidating a biological understanding of ASD. FXS is the most common heritable single gene cause of ASD, and is caused by 200 or more CGG trinucleotide repeats in the Fragile X Mental Retardation 1 (FMR1) gene, which silences the function of the gene through epigenetic mechanisms. This thesis aims to identify the neurobiological underpinnings of Fragile X

mommy monitor: the development of a mobile app to reduce the adverse maternal health experiences of immigrant women in canada Elsie amoako1; Aisha Lofters1,2 Institute of Health Policy, Management, and Evaluation, University of Toronto; 2MD/Ph.D Program

Methods: Qualitative, ethnographic, one-on-one semi-structured interviews were utilized to conduct a thematic analysis of participants’ perspectives. Results: The participants acknowledged the presence of prenatal care and services being provided by the healthcare system, though the majority did not attend prenatal classes. The immigrant women discussed a need for larger social support networks during and after pregnancy, as well as healthcare professionals who take initiative to understand their cultural

values and needs on an individual level. The participants highly preferred midwifery as a form of prenatal care, and were not concerned with receiving competent care, but rather cultural sensitivity, relying on personal cultural networks. Conclusion: Based on these findings, four final recommendations were made to provide a platform for the enhancement of prenatal care and services to reflect the needs of the immigrant women population. A mobile health application is being developed as a method of translating the knowledge produced through this study. Phase two of the study includes the development of the “Mommy Monitor” app in a mixed methods study which can be used by pregnant immigrant women in Canada. This app seeks to enhance surveillance, provide social networking access, peer counsellor support, as well as deliver a guideline for healthcare professionals to aid in implementing culturally sensitive healthcare.

m e d u cato r | A p r i l 2015 m e d u c a t o r | S P RING 2 0 1 7

Introduction: Research continues to show that immigrant women experience poorer birth outcomes compared to non-immigrant women in Canada. The main objectives of this study were to 1) explore the experiences of immigrant women with prenatal care, 2) determine the perceived relevance of topics taught in generic prenatal classes to immigrant women and 3) discuss the interplay between culture, perceived relevance, and use of prenatal care by immigrant women.

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FKBP5 GENETICS & THE STRESS RESPONSE AUTHORS: Takhliq Amir, Owen Luo ARTIST: Cathy Lu

Pathoprofile

INTRODUCTION Stress, generally defined as mental or emotional strain, primarily involves the hypothalamic-pituitary-adrenal (HPA) axis.1,2 In this process, hypothalamic neurons release corticotropin-releasing hormone, which indirectly leads to the secretion of glucocorticoids, such as cortisol, into the bloodstream.3-5 Circulating glucocorticoids act on receptors throughout the body, including the intracellular glucocorticoid receptor (GR).v The GR participates in a negative feedback loop with FK506 binding protein 51, or FKBP5, a co-chaperone protein that inhibits GR signalling in response to stress.3,5,6 This has significant implications for health and disease.

FKBP5-MEDIATED PATHWAY OF STRESS Hypothalamus

FKBP5 regulates GR sensitivity by binding to co-chaperone proteins of the receptor, lowering GR glucocorticoid-binding affinity and attenuating GR transcriptional activity.3,6 Upon glucocorticoid binding, FKBP5 is replaced by FK506-binding protein 52 (FKBP52/FKBP4), a co-chaperone protein with opposing functions.3 The GR controls FKBP5 gene transcription by 1) forming a homodimer that binds to glucocorticoid response element (GRE) sequences in introns of the FKBP5 gene, and 2) interacting as a monomer with other transcription factors.4 Thus, glucocorticoid release promotes FKBP5 expression, initiating the negative feedback loop and enabling cortisol self-regulation.5

Anterior Pituitary

Corticotropin-releasing hormone

Corticotropin

Glucocorticoids

To target cells

Bloodstream

Adrenal Cortex

REFERENCES 1. Richard S Lazarus and Susan Folkman. Stress, appraisal, and coping. Springer Publishing Company, 1984. 2. McEwen BS, Bowles NP, Gray JD, Hill MN, Hunter RG, Karatsoreos IN, Nasca C. Mechanisms of stress in the brain. Nature Neuroscience. 2015;18(10):1353-63. Available from: https:// www-ncbi-nlm-nih-gov.libaccess.lib.mcmaster.ca/pmc/articles/ PMC4933289/ [Accessed 27th February 2017]. 3. Zannas AS, Wiechmann T, Gassen NC, Binder EB. Gene–stress– epigenetic regulation of FKBP5: clinical and translational implications. Neuropsychopharmacology. 2016;41(1):261-274. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677131/ [Accessed 27th February 2017]. 4. Reul JM, Collins A, Saliba RS, Mifsud KR, Carter SD, GutierrezMecinas M, Qian X, Linthorst AC. Glucocorticoids, epigenetic control and stress resilience. Neurobiology of Stress. 2015;1:44-59. Available from: http://www.sciencedirect.com/science/article/pii/ S2352289514000095 [Accessed 27th February 2017]. 5. Menke A, Klengel T, Rubel J, Brückl T, Pfister H, Lucae S, Uhr M, Holsboer F, Binder EB. Genetic variation in FKBP5 associated with the extent of stress hormone dysregulation in major depression. Genes, Brain and Behavior. 2013;12(3):289-96. Available from: http://onlinelibrary.wiley.com.libaccess.lib.mcmaster.ca/ doi/10.1111/gbb.12026/full [Accessed 27th February 2017]. 6. Lee RS, Tamashiro KL, Yang X, Purcell RH, Huo Y, Rongione M, Potash JB, Wand GS. A measure of glucocorticoid load provided by DNA methylation of Fkbp5 in mice. Psychopharmacology. 2011;218(1):303-12. Available from: https://www.ncbi.nlm.nih. gov/pmc/articles/PMC3918452/ [Accessed 27th February 2017]. 7. Galigniana NM, Ballmer LT, Toneatto J, Erlejman AG, Lagadari M, Galigniana MD. Regulation of the glucocorticoid response to stress-related disorders by the Hsp90-binding immunophilin FKBP51. Journal of Neurochemistry. 2012;122(1):4-18. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1471-

4159.2012.07775.x/full [Accessed 27th February 2017]. 8. Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, Tang Y, Gillespie CF, Heim CM, Nemeroff CB, Schwartz AC. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. Jama. 2008;299(11):1291-305. Available from: 10.1001/ jama.299.11.1291 [Accessed 8th March 2017]. 9. Halldorsdottir T. Evidence Mounting for Gene-by-Environment Interactions at the FKBP5 Locus Predicting Psychiatric Symptoms. Biological Psychiatry. 2016;80(11):e89-91. Available from http:// journals1.scholarsportal.info/pdf/00063223/v80i0011/e89_emfgiatflpps.xml [Accessed 27th February 2017]. 10. Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ. Epigenetic programming by maternal behavior. Nature Neuroscience. 2004;7(8):847-54. Available from: 10.1038/nn1276 [Accessed 8th March 2017]. 11. Turecki G, Meaney MJ. Effects of the social environment and stress on glucocorticoid receptor gene methylation: a systematic review. Biological Psychiatry. 2016;79(2):87-96. Available from: http://dx.doi.org.libaccess.lib.mcmaster.ca/10.1016/j.biopsych.2014.11.022 [Accessed 27th February 2017]. 12. Hartmann J, Wagner KV, Liebl C, Scharf SH, Wang XD, Wolf M, Hausch F, Rein T, Schmidt U, Touma C, Cheung-Flynn J. The involvement of FK506-binding protein 51 (FKBP5) in the behavioral and

neuroendocrine effects of chronic social defeat stress. Neuropharmacology. 2012;62(1):332-9. Available from: http://www.sciencedirect.com/science/article/pii/S0028390811003297 [Accessed 1st Mar 2017] 13. Gaali S, Gopalakrishnan R, Wang Y, Kozany C, Hausch F. The chemical biology of immunophilin ligands. Current Medicinal Chemistry. 2011;18(35):5355-79. Available from: http://www.ingentaconnect.com/content/ben/cmc/2011/00000018/00000035/ art00004 [Accessed 1st Mar 2017] 14. Blackburn EA, Walkinshaw MD. Targeting FKBP isoforms with small-molecule ligands. Current Opinion in Pharmacology. 2011;11(4):365-71. Available from: http://www.sciencedirect. com/science/article/pii/S1471489211000592 [Accessed 2nd Mar 2017] 15. Gaali S, Kirschner A, Cuboni S, Hartmann J, Kozany C, Balsevich G, Namendorf C, Fernandez-Vizarra P, Sippel C, Zannas AS, Draenert R. Selective inhibitors of the FK506-binding protein 51 by induced fit. Nature Chemical Biology. 2015;11(1):33-7. Available from: http://www.nature.com/nchembio/journal/v11/n1/full/nch embio.1699.html [Accessed 2nd Mar 2017]

Glucocorticoids

GR Homodimer

FKBP5

Glucocorticoid Receptor (GR)

FKBP5

FKBP5 Nucleus GR

GR Negative Feedback

FKBP5 HSP90 FKBP5 HSP70

GR Glucocorticoid Response Elements

Fkbp5 and other GR targets

functional GRE is associated with enhanced FKBP5 transcription and subsequent GR resistance.3,6 This leads to further disinhibition of FKBP5 transcriptional regulation.3

CLINICAL IMPLICATIONS UPSTREAM FACTORS OF FKBP5 Chronic stress leads to elevated glucocorticoid levels. Gene-interaction studies have demonstrated that alleles associated with higher FKBP5 expression induce prolonged cortisol response and increase the risk of stress-related psychiatric disorders following trauma.3,6 FKBP5 polymorphisms disrupt HPA axis activity and thus the glucocorticoid negative feedback loop, causing variable susceptibility to major depressive disorder (MDD), bipolar disorder, post-traumatic stress disorder (PTSD), and increased suicide risk.5,6,7 A large crosssectional study observed associations between four single nucleotide polymorphisms (SNPs) within the FKBP5 gene and the severity of child abuse as a predictor of adult PTSD symptoms.8 One of the most commonly described polymorphisms is rs1360780 in intron 2 of FKBP5.5 In particular, the rs1360780 T allele upregulates FKBP5 mRNA expression, inducing excessive GR activation. This causes GR resistance and an extended cortisol response to stressors in healthy carriers.5,6,9 The variable effects of these polymorphisms contributes to the broad spectrum in the magnitude of HPA axis disruption in patients suffering from disorders such as MDD and PTSD.5 Additionally, epigenetic modifications regulate the glucocorticoid regulation pathway through the GR and FKBP5 genes.10 In particular, maternal behaviour, considered a protective influence on stressors and their appraisal, has been found in rodents to influence hippocampal GR expression in the offspring.10 Specifically, nurturing maternal behaviour induces long-lasting epigenetic alterations, such as decreased methylation upstream of the gene encoding the GR, reducing stress reactivity.10 Conversely, evidence has shown that DNA methylation of the FKBP5 gene increases stress susceptibility.11 In rs1360780 T allele carriers, demethylation in intron 7 of the

FKBP5 disinhibition is pathologically relevant to the development of psychiatric disease in humans and thus presents a potent therapeutic target.3 Through the use of FKBP5 gene knockouts in animal studies, scientists have elucidated that relative to wild-type controls, FKBP5 knockouts demonstrated increased resilience due to improved stress hormone signalling and stress-coping behaviours.12 These findings have propelled the discovery of efficacious pharmacological agents targeting FKBP5 activity. Previously, most FKBP5 ligands were unselective, with significant off-target interaction with the similar binding sites of homologous FKBP4.13,14 Recently, scientists have elucidated a class of potent and selective FKBP5 inhibitors known as SAFits, which have been found to promote HPA axis regulation and stress-coping behaviors.15 This evidence may potentially inform mechanistically new therapeutics for stress-related psychiatric diseases.

CONCLUSION Though the etiology of psychiatric diseases remains unclear, existing literature supports the role of gene-environment interactions in causing FKBP5 disinhibition and increased vulnerability to neurological illnesses. Excessive stress has long-term consequences for health and disease, particularly in a genetically vulnerable population, thus presenting FKBP5 and glucocorticoid dysregulation as a pertinent therapeutic target.

Newborn Screening and Whole Genome Sequencing:

A Perfect Match or an Emerging Ethical Crisis? ARTIST CATHY REN

ADAM WADE-VALLANCE

ABSTRACT

Canadian newborn screening (NBS) programs are successful in improving the prognosis of many affected neonates with early-onset disorders by enabling rapid diagnosis and treatment. However, many problems still exist with NBS programs including inconsistent coverage across provinces or territories, gaps in disease screening, and variable testing methodologies. Whole-genome sequencing (WGS) represents an increasingly cost-effective means of screening all genetic conditions with a single primary assay. Many benefits of WGS have been cited, including the ability to determine the exact causative mutation of a condition which could enable targeted therapy. Despite this, WGS in NBS carries serious ethical ramifications pertaining to disclosure of results, storage of data, and future development in NBS programs. Due to these factors, we are as-of-yet unprepared to incorporate WGS into Canadian NBS programs.

The expansion of NBS in Canada has spurred initiatives to develop assays which screen for multiple disorders simultaneously.2,3 Despite this advancement, NBS remains sub-optimal, with high false-positive rates requiring cumbersome re-testing and follow-up.6 Furthermore, coverage of disorders in Canadian NBS is disjointed as each province or territory coordinates its own NBS program.7-9 Although these programs are constantly advancing with ongoing studies assessing screening accuracy and benefits, a standardized technique such as whole-genome sequencing (WGS) might streamline the expansion and regulation of NBS.7-9 WGS identifies all six-billion base pairs in the human genome, giving it the capacity to diagnose any genetic disorder.6 In recent history, WGS has assumed a greater role in diagnosis and research due to dramatic cost reductions. The human genome project (1990-2003), developed the first reference sequence and cost a whopping 2.7 billion dollars.10 This cost plummeted to just $4000 in mid-2015, and presently, the cost has dropped down to $1000.3,10,11 Many scientists predict that costs will continue to drop, making WGS in NBS feasible in the future.3,10-11 Bodian et al. investigated the utility of WGS in a cohort of ~1700 neonates and found that WGS-based and conventional NBS diagnosis were highly concurrent.6 Additionally, WGS gave fewer false-positives, resolved inconclusive results, identified causative mutations, and required fewer sample collections from preterm infants.6 In some cases, it even detected nuances distinguishing closely-related conditions indistinguishable by conventional NBS.6 Although findings like these fuel excitement for WGS in NBS, its problem and promise remain one and the same; it would screen all genetic disorders, regardless of any NBS list.3 From this, an ethical quagmire arises that we are not yet prepared to face.3,11,12

m e d u cato r

s p r i n g 2017

opinion

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

Newborn screening (NBS) identifies treatable disorders in neonates through systematic testing.1-3 Upon diagnosis, prompt medical interventions can improve or manage the babyâ&#x20AC;&#x2122;s health.1-3 A disorder can be effectively screened if it is acuteonset, treatable, and has a simple and accurate diagnostic test. These factors have been enshrined in stringent requirements governing the incorporation of additional disorders into NBS programs.1,4,5

14 13

Disclosure of sequencing results represents one serious issue. NBS is designed to uncover actionable findings, whereas WGS would screen everything.4,5,11 For example, Huntingtonâ&#x20AC;&#x2122;s Disease is not screened by conventional NBS because it is not a childhood-onset disorder and lacks effective treatments. WGS, however, would detect the causative mutation. Informed children could mould their priorities to a diminished lifespan and

would be spared a devastating mid-life diagnosis. Yet, if uninformed, they would mature free from this mental burden. Many argue inaction, the status quo in conventional NBS, is preferable.11 This issue is compounded by the fact that WGS would uncover variants of uncertain significance or likely pathogenicity in every neonate, even healthy ones. Informing parents of these variants could cause needless anxiety, and confirming results would be expensive and time-consuming.

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Edited by AVRILYNN DING

Dr. John Waye is a professor in the Department of Pathology and Molecular Medicine at McMaster University and Head of the Molecular Diagnostic Genetics Service at Hamilton Health Sciences. His research program aims to identify relationships between the genotype and phenotype of human genetic disorders and develop statistical approaches to interpret forensic DNA evidence.

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Williams RA, Mamotte CD, Burnett JR. Phenylketonuria: An Inborn Error of Phenylalanine Metabolism. The Clinical Biochemist Reviews. 2008; 29(1): 31-41. Available from: https://www.researchgate.net/profile/Cyril_Mamotte/publication/5289279_Phenylketonuria_an_inborn_error_of_phenylalanine_metabolism/ links/0c960524b51fd67a84000000.pdf Newborn Screening Ontario. Screening History. [Online] Available from: https://www.newbornscreening.on.ca/en/about-screening/ diseases-screened/screening-history. Tarini BA, Goldenberg AJ. Ethical Issues with Newborn Screening in the Genomics Era. Annual Review of Genomics and Human Genetics. 2012; 13: 381-393. Available from:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3625041/ Wilson JMG, Jungner G. Principles and practice of screening for disease. Geneva: WHO; 1968. Available from: http://apps.who.int/ iris/handle/10665/37650 Andermann A, Blancquaert I, Beauchamp S, Déry V. Revisiting Wilson and Jungner in the genomic age: a review of screening criteria over the past 40 years. Bulletin of the World Health Organization. 2008;86(4): 317-319. Available from: http://www.scielosp.org/scielo.php?script=sci_arttext&pid =S0042-96862008000400018 Bodian DL, Klein E, Iyer RK, Wong WS, Kothiyal P, Stauffer D, Huddleston KC, Gaither AD, Remsburg I, Khromykh A, Baker RL. Utility of whole-genome sequencing for detection of newborn screening disorders in a population cohort of 1,696 neonates. Genetics in Medicine. 2015; 18(3): 221-230 Therrell BL, Adams J. Newborn screening in North America. Journal of inherited metabolic disease. 2007; 30(4): 447-65. Therrell BL, Padilla CD, Loeber JG, Kneisser I, Saadallah A, Borrajo GJ, Adams J. Current status of newborn screening worldwide: 2015. Seminars in perinatology. 2015; 39(3): 171-187. Caggana M, Jones EA, Shahied SI, Tanksley S, Hermerath CA, Lubin IM. Newborn screening: from Guthrie to whole genome sequencing. Public Health Reports. 2013; 128(2): 14-19. National Genome Research Institute. The Cost of Sequencing a Human Genome. [Online] Available from: https://www.genome. gov/sequencingcosts/ [Accessed March 4th 2017]. Knoppers BM, Howard H, Cornel M, Wright Clayton E, Sénécal K, Borry P. Whole genome sequencing in newborn screening? A Statement on the continued importance of targeted approaches in newborn screening programmes. European Journal of Human Genetics. 2015; 23, 1593-1600. Available from: https://lirias.kuleuven.be/bitst ream/123456789/472492/1/2014ASHG-NewBornPoster2014.pdf Botkin JR, Rothwell E. Whole Genome Sequencing and Newborn Screening. Current genetic medicine reports. 2016;4(1): 1-6. Available from: http://link.springer.com/article/10.1007/s40142-016-0084-3 Hanley WB. Newborn screening in Canada–Are we out of step? Paediatrics & child health. 2005;10(4): 203. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC2722527/ Andre Picard. Newborn screening: a resounding failure in Canada. Available from: http://www.theglobeandmail.com/ life/health-and-fitness/health/newbornscreening-a-resounding-failure-in-canada/ article18067921/. The Government of Canada. Canadian Human Rights Act. Available from: http://lawslois.justice.gc.ca/eng/acts/h-6/fulltext.html. Beckmann JS. Can we afford to sequence every newborn baby’s genome? Human mutation. 2015; 36(3): 283-286.

m e d u cato r

Reviewed by Dr. John Waye

opinion

be considered.11 Expansion would worsen existing problems with unclear or false results, leading to unwarranted anxiety and follow-up testing.3,6 Also, diseases screened in Canada are selected against stringent criteria; upholding these values mandates considerable time and work hours.4-5,11 WGS would direct attention towards genetic disorders it could easily screen rather than ones benefiting the babies most. For example, Canadian NBS is insufficient in assessing hearing impairment.13,14 Although a fix is underway, it is possible that disAnother important concern is data storage and us- orders with non-genetic diagnostic methods, like age.11 NBS samples are kept only short-term to hearing impairment, would be overshadowed in a enable re-testing, because babies cannot provide post-WGS world.13,14 WGS must be moulded to informed consent.11-14 Parental consent is either fit NBS, not the other way around. deemed implied or unnecessary, and no Canadian province requires explicit consent.11,13,14 Long- Lastly, the introduction of WGS into NBS proterm data storage, however, does require explicit grams might encourage ethical compromises to consent, as American lawsuits have demonstrat- achieve ‘great’ advancements. Consider the utiled.9 WGS would unearth information relevant to ity of being able to inform patients of high-penadult-onset disorders conditions. This would exac- etrance variants of their increased susceptibility erbate storage issues as there would be medical rea- to atherosclerosis. They might adopt a healthier son to retain information for the baby’s adulthood, lifestyle, extending their lifespan and saving the but no consensual basis to do so. The current ‘don’t government thousands in treatments and surgerask don’t tell’ philosophy would therefore be insuf- ies. Imagine the possibilities for genome-wideficient to inform WGS data management.2-4,12 association studies if 35 million Canadians were available as data points. Science and medicine Furthermore, there exist privacy concerns and the would together advance in leaps and bounds. Such potential for abuse of sequencing results by third momentous projects may have a place in modern parties.11 Insurance corporations that crave knowl- medicine, but not in the current NBS framework.11 edge of a person’s predisposition to disease when NBS is designed around children’s health and is determining life insurance premiums may seek to incompatible with expansion beyond this pure take advantage of such information, and saboteurs purpose.11 We are much further from this sciencould leak sensitive information about their op- tifically and medically utopic future in our ethics ponents. Genetic identity is not protected by the than our technology. This is a gap we must bridge Canadian Human Rights Code, so genetic dis- before seriously considering any such venture. crimination is legal.15 Therefore, legislation similar to Bill S-201 or an amendment to the Cana- Some argue Canadian NBS programs should dian Human Rights Code would need to precede screen more disorders by modernizing technolWGS in NBS to legally safeguard genetic iden- ogy to high-throughput techniques.13 This makes tity.12,15 Finally, it is important to question whether WGS very attractive. It would enable the addition a facility housing the genetic identity of millions of novel disorders to NBS lists in an economical of Canadians could ever be secure enough to exist. manner, albeit after substantial initial investment, and would also provide accurate diagnosis for all Another key question is the expansion of NBS pro- genetic disorders. WGS in NBS remains economgrams to include disorders detectable by WGS.11 ically unviable, but a future with affordable WGS Similarly to how tandem mass spectrometry ren- is approaching.10,16 The costs or benefits of transidered additional biochemical tests cheap after its tioning to genomic sequencing is irrelevant until initial cost, WGS would render testing costs for the associated ethical conundrums are reconciled genetic disorders negligible beyond the cost of so that the integrity of NBS is maintained in the performing the sequencing.11,12 This attribute face of WGS. ■ means WGS would be most cost-effective if many new disorders were screened.11,13 Although this seems intuitive, more factors than finance must

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Lifting the Price on Human Life: How Nonfinancial Donor Compensation Could Eradicate the Organ Trade

Compensation Enhances Health Outcomes,

Edward Li Bachelor of Health Sciences (Honours), Class of 2020 McMaster University Correspondence: lie6@mcmaster.ca

opinion

ABSTRACT

The increasing number of patients in need of organ transplantation has fostered the growth of an international black market in which the wealthy purchase kidneys, liver, or other tissue from vulnerable persons. Oftentimes, victims endure substandard care and are forced to consent to lifethreatening procedures for little to no compensation. Since voluntary donation alone is unable to reconcile supply with demand, more economically developed countries have begun to experiment with reimbursing donors for incurred expenses and creating procedural barriers for those who would prefer to opt out of post-mortem donation.1 However, poverty can be equally as problematic as the shortage of organs itself. In this regard, the ideal solution should eliminate the initial need for people to donate out of desperation. After relating the organ trade to issues of substandard care and criminal exploitation, it becomes evident that nonfinancial donor compensation, in the form of housing, tuition, insurance, or employment, could be an effective means of suppressing the illegal organ market and restoring basic rights to disadvantaged donors. INTRODUCTION

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S P RING 2 0 1 7

Among the legislatures of more economically developed countries, it is difficult to conceive of non-directed organ donation as anything other than an anonymous act of altruism. Advancements in medical science, particularly in relation to tissue rejection, have increased the accessibility of transplantation and the demand for organs worldwide.2 The practice has since expanded from altruistic arrangements to multinational, profitdriven transactions in which waitlisted patients from wealthy nations purchase organs from the impoverished. Due to the gap between supply and demand, it is not uncommon for countries such as the United States to accumulate twice as many patients as there are consenting donors and witness 22 waitlisted patient die each day (see Figure 1).3

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To address the global organ shortage crisis, a plethora of policies have been offered for debate, ranging from financial incentivization to presumed consent for post-mortem donation. Notably, in the Iranian system of paid kidney donation, 84% of donors fall below the poverty threshold.2 Additionally, the European model of presumed consent has failed to increase its procurement of living-donor organs, the most soughtafter commodity in transplant medicine.2 Thus, in lieu of the aforementioned schemes, this paper argues that nonfinancial donor compensation represents the most equitable and effective solution to the problems of substandard care, socioeconomic exploitation, and criminal activity underlying the organ trade. ARTIST CANDY NIU

Although transplantation surgery can result in significant complications, including blood clots, infection, and organ failure, these risks can be carefully weighed and mitigated in a regulated infrastructure where patient health is prioritized over potential profit. Instead, organ traffickers regularly condone substandard medical procedures that are dangerous to both donors and recipients. For this reason, waitlisted patients who gamble on the foreign organ trade are more likely to contract postoperative HIV or hepatitis B and C.5 Those who receive government compensation for publicly regulated organ donation would no longer have to endure covert medical malpractice in an effort to conceal illegal activity. Furthermore, an incentivized donation system could damage the integrity of informed consent if the idea of a financial reward inhibits potential donors from fully considering the risks of surgery and the burden of recovery. This effect would be most pronounced among the poorest participants, to whom financial compensation could seem irrefutable and, therefore, exploitative in nature. Accordingly, paid kidney donation is associated with depression, dissatisfaction, and discrimination.5

Alleviates the Financial Burden of Donation,

Limits Socioeconomic Exploitation,

Among impoverished countries, altruism, the conventional incentive for organ donation, can easily be substituted with threats of violence, sexual abuse, and other measures of coercion. On one hand, offering direct monetary payment in exchange for a kidney or liver could encourage potential donors in impoverished countries to pursue organ donation through a legally mandated route, stifling the supply of patrons who sustain the criminal trade. On the other hand, the external motivation provided by financial incentives could lower the perceived praiseworthiness of organ donation and ‘crowd out’ the intrinsic motivation upholding existing altruistic donors.9 The threat of financial incentives arousing disgust and medical mistrust is especially problematic given that affective attitudes were shown to be more powerful predictors of the decision to donate than cognitive factors.10 It follows that, in an interview study involving 155 next-of-kin, 6% of donor families stated that they would have withheld their consent if an incentive had been offered.11 Alternatively, the poverty-alleviating and crime-reducing dimensions of a nonfinancial donor compensation system would yield a certain ethical appeal over the moral suspicion elicited by the concept of organ commodification, restoring credibility to the concept of altruistic organ donation.

Edited by DEEKSHA KUNDAPUR

This article was reviewed by Dr. Arthur Matas, a transplant surgeon from the University of Minnesota. His research interests include: increasing access to transplantation, long-term living donor outcomes, and improving outcomes for transplant recipients.

Allen MB, Reese PP. Financial incentives for living kidney donation: ethics and evidence. Clin J Am Soc Nephrol 2013;8(12): 2031–2033. Available from: doi: 10.2215/ CJN.09820913 [Accessed 15th Jan 2017]. 2. Ghods AJ and Savaj S. Iranian model of paid and living-unrelated kidney donation. Clin J Am Soc Nephrol 2006;1(6): 1136-1145. Available from: doi: 10.2215/ CJN.00700206 [Accessed 23rd Feb 2017]. 3. Organ Procurement and Transplantation Network. U.S. Department of Health and HumanServices. Available from: https://optn.transplant.hrsa.gov/. [Accessed 23rd Feb 2017]. 4. Conzen KD, Doyle MBM, Chapman WC. Orthotopic liver transplantation. In: Jarnagin WR et al., editors. Blumgart’s surgery of the liver, biliary tract, and pancreas. Vol 1. 5th ed. Philadelphia: Elsevier Saunders; 2012. Figure 98A.1, Data from the Scientific Registry of Transplant Recipients (SRTR), 2009 OPTN/ SRTR Annual Report; 1722. 5. Shimazono Y. The state of the international organ trade: a provisional picture based on integration of available information. Bull World Health Organ 2007;85(12): 901-980. Available from: doi: 10.2471/BLT.06.039370. [Accessed 14th Jan 2017]. 6. United Nations Global Initiative to Fight Human Trafficking. Trafficking for organ trade. 2017. Available from: http://www.ungift. org/knowledgehub/en/about/trafficking-fororgan-trade.html. [Accessed 23rd Feb 2017]. 7. Naqvi SAA, Ali B, Mazhar F, Zafar MN, Rizvi SAH. A socioeconomic survey of kidney vendors in Pakistan. Transpl Int 2007; 20(11): 934-939. Available from: doi: 10.1111/j.1432-2277.2007.00529.x. [Accessed 16th Jan 2017]. 8. Ritter P. Legalizing the organ trade? Time 2008. Available from: http:// c o nt e nt . t i m e . c o m / t i m e/ w o r l d /a r t i cle/0,8599,1833858,00.html. [Accessed 21st Jan 2017]. 9. Promberger M, Marteau TM. When do financial incentives reduce intrinsic motivation? Comparing behaviours studied in psychological and economic literatures. Health Psychol 2013;32(9): 950-957. Available from: doi: 10.1037/a0032727. [Accessed 4th Mar 2017]. 10. Morgan SE, Stephenson MT, Harrison TR, Afifi WA, Long SD. Facts versus ‘feelings’: how rational is the decision to become an organ donor? J Health Psychol 2008;13(5): 644-58. Available from: doi: 10.1177/1359105308090936. [Accessed 5th Mar 2017]. 11. Falomir-Pichastor JM, Berent JA, Pereira A. Social psychological factors of post-mortem organ donation: a theoretical review of determinants and promotion strategies. Health Psychol Rev 2013;7(2): 202-247. Available from: doi: 10.1080/17437199.2011.570516 [Accessed 5th Mar 2017].

| S P RING 2 0 1 7

Reviewed by Dr. Arthur Matas

m e d u cato r

The current state of the organ trade gives the Conclusion wealthy preferential access to an extended life via exploitation of vulnerable populations, resembling a scaled-down version of modern slavery based So long as demand exceeds supply, the exchange on socioeconomic disparities. Of the people who of human organs, if not the gift of human life, contribute organs to Pakistan’s for-profit organ will persist in one form or another, whether market, two thirds are migrants, nearly 70% are it be illegal, authorized, or incentivized. As slaves or bonded labourers, and 90% are illiterate.7 medical researchers investigate the role of An institutionalized donor compensation system genetic engineering and three-dimensional could both increase the supply of transplantable printing in creating alternative sources of organs and reduce the population of vulnerable transplantable organs, policymakers are persons by offering social support as an incentive continually experimenting with new strategies for donation. Although legalization may produce for promoting organ donation. Aside from a noticeable increase in organ availability, the strictly increasing the availability of organ donors, poorest and neediest who depend on public however, a nonfinancial compensation system healthcare could become permanently affixed to offers a distinctive means of alleviating poverty, the transplant waitlist. To Professor A. Vathsala, restricting exploitation, and restoring confidence director of the renal transplantation program at in altruistic organ donation within impoverished Singapore’s National University Hospital, “such countries. Under this model, unearthing the payment institutionalizes the belief that the underground organ trade would be analogous to wealthy ill have property rights to the body parts lifting the price on basic human rights. ■ of the poor”.8

FIGURE 1: Supply-Demand Disparities in Liver Transplantation, United States, 1999-2008.4 Despite efforts by the Organ Procurement and Transplantation Network to increase the rate of kidney and liver donation in the United States, the number of deceased and living liver donors has remained relatively constant over a ten-year period, resulting in a persistent gap between the supply of transplantable organs and the number of patients on the national liver transplant waiting list.

opinion

As the demand for organs continues to rise, a growing minority of waitlisted patients from Canada, Europe, Israel, and the United States are offering their money to potential sellers from the poorest slums of the world – individuals who are willing to sacrifice a kidney for as little as $1000 in compensation.5 Moreover, the lasting economic benefit for donors is limited at best due to postoperative employment disability and the perceived deterioration of their health. In fact, when traffickers employ coercion, breech a mutually agreed upon contract, or harvest organs from patients who consented to unrelated surgical procedures, victims may receive no monetary compensation whatsoever.6 A nonfinancial donor compensation system would reroute undue profits from traffickers to impoverished donors in the form of employment training, low-income housing, tuition, health insurance, or provision of a government job. The advantage of nonfinancial incentives over direct monetary payment is not merely symbolic, as it provides binding assurance that government spending will be converted into socially responsible investments poised to raise the standard of living for its constituents.

and Reinstates Altruistic Donation.

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ARTIST KELSIE OU

ARTIST MICHAEL SUN

CRITICAL REVIEW

Regulatory T Cells in Allergic Asthma

mobeen mubasher1 Bachelor of Health Sciences (Honours) Program, Class of 2018, McMaster University Correspondence: mubasm3@mcmaster.ca

allergic asthma

Regulatory T cells

T cells play an active role in cellmediated immunity, an adaptive process of developing antigen (Ag)specific T cells to eliminate viral, bacterial, or parasitic infections or malignant cells.6 Before mature T cells gain a highly specialized function, they arise from pluripotent hematopoietic stem cells within the bone marrow and undergo lineage commitment based on stress signals.6 Upon maturation, these cells, now known as naive T cells, circulate within the blood and do not become activated until foreign antigenic peptides come in contact with professional APCs such as dendritic cells (DCs), B cells and macrophages.6 Upon activation, T cells will differentiate in an antigen-specific manner, and then proliferate and migrate to sites of inflammation. Many different subtypes of T cells exist, each with specialized roles in the body (Figure 1).6 Regulatory T cells (Tregs) are a class of CD4+ T cells (T-helper cells), which do not directly kill infected cells but activate cytotoxic cells to attack infected cells or stimulate B cells to secrete antibodies. Tregs play a key role in asthma but also aid in the maintenance of peripheral tolerance, modulation of immune responses and prevention of autoimmune diseases.7 Although the role of Tregs is still not yet well understood, a review by Corthay et al. has outlined a framework of their major functions. These roles include the prevention of autoimmune and immunopathological diseasesâ&#x20AC;&#x201D;by establishing and maintaining immunologic self-toleranceâ&#x20AC;&#x201D;as well as the induction of maternal tolerance to the fetus and regulation of other immune effectors and T cells.7

regulatory t cells in allergic asthma Multiple interactions between leukocytes and stromal lung cells are central to the process of homeostatic pulmonary regulation which

m e d u cato r | A p r i l 2015 m e d u cato r | s p r i n g 2017

According to Statistics Canada (2014), over 2.4 million Canadians aged 12 and older have been diagnosed with asthma.1 Currently, it is thought that asthma is responsible for over 250,000 deaths annually and billions of dollars in healthcare expenditure, through both direct medical costs and indirect losses in labour productivity.1,2 Asthma is a highly heterogeneous disease as its clinical presentation and immunological profile can vary substantially among those diagnosed.3 There are many possible phenotypes of asthma such as allergic asthma, which is typically characterized by long term inflammation of the airways in response to inhaled substances, known as allergens.3 Allergens such as pet dander, dust and mold, can cause difficulties in breathing and lead to a combination of hallmark symptoms such as bronchoconstriction, eosinophilia, airway remodeling, and airway hyper-responsiveness (AHR).4 Diagnosis of allergic asthma requires demonstration of elevated serum immunoglobulin E (IgE) antibody levels as well as a positive skin-prick test, which identifies reactions to allergens.5 Challenging subjects with inhaled allergen to which they have been sensitized, induces immediate release of

bronchoconstriction mediators from airway mast cells and basophils.

critical review

T regulatory cells (Tregs) are a subset of T cell leukocytes that play a key role in modulating the immune system, maintaining tolerance to self-antigens and suppressing excessive immune responses that go on to harm the host. Much like T helper (Th) cells, Tregs belong to a broader class of CD4+ T cells that develop from pluripotent hematopoietic stems cells in the bone marrow and mature in the thymus. Within the context of allergic asthma, Tregs are central to the process of pulmonary regulation by continuously combatting both immunogenic and harmless antigens. By releasing cytokines such as IL-10 and TGF-Ă&#x;, Tregs modulate the inflammatory Th2-type immune response which, when dysregulated can drive asthma development as well as the hallmark asthmatic signs- airway hyperresponsiveness, bronchoconstriction, and gland hyperplasia/ hypersecretion. This review will explore the function of Tregs as well as their modulatory role within allergic asthma.

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Cortex Cortex

critical review

continuously combat both immunogenic inflammatory cytokine that is central in this and harmless antigens.8 Both structural and process.8 Tregs such as CD25+Foxp3+ Treg cells Tregs take part in a major pathway proposed are not the only cells that secrete IL-10; CD8+ to contribute to airway immunity.8 Although, T cells, and CD4+ T helper cells (Th) cell other immunological cells have shown population, namely Th1 cells, Th2 cells, and regulatory potential, this paper will discuss Th17 cells do so as well.10 An abundance of Tregs and their ability to regulate and suppress studies have proposed a protective role of ILimmune activity in the lungs.9 10 in respiratory homeostasis.10 Secretion of IL-10 by innate immune and antigen-specific A study by Goswami et al. demonstrated that T-cells, such as IL-10 secreting type 1 Treg airway epithelial cells can initiate an immune (Tr1) cells have shown to limit inflammation FIGURE 1: and pathology in response to viral and bacterial Differentiation of T-cells within the response upon exposure to peptide-breaking thymus. Committed lymphoid pro- enzymes such as Retinal dehydrogenase pathogens by inhibiting Th1 response.11 genitors arise in the bone marrow 1 (RALDH-1), a retinoic acid producing migrate to the thymus. Early committed T cells lack expression of enzyme that promotes development of While IL-10 has a clear role in inflammation T-cell receptor (TCR), CD4 and CD8, immunosuppressive Tregs.9 Since RALDH-1 resolution, TGF-Î˛ is known to both initiate and are termed double-negative. is regulated by epithelial-derived matrix acute airway remodeling when induced Through a series of developments, by Th2 cytokines and initiate resolution these cells gain specific T-Cell re- metalloproteinase-7 (MMP-7), a deficiency ceptors and markers. The process in MMP-7 leads to augmented levels of of inflammation through tissue repair and of positive and negative selection Tregs in the lung and thus, an attenuated remodeling.12 Whether chronic asthma to allow for cells that are not harm9 develops as a result of poor inflammatory ful to self-cells and can success- response to the allergen challenge. A cytokine 13 synthesis inhibitory factor, interleukin 10 resolution or due to aberrant tissue repair fully read MHC. (IL-10), is an anti- response is still being researched, however Haematopoietic Haematopoietic TGF-Î˛ is likely a key mediator.12 Akbari et al precursor precursor (2002) demonstrated that repeated exposure of mice to low-dose allergen promoted the development of a Treg population that expressed membrane-bound TGF-Î˛.13 The DN2 DN2 DN3 DN3 transfer of these cells to naive mice was shown to prevent allergic sensitization. DN1 DN1 Furthermore, a higher dose of inhaled DN4 DN4 Cortical Cortical allergen stimulated the development epithelial epithelial of a Treg population that secreted cell cell high amounts of IL-10.13 Inadequate Inadequate TCR/co-receptor TCR/co-receptor signalling signalling

DP DP

Lymphoid Lymphoid progenitor progenitor

Death Deathbyby neglect neglect CD4-committed CD4-committedDP DP Negative Negative selection selection

Positive Positive selection selection

Medulla Medulla

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CD8-committed CD8-committedDP DP

CD8 CD8+ + SP SP

CD4 CD4+ + SP SP

Emigration Emigrationtotoperiphery periphery

Medullary Medullary epithelialcell/ cell/ Death Death epithelial dendritic dendriticcell cell

Adoptive transfer of CD4+ CD25+ Treg cells, a class of Tregs with CD25+ markers, was shown to suppress allergic inflammation and AHR via a mechanism dependent upon IL-10.8 Importantly, when CD4+ CD25+ Tregs were given to a diseased individual, existing inflammation was downregulated and further airway remodeling was prevented.14 On the other hand, depletion of CD4+CD25+ Tregs before sensitization to allergen was shown to magnify the severity of inflammation and AHR in the lungs.14 Depletion of CD4+25+ Tregs

resulted in increased numbers of airway APCs especially dendritic cells, as demonstrated with higher expression of activation markers, major histocompatibility complex class II, CD80, and CD86 and enhanced potential to promote effector T cell proliferation.8 Collectively, this information suggests that Tregs are implicated in regulation of allergic asthmatic immune symptoms, potentially through secretion of IL10 and TGF-β and by restraining function of APCs such as dendritic cells.8

current treatments

future directions Overall, there is a growing body of evidence suggesting a key role of Tregs in the intricate immunological homeostatic environment of the lung.8 However, a stronger understanding of Treg pathways within lung homeostasis is needed. Evidence of other regulatory cell populations such as IL-10 secreting natural killer (NK) cells, IL-17-producing γδ and NK cells have shown to suppress antigen-specific effector function and may be implicated in pulmonary infections.8,9 Furthermore, studies analyzing antigen-specific Tregs would be beneficial as currently, the exact subtypes and differentiation pathways of Tregs are not elucidated; therefore, studying the interaction between T cell lineage and environment may provide more insight.7,8 Ultimately, further investigation into the developmental and maturation process of Treg cells, as well as their effector functions, will be required. This may provide a better understand the pathobiology of allergic asthma and novel therapeutic management strategies. ■

Reviewed by John-Paul oliveria

Edited by avrilynn ding and arlinda deng 1.

3. 4. 5.

Government of Canada SC. Asthma, 2014 [Internet]. 2015 [cited 2016 Nov 10]. Available from: http://www.statcan.gc.ca/pub/82625-x/2015001/article/14179-eng.htm Okada H, Kuhn C, Feillet H, Bach J-F. The “hygiene hypothesis” for autoimmune and allergic diseases: an update. Clin Exp Immunol. 2010 Apr;160(1):1–9. Holgate ST. Pathogenesis of Asthma. Clin Exp Allergy. 2008 Jun 1;38(6):872–97. Olin JT, Wechsler ME. Asthma: pathogenesis and novel drugs for treatment. BMJ. 2014 Nov 24;349:g5517. O’Byrne PM, Inman MD. Airway Hyperresponsiveness. Chest. 2003 Mar;123(3, Supplement):411S – 416S.

Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma– Summary Report 2007. J Allergy Clin Immunol. 2007 Nov 1;120(5):S94–138. Bousquet J, Clark TJH, Hurd S, Khaltaev N, Lenfant C, O’Byrne P, et al. GINA guidelines on asthma and beyond. Allergy Eur. J. Allergy Clin. Immunol.2007;62:102–12. Chung, K., S. Wenzel, J. Brozek, A. Bush, M. Castro, P. Sterk, I. Adcock, E. Bateman, E. Bel, E. Bleecker, L. Boulet, C. Brightling, P. Chanez, S. Dahlen, R. Djukanovic, U. Frey, M. Gaga, P. Gibson, Q. Hamid, N. Jajour, T. Mauad, R. Sorkness, and W. Teague. 2013. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. European Respiratory Journal 43: 343-373.

Mukherjee AB, Zhang Z. Allergic Asthma: Influence of Genetic and Environmental Factors. J Biol Chem. 2011 Sep 23;286(38):32883–9. 10. Milgrom H, Fick RBJ, Su JQ, Reimann JD, Bush RK, Watrous ML, et al. Treatment of Allergic Asthma with Monoclonal Anti-IgE Antibody. N Engl J Med. 1999 Dec 23;341(26):1966–73. 11. Diamant Z, Gauvreau GM, Cockcroft DW, Boulet L-P, Sterk PJ, de Jongh FHC, et al. Inhaled allergen bronchoprovocation tests. J Allergy Clin Immunol. 2013 Nov;132(5):1045–55.e6. 12. Postma DS, Bleecker ER, Amelung PJ, Holroyd KJ, Xu J, Panhuysen CIM, et al. Genetic Susceptibility to Asthma — Bronchial Hyperresponsiveness Coinherited with a Major Gene for Atopy. N Engl J Med. 1995 Oct 5;333(14):894–900.

m e d u cato r | A p r i l 2015 m e d u cato r | s p r i n g 2017

Mr. John-Paul Oliveria is a PhD candidate in Medical Science at McMaster University, performing research in the cardio-respiratory lab under the supervision of Dr. Gauvreau. His research interests mainly include looking at the role of various B cell subtypes in allergic asthma. As an outstanding graduate student, Oliveria has been awarded both the Graduate Program Outstanding Achievement Award and a Graduate Student Teaching Assistant Excellence Award in May 2016.

13. Broere F, Apasov SG, Sitkovsky MV, Eden W van. A2 T cell subsets and T cell-mediated immunity. In: Nijkamp FP, Parnham MJ, editors. Principles of Immunopharmacology [Internet]. Birkhäuser Basel; 2011 [cited 2016 Nov 10]. p. 15–27. Available from: http://link.springer.com/chapter/10.1007/978-3-0346-0136-8_2 14. Germain RN. T-cell development and the CD4–CD8 lineage decision. Nat Rev Immunol. 2002 May;2(5):309–22. 15. Sharpe AH, Abbas AK. T-Cell Costimulation — Biology, Therapeutic Potential, and Challenges. N Engl J Med. 2006 Sep 7;355(10):973–5. 16. McCoy KD, Le Gros G. The role of CTLA-4 in the regulation of T cell immune responses. Immunol Cell Biol. 1999 Feb;77(1):1–10. 17. Corthay A. How do Regulatory T Cells Work? Scand J Immunol. 2009 Oct;70(4):326–36. 18. Hori S, Nomura T, Sakaguchi S. Control of Regulatory T Cell Development by the Transcription Factor Foxp3. Science. 2003 Feb 14;299(5609):1057– 61. 19. Rudensky AY. Regulatory T Cells and Foxp3. Immunol Rev. 2011 May;241(1):260–8. 20. Tarbell KV, Yamazaki S, Olson K, Toy P, Steinman RM. CD25+ CD4+ T Cells, Expanded with Dendritic Cells Presenting a Single Autoantigenic Peptide, Suppress Autoimmune Diabetes. J Exp Med. 2004 Jun 7;199(11):1467–77. 21. Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J, et al. In Vitro–expanded Antigen-specific Regulatory T Cells Suppress Autoimmune Diabetes. J Exp Med. 2004 Jun 7;199(11):1455–65. 22. Huter EN, Stummvoll GH, DiPaolo RJ, Glass DD, Shevach EM. Cutting Edge: Antigen-specific TGFβ-induced Regulatory T cells Suppress Th17-Mediated Autoimmune Disease. J Immunol Baltim Md 1950. 2008 Dec 15;181(12):8209– 13. 23. Lloyd CM, Hawrylowicz CM. Regulatory T Cells in Asthma. Immunity. 2009;31(3):438–49. 24. Hawrylowicz CM, O’Garra A. Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma. Nat Rev Immunol. 2005 Apr;5(4):271–83. 25. Goswami S, Angkasekwinai P, Shan M, Greenlee KJ, Barranco WT, Polikepahad S, et al. Divergent functions for airway epithelial matrix metalloproteinase 7 and retinoic acid in experimental asthma. Nat Immunol. 2009 May;10(5):496–503. 26. Ito T, Wang Y-H, Duramad O, Hori T, Delespesse GJ, Watanabe N, et al. TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med. 2005 Nov 7;202(9):1213–23. 27. Higgins SC, Lavelle EC, McCann C, Keogh B, McNeela E, Byrne P, et al. TollLike Receptor 4-Mediated Innate IL-10 Activates Antigen-Specific Regulatory T Cells and Confers Resistance to Bordetella pertussis by Inhibiting Inflammatory Pathology. J Immunol. 2003 Sep 15;171(6):3119–27. 28. Akbari O, Freeman GJ, Meyer EH, Greenfield EA, Chang TT, Sharpe AH, et al. Antigen-specific regulatory T cells develop via the ICOS–ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med. 2002 Sep;8(9):1024–32. 29. Lund JM, Hsing L, Pham TT, Rudensky AY. Coordination of Early Protective Immunity to Viral Infection by Regulatory T Cells. Science. 2008;320(5880):1220–4. 30. Zheng Y, Chaudhry A, Kas A, deRoos P, Kim JM, Chu T-T, et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses. Nature. 2009 Mar 19;458(7236):351–6. 31. Kearley J, Barker JE, Robinson DS, Lloyd CM. Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent. J Exp Med. 2005 Dec 5;202(11):1539–47. 32. Ryanna K, Stratigou V, Safinia N, Hawrylowicz C. Regulatory T cells in bronchial asthma. Allergy. 2009;64(3):335– 47. 33. Barrat FJ, Cua DJ, Boonstra A, Richards DF, Crain C, Savelkoul HF, et al. In Vitro Generation of Interleukin 10– producing Regulatory CD4+ T Cells Is Induced by Immunosuppressive Drugs and Inhibited by T Helper Type 1 (Th1)– and Th2-inducing Cytokines. J Exp Med. 2002 Mar 4;195(5):603–16.

critical review

Although the exact function, number of subtypes, and specific mechanisms pertaining to Tregs are currently being investigated, there are several treatments that can ameliorate allergic asthma symptoms by increasing or restoring Treg function.8 Allergen immunotherapy involves administering increasing doses of an allergen to which a client is sensitized in careful clinical conditions in order to increase tolerance to this allergen.8 Immunological studies have shown that immunotherapy can inhibit allergen-specific Th2 cell responses and promote an increased frequency of Treg IL-10-secretion immediately following therapy.9 Other treatments include Vitamin D and corticosteroid administration which have been historically used for controlling symptoms.8 Several studies have demonstrated that glucocorticoid treatment (both inhaled and systemic) correlates with increased IL-10 and Foxp3 gene and and/or protein expression in patients.15 Glucocorticoids, along with the active form of vitamin D, 1α,25dihydroxyvitmain D3, have shown to recruit IL-10-secreting tregs in both mouse models and humans.16 This information collectively

implies that broad-acting drugs such as corticosteroids or vitamin D can maintain, restore, or enhance Treg cell function in asthma through a mediatory capacity.8

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ARTIST DAVID HU

Understanding Shock and Kill A POTENTIAL HIV CURE

CRITICAL REVIEW

Sarah Ge, Parsa Mehraban Far, and Devin Roshan1 Bachelor of Health Sciences (Honours) Program, Class of 2019, McMaster University Correspondence: roshand@mcmaster.ca

The proviral latency of human immunodeficiency virus (HIV) remains a principal obstacle to curing the infection and halting disease pathogenesis. In fact, HIV infection remains incurable due to a long-lived latent reservoir of HIV within the central nervous system (CNS), as well as the most impervious reservoir, CD4+ T cells. This review evaluates “shock and kill” therapy, an emerging curative strategy that targets HIV reservoirs. The novel approach aims to “shock” latently infected cells by inducing HIV viral expression through latency reversing agents (LRA). Upon reactivation, the “kill” method refers to the termination of virus-infected cells by employing strategies involving HIV-specific CD8+ T cells. The potential benefits of purging immune cells of HIV-infected individuals and limiting the size of the latent reservoir must be assessed to advance the “shock and kill” technique.

HIV is a retrovirus whose hallmark replicative strategy employs reverse transcription to convert viral RNA into double-stranded DNA (dsDNA). This process generates a significant number of mutations in HIV, since reverse transcriptase is an error-prone enzyme that lacks a proofreading mechanism. Subsequent integration of the viral DNA into the host cell genome allows HIV to successfully utilize cell machinery to synthesize viral components.1 Assembled viral proteins are then exported via exploitation of the vesicular sorting pathway.2 Accelerated cell destruction and viral proliferation are multifactorial, as virions hijack apoptotic signalling, induce direct cytotoxicity, and initiate atypical immune activation.3

Multiple classes of drugs are administered in ART to target specific stages of HIV pathogenesis; the earliest include nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors.7 Recently, additional classes such as fusion and integrase inhibitors have emerged. Despite its therapeutic benefits, multidrug ART is accompanied by adverse side effects which can lead to chronic illnesses.2 Such conditions include liver toxicity and hypersensitivity syndrome, the latter of which develops due to a rigorous immune response to NRTIs and fusion inhibitors. The profound burdens of the growing HIV epidemic and associated chronic diseases on global health and primary care highlight the need to further investigate existing treatment methods.10

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Notably, HIV can infect both dividing and nondividing cells, such as neuronal glial cells, macrophages, and CD4+ T cells, with CD4+ T cells undergoing the highest rates of HIV infection.1 Hence, the virus is present in a myriad of organs, including the brain, gut, and placenta. Considered to be a part of the hematopoietic system, CD4+ T cells are immune cells that play a critical role in facilitating adaptive immunity.4 In response to an antigen, resting CD4+ T cells activate, proliferate, and differentiate to generate short-

Antiretroviral therapy (ART) employs a combination of ARV drugs that suppress HIV and halt disease progression by inhibiting viral replication.7 Treatment of HIV infection with a combination of three to five ARV drugs is more efficacious than monotherapy, and greatly reduces the odds of drug resistance. However, complete eradication of HIV in patients undergoing ART cannot be achieved due to the presence of the latent HIV reservoir.5 Moreover, ART is a lifelong treatment that requires rigorous adherence to maintain therapeutic drug levels. However, prolonged treatment is often unattainable in poor socioeconomic regions with low patient compliance, thus contributing to increased drug resistance and a decreased quality of life.8

critical review

HIV PATHOGENESIS

lived effector CD4+ T cells, which activate the adaptive immune system to defend the body.5 Most effector CD4+ T cells terminate, but a portion persists as memory cells that contribute to altered gene expression and enable long-term survival. Following integration into the host cell genome, HIV DNA is transcriptionally silent and unaffected by antiretroviral (ARV ) medications, giving rise to the phenomenon of viral latency. Ultimately, HIV latency exploits the immune system’s most intrinsic feature: the immunological memory that dwells within T cells.6

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transcriptional machinery. The inhibitor of NFκB (IκB) is responsible for the sequestration of this transcription factor in the cytoplasm. The pressing need for an HIV cure has spurred Consequently, inhibition of IκB allows NFa novel therapeutic approach that aims to κB to enter the nucleus, where it can activate eradicate the virus by depleting HIV reservoirs. HIV promoter region.13 Positive transcription Commonly referred to as “shock and kill”, this elongation factor (PTEF-b) is another therapy entails shocking latently infected cells essential protein that plays a critical role in the by inducing HIV viral expression and killing maintenance of HIV latency. The viral protein them following reactivation. A drug which trans-activator of transcription (TAT) is reverses latency increases HIV RNA levels to responsible for recruiting PTEF-b during the induce viral protein production.11 Following elongation phase of transcription. During this the shock stage, the viral particles are released process,TAT must directly compete for PTEF-b from the infected cells to be later purged by with another protein, bromodomain-containing the immune system.12 Recent advances in HIV protein 4 (BRD4). As a result, inhibitors research have highlighted shock and kill as a of BRD4 such as JQ1 have been shown to promising cure. In fact, multiple classes of increase viral transcription in cell line models.15 latency reversing agents (LRAs) have already been identified, with a select few currently Perhaps the most effective strategy to undergoing clinical investigation. Moreover, reverse latency entails the activation of recent studies have identified a novel method phosphokinase C (PKC). Stimulating the that achieves viral eradication by exploiting PKC pathway improves HIV transcription HIV-specific CD8+ T cells, a subset of immune through two related mechanisms: the cells that can recognize and kill infected cells.11 release of positive transcription factor NFTo prevent future infections, ART treatment κB inside the nucleus, and the induction must be maintained during shock and kill.12 of PTEF-b production and availability.13

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critical review

OVERVIEW OF THERAPEUTIC MECHANISM

the “shock” aspect

The “KILL” ASPECT

Different pathways can be targeted to increase HIV cellular transcription. One promising approach involves the upregulation of gene expression via epigenetic means. Existing enzymes, such as histone deacetylase and histone methyltransferase, maintain HIV latency by reducing DNA accessibility to transcription factors and inducing histone trimethylation to repress genetic expression, respectively.13 Consequently, histone deacetylase inhibitors and histone methyltransferase inhibitors have been subjects of rigorous investigation.13,14 A recent study of eight HIV patients demonstrated that treatment with vorinostat, a histone deacetylase inhibitor, caused a 4.8 fold increase in HIV RNA expression just six hours post-treatment.15 Histone methyltransferase inhibitors such as chaetocin and BIX-01294 have also been effective as LRAs in in vitro and ex vivo studies. In addition to epigenetic mechanisms, induction of positive transcription factors can further increase HIV viral expression to expose latently infected cells.13

After reactivation, the kill stage of therapy entails the purging of infected cells to eradicate viral reservoir and cure patients. It has been shown that HIV-specific CD8+ T cells can effectively kill reactivated CD4+ T cells in vitro.16 Multiple strategies have utilized HIV-specific CD8+ T cells to achieve viral eradication. Among these, adaptive transfer of HIV-specific CD8+ T cells, therapeutic vaccines, and immunomodulation have been intensely studied.11

Inducible transcription factors, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), are naturally present at very low levels in resting cells and are located outside of the nucleus, away from

Although HIV-infected individuals possess HIV-specific CD8+ T cells which are initially capable of killing infected cells, their effectiveness is gradually lost. In fact, HIVspecific CD8+ T cells isolated from acute and chronic HIV infection show functional and phenotypic differences. Therefore, the adaptive transfer of HIV-specific CD8+ T cells, which are derived in vitro to have increased persistence, may be a safe and effective approach to purging the infected cells.17 Therapeutic vaccines created using live attenuated vectors, peptides, and proteins have shown promising results in inducing CD8+ T cells. Boosting CD8+ T cells can also be achieved using immunomodulators that have been experimentally effective in reversing CD8+ T cell exhaustion.11

KEY CONSIDERATIONS

The shock and kill technique should be closely monitored, since HIV is associated with chronic diseases such as various neurocognitive disorders. Studies have suggested that reversed latency increases the risk of acute HIV syndromeassociated encephalitis, otherwise known as

conclusion Current HIV treatments are limited as they can only halt disease progression and require strict adherence to a rigorous drug regimen. With the advent of the shock and kill approach, the research community has become increasingly optimistic towards a potential cure for HIV. This technique is novel in that it ultimately targets the very machinery by which the virus evades the immune system and resides within host cells. If efficacious, the therapy can curb the current global HIV pandemic and simultaneously increase the quality of life of patients inflicted with the disease. However, it is pertinent to remain cognizant of the ramifications associated with shock and kill. The reversal of latency can trigger potentially detrimental side effects for patients, which is a high-priority area of research that requires thorough exploration. ■

Reviewed by DR. Kenneth L. Rosenthal Dr. Rosenthal is involved in teaching within the Undergraduate Health Sciences, Arts and Science, and Life Sciences Programs. At the graduate level, he teaches advanced immunology, virology, and pathology. The work of his laboratory aims to contribute to our understanding of transmission, infection, control, and prevention of relevant human pathogens, such as HIV and HSV-2.

Levy JA. Pathogenesis of human immunodeficiency virus infection. Microbiological reviews. 1993;57(1):183-289. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC372905/ [Accessed 20th January 2017]. Simon V, Ho DD and Karim QA. HIV/AIDS epidemiology, pathogenesis, prevention, and treatment. The Lancet. 2006;368(9534):489504. Available from: doi:10.1016/S01406736(06)69157-5 [Accessed 20th January 2017]. Cummins NW and Badley AD. Mechanisms of HIV-associated lymphocyte apoptosis: 2010. Cell death & disease. 2010;1(11):e99. Available from: doi:10.1038/cddis.2010.77 [Accessed 20th January 2017]. Luckheeram, Rishi Vishal et al. CD4+T Cells: Differentiation And Functions. Clinical and Developmental Immunology. 2012;2012(2012). Available from: doi:10.1155/2012/925135 [Accessed 20th January 2017]. Dahabieh M, Battivelli E and Verdin E. Under-

standing HIV latency: the road to an HIV cure. Annual review of medicine. 2015;66:40721. Available from: doi:10.1146/annurevmed-092112-152941 [Accessed 20th January 2017]. Siliciano RF and Greene WC. HIV latency. Cold Spring Harbor perspectives in medicine. 201;1(1):a007096. Available from: doi:10.1101/ cshperspect.a007096 [Accessed 20th January 2017]. World Health Organization. ARV treatment guidelines and technical and operational recommendations for ART. Available from: http:// www.who.int/3by5/publications/briefs/oms09arvguidelines.pdf?ua=1 [Accessed 20th January 2017]. Siliciano JD and Siliciano RF. Latency and viral persistence in HIV-1 infection. The Journal of clinical investigation. 2000;106(7):823-5. Available from: doi:10.1172/JCI11246 [Accessed 20th January 2017]. Lugassy DM, Farmer BM and Nelson LS. Meta-

bolic and hepatobiliary side effects of antiretroviral therapy (ART). Emergency medicine clinics of North America. 2010;28(2):409-19. Available from: doi:10.1016/j.emc.2010.01.011. [Accessed 20th January 2017]. 10. Mannheimer SB, Matts J, Telzak E, Chesney M, Child C, Wu AW, Friedland G and The Terry Beirn Community Programs for Clinical Research on AIDS. Quality of life in HIV-infected individuals receiving antiretroviral therapy is related to adherence. AIDS care. 2005;17(1):1022. Available from: http://www.tandfonline. com/doi/full/10.1080/095401204123313050 98 [Accessed 20th January 2017]. 11. Trautmann L. Kill: boosting HIV-specific immune responses. Curr Opin HIV AIDS. 2016;11(4):409–16. Available from: doi:10.1097/COH.0000000000000286 [Accessed 20th January 2017]. 12. Deeks SG. HIV: Shock and kill. Nature. 2012;487(7408):439–40. Available from: doi:10.1038/487439a [Accessed 20th Janu-

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ary 2017]. 13. Darcis G, Van Driessche B, Van Lint C. Preclinical shock strategies to reactivate latent HIV-1: an update. Curr Opin HIV AIDS. 2016;11(4):388–93. Available from: doi:10.1097/COH.0000000000000288 [Accessed 20th January 2017]. 14. Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012;487(7408):482–5. Available from: doi:10.1038/nature11286 [Accessed 20th January 2017]. 15. Archin NM, Margolis DM. Emerging strategies to deplete the HIV reservoir. Curr Opin Infect Dis. 2014;27(1):29–35. Available from: doi:10.1097/QCO.0000000000000026 [Accessed 20th January 2017]. 16. Shan L, Deng K, Shroff NS, Durand CM, Rabi SA, Yang H-C, et al. Stimulation of HIV1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity. 2012;36(3):491– 501. Available from: doi:10.1016/j.immuni.2012.01.014 [Accessed 20th January 2017]. 17. Lam S, Bollard C. T CELL THERAPIES FOR HIV. Immunotherapy. 2013;5(4):407–14. Available from: doi:10.2217/imt.13.23 [Accessed 20th January 2017]. 18. Gallo RC. Shock and kill with caution. Science. 2016;354(6309):177-8. Available from: doi:10.1126/science.aaf8094 [Accessed 20th January 2017]. 19. Gama L, Abreu CM, Shirk EN, Price SL, Li M, Laird GM, Pate KA, Wietgrefe SW, O’connor SL, Pianowski L and Haase AT. Reactivation of simian immunodeficiency virus reservoirs in the brain of virally suppressed macaques. AIDS (London, England). 2017;31(1):5. Available from: doi:10.1097/ QAD.0000000000001267 [Accessed 20th January 2017]. 20. Dental C, Proust A, Ouellet M, Barat C and Tremblay MJ. HIV-1 Latency-Reversing Agents Prostratin and Bryostatin-1 Induce Blood-Brain Barrier Disruption/Inflammation and Modulate Leukocyte Adhesion/ Transmigration. J Immunol Baltim Md 1950. 2016;198(3):1229-1241. Available from: doi:10.4049/jimmunol.1600742 [Accessed 20th January 2017].

critical review

Despite the scientific promise of the shock and kill technique, one must consider the therapy’s efficacy as well as associated side effects. Notably, the approach relies on the condition that all latently infected cells will be re-activated and subsequently eliminated by cytotoxic T lymphocytes, an assumption that lacks sufficient evidence. It is speculated that the usage of weak LRAs accounts for this inadequacy, highlighting the need for more efficacious agents. Moreover, ART cannot be presumed to completely block the released virions from newly infected cells. Specifically, cells localized in the brain and lymphoid tissues may not receive the threshold concentration of ARV drugs required for viral suppression. This renders the efficacy of drugs that target reactivated viruses in these anatomical sites highly debatable. Another potential ramification associated with LRAs is that they can act as agonists which activate uninfected T cells, rendering these cells vulnerable to HIV infection. Other non-HIV viruses, including human herpes and hepatitis C viruses, can similarly be reactivated, leading to detrimental side effects. Further LRA-associated conditions may result from the targeting of host factors and the modulation of host gene expression, which include inheritable epigenetic markers.18

brain inflammation.19 Several LRAs induce dose-dependent breakdown of endothelial integrity and permeabilize the blood-brain barrier (BBB). Although this could improve the access of ART drugs to the CNS during shock and kill, opening of the BBB is often associated with neurological diseases. Moreover, LRAs such as prostratin and bryostatin-1 cause the microvascular endothelial cells of the brain to secrete inflammatory factors, a phenomenon associated with disease progression. Evidently, more research is required to determine the safety of these drugs.20

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INTERVIEW SPOTLIGHT

ANNE MCKEAGE Former archivist and history of health and medicine librarian Kevin CHEN1, ASHLEY LAM2 Bachelor of Health Sciences (Honours), Class of 2020, McMaster University 2 Bachelor of Health Sciences (Honours), Class of 2018, McMaster University

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Anne McKeage was the former Archivist and History of Health and Medicine Librarian of the Health Sciences Library. We had the opportunity to sit down with Anne and discuss her work at McMaster. Curious to learn more about what goes on behind the scenes, we asked Anne to share with us her various experiences in gathering and organizing material for the History of Health and Medicine collection.

 Could you please tell us about your time here at McMaster and about the History of Health and Medicine collection?

I was in charge of the historical collections, which include the books in the reading room, the Archives that are tucked away, and the Rare Book Room. The focus of these resources is the history of health sciences in the 19th and 20th centuries – not only pertaining to medicine, but also to nursing and midwifery. We started with a tiny budget, so most of the items were actually donated by retiring faculty. In addition to biographies and autobiographies, the collection includes pamphlets that were given to young mothers and educational materials that were used to teach midwives, anesthesiologists, radiologists, and military physicians. Out in the reading room, resources cover the history of all the health disciplines, but exclude specialized material. You won’t find some ponderous tome on niche equipment because the collection is geared towards supporting undergraduates’ interests. The purpose of the Archives is to preserve history. The

birth control at the time. The collection used to rely on hard copies, but fortunately, a lot of it is now digital. There is simply not enough physical room in the library to store everything, and it’s very difficult for one person to collect and organize it all. There’s never enough space, and there are never enough people! However, I tried to prioritize the most important resources, like the administrative records that include the most important decisions. Everything else trickles down from there. If you have those records, you have the basic history. As for the digital collection, our hard drives include digitized photographs and records. This system makes it a lot easier to collect and find items, which ultimately will be accessible to the public in a few years.

 What was a regular day like as the archivist of the History of Health and Medicine library?

The Archives also cover the history underlying McMaster’s Faculty of Health Sciences. Meeting minutes, status reports, and annual reports may seem dry in and of themselves, but they represent the decisions that have been made by the faculty. All of these things are in our collections, waiting for someone to find and study them.

“I LOVE THE PAST ... I WAS VERY FORTUNATE THAT I WAS SO FASCINATED BY THE SUBJECT MATTER. IN FACT, IT WAS REALLY DIFFICULT TO GIVE THE BOOKS BACK! I WANTED TO READ EVERYTHING SO I DID A LOT OF READING – IT WAS MY WEEKEND AND EVENING READING.”

I’d also buy books for the historical collections. I would find a title and send a request to Acquisition for them to purchase a copy, or I would get a phone call from a donor saying, “I’m a

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All of the work was front-loaded. Data entry was very time consuming, but necessary. This process allowed me to find everything needed by a PR person in a quick, five minute search. If I had to go through the collections manually to find a face, I wouldn’t have known what Dr. Smith looked like, so someone else would have had to come into the library to identify him for me. A five minute search would have taken five hours instead. Anything that looks easy now has had a lot of work put into it to make it look easy.

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The Rare Book Room uses the same classification system as the rest of the library. Often, the books included are quite old – some are from the 1920s or even earlier, and are thus too ripped or fragile to circulate. On top of that, these items are rare. This could mean that only one or two copies exist, like the manuscript of a book that was never published. As well, some publishing offices do not keep old pamphlets, which are really interesting and informative historical artefacts. An example would be the birth control pamphlets provided by a sex education clinic in 1920. They are completely different from the ones distributed in 2017, but show the understanding of

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Archives cover all of the Hamilton Health Sciences hospitals, which are governed by one central administration that controls purchasing. This arrangement saves money because smaller hospitals do not need to buy resources individually for their own archives. Hamilton’s healthcare system has always benefited from a well-connected network; the hospitals have even shared a common laundry service since the 1950s.

On a regular day, I’d go through boxes of records that would come in, file by file. Perhaps the Department of Medicine had opened up an old closet and found that it was full of records. After going through them, I would send them a summary of the contents. Then, I would organize the records, putting them in chronological order before entering them into the database. Photographs, in particular, can be quite useful. For example, if someone wanted to pay tribute to Dr. Smith when he retired, I could quickly pull up all of the photos of him at old events and parties using the keyword search function of the digital database. This year is also the Faculty of Health Sciences’ 50th anniversary, so many departments and faculty members have been asking for photographs and fact-checking dates in preparation for retrospectives.

retired nurse and I have all these books. Are you interested?” I’d say “Absolutely!” Hopefully, I could then meet the donor at their office or home. Donors receive a tax receipt and a notice of acknowledgement in the library catalogue. You can pull up a list of all the things that somebody’s donated. It’s a bit of an ego booster! It’s also a great way to build the collection with material we can’t afford to buy.

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interview spotlight table of contents

What sparked your interest in the history of the health sciences? What do you find most important about your studies?

My undergraduate degree was in history, so I love history. I love the past. I accepted this post as the Archivist and History of Health and Medicine Librarian and then it was just a question of reading everything. I was very fortunate that I was so fascinated by the subject matter. In fact, it was really difficult to give the books back! I wanted to read everything so I did a lot of reading – it was my weekend and evening reading. I’d also talk to people: researchers writing their PhD in the history of anaesthesiology would come down to talk to me, and I would learn so much. It was never tedious that way.

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It seems like there are new additions to the collection every now and then, but if you were to choose your favourite or most interesting item from the collection, what would it be?

There’s a particular collection that I like, a photograph collection from the Chedoke Hospital, which just closed. It had its time – it used to be the Mountain Sanatorium, the tuberculosis sanatorium for Hamilton-Wentworth. About ten years ago, I received a phone call informing me that they’d found photographs in a filing cabinet with the help of a locksmith after the key was lost. When they asked if I wanted the photos, I didn’t even need to ask what the subject matter of the collection was because I knew it was from Chedoke. So I went up with boxes and unloaded them very quickly because I wanted to dive right in. I unloaded the three-drawer filing cabinet full of photographs. They were all negatives, which explains why they were saved; the pictures were small, relatively speaking, and nobody knew what they were. I found out that they were pictures of Chedoke, capturing everything that they had done there between the 1950s and 60s. It was such a great find. One day, they will be used because they show Chedoke Hospital’s history - how Mountain Sanatorium evolved into a general hospital. This wonderful find survived by the skin of its teeth. I’m rather proud of that collection because if I had not taken that phone call, it would have been lost. One issue is that many of the people in these photographs have not been named. I can identify the principal people,

like the superintendent and some of the head nurses, but everybody else remains anonymous. That’s kind of a shame, because with names, you get the genealogists who are interested in seeing their mothers as young nurses, their fathers as young doctors, and their parents as patients… That’s what labelled photographs are good for.

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Finally, what is the best way for an undergraduate student to engage or make use of the History of Health and Medicine Collection?

Well, if you’re studying history, geography, anthropology, English, or anything with historical events, lots of research material can be found here. For example, I know that Dr. Ann Herring of Anthropology uses the collections extensively because she has a fourthyear class that studies the history of a disease in Hamilton. Students take an aspect of the history of diphtheria in Hamilton-Wentworth, for example, and their aspect becomes a chapter of a book that is read and peer-reviewed by Dr. Herring. Then it’s all professionally published and suddenly the students are contributors to a publication. The course pulls students right across campus to use the Health Sciences Library and our historical collections. We become siloed so easily – we should explore what the campus and city each have to offer, like the Planetarium or the greenhouse at McMaster. It’s all here if we just explore it! Then, you can grow in so many ways beyond the information that you learn in classrooms. You learn how to think, how to research, how to talk, how to create, and how to defend your position. It’s really great training. Anyone can use the collection, you just have think expansively. (Post-interview: There are also some really beautiful biographies on some of the big names in medicine. For example, there are two histories on the writing of Gray’s Anatomy that talk about who Gray was, who his illustrator was, and more. Reading these would be a great way to get into the history of medicine.)

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How can students access these resources?

Everything excluding the contents of the Rare Book Room are accessible with your student card. It all has the same times and conditions for borrowing. The materials in the Rare Book Room are listed in the catalogue, and you can make an appointment to use the material within the room. You can even take photographs of it with your phone, or ask to scan it. The material in the catalogue tends to have “Early Works” in the title, like “Diphtheria: Early Works,” and then you just have to look at the location of the collection. Undergraduate students are free to use the collection – you just need to make an appointment. There are no weekend or evening hours, though, so you do have to learn to manage your time! ■

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Journal of the 10.1001/jama.297.8.831 [Accessed 11th March 2017]. http://www.cacuss.ca/_Library/Provincial_Reports/cacuss_health 6. Canadian Association of College and University Student Service physicians: Implications for patient safety and continuity of care. Journal of the 6. Canadian Association of College and University Student Canadian 3. Kripalani S, LeFevre F, Phillips CO, Williams MV, Basaviah P, Baker DW. Deficits in 3. Kripalani S, LeFevre F, Phillips CO, Williams MV, Basaviah P, Baker DW. Deficits in 6. Canadian Association of College and University Student Services. Canadian 3. Kripalani S, LeFevreH,F,Verger Phillips Williams MV,Association. Basaviah P, 2007;297(8):831-41. Baker DW. Deficits intervention characteristics are rela [Accessed 11th March 2017] 4. in Braithwaite J. Between-group behaviour in health care: Gaps, edges, boundaries, 1. 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