Issue 24 by The Meducator

DECEMBER 2013 | ISSUE 24

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LIVING WITH DISABILITIES IN A HOSTILE ENVIRONMENT A C lo s e r Lo o k at C e r e b ra l Pa l s y

dr. Stephen Walter A pp ly i n g B i o s tat i s t i c s B e yo n d D i s c i p l i n a ry B o u n d a r i e s

Sex-Selective Abortion More Than Just an Ec o n o m i c I s s u e

table of

contents DECEMBER 2013 ISSUE 24 INTRODUCTION 02 MEDBULLETIN 03 PATHOPROFILE 06 FORUMSPACE 07 OPINION 09 GLOBAL PERSPECTIVE 11 NEUROABSTRACTS 14 CRITICAL REVIEWS 15 INTERVIEW SPOTLIGHT 31 CONTRIBUTORS 34

table of contents

Cover Art by Mark Belan

11 GLOBAL PERSPECTIVE: THE MENTAL HANDICAP OF A HOSTILE ENVIRONMENT Children with cerebral palsy often receive support in Western societies, but this is not always the case in many places around the world. Hannah Roche recounts her personal experience working at an orphanage in Guinea, and discusses some social barriers to child care and rehabilitation in the developing world.

15 CRITICAL REVIEW: COMMUNITYBASED INTERVENTIONS Non-governmental organizations (NGOs) often play controversial roles in the healthcare sectors of many developing countries. Nikita Arora discusses how new community-based intervention techniques may help NGOs to offer more sustainable support.

19 CRITICAL REVIEW: NEUROPROTECTIVE AGENTS IN TRAUMATIC BRAIN INJURY

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There is more to a brain concussion than just physical damage. Helen Genis delves into the cellular processes that follow after traumatic brain injury. Understanding these mechanisms may help to develop neuroprotective agents for the prevention of life-long disabilities after concussions.

23 CRITICAL REVIEW: TONAL HARMONY Music and tonal languages are known to share similar neural pathways. Maxwell Tran and Ishan Aditya discuss how the two are related and how they may be beneficial in language acquisition and Autism Spectrum Disorders.

27 CRITICAL REVIEW: PATHOGENIC FOODBORNE BACTERIA DETECTION Foodborne illnesses are a large concern for the public. Grace Zhang takes a look at current and novel methods of detecting foodborne bacteria, which is a critical step in preventing related epidemics.

Thank you for picking up Issue 24 of The Meducator, McMaster’s undergraduate health sciences journal. The field of health sciences is like a web comprised of intertwining disciplines, all working together to improve health at the individual, societal, and global scale. As such, this issue aims to highlight the interdisciplinary nature of the field, and illustrate how each thread is essential to improving human health as a whole. On one end, this issue features a wide array of topics that explore the health sciences at a larger scale. The brand new Global Perspective article allows authors to discuss healthcare issues in the context of their own experiences working within a community. In this piece, Hannah Roche discusses barriers to healthcare faced by children with cerebral palsy in Ghana due to societal stigmas. Elaborating on the impact of society on healthcare, the Opinion piece by Stephanie Wan explores the cultural pressures and ethical implications in the controversial phenomenon of sex-selective abortion. Furthermore, in the Forumspace, Asha Behdinan and Cheryl Young discuss the complex issue of multimorbidity, and offer various potential solutions to address this problem. Finally, Nikita Arora’s Critical Review uses Malawi as an example to discuss how NGOs can partner with communities to provide more effective and sustainable aid. Complementing the larger-scale perspectives, this issue then brings to focus the finer aspects of the health sciences. Grace Zhang’s Critical Review discusses current and developing technologies available for detecting foodborne pathogens. Meanwhile, Helen Genis writes about the complex cellular mechanisms revolving around traumatic brain injury. Delving into neural circuits, Maxwell Tran and Ishan Aditya explore the complementary relationship between music and tonal languages, and its implications in treating communication disorders. Furthermore, look out for the new PathoProfile piece, which is a collaborative project by The Meducator editors and artists that visually depicts the pathophysiological mechanisms underlying various human diseases. In this issue, Annie Cheung, Arlinda Deng, and Annie Zhu focus on lupus nephritis, an inflammatory disease of the kidney.

introduction

INTRODUCTION ISSUE 24

dear reader,

Additionally, our Interview Spotlight features an insightful interview with Dr. Stephen Walter, who was one of four McMaster faculty members to be recently elected as a fellow of the Royal Society of Canada. Here, Dr. Walter talks about the interdisciplinary nature of his work in statistical methods, and shares some advice to undergraduate students who are considering various career choices.

Enjoy your read!

YASMEEN MANSOOR

U Cr A T| O RD e| cA eP RmI bL e2r0 12 30 1 3 m e d uM c aE D to

We would like offer our deepest gratitude to our talented staff for sharing the vision of McMaster’s undergraduate health sciences journal and bringing our 24th issue to life. Our diligent Editorial Board has not only been refining this issue to perfection, but has also been regularly engaging undergraduate students through our new blog at www.meducator. org. Meanwhile, the creative eye of our Graphics & Design Team has once again rendered The Meducator as a vibrant and dynamic read. Last but not least, our new Video Team has further extended the reach of The Meducator by communicating ideas in the health sciences in an engaging video format. This publication would not be possible without the dedicated support of our staff, authors, and readers. We truly hope to bring into perspective the multidimensional facets of the field of health sciences, and spark inspiration and curiosity amongst the undergraduate community.

JOHNNY-WEI BAI

MEDBULLETIN NEuroScience

SuperBacteria

BO NNIE C HE UN G

AB R AH AM R ED D A

Dementia in the elderly is rapidly becoming a major issue. In Canada alone, a new case of dementia develops every 5 minutes. 1 Although current research on agerelated dementia is primarily concerned with creating new drug treatments, a recent study has shown that social interventions may be just as promising.

The rising incidence of antibiotic resistance and the emergence of new pathogens have highlighted the need for improving the effectiveness of current antibiotics instead of exclusively expanding our antibacterial arsenal. This issue has become increasingly important in the case of Gram-negative bacteria, which display considerably more antibiotic resistance than Gram-positive bacteria. The enhanced resistance results from the additional lipopolysaccharide membrane of Gram-negative bacteria. However, new research conducted at Boston University has shown that silver ions may hold the key to making Gramnegative bacteria susceptible to antimicrobial treatments. 1

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THE SILVER LINING TO Teaching an old bee new tricks: reversing brain aging ANTIBIOTIC RESISTANCE

A study by Baker et al. 2 has demonstrated the power of social interventions in a colony of honeybees. Young bee workers begin their lives as “nurse” bees that care for the nest and larvae. They then grow to become “foragers” that hunt for food. It has been shown that brain function rapidly declines with age in foragers while staying relatively intact in nurse bees who remain sheltered within the nest. The study’s aim was to see what would happen if these foragers reverted back to performing the activities of nurse bees and if neural plasticity could be rescued.

Ramirez and colleagues also showed that silver ions are able to restore antibiotic susceptibility to previously resistant bacterial strains. Using mice whose urinary tracts were infected with a resistant strain of E.coli , experimenters found that neither silver nor antibiotics on their own were effective. However, when mice were treated with antibiotics in conjunction with silver ions, the researchers found that the combination proved lethal to the E.coli bacteria. 1

These results suggest that modifying behaviour based on one’s social environment can reverse brain aging. Since social intervention programs are less costly than drug development, 3 such programs may be key to treating and preventing dementia.

Ramirez highlighted the ability of silver ions to increase the membrane permeability of Gram-negative bacteria, thereby sensitizing the bacteria to vancomycin, a Gram-positivespecific antibiotic. The finding is especially intriguing because it suggests the potential to increase the applicability of existing antibacterial drugs by coupling them with silver ions.

1, Alzheimer Society of Canada. Facts about dementia [Internet]. 2012 [updated 2012 Sept 11; cited 2013 Sept 10]. Available from: http://www.alzheimer.ca/en/on/About-dementia/Dementias/Whatis-dementia/Facts-about-dementia 2. Baker N, Wolschin F, Amdam GV. Age-related learning deficits can be reversible in honeybees Apis mellifera. Exp Geron 2012 May;47(10):764-772. 3. ScienceDaily. Bees can ‘turn back time,’ reverse brain aging [Internet]. 2012 [updated 2012 Jul 3; cited 2013 Sept 10]. Available from: http://www.sciencedaily.com/releases/2012/07/120703172547.htm 4. Honey Bee Takes Nectar [Image from the internet]. Available from http://en.wikipedia.org/wiki/ File:Honey_Bee_takes_Nectar.JPG [accessed 27 Oct 2013]

1. Morones-Ramirez J. Silver enhances antibiotic activity against Gram-negative bacteria. Science Translational Medicine. 2013 Jun 19; 5 (190): 1-11 2. Bacteria [Image from the internet]. Available from http://images.sciencedaily. com/2008/09/080918192836-large.jpg [accessed 27 Oct 2013]

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The investigators first removed the younger nurse bees from the nest, leaving only the older foragers, larvae, and queen behind. Some foragers reverted to nurse bees to make up for this loss, caring for the nest and brood, while others remained as foragers. After ten days, the reverted nurse bees significantly improved their learning abilities, effectively reversing the brain aging process. This behavioural finding was supported by data obtained through mass spectrometry of brain tissue. Specifically, it was found that proteins involved in cellular maintenance and protection against dementia were increased. 2

Jose Morones-Ramirez and colleagues reported the ability of silver ions to react with hydrogen peroxide to produce hydroxyl radicals, which readily react to disrupt disulfide bond formation, metabolism, and iron homeostasis in Gramnegative bacteria. 1 The disruption of these cellular processes increases membrane permeability and enhances the activity of antibiotics against Gram-negative bacteria.

Cell Biology

Gene PatentS

AV RILYNN D ING

KACPER NIB UR SKI

Over the past 50 years, stem cell therapy has aimed to use the regenerating and differentiating abilities of stem cells to grow new tissues and replace diseased or damaged ones. 1 While scientists have developed many techniques to generate and culture stem cells in vitro , challenges remain when introducing them into mammalian models for clinical treatments. However, recent research led by Manuel Serrano at the Spanish National Cancer Research Centre successfully reprogrammed adult mouse cells in vivo to become induced pluripotent stem (iPS) cells, a laboratory equivalent of embryonic stem cells.

Two fundamental bases often decide one’s lot in life: wealth and genetics. Recently, the two came together when the Supreme Court of America ruled, in a 9-0 unanimous decision, that natural genes could not be patented. 1

The scientists genetically engineered mice to express the four genetic factors capable of inducing pluripotency in somatic cells: Oct4, Sox2, Klf4 and c-Myc. The gene’s expression levels were controlled using varying dosages of an antibiotic, doxycycline. After treating mice with low doxycycline doses, the researchers found teratomas in many of their organs. Teratomas are tumours containing multiple cell types, which result from disorganized differentiation of pluripotent cells, and are indicative of cellular reprogramming. Researchers also found iPS cells circulating in the mice’s blood. These in vivo generated iPS cells are genetically closer to embryonic stem cells at an early developmental stage than standard in vitro iPS cells. The in vivo iPS cells are also capable of forming embryo-like structures and trophoblast giant cells, placental cells that cannot be formed by other artificial stem cells. 1

The legal ruling centered around two genes, BRCA 1 and BRCA 2 , which are paramount in the diagnosis of breast and ovarian cancers. 1,2 Carriers with mutations to these genes are approximately 80% more likely to develop some form of aggressive cancer. Preliminary clinical tests, previously and exclusively owned by Myriad Genetics, were necessary to detect these mutations. Due to a previous patent that ensured sole rights to Myriad Genetics, however, these medical tests were inaccessible to some patients as a result of their increased costs. 3

Inducing stem cells in vivo over in vitro

The decision sought to reverse this exclusivity by ensuring that isolated DNA from natural sources, no matter the extensive research, localization, and purification techniques, could not be legally “invented”. 1 Synthetic DNA, however, could very well be patented, the decision stated, as it is a “human-made invention.” This verdict has far-reaching ramifications beyond human DNA as it leads into questions involving the inventorship of microbial, plant, and other animal genes. 2 Furthermore, it may have an adverse effect on biotechnology companies as the investment of human genetic research may be compromised by the inability to patent a final product.

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1. Liptak, A. Justices, 9-0, Bar Patenting Human Genes. The New York Times. 2013 Jun 13. 2. Than, K. 7 Takeaways From Supreme Court’s Gene Patent Decision. National Geographic Daily News. 2013 Jun 14. 3. Ellis, J. Opinion: On Patenting Genes. The Scientist. 2013 Jun 18. 4. Genome [Image from the internet]. Available from http://i.huffpost.com/gen/968322/thumbs/oGENOME-facebook.jpg [accessed 27 Oct 2013]

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1. Bathesda MD. Stem Cell Basics. National Institutes of Health, U.S. Department of Health and Human Services, 2009 [cited 2013 Sept 15] Available from: http://stemcells.nih.gov/info/basics/Pages/ Default.aspx 2. Abad M, Mosteiro L, Pantoja C, Canamero M, Rayon T, Ors I, et al. Reprogramming in vivo produces teratomas and iPS cells with totipotency features. Nature. 2013[cited 2013 Sept 11]. doi: 10.1038/ nature12586 3. Cells Web [Image from the internet]. Available from: http://wid.wisc.edu/content/uploads/2012/09/ cells-web-550x367.jpg [accessed 27 Oct 2013]

Siding with the American Civil Liberties Union (ACLU) against the Utah-based Myriad Genetics Corporation, the legal decision was heralded as a step forward by civil liberty groups and as a disincentive to research by disgruntled biotech corporations.

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In vivo cellular reprogramming has great implications for regenerative medicine, bypassing the need to grow cells outside of the body and functionally integrate them back. The findings suggest not only that in vivo reprogramming is feasible, but that it also generates iPS cells with greater differentiation capacities than standard stem cells. Future research will focus on controlling the differentiation of in vivo iPS cells to regenerate specific cells without producing tumours.

IS Outlawing natural gene patents Harmful?

Lifestyle

Society

ISHA N A D I TYA

MAYLYNN D IN G

Obesity has become so prevalent in the world that it is now classified as a disease due to its multiple complications. 1,2 In fact, this condition is now known to affect the entire body, including the immune system. When the body is in a state of obesity, it tends to secrete inflammatory mediators called chemokines, which are produced by immune cells in the body.

In 2009, the term “third-hand smoke” (THS) was coined by Dr. Jonathan Winickoff’s team at the Dana-Farber/Harvard Cancer Center to describe toxic tobacco smoke contaminants that accumulate on surfaces. 1 A critical property of THS is its tendency to undergo chemical transformations to produce secondary toxicants. A 2010 study demonstrated residual nicotine’s ability to react with common indoor air pollutants, specifically ozone and nitrous acid, to produce a class of potent carcinogens called tobacco-specific nitrosamines (TSNAs). 2

Dr. Samaan and colleagues from McMaster University decided to study Chemokine (C-C motif) Ligand 2 (CCL2) because very little is known about the immune response of this factor. 3 The initiation and propagation stages of the inflammatory responses in obesity occur when these chemokines are secreted into muscle and adipose tissue. The study aimed to determine whether CCL2 levels are higher in obese children when compared to lean controls and if fitness plays a role in reducing the concentration of CCL2 levels in the body. The study involved a group of 18 obese and 18 lean children in which half of each group was placed into a “high” fitness group while the other half was placed into a “low” fitness group. An aerobics fitness test was performed using a cycle ergometer in which the resistance was gradually increased every two minutes. Serum insulin and CCL2 variables were measured using an enzyme-linked immunosorbent assay (ELISA) technique. The results of the experiment confirmed the hypothesis that CCL2 levels were higher in obese children and children of the “low” fitness group, thus supporting the link between exercise and inflammation.

THIRD HAND SMOKE: A GROWING CONCERN

Recently, a research team led by Dr. Bo Hang at the Lawrence Berkeley National Laboratory established a direct link between THS and damage in a cell’s genetic material, or genotoxicity. 3 To simulate acute and chronic THS, researchers exposed chromatography paper strips to tobacco smoke in a closed chamber for varying lengths of time. The compounds on the paper strips were extracted and then used to treat human liver cell lines. Cultured cells were then probed for DNA breaks and oxidation – both strong indicators of genotoxicity. Cells treated with acute or chronic THS extracts had notably more DNA breaks than untreated cells. Cells treated with chronic THS extract exhibited the highest levels of DNA oxidation and TSNA concentration. This suggests that THS becomes more toxic over time. THS extracts reacted with nitrous acid contained more NNA, a THS-specific carcinogen, than unreacted extracts – further evidence of the dangers of THS chemical transformation. 3

Further study of the inflammatory pathways of these chemokines will establish new avenues for drug development and lifestyle plans that will help combat the aptly-named epidemic of “globesity”. 3

The study is the first to show the genotoxicity of THS to human cells and to compare acute THS exposure with chronic THS exposure. Future research will focus on understanding the chemistry of THS reaction with DNA and testing the genotoxic effects of THS in vivo .

1. Thomson, A. Obesity now recognized as a disease. CBC News. 2013 Jun [cited 2013 Sept. 14]; Available from: http://www.cbc.ca/news/health/obesity-now-recognized-as-adisease-1.1320011 2 Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity and trends in body mass index among US children and adolescents, 1999-2010.~Journal of the American Medical Association 2012;307(5):483-490. 3 Samaan MC., Obeid J., Nguyen T., Thabane L., Timmons BW. Chemokine (C-C motif) Ligand 2 is a potential biomarker of inflammation & physical fitness in obese children: a cross-sectional study 4. Obesity [Image from the internet]. Available from http://thinkprogress.org/wp-content/ uploads/2012/05/obesity4.jpg [accessed 27 Oct 2013]

1. Winickoff JP, Friebely J, Tanski SE, Sherrod C, Matt GE, Hovell MF, McMillen RC. Beliefs About the Health Effects of “Thirdhand” Smoke and Home Smoking Bans. Pediatrics. 2009 Jan 1; 123(1):e74-e79. 2. Sleiman M, Gundel LA, Pankow JF, Jacob P, Singer BC, Destaillats H. Formation of carcinogens indoors by surface-mediated reactions of nicotine with nitrous acid, leading to potential thirdhand smoke hazards. Proceedings of the National Academy of Sciences. 2010 Feb 8; 107(15):6576-6581. 3. Hang B, Sarker AH, Havel C, Saha S, Hazra T, Schick S, Jacob P, Rehan V, Chenna A, Sharan D, Sleiman M, Destaillats H, Gundel LA. Thirdhand smoke causes DNA damage in human cells. Mutagenesis. 2013 Jul; 28(4):381-391. 4. Smoke and Fish Desktop [Image from the internet]. Available from http://www.wallpopr.com/wallpaper/2013/02/01/smoke-and-fish-hd-desktop-high-definition.jpg [accessed 27 Oct 2013]

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The Role of Exercise in Obesity

Lupus nephritis (LN) is the inflammation of the kidney caused by systemic lupus erythematosus (SLE), which is an autoimmune disease involving neutrophils. Neutrophils are a class of circulating immune cells that can immobilize and kill invading microbes by generating neutrophil extracellular traps (NETs). In usual circumstances, NETs are removed from the body in order to maintain tissue homeostasis and avoid autoimmunity. However, it has been implicated that there is an impairment of NET degradation in LN, resulting in the initiation of an auto-inflammatory response that involves the production of autoantibodies against neutrophil DNA and proteins. LN is characterized by renal inflammation, progressive renal dysfunction, and often mortality. 1

1) During bacterial infection, neutrophils are recruited to infection sites and undergo a unique form of programmed cell death called NETosis. NETosis involves the release of antimicrobial neutrophil extracellular traps (NETs), comprised of DNA and antimicrobial proteins, which are able to immobilize and degrade pathogens. 2,3

2) DNase, an enzyme floating in the serum, normally degrades and clears the NETs deposited in the tissue. The removal of NETs is essential for maintaining homeostasis. 1

death program leads to neutrophil extracellular traps. J Cell Biol. 2007 Jan 15;176(2):231–41. 4. Borchers AT, Leibushor N, Naguwa SM, Cheema GS, Shoenfeld Y, Gershwin ME. Lupus nephritis: a critical review. Autoimmun Rev. 2012 Dec;12(2):174–94. 5. Van Bavel CC, Fenton KA, Rekvig OP, van der Vlag J, Berden JH. Glomerular targets of nephritogenic autoantibodies in systemic lupus erythematosus. Arthritis Rheum. 2008 Jul;58(7):1892–9.

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Hakkim A, Fürnrohr BG, Amann K, Laube B, Abed UA, Brinkmann V, et al. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci USA. 2010 May 25;107(21):9813–8. 2. Kaplan MJ, Radic M. Neutrophil extracellular traps: double-edged swords of innate immunity. J Immunol. 2012 Sep 15;189(6):2689–95. 3. Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, et al. Novel cell

4) Due to the impaired degradation of NETs, autoantibodies are produced against the DNA, histones, and proteins present in the NET. These antibodies bind to neutrophil antigens to form immune complexes. 1

5) Immune complexes deposit in the renal corpuscle, possibly through either passively becoming trapped in the narrow capillaries of the glomerulus, 4 or through the cross-reaction of antineutrophil autoantibodies against extracellular matrix molecules of the glomerular basement membrane. 5 The accumulation of immune complexes within the glomerulus induces chronic inflammation, damaging renal structures and leading to renal dysfunction. 4

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3) In LN, it has been observed that patients have impaired NET degradation. This may be due to upregulation of the DNAse I inhibitor, G-actin. 1

C O NT RIBU T ORS A NNIE C HEUNG A RLINDA DENG A NNIE Z HU

FORUMSPACE

Multimorbidity in Ontario

Integrated approaches to address a multifaceted problem

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

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CHERYL YOUNG Bachelor of Health Sciences (Honours) Program Global Health Specialization, Class of 2014 Fellow at McMaster Health Forum

Introduction The McMaster Health Forum convened a stakeholder dialogue on the topic of multimorbidity in Ontario on October 21, 2013. The Forum, in consultation with expert informants, created an issue brief which outlines the problem. They also described three elements of an effective approach to addressing the problem, and implementation considerations.1

WHAT IS THE PROBLEM?

ASHA BEHDINAN Arts & Science (Honours) Program, Class of 2015 Research Assistant at McMaster Health Forum

effects of multimorbidity vary across socioeconomic groups. For instance, level of income is a social determinant of health, as the lowest-income Canadians have been found to be three times more likely to suffer from multiple chronic conditions than the richest Canadians.5 It has also been found that aging adults are disproportionally affected; only 13% of adults between the ages of 20-39 faced with multimorbidity compared to 82% of Canadians above 80 years of age.6

There are many health risks associated with multimorbidity, such as a reduced quality of life, As the population of Canada ages, it is evident that lowered functionality, and greater use of healthcare an increasing number of patients will be faced with services.7 There are also associated risks when managing multiple medical conditions.2 Patients considering treatment options for patients with who are affected by two or more conditions multimorbidity. A lack of guidelines that provide are described as exhibiting multimorbidity. health care practitioners with a clear approach Multimorbid cases account for only a small as to how to treat patients with multimorbidity fraction of the total patient population, and yet, exacerbates this issue.8 Furthermore, due to the they account for two thirds of total provincial possibility of facing multiple outcomes from healthcare costs.3 Yet despite the high amount of treatment, it becomes increasingly difficult to resources consumed by these patients, the care they balance all of these outcomes while still considering receive is often ineffective.4 Recognition of this the patientâ&#x20AC;&#x2122;s goals and values.9 Ultimately, the has led to growing support need for patient-focused guidelines to replace for the implementation current disease-focused guidelines for treatment of policy changes that approaches is key, especially when patients are The lowest-income provide care for patients faced with multiple, discordant diseases.10 Canadians have been with multimorbidity. found to be three times The fragmented model for delivery of care is also as likely to suffer When considering the a key issue for patients with multimorbidity. The from multiple chronic scope and impact of this prevalence of approaches based on addressing a decisions than the system-wide issue, one single disease poses a barrier when treating the richest Canadians.5 must recognize that the increasing number of patients with multiple

APPROACHES TO ADDRESS THE PROBLEM Many factors must be taken into consideration when discussing approaches to address the complex issue of multimorbidity. The Forum identified three possible elements of a comprehensive approach to address the problem, and then identified and appraised systematic reviews relevant to each of the three elements.

education, information technology, and home-based support systems.17,18,19

IMPLEMENTATION CONSIDERATIONS In addition to considering elements and approaches to address the problems, potential barriers to implementing integrated approaches must be considered at a variety of levels. At the individual level, patients may resist models that can significantly disrupt their existing, long-established relationships with their healthcare providers. At the level of providers, there may exist efforts to resist the single disease focus that practitioners have been accustomed to. Additionally, systems may lack the political will to scale up promising pilot programs.1

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The first element is the support of all healthcare providers to improve care for patients with multimorbidity. In order to best meet this element, it is important to identify the unique contexts in which models of care are needed, such as children or adults with mental illness.15 The second element is the enablement of health care providers to identify and use guidelines that meet the needs of patients with multimorbidity. This More details on possible integrated approaches to may require public disease guidelines to address multimorbidity in Ontario, as identified include a section about multimorbidity,16 by the McMaster Health Forum, are available and the development of a patient-centred in the Forum issue brief, which can be found at approach rather than one that is disease- http://www.mcmasterhealthforum.org/. oriented.15 The third is the empowerment of healthcare providers to efficiently support patients self-management. This can mean drawing from models that focus on patient

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Each element has unique or shared barriers, but there are also ‘windows of opportunity’ for implementing the elements. Over the past decade, the primary care sector has become the focus of investments, which opens up opportunity for innovative alternative delivery models. Despite hesitation, some regulatory bodies that produce guidelines are becoming increasingly aware of multimorbidity as a challenge, and many patients themselves are keen to actively manage their conditions. Finally, a large deficit and limited economic growth comprise the difficult fiscal situation in Ontario that can be conducive to policymakers embracing innovative approaches to solving new challenges.1 ■

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chronic conditions. The limited time frame in which patients interact with their primary care physicians, coupled with the fact that patients may see multiple specialists for each of their conditions contributes to this fragmentation and often results in uncoordinated patient care.11,12 Moreover, there is a significant burden on informal caregivers, as patients with increasingly complex health conditions tend to rely more heavily on these types of caregivers to meet their needs.13 The financial burden on healthcare providers must be considered, since current models do not adequately compensate for integrated care approaches.14

1. Wilson MG, Gauvin F-P, Lavis JN. Issue Brief: Designing Integrated Approaches to Support People with Multimorbidity in Ontario. Hamilton, Canada: McMaster Health Forum, 21 October 2013. 2. Fortin M, Bravo G, Hudon C, Lapointe L, Almirall J, Dubois MF et al. Relationship between multimorbidity and health-related quality of life of patients in primary care. Quality of Life Research 2006;15(1):83-91. 3. Wodchis WP, Austin P, Newman A, Corallo A, Henry D. The Concentration of Healthcare Spending: Little Ado (yet) About Much (Money). 2012 May 30; Montreal, Canada: Canadian Association for Health Services and Policy Research Conference; 2012. 4. Boyd CM, Fortin M. Future of multimorbidity research: How should understanding of multimorbidity inform health system design? Public Health Reviews 2010;32(2):451-74. 5. World Health Organization. Innovative Care for Chronic Conditions: Building Blocks for Action: Global Report. Geneva, Switzerland: World Health Organization; 2002. 6. Health Council of Canada. Population Patterns of Chronic Health Conditions in Canada - A Data Supplement to Why Healthcare Renewal Matters: Learning from Canadians with Chronic Health Conditions. Toronto: Health Council of Canada; 2007. 7. Marengoni A, Angleman S, Melis R, Mangialasche F, Karp A, Garmen A et al. Aging with multimorbidity: A systematic review of the literature. Ageing Research Reviews 2011;10(4):430-9. 8. Lugtenberg M, Burgers JS, Clancy C, Westert GP, Schneider E. Current guidelines have limited applicability to patients with comorbid conditions: A systematic analysis of evidence-based guidelines. PLoS ONE 2011;6(10):e25987. 9. Smith SM, Soubhi H, Fortin M, Hudon C, O’Dowd T. Interventions for improving outcomes in patients with multimorbidity in primary care and community settings. Cochrane Database of Systematic Reviews 2012;(4):1-70. 10. Lugtenberg M, Burgers JS, Clancy C, Westert GP, Schneider E. Current guidelines have limited applicability to patients with comorbid conditions: A systematic analysis of evidence-based guidelines. PLoS ONE 2011;6(10):e25987. 11. Bodenheimer T. Helping patients improve their health-related behaviors: What system changes do we need? Disease Management 2005;8(5):319-30. 12. Schoen C, Osborn R, How SK, Doty MM, Peugh J. In chronic condition: Experiences of patients with complex health care needs, in eight countries, 2008. Health Affairs 2009;28(1):w1-16. 13. Boyd CM, Fortin M. Future of multimorbidity research: How should understanding of multimorbidity inform health system design? Public Health Reviews 2010;32(2):451-74. 14. Tinetti M.E., Fried TR, Boyd CM. Designing health care for the most common chronic condition - Multimorbidity. JAMA: The Journal of the American Medical Association 2012;307(23):2493-4. 15. Marengoni A, Angleman S, Melis R, Mangialasche F, Karp A, Garmen A et al. Aging with multimorbidity: A systematic review of the literature. Ageing Research Reviews 2011;10(4):430-9. 16. Fabbri LM, Boyd C, Boschetto P, Rabe KF, Buist AS, Yawn B et al. How to integrate multiple comorbidities in guideline development. Proceedings of the American Thoracic Society 2012;9:1-8. 17. Berzins K, Reilly S, Abell J, Hughes J, Challis D. UK self-care support initiatives for older patients with long-term conditions: A review. Chronic Illness 2009;5(1):56-72. 18. Tran K, Polisena J, Coyle D, Coyle K, Kluge EW, Cimon K et al. Home telehealth for chronic disease management. Ottawa, Canada: Canadian Agency for Drugs and Technologies in Health; 2008. 19. Gaikwad R, Warren J. The role of homebased information and communications technology interventions in chronic disease management: A systematic literature review. Health Informatics Journal 2009;15(2):122-46.

Sex-Selective Abortion MORE THAN AN ECONOMIC ISSUE Stephanie Wan

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D ecem b er 2 0 1 3

opinion

Arts & Science (Honours) Program, Class of 2015 McMaster University

scarcer. It is claimed that young women in China are already at a premium as potential mates because strong sex-selection has been going on ever since the one child policy was introduced in the early 1980s”.4 Becker and Posner argue that with fewer women on the marriage market, their worth will increase, which in turn reduces discrimination against them.4 However, whether women will truly benefit from this “scarcity” is left unsupported. It is equally unclear whether the principles of laissez faire economics will apply to individuals. No study has yet to conclusively support these claims.

The first ultrasound image of a fetus was published in the mid 1950s.1 Though this feat was a technical revolution because it incorporated sonar phenomena into the field of obstetrics, it was the image itself that resonated with individuals in and outside of the medical profession. For In a more critical light, Becker and Posner fail to consider physicians, the development of the ultrasound allowed for the negative externalities that may arise as a result of this prenatal detection of fetal abnormalities.1 For mothers, it scarcity, such as sex trafficking or prostitution.5 The recent provided a powerful visual to conceptualize the otherwise emergence of the subdivision “security demographics” is a abstract physiological changes they were experiencing. No testament to the growing concerns surrounding abnormal longer did the fetus’ health status depend on the mother’s population ratios. Hudson and Boer (2002) suggest that a account of her experience; the fetus became a patient in system of too few women would lead to a higher proportion its own respect. Since then, a plethora of ethical questions of unmarried men.6 Some studies make correlative claims have emerged, all of which center upon one basic question: on the higher crime rates in populations associated with should a fetus be considered a person? And if so, does a unmarried men.6 Others cite the highest proportion of fetus have rights? So far, no simple answer has emerged. export brides from North Korea to China.2 Contrary to However, in countries where a dominant male preference the suggestion of Becker and Posner, scarcity of women exists, the lowering costs of ultrasound technology has may further perpetuate discriminatory attitudes towards led to ethical concerns over whether it is permissible to women, not placate them. terminate a pregnancy on the basis of gender. These economic arguments are an incomplete paradigm and perhaps even ask the wrong question. Reducing the Economic Considerations debate to nothing more than a calculation of aggregate The sex ratio in China hovers at about 121 boys for gain versus loss oversimplifies the issue, ignoring the every 100 girls and in India at about 112 to 100. Several complex cast of players who inform and are affected by predictions have been made about the economic the decision to perform SSA. Such utilitarian discussions implications of a skewed sex ratio caused by prenatal may be overlooking the cultural and social frameworks screening.2 Sex-selective abortion (SSA) advocates often that perpetuate SSA. cite Wei and Zhang’s study which showed that sex ratio imbalance stimulates entrepreneurial activities, with men Perhaps a more complete debate would include a driven to increase their wealth in hopes of boosting their discussion of the principle of autonomy. The idea that viability in the marriage market.3 Other SSA defenders individuals should have the right to self-governance focus more on prosperity and economic gains, specifically often dictates whether an act is considered ethically on an individualized front. Becker and Posner4 famously permissible. In Hvistendahl’s popular book, Unnatural advocated that selecting against girls will help placate Selection Choosing Boys Over Girls and the Consequences of other forms of female discrimination: “As children a World Full of Men, she claims that women are acting become adults in cohorts with a high ratio of boys, the autonomously because of their ability to choose the advantage of girls and women increases since they are gender of their sex, gaining respect and honour in their

4. 5.

7. 8.

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1. Nicolson M, Flemming J. Imaging and Imagining the Fetus. Maryland: John Hopkins University Press; 2013. 2. Hvistendahl M. Unnatural selection: Choosing Boys over Girls and the Consequences of a World Full of Men. New York: PublicAffairs; 2011. 3. Wei S, Zhang X. The competitive saving motive: evidence from rising sex ratios and saving rates in China. NBER Working Paper 2009. 4. Becker G, Posner R. Sex selection, Posner’s comment. 2007 Nov 2; Gary Becker and Richard Posner Blog. 5. Moazam F. Feminist discourse on sex screening and selective abortion of female fetuses. 2004. Bioethics, Vol. 18, 1467-8519. 6. Den Boer A, Hudson V. A Surplus of Men, A Deficit of Peace: Security and Sex Ratios in Asia’s Largest States. International Security. 2002: 26(4): 5-39. 7. Zilberberg J. Sex selection and restricting abortion and sex determination. Bioethics. 2007 Nov;21(9):517–9. 8. Golley J, Tyers R. China’s Gender Imbalance and its Economic Performance. 2012. The China Story.

Dr. Mark Vorobej is a Ph. D. (Toronto) professor at McMaster with research interests centering in logic, ethics, and epistemology. As a contemporary logician, his publications span a large range of issues. Among his many influential works are “Just War Theory and the Invasion of Afghanistan” in Peace Research (2009) and “Timeless Reasons” in Philosophical Studies (1988).

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Reviewed by DR. MARK VOROBEJ

opinion

respective societies.2 Julie Zilberberg goes a step further in saying that such interventions are morally justified because they allow women to exercise their reproductive rights, example, women may freely choose to bear ensuring survival and preservation of honour, a female under these circumstances, but it is as defined within their societies.7 highly unlikely that these pressures qualify as a realistic option; divorce or failure to bear While most agree that autonomy should be a son may be deemed shameful by family considered, it is also important to consider the and community members. Just because we extent to which these women are autonomous. have a choice doesn’t necessarily mean that This is not an easy task, and may complicate choice is viable, as both implicit and explicit Zilberberg7 and Hvistenahl’s2 decisive claims expectations may limit the extent of one’s about these women’s accountability in the autonomy. act of performing SSA. Among the many intricacies, decision-making is seldom ever an In part, we are shaped by what our society individual choice. Other family members such expects of us, but the degree to which one can as sisters, brothers, husbands, and in-laws decisively demarcate the boundaries between all may exert explicit and extreme pressures what is coerced and non-coerced remains urging mothers to have a sex determination unanswered. Since the decision to terminate test. Avoiding the threat of divorce upon a pregnancy heavily relies on an external party, unsuccessfully bearing a son often serves as a whether direct or indirect, mothers cannot be motivation to undergo SSA. viewed as an isolated decision maker. Rather, she forms part of an interconnected web of Implicit pressures may be involved as individuals, many of whom exert cultural well. There are numerous socioeconomic and societal pressures on maternal decision. factors that help to sustain and proliferate More recently, China’s goal of reducing the the traditional preference for sons. Well- sex imbalance has been declared a national documented societal practices may be as priority, aiming for 115 newborn males for coercive as direct threats; for example, the every 100 females by 2015.8 Though much established dowry system exerts pressures of their discussion is based on economic on families to save for a female’s marriage. prosperity, the story that follows may be Though the mere existence of cultural more complicated. The question of what it and social expectations is not sufficient to means to be truly autonomous will continue deem these external pressures forceful and to complicate a debate that so far has constraining, lacking any other reasonable concentrated on economic concerns. ■ alternatives can be considered coercive. For

The Mental Handicap of a Hostile Environment Hannah P. Roche Bachelor of Health Sciences (Honours), Class of 2017 Correspondence should be addressed to hannah.roche@learnlink.mcmaster.ca

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global perspective

GLOBAL PERSPECTIVE

ARTIST David Hu

Defining Development As the Western world continues to progress to new heights of development, the emphasis on the care and rehabilitation of children living with physical and mental disabilities becomes more focused. In schools across the developed world, clubs and societies are formed to promote the integration of students with disabilities. Many educational and social institutions have a zero tolerance policy concerning discrimination against children with mental and physical challenges. Innumerable charities, companies, and organizations raise funds and awareness in support of these children. However, this is not the case in the vast majority of the world. In cultures where ‘different’ is commonly associated with ‘unwanted’, children with mental and physical disabilities are often abandoned, neglected, and tossed aside. How is it that something that defines the word special in certain places can be the same thing that makes children undesirable in others? Perhaps the answer lies in the child’s environmental, social, and economic environment.

Walking Alongside I was given the unique opportunity to travel to Equatorial Guinea this past year, and live in a humble centre that became my home for four months. The Kids in Crisis Centre, located in Guinea’s capital of Conakry, offers a home, love, and a family to the least wanted and most fragile children in Guinea. I worked as a nutrition and health counselor alongside children from all health and family backgrounds. “...we tend to focus on Alice* was found by the side of the road at the age of 3, unable the number of children to walk or talk and extremely affected and their malnourished. Jerry* recently current situation, turned two years old, yet most overlooking the crucial who saw him assumed him to question as to how these be no older than 6 months old. children came to be where I had the immense privilege of they are today.” walking – literally – alongside

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these children throughout their struggle for normality. Some non-profit organizations are able to assist children like Alice and Jerry by providing physiotherapy or assistive devices to aid in physical development. A walker was donated to the centre, which Alice and I would use to practice walking up and down the compound. Day after day she grew stronger, and the new challenge became to help her put her ‘walker days’ behind her and teach her to take her first steps on her own two feet. What we take for granted every single day, she has to fight for. Jerry is a beautiful two year-old boy, but while other boys his age were eating rice and curry, going down slides, and learning how to ride tricycles,

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When we think of orphanages and childcare in developing countries such as Guinea, we tend to focus on the number of children affected and their current situation, overlooking the crucial question of how these children came to be where they are today. For children like Alice* and Jerry*, who are living in a centre in Guinea’s capital city, Conakry, their circumstances were not a result of parental death. Rather, both children were abandoned by their families as a result of being born with physical and mental impairment due to cerebral palsy (CP) – a neurological condition resulting from brain damage during in utero development, at birth, or in early childhood.5 The

In North America, cerebral palsy affects approximately 2-3 in every 1000 children.5,6 Due to paucity of data, the cerebral palsy statistics for Guinea are currently unknown or inaccurate.7 However, a study published in Pediatrics (Official Journal of the American Academy of Pediatrics) indicates that the prevalence of CP was higher among children whose families lived in lowand middle- socioeconomic communities than among those whose families lived in high-income communities.8 A study of California births in 1983–1985 suggested that African-American ethnicity is associated with increased risk of CP.9 As the vast majority – more than three quarters – of Guinean children are from extremely lowincome families3 and of African ethnicity, one may suggest that the prevalence is higher.

global perspective

Guinea is a small country located in West Africa with a beautiful coastline on the Atlantic Ocean and a vast potential for wealth in its rich mineral deposits. It is also a country ravaged by civil war, continued political instability, many forms of injustice, rampant corruption, and an unending cycle of poverty.1 Despite being the top bauxite exporter in West Africa2 and having the potential to be one of the wealthiest African nations, 77% of the Guinean population lives on less than two dollars a day.3 Guinea is ranked 178th out of 187 countries on the Human Development Index (HDI) of the United Nations Development Programme (UNDP).4 This ranking is a globally standardized way of classifying countries according to life expectancy, education and income. Higher ranking indicates increasingly advanced development. A result of these circumstances is that having a disability of any kind in a country like Guinea is a severe disadvantage for something we in the developed world take for granted every single day – survival.

name cerebral palsy comes from ‘cerebrum’, which is the area of the brain that is affected, and ‘palsy,’ meaning paralysis.6 Since, the average Guinean family makes less money in a day than a Tim Horton’s coffee costs, the result is a desperate and heartbreaking one – the child is often left to die.

*Names have been changed to maintain anonymosity.

Jerry could not eat solid food or sit up by himself. With physical therapy, love, and attention, Jerry began to show small signs of improvement. As the days progressed, he was finally able to support his own weight while sitting. He also began to eat more than simple formula.

global perspective

“For a child with cerebral palsy born into a developed country like Canada, the opportunities for therapy and developmental rehabilitation are plentiful limitless. But in a country like Guinea where such things are unheard of, let alone accessible, there must be a move to incorporate rehabilitation into the everyday routine of daily life.”

I spent hours in hospitals and clinics where paper documentation was the only method of record-keeping and healthcare providers were often not even legally licensed to practice. Due to the constant instability in the Guinean government and the dire need for infrastructure in the health care system, accurate statistics for cerebral palsy as well as for treatment and prevention programs cannot be found.

Future Steps

A recent study by McMaster University, in conjunction with researchers at the University of Alberta’s Faculty of Rehabilitation Medicine and Alberta Health Services in Calgary, has developed a new and successful program that focuses on the child’s environment rather than the rehabilitation of physical bodies.10 This is called ‘context-focused’ intervention. The study divided children aged one to six into two categories of therapy: contextbased and child-based therapy. Johanna Darrah, a Professor of Physical Therapy in the Faculty of Rehabilitation Medicine at the University of Alberta, said the experience with context therapy

was positive: “The benefits of working in the child’s natural environment were striking.”11 For a child with cerebral palsy born into a developed country like Canada, the opportunities for therapy and developmental rehabilitation are plentiful. However, in a country like Guinea where such things are unheard of, let alone accessible, there must be a move to incorporate rehabilitation into the everyday routine of life. In addressing the neglect of children with cerebral palsy and similar conditions in countries like Guinea, it is too easy to only see the superficial issues that evoke feelings of resentment and indignation in those of us who are outsiders. Unfortunately, the problem runs far deeper than social discrimination and cannot be explained away using cultural stigmas. This is not an issue of awareness but rather one of connectedness, as the argument for the symbiotic relationship between child and environment is indisputable. It is recognizing that the brutal and inevitable cycle of corruption, greed, and poverty results in the unjust accuracy of the statement ‘the survival of the fittest’. Poverty, in this sense, stretches farther than economic terms and instead becomes a death-sentence to children with disabilities. Yet this is not where stories of children like Alice and Jerry should end. As people across the world from every social, economic, and ethnic status begin to see that the value of human life transcends physical and mental differences, we will begin to notice a shift towards a community that finds survival value in others rather than simply valuing survival. ■

Special thanks to Mercy Ships International for their continued guidance and support.

Reviewed by Meghna Dua Meghna Dua received her undergraduate degree in 2011 from McMaster’s Bachelor of Health Sciences Honours program with a specialization in Global Health. She then completed a MSc in Global Health at McMaster in 2012 and is currently an MD Candidate in the Class of 2015 at McMaster’s Michael G. DeGroote School of Medicine. Her research interests are in maternal health within an international and global context. Edited by BRANAVAN MANORANJAN

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BBC News. Guinea Profile [Internet]. 2013 Oct 1 [cited 2013 Aug 3]. Available from: http://www.bbc.co.uk/news/world-africa-13442051 2. Bloomberg. Guinea to triple bauxite output to meet China demand [Internet]. [Cited: 2013 August 3].Available from: http://www.mineweb.com/ m i n ewe b / co nte nt / e n / m i n ewe b - fas t news?oid=182539&sn=Detail 3. Goldman A. Poverty and poor governance in the land of plenty: Assessing an oil dividend in equatorial Guinea. Center for Global Development. 2011. 4. UNDP. Guinea country profile: Human Development Indicators. [Cited 2013 September 20] Available from: http://hdrstats. undp.org/en/countries/profiles/GIN.html

5. Michigan State University. About Cerebral Palsy. 2013 [Cited: 2013 September 20]. Available at: http://www.epi.msu.edu/ cpon/cp.html 6. Centre for Disease Control and Prevention. Facts about Cerebral Palsy. 2013 [Cited: 2013 Sept 20]. Available at: http://www. cdc.gov/ncbddd/cp/facts.html 7. Right Diagnosis. Statistics by Country for Cerebral Palsy. 2013 [Cited: 2013 Sept 5]. Available from: http://www.rightdiagnosis. com/c/cerebral_palsy/stats-country.htm 8. Wu YW, Xing G, Fuentes-Afflick E, Danielson B, Smith LH, Gilbert WM. Racial, ethnic, and socioeconomic disparities in the prevalence of cerebral palsy. Pediatrics. 2011 Mar;127(3):e674–681.

9. Cummins SK, Nelson KB, Grether JK, Velie EM. Cerebral palsy in four northern California counties, births 1983 through 1985. J. Pediatr. 1993 Aug;123(2):230–7. 10. Darrah J, Law M C, Pollock N, Wilson B, Russell D J, Walter S D, et al . Context therapy: a new intervention approach for children with cerebral palsy. Developmental Medicine & Child Neurology 2011; 53(7): 615-620. http://www.sciencedaily.com/ releases/2011/08/110817153823.htm (accessed 10 September 2013). 11. McMaster University. Change the environment, not the child. 2011 [Cited: 2013 Aug 4] Available from: http://www.mcmaster. ca/opr/html/opr/media/main/NewsReleases/Changetheenvironmentnotthechild. htm

NEUROABSTRACTS

Award-winning abstracts and presentations from the May 2013 NeuroXchange Conference

Cortical thickness in children of parents diagnosed with bipolar disorder Corinne Oliver1, Lindsay Hanford2, Geoffrey B. Hall4, Roberto B. Sassi3 Undergraduate Student, McMaster University, 2 Graduate Student, MiNDS Program, McMaster University, 3 Mood Disorders Program, St. Joseph’s Healthcare, 4 Department of Psychology, McMaster University. Correspondence should be addressed to: corinneoliver918@hotmail.com

Bipolar disorder (BD) is associated with reduced cortical thickness in prefrontal and temporal cortical areas responsible for affect regulation. Children of parents diagnosed with bipolar disorder (high-risk (HR) offspring) are at risk of developing a psychiatric illness, and may have cortical abnormalities in affect regulating pathways prior to the onset of any psychiatric disorder. The current study is investigating cortical abnormalities in children at risk of developing bipolar disorder to better understand the developmental trajectories of psychopathology. Twentyfour HR bipolar offspring (average age = 13.7 (2.69) years, 12 females), and 9 age and sex matched healthy controls (HC) (average age = 12.9 (2.70) years, 5 females) were included in this study. Structural brain

scans were administered and measures of cortical thickness were extracted and compared between the HR and HC offspring. HR offspring had significantly decreased cortical thickness in the left superior frontal gyrus, BA 6 (t=4.23 and t=3.57), the left posterior cingulate, BA 30 (t=3.49 and t=3.44) compared to HC offspring. Further analysis of subgroups of the HR population found additional areas of cortical abnormalities in the frontal and temporal cortex. The significant cortical differences found between HC children and HR bipolar offspring suggest that neurobiological markers of risk and resilience can be identified in children at risk of developing BD.

Samantha Leahy Undergraduate Student, University of Windsor. Correspondence should be addressed to: leahys92@gmail.com

The standard pathophysiology in neurodegenerative diseases, such as Parkinson’s disease (PD), is caused by loss of dopaminergic neurons. Mitochondrial dysfunction and oxidative stress have been implicated in these types of neuronal death. It has been shown that exposure to environmental toxins such as paraquat, a commonly used herbicide, can lead to an increase in the incidence of PD. So far, there is no effective therapeutic treatment that can halt the progression of the neurodegeneration. We have been conducting research on a water soluble formulation of CoQ10 (Ubisol-QE) and are testing its ability to protect neurons in vivo. It has previously been shown that Ubisol-QE prevents progression of neurodegeneration in rat models of PD postinjury. We wanted to determine the duration of Ubisol-QE treatment required to effectively sustain neuroprotection. Therefore, over the 8-week treatment portion of the experiment, one group of paraquat

exposed rats were treated for the entire time with Ubisol-QE, while another had their treatment withdrawn after 4 weeks. We evaluated the neuroprotective effects by the number of tyrosine hydroxylase positive neurons in the substantia nigra region of the brain of animals who were given continuous treatment and those of whom who had their treatment withdrawn. The results suggest that Ubisol-QE has a significant effect after 8 weeks of treatment, indicating that longer duration of the treatment is needed. In observing the results from the neuromotor decline experiments, the treatment group had far less hind leg slips than the untreated groups, reflecting the protection that was seen in the immunohistochemical results. Consequently it can be suggested that Ubisol-QE could be an effective treatment to halt the neurodegeneration found in PD patients.

neuroabstracts

Ubisol-QE as a Therapeutic Treatment for Paraquat Induced Neurodegeneration In Rat Model of Parkinson’s DiSease

GSK-3 Beta inhibition more strongly blocks acquisition than expression of amphetamine-produced conditioned place preference in rats R. WICKENS, R. J. BENINGER Undergradute Student, Queen’s University. Correspondence should be addressed to: rebekah.wickens@queensu.ca

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phase. Due to studies more strongly implicating signaling molecules in acquisition rather than expression of learning, we hypothesized a block of acquisition of CPP at doses that fail to block expression of CPP. Results supported this hypothesis: the 1.0 mg/kg dose of SB 216763 failed to block either acquisition or expression of CPP; the 2.0 mg/kg dose blocked acquisition, but not expression of CPP; and the 2.5 mg/kg dose blocked both acquisition and expression of CPP. These results indicate that inhibiting GSK-3β may attenuate incentive learning differentially in acquisition versus expression of conditioning. (Funded by NSERC)

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Dopamine (DA) has been implicated in behavioural sensitization and incentive learning. The signaling molecule glycogen synthase kinase3β (GSK-3β), activated downstream of DA D2-like receptors, affects DA-mediated behaviours. For example, inhibition of GSK-3β attenuates locomotor sensitization to psychomotor stimulant drugs. Few studies have examined the effects of GSK-3β inhibition in incentive learning paradigms. We examined the effects of GSK-3β inhibition on incentive learning produced by amphetamine (1.5 mg/kg) in the conditioned place preference (CPP) paradigm. The selective GSK-3 inhibitor SB 216763 was administered intraperitoneally to male Wistar rats at doses of 1.0, 2.0, and 2.5 mg/kg during the acquisition or expression

ARTIST Annie Zhu

CRITICAL REVIEW

Community-based Interventions International Development, Government, and Community 15

NIKITA ARORA Bachelor of Health Sciences (Honours) Program, Class of 2016 Correspondence should be addressed to: nikita.arora@learnlink.mcmaster.ca

ABSTRACT Non-governmental organizations (NGOs) are often criticized for their work in the healthcare sectors of developing countries. Recently, they have been moving from a projectized to sectoral support approach in an attempt to respond to this critique. Community-based intervention is a sectoral technique that can be used to exploit the community as a resource to provide the community itself with support in ways that the limited human resources in the healthcare sectors of developing countries currently cannot. The peer group intervention and community health worker are both tested strategies that have resulted in positive outcomes in the healthcare sectors of disadvantaged areas. Although community support systems may be limited in technical skill, a new body of research indicates that this intervention can nonetheless be a predictor of improved management of chronic illnesses that present high disease burden. By working with local stakeholders, NGOs may be able to effectively facilitate this intervention to promote sustainable positive health outcomes. By evaluating the effectiveness of the community-based intervention in Human Immunodeficiency Virus/ Acquired Immunodeficiency Syndrome (HIV/AIDS) management in Malawi, a greater understanding of its role can be gained in a more tangible manner.

Introduction

Case Study Background – Malawi’s Context

Peer Groups There are many types of community-based interventions, all with the goal of taking advantage of the community as a resource to improve health outcomes. The first of these interventions is the peer group in which participants discuss a certain healthcare issue by which they may be affected.10 This intervention is based on Albert Bandura’s social-cognitive learning theory model, which describes an improvement in selfefficacy or self-confidence as a means to promote behavioural change.11 Promoting behavioural change is instrumental in disease prevention in developing countries where HIV/AIDS is endemic.

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Peer group intervention is a technique in which a natural community leader is trained to facilitate group discussion about a certain topic with affected or interested individuals in the community. These interventions increase the peer group leaders’ as well as the participants’ understanding of their personal control, decisionmaking, and critical awareness of social and political environments. Participants are also able to increase their community engagement to accomplish

One in twenty pregnant women IN SUB-SAHARAN AFRICA have access to Mother-toChild Transmission Prevention programmes.3

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Human resources in Malawi’s healthcare sector are scarce, particularly due to low salaries and poor working conditions provided by the Ministry of Health (MOH). In Malawi, 50% of all healthcare posts in the MOH are unfilled.4 Qualified healthcare professionals are inclined to work abroad or with NGOs and aid organizations.5 This internal brain drain contributes to the MOH’s low capacity to manage diseases such as HIV/AIDS. In Malawi, it is estimated that there are 7435 people living with HIV/AIDS per physician.6 In sub-Saharan Africa,

While the healthcare sector is unable to manage the HIV/AIDS epidemic, the general population continues to engage in behaviours which lead to the spread of HIV. Factors such as gender inequality, conservative culture, and economic issues contribute to these behaviours. With respect to gender inequality and cultural values, male dominance over sexuality makes it difficult for females to negotiate safe and/or protected sex. Double standards also allow and in some cases, encourage men to have multiple partners.7 Moreover, when families pass through important events such as births or deaths, women are not allowed to have sex. While the women remain abstinent, men may seek sex elsewhere and later infect their monogamous partners.8 Some parents may even advise their daughters to buy their own personal items even though they are aware that their daughters’ only possible source of income is sexual intercourse.9 Economic issues, such as men traveling to urban centres to find work, increase the likelihood of divorce, multiple partners, and casual sex.7 Even if couples are together, they may not be able to afford or access protection.8

critical review

The role of the non-governmental organization (NGO) in the healthcare sector of developing countries is a highly debated subject because of controversial and potentially harmful interventions implemented in the past.1 Developed areas predominantly use a health care strategy in which highly skilled and specialized physicians deliver healthcare with sophisticated technology. Although international NGOs often try to apply this same approach to international development, severe human resource deficiencies in disadvantaged communities render such a strategy ineffective.3 Community-based intervention is one way in which human resource deficiencies can be overcome. Malawi is a country representative of many of the issues which developing countries face. Thus, the model of community-based intervention in the management of Human Immunodeficiency Virus/ Acquired Immunodeficiency Syndrome (HIV/ AIDS) within Malawi can be utilized to understand how healthcare initiatives can be better implemented by NGOs in developing countries.

1.5% of adults receive HIV testing and counselling, and 5% of pregnant women have access to Mother-to-Child Transmission Prevention programmes.3

The relationship between foreigners and local citizens when imparting healthcare services and knowledge is often unstable due to the history of colonialism in many developing countries, especially in sub-Saharan Africa. Thus, locally chosen peer group leaders enable residents to build trust and disseminate knowledge more efficiently.11 The native status In Malawi, although of the peer group leaders also allows them to 50% of women with address HIV/AIDS prevention by connecting HIV receive Motherthe training they receive with their cultural to-Child Transmission context. For example, prior to training, leaders Prevention, only express that they are often exposed to HIV6-15% of HIV-exposed prevention messages from sources such as the infants receive an HIV radio. However, these messages are discounted 14 test. due to certain cultural beliefs. For example, the words “sexual intercourse” are often considered to be foul language.11 By integrating cultural context into their training, local leaders can easily address these stigmas in group discussions. Furthermore, they can readily identify effective strategies to provide HIV/AIDS education, such as through plays, dramas, poems, and group teaching methods.11 In the past, leaders found that discussing HIV/AIDS was also extremely effective at church organizations,11 in a context where low-HIV-risk behaviours, such as abstinence and monogamous relationships, were promoted.8 In fact, instead of trying to form new peer groups, it is often beneficial to approach spiritual groups that already exist in churches to provide support.4 The outcomes of this combination of cultural context and HIV/AIDS education in peer group discussions are mainly positive. Peer group discussions help participants with infection combat loneliness and share knowledge about ways in which they can adopt a lifestyle that includes adherence to antiretroviral therapy (ART) – therapy which targets retroviruses such as HIV.2 Additionally, these sessions give participants increased selfefficacy and hope, by providing them with the tools necessary to grapple with a condition as daunting as HIV/AIDS. Participants understand that they can avoid infection if they decrease high-HIV-risk behaviours and increase preventative measures such as condom use.7

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the community health worker (CHW) – a layperson who is trained in certain niche healthcare work. CHWs can extend healthcare services by providing emotional support, counselling, adherence support, and home-based care.2 CHWs are managed by healthcare professionals such as nurses, who provide them with support and instructions.12 This kind of task shifting helps healthcare professionals take on leadership roles to manage CHWs, perform the technical aspects of their jobs more effectively, and decentralize healthcare operations to reach remote areas.13 One of the major benefits of CHWs is their provision of longitudinal care. In Malawi, although 50% of women with HIV receive Mother-toChild Transmission Prevention, only 6-15% of HIV-exposed infants receive an HIV test. HIVinfected babies then experience fast immune system deterioration and disease progression, as well as high mortality without early ART. This demonstrates that low retention and loss to followup are significant issues in Malawian healthcare. Community support can offer a solution to these problems by allowing for continuity of healthcare support in areas where healthcare is usually very discontinuous, reducing the loss to follow-up.14 For example, when women are pregnant, CHWs can act as case coordinators from the time of HIV/AIDS diagnosis of the mother at antenatal care, to early infant diagnosis, to infant treatment. Thus, CHWs can serve as stable positive role models and resources in high-prevalence communities.10 If formalized, the creation of a separate cadre of CHWs specifically trained to provide healthcare services may be a cost-effective solution to inadequate healthcare in developing regions. In a study assessing health literacy using patient characteristics and community support as predictors of two-year positive health outcomes, the latter yielded the strongest positive effect on health outcomes. Physical outcomes in HIV/ AIDS patients such as CD4+ T-cell counts and maintenance of viral suppression were also most improved by community support.2

Limitations of CommunityBased Interventions

Community Health WorkerS

The community-based intervention in general can be an effective way to enhance the capacity of public health operations. In the Thyolo district in Malawi for example, health provision centres have a maximum of only 400 hospital beds. In contrast, decentralized community care supports over 5000 people, 2000 of whom are affected by advanced HIV/AIDS.13

Healthcare professionals in Malawi are overburdened, limited to their technical roles, and cannot provide much emotional support or medical follow-up to their patients. Thus, a type of valuable community support used extensively in Malawi is

However, the CHW model still requires development, as CHWs have identified some systemic barriers that limit their effectiveness. An example of a barrier is the lack of continuing education regarding government policy changes

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critical review

their own goals. These outcomes are referred to as psychological empowerment and allow people to challenge cultural norms that cause stigmatization of HIV/AIDS discussion. Peer group leaders also report an increase in their own knowledge of HIV and HIV-prevention behaviour. This allows leaders to see themselves as change agents in order to ultimately reduce the high-risk behaviours of the people in their communities, neighbourhoods and workplaces.

and treatment guidelines recommended by health centres. It is thus essential for CHWs to understand the guidelines that encompass their roles through continual training by governmental entities.15 Additionally, most of the communitybased interventions currently under research are run at least partially by NGOs. Thus, when feedback is collected, people tend to emphasize the positive aspects of the program for fear of NGOs pulling back funds. To avoid this, capacity development and feedback mechanisms originating from the government are essential to further assess intervention effectiveness.11 Therefore, government involvement in CHW and peer group leader recruitment, selection, training protocol standardization, and provision of continuous retention incentives is critical to sustainably extend community-based interventions.16

underutilized in developing areas because they do not meet the needs of the people.1 It is essential for NGOs to understand that their practices may not necessarily benefit the target country, despite their humanitarian intentions. Usage of communitybased approaches is rare as NGOs usually focus on approaches that excessively rely on foreigners. In some cases, this may compromise independence of the country’s own activities and promote dependence on the NGOs.17

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Reviewed by DR. Eli Tshibwabwa let P. Implementing joint TB and HIV interventions in a rural district of Malawi: is there a role for an international non-governmental organisation? Int J Tuberc Lung Dis 2004 Sep;8(9):10581064. 5. Zachariah R, Teck R, Buhendwa L, Fitzerland M, Labana S, Chinji C, et al. Community support is associated with better antiretroviral treatment outcomes in a resource-limited rural district in Malawi. Trans R Soc Trop Med Hyg 2007 Jan 1;101(1):79-84. 6. Van Damme W, Kegels G. Health System Strengthening and Scaling Up Antiretroviral Therapy: The Need for ContextSpecific Delivery Models: Comment on Schneider et al. Reprod Health Matters 2006 May 1;14(27):24-26. 7. Kaponda CPN, Norr KF, Crittenden KS,

21.

22.

23.

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Cassels A. Health sector reform: Key issues in less developed countries. J Int Dev 1995 May 1;7(3):329-347. 2. Wouters E, Van Damme W, Van Loon F, van Rensburg D, Meulemans H. Public-sector ART in the Free State Province, South Africa: Community support as an important determinant of outcome. Soc Sci Med 2009 10;69(8):1177-1185. 3. Ellard D, Simkiss D, Quenby S, Davies D, Kandala NB, Kamwendo F, et al. The impact of training non-physician clinicians in Malawi on maternal and perinatal mortality: a cluster randomised controlled evaluation of the enhancing training and appropriate technologies for mothers and babies in Africa (ETATMBA) project. BMC Pregnancy Childbirth 2012 Oct 25;12:1162393-12-116. 4. Zachariah R, Teck R, Harries AD, Humb-

Edited by NICOLE FALZONE

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Dr. Eli Tshibwabwa is an Assistant Professor with the Department of Radiology and is currently involved in the facilitation of the Masters of Science in Global Health program at McMaster University. He has worked on global health projects in a variety of countries with diverse socioeconomic and cultural statuses and has served on the Board of Directors for the Canadian Coalition for Global Health Research. His interests lie primarily in the intersection of mentorship and teaching, evidence-based medicine and global health.

critical review

That being said, NGOs can fill many gaps in regards to human and financial resource deficiencies in developing countries through their experience working with various stakeholders such as the MOH.5 Thus, the NGO can do meaningful work if it works with local stakeholders to implement community-based interventions in response to the community’s specific strengths, weaknesses, and Although volunteer CHWs and peer group leaders needs. For example, Malawi has comprehensive have expressed a strong willingness to continue record-keeping systems at its hospitals and health juggling many roles,10 it is unrealistic to expect centres. Summaries are sent to district hospitals, them to do so forever. Volunteers receive incentives which are then entered into electronic databases such as rain boots, rain coats, bicycles, seed grain, at the national level. This efficient feedback and and fertilizer for private or community farms.4 Such information system can be used by NGOs to unsustainable payment methods will not facilitate implement community-based interventions.3 long-term community support in the healthcare sector. Also, while the community is a good Future Public Health resource that is currently untapped, it will ultimately Interventions reach a threshold. Ideally, these responsibilities should be taken on by the Ministry of Health (MOH), since community-based interventions Working with local stakeholders can increase their may cause policy-makers to disengage from taking ownership and accountability. This collaboration on these responsibilities. Thus, it is important to also allows the NGO to align its work with the goals cultivate a collective sense of responsibility between identified by the target country and use pre-existing 1 community leaders, health representatives, NGOs, structures to improve health outcomes. This is and the ministry through a forum for discussion important to avoid undermining or competing with to ensure continuous progress towards effective local work. Hence, the role of the NGO is one of mediation – to take advantage of the community healthcare delivery.13 as a resource and thereby manage chronic illnesses such as HIV/AIDS. Consequently, communityThe Role of the NGO based intervention may allow communities to take control of their own healthcare. It is only through NGOs are often criticized for their work in the promotion of such community-focused behavioural healthcare sector because of their short-term changes can the NGO contribute to sustainable projectized approach, lack of cultural context, and positive health outcomes and ultimately ensure implementation of policies inconsistent with the an effective exit strategy, enabling disadvantaged needs of the people. It is a common misconception communities to develop effective healthcare delivery that any type of healthcare policy is better than what infrastructure. ■ is currently in place. However, studies demonstrate that many healthcare services already exist and are

Norr JL, McCreary LL, Kachingwe SI, et al. Outcomes of an HIV Prevention Peer Group Intervention for Rural Adults in Malawi. Health Education & Behavior 2011 Apr 1;38(2):159-170. McCreary LL, Kaponda CPN, Norr KF, Jere DLN, Chipeta CH, Davis KK, et al. Rural Malawians’ Perceptions of HIV risk behaviors and their sociocultural context. AIDS Care 2008 09/01; 2013 Sept;20(8):946-957. Kaponda CPN, Dancy BL, Norr KF, Kachingwe SI, Mbeba MM, Jere DL. Research Brief: Community Consultation to Develop an Acceptable and Effective Adolescent HIV Prevention Intervention. Journal of the Association of Nurses in AIDS Care 2007;18(2):7277. Mbeba MM, Kaponda CP, Jere DL, Kachingwe SI, Crittenden KS, McCreary LL, et al. Peer group intervention reduces personal HIV risk for Malawian health workers. J Nurs Scholarsh 2011 Mar;43(1):72-81. McCreary LL, Kaponda CPN, Davis K, Kalengamaliro M, Norr KF. Empowering Peer Group Leaders for HIV Prevention in Malawi. Journal of Nursing Scholarship 2013 Sept 1;45(3):288-297. Msyamboza KP, Savage EJ, Kazembe PN, Gies S, Kalanda G, D’Alessandro U, et al. Community-based distribution of sulfadoxine-pyrimethamine for intermittent preventive treatment of malaria during pregnancy improved coverage but reduced antenatal attendance in southern Malawi. Trop Med Int Health 2009 Feb;14(2):183189. Zachariah R, Teck R, Buhendwa L, Labana S, Chinji C, Humblet P, et al. How can the community contribute in the fight against HIV/AIDS and tuberculosis? An example from a rural district in Malawi. Trans R Soc Trop Med Hyg 2006 Feb 1;100(2):167-175. Kim MH, Ahmed S, Buck WC, Preidis GA, Hosseinipour MC, Bhalakia A, et al. The Tingathe programme: a pilot intervention using community health workers to create a continuum of care in the prevention of mother to child transmission of HIV (PMTCT) cascade of services in Malawi. J Int AIDS Soc 2012 Jul 11;15 Suppl 2:17389. Puchalski Ritchie LM, van Lettow M, Barnsley J, Chan AK, Joshua M, Martiniuk AL, et al. Evaluation of lay health workers’ needs to effectively support anti-tuberculosis treatment adherence in Malawi. Int J Tuberc Lung Dis 2012 Nov;16(11):1492-1497. Celletti F, Wright A, Palen J, Frehywot S, Markus A, Greenberg A, et al. Can the deployment of community health workers for the delivery of HIV services represent an effective and sustainable response to health workforce shortages? Results of a multicountry study. AIDS 2010;24. GILSON L, SEN PD, MOHAMMED S, MUJINJA P. The potential of health sector nongovernmental organizations: policy options. Health Policy Plan 1994 Mar 1;9(1):14-24. Banda G, Kafulafula G, Nyirenda E, Taulo F, Kalilani L. Acceptability and experience of supportive companionship during childbirth in Malawi. BJOG 2010 Jul;117(8):937-945. Lukas CV, Holmes SK, Cohen AB, Restuccia J, Cramer IE, Shwartz M, et al. Transformational change in health care systems: An organizational model. Health Care Manage Rev 2007;32(4). Pagel C, Lewycka S, Colbourn T, Mwansambo C, Meguid T, Chiudzu G, et al. Estimation of potential effects of improved community-based drug provision, to augment health-facility strengthening, on maternal mortality due to post-partum haemorrhage and sepsis in subSaharan Africa: an equityeffectiveness model. The Lancet 2009 Oct;374(9699):14411448. Rosato M, Mwansambo C, Lewycka S, Kazembe P, Phiri T, Malamba F, et al. MaiMwana women’s groups: a community mobilisation intervention to improve mother and child health and reduce mortality in rural Malawi. Malawi Med J 2010 Dec;22(4):112-119. Travis P, Bennett S, Haines A, Pang T, Bhutta Z, Hyder AA, et al. Overcoming healthsystems constraints to achieve the Millennium Development Goals. The Lancet 4; 2004 Sept;364(9437):900-906. Van Damme W, Kober K, Laga M. The real challenges for scaling up ART in sub-Saharan Africa. AIDS 2006;20(5).

critical review 2

ARTIST Mark Belan

CRITICAL REVIEW

Neuroprotective Agents for Traumatic Brain Injury THEORETICAL THERAPY OR THE FUTURE OF TREATMENT? 19

HELEN GENIS Bachelor of Health Sciences (Honours) Program, Class of 2017 Correspondence should be addressed to: olena.genis@learnlink.mcmaster.ca

ABSTRACT An increasing awareness of concussions in sports has led researchers to uncover that brain tissue damage is not instantaneous, but rather a delayed process following the initial injury. Recently, neuroprotective agents have been developed that will be administered after injury to reduce the effects of Traumatic Brain Injury (TBI). These agents include NMDA receptor antagonists that aim to interfere with excitotoxicity and reduce neuronal death. While these agents have improved learning and cognitive performance in animal models, their effects have not been as positive in clinical trials. Calpain inhibitors have also shown neuroprotective effects, and protect against axonal damage in the white matter of the brain. In the future, a better understanding of the cellular mechanisms of TBI will allow better development of neuroprotective agents for clinical use.

behaviourally, and emotionally.7 Even small concussions can result in difficulties performing everyday tasks and returning to jobs.8, 9

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These long-term disabilities and difficulties in memory, learning, and cognitive performance often result from delayed subcellular processes that occur days, and sometimes weeks, after the initial injury. Such cellular mechanisms include excitotoxicity and white matter injury, which can lead to neuronal death and axotomy, respectively. Although there is no current clinical treatment available to reduce their progression, the future promises IntroductioN a greater understanding of the biological processes that occur in the brain following Athletes and injuries have always gone hand TBI. This understanding could allow for in hand, and an estimated 300,000 sport- the development of neuroprotective agents related concussions occur in the United States that can be administered to patients with each year.1 In the last decade, however, there TBI in order to disrupt damaging cellular has been a growing concern for diagnosis mechanisms. and prevention of further injury. For example, recent concussion management practices DIAGNOSIS recommend 24-48 hours of rest.2 While this prevents the athlete from sustaining In order to effectively treat TBI, there needs another concussion during that time, it does to be an accurate and efficient method of not stop the underlying cellular mechanisms diagnosing the injury and the assessing the that occur in the brain after injury. Many level of severity. Currently, physicians use the athletes will return to play within two weeks Glasgow Coma Scale (GCS), neurological after their symptoms seemingly vanish, examinations, and computed tomography unaware that neurophysiological deficits in (CT) imaging to diagnose TBI.10 The GCS cognitive performance and memory exist for rating is used to assess a patientâ&#x20AC;&#x2122;s conscious at least six months post-concussion.3,4 As a state and therefore determine the level of result, concussions should be monitored for severity; a GCS score of 3-8 detrimental changes in behaviour and mental classifies severe TBI, 9-12 status, and should be considered a serious indicates moderate TBI, medical concern. and 13-15 describes mild Traumatic Brain Injury TBI.11 While this makes the (TBI) is a significant Concussion management and treatment in GCS useful in measuring a global health concern athletes is one of the most critical challenges patientâ&#x20AC;&#x2122;s neurological state and a major cause of in sports medicine. Concussion is the most and providing information on mortality; in the United frequent form of mild traumatic brain injury possible outcomes, it does not States alone, it is (mTBI) that affects not only athletes, but show the physiological source estimated that 1.7 million also people who are involved in motor vehicle of the symptoms, and can be people experience TBIS accidents, recreational activities, and falls.5 complicated by drug use and annually, resulting in Traumatic brain injury (TBI) is a significant multiple traumas.12 52,000 deaths.5,6 global health concern and a major cause of mortality; in the United States alone, it is In general, mild traumatic estimated that 1.7 million people experience brain injury is often difficult TBIs annually, resulting in 52,000 deaths.5,6 to diagnose due to limitations in available Furthermore, at least 5.3 million individuals technology and our understanding of cellular live with a lifelong disability caused by TBI, mechanisms. The current applications of CT which affects them physically, cognitively, and magnetic resonance imaging (MRI) scans

are limited in the case of mTBIs. Scans often appear normal, either because there is no structural damage to the patient’s brain or the scans do not have the resolution to visualize the microscopic damage that occurs in mTBI cases.13 This leads to incomplete medical treatment for many patients since their MRI and CT scans show no detectable pathologies. Instead, the patients are released once they stop exhibiting clinical symptoms. Ultimately, understanding the full cellular mechanism behind TBI will lead to better diagnosis and treatment.

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critical review

CELLULAR MECHANISMS: EXCITOTOXICITY

Until recently, it was thought that the initial physical impact to the brain was the ultimate cause of brain tissue damage. However, in the past two decades, experiments have shown that secondary injury – the delayed cellular mechanisms that occur hours and even days after the initial injury – is actually responsible.14 Since this process evolves over time, there may be an opportunity to introduce neuroprotective therapies that will reduce brain damage. Research has uncovered that one of the major processes responsible for Recently, RAT MODELS neuron damage in TBI is HAVE shown that excitotoxicity, which involves multiple post-injury a large release of the excitatory administrations of neurotransmitter glutamate which subsequently leads an NMDA antagonist to neuronal death.14 Under INCREASE THE NUMBER OF normal conditions in the SURVIVING NEURONS IN THE brain, glutamate is released HiPPOCAMPUS AND improve into the synaptic cleft where learning and cognitive it increases in concentration, performance.20 but quickly decreases within a milliseconds.15 This is a result of the glutamateglutamine shuttle in which astrocytes convert glutamate into glutamine, and the resulting glutamine diffuses readily back into the neuronal membrane.15 However, following TBI, cell membranes are compromised and release K+ as well as Na+ and Ca2+. This results in the depolarization of the membrane.14 The injury also causes mitochondrial dysfunction, which leads to reduced rates of ATP synthesis and a decreased activity of the enzyme Na+K+-ATPase.17,18 Therefore, membrane depolarization increases, causing an influx of Ca2+ through voltage-dependent channels and a release of glutamate.14 However, the glutamate-glutamine shuttle does not uptake the majority of the glutamate because of a down-regulation of glutamate transporters,

and an altered Na+/K+ gradient that decreases glutamate transport capacity.19 As a result, increased levels of extracellular glutamate activate glutamate receptors (NMDA and AMPA) cause a neuronal influx of Ca2+, This results in cell death by necrotic or apoptotic mechanisms. Since glutamate receptors mediate neuronal death, glutamate receptor antagonists have been studied in rat models as a possible neuroprotective treatment. Recently, it has been shown that multiple post-injury administrations of an NMDA antagonist increase the number of surviving neurons in the hippocampus and improve learning and cognitive performance.20 However, clinical trials using glutamate receptor antagonists have not been as successful. One study focused on treating severe TBIs using Selfotel, a competitive NMDA receptor blocker, but was terminated during the third phase of the clinical trial after preliminary reports showed no positive outcomes.21 Other studies reported no adverse effects, but also have insufficient data to conclude that NMDA antagonists display neuroprotective effects in patients with TBI.22 This may be because a majority of NMDA antagonists cannot readily cross the blood-brain barrier.23 As such, physicians would have to administer larger doses than given in the animal models to achieve the same neuroprotective effects.24 Unfortunately, this could also result in systemic toxicity in the patient. In addition, NMDA receptor antagonists can result in further damage if administered outside its limited therapeutic window.25 This is because glutamate receptor antagonists interfere with “upstream” signals, which subsequently affect various “downstream” signaling pathways. Furthermore, since there are many pathways that may result in neuronal death, using glutamate receptor antagonists to limit the calcium influx will not guarantee neuronal survival. In the future, researchers should focus on TBI treatments that may block multiple pathways involved in neuronal death.

WHITE MATTER INJURY Another possible neuroprotective treatment for TBI targets white matter injury. White matter is the area of the brain that consists of glial cells and myelinated axons that transmit signals between different areas of grey matter in the brain. Diffuse axonal injury (DAI) has shown a strong association with TBI and appears in about 50% of TBI patients who require hospitalization.26 Until recently, it was believed that the initial impact to the brain caused mechanical tearing in the majority of the axons, or axotomy. Research conducted in the last decade, however, suggests that the main mechanism is secondary or delayed axotomy

primary locations of injury in DAI. While administering the treatment post-injury in animals was successful in protecting the axonal structure, the surviving axons were not as functional as the normal axons.30 Other drawbacks of calpain inhibitors include their relatively low solubility and metabolic instability. Thus, the pharmocodynamics of calpain inhibitors must be optimized prior to their use in clinical trials.32

Although no clinical treatment for TBI has been proven effective, calpain inhibitors have already shown neuroprotective capabilities in animal models.30,31 Unlike glutamate receptor antagonists, calpains remain largely inactivated under normal conditions.32 As a result, inhibiting calpains would not have many unfavourable side effects on the rest of the central nervous system (CNS) and would instead provide significant protection to white matter tracts. Moreover, calpain inhibitors administrated up to four hours post-injury in mice models have shown to be as effective as those administered immediately.31 This is a significant advantage since most patients require time to be diagnosed once they reach the hospital, and medication is often not administered until much later. Calpain inhibitors have also shown to maintain both axonal function and structural integrity in the corpus callosum, lasting 14 days following the initial injury.30 The corpus callosum, which is the white matter tract connecting the left and right hemispheres in the brain, is one of the

Traumatic brain injury is a significant health concern that can result in life-long disability, or even death. Current diagnosis is largely based on the Glasgow Coma Scale, neurological assessment, and CT imaging; however, both GCS scores and neuroimaging lack the ability to detecting the physiological consequences of having sustained a concussion. Although TBI is initiated by blunt force trauma or by rapid acceleration-deceleration movements, damage to the brain largely as a result of secondary injury. During this time, cellular processes such as excitotoxicity and abnormal calcium homeostasis results in neuronal death and axonal damage in white matter. Glutamate receptor antagonists and calpain inhibitors are being examined as possible neuroprotective agents, and have shown better functional outcomes by protecting axonal structure in animal models. Further research into the cellular mechanisms that occur during secondary injury is warranted, and will allow for the development of novel neuroprotective agents. ■

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tion and Control, 2010. 7. National Institutes of Health. Rehabilitation of persons with traumatic brain injury. NIH consensus statement. 1998; 16(1): 26-28. 8. Alves W, and Macciocchi SN, and Barth JT. Postconcussive symptoms after uncomplicated mild head injury.J Head Trauma Rehabil . 1993; 8(3): 48-59. 9. Englander J, Hall K, Stimpson T, Chaffin S. Mild traumatic brain injury in an insured population: subjective complaints and return to employment. Brain Inj. 1992;6(2):161– 166. 10. Sharma R, and Laskowitz DT. Biomarkers in traumatic brain injury. Current Neurol Neurosci Rep. 2012; 12(5): 560-569. 11. Van Baalen B, Odding E, Mass AI, Ribbers GM, Bergen MP, and Stam HJ. Traumatic brain injury: classification of initial severity and determination of functional outcome. Disabil Rehabil. 2003; 25(1): 9-18. 12. Papa L et al. Use of biomarkers for diagnosis and management of traumatic brain injury patients. Expert Opin Med Diagn. 2008; 2(8): 937-945 13. Borg J, et al. Diagnostic procedures in mild traumatic brain injury:

Edited by Bernard Ho

Guskiewicz et al. Cumulative effects associated with recurrent concussion in collegiate football players. JAMA. 2003; 290(19): 2549-2555. Tator, CH. Concussions and their consequences: current diagnosis, management and prevention. Can Med Assoc J . 2013; 185(11): 975979. Baillargeon A, Lassonde M, Leclerc S, and Ellemberg D. Neuropsychological and neurophysiological assessment of sport concussion in children, adolescents and adults. Brain Inj . 2012; 26(3): 211-220. Rhine, D. J., and T. Lamvohee. Comparative incidence of concussion and return to play time in two Canadian minor hockey groups over the 2011–2012 season. Br J Sports Med . 2013; 47(5): e1-e1. Thurman, DJ, Alverson C, Dunn KA, Guerreno J and Sniezek JE. Traumatic brain injury in the United States: a public health perspective.J Head Trauma Rehabil . 1999; 14(6): 602-615. Traumatic brain injury in the United States: emergency department visits, hospitalizations, and deaths, 2002-2006. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Injury Preven-

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Dr. Eugene Park holds a Ph..D. from the University of Toronto, Institute of Medical Sciences, and is currently working as a senior research associate at St. Michael’s Hospital in the lab of Dr. Andrew Baker. Dr. Park uses a controlled blast injury model to evaluate mechanisms of white matter injury following blast trauma. He is also interested in the mechanisms of cellular and axonal injury in other brain injury models, with the ultimate goal of developing novel therapies to treat concussion.

Conclusion

results of the WHO collaborating centre task force on mild traumatic brain injury. J Rehabil Med. 2004; 36(0): 61-75. 14. Park, E, Bell J.D., and Baker A.J. Traumatic brain injury: Can the consequences be stopped?. Can Med Assoc J. 2008; 178(9): 1163-1170. 15. Bak LK, Schousboe A, and Waagepetersen HS. The glutamate/GABA‐ glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. J Neurochem. 2006; 98(3): 641-653. 16. Mattson MP., and Scheff SW. Endogenous neuroprotection factors and traumatic brain injury: mechanisms of action and implications for therapy. J Neurotrauma. 1994; 11(1): 3-33. 17. Robertson, CL. Mitochondrial dysfunction contributes to cell death following traumatic brain injury in adult and immature animals. J Bioenerg Biomembr. 2004; 36(4): 363-368. 18. Lifshitz J., Sullivan PG., Hovda DA, Wieloch T, & McIntosh, TK.Mitochondrial damage and dysfunction in traumatic brain injury. Mitochondrion. 2004; 4(5): 705-713. 19. Yi, JH, & Hazell AS. Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury. Neurochem Int. 2006; 48(5): 394-403. 20. Wang T, Huang XJ, Van KC, Went GT, Nguyen JT and Lyeth BG. Amantadine Improves Cognitive Outcome and Increases Neuronal Survival after Fluid Percussion TBI in Rats. J Neurotrauma. 2013. 21. Morris GF, Bullock R, Marshall SB, Marmarou A, Maas A, and Marshall LF. Failure of the competitive Nmethyl-D-aspartate antagonist Selfotel (CGS 19755) in the treatment of severe head injury: results of two phase III clinical trials. J Neurosurg. 1999; 91(5): 737-743. 22. Bullock, M., et al. An Open label study of CP 101,606 in subjects with a severe traumatic head injury or spontaneous intracerebral hemorrhage. Ann N Y Acad Sci. 1999; 890(1): 51-58. 23. Arrowsmith JE, Harrison MJ, Newman SP, Stygall J, Timberlake N, and Pugsley WB. Neuroprotection of the Brain During Cardiopulmonary Bypass A Randomized Trial of Remacemide During Coronary Artery Bypass in 171 Patients. Stroke. 1998; 29(11): 2357-2362. 24. Muir KW, and Lees KR. Clinical experience with excitatory amino acid antagonist drugs. Stroke. 1995; 26(3): 503-513. 25. Steinberg GK, Panahian N, PérezPinzón, MA, Sun GH, Modi MW, & Sepinwall, J. Narrow temporal therapeutic window for NMDA antagonist protection against focal cerebral ischaemia. Neurobiol Dis. 1995; 2(2): 109-118. 26. Meythaler JM, Peduzzi JD, Eleftheriou E, and Novack TA. Current concepts: Diffuse axonal injury associated traumatic brain injury. Arch Phys Med Rehabil 2001;82(10): 1461-1471. 27. Büki A., and Povlishock JT. All roads lead to disconnection?–Traumatic axonal injury revisited. Acta Neurochir (Wien) . 2006;148(2): 181-194. 28. Bains M et al. Pharmacological analysis of the cortical neuronal cytoskeletal protective efficacy of the calpain inhibitor SNJ 1945 in a mouse traumatic brain injury model. J Neurochem. 2013. 29. Saatman KE, Creed J, and Raghupathi R. Calpain as a therapeutic target in traumatic brain injury. Neurotherapeutics. 2010;7(1): 31-42. 30. Ai J, Liu E, Wang J, Chen Y, Yu J, Baker AJ. Calpain inhibitor MDL-28170 reduces the functional and structural deterioration of corpus callosum following fluid percussion injury. Journal of neurotrauma. 2007;24(6): 960978. 31. Kupina NC et al. The novel calpain inhibitor SJA6017 improves functional outcome after delayed administration in a mouse model of diffuse brain injury. J Neurotrauma. 2001;18(11): 1229-1240. 32. Wang KW, Larner SF, Robinson G, and Hayes RL. Neuroprotection targets after traumatic brain injury. Curr Opin Neurol. 2006; 19(6): 514-519.

critical review

that evolves following the initial impact.27 This has been largely attributed to high levels of intracellular calcium that activates a group of enzymes known as calpains. These enzymes degrade intracellular proteins such as αII-spectrin, a protein responsible for the structure and shape of the axon. Over time, the breakdown of spectrin causes damage to the cytoskeleton network. Recent studies have shown that the frequency of calpainmediated spectrin-proteolysis increases over time, suggesting that axonal damage is a delayed process.28, 29

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ARTIST MARK BELAN

CRITICAL REVIEW

Tonal Harmony

T H E I N T E R PLAY B E T W E E N M U S I C A N D TO N A L LA N G U AG E S 23

MAXWELL TRAN AND ISHAN ADITYA Bachelor of Health Sciences (Honours) Program, Class of 2017 Correspondence should be addressed to: maxwell.tran@learnlink.mcmaster.ca and ishan.aditya@learnlink.mcmaster.ca

ABSTRACT This paper presents a summary of current research on the synergies between music and language, especially tonal languages. Since music and language are processed by similar brain structures, research studies have found that individuals with a tonal language background tend to be better at discriminating pitch in music. As well, musically experienced individuals are found to be more proficient at detecting speech-based stimuli. Due to this relationship between music and language, music-based therapies are being created to improve language acquisition and to treat communication deficits associated with developmental disorders.

music post-surgery has been found to reduce sedation.13 Scientific literature provides ample credence for the wide-ranging therapeutic applications of music.

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Researchers have noted that autistic children tend to have enhanced pitch memory and discrimination capabilities as compared to nonautistic children.14,15 Darrow and Armstrong observed that musicbased activities provide nonintimidating experiences that Introduction: MUSIC, LANGUAGE, encourage children with ASDs to step out of their comfort zone, explore various musical AND THE BRAIN instruments at their own pace, and develop Music and speech are forms of expression direct communication with the therapist. 16 that rely on the ability of the brain to process Researchers theorized that training in music them. An intrinsically temporal activity, music may help alleviate some of the core autism involves the integration of sensory, motor, and challenges of attention, non-verbal, and affective systems.1 Music and language resemble language-based or verbal communication, each other because they are both hierarchically poor motor performance, and behavioural arranged. Notes and keys or letters and syllables problems.17 Based on this observation, musicform the lower level units which integrate to based therapies have been increasingly used in form higher-level units, such as chords and communicating with children with ASDs.18 melodies or words and sentences.2 Moreover, It is estimated that nearly 12% of autism both music and language involve cognitive interventions and 45% of alternate treatment processes of attention and memory.3,4,5 Due to strategies in schools are music-based.18, 19 these similarities, music is currently being used as a treatment for developmental disorders COGNITIVE NEUROSCIENCE OF characterized by poor communication, such as MUSIC AND TONAL LANGUAGES autism spectrum disorders (ASDs), attention deficit hyperactivity disorder (ADHD), Yip classified 60 to 70 percent of existing aphasia, and dyslexia.6,7,8 languages as tone-based. Tonal languages revolve around lexical tones instead of words, MUSIC AS A THERAPEUTIC TOOL so the pitch contour of a particular word influences the core meaning Recently, music has been shown to lessen of that word.20 For example: the pain and anxiety. In a comprehensive research Thai tonal language consists of five “Music is the one review of more than 1,000 patients suffering tones: three level tones (low, mid, incorporeal entrance from coronary artery disease, Bradt and high) and two contour tones (rising, into the higher world Dileo found that listening to music alleviated falling). By contrast, English is not of knowledge which the anxiety resulting from the disease, as a tonal language because words comprehends mankind reflected in reduction of heart rate and blood like ‘piano’ and ‘book’ have the but which mankind pressure.10 Later, Bradshaw et al. found that same tone regardless of the pitch cannot comprehend” listening to music reduced the intensity of pattern used for pronunciation. – Ludwig van Beethoven responses to pain stimuli.11 Prescribing music listening to patients with anxious personality An experiment by Stevens, Keller, traits was particularly effective. Music is and Tyler examined the effect of a dynamic, complex, and emotionally engaging tonal language background (Thai) compared to enough to activate sensory pathways in the a non-tonal language background (Australian brain that compete with pain pathways. In a English) with regards to discriminating pitch research review led by Chanda and Levitin, contour in speech and music.21 Subjects were listening to music reduced levels of the presented with two-syllable spoken-word stress hormone cortisol.12 In fact, listening to stimuli in Thai and English with weak-strong

Communication

SocialEmotional Elements of Music Theory Listening Singing Music making Rhythmic Movements

critical review D ecem b er 2 0 1 3 | meducator

Joint action and perception facilitate a shared purpose, shared affect, and bonding between individuals.

Motor

SensoryPerceptual

Behavioural

FIGURE 1: Influence of musical experiences on development. Musical experiences may directly or indirectly affect the development of the perceptuomotor, communication, social-emotional, and behavioural domains of the brain.9 For example, auditory perception and movement – activities involved with music making – allow for verbal communication, which is lacking in some autistic children.

Auditory perception and associated movement together with facilitate verbal communication.

Positive emotions lead to reduced negative behaviours and vice-versa.

There are likely neural underpinnings for the auditory capabilities of tonal language speakers. Based on functional magnetic resonance imaging results, only tonal language speakers displayed activation of the left frontal operculum near Broca’s area, which is important for understanding language.23 Their brains identified the functional properties of pitch pattern stimuli rather than the auditory properties, thereby resulting in the activation of language-specific mechanisms. Another theory is that neuroplasticity in the brainstems of tonal language speakers contributes to heightened perception of the linguistic elements of speech.24 Neuroplasticity enables neurons in the brain to remunerate for injury and adjust to environmental changes. One mechanism involved is axonal sprouting, whereby nerve endings are generated to form new pathways.

Music and language have a bi-directional relationship in the sense that musical training has a positive impact on tonal language acquisition. In one study, English-speaking musicians and nonstress patterns. Each word was announced twice musicians were exposed to Mandarin tones of and subjects determined whether the repetition the syllable “sa”.25 None of the participants had of the word had the same or different intonation. prior experience with Mandarin, yet musicians In the next task, subjects listened to pairs of were almost 25% better at identifying the musical intervals and were asked to identify the lexical tones. A second study by Slevc and intervals as same or different. Results showed Miyake found a strong correlation between that tonal language speakers identified pitch musical ability and tonal memory as well as changes more quickly and accurately for Thai tonal memory production.26 The effect of music and English words. Moreover, while tonal on tonal language acquisition can be explained and non-tonal language speakers had similar by the fact that compared to non-musicians, accuracy for the musical tasks, tonal language musicians exhibit faster and more rigorous speakers had significantly faster reaction times auditory brainstem responses to all types to pitch changes. of auditory stimuli.27 As a result, musicians are better at processing musical intervals, From a cognitive neuroscience perspective, communicative sounds, and speech stimuli there are several theories that could explain with pitch contours. this enhanced auditory perception in tonal language speakers. Firstly, individuals from IMPLICATIONS OF THE RESEARCH different cultures demonstrate different brain function lateralization. In response to pitch The evident and consistent relationship stimuli resembling linguistic tones, Mandarin between music and language has numerous Chinese (and similarly, Thai) speakers applications within the healthcare field. The demonstrated increased activation in the bi-directionality between music and language brain’s left hemisphere, which is responsible can be used to create specific music-based for language ability.22 Meanwhile, English rehabilitation treatments for individuals with speakers showed a greater activation in the speech impairments due to old age or stroke. brain’s right hemisphere, which controls visual At the other end of the age spectrum, musicprocesses. The success of Thai speakers, relative based treatments can help children struggling to English speakers, in the Stevens, Tyler, and with language acquisition. In either case, the Keller experiment may be attributed to the distinction must be made of the language language-based auditory items presented. background – tonal versus non-tonal – so that

therapeutic efforts are more targeted. Moreno et al. randomly assigned eight-year old non-musician children to receive music or painting training.28 Results showed that the musically trained children responded significantly better to language-based stimuli, as they exhibited superior discrimination of pitch variations in speech. Another application of the bi-directionality between music and language is in the treatment of autistic individuals. A recently developed music-based intervention, an auditory-motor mapping training, consists of three parts: singing, rhythmic motor activity (e.g. drum playing), and imitative repetition.29 Auditory-motor mapping training strengthened the association between the frontal and temporal lobes of the brain, which are atypical in autistic patients and may be responsible for impaired communication skills. Thus, auditory-motor mapping training can be applied to help autistic patients acquire tonal languages.

FUTURE RESEARCH

Researchers have noted cultural differences in philosophy of life and living between East Asians and Westerners. Due to these culturally learned behaviours, East Asians tend to have a more interdependent and holistic approach to life.32,33

1Alluri V, Toiviainen P, Jääskeläinen LP, Glerean E, Sams M, Brattico E. Large-scale brain networks emerge from dynamic processing of musical timbre, key and rhythm. NeuroImage. 2011 Feb 15; 59(4):3677–3689. Molnar-Szakacs I, Overy K. (2006). Music and mirror neurons: from motion to ‘e’ motion. Neuroscience. 2006; 1:235–241. doi:10.1093/scan/ nsl029. Foxton JM, Talcott JB, Witton C, Hal B, McIntyre F, Griffiths TD. Reading skills are related to global, but not local, acoustic pattern perception. Nat. Neurosci. 2003; 6:343–344. doi: 10.1038/nn1035. Kraus N, Chandrasekaran B. Music training for the development of auditory skills. Neurosci, 11. 2010; 599– 605. doi:/10.1038/nrn2882. Patel AD, Peretz I, Tramo M, Labreque R. Processing prosodic and musical patterns: a neuropsychological investigation. Brain Lang. 1998; 61:123– 144. doi: 0.1006/brln.1997.1862. Schlaug G, Marchina S, Wan CY. The use of non-invasive brain stimulation techniques to facilitate recovery from post-stroke aphasia. Neuropsychological Review. 2011; 21:288-301. Tallal P, Gaab N. Dynamic auditory processing, musical experience and language development. Trends

Neurosci. 2006; 29:382–390. doi: 10.1016/j.tins.2006.06.003. 8. Trainor LJ. The Neural Roots of Music. Nature. 2008; 598 -599. 9. Srinivasan AN, Bhat SM. A review of “Music and Movement” therapies for children with autism: embodied interventions for multi-system development. Frontiers in Integrative Science. 2013; 7. doi: 10.3389/ fnint.2013.00022. 10. Bradt J, Dileo C. Music for stress and anxiety reduction in coronary heart disease patients. Cochrane Database of Systematic Reviews. 2009; 2. doi:0.1002/14651858.CD006577. pub2 11. Bradshaw DH, Donaldson GW, Jacobson RC, Nakamura Y, Chapman CR. Individual differences in the effects of music engagement on responses to painful stimulation. The Journal of Pain. 2011; 12 (12):1262. doi:10.1016/j. jpain.2011.08.010 12. Chanda M, Levitin D. The neurochemistry of music. Trends in Cognitive Sciences. 2013; 17(4):179-193. doi: 10.1016/j.tics.2013.02.007 13. Nilsson U. The Anxiety- and Pain-Reducing Effects of Music Interventions: A Systematic Review. Association of periOperative Registered Nurses Journal. 2008; 87(4):780-807.

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The existing research findings support the idea of bi-directionality between music and language, especially tonal languages.4,30 There is a positive correlation between language ability and music, and this relationship may serve to enhance the efficacy of therapeutic musical interventions for the brain. ■

Dr. Michael Wong (B.Sc., Ph.D.) is a professor at McMaster University in the Faculty of Health Sciences. His research involves applying a combination of physics, neurophysiology, and probability calculus to investigate tactile spatial acuity. The themes of his research include exploring the concept of enhanced tactile perception in the blind, and changes in tactile acuity during development and aging.

There is an inherent methodological challenge in conducting studies on the relationship of music and tonal languages. Inconsistencies occur due to lack of a clear definition for tonal language and music in the participant populations of the studies. The participant groups discussed above differ in their level of language and musical skill level. Acquisition of skill in some cases was acquired by exposure to speech within one’s family or cultural setting as opposed to formal language education. Therefore, the level of language skill cannot be categorised as systematically as acquisition of musical skill. These factors increase the difficulty of making accurate comparisons or predictions across populations.31

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Reviewed by Dr. MICHAEL WoNG

The age of subjects may also impact the efficacy of music-based language therapies. Brain plasticity is highest when subjects are young.31 As a result, children, teenagers, adults, and seniors could respond differently to musicbased treatments.

14. Heaton P. Pitch, memory, labelling and dis-embedding in autism. 2003 J. Child Psychol. Psychiatry. 2003; 44:543–551. 15. Bonnel A, Mottron L, Peretz I, Trudel M, and Gallun E. Enhanced pitch sensitivity in individuals with autism: a signal detection analysis. Journal of Cognitive. Neuroscience 2003; 15:226–235. 16. Darrow AA, Armstrong T. Research on music and autism: implications for music educators. Update Appl. Res. Music Edu. 1999; 18:15–20. 17. Srinivasan AN, Bhat SM. A review of “Music and Movement” therapies for children with autism: embodied interventions for multi-system development. Frontiers in Integrative Science. 2013; 7. doi: 10.3389/ fnint.2013.00022. 18. Hess K, Morrier M, Heflin L, and Ivey M. Autism treatment survey: services received by children with autism spectrum disorders in public school class- rooms. Journal of Autism Development Disorders. 2008; 38:961–971. 19. Simpson R, deBoer-Ott S, Griswold D, Myles B, Byrd S, Ganz J. Autism spectrum disorders: interventions and treatments for children and youth. Thousand Oaks, CA: Corwin Press 2005. 20. Yip M. Tone. Cambridge: Cambridge University Press, 2002. 21. Stevens CJ, Keller PE, Tyler, MD. Tonal language background and detecting pitch contour in spoken and musical items. Psychology of Music. 2013; 4(1):59-74. doi: 10.1177/0305735611415749. 22. Klein D, Zatorre RJ, Milner B, Zhao V. A cross-linguistic PET study of tone perception in Mandarin Chinese and English speakers. NeuroImage. 2001; 13:646-653. 23. Gandour J, Wong D, & Hutchins G. Pitch processing in the human brain is influenced by language experience. Neuro Report. 1998; 9:2115-2119. 24. Krishnan A, Gandour JT, Bidelman GM. The effects of tone language experience on pitch processing in the brainstem. Journal of Neurolinguistics. 2010; 23(1); 81–95. 25. Lee CY, Hung TH. Identification of Mandarin tones by English-speaking musicians and non-musicians. The Journal of the Acoustical Society of America. 2008; 124:3235. doi: 10.1121/1.2990713. 26. Slevc L, Miyake A. Individual differences in second-language proficiency: does musical ability matter? Psychological Science. 2006; 17:675–681. 27. Wong P, Skoe E, Russo N, Dees T, and Kraus N. Musical experience shapes human brainstem encoding of linguistic pitch patterns. Nat. Neurosci. 2007; 10:420–422. 28. Moreno S, Marques C, Santos A, Santos, M, Castro SL, Besson M. Musical training influences linguistic abilities in 8-year-old children: more evidence for brain plasticity. Cereb Cortex. 2009; 19:712–723.doi:10.1093/cercor/bhn120. 29. Yan C, Schlaug G. Neural pathways for language in autism: the potential for music-based treatments. Future Neurology. 2010; 5(6):797-805. 30. Patel AD. Language, music, and the brain: a resource-sharing framework, in language and music as cognitive systems, eds. Rebuschat P, Rohrmeier M, Hawkins J, Cross I, Oxford: Oxford University Press, 204–223, 2012. 31. Herholz S, Zatorre R. Musical training as a framework for brain plasticity: behaviour, function, and structure. Neuron. 2012; 76:486–502. doi: 10.1016/j.neuron.2012.10.011. 32. Chua HF, Boland JE, Nisbett RE. Cultural variation in eye movements during scene perception. Proc Natl. Acad. Sci. U.S.A.. 2005; 102:12629–12633. doi: 10.1073/ pnas.0506162102. 33. Nisbett RE, Peng K, Choi I, Norenzayan A. Culture and systems of thought: holistic versus analytic cognition. Psychol. Rev. 2001; 108:291–310. doi:10.1037/0033-295X.108.2.291. 34. Molnar-Szakacs I, Overy K. (2006). Music and mirror neurons: from motion to ‘e’ motion. Neuroscience. 2006; 1:235–241. doi:10.1093/scan/ nsl029.

critical review

Since musical functioning has been shown to ease pain and anxiety, future research is expected to focus on various facets of the relationship between music and language.30 Researchers also plan to use musical training to enhance neural connections by applying the concepts of neuroplasticity and axonal sprouting.31 It will be advantageous to conduct longitudinal studies with a large sample size to determine if there are different developmental trajectories for melody, rhythm, and memory with respect to language and, in particular, to tonal languages.

In contrast, “Westerners tend to be more individualistic, independent, and analytic.”33 These cultural differences influence musical perception, which, in turn, may determine the effectiveness of music as a therapeutic tool across cultures. However, this hypothesis needs to be systematically tested.

critical review 4

ARTIST ANNIE ZHU

CRITICAL REVIEW

Foodborne Pathogenic Bacteria Detection A n E va l uatio n of C urre n t a n d D e v e lo p i n g M ethods 27

GRACE ZHANG Bachelor of Health Sciences (Honours) Program, Class of 2016 Correspondence should be addressed to: grace.zhang@learnlink.mcmaster.ca

ABSTRACT Epidemics arising from foodborne pathogenic bacteria are a major public health concern. There is a critical need for the development and integration of sensitive and effecient methods for foodborne pathogen detection. Beyond this, detection should ideally be rapid, inexpensive, and easy to operate without extensive training or expertise. Although conventional techniques, involving plating followed by various biochemical tests can reliably detect bacteria at low concentrations, the time required to obtain a result is often impractical. Techniques used in conjunction with conventional methods include immunological tests and nucleic acid-based tests; these have been adapted for simultaneous screening of multiple bacterial strains. Flow cytometry has recently been applied to bacterial detection with considerable success. Biosensors, devices that convert biological activity into a measurable electrical signal, have recently gained attention as a potential method for rapid sample screening. This review aims to summarize and evaluate current methods for foodborne pathogenic bacteria detection.

Introduction

Culture methods are conventional detection methods that begin with pre-enrichment of food samples to increase pathogenic bacterial concentrations to detectable levels, and to resuscitate bacteria injured but not killed by the treatments used in food processing.7-9 These samples are then transferred to selective media, which only allows specific bacterial strains to grow, and the selectively enriched samples are subjected to various biochemical assays to test for the presence of the bacteria of interest.5 Although this process is highly effective, it requires complex, labour-intensive tests.8 Furthermore, these tests typically require approximately three to seven days to obtain a result, which is often impractical in situations involving screening of foods with short shelf lives.5,10

critical review

Foodborne pathogens are a growing public health concern. Estimates for the annual number of foodborne disease episodes in Canada range from 4 million 1 to 11 million,2 depending on the methods of approximation used. Of these cases, only 40% are attributed to 30 known and accepted foodborne pathogens, suggesting the existence of additional pathogens that are not yet identified.1 Canadian cases of food-related acute gastrointestinal illness are believed to represent an annual per capita cost of $115 CAD.2 The global nature of food trade further increases the spread of foodborne pathogens.3,4

non-pathogenic strains that may also be present in foods.8

In recent years, the focus has been on the development of more rapid and sensitive procedures for detecting and enumerating bacteria from food samples.9 Some of these methods include antibody-based tests, nucleic acid-based tests, flow cytometry, and biosensors.

Immunological Tests

FIGURE 1: Sandwich Elisa Protocol. 1) Primary antibody is fixed onto the surface of reaction. 2) The food sample is added, and target antigens (either bacterial cells or specific toxins secreted by bacteria) bind to the primary antibody. Any unbound substances are then washed off. 3) A secondary, enzymeconjugated antibody is added. This antibody will only bind if the antigen is present. Unbound antibody is then washed off. 4) A colourless substrate is added. The enzyme, if present, converts the substrate to a coloured, detectable form.

Substrate

(detectable form)

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Immunological assays are based on antibodyantigen interactions to detect bacteria. Antibodies Common foodborne pathogenic bacteria causing specific to an antigen, whether it be the bacteria human disease include Staphylococcus aureus, itself or a compound secreted by the bacteria, are Campylobacter, Salmonella serotypes, Listeria raised by exposing animals to those antigens.11 monocytogenes, Shigella, and enterohemorrhagic One of the most common immunological and enteropathogenic strains of Escherichia technique is the enzyme-linked immunosorbent coli.4-6 Food poisoning is often associated with assay (ELISA), which involves forming a tworaw or undercooked meats and eggs; however, antibody complex with the target antigen between many different strains of pathogenic bacteria them, and allows for quantification of the bound have also been reported in prepared foods, dairy antibody through an enzyme-mediated colour products, leafy vegetables, and shellfish.4,7 change reaction (see figure 1).11-13 Effective bacterial detection methods are Substrate (undetectable form) essential for controlling the spread of foodborne Specific antibodies Enzyme-conjugated pathogens, as they permit the withholding of are raised to a Secondary Antibody 5 food products suspected to be contaminated. bacterial strain and These methods must be rapid, as susceptible Antigen as a result, only one foods often have a limited shelf life. They must type of bacteria also be sensitive enough to detect trace amounts can be screened Primary of bacteria (the infectious dosage of E. coli for in each assay. Antibody O157:H7 can be as low as 10 cells), and to However, various distinguish pathogenic bacteria from the many

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critical review

forms of ELISA have been developed to combat Laser Bacteria this issue, as well as to Food increase assay sensitivity Sample and decrease assay time. In Fluid Flow multiplexed immunoassays, each ELISA plate well Forward Scatter has multiple internal Detector sub wells. This allows for Side Scatter Fluorescence Detector Detectors the simultaneous use of multiple antibodies (one in each sub well) in order to detect multiple strains of bacteria. Multiplexed FIGURE 2: Schematic of a typical flow cytometry system setup. immunoassays have been demonstrated to be Bacteria passing the laser beam effective in detecting a combination of Escherichia cause light diffraction, which is coli O157:H7, Yersinia enterocolitica, Salmonella measured as a combination of typhimurium, and Listeria monocytogenes.14,15 forward scatter and side scatter. Photoreceptors are also present Immunochromatography strip tests have primary to capture light emitted by the and secondary antibodies fixed on different areas fluorescent labels. Lenses filter of a strip; the presence of the target antigen will out wavelengths of light so that allow the primary antibody to be displaced and each photoreceptor only detects a specific wavelength. migrate to interact with the secondary antibody, which produces a qualitative colour change. This can be used as a rapid and inexpensive initial screening for a specific foodborne pathogen.16

Although immunological detection methods are generally reliable, the specificity of the test is limited by the quality of the antibody used.5,11 Inadequate sensitivity often necessitates an enrichment step to increase bacteria count in the food sample, thus increasing the time required to deliver the result.5

Nucleic Acid-Based Tests

bacterial strains.19 Other modifications of PCR detection include real-time PCR, which detects the amplified DNA in real time and allows DNA to be quantified.20, 21 This also eliminates the need to perform gel electrophoresis after PCR in order to visualize amplified DNA.21 A primary drawback of PCR foodborne pathogen detection is the requirement for an extremely clean DNA template: various contaminants derived from food samples can interfere with DNA polymerase activity to produce falsenegative results.4,11 Additionally, because PCR only detects the presence of target genomic DNA, it cannot provide information on whether toxins secreted by bacteria are present, or whether the bacteria are alive.22, 23

Flow Cytometry Flow cytometry differs from immunological and nucleic acid-based techniques because it detects bacteria by measuring physical parameters, rather than through chemical interaction.8,24 Cells in a test sample, which may be fluorescently stained by a specific antibody or dye, are passed singlefile through a very narrow channel across a beam of light, usually a laser beam. As the bacteria flow past the laser beam, lenses and photocells detect light scatter and fluorescence (See Figure 2). These light scatter patterns provide information about the size and shape of the bacteria, as well as particle density within the cell.11,24 However, the physical data provided by flow cytometry is not specific enough to distinguish between similar strains of bacteria. To overcome this, fluorescent labels specific to strains of interest are used.24 Modern instruments can simultaneously measure fluorescence at more than ten different wavelengths, allowing for the detection of many bacterial strains at once.25 Fluorescent stain systems have also been adapted for use in distinguishing between live and dead cells: these employ a fluorescent stain that can only enter the cell and bind to its nucleic acid target if the cell membrane is compromised.26

Nucleic acid-based tests allow for recognition of target pathogens by probing for specific DNA or RNA sequences. Traditional DNA probes consisted of a 15-30 nucleotide base sequence labelled radioactively or fluorescently for detection.11 However, modern DNA-based methods usually employ polymerase chain reaction (PCR). In this procedure, primers with nucleotide sequences complementary to a sequence of the target bacteriaâ&#x20AC;&#x2122;s genome are added in vitro to a genomic DNA sample, along with the DNA polymerase enzyme. If the target Flow cytometry is a rapid technique that can DNA sequence is present, the primers will anneal detect up to 100 000 cells/s.25 Another distinct and allow this sequence to be amplified and advantage is its ability to identify subpopulations subsequently detected through gel electrophoresis. of bacteria even if nothing is known about them. Because PCR involves the amplification of This is contrasting with immunological and genetic information from the original sample, it nucleic acid-based methods, which can only has higher sensitivity than most other tests.17,18 detect bacteria for which antibodies have been developed, or genomic data is known.25 Flow Although PCR traditionally involves the use of cytometry has been demonstrated to successfully a single pair of primers to detect the presence of detect strains of E. coli in food products such a single DNA sequence, multiplex PCR systems as apple juice, milk, and ground beef. However, have been designed to allow for the use of multiple a pre-treatment process must be performed to primer pairs to simultaneously screen for several eliminate non-bacterial particles that interfere

with effective bacterial detection because they diffract light to generate background noise.27,28

Biosensors One of the most rapidly growing areas in foodborne pathogen detection is the development of biosensors. Biosensors are detection systems consisting of a bioreceptor, which recognizes target bacteria, and a transducer, which converts the bacteria-bioreceptor interaction into a measurable electrical signal.4,29 There are currently multiple types of bioreceptor-transducer systems available: most modern transducers are either optical, mass-sensitive, or electrochemical.4,12,30

Biosensor systems have the common advantage that the pathogens do not need to be labelled prior to detection, and they are thus capable of producing results very rapidly. These methods generally require little to no sample pre-treatment as compared to conventional methods.8

Conclusion and Future Steps

Early screening of food products is an important measure to prevent epidemics relating to foodborne pathogens. Current emphasis is on the development of techniques that allow for the rapid, inexpensive characterization of food samples. Conventional, immunological, and nucleic acid-based methods provide reliable results, but are slow and require specialized equipment and personnel. Flow cytometry is an effective detection method with potential Mass-based biosensors employ a piezoelectric for integration into the food inspection system, crystal, which can be induced by an electrical especially with the recent development of 33 Biosensors, signal to vibrate at a certain frequency.4 This disposable microfluidic chips. notable for their speed, inexpensiveness, and crystal is coated with antibodies for the antigen minimal sample pre-treatment, are another of interest. When antigens from the sample bind to the antibodies coated on this crystal, emergence in the field of foodborne pathogen they decrease its vibrational frequency by a detection. However, biosensor performance, magnitude that corresponds directly to the particularly in terms of sensitivity and specificity, added mass.4,12,30 A flow-through piezoelectric is still unreliable. Further advancements must be assay has been shown to detect E. Coli with a made before biosensors are robust enough to be measuring cycle of under 10 minutes; however, accepted as a standard in food microbiological the system was not sensitive enough to reliably testing. ■ detect bacteria at concentrations less than 106 colony forming units (CFU)/mL.31 6.

Tauxe RV. Emerging foodborne pathogens. International Journal of Food Microbiology. 2002;78(1-2):31-41. 7. Mukherjee A, Speh D, Dyck E, DiezGonzalez F. Preharvest Evaluation of Coliforms, Escherichia coli, Salmonella, and Escherichia coli O157:H7 in Organic and Conventional Produce Grown by Minnesota Farmers. Journal of Food Protection. 2004;67(5):894-900. 8. Ivnitski D, Abdel-Hamid I, Atanasov P, Wilkins E. Biosensors for detection of pathogenic bacteria. Biosensors and Bioelectronics. 1999;14(7):599-624. 9. Gracias KS, McKillip JL. A review of conventional detection and enumeration methods for pathogenic bacteria in food. Canadian Journal of Microbiology. 2004;50(11):883-90. 10. Alocilja EC, Radke SM. Market analysis of biosensors for food safety. Biosensors and Bioelectronics. 2003;18(56):841-6.

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Dr. Min Lin is a microbiologist at the Canadian Food Inspection Agency, and an adjunct professor at the University of Ottawa. Current research being conducted in his lab uses immunological and molecular biology techniques to characterize the cell surfaces of various pathogenic bacterial strains, and to develop bacterial detection methods based on these cell surface features.

Thomas MK, Murray R, Flockhart L, Pintar K, Pollari F, Fazil A, et al. Estimates of the Burden of Foodborne Illness in Canada for 30 Specified Pathogens and Unspecified Agents, Circa 2006. Foodborne Pathogens and Disease. 2013;10(7):639-48. 2. Thomas MK, Majowicz SE, Pollari F, Sockett PN. Burden of acute gastrointestinal illness in Canada, 1999-2007: interim summary of NSAGI activities. Canada communicable disease report. 2008;34(5):8-15. 3. O’Brien SJ. The public health impact of food-related illness. Current opinion in infectious diseases. 2012;25(5):537-45. 4. Velusamy V, Arshak K, Korostynska O, Oliwa K, Adley C. An overview of foodborne pathogen detection: In the perspective of biosensors. Biotechnology Advances. 2010;28(2):232-54. 5. Swaminathan B, Feng P. Rapid Detection of Food-Borne Pathogenic Bacteria. Annual Review of Microbiology. 1994;48(1):40126.

Reviewed by Dr. Min Lin

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Electrochemical transducers are further broken down into amperiometric, potentiometric, impedimetric, and conductometric types, which detect

11. de Boer E, Beumer RR. Methodology for detection and typing of foodborne microorganisms. International Journal of Food Microbiology. 1999;50(1):119-30. 12. Lazcka O, Campo F, Munoz FX. Pathogen detection: a perspective of traditional methods and biosensors. Biosensors and Bioelectronics. 2007;22(7):1205-17. 13. Notermans S, Wernars K. Immunological methods for detection of foodborne pathogens and their toxins. International Journal of Food Microbiology. 1991;12(1):91-102. 14. Magliulo M, Simoni P, Guardigli M, Michelini E, Luciani M, Lelli R, et al. A rapid multiplexed chemiluminescent immunoassay for the detection of Escherichia coli O157: H7, Yersinia enterocolitica, Salmonella typhimurium, and Listeria monocytogenes pathogen bacteria. Journal of agricultural and food chemistry. 2007;55(13):4933-9. 15. Karoonuthaisiri N, Charlermroj R, Uawisetwathana U, Luxananil P, Kirtikara K, Gajanandana O. Development of antibody array for simultaneous detection of foodborne pathogens. Biosensors and Bioelectronics. 2009;24(6):1641-8. 16. Shim W-B, Choi J-G, Kim J-Y, Yang Z-Y, Lee K-H, Kim M-G, et al. Production of monoclonal antibody against Listeria monocytogenes and its application to immunochromatography strip test. Journal of microbiology and biotechnology. 2007;17(7):1152-61. 17. Scheu PM, Berghof K, Stahl U. Detection of pathogenic and spoilage micro-organisms in food with the polymerase chain reaction. Food microbiology. 1998;15(1):13-31. 18. Naravaneni R, Jamil K. Rapid detection of food-borne pathogens by using molecular techniques. Journal of medical microbiology. 2005;54(1):51-4. 19. Kim JS, Lee GG, Park JS, Jung YH, Kwak HS, Kim SB, et al. A novel multiplex PCR assay for rapid and simultaneous detection of five pathogenic bacteria: Escherichia coli O157: H7, Salmonella, Staphylococcus aureus, Listeria monocytogenes, and Vibrio parahaemolyticus. Journal of Food Protection. 2007;70(7):1656-62. 20. Malorny B, Paccassoni E, Fach P, Bunge C, Martin A, Helmuth R. Diagnostic real-time PCR for detection of Salmonella in food. Applied and Environmental Microbiology. 2004;70(12):7046-52. 21. Fricker M, Messelhäußer U, Busch U, Scherer S, Ehling-Schulz M. Diagnostic real-time PCR assays for the detection of emetic Bacillus cereus strains in foods and recent food-borne outbreaks. Applied and Environmental Microbiology. 2007;73(6):1892-8. 22. Wang RF, Cao WW, Cerniglia CE. A universal protocol for PCR detection of 13 species of foodborne pathogens in foods. Journal of Applied Microbiology. 1997;83(6):727-36. 23. Leonard P, Hearty S, Brennan J, Dunne L, Quinn J, Chakraborty T, et al. Advances in biosensors for detection of pathogens in food and water. Enzyme and Microbial Technology. 2003;32(1):3-13. 24. Veal DA, Deere D, Ferrari B, Piper J, Attfield PV. Fluorescence staining and flow cytometry for monitoring microbial cells. Journal of immunological methods. 2000;243(1):191210. 25. Comas-Riu J, Rius Nr. Flow cytometry applications in the food industry. Journal of industrial microbiology & biotechnology. 2009;36(8):999-1011. 26. Boulos L, Prevost M, Barbeau B, Coallier J, Desjardins R. LIVE/DEAD BacLight : application of a new rapid staining method for direct enumeration of viable and total bacteria in drinking water. Journal of microbiological methods. 1999;37(1):77-86. 27. Yamaguchi N, Sasada M, Yamanaka M, Nasu M. Rapid detection of respiring Escherichia coli O157: H7 in apple juice, milk, and ground beef by flow cytometry. Cytometry Part A. 2003;54(1):27-35. 28. Hegde NV, Jayarao BM, DebRoy C. Rapid detection of the top six non-O157 Shiga toxin-producing Escherichia coli O groups in ground beef by flow cytometry. Journal of clinical microbiology. 2012;50(6):2137-9. 29. Deisingh AK, Thompson M. Biosensors for the detection of bacteria. Canadian Journal of Microbiology. 2004;50(2):69-77. 30. Arora P, Sindhu A, Dilbaghi N, Chaudhury A. Biosensors as innovative tools for the detection of food borne pathogens. Biosensors and Bioelectronics. 2011;28(1):1-12. 31. Pohanka M, Skládal P, Pavlis O. Label-Free Piezoelectric Immunosensor for Rapid Assay of Escherichia coli. Journal of Immunoassay and Immunochemistry. 2007;29(1):70-9. 32. Pal S, Ying W, Alocilja EC, Downes FP. Sensitivity and specificity performance of a direct-charge transfer biosensor for detecting Bacillus cereus in selected food matrices. Biosystems Engineering. 2008;99(4):461-8. 33. Sakamoto C, Yamaguchi N, Nasu M. Rapid and simple quantification of bacterial cells by using a microfluidic device. Applied and Environmental Microbiology. 2005;71(2):1117-21.

critical review

Optical transducers are based on the recognition of an optical change. In a surface plasmon resonance (SPR) biosensor, a certain wavelength of electromagnetic radiation generates resonance in the electron cloud of a thin metal (usually gold) coat on the transducer surface. Interaction of the antigen of interest with this surface alters its refractive index, which changes the wavelength required for electron resonance.4,23,30 SPR has been successful in detecting both whole bacteria and secreted toxins.30 SPR-based biosensors are limited by the high cost and large size of equipment required, but portable systems have been made commercially available, and have been demonstrated to successfully detect E.coli O157:H7.4,12,23

changes in current, voltage, impedance, and conductance respectively, as a result of antigenbioreceptor interactions.4,30 These systems are inexpensive, and can even be manufactured as disposable chips.30 Pal et al.32 report a conductometric biosensor detecting pure Bacillus cereus cultures that were inoculated into food at concentrations as low as 35.3 CFU/ mL, and with a detection time of six minutes. However, lack of specificity in electrochemical transducers is a common problem; other electroactive compounds present in the sample can often interfere with detection.30

INTERVIEW SPOTLIGHT AVRILYNN DING Bachelor of Health Sciences (Honours) Program, Class of 2017 MAYLYNN DING Bachelor of Health Sciences (Honours) Program, Class of 2017

dr.stephen walter

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How did you become interested in biostatistics, and in particular, latent class models?

I started off as an undergraduate in mathematics, which can be a very theoretical discipline. While studying in London, I became interested in applying mathematics. I ended up going to Edinburgh to work on my Ph.D. in an unusual arrangement at the time. I was jointly supervised by the professor of statistics and the professor of radiology. For my Ph.D. project, I did some work on the reliability and accuracy of reading X-rays. Fairly early on, I recognized that although sometimes physicians  Dr. STEPHEN WALTER is a Professor Emeritus in would claim that a diagnosis the Department of Clinical Epidemiology and Biostatistics is completely accurate, that’s at McMaster University. He is also an Associate Member usually not the case. Errors, of the Department of Mathematics and Statistics. Dr. in fact, happen for all sorts of Walter has developed an international reputation for reasons and that’s what led creating and applying statistical methods in biomedical me to latent class modelling. research, particularly for the evaluation of diagnostic If you’re not familiar, the tests. His past positions include Chair of the International latent class model does not Clinical Epidemiology Network, Editor of the American assume any of the observations Journal of Epidemiology, and Section Editor for the Wiley you make on a patient are Encyclopedia of Biostatistics. Most recently, Dr. Walter was completely accurate. You can inducted as a Fellow into The Royal Society of Canada. use triangulation between all of

BEYOND DISCIPLINARY BOUNDARIES

was about five months. It really opened my eyes as to what was going on in some other countries. During the time I’ve been at McMaster we’ve had a number of initiatives. Notably there was an organization called INCLEN (International Clinical Epidemiology Network). We worked in about 25 developing countries to select medical schools and develop their research capacity by bringing people to McMaster for training. The trainees’ responsibility was to develop research programs to implement back home. Conducting follow-up visits allowed me to continue my travel addiction. I travelled to India, South America, and parts of Africa on many occasions. Of course, that exposed me to a wide variety of cultures and how we, in more privileged parts of the world, can help. Sometimes it was a fantastic success and everything took root; other times we got snared in politics and difficulties in the local environment.

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MAXWELL TRAN Bachelor of Health Sciences (Honours) Program, Class of 2017

the data points on the patient to assess the accuracy of the method and come out with a probability of who has the condition and who doesn’t. The goal of latent class analysis is to provide a good estimate of diagnostic accuracy. You can get a handle on the false positive and negative rates of a test, and determine its overall accuracy. I’ve worked for several years now on the evaluation of cancer screening programs where there are critical issues about false negative and positive readings. With latent class analysis, we can look at the trade-off between correct and false results in both directions.

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In the past, you have spoken highly of McMaster’s interdisciplinary approach. Could you provide an example of how such an approach has impacted your research?

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Well, there are so many examples! My department, and health sciences in general, has fairly weak disciplinary boundaries. I was frequently involved in clinical studies primarily as a statistician, while being fully accepted as a co-investigator. That might have been quite difficult

When I was young, my parents would take us on holidays to continental Europe, which at that time was a big deal. After I completed my undergraduate degree, I had a life-changing experience as a member of an overland expedition from several British universities to India. We drove across through Turkey and Iran, Afghanistan, Pakistan, and more. We spent about a month in India visiting various other sister universities. The whole trip

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How did you decide to get involved in international research? Did it bring any new challenges?

The particular project was led by Dr. Mark Loeb, who is a medicine professor here [at McMaster University]. The notion was that the Hutterites live in relatively small, isolated communities. Because of the logistics of that particular study where we randomized people to either receive the active flu vaccine or not, we had to do it one community at a time. In other words, we couldn’t randomize easily at the individual level. Additionally, we felt there was an advantage to either vaccinating, or using as a control an entire community. We were looking at herd immunity effects in addition to individual outcomes. The Hutterite communities were ideal from the objectives of the research in that they were “smallish”, with typically 100-150 people, and relatively isolated. There was not a great deal of contamination in those communities by other people or between communities. We hoped that if the vaccine had an interventional effect, it would be seen in the Hutterite communities. It would have been much more difficult to see the effect in larger communities, such as the one we live in now.

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You were part of a team that researched the effects of influenza vaccinations of children on infection rates in rural Hutterite communities. Why did you choose Hutterite communities in particular?

in other institutions where there are much more rigid departmental and disciplinary boundaries. For example, we did a large study of melanoma that led to important findings about the effects of sunbeds and tanning, which quite recently led to legislation around the world against young people using commercial tanning facilities. Our study was actually the largest one used by the World Health Organization as part of its evidence base for its recommendation to countries to adopt the legislation. Again, I’m very proud of that and that’s something that probably wouldn’t have happened in many other institutions because a lot of different skills were required: clinical contacts, clinical expertise, design, analysis, logistics. All of those things had to come together in the right way.

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What advice can you give to undergraduate students who may be interested in pursuing the same line of work?

I would have to say that at the undergraduate level, it’s probably quite difficult to know what it’s going to be like as a graduate student. So my advice, I suppose, is to keep “WHEN YOU’re on a your options open. Obviously collaborative team, the focus on the things that you like statistician is the person doing—the subjects you like in the backroom working doing—because it’s got to be fun. on the nuts and bolts of Otherwise it’s a waste of your the study... the proper time. Fun is a big component of design and analysis of research work, I think. If you’re the study is absolutely having fun, it all goes much central to the project’s better. Don’t be afraid to ask success” “silly” questions. Students come to me all the time and they will say, “I’ve got a quick question”, or a “silly question”, or a “stupid question”. I always say to them, “there’s never a silly question”. The answer may be silly, but you’ll have to judge that.

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If you had the chance to give ADVICE TO YOUR undergraduate SELF, what would it be?

I’ve had a habit, which I was informed about by David Sackett; he was actually the first Chair of our department in clinical epidemiology and biostatistics. He is a man I respect enormously. One thing I do remember him saying was, you need to take a day a week for yourself. Shut yourself away somewhere, it can be at home, it could be in your office but just close the door. But don’t answer the phone, don’t answer any letters, don’t do

anything like that. Just focus on what really seems to be of interest to you at the moment. It could be something new, a new idea. Take that time to read that paper that you’ve had on your desk for a couple weeks. So if you do that, if you do that religiously, take even one day a week as a minimum, it can be enormously productive. It’s a stimulus and a catalyst to whatever else happens during the week. So I think that would be the one gem I would like to pass on from David Sackett.

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What do you consider to be your greatest achievement so far?

I’m very pleased that some of the methods we’ve developed have been put into use by people around the world. I feel like that’s a contribution to absolute knowledge. Good, solid method is something that everyone can pick up and its properties are indisputable. That’s a little different from the results of any particular study in biomedical research, where there’s always room for interpretation. I’m also very proud to have been a co-investigator with colleagues in a number of clinical areas. I mentioned surgery before, where doing randomized trials was almost unheard of a few years ago. I’ve also been involved with things like vaccine studies and studies with colleagues in intensive care. All of those research studies had a very big impact in the clinical community.

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This year, you are one of four faculty members from McMaster University to be elected to the Royal Society of Canada. What did it mean to you to receive this recognition?

It was a big surprise, first of all. To be quite honest, I don’t really know what it means yet because the formal induction ceremony isn’t until next month. But it was particularly touching this year because as I looked at the nominees from around the country, I believe I’m the only statistician. There are usually one or two. This is gratifying because often when you’re on a collaborative team, the statistician is the person in the backroom working on the nuts and bolts of the study. It’s usually the lead clinician you’ll see in front of the press cameras when the study is announced. So I think that for me is rewarding. It’s a recognition of biostatistics, which many people don’t realize runs through a very high percentage of biomedical research studies. It is often absolutely crucial; the proper design and analysis of the study is absolutely central to the project’s success. Without it, [the project] just wouldn’t mean very much. There often isn’t a very strong correlation between that and the way it is perceived by the public later on. ■ watch the interview online at www.youtube.com/meducatorTV

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