Digital Commons Network^™

Families' Healthcare Experiences For Children With Inherited Metabolic Diseases: Protocol For A Mixed Methods Cohort Study, Andrea J. Chow, Ryan Iverson, Monica Lamoureux, Kylie Tingley, Isabel Jordan, Nicole Pallone, Maureen Smith, Zobaida Al-Baldawi, Pranesh Chakraborty, Jamie Brehaut, Alicia Chan, Eyal Cohen, Sarah Dyack, Lisa Jane Gillis, Sharan Goobie, Ian D. Graham, Cheryl R. Greenberg, Jeremy M. Grimshaw, Robin Z. Hayeems, Shailly Jain-Ghai, Ann Jolly, Sara Khangura, Jennifer J. Mackenzie, Nathalie Major, John J. Mitchell, Stuart G. Nicholls

Paediatrics Publications

Introduction Children with inherited metabolic diseases (IMDs) often have complex and intensive healthcare needs and their families face challenges in receiving high-quality, family centred health services. Improvement in care requires complex interventions involving multiple components and stakeholders, customised to specific care contexts. This study aims to comprehensively understand the healthcare experiences of children with IMDs and their families across Canada. Methods and analysis A two-stage explanatory sequential mixed methods design will be used. Stage 1: quantitative data on healthcare networks and encounter experiences will be collected from 100 parent/guardians through a care map, 2 baseline questionnaires and 17 weekly diaries …

Can A Lifestyle Genomics Intervention Motivate Patients To Engage In Greater Physical Activity Than A Population-Based Intervention? Results From The Now Randomized Controlled Trial, Justine R. Horne, Jason Gilliland, Tara Leckie, Colleen O'Connor, Jamie A. Seabrook, Janet Madill

Paediatrics Publications

Background: Lifestyle genomics (LGx) is a science that explores interactions between genetic variation, lifestyle components such as physical activity (PA), and subsequent health- and performance-related outcomes. The objective of this study was to determine whether an LGx intervention could motivate enhanced engagement in PA to a greater extent than a population-based intervention. Methods: In this pragmatic randomized controlled trial, participants received either the standard, population-based Group Lifestyle BalanceTM (GLB) program intervention or the GLB program in addition to the provision of LGx information and advice (GLB + LGx). Participants (n = 140) completed a 7-day PA recall at baseline, 3, …

Can A Lifestyle Genomics Intervention Motivate Patients To Engage In Greater Physical Activity Than A Population-Based Intervention? Results From The Now Randomized Controlled Trial, Justine R. Horne, Jason Gilliland, Tara Leckie, Colleen O'Connor, Jamie A. Seabrook, Janet Madill

Paediatrics Publications

Background: Lifestyle genomics (LGx) is a science that explores interactions between genetic variation, lifestyle components such as physical activity (PA), and subsequent health- and performance-related outcomes. The objective of this study was to determine whether an LGx intervention could motivate enhanced engagement in PA to a greater extent than a population-based intervention. Methods: In this pragmatic randomized controlled trial, participants received either the standard, population-based Group Lifestyle BalanceTM (GLB) program intervention or the GLB program in addition to the provision of LGx information and advice (GLB + LGx). Participants (n = 140) completed a 7-day PA recall at baseline, 3, …

Prevalence And Clinical Features Of Inflammatory Bowel Diseases Associated With Monogenic Variants, Identified By Whole-Exome Sequencing In 1000 Children At A Single Center, Eileen Crowley, Neil Warner, Jie Pan, Sam Khalouei, Abdul Elkadri, Karoline Fiedler, Justin Foong, Andrei L Turinsky, Dana Bronte-Tinkew, Shiqi Zhang

Paediatrics Publications

BACKGROUND & AIMS: A proportion of infants and young children with inflammatory bowel diseases (IBDs) have subtypes associated with a single gene variant (monogenic IBD). We aimed to determine the prevalence of monogenic disease in a cohort of pediatric patients with IBD.

METHODS: We performed whole-exome sequencing analyses of blood samples from an unselected cohort of 1005 children with IBD, aged 0-18 years (median age at diagnosis, 11.96 years) at a single center in Canada and their family members (2305 samples total). Variants believed to cause IBD were validated using Sanger sequencing. Biopsies from patients were analyzed by immunofluorescence and …

Are Specific Learning Disorders Truly Specific, And Are They Disorders?, Lien Peters, Daniel Ansari

Brain and Mind Institute Researchers' Publications

© 2019 The Authors Specific learning disorders, such as dyslexia and dyscalculia, are frequently studied to inform our understanding of cognitive development, genetic mechanisms and brain function. In this Opinion Paper, we discuss limitations of this research approach, including the use of arbitrary criteria to select groups of children, heterogeneity within groups and overlap between domains of learning. By drawing on evidence from cognitive science, neuroscience and genetics, we propose an alternative, dimensional framework. We argue that we need to overcome the problems associated with a categorical approach by taking into account interacting factors at multiple levels of analysis that …

Functional Network Resilience To Pathology In Presymptomatic Genetic Frontotemporal Dementia, Timothy Rittman, Robin Borchert, Simon Jones, John Van Swieten, Barbara Borroni, Daniela Galimberti, Mario Masellis, Maria Carmela Tartaglia, Caroline Graff, Fabrizio Tagliavini, Giovanni B. Frisoni, Robert Laforce, Elizabeth Finger, Alexandre Mendonça, Sandro Sorbi, Jonathan D. Rohrer, James B. Rowe, Sónia Afonso, Maria Rosario Almeida, Sarah Anderl-Straub, Christin Andersson, Anna Antonell, Silvana Archetti, Andrea Arighi, Mircea Balasa, Myriam Barandiaran, Nuria Bargalló, Robart Bartha, Benjamin Bender, Luisa Benussi, Valentina Bessi, Giuliano Binetti

Medical Biophysics Publications

© 2019 The Authors The presymptomatic phase of neurodegenerative diseases are characterized by structural brain changes without significant clinical features. We set out to investigate the contribution of functional network resilience to preserved cognition in presymptomatic genetic frontotemporal dementia. We studied 172 people from families carrying genetic abnormalities in C9orf72, MAPT, or PGRN. Networks were extracted from functional MRI data and assessed using graph theoretical analysis. We found that despite loss of both brain volume and functional connections, there is maintenance of an efficient topological organization of the brain's functional network in the years leading up to the estimated age …

Development Of Criteria For Epilepsy Genetic Testing In Ontario, Canada, Puneet Jain, Danielle Andrade, Elizabeth Donner, David Dyment, Asuri N. Prasad, Sharan Goobie, Kym Boycott, Matthew Lines, O. Carter Snead

Paediatrics Publications

Multiple genes/variants have been implicated in various epileptic conditions. However, there is little general guidance available on the circumstances in which genetic testing is indicated and test selection in order to guide optimal test appropriateness and benefit. This is an account of the development of guidelines for genetic testing in epilepsy, which have been developed in Ontario, Canada. The Genetic Testing Advisory Committee was established in Ontario to review the clinical utility and validity of genetic tests and the provision of genetic testing in Ontario. As part of their mandate, the committee also developed recommendations and guidelines for genetic testing …

Study Protocol Of A Pragmatic Randomized Controlled Trial Incorporated Into The Group Lifestyle Balance™ Program: The Nutrigenomics, Overweight/Obesity And Weight Management Trial (The Now Trial), Justine Horne, Jason A. Gilliland, Colleen O’Connor,, Jamie A. Seabrook, Peter Hannaberg, Janet Madill

Human Environments Analysis Lab (HEAL)

Background

The nutrigenomics, overweight/obesity and weight management trial (NOW Trial) is a pragmatic randomized controlled trial of community-dwelling adults recruited from the Group Lifestyle Balance™ (GLB™) Program. The GLB™ Program (formerly referred to as the Diabetes Prevention Program) is an evidence-based, intensive weight management program, which was offered to overweight/obese patients (BMI ≥ 25.0 kg/m2) in a rural Ontario community.

Methods

Patients enrolled in the GLB™ Program were invited to participate in this study. GLB™ groups were randomized 1:1 to receive either the standard GLB™ program + population-based lifestyle advice for weight management, or a modified GLB™ program + personalized, …

The Clinical Impact Of Copy Number Variants In Inherited Bone Marrow Failure Syndromes, Nicolas Waespe, Santhosh Dhanraj, Manju Wahala, Elena Tsangaris, Tom Enbar, Bozana Zlateska, Hongbing Li, Robert J Klaassen, Conrad V Fernandez, Geoff D E Cuvelier, John K Wu, Yves D Pastore, Mariana Silva, Jeffrey H Lipton, Joseé Brossard, Bruno Michon, Sharon Abish, Macgregor Steele, Roona Sinha, Mark J Belletrutti, Vicky R Breakey, Lawrence Jardine, Lisa Goodyear, Liat Kofler, Michaela Cada, Lillian Sung, Mary Shago, Stephen W Scherer, Yigal Dror

Paediatrics Publications

Inherited bone marrow failure syndromes (IBMFSs) comprise a genetically heterogeneous group of diseases with hematopoietic failure and a wide array of physical malformations. Copy number variants (CNVs) were reported in some IBMFSs. It is unclear what impact CNVs play in patients evaluated for a suspected diagnosis of IBMFS. Clinical and genetic data of 323 patients from the Canadian Inherited Marrow Failure Registry from 2001 to 2014, who had a documented genetic work-up, were analyzed. Cases with pathogenic CNVs (at least 1 kilobasepairs) were compared to cases with other mutations. Genotype-phenotype correlations were performed to assess the impact of CNVs. Pathogenic …

Alagille Syndrome: Clinical Perspectives, Maha Saleh, Binita M. Kamath, David Chitayat

Paediatrics Publications

Alagille syndrome is an autosomal dominant, complex multisystem disorder characterized by the presence of three out of five major clinical criteria: cholestasis with bile duct paucity on liver biopsy, congenital cardiac defects (with particular involvement of the pulmonary arteries), posterior embryotoxon in the eye, characteristic facial features, and butterfly vertebrae. Renal and vascular abnormalities can also occur. Inter- and intrafamilial variabilities in the clinical manifestations are common. We reviewed the clinical features and management as well as the molecular basis of Alagille syndrome.

Association Between Mapt Haplotype And Memory Function In Patients With Parkinson's Disease And Healthy Aging Individuals, Sophie E. Winder-Rhodes, Adam Hampshire, James B. Rowe, Jonathan E. Peelle, Trevor W. Robbins, Adrian M. Owen, Roger A. Barker

Brain and Mind Institute Researchers' Publications

Genetic variation is associated with differences in the function of the brain as well as its susceptibility to disease. The common H1 haplotypic variant of the microtubule-associated protein tau gene (MAPT) has been related to an increased risk for Parkinson's disease (PD). Furthermore, among PD patients, H1 homozygotes have an accelerated progression to dementia. We investigated the neurocognitive correlates of MAPT haplotypes using functional magnetic resonance imaging. Thirty-seven nondemented patients with PD (19 H1/H1, 18 H2 carriers) and 40 age-matched controls (21 H1/H1, 19 H2 carriers) were scanned during performance of a picture memory encoding task. Behaviorally, H1 homozygosity was …

Divergent Transcriptional Responses To Low Temperature Among Populations Of Alpine And Lowland Species Of New Zealand Stick Insects (Micrarchus)., Luke T Dunning, Alice B Dennis, Brent J Sinclair, Richard D Newcomb, Thomas R Buckley

Biology Publications

In widespread and genetically structured populations, temperature variation may lead to among-population differentiation of thermal biology. The New Zealand stick insect genus Micrarchus contains four species that inhabit different thermal environments, two of which are geographically widespread. RNA-Seq and quantitative PCR were used to investigate the transcriptional responses to cold shock among lowland and alpine species to identify cold-responsive transcripts that differ between the species and to determine whether there is intraspecific geographical variation in gene expression. We also used mitochondrial DNA, nuclear 28S ribosomal DNA and transcriptome-wide SNPs to determine phylogeographic structure and the potential for differences in genetic …

Molecular Imaging To Target Transplanted Muscle Progenitor Cells, Kelly Gutpell, Rebecca Mcgirr, Lisa Hoffman

Anatomy and Cell Biology Publications

Duchenne muscular dystrophy (DMD) is a severe genetic neuromuscular disorder that affects 1 in 3,500 boys, and is characterized by progressive muscle degeneration(1, 2). In patients, the ability of resident muscle satellite cells (SCs) to regenerate damaged myofibers becomes increasingly inefficient(4). Therefore, transplantation of muscle progenitor cells (MPCs)/myoblasts from healthy subjects is a promising therapeutic approach to DMD. A major limitation to the use of stem cell therapy, however, is a lack of reliable imaging technologies for long-term monitoring of implanted cells, and for evaluating its effectiveness. Here, we describe a non-invasive, real-time approach to evaluate the success of myoblast …

The Role Of Brain-Derived Neurotrophic Factor Genotype, Parental Depression, And Relationship Discord In Predicting Early-Emerging Negative Emotionality, Elizabeth P. Hayden, Daniel N. Klein, Lea R. Dougherty, Thomas M. Olino, Margaret W. Dyson, C. Durbin, Haroon I. Sheikh, Shiva M. Singh

Paediatrics Publications

The brain-derived neurotrophic factor (BDNF) gene is a plausible candidate for early-emerging negative emotionality (NE), and evidence suggests that the effects of this gene may be especially salient in the context of familial risk for child maladjustment. We therefore examined whether the single-nucleotide polymorphism producing a valine-to-methionine substitution at codon 66 (val66met) of the BDNF gene was associated with childhood NE, in the context of parental depression and relationship discord. A sample of 413 three-year-old children was assessed for NE using standardized laboratory measures. The children's parents completed clinical interviews as well as a measure of marital satisfaction. Children with …

Morally Justifying Oncofertility Science, Carolyn Mcleod

Philosophy Publications

Is research aimed at preserving the fertility of cancer patients morally justified? A satisfying answer to this question is missing from the literature on oncofertility. Rather than provide an answer, which is impossible to do in a short space, this paper explains what it would take to provide such justification.

Ab Initio Exon Definition Using An Information Theory-Based Approach, Peter K. Rogan

Biochemistry Publications

Transcribed exons in genes are joined together at donor and acceptor splice sites precisely and efficiently to generate mRNAs capa ble of being translated into proteins. The sequence variability in individual splice sites can be modeled using Shannon information theory. In the laboratory, the degree of individual splice site use is inferred from the structures of mRNAs and their relative abundance. These structures can be predicted using a bipartite information theory framework that is guided by current knowledge of biological mechanisms for exon recognition. We present the results of this analysis for the complete dataset of all expressed human exons.

Aristotle’S Worst Idea, John Thorp

Philosophy Presentations

No abstract provided.

Disparate Associations Of A Functional Promoter Polymorphism In Pck1 With Carotid Wall Ultrasound Traits, Robert A. Hegele, Khalid Z. Al-Shali, Andrew A. House, Anthony J.G. Hanley, Stewart B. Harris, Mary Mamakeesick, Aaron Fenster, Bernard Zinman, Henian Cao, J. David Spence

Department of Medicine Publications

Background and Purpose - Cytosolic phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32), encoded by PCK1, catalyzes the first committed step in gluconeogenesis. We previously showed that a -232C>G promoter polymorphism within a cis-acting element required for basal and cAMP-mediated PCK1 gene transcription results in loss of negative regulation by insulin, contributing to worsened metabolic control in the context of insulin resistance. We hypothesized that this polymorphism would be associated with carotid atherosclerosis in a sample of 150 aboriginal Canadians. Methods - Dependent variables were 2 distinct carotid traits, namely intima-media thickness (IMT) assessed using B-mode ultrasound and total carotid plaque volume …

Noninvasive Phenotypes Of Atherosclerosis: Similar Windows But Different Views, J. David Spence, Robert A. Hegele

Department of Medicine Publications

Background and Purpose-Noninvasive measures of atherosclerosis, such as carotid intima-media thickness, total carotid plaque area, and carotid stenosis, probably represent different phenotypes with distinct determinants. For instance, total carotid plaque area may reflect atherosclerotic lesion size more closely than carotid stenosis, which instead may reflect hemodynamic compromise within the arterial lumen. Methods-In 1821 patients from a Premature Atherosclerosis Clinic, we studied determinants of total carotid plaque area and carotid stenosis as measured by ultrasound using multivariate regression analysis with traditional risk factors and some emerging risk factors. Results-Regression modeling showed that (1) traditional atherosclerosis risk factors were more strongly associated …

Lipoprotein Lipase (Lpl) Gene Variation And Progression Of Carotid Artery Plaque, J. David Spence, Matthew R. Ban, Robert A. Hegele

Department of Medicine Publications

Background and Purpose - Coding single nucleotide polymorphisms (cSNPs) in the lipoprotein lipase (LPL) gene have been associated with lipoprotein phenotypes and vascular disease risk. We studied the association between LPL cSNPs and a novel noninvasive measure of disease, namely, cross-sectional carotid plaque area (CPA) on B-mode ultrasound. Methods - Four hundred fifty-two patients from an atherosclerosis prevention clinic had determinations of baseline and total CPA. Traditional atherosclerosis risk factors were recorded, and the LPL D9N, N291S, and S447X cSNPs were genotyped. Multiple regression analysis was used to identify determinants of CPA. Results - Minor allele frequencies for LPL D9N, …

Plasma Homocyst(E)Ine Concentration, But Not Mthfr Genotype, Is Associated With Variation In Carotid Plaque Area, J. David Spence, M. Rene Malinow, Peter A. Barnett, Ali J. Marian, David Freeman, Robert A. Hegele

Department of Medicine Publications

Background and Purpose - Elevated plasma homocyst(e)ine [H(e)] concentration is associated with premature atherosclerosis. A common cause of elevated plasma H(e) concentration is a thermolabile mutation (677T) in the gene encoding methylenetetrahydrofolate reductase (MTHFR). We sought to determine whether plasma H(e) concentration or MTHFR genotype would be more strongly associated with carotid plaque area (CPA), a potential intermediate phenotype of atherosclerosis. Methods - In 307 subjects who were ascertained through a premature atherosclerosis clinic, we measured CPA with 2- dimensional ultrasound and also determined traditional atherosclerosis risk factors, in addition to plasma H(e) concentration and MTHFR genotypes. Results - We …