Genetic-epidemiologic analysis of X-inactivation skewing in human females : suggestive evidence for two distinct traits

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Non-conventional advertising formats in television versus spots: An analysis based on the generated recall

Advertising investment and audience figures indicate that television continues to lead as a mass advertising medium. However, its effectiveness is questioned due to problems such as zapping, saturation and audience fragmentation. This has favoured the development of non-conventional advertising formats. This study provides empirical evidence for the theoretical development. This investigation analyzes the recall generated by four non-conventional advertising formats in a real environment: short programme (branded content), television sponsorship, internal and external telepromotion versus the more conventional spot. The methodology employed has integrated secondary data with primary data from computer assisted telephone interviewing (CATI) were performed ad-hoc on a sample of 2000 individuals, aged 16 to 65, representative of the total television audience. Our findings show that non-conventional advertising formats are more effective at a cognitive level, as they generate higher levels of both unaided and aided recall, in all analyzed formats when compared to the spot.

Metabolic signatures of Huntington's disease (HD): 1H NMR analysis of the polar metabolome in post mortem human brain

Huntington’s disease (HD) is an autosomal neurodegenerative disorder affecting approximately 5-10 persons per 100,000 worldwide. The pathophysiology of HD is not fully understood but the age of onset is known to be highly dependent on the number of CAG triplet repeats in the huntingtin gene. Using 1H NMR spectroscopy this study biochemically profiled 39 brain metabolites in post-mortem striatum (n=14) and frontal lobe (n=14) from HD sufferers and controls (n=28). Striatum metabolites were more perturbed with 15 significantly affected in HD cases, compared with only 4 in frontal lobe (P<0.05; q<0.3). The metabolite which changed most overall was urea which decreased 3.25-fold in striatum (P<0.01). Four metabolites were consistently affected in both brain regions. These included the neurotransmitter precursors tyrosine and L-phenylalanine which were significantly depleted by 1.55-1.58-fold and 1.48-1.54-fold in striatum and frontal lobe, respectively (P=0.02-0.03). They also included L-leucine which was reduced 1.54-1.69-fold (P=0.04-0.09) and myo-inositol which was increased 1.26-1.37-fold (P<0.01). Logistic regression analyses performed with MetaboAnalyst demonstrated that data obtained from striatum produced models which were profoundly more sensitive and specific than those produced from frontal lobe. The brain metabolite changes uncovered in this first 1H NMR investigation of human HD offer new insights into the disease pathophysiology. Further investigations of striatal metabolite disturbances are clearly warranted.

Ethical reasoning through simulation: a phenomenological analysis of student experience

Background
Medical students transitioning into professional practice feel underprepared to deal with the emotional complexities of real-life ethical situations. Simulation-based learning (SBL) may provide a safe environment for students to probe the boundaries of ethical encounters. Published studies of ethics simulation have not generated sufficiently deep accounts of student experience to inform pedagogy. The aim of this study was to understand students’ lived experiences as they engaged with the emotional challenges of managing clinical ethical dilemmas within a SBL environment.

Methods
This qualitative study was underpinned by an interpretivist epistemology. Eight senior medical students participated in an interprofessional ward-based SBL activity incorporating a series of ethically challenging encounters. Each student wore digital video glasses to capture point-of-view (PoV) film footage. Students were interviewed immediately after the simulation and the PoV footage played back to them. Interviews were transcribed verbatim. An interpretative phenomenological approach, using an established template analysis approach, was used to iteratively analyse the data.

Results
Four main themes emerged from the analysis: (1) ‘Authentic on all levels?’, (2)‘Letting the emotions flow’, (3) ‘Ethical alarm bells’ and (4) ‘Voices of children and ghosts’. Students recognised many explicit ethical dilemmas during the SBL activity but had difficulty navigating more subtle ethical and professional boundaries. In emotionally complex situations, instances of moral compromise were observed (such as telling an untruth). Some participants felt unable to raise concerns or challenge unethical behaviour within the scenarios due to prior negative undergraduate experiences.

Conclusions
This study provided deep insights into medical students’ immersive and embodied experiences of ethical reasoning during an authentic SBL activity. By layering on the human dimensions of ethical decision-making, students can understand their personal responses to emotion, complexity and interprofessional working. This could assist them in framing and observing appropriate ethical and professional boundaries and help smooth the transition into clinical practice.

Reducing child conduct disordered behaviour and improving parent mental health in disadvantaged families: a 12 month follow-up and cost analysis of a parenting intervention

The effectiveness of the Incredible Years Basic parent programme (IYBP) in reducing child conduct problems and improving parent competencies and mental health was examined in a 12-month follow-up. Pre- to post-intervention service use and related costs were also analysed. A total of 103 families and their children (aged 32–88 months), who previously participated in a randomised controlled trial of the IYBP, took part in a 12-month follow-up assessment. Child and parent behaviour and well-being were measured using psychometric and observational measures. An intention-to-treat analysis was carried out using a one-way repeated measures ANOVA. Pairwise comparisons were subsequently conducted to determine whether treatment outcomes were sustained 1 year post-baseline assessment. Results indicate that post-intervention improvements in child conduct problems, parenting behaviour and parental mental health were maintained. Service use and associated costs continued to decline. The results indicate that parent-focused interventions, implemented in the early years, can result in improvements in child and parent behaviour and well-being 12 months later. A reduced reliance on formal services is also indicated.

Exploring the effects of a universal classroom management training programme on teacher and child behaviour: a group randomised controlled trial and cost analysis

Teachers frequently struggle to cope with conduct problems in the classroom. The aim of this study was to assess the effectiveness of the Incredible Years Teacher Classroom Management Training Programme for improving teacher competencies and child adjustment. The study involved a group randomised controlled trial which included 22 teachers and 217 children (102 boys and 115 girls). The average age of children included in the study was 5.3 years (standard deviation = 0.89). Teachers were randomly allocated to an intervention group (n = 11 teachers; 110 children) or a waiting-list control group (n = 11; 107 children). The sample also included 63 ‘high-risk’ children (33 intervention; 30 control), who scored above the cut-off (>12) on the Strengths and Difficulties Questionnaire for abnormal socioemotional and behavioural difficulties. Teacher and child behaviours were assessed at baseline and 6 months later using psychometric and observational measures. Programme delivery costs were also analysed. Results showed positive changes in teachers’ self-reported use of positive classroom management strategies (effect size = 0.56), as well as negative classroom management strategies (effect size = −0.43). Teacher reports also highlight improvements in the classroom behaviour of the high-risk group of children, while the estimated cost of delivering the Incredible Years Teacher Classroom Management Training Programme was modest. However, analyses of teacher and child observations were largely non-significant. A need for further research exploring the effectiveness and cost-effectiveness of the Incredible Years Teacher Classroom Management Training Programme is indicated.

Evaluating a School Community Linked Physical Activity Intervention Programme: a Multi-level Analysis.

Previous research has highlighted the importance of positive physical activity (PA) behaviors during childhood to promote sustained active lifestyles throughout the lifespan (Telama et al. 2005; 2014). It is in this context that the role of schools and teachers in facilitating PA education is promoted. Research suggests that teachers play an important role in the attitudes of children towards PA (Figley 1985) and schools may be an efficient vehicle for PA provision and promotion (McGinnis, Kanner and DeGraw, 1991; Wechsler, Deveraux, Davis and Collins, 2000). Yet despite consensus that schools represent an ideal setting from which to ‘reach’ young people (Department of Health and Human Services, UK, 2012) there remains conceptual (e.g. multi-component intervention) and methodological (e.g. duration, intensity, family involvement) ambiguity regarding the mechanisms of change claimed by PA intervention programmes. This may, in part, contribute to research findings that suggest that PA interventions have had limited impact on children’s overall activity levels and thereby limited impact in reducing children’s metabolic health (Metcalf, Henley & Wilkin, 2012). A marked criticism of the health promotion field has been the focus on behavioural change while failing to acknowledge the impact of context in influencing health outcomes (Golden & Earp, 2011). For years, the trans-theoretical model of behaviour change has been ‘the dominant model for health behaviour change’ (Armitage, 2009); this model focusses primarily on the individual and the psychology of the change process. Arguably, this model is limited by the individual’s decision-making ability and degree of self-efficacy in order to achieve sustained behavioural change and does not take account of external factors that may hinder their ability to realise change. Similar to the trans-theoretical model, socio-ecological models identify the individual at the focal point of change but also emphasises the importance of connecting multiple impacting variables, in particular, the connections between the social environment, the physical environment and public policy in facilitating behavioural change (REF). In this research, a social-ecological framework was used to connect the ways a PA intervention programme had an impact (or not) on participants, and to make explicit the foundational features of the programme that facilitated positive change. In this study, we examined the evaluation of a multi-agency approach to a PA intervention programme which aimed to increase physical activity, and awareness of the importance of physical activity to key stage 2 (age 7-12) pupils in three UK primary schools. The agencies involved were the local health authority, a community based charitable organisation, a local health administrative agency, and the city school district. In examining the impact of the intervention, we adopted a process evaluation model in order to better understand the mechanisms and context that facilitated change. Therefore, the aim of this evaluation was to describe the provision, process and impact of the intervention by 1) assessing changes in physical activity levels 2) assessing changes in the student’s attitudes towards physical activity, 3) examining student’s perceptions of the child size fitness equipment in school and their likelihood of using the equipment outside of school and 4) exploring staff perceptions, specifically the challenges and benefits, of facilitating equipment based exercise sessions in the school environment. Methodology, Methods, Research Instruments or Sources Used Evaluation of the intervention was designed as a matched-control study and was undertaken over a seven-month period. The school-based intervention involved 3 intervention schools (n =436; 224 boys) and one control school (n=123; 70 boys) in a low socioeconomic and multicultural urban setting. The PA intervention was separated into two phases: a motivation DVD and 10 days of circuit based exercise sessions (Phase 1) followed by a maintenance phase (Phase 2) that incorporated a PA reward program and the use of specialist kid’s gym equipment located at each school for a period of 4 wk. Outcome measures were measured at baseline (January) and endpoint (July; end of academic school year) using reliable and valid self-report measures. The children’s attitudes towards PA were assessed using the Children’s Attitudes towards Physical Activity (CATPA) questionnaire. The Physical Activity Questionnaire for Children (PAQ-C), a 7-day recall questionnaire, was used to assess PA levels over a school week. A standardised test battery (Fitnessgram®) was used to assess cardiovascular fitness, body composition, muscular strength and endurance, and flexibility. After the 4 wk period, similar kid’s equipment was available for general access at local community facilities. The control school did not receive any of the interventions. All physical fitness tests and PA questionnaires were administered and collected prior to the start of the intervention (January) and following the intervention period (July) by an independent evaluation team. Evaluation testing took place at the individual schools over 2-3 consecutive days (depending on the number of children to be tested at the school). Staff (n=19) and student perceptions (n = 436) of the child sized fitness equipment were assessed via questionnaires post-intervention. Students completed a questionnaire to assess enjoyment, usage, ease of use and equipment assess and usage in the community. A questionnaire assessed staff perceptions on the delivery of the exercise sessions, classroom engagement and student perceptions. Conclusions, Expected Outcomes or Findings Findings showed that both the intervention (16.4%) and control groups increased their PAQ-C score by post-intervention (p < 0.05); with the intervention (17.8%) and control (21.3%) boys showing the greatest increase in physical activity levels. At post-intervention, there was a 5.5% decline in the intervention girls’ attitudes toward PA in the aesthetic subdomains (p = 0.009); whereas the control boys had an increase in positive attitudes in the health domain (p = 0.003). No significant differences in attitudes towards physical activity were observed in any other domain for either group at post-intervention (p > 0.05). The results of the equipment questionnaire, 96% of the children stated they enjoyed using the equipment and would like to use the equipment again in the future; however at post-intervention only 27% reported using the equipment outside of school in the last 7 days. Students identified the ski walker (34%) and cycle (32%) as their favorite pieces of equipment; with the single joint exercises such as leg extension and bicep/tricep machine (<3%) as their least favorite. Key themes from staff were that the equipment sessions were enjoyable, a novel activity, children felt very grown-up, and the activity was linked to a real fitness experience. They also expressed the need for more support to deliver the sessions and more time required for each session. Findings from this study suggest that a more integrated approach within the various agencies is required, particularly more support to increase teachers pedagogical content knowledge in physical activity instruction which is age appropriate. Future recommendations for successful implementation include sufficient time period for all students to access and engage with the equipment; increased access and marketing of facilities to parents within the local community, and professional teacher support strategies to facilitate the exercise sessions.

Integrated Reporting in OMXS30 companies - An Analysis of Human Capital Disclosures

Background and Problem: Sustainability reporting is a growing interest in today’s organizations and it is essential to report on non-financial matters. Many of the existing frameworks have been criticized for being used only of symbolical reasons which is why the concept of integrated reporting and the <IR> framework have been developed. One of the cornerstones in the <IR> framework is human capital which is one of the most valuable assets in an organization. Traditionally, employee costs have only been treated as an expense and there have been limited disclosures in corporate reports. In the current business world it is instead seen as an investment in human resources. Since previous studies have shown an increase of human capital disclosures when corporate reports become integrated, integrated reporting might be the solution to this problem. Purpose: The purpose of this study is to examine if there are differences in human capital disclosures between integrated reports and separate annual and sustainability reports in companies listed at OMXS30. Delimitations: This study’s empirical examination is limited to include the companies listed at Stockholm OMX30. Only corporate reports issued for the year 2014 are treated. Methodology: For this study a self-constructed disclosure scoreboard with human capital- related items has been used to collect data from the companies’ corporate reports. Also additional information beyond the pre-determined items has been collected to extend the data collection. Empirical Results and Conclusion: The results show that human capital seems to be a subject that is relatively little reported about. The integrated reporting companies do not disclose more information compared to non-integrated reporting companies. However, the results show that integrated reporting companies seem to have a more future-oriented focus and that the disclosures are more dispersed throughout the reports. It can be concluded that company sector and size do not affect the amount or type of information. 

Functional analysis of the 5′ flanking region of the human G6PC3 gene: regulation of promoter activity by glucose, pyruvate, AMP kinase and the pentose phosphate pathway

G6PC3 is a widely expressed isoform of glucose-6-phosphatase, found in many foetal and adult tissues. Mutations in this gene cause developmental abnormalities and severe neutropenia due to abolition of glucose recycling between the cytoplasm and endoplasmic reticulum. Low G6PC3 expression as a result of promoter polymorphisms or dysregulation could produce similar outcomes. Here we investigated the regulation of human G6PC3 promoter activity. HeLa and H4IIE cells were transiently transfected with G6PC3 promoter coupled to the firefly luciferase gene, and promoter activity was measured by dual luciferase assay. Activity was highest in a 453 bp segment of the G6PC3 promoter, from − 455 to − 3 relative to the transcriptional start site. This promoter was unresponsive to glucostatic hormones. Its activity increased significantly between 1 and 5.5 mM glucose, and was not elevated further by glucose concentrations up to 25 mM. Pyruvate increased its activity, but β-hydroxybutyrate and sodium acetate did not. Promoter activity was reduced by inhibitors of hexokinase, glyceraldehyde phosphate dehydrogenase and the oxidative branch of the pentose phosphate pathway, but not by a transketolase inhibitor. Deletion of two adjacent Enhancer-boxes (− 274 to − 279 and − 299 to − 304) reduced promoter activity and abolished the glucose effect, suggesting they could function as a glucose response element. Deletion of an additional downstream 140 bp (− 140 to − 306) restored activity, but not the glucose response, suggesting the presence of repressor elements in this region. 5-Aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR) reduced promoter activity, showing dependence on AMP-kinase. Regulation of the G6PC3 promoter is thus radically different to that of the hepatic isoform, G6PC. It is sensitive to carbohydrate, but not to fatty acid metabolites, and at much lower physiological concentrations. Based on these findings, we speculate that reduced G6PC3 expression could occur during hypoglycemic episodes in vivo, which are common in utero and in the postnatal period. If such episodes lower G6PC3 expression they could place the foetus or infant at risk of impaired immune function and development, and this possibility requires further examination both in vitro and in vivo.

Analysis and modelling of immune cell behaviour in lymph nodes based on multi-photon imaging

This thesis presents quantitative studies of T cell and dendritic cell (DC) behaviour in mouse lymph nodes (LNs) in the naive state and following immunisation. These processes are of importance and interest in basic immunology, and better understanding could improve both diagnostic capacity and therapeutic manipulations, potentially helping in producing more effective vaccines or developing treatments for autoimmune diseases. The problem is also interesting conceptually as it is relevant to other fields where 3D movement of objects is tracked with a discrete scanning interval. A general immunology introduction is presented in chapter 1. In chapter 2, I apply quantitative methods to multi-photon imaging data to measure how T cells and DCs are spatially arranged in LNs. This has been previously studied to describe differences between the naive and immunised state and as an indicator of the magnitude of the immune response in LNs, but previous analyses have been generally descriptive. The quantitative analysis shows that some of the previous conclusions may have been premature. In chapter 3, I use Bayesian state-space models to test some hypotheses about the mode of T cell search for DCs. A two-state mode of movement where T cells can be classified as either interacting to a DC or freely migrating is supported over a model where T cells would home in on DCs at distance through for example the action of chemokines. In chapter 4, I study whether T cell migration is linked to the geometric structure of the fibroblast reticular network (FRC). I find support for the hypothesis that the movement is constrained to the fibroblast reticular cell (FRC) network over an alternative 'random walk with persistence time' model where cells would move randomly, with a short-term persistence driven by a hypothetical T cell intrinsic 'clock'. I also present unexpected results on the FRC network geometry. Finally, a quantitative method is presented for addressing some measurement biases inherent to multi-photon imaging. In all three chapters, novel findings are made, and the methods developed have the potential for further use to address important problems in the field. In chapter 5, I present a summary and synthesis of results from chapters 3-4 and a more speculative discussion of these results and potential future directions.

Analysis of the moisture effect on the mechanical behaviour of an adhesively bonded joint under proportional multi-axial loads

The objective of the study is to identify the 3D behaviour of an adhesive in an assembly, and to take into account the effect of ageing in a marine environment. To that end, three different tests were employed. Gravimetric analyses were used to determine the water diffusion kinetics in the adhesive. Bulk tensile tests were performed to highlight the effects of humid ageing on the adhesive behaviour. Modified Arcan tests were performed for several ageing times to obtain the experimental database which was necessary to identify constitutive models. A Mahnken-Schlimmer type model was determined for the unaged state according to a procedure developed in a previous study. This identification used inverse techniques. It was based on the unaged modified Arcan results and on a coupling between an optimisation routine and finite-element analysis. Then, a global inverse identification procedure was developed. Its aim was to relate the unaged parameters to the moisture concentration and overcome the difficulties usually associated with ageing of bonded assemblies in a humid environment: a non-uniformity of the stress state and a gradient of mechanical properties in the adhesive. This procedure was similar to the one used in the first part but needed modified Arcan results for several ageing times. It also required an initial assumption for the evolution of the Mahnken-Schlimmer parameters with the moisture concentration.

The cytokinesis-block micronucleus (CBMN) assay in human populations exposed to styrene: a systematic review and meta-analysis

Styrene is a building-block of several compounds used in a wide array of materials and products. The most important human exposure to this substance occurs in industrial settings, especially among reinforced-plastics industry workers. The effect of occupational exposure to styrene on cytogenetics biomarkers has been previously reviewed with positive association observed for chromosomal aberrations, and inconclusive data for the micronucleus assay. Some limitations were noted in those studies, including inadequate exposure assessment and poor epidemiological design. Furthermore, in earlier studies micronuclei frequency was measured with protocols not as reliable as cytokinesis-block micronucleus (CBMN) assay. Aim of the present systematic review and meta-analysis is to investigate genomic instability and DNA damage as measured by the CBMN assay in lymphocytes of subjects exposed to styrene. A total of 11 studies published between 2004 and 2012 were included in the meta-analysis encompassing 479 styrene-exposed workers and 510 controls. The quality of each study was estimated by a quality scoring system which ranked studies according to the consideration of major confounders, exposure characterization, and technical parameters. An overall increase of micronuclei frequencies was found in styrene-exposure workers when compared to referents (meta-MR 1.34; 95% CI 1.18–1.52), with significant increases achieved in six individual studies. The consistency of results in individual studies, the independence of this result from major confounding factors and from the quality of the study strengthens the reliability of risk estimates and supports the use of the CBMN assay in monitoring genetic risk in styrene workers.