My place through my eyes : a social constructionist approach to researching the relationships between socioeconomic living contexts and physical activity

There is a growing evidence-base in the epidemiological literature that demonstrates significant associations between people’s living circumstances – including their place of residence – and their health-related practices and outcomes (Leslie, 2005; Karpati, Bassett, & McCord, 2006; Monden, Van Lenthe, & Mackenbach, 2006; Parkes & Kearns, 2006; Cummins, Curtis, Diez-Roux, & Macintyre, 2007; Turrell, Kavanagh, Draper, & Subramanian, 2007). However, these findings raise questions about the ways in which living places, such as households and neighbourhoods, figure in the pathways connecting people and health (Frolich, Potvin, Chabot, & Corin, 2002; Giles-Corti, 2006; Brown et al, 2006; Diez Roux, 2007). This thesis addressed these questions via a mixed methods investigation of the patterns and processes connecting people, place, and their propensity to be physically active. Specifically, the research in this thesis examines a group of lower-socioeconomic residents who had recently relocated from poorer suburbs to a new urban village with a range of health-related resources. Importantly, the study contrasts their historical relationship with physical activity with their reactions to, and everyday practices in, a new urban setting designed to encourage pedestrian mobility and autonomy. The study applies a phenomenological approach to understanding living contexts based on Berger and Luckman’s (1966) conceptual framework in The Social Construction of Reality. This framework enables a questioning of the concept of context itself, and a treatment of it beyond environmental factors to the processes via which experiences and interactions are made meaningful. This approach makes reference to people’s histories, habituations, and dispositions in an exploration between social contexts and human behaviour. This framework for thinking about context is used to generate an empirical focus on the ways in which this residential group interacts with various living contexts over time to create a particular construction of physical activity in their lives. A methodological approach suited to this thinking was found in Charmaz’s (1996; 2001; 2006) adoption of a social constructionist approach to grounded theory. This approach enabled a focus on people’s own constructions and versions of their experiences through a rigorous inductive method, which provided a systematic strategy for identifying patterns in the data. The findings of the study point to factors such as ‘childhood abuse and neglect’, ‘early homelessness’, ‘fear and mistrust’, ‘staying indoors and keeping to yourself’, ‘conflict and violence’, and ‘feeling fat and ugly’ as contributors to an ongoing core category of ‘identity management’, which mediates the relationship between participants’ living contexts and their physical activity levels. It identifies barriers at the individual, neighbourhood, and broader ecological levels that prevent this residential group from being more physically active, and which contribute to the ways in which they think about, or conceptualise, this health-related behaviour in relationship to their identity and sense of place – both geographic and societal. The challenges of living well and staying active in poorer neighbourhoods and in places where poverty is concentrated were highlighted in detail by participants. Participants’ reactions to the new urban neighbourhood, and the depth of their engagement with the resources present, are revealed in the context of their previous life-experiences with both living places and physical activity. Moreover, an understanding of context as participants’ psychological constructions of various social and living situations based on prior experience, attitudes, and beliefs was formulated with implications for how the relationship between socioeconomic contextual effects on health are studied in the future. More detailed findings are presented in three published papers with implications for health promotion, urban design, and health inequalities research. This thesis makes a substantive, conceptual, and methodological contribution to future research efforts interested in how physical activity is conceptualised and constructed within lower socioeconomic living contexts, and why this is. The data that was collected and analysed for this PhD generates knowledge about the psychosocial processes and mechanisms behind the patterns observed in epidemiological research regarding socioeconomic health inequalities. Further, it highlights the ways in which lower socioeconomic living contexts tend to shape dispositions, attitudes, and lifestyles, ultimately resulting in worse health and life chances for those who occupy them.

Genetic, functional, and histopathological evaluation of two C-terminal BRCA1 missense variants

Background: The vast majority of BRCA1 missense sequence variants remain uncharacterised for their possible effect on protein expression and function, and therefore are unclassified in terms of their pathogenicity. BRCA1 plays diverse cellular roles and it is unlikely that any single functional assay will accurately reflect the total cellular implications of missense mutations in this gene. Objective: To elucidate the effect of two BRCA1 variants, 5236G>C (G1706A) and 5242C>A (A1708E) on BRCA1 function, and to survey the relative usefulness of several assays to direct the characterisation of other unclassified variants in BRCA genes. Methods and Results: Data from a range of bioinformatic, genetic, and histopathological analyses, and in vitro functional assays indicated that the 1708E variant was associated with the disruption of different cellular functions of BRCA1. In transient transfection experiments in T47D and 293T cells, the 1708E product was mislocalised to the cytoplasm and induced centrosome amplification in 293T cells. The 1708E variant also failed to transactivate transcription of reporter constructs in mammalian transcriptional transactivation assays. In contrast, the 1706A variant displayed a phenotype comparable to wildtype BRCA1 in these assays. Consistent with functional data, tumours from 1708E carriers showed typical BRCA1 pathology, while tumour material from 1706A carriers displayed few histopathological features associated with BRCA1 related tumours. Conclusions: A comprehensive range of genetic, bioinformatic, and functional analyses have been combined for the characterisation of BRCA1 unclassified sequence variants. Consistent with the functional analyses, the combined odds of causality calculated for the 1706A variant after multifactorial likelihood analysis (1:142) indicates a definitive classification of this variant as "benign". In contrast, functional assays of the 1708E variant indicate that it is pathogenic, possibly through subcellular mislocalisation. However, the combined odds of 262:1 in favour of causality of this variant does not meet the minimal ratio of 1000:1 for classification as pathogenic, and A1708E remains formally designated as unclassified. Our findings highlight the importance of comprehensive genetic information, together with detailed functional analysis for the definitive categorisation of unclassified sequence variants. This combination of analyses may have direct application to the characterisation of other unclassified variants in BRCA1 and BRCA2.

Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF