The GSTM1 null genotype confers an increased risk for Solar Keratosis Development in an Australian Caucasian Population

Solar keratoses affect approximately 50% of Australian Caucasians aged over 40 y. Solar keratoses can undergo malignant transformation into squamous cell carcinoma followed by possible metastasis and are risk factors for basal cell carcinoma, melanoma, and squamous cell carcinoma. The glutathione-S-transferase genes play a part in detoxification of carcinogens and mutagens, including some produced by ultraviolet radiation. This study examined the role of glutathione-S-transferase M1, T1, P1, and Z1 gene polymorphisms in susceptibility to solar keratoses development. Using DNA samples from volunteers involved in the Nambour Skin Cancer Prevention Trial, allele and genotype frequencies were determined using polymerase chain reaction and restriction enzyme digestion. No significant differences were detected in glutathione-S-transferase P1 and glutathione-S-transferase Z1 allele or genotype frequencies; however, a significant association between glutathione-S-transferase M1 genotypes and solar keratoses development was detected (p=0.003) with null individuals having an approximate 2-fold increase in risk for solar keratoses development (odds ratio: 2.1; confidence interval: 1.3-3.5) and a significantly higher increase in risk in conjunction with high outdoor exposure (odds ratio: 3.4; confidence interval: 1.9-6.3). Also, a difference in glutathione-S-transferase T1 genotype frequencies was detected (p=0.039), although considering that multiple testing was undertaken, this was found not to be significant. Fair skin and inability to tan were found to be highly significant risk factors for solar keratoses development with odds ratios of 18.5 (confidence interval: 5.7-59.9) and 7.4 (confidence interval: 2.6-21.0), respectively. Overall, glutathione-S-transferase M1 conferred a significant increase in risk of solar keratoses development, particularly in the presence of high outdoor exposure and synergistically with known phenotypic risk factors of fair skin and inability to tan.

Melanocortin-1 receptor genotype is a risk factor for basal and squamous cell carcinoma

MC1R gene variants have previously been associated with red hair and fair skin color, moreover skin ultraviolet sensitivity and a strong association with melanoma has been demonstrated for three variant alleles that are active in influencing pigmentation: Arg151Cys, Arg160Trp, and Asp294His. This study has confirmed these pigmentary associations with MC1R genotype in a collection of 220 individuals drawn from the Nambour community in Queensland, Australia, 111 of whom were at high risk and 109 at low risk of basal cell carcinoma and squamous cell carcinoma. Comparative allele frequencies for nine MC1R variants that have been reported in the Caucasian population were determined for these two groups, and an association between prevalence of basal cell carcinoma, squamous cell carcinoma, solar keratosis and the same three active MC1R variant alleles was demonstrated [odds ratio = 3.15 95% CI (1.7, 5.82)]. Three other commonly occurring variant alleles: Val60Leu, Val92Met, and Arg163Gln were identified as having a minimal impact on pigmentation phenotype as well as basal cell carcinoma and squamous cell carcinoma risk. A significant heterozygote effect was demonstrated where individuals carrying a single MC1R variant allele were more likely to have fair and sun sensitive skin as well as carriage of a solar lesion when compared with those individuals with a consensus MC1R genotype. After adjusting for the effects of pigmentation on the association between MC1R variant alleles and basal cell carcinoma and squamous cell carcinoma risk, the association persisted, confirming that presence of at least one variant allele remains informative in terms of predicting risk for developing a solar-induced skin lesion beyond that information wained through observation of pigmentation phenotype.

In their own words : adolescents strategies to prevent friend's risk taking

Injury is a significant public health problem among youth. A primary cause of adolescent injury is risk-taking behavior, including alcohol use, interpersonal violence and road-related risks. A novel approach to prevention is building on friendships by encouraging adolescents to intervene into their friends’ risk taking. Fifty-one early adolescents (13-14 years) and 44 older adolescents (16-17 years) from two Australian schools participated in focus groups, aiming to explore stories of intervening. Findings showed preference for talking to friends; however, participants also spoke to adults, monitored friends’ behavior and planned ahead. Close friendships, perceived harm, and self-efficacy influenced the likelihood of intervening. These findings have implications for the design of risk and injury prevention programs, by suggesting strategies to promote adolescents’ communicative ability for risk reduction. The findings also highlight the language and dialogue of adolescents and suggest that methods for increasing intervening behavior should focus on building social connectedness and increasing self-efficacy.

Chlamydia muridarum lung infection in infants alters hematopoietic cells to promote allergic airway disease in mice

Background Viral and bacterial respiratory tract infections in early-life are linked to the development of allergic airway inflammation and asthma. However, the mechanisms involved are not well understood. We have previously shown that neonatal and infant, but not adult, chlamydial lung infections in mice permanently alter inflammatory phenotype and physiology to increase the severity of allergic airway disease by increasing lung interleukin (IL)-13 expression, mucus hyper-secretion and airway hyper-responsiveness. This occurred through different mechanisms with infection at different ages. Neonatal infection suppressed inflammatory responses but enhanced systemic dendritic cell:T-cell IL-13 release and induced permanent alterations in lung structure (i.e., increased the size of alveoli). Infant infection enhanced inflammatory responses but had no effect on lung structure. Here we investigated the role of hematopoietic cells in these processes using bone marrow chimera studies. Methodology/Principal Findings Neonatal (<24-hours-old), infant (3-weeks-old) and adult (6-weeks-old) mice were infected with C. muridarum. Nine weeks after infection bone marrow was collected and transferred into recipient age-matched irradiated naïve mice. Allergic airway disease was induced (8 weeks after adoptive transfer) by sensitization and challenge with ovalbumin. Reconstitution of irradiated naïve mice with bone marrow from mice infected as neonates resulted in the suppression of the hallmark features of allergic airway disease including mucus hyper-secretion and airway hyper-responsiveness, which was associated with decreased IL-13 levels in the lung. In stark contrast, reconstitution with bone marrow from mice infected as infants increased the severity of allergic airway disease by increasing T helper type-2 cell cytokine release (IL-5 and IL-13), mucus hyper-secretion, airway hyper-responsiveness and IL-13 levels in the lung. Reconstitution with bone marrow from infected adult mice had no effects. Conclusions These results suggest that an infant chlamydial lung infection results in long lasting alterations in hematopoietic cells that increases the severity of allergic airway disease in later-life.

A genetic variant located in miR-423 is associated with reduced breast cancer risk

Background/Aim: Since microRNAs (miRNAs) act as translational regulators of multiple genes, single nucleotide polymorphisms (SNP) in them can have potentially wide-ranging effects. Using an association approach, this research examined the effects of the rs6505162 SNP, an A>C polymorphism located in the premiRNA region of miR-423, on breast cancer development. Materials and Methods: Caucasian Australian women with breast cancer and controls matched for age and ethnicity were genotyped for rs6505162 and their genotypic and allelic frequencies analysed for significant differences. Results: Analysis indicated that there were significant differences between the case and control populations (χ 2=6.70, p=0.035), with the CC genotype conferring reduced risk of breast cancer development (odds ratio=0.50 95% confidence interval=0.27-0.92, p=0.03). Conclusion: Further functional research is required to determine the mechanism of action of this SNP on miRNA function.

High-risk, high-stake relationships: building effective industry-university partnerships for Work Integrated Learning (WIL)

Many industry peak and professional bodies advocate students undertake professional work placements as a key work integrated learning (WIL) experience in accredited university degree courses. However, mismatched expectations and gaps in the way industry partners (IPs) are supported during these work placements can place these high-stake alliances at risk. A review of models and strategies supporting industry partners indicates many are contingent on the continued efforts of well-networked individuals in both universities and IP organisations to make these connections work. It is argued that whilst these individuals are highly valued they often end up representing a whole course or industry perspective, not just their area of expertise. Sustainable partnership principles and practices with shared responsibility across stakeholder groups are needed instead. This paper provides an overview of work placement approaches in the disciplines of business, engineering and urban development at an Australian, metropolitan university. Employing action research and participatory focus group methodologies, it gathers and articulates recommendations from associated IPs on practical suggestions and strategies to improve relationships and the resultant quality of placements.

The effects of risk factors and protective factors on influencing engagement in risky behaviours and injury experiences for high-risk adolescents

High-risk adolescents are most vulnerable to the negative outcomes of risk taking behaviour, such as injury. It has been theorised by Jessor (1987) that adolescent risk behaviours (e.g. violence, alcohol use) can be predicted by assessing the risk factors (e.g. peer models for violence) and protective factors (e.g. school connectedness) in a young person’s life. The aim of this research is to examine the influence of risk factors and protective factors on the proneness of high-risk adolescents to engage in risky behaviour. 2,521 Grade 9 students (13-14 years of age) from 35 schools in Queensland, Australia participated in this study. The findings examine the influence of risk factors and protective factors on self-reported risky behaviour and injury experiences for adolescents who have been categorized as high-risk. Thereby, providing insight that may be used to target preventive interventions aimed at high-risk adolescents.

Mainstreaming climate change adaptation : An incremental approach to disaster risk management in Australia

In this paper we argue that rationalist ‘predict then act’ approaches to disaster risk management (DRM) policy promote unrealistic public expectations of DRM provisions, the avoidance of decision making by political elites, an over-reliance on technical expertise and engineering solutions to reducing exposure to natural events, and a reactive approach to DRM overall. We propose an alternative incrementalist approach that focuses on managing uncertainties rather than reducing them and building resilience not simply through the reduction of hazard exposure, but also through the ongoing reduction of community vulnerability, the explicit consideration of normative priorities, and more effective community engagement in climate risk debates.

Postnatal depression in Central Vietnam

Postnatal depression (PND) is a significant global health issue, which not only impacts maternal wellbeing, but also infant development and family structures. Mental health disorders represent approximately 14% of global burden of disease and disability, including low and middle-income countries (LMIC), and PND has direct relevance to the Millennium Development Goals of reducing child mortality, improving maternal health, and creating global partnerships (United Nations, 2012; Guiseppe, Becker & Farmer, 2011). Emerging evidence suggests that PND in LMIC is similar to, or higher than in high-income countries (HIC), however, less than 10% of LMIC have prevalence data available (Fisher, Cabral de Mello, & Izutsu 2009; Lund et al., 2011). Whilst a small number of studies on maternal mental disorders have been published in Vietnam, only one specifically focuses on PND in a hospital-based sample. Also, community based mental health studies and information on mental health in rural areas of Vietnam is still scarce. The purpose of this study was to determine the prevalence of PND, and its associated social determinants in postnatal women in Thua Thien Hue Province, Central Vietnam. In order to identify social determinants relevant to the Central Vietnamese context, two qualitative studies and one community survey were undertaken. Associations between maternal mental health and infant health outcomes were also explored. The study was comprised of three phases. Firstly, iterative, qualitative interviews with Vietnamese health professionals (n = 17) and postpartum women (n = 15) were conducted and analysed using Kleinman's theory of explanatory models to identify narratives surrounding PND in the Vietnamese context (Kleinman, 1978). Secondly, a participatory concept mapping exercise was undertaken with two groups of health professionals (n = 12) to explore perceived risk and protective factors for postnatal mental health. Qualitative phases of the research elucidated narratives surrounding maternal mental health in the Vietnamese context such as son preference, use of traditional medicines, and the popularity of confinement practices such as having one to three months of complete rest. The qualitative research also revealed the construct of depression was not widely recognised. Rather, postpartum changes in mood were conceptualised as a loss of 'vital strength' following childbirth or 'disappointment'. Most women managed postpartum changes in mood within the family although some sought help from traditional medicine practitioners or biomedical doctors. Thirdly, a cross-sectional study of twelve randomly selected communes (six urban, six rural) in Thua Thien Hue Province was then conducted. Overall, 465 women with infants between 4 weeks and six months old participated, and 431 questionnaires were analysed. Women from urban (n = 216) and rural (n = 215) areas participated. All eligible women completed a structured interview about their health, basic demographics, and social circumstances. Maternal depression was measured using the Edinburgh Postnatal Depression Scale (EPDS) as a continuous variable. Multivariate generalised linear regression was conducted using PASW Statistics version 18.0 (2009). When using the conventional EPDS threshold for probable depression (EPDS score ~ 13) 18.1% (n = 78) of women were depressed (Gibson, McKenzie-McHarg, Shakespeare, Price & Gray, 2009). Interestingly, 20.4% of urban women (n = 44) had EPDS scores~ 13, which was a higher proportion than rural women, where 15.8% (n = 34) had EPDS scores ~ 13, although this difference was not statistically significant: t(429) = -0.689, p = 0.491. Whilst qualitative narratives identified infant gender and family composition, and traditional confinement practices as relevant to postnatal mood, these were not statistically significant in multivariate analysis. Rather, poverty, food security, being frightened of your husband or family members, experiences of intimate partner violence and breastfeeding difficulties had strong statistical associations. PND was also associated with having an infant with diarrhoea in the past two weeks, but not infant malnutrition or acute respiratory infections. This study is the first to explore maternal mental health in Central Vietnam, and provides further evidence that PND is a universally experienced phenomenon. The independent social risk factors of depressive symptoms identified such as poverty, food insecurity, experiences of violence and powerlessness, and relationship adversity points to women in a context of social suffering which is relevant throughout the world (Kleinman, Das & Lock, 1997). The culturally specific risk factors explored such as infant gender were not statistically significant when included in a multivariable model. However, they feature prominently in qualitative narratives surrounding PND in Vietnam, both in this study and previous literature. It appears that whilst infant gender may not be associated with PND per se, the reactions of close relatives to the gender of the baby can adversely affect maternal wellbeing. This study used a community based participatory research approach (CBPR) (Israel.2005). This approach encourages the knowledge produced to be used for public health interventions and workforce training in the community in which the research was conducted, and such work has commenced. These results suggest that packages of interventions for LMIC devised to address maternal mental health and infant wellbeing could be applied in Central Vietnam. Such interventions could include training lay workers to follow up postpartum women, and incorporating mental health screening and referral into primary maternal and child health care (Pate! et al., 2011; Rahman, Malik, Sikander & Roberts, 2008). Addressing the underlying social determinants of PND through poverty reduction and violence elimination programs is also recommended.

Understanding the impact of legislative changes on child car seating and restraint practices in regional Queensland

Road crashes contribute to a significant amount of child mortality and morbidity in Australia. In fact, passenger injuries contribute to the majority of child crash road trauma. A number of factors contribute to child injury and death in motor vehicles, including inappropriate seating position, inappropriate choice of restraint, and incorrect installation and use of child restraints. Prior to March 2010, child restraint legislation in Queensland only required children twelve months and younger to be seated in a properly adjusted and fastened child restraint. This legislation left older infants and young children potentially suboptimally protected. From March 2010, new legislation specified seating position and type of child restraint required, depending on the age of the child. This research was underpinned by the Health Belief Model (HBM), which explores health related behaviour, behaviour change, environmental factors influencing behaviour change (including legislative changes) and is flexible enough to be used in relation to parents' health practices for their children, rather than parent health directly. This thesis investigates the extent to which the changes to child restraint legislation have led parents in regional areas of Queensland to use appropriate restraint practices for their children and determines the extent to which the constructs of the HBM, parental perceptions, barriers and environmental factors contribute to the appropriateness of child seating and restraint use. Study One included three sets of observations taken in two regional cities of Queensland prior to the legislative amendment, during an educative period of six months, and after the enactment of the legislation. Each child's seating position and restraint type were recorded. Results showed that the proportion of children observed occupying the front seat decreased by 15.6 per cent with the announcement the legislation. There was no decrease in front seat use at the enactment of the legislation. The proportion of children observed using dedicated child restraints increased by 8.8 per cent with the announcement of the legislation when there was one child in the vehicle. Further, there was a 10.1 per cent increase in the proportion of children observed using a seat belt that fit with the announcement when there was one child in the vehicle and with the enactment of the legislation regardless of the number of children in the vehicle (21.8 per cent for one child, 39.7 per cent for two children and 40.2 per cent for three or more children). Study Two comprised initial intercept interviews, later followed up by telephone, with parents with children aged eight years and younger at the announcement and telephone interviews at the enactment of the legislation in one regional city in Queensland. Parents reported their child restraint practices, and opinions, knowledge and understanding of the requirements of the new legislation. Parent responses were analysed in terms of the constructs in the HBM. When asked which seating position their child 'usually' used, parents reported child front seat use was nil (0.0 per cent) and did not change with the enactment of the legislative amendment. However, when parents were asked whether they allowed children to use the front seat at some point within the six months prior to the interview, reported child front seat use was 7 (5.4 per cent) children at T2 and 10 (9.6 per cent) at T3. Reported use of age-appropriate child restraints did not increase with the enactment of the legislation (p = 0.77, ns). Parents reported restraint practices were classed as either appropriate or inappropriate. Parents who reported appropriate restraint practices were those whose children were sitting in optimal restraints and seating positions for their age according to the requirements of the legislation. Parents who reported inappropriate restraint practices were those who had one or more children who were suboptimally restrained or seated for their age according to the requirements of the legislation. Neither parents' perceptions about their susceptibility of being in a crash nor the likelihood of severity of child injury if involved in a crash yielded significant differences in the appropriateness of reported parent restraint practices over time with the enactment of the legislation. A trend in the data suggested parents perceived a benefit to using appropriate restraint practices was to avoid fines and demerit points. Over 75 per cent of parents who agreed that child restraints provide better protection for children than an adult seat belt reported appropriately seating and restraining their children (2 (1) = 8.093, p<.05). The self-efficacy measure regarding parents' confidence in installing a child restraint showed a significant association with appropriate parental restraint practices (2 (1) = 7.036, p<.05). Results suggested that some parents may have misinterpreted the announcement of the legislative amendment as the announcement of the enforcement of the legislation instead. Some parents who correctly reported details of the legislation did not report appropriate child restraint practices. This finding shows that parents' knowledge of the legislative amendment does not necessarily have an impact on their behaviour to appropriately seat and restrain children. The results of these studies have important implications for road safety and the prevention of road-related injury and death to children in Queensland. Firstly, parents reported feeling unsure of how to install restraints, which suggests that there may be children travelling in restraints that have not been installed correctly, putting them at risk. Interventions to alert and encourage parents to seek advice when unsure about the correct installation of child restraints could be considered. Secondly, some parents in this study although they were using the most appropriate restraint for their children, reported using a type that was not the most appropriate restraint for the child's age according to the legislation. This suggests that intervention may be effective in helping parents make a more accurate choice of the most appropriate type of restraint to use with children, especially as the child ages and child restraint requirements change. Further research could be conducted to ascertain the most effective methods of informing and motivating parents to use the most appropriate restraints and seating positions for their children, as these results show a concerning disparity between reported restraint practices and those that were observed.

The association of single nucleotide polymorphisms with endometrial cancer risk and prognosis

Endometrial cancer is one of the most common female diseases in developed nations and is the most commonly diagnosed gynaecological cancer in Australia. The disease is commonly classified by histology: endometrioid or non-endometrioid endometrial cancer. While non-endometrioid endometrial cancers are accepted to be high-grade, aggressive cancers, endometrioid cancers (comprising 80% of all endometrial cancers diagnosed) generally carry a favourable patient prognosis. However, endometrioid endometrial cancer patients endure significant morbidity due to surgery and radiotherapy used for disease treatment, and patients with recurrent disease have a 5-year survival rate of less than 50%. Genetic analysis of women with endometrial cancer could uncover novel markers associated with disease risk and/or prognosis, which could then be used to identify women at high risk and for the use of specialised treatments. Proteases are widely accepted to play an important role in the development and progression of cancer. This PhD project hypothesised that SNPs from two protease gene families, the matrix metalloproteases (MMPs, including their tissue inhibitors, TIMPs) and the tissue kallikrein-related peptidases (KLKs) would be associated with endometrial cancer susceptibility and/or prognosis. In the first part of this study, optimisation of the genotyping techniques was performed. Results from previously published endometrial cancer genetic association studies were attempted to be validated in a large, multicentre replication set (maximum cases n = 2,888, controls n = 4,483, 3 studies). The rs11224561 progesterone receptor SNP (PGR, A/G) was observed to be associated with increased endometrial cancer risk (per A allele OR 1.31, 95% CI 1.12-1.53; p-trend = 0.001), a result which was initially reported among a Chinese sample set. Previously reported associations for the remaining 8 SNPs investigated for this section of the PhD study were not confirmed, thereby reinforcing the importance of validation of genetic association studies. To examine the effect of SNPs from the MMP and KLK families on endometrial cancer risk, we selected the most significantly associated MMP and KLK SNPs from genome-wide association study analysis (GWAS) to be genotyped in the GWAS replication set (cases n = 4,725, controls n = 9,803, 13 studies). The significance of the MMP24 rs932562 SNP was unchanged after incorporation of the stage 2 samples (Stage 1 per allele OR 1.18, p = 0.002; Combined Stage 1 and 2 OR 1.09, p = 0.002). The rs10426 SNP, located 3' to KLK10 was predicted by bioinformatic analysis to effect miRNA binding. This SNP was observed in the GWAS stage 1 result to exhibit a recessive effect on endometrial cancer risk, a result which was not validated in the stage 2 sample set (Stage 1 OR 1.44, p = 0.007; Combined Stage 1 and 2 OR 1.14, p = 0.08). Investigation of the regions imputed surrounding the MMP, TIMP and KLK genes did not reveal any significant targets for further analysis. Analysis of the case data from the endometrial cancer GWAS to identify genetic variation associated with cancer grade did not reveal SNPs from the MMP, TIMP or KLK genes to be statistically significant. However, the representation of SNPs from the MMP, TIMP and KLK families by the GWAS genotyping platform used in this PhD project was examined and observed to be very low, with the genetic variation of four genes (MMP23A, MMP23B, MMP28 and TIMP1) not captured at all by this technique. This suggests that comprehensive candidate gene association studies will be required to assess the role of SNPs from these genes with endometrial cancer risk and prognosis. Meta-analysis of gene expression microarray datasets curated as part of this PhD study identified a number of MMP, TIMP and KLK genes to display differential expression by endometrial cancer status (MMP2, MMP10, MMP11, MMP13, MMP19, MMP25 and KLK1) and histology (MMP2, MMP11, MMP12, MMP26, MMP28, TIMP2, TIMP3, KLK6, KLK7, KLK11 and KLK12). In light of these findings these genes should be prioritised for future targeted genetic association studies. Two SNPs located 43.5 Mb apart on chromosome 15 were observed from the GWAS analysis to be associated with increased endometrial cancer grade, results that were validated in silico in two independent datasets. One of these SNPs, rs8035725 is located in the 5' untranslated region of a MYC promoter binding protein DENND4A (Stage 1 OR 1.15, p = 9.85 x 10P -5 P, combined Stage 1 and in silico validation OR 1.13, p = 5.24 x 10P -6 P). This SNP has previously been reported to alter the expression of PTPLAD1, a gene involved in the synthesis of very long fatty acid chains and in the Rac1 signaling pathway. Meta-analysis of gene expression microarray data found PTPLAD1 to display increased expression in the aggressive non-endometrioid histology compared with endometrioid endometrial cancer, suggesting that the causal SNP underlying the observed genetic association may influence expression of this gene. Neither rs8035725 nor significant SNPs identified by imputation were predicted bioinformatically to affect transcription factor binding sites, indicating that further studies are required to assess their potential effect on other regulatory elements. The other grade- associated SNP, rs6606792, is located upstream of an inferred pseudogene, ELMO2P1 (Stage 1 OR 1.12, p = 5 x 10P -5 P; combined Stage 1 and in silico validation OR 1.09, p = 3.56 x 10P -5 P). Imputation of the ±1 Mb region surrounding this SNP revealed a cluster of significantly associated variants which are predicted to abolish various transcription factor binding sites, and would be expected to decrease gene expression. ELMO2P1 was not included on the microarray platforms collected for this PhD, and so its expression could not be investigated. However, the high sequence homology of ELMO2P1 with ELMO2, a gene important to cell motility, indicates that ELMO2 could be the parent gene for ELMO2P1 and as such, ELMO2P1 could function to regulate the expression of ELMO2. Increased expression of ELMO2 was seen to be associated with increasing endometrial cancer grade, as well as with aggressive endometrial cancer histological subtypes by microarray meta-analysis. Thus, it is hypothesised that SNPs in linkage disequilibrium with rs6606792 decrease the transcription of ELMO2P1, reducing the regulatory effect of ELMO2P1 on ELMO2 expression. Consequently, ELMO2 expression is increased, cell motility is enhanced leading to an aggressive endometrial cancer phenotype. In summary, these findings have identified several areas of research for further study. The results presented in this thesis provide evidence that a SNP in PGR is associated with risk of developing endometrial cancer. This PhD study also reports two independent loci on chromosome 15 to be associated with increased endometrial cancer grade, and furthermore, genes associated with these SNPs to be differentially expressed according in aggressive subtypes and/or by grade. The studies reported in this thesis support the need for comprehensive SNP association studies on prioritised MMP, TIMP and KLK genes in large sample sets. Until these studies are performed, the role of MMP, TIMP and KLK genetic variation remains unclear. Overall, this PhD study has contributed to the understanding of genetic variation involvement in endometrial cancer susceptibility and prognosis. Importantly, the genetic regions highlighted in this study could lead to the identification of novel gene targets to better understand the biology of endometrial cancer and also aid in the development of therapeutics directed at treating this disease.

Closing the case of APOE in multiple sclerosis : no association with disease risk in over 29,000 subjects

Background Single nucleotide polymorphisms (SNPs) rs429358 (ε4) and rs7412 (ε2), both invoking changes in the amino-acid sequence of the apolipoprotein E (APOE) gene, have previously been tested for association with multiple sclerosis (MS) risk. However, none of these studies was sufficiently powered to detect modest effect sizes at acceptable type-I error rates. As both SNPs are only imperfectly captured on commonly used microarray genotyping platforms, their evaluation in the context of genome-wide association studies has been hindered until recently. Methods We genotyped 12 740 subjects hitherto not studied for their APOE status, imputed raw genotype data from 8739 subjects from five independent genome wide association studies datasets using the most recent high-resolution reference panels, and extracted genotype data for 8265 subjects from previous candidate gene assessments. Results Despite sufficient power to detect associations at genome-wide significance thresholds across a range of ORs, our analyses did not support a role of rs429358 or rs7412 on MS susceptibility. This included meta-analyses of the combined data across 13 913 MS cases and 15 831 controls (OR=0.95, p=0.259, and OR 1.07, p=0.0569, for rs429358 and rs7412, respectively). Conclusion Given the large sample size of our analyses, it is unlikely that the two APOE missense SNPs studied here exert any relevant effects on MS susceptibility.

Building an augmented map for road risk assessment

Recent road safety statistics show that the decades-long fatalities decreasing trend is stopping and stagnating. Statistics further show that crashes are mostly driven by human error, compared to other factors such as environmental conditions and mechanical defects. Within human error, the dominant error source is perceptive errors, which represent about 50% of the total. The next two sources are interpretation and evaluation, which accounts together with perception for more than 75% of human error related crashes. Those statistics show that allowing drivers to perceive and understand their environment better, or supplement them when they are clearly at fault, is a solution to a good assessment of road risk, and, as a consequence, further decreasing fatalities. To answer this problem, currently deployed driving assistance systems combine more and more information from diverse sources (sensors) to enhance the driver's perception of their environment. However, because of inherent limitations in range and field of view, these systems' perception of their environment remains largely limited to a small interest zone around a single vehicle. Such limitations can be overcomed by increasing the interest zone through a cooperative process. Cooperative Systems (CS), a specific subset of Intelligent Transportation Systems (ITS), aim at compensating for local systems' limitations by associating embedded information technology and intervehicular communication technology (IVC). With CS, information sources are not limited to a single vehicle anymore. From this distribution arises the concept of extended or augmented perception. Augmented perception allows extending an actor's perceptive horizon beyond its "natural" limits not only by fusing information from multiple in-vehicle sensors but also information obtained from remote sensors. The end result of an augmented perception and data fusion chain is known as an augmented map. It is a repository where any relevant information about objects in the environment, and the environment itself, can be stored in a layered architecture. This thesis aims at demonstrating that augmented perception has better performance than noncooperative approaches, and that it can be used to successfully identify road risk. We found it was necessary to evaluate the performance of augmented perception, in order to obtain a better knowledge on their limitations. Indeed, while many promising results have already been obtained, the feasibility of building an augmented map from exchanged local perception information and, then, using this information beneficially for road users, has not been thoroughly assessed yet. The limitations of augmented perception, and underlying technologies, have not be thoroughly assessed yet. Most notably, many questions remain unanswered as to the IVC performance and their ability to deliver appropriate quality of service to support life-saving critical systems. This is especially true as the road environment is a complex, highly variable setting where many sources of imperfections and errors exist, not only limited to IVC. We provide at first a discussion on these limitations and a performance model built to incorporate them, created from empirical data collected on test tracks. Our results are more pessimistic than existing literature, suggesting IVC limitations have been underestimated. Then, we develop a new CS-applications simulation architecture. This architecture is used to obtain new results on the safety benefits of a cooperative safety application (EEBL), and then to support further study on augmented perception. At first, we confirm earlier results in terms of crashes numbers decrease, but raise doubts on benefits in terms of crashes' severity. In the next step, we implement an augmented perception architecture tasked with creating an augmented map. Our approach is aimed at providing a generalist architecture that can use many different types of sensors to create the map, and which is not limited to any specific application. The data association problem is tackled with an MHT approach based on the Belief Theory. Then, augmented and single-vehicle perceptions are compared in a reference driving scenario for risk assessment,taking into account the IVC limitations obtained earlier; we show their impact on the augmented map's performance. Our results show that augmented perception performs better than non-cooperative approaches, allowing to almost tripling the advance warning time before a crash. IVC limitations appear to have no significant effect on the previous performance, although this might be valid only for our specific scenario. Eventually, we propose a new approach using augmented perception to identify road risk through a surrogate: near-miss events. A CS-based approach is designed and validated to detect near-miss events, and then compared to a non-cooperative approach based on vehicles equiped with local sensors only. The cooperative approach shows a significant improvement in the number of events that can be detected, especially at the higher rates of system's deployment.

Incidence of hypotony and sympathetic ophthalmia following trans scleral cyclophotocoagulation for glaucoma and a report of risk factors

Background: To report the incidence and risk factors for hypotony and estimate the risk of sympathetic ophthalmia following diode laser trans-scleral cyclophotocoagulation (TSCPC). Design: Retrospective study using data from a private tertiary glaucoma clinic and review of the literature. Participants: Seventy eyes of 70 patients with refractory glaucoma who received TSCPC treatment. Methods: Review of the records of consecutive patients who underwent TSCPC by a single ophthalmic surgeon and review of the literature. Main Outcome Measures: Hypotony (including phthisis bulbi), sympathetic ophthalmia. Results: Seven eyes (10%; CI 5-19%) developed hypotony and included 4 eyes that developed phthisis. Higher total energy delivered during TSCPC treatment was associated with an increased risk of hypotony: eyes that developed hypotony received a mean total energy of 192.5 ± 73.2 joules, compared to a mean of 152.9 ± 83.2 joules in hypotony-free cases. The difference in mean energy delivered between the hypotony and non-hypotony group was 38.53 (95% CI: -27.57 to 104.63). The risk of sympathetic ophthalmia estimated from a review of the published literature and current series was one in 1512, or 0.07% (CI 0.03% - 0.17%). Conclusions: Total laser energy is one of several risk factors that act in a sufficient component cause-model to produce hypotony in an individual patient. The small sample size precluded inference for other individual putative risk factors but titrating laser energy may help decrease the occurrence of hypotony. The risk of sympathetic ophthalmia calculated from the literature is likely an overestimate caused by publication bias.

Rethinking disaster risk management and climate change adaptation

Australian governments face the twin challenges of dealing with extreme weather-related disasters (such as floods and bushfires) and adapting to the impacts of climate change. These challenges are connected, so any response would benefit from a more integrated approach across and between the different levels of government.This report summarises the findings of an NCCARF-funded project that addresses this problem. The project undertook a three-way comparative case study of the 2009 Victorian bushfires, the 2011 Perth Hills bushfires, and the 2011 Brisbane floods. It collected data from the official inquiry reports into each of these events, and conducted new interviews and workshops with key stakeholders. The findings of this project included recommendations that range from the conceptual to the practical. First, it was argued that a reconceptualization of terms such as ‘community’ and ‘resilience’ was necessary to allow for more tailored responses to varying circumstances. Second, it was suggested that the high level of uncertainty inherent in disaster risk management and climate change adaptation requires a more iterative approach to policymaking and planning. Third, some specific institutional reforms were proposed that included: 1) a new funding mechanism that would encourage collaboration between and across different levels of government, as well as promoting partnerships with business and the community; 2) improving community engagement through new resilience grants run by local councils; 3) embedding climate change researchers within disaster risk management agencies to promote institutional learning, and; 4) creating an inter-agency network that encourages collaboration between organisations.