Modelling, collaboration and integration : a case study for the delivery of public buildings

An evolution in the use of digital modelling has occurred in the Queensland Department of Public Works Division of Project Services over the last 20 years from: the initial implementation of computer aided design and documentation (CADD); to experimentation with building information modelling (BIM); to embedding integrated practice (IP); to current steps towards integrated project delivery (IPD) including the active involvement of consultants and contractors in the design/delivery process. This case study is one of three undertaken through the Australian Sustainable Built Environment National Research Centre investigating past R&D investment. The intent of these cases is to inform the development of policy guidelines for future investment in the construction industry in Australia. This research is informing the activities of CIB Task Group 85 R&D Investment and Impact. The uptake of digital modelling by Project Services has been approached through an incremental learning approach. This has been driven by a strong and clear vision with a focus on developing more efficient delivery mechanisms through the use of new technology coupled with process change. Findings reveal an organisational focus on several areas including: (i) strategic decision making including the empowerment of innovation leaders and champions; (ii) the acquisition and exploitation of knowledge; (iii) product and process development (with a focus on efficiency and productivity); (iv) organisational learning; (v) maximising the use of technology; and (vi) supply chain integration. Key elements of this approach include pilot projects, researcher engagement, industry partnerships and leadership.

Measurement error of rearfoot kinematics during running between a 100Hz and 30Hz camera

Background: Measurement accuracy is critical for biomechanical gait assessment. Very few studies have determined the accuracy of common clinical rearfoot variables between cameras with different collection frequencies. Research question: What is the measurement error for common rearfoot gait parameters when using a standard 30Hz digital camera compared to 100Hz camera? Type of study: Descriptive. Methods: 100 footfalls were recorded from 10 subjects ( 10 footfalls per subject) running on a treadmill at 2.68m/s. A high-speed digital timer, accurate within 1ms served as an external reference. Markers were placed along the vertical axis of the heel counter and the long axis of the shank. 2D coordinates for the four markers were determined from heel strike to heel lift. Variables of interest included time of heel strike (THS), time of heel lift (THL), time to maximum eversion (TMax), and maximum rearfoot eversion angle (EvMax). Results: THS difference was 29.77ms (+/- 8.77), THL difference was 35.64ms (+/- 6.85), and TMax difference was 16.50ms (+/- 2.54). These temporal values represent a difference equal to 11.9%, 14.3%, and 6.6% of the stance phase of running gait, respectively. EvMax difference was 1.02 degrees (+/- 0.46). Conclusions: A 30Hz camera is accurate, compared to a high-frequency camera, in determining TMax and EvMax during a clinical gait analysis. However, relatively large differences, in excess of 12% of the stance phase of gait, for THS and THL variables were measured.

Perception and reality : meeting Australia’s physical activity guidelines for 12-18 year olds

Governments regularly publish empirically derived minimum physical activity (PA) guidelines for youth, in response to the ongoing trend of youth physical inactivity. The purpose of this investigation was to explore parents’ awareness of the national PA guidelines for youth, and adolescents’ and their parents’ perceptions of adolescent PA, and compare these to self-reported adolescent PA. A total of 115 adolescents (aged 12-14) and their parents completed questionnaire assessments. Parents responded to questions concerning their awareness of the national PA guidelines, and whether they believed their child to be sufficiently active. Adolescents completed the International Physical Activity Questionnaire for Adolescents, and questions concerning their perceived level of PA. Adolescents were deemed sufficiently active if they participated in an average of at least 60 minutes of moderate-to-vigorous PA each day. Overall, 104 (90.4%) adolescents and their parents had complete data sets and were included in the analysis. Of the 45 (43.3%) sufficiently and 59 (56.7%) insufficiently active adolescents, 42 (93%) and 41 (69.5%) respectively believed that they were active enough for good general health. Additionally, 41 (91.1%) parents of active and 44 (74.6%) parents of inactive adolescents either agreed or strongly agreed that their child participates in sufficient PA for good general health. Twenty-four (53.3%) parents of active adolescents were unaware of the national PA guidelines, with 10 (22.2%) neither aware or unaware, and 11 (24.4%) aware. Similar results were found for the parents of inactive adolescents with 31 (52.5%) unaware, 17 (28.8%) neither aware or unaware, and 11 (18.6%) aware. These results suggest that the youth PA guidelines are being inadequately received by both adolescents, and their parents. Opportunities to effectively communicate these guidelines such as embedment in curriculum for adolescents, or the dissemination of materials for parents, should be maximised by appropriate authorities.

A case study of interactions between flood flow and buildings in an urban environment : Gardens Point during the 12-13 January 2011 flood of the Brisbane River (Australia)

Flood flows in inundated urban environment constitute a natural hazard. During the 12- 13 January 2011 flood of the Brisbane River, detailed water elevation, velocity and suspended sediment data were recorded in an inundated street at the peak of the flood. The field observations highlighted a number of unusual flow interactions with the urban surroundings. These included some slow fluctuations in water elevations and velocity with distinctive periods between 50 and 100 s caused by some local topographic effect (choking), superposed with some fast turbulent fluctuations. The suspended sediment data highlighted some significant suspended sediment loads in the inundated zone.

Spectroscopic studies of the adsorption and reactions of chlorofluorocarbons (CFC-11 and CFC-12) and hydrochlorofluorocarbon (HCFC-22) on oxide surfaces

Raman and Fourier transform infrared (FT-IR) spectroscopy have been applied to a systematic investigation of the adsorption and decomposition of dichlorodifluoromethane (CCl2F2, CFC-12), fluorotrichloromethane (CCl3F, CFC-11), chlorodifluoromethane (CHClF2, HCFC-22) and molecular chlorine on oxide surfaces. Additionally, the effects of heating and ultraviolet photolysis of the CFC and HCFCs adsorbed on the oxide surfaces have been investigated. Spectral features for these species indicated a small wavenumber shift (1-6 cm-1) associated with the adsorbed phase. Some evidence, specifically the appearance of the Raman band at 507 cm-1, is presented to show that chlorine decomposition species are associated with these oxide surfaces. It was concluded that the new spectral feature (at ca. 507 cm-1) related with the decomposition of the CFC and HCFC molecules was an important indicator of the extent to which the reaction between the adsorbed CFC and HCFC and oxide surface has taken place. The extent of CFC-surface interaction has been quantified in terms of a maximum (Raman) frequency shift parameter (AM). Wavenumber shifts suggest both cation-adsorbate and non-specific adsorption interactions are occurring in the internal channels of the zeolites. Slow decomposition of the adsorbed CFCs under ultraviolet-visible photolysis (at ? > 300 nm) and/or thermal treatment was observed spectroscopically. Using FT-IR spectroscopy, the formation of gas-phase products (CO, CO2, HCl) both onyn photolysis and heating was evident. Results of these measurements are compared with the observed atmospheric reactivity of these compounds.

The role of intensity of interval training on fat oxidation and eating behaviour in overweight/obese men

The increasing prevalence of obesity in society has been associated with a number of atherogenic risk factors such as insulin resistance. Aerobic training is often recommended as a strategy to induce weight loss, with a greater impact of high-intensity levels on cardiovascular function and insulin sensitivity, and a greater impact of moderate-intensity levels on fat oxidation. Anaerobic high-intensity (supramaximal) interval training has been advocated to improve cardiovascular function, insulin sensitivity and fat oxidation. However, obese individuals tend to have a lower tolerance of high-intensity exercise due to discomfort. Furthermore, some obese individuals may compensate for the increased energy expenditure by eating more and/or becoming less active. Recently, both moderate- and high-intensity aerobic interval training have been advocated as alternative approaches. However, it is still uncertain as to which approach is more effective in terms of increasing fat oxidation given the issues with levels of fitness and motivation, and compensatory behaviours. Accordingly, the objectives of this thesis were to compare the influence of moderate- and high-intensity interval training on fat oxidation and eating behaviour in overweight/obese men. Two exercise interventions were undertaken by 10-12 overweight/obese men to compare their responses to study variables, including fat oxidation and eating behaviour during moderate- and high-intensity interval training (MIIT and HIIT). The acute training intervention was a methodological study designed to examine the validity of using exercise intensity from the graded exercise test (GXT) - which measured the intensity that elicits maximal fat oxidation (FATmax) - to prescribe interval training during 30-min MIIT. The 30-min MIIT session involved 5-min repetitions of workloads 20% below and 20% above the FATmax. The acute intervention was extended to involve HIIT in a cross-over design to compare the influence of MIIT and HIIT on eating behaviour using subjective appetite sensation and food preference through the liking and wanting test. The HIIT consisted of 15-sec interval training at 85 %VO2peak interspersed by 15-sec unloaded recovery, with a total mechanical work equal to MIIT. The medium term training intervention was a cross-over 4-week (12 sessions) MIIT and HIIT exercise training with a 6-week detraining washout period. The MIIT sessions consisted of 5-min cycling stages at ±20% of mechanical work at 45 %VO2peak, and the HIIT sessions consisted of repetitive 30-sec work at 90 %VO2peak and 30-sec interval rests, during identical exercise sessions of between 30 and 45 mins. Assessments included a constant-load test (45 %VO2peak for 45 mins) followed by 60-min recovery at baseline and the end of 4-week training, to determine fat oxidation rate. Participants’ responses to exercise were measured using blood lactate (BLa), heart rate (HR) and rating of perceived exertion (RPE) and were measured during the constant-load test and in the first intervention training session of every week during training. Eating behaviour responses were assessed by measuring subjective appetite sensations, liking and wanting and ad libitum energy intake. Results of the acute intervention showed that FATmax is a valid method to estimate VO2 and BLa, but is not valid to estimate HR and RPE in the MIIT session. While the average rate of fat oxidation during 30-min MIIT was comparable with the rate of fat oxidation at FATmax (0.16 ±0.09 and 0.14 ±0.08 g/min, respectively), fat oxidation was significantly higher at minute 25 of MIIT (P≤0.01). In addition, there was no significant difference between MIIT and HIIT in the rate of appetite sensations after exercise, but there was a tendency towards a lower rate of hunger after HIIT. Different intensities of interval exercise also did not affect explicit liking or implicit wanting. Results of the medium-term intervention indicated that current interval training levels did not affect body composition, fasting insulin and fasting glucose. Maximal aerobic capacity significantly increased (P≤0.01) (2.8 and 7.0% after MIIT and HIIT respectively) during GXT, and fat oxidation significantly increased (P≤0.01) (96 and 43% after MIIT and HIIT respectively) during the acute constant-load exercise test. RPE significantly decreased after HIIT greater than MIIT (P≤0.05), and the decrease in BLa was greater during the constant-load test after HIIT than MIIT, but this difference did not reach statistical significance (P=0.09). In addition, following constant-load exercise, exercise-induced hunger and desire to eat decreased after HIIT greater than MIIT but were not significant (p value for desire to eat was 0.07). Exercise-induced liking of high-fat sweet (HFSW) and high-fat non-sweet (HFNS) foods increased after MIIT and decreased after HIIT (p value for HFNS was 0.09). The intervention explained 12.4% of the change in fat intake (p = 0.07). This research is significant in that it confirmed two points in the acute study. While the rate of fat oxidation increased during MIIT, the average rate of fat oxidation during 30-min MIIT was comparable with the rate of fat oxidation at FATmax. In addition, manipulating the intensity of acute interval exercise did not affect appetite sensations and liking and wanting. In the medium-term intervention, constant-load exercise-induced fat oxidation significantly increased after interval training, independent of exercise intensity. In addition, desire to eat, explicit liking for HFNS and fat intake collectively confirmed that MIIT is accompanied by a greater compensation of eating behaviour than HIIT. Findings from this research will assist in developing exercise strategies to provide obese men with various training options. In addition, the finding that overweight/obese men expressed a lower RPE and decreased BLa after HIIT compared with MIIT is contrary to the view that obese individuals may not tolerate high-intensity interval training. Therefore, high-intensity interval training can be advocated among the obese adult male population. Future studies may extend this work by using a longer-term intervention.

Genome-wide association study reveals three susceptibility loci for common migraine in the general population

Migraine is a common, heterogeneous and heritable neurological disorder. Its pathophysiology is incompletely understood, and its genetic influences at the population level are unknown. In a population-based genome-wide analysis including 5,122 migraineurs and 18,108 non-migraineurs, rs2651899 (1p36.32, PRDM16), rs10166942 (2q37.1, TRPM8) and rs11172113 (12q13.3, LRP1) were among the top seven associations (P < 5 × 10(-6)) with migraine. These SNPs were significant in a meta-analysis among three replication cohorts and met genome-wide significance in a meta-analysis combining the discovery and replication cohorts (rs2651899, odds ratio (OR) = 1.11, P = 3.8 × 10(-9); rs10166942, OR = 0.85, P = 5.5 × 10(-12); and rs11172113, OR = 0.90, P = 4.3 × 10(-9)). The associations at rs2651899 and rs10166942 were specific for migraine compared with non-migraine headache. None of the three SNP associations was preferential for migraine with aura or without aura, nor were any associations specific for migraine features. TRPM8 has been the focus of neuropathic pain models, whereas LRP1 modulates neuronal glutamate signaling, plausibly linking both genes to migraine pathophysiology.

Variants in the human potassium channel gene (KCNN3) are associated with migraine in a high risk genetic isolate

The calcium-activated potassium ion channel gene (KCNN3) is located in the vicinity of the familial hemiplegic migraine type 2 locus on chromosome 1q21.3. This gene is expressed in the central nervous system and plays a role in neural excitability. Previous association studies have provided some, although not conclusive, evidence for involvement of this gene in migraine susceptibility. To elucidate KCNN3 involvement in migraine, we performed gene-wide SNP genotyping in a high-risk genetic isolate from Norfolk Island, a population descended from a small number of eighteenth century Isle of Man ‘Bounty Mutineer’ and Tahitian founders. Phenotype information was available for 377 individuals who are related through the single, well-defined Norfolk pedigree (96 were affected: 64 MA, 32 MO). A total of 85 SNPs spanning the KCNN3 gene were genotyped in a sub-sample of 285 related individuals (76 affected), all core members of the extensive Norfolk Island ‘Bounty Mutineer’ genealogy. All genotyping was performed using the Illumina BeadArray platform. The analysis was performed using the statistical program SOLAR v4.0.6 assuming an additive model of allelic effect adjusted for the effects of age and sex. Haplotype analysis was undertaken using the program HAPLOVIEW v4.0. A total of four intronic SNPs in the KCNN3 gene displayed significant association (P < 0.05) with migraine. Two SNPs, rs73532286 and rs6426929, separated by approximately 0.1 kb, displayed complete LD (r 2 = 1.00, D′ = 1.00, D′ 95% CI = 0.96–1.00). In all cases, the minor allele led to a decrease in migraine risk (beta coefficient = 0.286–0.315), suggesting that common gene variants confer an increased risk of migraine in the Norfolk pedigree. This effect may be explained by founder effect in this genetic isolate. This study provides evidence for association of variants in the KCNN3 ion channel gene with migraine susceptibility in the Norfolk genetic isolate with the rarer allelic variants conferring a possible protective role. This the first comprehensive analysis of this potential candidate gene in migraine and also the first study that has utilised the unique Norfolk Island large pedigree isolate to implicate a specific migraine gene. Studies of additional variants in KCNN3 in the Norfolk pedigree are now required (e.g. polyglutamine variants) and further analyses in other population data sets are required to clarify the association of the KCNN3 gene and migraine risk in the general outbred population.

Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20

To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13-14 (rs703842, P = 5.4 x 10(-11); rs10876994, P = 2.7 x 10(-10); rs12368653, P = 1.0 x 10(-7)) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 x 10(-7); rs1569723, P = 2.9 x 10(-7)). Both loci are also associated with other autoimmune diseases. We also replicated several known MS associations (HLA-DR15, P = 7.0 x 10(-184); CD58, P = 9.6 x 10(-8); EVI5-RPL5, P = 2.5 x 10(-6); IL2RA, P = 7.4 x 10(-6); CLEC16A, P = 1.1 x 10(-4); IL7R, P = 1.3 x 10(-3); TYK2, P = 3.5 x 10(-3)) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001).

Impact of a school-based food garden on attitudes and identification skills regarding vegetables and fruit : a 12-month intervention trial

Objective To determine changes in ability to identify specific vegetables and fruits, and attitudes towards vegetables and fruit, associated with the introduction of a school-based food garden. Design A 12-month intervention trial using a historical control (control n 132, intervention n 120), class-based, self-administered questionnaires requiring one-word answers and 3-point Likert scale responses. Setting A state primary school (grades 4 to 7) in a low socio-economic area of Brisbane, Australia. Intervention The introduction of a school-based food garden, including the funding of a teacher coordinator for 11 h/week to facilitate integration of garden activities into the curriculum. Main outcome measures Ability to identify a series of vegetables and fruits, attitudes towards vegetables and fruit. Analysis Frequency distributions for each item were generated and χ2 analyses were used to determine statistical significance. Exploratory factor analysis was employed to detect major trends in data. Results The intervention led to enhanced ability to identify individual vegetables and fruits, greater attention to origins of produce (garden-grown and fresh), changes to perceived consumption of vegetables and fruits, and enhanced confidence in preparing fruit and vegetable snacks, but decreased interest in trying new fruits. Conclusions The introduction of this school-based food garden was associated with skill and attitudinal changes conducive to enhancing vegetable and fruit consumption. The ways in which such changes might impact on dietary behaviours and intake require further analysis.

Evaluating patient presentations for care delivered by emergency nurse practitioners : a retrospective analysis of 12 months

Background The delivery of quality patient care in the emergency department (ED) is emerging as one of the most important service indicators to be measured in health services today. The emergency nurse practitioner role was implemented as a service innovation in a Emergency & Trauma Centre (ETC), Melbourne, Australia, in July 2004 .The primary aim of the role was intended to enhance healthcare services, improve the efficiency and timely delivery of high quality care to patients. Aim To conduct a retrospective study of patient presentations at the ETC to obtain a profile of the characteristics of patients managed by emergency nurse practitioners. Specifically the objectives of the study were to: 1) examine the demographics of the patient population 2) evaluate data on emergency department service indicators for this patient cohort Method All patients presenting to the ETC from January 01 2011 to December 31 2011 and managed by emergency nurse practitioners were included in the review. Data collection included baseline demographics, waiting times to be seen, length of stay, emergency department discharge diagnoses and referral patterns. Data were extracted and imported directly from the emergency department Patient Information System (Cerner log), for the specified time frame. Results A total of 5212 patients were reviewed in the study period. The median age of patients was 35 years and 61% of patients were male. The most common discharge diagnosis was open wounds to hand/wrist. Waiting times to be seen by the emergency nurse practitioner were 14 minutes and length of stay for patients with a discharge disposition of home were 122 minutes. Conclusions This study has provided information on patient baseline characteristics and performance on important service indicators for this patient sample that will inform further research to evaluate specific outcomes of the emergency nurse practitioner service.

Analysis of Sdhd and Mmp12 in an affected solar keratosis and control cohort

The incidence of Squamous Cell Carcinoma (SCG) is growing in certain populations to the extent that it is now the most common skin lesion in young men and women in high ultraviolet exposure regions such as Queensland. In terms of incidence up to 40% of the Australian population over 40 years of age is thought to possess the precancerous Solar Keratosis (SK) lesion and with a small, but significant, chance of progression into SCC, understanding the genetic events that play a role in this process is essential. The major aims of this study were to analyse whole blood derived samples for DNA aberrations in genes associated with tumour development and cellular maintenance, with the ultimate aim of identifying genes associated with non-melanoma skin cancer development. More specifically the first aim of this project was to analyse the SDHD and MMP12 genes via Dual-Labelled Probe Real-Time PCR for copy number aberrations in an affected Solar Keratosis and control cohort. It was found that 12 samples had identifiable copy-number aberrations in either the SDHD or MMP12 gene (this means that a genetic section of either of these two genes is aberrantly amplified or deleted), with five of the samples exhibiting aberrations in both genes. The significance of this study is the contribution to the knowledge of the genetic pathways that are malformed in the progression and development of the pre-cancerous skin lesion Solar Keratosis. © 2008 Springer Science+Business Media, LLC.

The University of Queensland St Lucia campus 1.22 MW photovoltaic array

At the time of its official opening on 15 July 2011, The University of Queensland 1.22 MW array was the largest flat-panel PhotoVoltaic (PV) array in Australia. This PV array consists of over 5000 Trina Solar 240 Wp polycrystalline silicon PV modules installed across four rooftops at the St Lucia campus. Grid connection was achieved with 85 12.5 kW three phase and four 5 kW single phase grid connect inverters manufactured by Power-One. The site also includes one 8.4 kWp SolFocus concentrating solar 2 axis tracking PV array. Site wide monitoring and data logging of all DC, AC and environmental quantities will allow this array to be a rich source of research data. The site will also include a 200 kW 400 kWh zinc bromine energy storage system by Redflow, and associated power quality metering and monitoring. This paper presents highlights of the project feasibility study which included a site survey, shading analysis, and technology and triple bottom line assessment. A detailed description of the final technical implementation including discussion of alterative options considered is given. Finally, example initial data showing yield, trends and early example experimental results are presented.

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.

Actigraphy assessment of mother's sleep at 6, 12 & 18 weeks postpartum

Introduction: Mothers’ sleep during the postpartum period is commonly characterised by bouts of sleep across the night, resulting in low sleep efficiency and daytime sleepiness. Understanding of the nature of mothers’ sleep disruption needs to incorporate indices of both sleep quantity and sleep quality, but objective assessment of sleep disturbance experienced during the first postpartum months has not been investigated in great detail. This longitudinal study aimed to objectively measure mothers’ sleep during the first 18 weeks postpartum, to ascertain the level of sleep disturbance experienced. Method: Eleven mothers (Mean age = 29.82, SD = 4.45) from Australia wore Actiwatch-2 devices for up to 7 days and nights at 6, 12 and 18 weeks postpartum. For each night of recording, a number of sleep bouts were identified. Total sleep time (TST) was calculated as the total number of minutes across the night within these bouts. Sleep efficiency was calculated as the percentage of minutes across the night classified as being part of a sleep bout, with higher scores indicating higher efficiency. Sleep quality captured the efficiency of sleep within sleep bouts, and was calculated as the percentage of epochs classified as sleep within sleep bouts, with higher scores indicating higher sleep quality. Results: At 6 weeks postpartum, mean total sleep time was 420.22 minutes (SD = 50.61). Total sleep time did not significantly differ across the assessment; however there was a trend towards an increase over time. Sleep efficiency increased across the time periods (F(2,10) = 10.30, p = .001), with a significant increase between week 12 and week 18. At 6 weeks postpartum, mean sleep quality was 93.15% (SD = 2.68) and scores did not significantly change across the assessment periods. While there was no relationship between sleep efficiency and sleep quality during weeks 6 and 12, a significant positive relationship was observed at week 18, r2 = .52, p = .013. Conclusions: Within this sample, a low level of disruption was consistently shown within the mothers’ night time sleep bouts. However, overall sleep efficiency suggested a significant proportion of time spent awake between sleep bouts. While TST remained stable over time, overall sleep efficiency improved, suggesting the mothers’ sleep was becoming more consolidated. A single sleep bout a night was not often experienced.