Risk analysis of prostate cancer in PRACTICAL, a multinational consortium, using 25 known prostate cancer susceptibility loci

Background Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. Methods We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS).We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived agespecific absolute risks of developing prostate cancer by PRS stratum and family history. Results The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2-5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). Conclusions Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. Impact:We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs.

Study of miRNA polymorphisms and their potential association with breast cancer risk in Australian Caucasian populations

This project established a large and well characterised prospective breast cancer DNA biobank and used this biobank to conduct genetic studies in breast cancer. The thesis presented the results of these high-throughput genotyping studies in two separate Australian Caucasian case-control populations and identified association between three novel genetic variants in microRNA genes and breast cancer risk.

Crash risk perception of sleepy driving and its comparisons with drink driving and speeding: Which behavior is perceived as the riskiest?

- Objective Driver sleepiness is a major crash risk factor, but may be under-recognized as a risky driving behavior. Sleepy driving is usually rated as less of a road safety issue than more well-known risky driving behaviors, such as drink driving and speeding. The objective of this study was to compare perception of crash risk of sleepy driving, drink driving, and speeding. - Methods In total, 300 Australian drivers completed a questionnaire that assessed crash risk perceptions for sleepy driving, drink driving, and speeding. Additionally, the participants perception of crash risk was assessed for five different contextual scenarios that included different levels of sleepiness (low, high), driving duration (short, long), and time of day/circadian influences (afternoon, night-time) of driving. - Results The analysis confirmed that sleepy driving was considered a risky driving behavior, but not as risky as high levels of speeding (p < .05). Yet, the risk of crashing at 4 am was considered as equally risky as low levels of speeding (10 km over the limit). The comparisons of the contextual scenarios revealed driving scenarios that would arguably be perceived as quite risky due to time of day/circadian influences were not reported as high risk. - Conclusions The results suggest a lack of awareness or appreciation of circadian rhythm functioning, particularly the descending phase of circadian rhythm that promotes increased sleepiness in the afternoon and during the early hours of the morning. Yet, the results suggested an appreciation of the danger associated with long distance driving and driver sleepiness. Further efforts are required to improve the community’s awareness of the impairing effects from sleepiness and in particular, knowledge regarding the human circadian rhythm and the increased sleep propensity during the circadian nadir.

Spontaneous and episodic volunteers: The legislative, insurance and risk management framework

Baby Boomers are a generation of life long association joiners, but following generations prefer spontaneous and episodic volunteering. This trend is apparent not only during natural disasters, but in most other spheres of volunteering. Legal liability for such volunteers is a growing concern, which unresolved, may dampen civic participation. We critically examine the current treatment of these liabilities through legislation, insurance and risk management.

Antithrombin III associated with fibrinogen predicts the risk of cerebral ischemic stroke

Background and purpose: The purpose of this study is to examine the feasibility of developing plasma predictive value biomarkers of cerebral ischemic stroke before imaging evidence is acquired. Methods: Blood samples were obtained from 198 patients who attended our neurology department as emergencies - with symptoms of vertigo, numbness, limb weakness, etc. - within 4.5 h of symptom onset, and before imaging evidence was obtained and medical treatment. After the final diagnosis was made by MRI/DWI/MRA or CTA in the following 24-72 h, the above cases were divided into two groups: stroke group and non-stroke group according to the imaging results. The levels of baseline plasma antithrombin III (AT-III), thrombin-antithrombin III (TAT), fibrinogen, D-dimer and high-sensitivity C-reactive protein (hsCRP) in the two groups were assayed. Results: The level of the baseline AT-III in the stroke group was 118.07 ± 26.22%, which was lower than that of the non-stroke group (283.83 ± 38.39%). The levels of TAT, fibrinogen, hsCRP were 7.24 ± 2.28 μg/L, 5.49 ± 0.98 g/L, and 2.17 ± 1.07 mg/L, respectively, which were higher than those of the non-stroke group (2.53 ± 1.23 μg/L, 3.35 ± 0.50 g/L, 1.82 ± 0.67 mg/L). All the P-values were less than 0.001. The D-dimer level was 322.57 ± 60.34 μg/L, which was slightly higher than that of the non-stroke group (305.76 ± 49.52 μg/L), but the P-value was 0.667. The sensitivities of AT-III, TAT, fibrinogen, D-dimer and hsCRP for predicting ischemic stroke tendency were 97.37%, 96.05%, 3.29%, 7.89%, but the specificity was 93.62%, 82.61%, 100% and 100%, respectively, and all the P-values were less than 0.001. High levels of D-dimer and hsCRP were mainly seen in the few cases with severe large-vessel infarction. Conclusions: Clinical manifestations of acute focal neurological deficits were associated with plasma AT-III and fibrinogen. These tests might help the risk assessment of acute cerebral ischemic stroke and/or TIA with infarction tendency in the superacute stage before positive imaging evidence is obtained.

Correlation of macrophage location and plaque stress distribution using USPIO-enhanced MRI in a patient with symptomatic severe carotid stenosis: A new insight into risk stratification

High resolution, USPIO-enhanced MR imaging can be used to identify inflamed atherosclerotic plaque. We report a case of a 79-year-old man with a symptomatic carotid stenosis of 82%. The plaque was retrieved for histology and finite element analysis (FEA) based on the preoperative MR imaging was used to predict maximal Von Mises stress on the plaque. Macrophage location correlated with maximal predicted stresses on the plaque. This supports the hypothesis that macrophages thin the fibrous cap at points of highest stress, leading to an increased risk of plaque rupture and subsequent stroke.

Predicting occupant risk indicators for frontal impacts with redirective crash cushions

Crash cushions are devices deployed on the road network in order to shield fixed roadside hazards and the non-crashworthy ends of road safety barriers. However crash cushions vary in terms of configuration and operation, meaning that different devices may also vary in terms of ability to mitigate occupant risk. In this study, data derived from crash testing of eleven redirective crash cushions is used as the base input to a numerical procedure for calculation of occupant risk indicators Occupant Impact Velocity (OIV), Occupant Ridedown Acceleration (ORA) and longitudinal Acceleration Severity Index (ASI) for a range of simulated impacting vehicles (mass 800 kg to 2,500 kg) impacting each crash cushion at a range of impact speeds (18 m/s to 32 m/s). The results may be interpreted as demonstrating firstly that enhanced knowledge of the performance of a device over a range of impact conditions, i.e., beyond the crash testing, may assist in determining the crash cushion most suited to a particular application; secondly that a more appropriate conformance test for occupant risk would be a frontal impact by a small (light) vehicle travelling parallel to and aligned with the centreline of the crash cushion; and thirdly that current documented numerical procedures for calculating occupant risk indicators may require review.

Roles of forced nicotine exposure and Comt gene disruption in the development of addiction-related behavioural and neurochemical changes in mice

Activation of midbrain dopamine systems is thought to be critically involved in the addictive properties of abused substances. Drugs of abuse increase dopamine release in the nucleus accumbens and dorsal striatum, which are the target areas of mesolimbic and nigrostriatal dopamine pathways, respectively. Dopamine release in the nucleus accumbens is thought to mediate the attribution of incentive salience to rewards, and dorsal striatal dopamine release is involved in habit formation. In addition, changes in the function of prefrontal cortex (PFC), the target area of mesocortical dopamine pathway, may skew information processing and memory formation such that the addict pays an abnormal amount of attention to drug-related cues. In this study, we wanted to explore how long-term forced oral nicotine exposure or the lack of catechol-O-methyltransferase (COMT), one of the dopamine metabolizing enzymes, would affect the functioning of these pathways. We also wanted to find out how the forced nicotine exposure or the lack of COMT would affect the consumption of nicotine, alcohol, or cocaine. First, we studied the effect of forced chronic nicotine exposure on the sensitivity of dopamine D2-like autoreceptors in microdialysis and locomotor activity experiments. We found that the sensitivity of these receptors was unchanged after forced oral nicotine exposure, although an increase in the sensitivity was observed in mice treated with intermittent nicotine injections twice daily for 10 days. Thus, the effect of nicotine treatment on dopamine autoreceptor sensitivity depends on the route, frequency, and time course of drug administration. Second, we investigated whether the forced oral nicotine exposure would affect the reinforcing properties of nicotine injections. The chronic nicotine exposure did not significantly affect the development of conditioned place preference to nicotine. In the intravenous self-administration paradigm, however, the nicotine-exposed animals self-administered nicotine at a lower unit dose than the control animals, indicating that their sensitivity to the reinforcing effects of nicotine was enhanced. Next, we wanted to study whether the Comt gene knock-out animals would be a suitable model to study alcohol and cocaine consumption or addiction. Although previous work had shown male Comt knock-out mice to be less sensitive to the locomotor-activating effects of cocaine, the present study found that the lack of COMT did not affect the consumption of cocaine solutions or the development of cocaine-induced place preference. However, the present work did find that male Comt knock-out mice, but not female knock-out mice, consumed ethanol more avidly than their wild-type littermates. This finding suggests that COMT may be one of the factors, albeit not a primary one, contributing to the risk of alcoholism. Last, we explored the effect of COMT deficiency on dorsal striatal, accumbal, and prefrontal cortical dopamine metabolism under no-net-flux conditions and under levodopa load in freely-moving mice. The lack of COMT did not affect the extracellular dopamine concentrations under baseline conditions in any of the brain areas studied. In the prefrontal cortex, the dopamine levels remained high for a prolonged time after levodopa treatment in male, but not female, Comt knock-out mice. COMT deficiency induced accumulation of 3,4-dihydroxyphenylacetic acid, which increased further under levodopa load. Homovanillic acid was not detectable in Comt knock-out animals either under baseline conditions or after levodopa treatment. Taken together, the present results show that although forced chronic oral nicotine exposure affects the reinforcing properties of self-administered nicotine, it is not an addiction model itself. COMT seems to play a minor role in dopamine metabolism and in the development of addiction under baseline conditions, indicating that dopamine function in the brain is well-protected from perturbation. However, the role of COMT becomes more important when the dopaminergic system is challenged, such as by pharmacological manipulation.

Process Analytical Technology Approach on Fluid Bed Granulation and Drying : Identifying Critical Relationships and Constructing the Design Space

Fluid bed granulation is a key pharmaceutical process which improves many of the powder properties for tablet compression. Dry mixing, wetting and drying phases are included in the fluid bed granulation process. Granules of high quality can be obtained by understanding and controlling the critical process parameters by timely measurements. Physical process measurements and particle size data of a fluid bed granulator that are analysed in an integrated manner are included in process analytical technologies (PAT). Recent regulatory guidelines strongly encourage the pharmaceutical industry to apply scientific and risk management approaches to the development of a product and its manufacturing process. The aim of this study was to utilise PAT tools to increase the process understanding of fluid bed granulation and drying. Inlet air humidity levels and granulation liquid feed affect powder moisture during fluid bed granulation. Moisture influences on many process, granule and tablet qualities. The approach in this thesis was to identify sources of variation that are mainly related to moisture. The aim was to determine correlations and relationships, and utilise the PAT and design space concepts for the fluid bed granulation and drying. Monitoring the material behaviour in a fluidised bed has traditionally relied on the observational ability and experience of an operator. There has been a lack of good criteria for characterising material behaviour during spraying and drying phases, even though the entire performance of a process and end product quality are dependent on it. The granules were produced in an instrumented bench-scale Glatt WSG5 fluid bed granulator. The effect of inlet air humidity and granulation liquid feed on the temperature measurements at different locations of a fluid bed granulator system were determined. This revealed dynamic changes in the measurements and enabled finding the most optimal sites for process control. The moisture originating from the granulation liquid and inlet air affected the temperature of the mass and pressure difference over granules. Moreover, the effects of inlet air humidity and granulation liquid feed rate on granule size were evaluated and compensatory techniques used to optimize particle size. Various end-point indication techniques of drying were compared. The ∆T method, which is based on thermodynamic principles, eliminated the effects of humidity variations and resulted in the most precise estimation of the drying end-point. The influence of fluidisation behaviour on drying end-point detection was determined. The feasibility of the ∆T method and thus the similarities of end-point moisture contents were found to be dependent on the variation in fluidisation between manufacturing batches. A novel parameter that describes behaviour of material in a fluid bed was developed. Flow rate of the process air and turbine fan speed were used to calculate this parameter and it was compared to the fluidisation behaviour and the particle size results. The design space process trajectories for smooth fluidisation based on the fluidisation parameters were determined. With this design space it is possible to avoid excessive fluidisation and improper fluidisation and bed collapse. Furthermore, various process phenomena and failure modes were observed with the in-line particle size analyser. Both rapid increase and a decrease in granule size could be monitored in a timely manner. The fluidisation parameter and the pressure difference over filters were also discovered to express particle size when the granules had been formed. The various physical parameters evaluated in this thesis give valuable information of fluid bed process performance and increase the process understanding.

Engaging at-risk vocational education students with mobile devices

The potential of using mobile devices to increase learner engagement within a small group of at-risk vocational education students was studied through a qualitative case study. It was found that the use of mobile devices could be a strategy educators may use to reduce the barriers these students often encounter within traditional classrooms. Notions of interactivity, ease of use, existing familiarity and fluency were found to be fundamental variables that were central to the group's use of mobile devices. The study provides direction for educators looking for innovative ways to engage students who struggle in a classroom situation.

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region.

Generalizability of established prostate cancer risk variants in men of African ancestry

Genome-wide association studies have identified more than 80 risk variants for prostate cancer, mainly in European or Asian populations. The generalizability of these variants in other racial/ethnic populations needs to be understood before the loci can be used widely in risk modeling. In our study, we examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls of African ancestry. We performed association testing for each variant using logistic regression adjusted for age, study and global ancestry. Of the 82 known risk variants, 68 (83%) had effects that were directionally consistent in their association with prostate cancer risk and 30 (37%) were significantly associated with risk at p < 0.05, with the most statistically significant variants being rs116041037 (p = 3.7 × 10(-26) ) and rs6983561 (p = 1.1 × 10(-16) ) at 8q24, as well as rs7210100 (p = 5.4 × 10(-8) ) at 17q21. By exploring each locus in search of better markers, the number of variants that captured risk in men of African ancestry (p < 0.05) increased from 30 (37%) to 44 (54%). An aggregate score comprised of these 44 markers was strongly associated with prostate cancer risk [per-allele odds ratio (OR) = 1.12, p = 7.3 × 10(-98) ]. In summary, the consistent directions of effects for the vast majority of variants in men of African ancestry indicate common functional alleles that are shared across populations. Further exploration of these susceptibility loci is needed to identify the underlying biologically relevant variants to improve prostate cancer risk modeling in populations of African ancestry.

Factors potentiating the risk of sudden infant death syndrome associated with the prone position

Background. In several studies the sudden infant death syndrome (SIDS) has been significantly associated with sleeping in the prone position. It is not known how the prone position increases the risk of SIDS. Methods. We analyzed data from a case-control study (58 infants with SIDS and 120 control infants) and a prospective cohort study (22 infants with SIDS and 213 control infants) in Tasmania. Interactions were examined in matched analyses with a multiplicative model of interaction. Results. In the case-control study, SIDS was significantly associated with sleeping in the prone position, as compared with other positions (unadjusted odds ratio, 4.5; 95 percent confidence interval, 2.1 to 9.6). The strength of this association was increased among infants who slept on natural-fiber mattresses (P = 0.05), infants who were swaddled (P = 0.09), infants who slept in heated rooms (P = 0.006), and infants who had had a recent illness (P = 0.02). These variables had no significant effect on infants who did not sleep in the prone position. A history of recent illness was significantly associated with SIDS among infants who slept prone (odds ratio, 5.7; 95 percent confidence interval, 1.8 to 19) but not among infants who slept in other positions (odds ratio, 0.83). In the cohort study, the risk of SIDS was greater among infants who slept prone on natural-fiber mattresses (odds ratio, 6.6; 95 percent confidence interval, 1.3 to 33) than among infants who slept prone on other types of mattresses (odds ratio, 1.8). Conclusions. When infants sleep prone, the elevated risk of SIDS is increased by each of four factors: the use of natural-fiber mattresses, swaddling, recent illness, and the use of heating in bedrooms.

A potential epigenetic marker mediating serum folate and vitamin B12 levels contributes to ischemic stroke risk

Background and Purpose Stroke is a multifactorial disease that may be associated with aberrant DNA methylation profiles.We investigated epigenetic dysregulation for the MTHFR gene among ischaemic stroke patients. Methods Cases (n=297) and controls (n=110) were recruited after obtaining signed written informed consent, following a screening process against the inclusion/exclusion criteria. Serum vitamin metabolites (folate, vitamin B12 and homocysteine) were determined using immunoassays and methylation profiles for CpGs A and B in the MTHFR gene were determined using bisulfitepyrosequencing method. Results Methylation of MTHFR significantly increased the susceptibility risk for ischemic stroke. In particular, CpG A outperformed CpG B in mediating folate and vitamin B12 levels to increase ischemic stroke susceptibility risks by 4.73 fold. CpGs A and B were not associated with either serum homocysteine levels or ischemic stroke severity. Conclusion CpG A is a potential epigenetic marker in mediating serum folate and vitamin B12 to contribute to ischemic stroke.

'Work it out': Evaluation of a chronic condition self-management program for urban Aboriginal and Torres Strait Islander people with or at risk of cardiovascular disease

This thesis evaluates a chronic condition self-management program for Aboriginal and Torres Strait Islander people in urban south-east Queensland who have or are at risk of cardiovascular disease. Outcomes showed short-term improvements for some anthropometry measures which could be a trend for improvement in other anthropometry indicators over the longer term. The program was of particular benefit for participants who had several social and emotional wellbeing conditions. The use of an Aboriginal and Torres Strait Islander conceptual framework was critical in undertaking culturally competent quantitative research in this project.