Association between prostinogen (KLK15) genetic variants and prostate cancer risk and aggressiveness in Australia and a meta-analysis of GWAS data

Background: Kallikrein 15 (KLK15)/Prostinogen is a plausible candidate for prostate cancer susceptibility. Elevated KLK15 expression has been reported in prostate cancer and it has been described as an unfavorable prognostic marker for the disease. Objectives: We performed a comprehensive analysis of association of variants in the KLK15 gene with prostate cancer risk and aggressiveness by genotyping tagSNPs, as well as putative functional SNPs identified by extensive bioinformatics analysis. Methods and Data Sources: Twelve out of 22 SNPs, selected on the basis of linkage disequilibrium pattern, were analyzed in an Australian sample of 1,011 histologically verified prostate cancer cases and 1,405 ethnically matched controls. Replication was sought from two existing genome wide association studies (GWAS): the Cancer Genetic Markers of Susceptibility (CGEMS) project and a UK GWAS study. Results: Two KLK15 SNPs, rs2659053 and rs3745522, showed evidence of association (p, 0.05) but were not present on the GWAS platforms. KLK15 SNP rs2659056 was found to be associated with prostate cancer aggressiveness and showed evidence of association in a replication cohort of 5,051 patients from the UK, Australia, and the CGEMS dataset of US samples. A highly significant association with Gleason score was observed when the data was combined from these three studies with an Odds Ratio (OR) of 0.85 (95% CI = 0.77-0.93; p = 2.7610 24). The rs2659056 SNP is predicted to alter binding of the RORalpha transcription factor, which has a role in the control of cell growth and differentiation and has been suggested to control the metastatic behavior of prostate cancer cells. Conclusions: Our findings suggest a role for KLK15 genetic variation in the etiology of prostate cancer among men of European ancestry, although further studies in very large sample sets are necessary to confirm effect sizes.

Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript

Abstract Genome-wide association studies (GWAS) have identified more than 30 prostate cancer (PrCa) susceptibility loci. One of these (rs2735839) is located close to a plausible candidate susceptibility gene, KLK3, which encodes prostate-specific antigen (PSA). PSA is widely used as a biomarker for PrCa detection and disease monitoring. To refine the association between PrCa and variants in this region, we used genotyping data from a two-stage GWAS using samples from the UK and Australia, and the Cancer Genetic Markers of Susceptibility (CGEMS) study. Genotypes were imputed for 197 and 312 single nucleotide polymorphisms (SNPs) from HapMap2 and the 1000 Genome Project, respectively. The most significant association with PrCa was with a previously unidentified SNP, rs17632542 (combined P = 3.9 × 10−22). This association was confirmed by direct genotyping in three stages of the UK/Australian GWAS, involving 10,405 cases and 10,681 controls (combined P = 1.9 × 10−34). rs17632542 is also shown to be associated with PSA levels and it is a non-synonymous coding SNP (Ile179Thr) in KLK3. Using molecular dynamic simulation, we showed evidence that this variant has the potential to introduce alterations in the protein or affect RNA splicing. We propose that rs17632542 may directly influence PrCa risk.

Novel molecular markers of Chlamydia pecorum genetic diversity in the koala (Phascolarctos cinereus)

Background Chlamydia pecorum is an obligate intracellular bacterium and the causative agent of reproductive and ocular disease in several animal hosts including koalas, sheep, cattle and goats. C. pecorum strains detected in koalas are genetically diverse, raising interesting questions about the origin and transmission of this species within koala hosts. While the ompA gene remains the most widely-used target in C. pecorum typing studies, it is generally recognised that surface protein encoding genes are not suited for phylogenetic analysis and it is becoming increasingly apparent that the ompA gene locus is not congruent with the phylogeny of the C. pecorum genome. Using the recently sequenced C. pecorum genome sequence (E58), we analysed 10 genes, including ompA, to evaluate the use of ompA as a molecular marker in the study of koala C. pecorum genetic diversity. Results Three genes (incA, ORF663, tarP) were found to contain sufficient nucleotide diversity and discriminatory power for detailed analysis and were used, with ompA, to genotype 24 C. pecorum PCR-positive koala samples from four populations. The most robust representation of the phylogeny of these samples was achieved through concatenation of all four gene sequences, enabling the recreation of a "true" phylogenetic signal. OmpA and incA were of limited value as fine-detailed genetic markers as they were unable to confer accurate phylogenetic distinctions between samples. On the other hand, the tarP and ORF663 genes were identified as useful "neutral" and "contingency" markers respectively, to represent the broad evolutionary history and intra-species genetic diversity of koala C. pecorum. Furthermore, the concatenation of ompA, incA and ORF663 sequences highlighted the monophyletic nature of koala C. pecorum infections by demonstrating a single evolutionary trajectory for koala hosts that is distinct from that seen in non-koala hosts. Conclusions While the continued use of ompA as a fine-detailed molecular marker for epidemiological analysis appears justified, the tarP and ORF663 genes also appear to be valuable markers of phylogenetic or biogeographic divisions at the C. pecorum intra-species level. This research has significant implications for future typing studies to understand the phylogeny, genetic diversity, and epidemiology of C. pecorum infections in the koala and other animal species.

Development and feasibility of a smartphone, ECG and GPS based system for remotely monitoring exercise in cardiac rehabilitation

Background Despite its efficacy and cost-effectiveness, exercise-based cardiac rehabilitation is undertaken by less than one-third of clinically eligible cardiac patients in every country for which data is available. Reasons for non-participation include the unavailability of hospital-based rehabilitation programs, or excessive travel time and distance. For this reason, there have been calls for the development of more flexible alternatives. Methodology and Principal Findings We developed a system to enable walking-based cardiac rehabilitation in which the patient's single-lead ECG, heart rate, GPS-based speed and location are transmitted by a programmed smartphone to a secure server for real-time monitoring by a qualified exercise scientist. The feasibility of this approach was evaluated in 134 remotely-monitored exercise assessment and exercise sessions in cardiac patients unable to undertake hospital-based rehabilitation. Completion rates, rates of technical problems, detection of ECG changes, pre- and post-intervention six minute walk test (6 MWT), cardiac depression and Quality of Life (QOL) were key measures. The system was rated as easy and quick to use. It allowed participants to complete six weeks of exercise-based rehabilitation near their homes, worksites, or when travelling. The majority of sessions were completed without any technical problems, although periodic signal loss in areas of poor coverage was an occasional limitation. Several exercise and post-exercise ECG changes were detected. Participants showed improvements comparable to those reported for hospital-based programs, walking significantly further on the post-intervention 6 MWT, 637 m (95% CI: 565–726), than on the pre-test, 524 m (95% CI: 420–655), and reporting significantly reduced levels of cardiac depression and significantly improved physical health-related QOL. Conclusions and Significance The system provided a feasible and very flexible alternative form of supervised cardiac rehabilitation for those unable to access hospital-based programs, with the potential to address a well-recognised deficiency in health care provision in many countries. Future research should assess its longer-term efficacy, cost-effectiveness and safety in larger samples representing the spectrum of cardiac morbidity and severity.

Validation of a new hand-held electronic data capture method for continuous monitoring of subjective appetite sensations

Background When large scale trials are investigating the effects of interventions on appetite, it is paramount to efficiently monitor large amounts of human data. The original hand-held Electronic Appetite Ratings System (EARS) was designed to facilitate the administering and data management of visual analogue scales (VAS) of subjective appetite sensations. The purpose of this study was to validate a novel hand-held method (EARS II (HP® iPAQ)) against the standard Pen and Paper (P&P) method and the previously validated EARS. Methods Twelve participants (5 male, 7 female, aged 18-40) were involved in a fully repeated measures design. Participants were randomly assigned in a crossover design, to either high fat (>48% fat) or low fat (<28% fat) meal days, one week apart and completed ratings using the three data capture methods ordered according to Latin Square. The first set of appetite sensations was completed in a fasted state, immediately before a fixed breakfast. Thereafter, appetite sensations were completed every thirty minutes for 4h. An ad libitum lunch was provided immediately before completing a final set of appetite sensations. Results Repeated measures ANOVAs were conducted for ratings of hunger, fullness and desire to eat. There were no significant differences between P&P compared with either EARS or EARS II (p > 0.05). Correlation coefficients between P&P and EARS II, controlling for age and gender, were performed on Area Under the Curve ratings. R2 for Hunger (0.89), Fullness (0.96) and Desire to Eat (0.95) were statistically significant (p < 0.05). Conclusions EARS II was sensitive to the impact of a meal and recovery of appetite during the postprandial period and is therefore an effective device for monitoring appetite sensations. This study provides evidence and support for further validation of the novel EARS II method for monitoring appetite sensations during large scale studies. The added versatility means that future uses of the system provides the potential to monitor a range of other behavioural and physiological measures often important in clinical and free living trials.

Persistence of multiple genetic lineages within intra-host populations of Ross River virus

We examined the structure and extent of genetic diversity in intrahost populations of Ross River virus (RRV) in samples from six human patients, focusing on the nonstructural (nsP3) and structural (E2) protein genes. Strikingly, although the samples were collected from contrasting ecological settings 3,000 kilometers apart in Australia, we observed multiple viral lineages in four of the six individuals, which is indicative of widespread mixed infections. In addition, a comparison with previously published RRV sequences revealed that these distinct lineages have been in circulation for at least 5 years, and we were able to document their long-term persistence over extensive geographical distances

An ingenious decision support system for remote health monitoring of pregnant women

Maternal deaths have been a critical issue for women living in rural and remote areas. The need to travel long distances, the shortage of primary care providers such as physicians, specialists and nurses, and the closing of small hospitals have been problems identified in many rural areas. Some research work has been undertaken and a few techniques have been developed to remotely measure the physiological condition of pregnant women through sophisticated ultrasound equipment. There are numerous ways to reduce maternal deaths, and an important step is to select the right approaches to achieving this reduction. One such approach is the provision of decision support systems in rural and remote areas. Decision support systems (DSSs) have already shown a great potential in many health fields. This thesis proposes an ingenious decision support system (iDSS) based on the methodology of survey instruments and identification of significant variables to be used in iDSS using statistical analysis. A survey was undertaken with pregnant women and factorial experimental design was chosen to acquire sample size. Variables with good reliability in any one of the statistical techniques such as Chi-square, Cronbach’s á and Classification Tree were incorporated in the iDSS. The decision support system was developed with significant variables such as: Place of residence, Seeing the same doctor, Education, Tetanus injection, Baby weight, Previous baby born, Place of birth, Assisted delivery, Pregnancy parity, Doctor visits and Occupation. The ingenious decision support system was implemented with Visual Basic as front end and Microsoft SQL server management as backend. Outcomes of the ingenious decision support system include advice on Symptoms, Diet and Exercise to pregnant women. On conditional system was sent and validated by the gynaecologist. Another outcome of ingenious decision support system was to provide better pregnancy health awareness and reduce long distance travel, especially for women in rural areas. The proposed system has qualities such as usefulness, accuracy and accessibility.

Effective discrimination of acoustic emission source signals for structural health monitoring

Acoustic emission (AE) is the phenomenon where stress waves are generated due to rapid release of energy within a material caused by sources such as crack initiation or growth. AE technique involves recording the stress waves by means of sensors and subsequent analysis of the recorded signals to gather information about the nature of the source. Though AE technique is one of the popular non destructive evaluation (NDE) techniques for structural health monitoring of mechanical, aerospace and civil structures; several challenges still exist in successful application of this technique. Presence of spurious noise signals can mask genuine damage‐related AE signals; hence a major challenge identified is finding ways to discriminate signals from different sources. Analysis of parameters of recorded AE signals, comparison of amplitudes of AE wave modes and investigation of uniqueness of recorded AE signals have been mentioned as possible criteria for source differentiation. This paper reviews common approaches currently in use for source discrimination, particularly focusing on structural health monitoring of civil engineering structural components such as beams; and further investigates the applications of some of these methods by analyzing AE data from laboratory tests.

Health monitoring of buildings during construction and service stages using vibration characteristics

Columns and walls in buildings are subjected to a number of load increments during the construction and service stages. The combination of these load increments and poor quality construction can cause defects in these structural components. In addition, defects can also occur due to accidental or deliberate actions by users of the building during construction and service stages. Such defects should be detected early so that remedial measures can be taken to improve life time serviceability and performance of the building. This paper uses micro and macro model upgrading methods during construction and service stages of a building based on the mass and stiffness changes to develop a comprehensive procedure for locating and detecting defects in columns and walls of buildings. Capabilities of the procedure are illustrated through examples.

Assessment of “change in flexibility method” in structural health monitoring systems

The modern structural diagnosis process is rely on vibration characteristics to assess safer serviceability level of the structure. This paper examines the potential of change in flexibility method to use in damage detection process and two main practical constraints associated with it. The first constraint addressed in this paper is reduction in number of data acquisition points due to limited number of sensors. Results conclude that accuracy of the change in flexibility method is influenced by the number of data acquisition points/sensor locations in real structures. Secondly, the effect of higher modes on damage detection process has been studied. This addresses the difficulty of extracting higher order modal data with available sensors. Four damage indices have been presented to identify their potential of damage detection with respect to different locations and severity of damage. A simply supported beam with two degrees of freedom at each node is considered only for a single damage cases throughout the paper.

Genetic algorithms to schedule container transfers at multimodal terminals

Optimising the container transfer schedule at the multimodal terminals is known to be NP-hard, which implies that the best solution becomes computationally infeasible as problem sizes increase. Genetic Algorithm (GA) techniques are used to reduce container handling/transfer times and ships' time at the port by speeding up handling operations. The GA is chosen due to the relatively good results that have been reported even with the simplest GA implementations to obtain near-optimal solutions in reasonable time. Also discussed, is the application of the model to assess the consequences of increased scheduled throughput time as well as different strategies such as the alternative plant layouts, storage policies and number of yard machines. A real data set used for the solution and subsequent sensitivity analysis is applied to the alternative plant layouts, storage policies and number of yard machines.

Assessing the representativeness of a groundwater quality monitoring network

The monitoring sites comprising a state of the environment (SOE) network must be carefully selected to ensure that they will be representative of the broader resource. Hierarchical cluster analysis (HCA) is a data-driven technique that can potentially be employed to assess the representativeness of a SOE monitoring network. The objective of this paper is to explore the use of HCA as an approach for assessing the representativeness of the New Zealand National Groundwater Monitoring Programme (NGMP), which is comprised of 110 monitoring sites across the country.