Osteoimmunomodulation: A new aspect for the development and evaluation of bone biomaterials

This thesis successfully introduced the intellectual framework of immunology in the development of bone biomaterials. The project identified the regulatory role of biomaterials to the immune-response in terms of bone formation and healing of bone defects. The novel methods developed in the project will significantly change the ways of biomaterials assessment and evaluation.

Evaluation framework to assess orthopaedic procedures

Introduction & aims The demand for evidence of efficacy of treatments in general and orthopaedic surgical procedures in particular is ever increasing in Australia and worldwide. The aim of this study is to share the key elements of an evaluation framework recently implemented in Australia to determine the efficacy of bone-anchored prostheses. Method The proposed evaluation framework to determine the benefit and harms of bone-anchored prostheses for individuals with limb loss was extracted from a systematic review of the literature including seminal studies focusing on clinical benefits and safety of procedures involving screw-type implant (e.g., OPRA) and press-fit fixations (e.g., EEFT, ILP, OPL). [1-64] Results The literature review highlighted that a standard and replicable evaluation framework should focus on: • The clinical benefits with a systematic recording of health-related quality of life (e.g., SF-26, Q-TFA), mobility predictor (e.g., AMPRO), ambulation abilities (e.g., TUG, 6MWT), walking abilities (e.g., characteristic spatio-temporal) and actual activity level at baseline and follow-up post Stage 2 surgery, • The potential harms with systematic recording of residuum care, infection, implant stability, implant integrity, injuries (e.g., falls) after Stage 1 surgery. There was a general consensus around the instruments to monitor most of the benefits and harms. The benefits could be assessed using a wide spectrum of complementary assessments ranging from subjective patient self-reporting to objective measurements of physical activity. However, this latter was assessed using a broad range of measurements (e.g., pedometer, load cell, energy consumption). More importantly, the lack of consistent grading of infections was sufficiently noticeable to impede cross-fixation comparisons. Clearly, a more universal grading system is needed. Conclusions Investigators are encouraged to implement an evaluation framework featuring the domains and instruments proposed above using a single database to facilitate robust prospective studies about potential benefits and harms of their procedure. This work is also a milestone in the development of national and international clinical outcome registries.

'Sink or swim': An evaluation of the clinical characteristics of individuals with high bone mass

Summary High bone mineral density on routine dual energy X-ray absorptiometry (DXA) may indicate an underlying skeletal dysplasia. Two hundred fifty-eight individuals with unexplained high bone mass (HBM), 236 relatives (41% with HBM) and 58 spouses were studied. Cases could not float, had mandible enlargement, extra bone, broad frames, larger shoe sizes and increased body mass index (BMI). HBM cases may harbour an underlying genetic disorder. Introduction High bone mineral density is a sporadic incidental finding on routine DXA scanning of apparently asymptomatic individuals. Such individuals may have an underlying skeletal dysplasia, as seen in LRP5 mutations. We aimed to characterize unexplained HBM and determine the potential for an underlying skeletal dysplasia. Methods Two hundred fifty-eight individuals with unexplained HBM (defined as L1 Z-score ≥ +3.2 plus total hip Z-score ≥ +1.2, or total hip Z-score ≥ +3.2) were recruited from 15 UK centres, by screening 335,115 DXA scans. Unexplained HBM affected 0.181% of DXA scans. Next 236 relatives were recruited of whom 94 (41%) had HBM (defined as L1 Z-score + total hip Z-score ≥ +3.2). Fifty-eight spouses were also recruited together with the unaffected relatives as controls. Phenotypes of cases and controls, obtained from clinical assessment, were compared using random-effects linear and logistic regression models, clustered by family, adjusted for confounders, including age and sex. Results Individuals with unexplained HBM had an excess of sinking when swimming (7.11 [3.65, 13.84], p < 0.001; adjusted odds ratio with 95% confidence interval shown), mandible enlargement (4.16 [2.34, 7.39], p < 0.001), extra bone at tendon/ligament insertions (2.07 [1.13, 3.78], p = 0.018) and broad frame (3.55 [2.12, 5.95], p < 0.001). HBM cases also had a larger shoe size (mean difference 0.4 [0.1, 0.7] UK sizes, p = 0.009) and increased BMI (mean difference 2.2 [1.3, 3.1] kg/m 2, p < 0.001). Conclusion Individuals with unexplained HBM have an excess of clinical characteristics associated with skeletal dysplasia and their relatives are commonly affected, suggesting many may harbour an underlying genetic disorder affecting bone mass.

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

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

Evaluation of safety treatments at roadwork zones

A major 3-year research project to improve safety at roadworks has recently been completed by the Centre for Accident Research and Road Safety – Queensland (CARRS-Q) and industry partners. This project involved developing strategies to mitigate roadwork hazards including speeding. This paper presents three on-road evaluation studies on the effectiveness of some current and new safety treatments: use of pilot vehicles, variable message signage (VMS), police enforcement with and without VMS, and remote-controlled traffic control devices. The speed reduction potential of pilot vehicles was evaluated at a highway site. Results showed that pilot vehicles reduced average speeds within the work area, but not at a downstream location. Combinations of VMS and police enforcement were evaluated at a motorway site and results showed that police enforcement accompanied with VMS had greater effects on reducing speeds than either of these treatments alone. Three new remote-controlled traffic control devices—red and amber lights, red light and amber arrow, and a robotic stop/slow sign—were evaluated at a highway site. Results showed that the red light and amber arrow option produced consistent effects on the speeds at the approach to traffic controls and at a location inside the work area. This paper presents the first rigorous evaluations of these roadwork safety treatments in Queensland.

Managing the impacts of sugarcane farming on the Great Barrier Reef: An evaluation of the implementation of the Polluter Pays Principle

This report provides an evaluation of the implementation of the Polluter Pays Principle (PPP) – a principle of international environmental law – in the context of pollution from sugarcane farming affecting Australia’s Great Barrier Reef (GBR). The research was part of an experiment to test methods for evaluating the effectiveness of environmental laws. Overall, we found that whilst the PPP is reflected to a limited extent in Australian law (more so in Queensland law, than at the national level), the behaviour one might expect in terms of implementing the principle was largely inadequate. Evidence of a longer term, explicit commitment to the PPP was particularly weak.

Evaluation of ion exchange as a pre-treatment option for coal seam gas water

The Coal Seam Gas (CSG) industry in Australia has grown significantly in recent years. During the gas extraction process, water is also recovered which is brackish in character. In order to facilitate beneficial reuse of the water, the CSG industry has primarily invested in Reverse Osmosis (RO) as the primary method for associated water desalination. However, the presence of alkaline earth ions in the water combined with the inherent alkalinity of the water may result in RO membrane scaling. Consequently, weak acid cation (WAC) synthetic ion exchange resins were investigated as a potential solution to this potential problem. It was shown that resins were indeed highly efficient at treating single and multi-component solutions of alkaline earth ions. The interaction of the ions with the resin was found to be considerably more complex that previously reported.

Improving SEA procedures within Italian regions: Towards a more effective evaluation of urban sustainability

Sustainable urban development, a major issue at global scale, will become more relevant according to population growth predictions in developed and developing countries. Societal and international recognition of sustainability concerns led to the development of specific tools and procedures, known as sustainability assessments/appraisals (SA). Their effectiveness however, considering that global quality life indicators have worsened since their introduction, has promoted a re-thinking of SA instruments. More precisely, Strategic Environmental Assessment (SEA), – a tool introduced in the European context to evaluate policies, plans, and programmes (PPPs), – is being reconsidered because of several features that seem to limit its effectiveness. Over time, SEA has evolved in response to external and internal factors dealing with technical, procedural, planning and governance systems thus involving a shift of paradigm from EIA-based SEAs (first generation protocols) towards more integrated approaches (second generation ones). Changes affecting SEA are formalised through legislation in each Member State, to guide institutions at regional and local level. Defining SEA effectiveness is quite difficult. Its’ capacity-building process appears quite far from its conclusion, even if any definitive version can be conceptualized. In this paper, we consider some European nations with different planning systems and SA traditions. After the identification of some analytical criteria, a multi-dimensional cluster analysis is developed on some case studies, to outline current weaknesses.

Improving SEA prodedures within Italian regions: Towards a more effective evaluation of urban sustainability

Sustainable urban development, a major issue at global scale, will become more relevant according to population growth predictions in developed and developing countries. Societal and international recognition of sustainability concerns led to the development of specific tools and procedures, known as sustainability assessments/appraisals (SA). Their effectiveness however, considering that global quality life indicators have worsened since their introduction, has promoted a re-thinking of SA instruments. More precisely, Strategic Environmental Assessment (SEA), – a tool introduced in the European context to evaluate policies, plans, and programmes (PPPs), – is being reconsidered because of several features that seem to limit its effectiveness. Over time, SEA has evolved in response to external and internal factors dealing with technical, procedural, planning and governance systems thus involving a shift of paradigm from EIA-based SEAs (first generation protocols) towards more integrated approaches (second generation ones). Changes affecting SEA are formalised through legislation in each Member State, to guide institutions at regional and local level. Defining SEA effectiveness is quite difficult. Its’ capacity-building process appears quite far from its conclusion, even if any definitive version can be conceptualized. In this paper, we consider some European nations with different planning systems and SA traditions. After the identification of some analytical criteria, a multi-dimensional cluster analysis is developed on some case studies, to outline current weaknesses.

Evaluation of a Multispectral Camera on a UAV for Agricultural Applications

Australian farmers have used precision agriculture technology for many years with the use of ground – based and satellite systems. However, these systems require the use of vehicles in order to analyse a wide area which can be time consuming and cost ineffective. Also, satellite imagery may not be accurate for analysis. Low cost of Unmanned Aerial Vehicles (UAV) present an effective method of analysing large plots of agricultural fields. As the UAV can travel over long distances and fly over multiple plots, it allows for more data to be captured by a sampling device such as a multispectral camera and analysed thereafter. This would allow farmers to analyse the health of their crops and thus focus their efforts on certain areas which may need attention. This project evaluates a multispectral camera for use on a UAV for agricultural applications.

A critical evaluation of literature on robot path planning in dynamic environment

Robot Path Planning (RPP) in dynamic environments is a search problem based on the examination of collision-free paths in the presence of dynamic and static obstacles. Many techniques have been developed to solve this problem. Trapping in a local minima and maintaining a Real-Time performance are known as the two most important challenges that these techniques face to solve such problem. This study presents a comprehensive survey of the various techniques that have been proposed in this domain. As part of this survey, we include a classification of the approaches and identify their methods.

“It puts a human face on the researched”: A qualitative evaluation of an Indigenous research governance model

Objective This study aimed to describe the Inala Aboriginal and Torres Strait Islander Community Jury for Health Research, and evaluate its usefulness as a model of Indigenous research governance within an urban Indigenous primary health care service from the perspectives of Jury members and researchers. Methods Informed by a phenomenological approach and using narrative inquiry, a focus group was conducted with Jury members and key informant interviews were undertaken with researchers who had presented to the Community Jury in its first year of operation. Results The Jury was a site of identity work for researchers and Jury members, providing an opportunity to observe and affirm community cultural protocols. Although researchers and Jury members had differing levels of research literacy, the Jury processes enabled respectful communication and relationships to form which positively influenced research practice, community aspirations and clinical care. Discussion The Jury processes facilitated transformative research practice among researchers, and resulted in transference of power from researchers to the Jury members to the mutual benefit of both. Conclusion Ethical Indigenous health research practice requires an engagement with Indigenous peoples and knowledges at the research governance level, not simply as subjects or objects of research.

The ATHEROMA (Atorvastatin Therapy: Effects on Reduction of Macrophage Activity) Study. Evaluation using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging in carotid disease

Objectives: The aim of this study was to evaluate the effects of low-dose (10 mg) and high-dose (80 mg) atorvastatin on carotid plaque inflammation as determined by ultrasmall superparamagnetic iron oxide (USPIO)-enhanced carotid magnetic resonance imaging (MRI). The hypothesis was that treatment with 80 mg atorvastatin would demonstrate quantifiable changes in USPIO-enhanced MRI-defined inflammation within the first 3 months of therapy. Background: Preliminary studies indicate that USPIO-enhanced MRI can identify macrophage infiltration in human carotid atheroma in vivo and hence may be a surrogate marker of plaque inflammation. Methods: Forty-seven patients with carotid stenosis >40% on duplex ultrasonography and who demonstrated intraplaque accumulation of USPIO on MRI at baseline were randomly assigned in a balanced, double-blind manner to either 10 or 80 mg atorvastatin daily for 12 weeks. Baseline statin therapy was equivalent to 10 mg of atorvastatin or less. The primary end point was change from baseline in signal intensity (ΔSI) on USPIO-enhanced MRI in carotid plaque at 6 and 12 weeks. Results: Twenty patients completed 12 weeks of treatment in each group. A significant reduction from baseline in USPIO-defined inflammation was observed in the 80-mg group at both 6 weeks (ΔSI 0.13; p = 0.0003) and at 12 weeks (ΔSI 0.20; p < 0.0001). No difference was observed with the low-dose regimen. The 80-mg atorvastatin dose significantly reduced total cholesterol by 15% (p = 0.0003) and low-density lipoprotein cholesterol by 29% (p = 0.0001) at 12 weeks. Conclusions: Aggressive lipid-lowering therapy over a 3-month period is associated with significant reduction in USPIO-defined inflammation. USPIO-enhanced MRI methodology may be a useful imaging biomarker for the screening and assessment of therapeutic response to "anti-inflammatory" interventions in patients with atherosclerotic lesions. (Effects of Atorvastatin on Macrophage Activity and Plaque Inflammation Using Magnetic Resonance Imaging [ATHEROMA]; NCT00368589).

Linking spatial stock dynamics and economics: Evaluation of indicators and fishery management for the travelling eastern king prawn (Melicertus plebejus)

Reduced economic circumstances havemoved management goals towards higher profit, rather than maximum sustainable yields in several Australian fisheries. The eastern king prawn is one such fishery, for which we have developed new methodology for stock dynamics, calculation of model-based and data-based reference points and management strategy evaluation. The fishery is notable for the northward movement of prawns in eastern Australian waters, from the State jurisdiction of New South Wales to that of Queensland, as they grow to spawning size, so that vessels fishing in the northern deeper waters harvest more large prawns. Bioeconomic fishing data were standardized for calibrating a length-structured spatial operating model. Model simulations identified that reduced boat numbers and fishing effort could improve profitability while retaining viable fishing in each jurisdiction. Simulations also identified catch rate levels that were effective for monitoring in simple within-year effort-control rules. However, favourable performance of catch rate indicators was achieved only when a meaningful upper limit was placed on total allowed fishing effort. Themethods and findings will allow improved measures for monitoring fisheries and inform decision makers on the uncertainty and assumptions affecting economic indicators.

Sediment concentration prediction and statistical evaluation for annual load estimation

We consider the development of statistical models for prediction of constituent concentration of riverine pollutants, which is a key step in load estimation from frequent flow rate data and less frequently collected concentration data. We consider how to capture the impacts of past flow patterns via the average discounted flow (ADF) which discounts the past flux based on the time lapsed - more recent fluxes are given more weight. However, the effectiveness of ADF depends critically on the choice of the discount factor which reflects the unknown environmental cumulating process of the concentration compounds. We propose to choose the discount factor by maximizing the adjusted R-2 values or the Nash-Sutcliffe model efficiency coefficient. The R2 values are also adjusted to take account of the number of parameters in the model fit. The resulting optimal discount factor can be interpreted as a measure of constituent exhaustion rate during flood events. To evaluate the performance of the proposed regression estimators, we examine two different sampling scenarios by resampling fortnightly and opportunistically from two real daily datasets, which come from two United States Geological Survey (USGS) gaging stations located in Des Plaines River and Illinois River basin. The generalized rating-curve approach produces biased estimates of the total sediment loads by -30% to 83%, whereas the new approaches produce relatively much lower biases, ranging from -24% to 35%. This substantial improvement in the estimates of the total load is due to the fact that predictability of concentration is greatly improved by the additional predictors.