David W Smith

University of Western Australia, Perth City, Western Australia, Australia

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Publications (114)251.43 Total impact

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    ABSTRACT: Renal arterial-to-venous (AV) oxygen shunting limits oxygen delivery to renal tissue. To better understand how oxygen in arterial blood can bypass renal tissue, we quantified the radial geometry of AV pairs and how it differs according to arterial diameter and anatomical location. We then estimated diffusion of oxygen in the vicinity of arteries of typical geometry using a computational model. The kidneys of 6 rats were perfusion fixed and the vasculature filled with silicone rubber (Microfil®). A single section was chosen from each kidney and all arteries (n = 1628) identified. Intrarenal arteries were largely divisible into two 'types', characterized by the presence or absence of a close physical relationship with a paired vein. Arteries with a close physical relationship with a paired vein were more likely to have a larger rather than smaller diameter, and more likely to be in the inner-cortex than the mid- or outer-cortex. Computational simulations indicated that direct diffusion of oxygen from an artery to a paired vein can only occur when the two vessels have a close physical relationship. However, even in the absence of this close relationship oxygen can diffuse from an artery to periarteriolar capillaries and venules. Thus, AV oxygen shunting in the proximal pre-glomerular circulation is dominated by direct diffusion of oxygen to a paired vein. In the distal pre-glomerular circulation, it may be sustained by diffusion of oxygen from arteries to capillaries and venules close to the artery wall, which is subsequently transported to renal veins by convection.
    American journal of physiology. Renal physiology 09/2014; · 3.61 Impact Factor
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    ABSTRACT: Parental attitudes towards vaccination significantly influence vaccine uptake. The A(H1N1)pdm09 influenza pandemic was followed in 2010 by an unprecedented increase in febrile reactions in children receiving trivalent inactivated influenza vaccine manufactured by bioCSL. Uptake of TIV in children <5 years in Western Australia (WA) decreased in 2010 and has remained low. The impact of pandemic A(H1N1)pdm09 and adverse-events on parental attitudes towards vaccination is uncertain.
    Vaccine. 05/2014;
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    ABSTRACT: There are few studies evaluating the effectiveness of trivalent influenza vaccination (TIV) in young children, particularly in children <2 years. The Western Australian Influenza Vaccine Effectiveness Study commenced in 2008 to evaluate a program providing TIV to children aged 6 to 59 months. An observational study enrolling children with influenza-like illness presenting to a tertiary pediatric hospital was conducted (2008-2012). Vaccination status was determined by parental questionnaire and confirmed via the national immunization register and/or vaccine providers. Respiratory virus polymerase chain reaction and culture were performed on nasopharyngeal samples. The test-negative design was used to estimate vaccine effectiveness (VE) by using 2 control groups: all influenza test-negative subjects and other-virus-detected (OVD) subjects. Adjusted odds ratios were estimated from models with season, month of disease onset, age, gender, indigenous status, prematurity, and comorbidities as covariates. Subjects enrolled in 2009 were excluded from VE calculations. Of 2001 children enrolled, influenza was identified in 389 (20.4%) children. Another respiratory virus was identified in 1134 (59.6%) children. Overall, 295 of 1903 (15.5%) children were fully vaccinated and 161 of 1903 (8.4%) children were partially vaccinated. Vaccine uptake was significantly lower in 2010-2012 after increased febrile adverse events observed in 2010. Using test-negative controls, VE was 64.7% (95% confidence interval [CI]: 33.7%-81.2%). No difference in VE was observed with OVD controls (65.8%; 95% CI: 32.1%-82.8%). The VE for children <2 years was 85.8% (95% CI: 37.9%-96.7%). This study reveals the effectiveness of TIV in young children over 4 seasons by using test-negative and OVD controls. TIV was effective in children aged <2 years. Despite demonstrated vaccine effectiveness, uptake of TIV remains suboptimal.
    PEDIATRICS 04/2014; · 4.47 Impact Factor
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    ABSTRACT: Wnt/beta-catenin signaling is involved in different stages of mammalian development and implicated in various cancers (e.g. colorectal cancer). Recent experimental and computational studies have revealed characteristics of the pathway, however a cell-specific spatial perspective is lacking. In this study, a novel 3D confocal quantitation protocol is developed to acquire spatial (two cellular compartments: nucleus and cytosol-membrane) and temporal quantitative data on target protein (e.g. beta-catenin) concentrations in Human Epithelial Kidney cells (HEK293T) during perturbation (with either cycloheximide or Wnt3A). Computational models of the Wnt pathway are constructed and interrogated based on this data. A single compartment Wnt pathway model is compared with a simple beta-catenin two compartment model to investigate Wnt3A signaling in HEK293T cells. When protein synthesis is inhibited, beta-catenin decreases at the same rate in both cellular compartments, suggesting diffusional transport is fast compared to beta-catenin degradation in the cytosol. With Wnt3A stimulation, the total amount of beta-catenin rises throughout the cell, however the increase is initially (~first hour) faster in the nuclear compartment. While both models were able to reproduce the whole cell changes in beta-catenin, only the compartment model reproduced the Wnt3A induced changes in beta-catenin distribution and it was also the best fit for the data obtained when active transport was included alongside passive diffusion transport. This integrated 3D quantitation imaging protocol and computational modeling approach allowed cell-specific compartment models of the signaling pathways to be constructed and analyzed. The Wnt models constructed in this study are the first for HEK293T and have suggested potential roles of inter-compartment transport to the dynamics of signaling.
    BMC Systems Biology 04/2014; 8(1):44. · 2.98 Impact Factor
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    ABSTRACT: Murray Valley encephalitis virus (MVEV) is the most serious of the endemic arboviruses in Australia. It was responsible for six known large outbreaks of encephalitis in south-eastern Australia in the 1900s, with the last comprising 58 cases in 1974. Since then MVEV clinical cases have been largely confined to the western and central parts of northern Australia. In 2011, high-level MVEV activity occurred in south-eastern Australia for the first time since 1974, accompanied by unusually heavy seasonal MVEV activity in northern Australia. This resulted in 17 confirmed cases of MVEV disease across Australia. Record wet season rainfall was recorded in many areas of Australia in the summer and autumn of 2011. This was associated with significant flooding and increased numbers of the mosquito vector and subsequent MVEV activity. This paper documents the outbreak and adds to our knowledge about disease outcomes, epidemiology of disease and the link between the MVEV activity and environmental factors. Clinical and demographic information from the 17 reported cases was obtained. Cases or family members were interviewed about their activities and location during the incubation period. In contrast to outbreaks prior to 2000, the majority of cases were non-Aboriginal adults, and almost half (40%) of the cases acquired MVEV outside their area of residence. All but two cases occurred in areas of known MVEV activity. This outbreak continues to reflect a change in the demographic pattern of human cases of encephalitic MVEV over the last 20 years. In northern Australia, this is associated with the increasing numbers of non-Aboriginal workers and tourists living and travelling in endemic and epidemic areas, and also identifies an association with activities that lead to high mosquito exposure. This outbreak demonstrates that there is an ongoing risk of MVEV encephalitis to the heavily populated areas of south-eastern Australia.
    PLoS Neglected Tropical Diseases 01/2014; 8(1):e2656. · 4.57 Impact Factor
  • Brian N. Cox, David W. Smith
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    ABSTRACT: Recent theoretical simulations of amelogenesis and network formation and new, simple analyses of the basic multicellular unit (BMU) allow estimation of the order of magnitude of the strain energy density in populations of living cells in their natural environment. A similar simple calculation translates recent measurements of the force–displacement relation for contacting cells (cell–cell adhesion energy) into equivalent volume energy densities, which are formed by averaging the changes in contact energy caused by a cell׳s migration over the cell׳s volume. The rates of change of these mechanical energy densities (energy density rates) are then compared to the order of magnitude of the metabolic activity of a cell, expressed as a rate of production of metabolic energy per unit volume. The mechanical energy density rates are 4–5 orders of magnitude smaller than the metabolic energy density rate in amelogenesis or bone remodeling in the BMU, which involve modest cell migration velocities, and 2–3 orders of magnitude smaller for innervation of the gut or angiogenesis, where migration rates are among the highest for all cell types. For representative cell–cell adhesion gradients, the mechanical energy density rate is 6 orders of magnitude smaller than the metabolic energy density rate. The results call into question the validity of using simple constitutive laws to represent living cells. They also imply that cells need not migrate as inanimate objects of gradients in an energy field, but are better regarded as self-powered automata that may elect to be guided by such gradients or move otherwise.
    Journal of the Mechanics and Physics of Solids 01/2014; 71:239–252. · 4.29 Impact Factor
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    ABSTRACT: An increase in off-season (June to September) Ross River virus (RRV) notifications from the greater Perth metropolitan area was observed from 2006 to 2009. We investigated the increase to determine whether it is likely to have reflected a true increase in off-season cases. A single positive RRV IgM test result is sufficient for RRV notification but where follow-up testing was performed, the positive predictive value of an IgM test where IgG was negative was very low in the off-season and also in the season when using the only commercially available test kit. The increase in off-season notifications was not associated with an increase in off-season testing. Some Perth laboratories use more stringent notification criteria than the nationally agreed RRV case definition, and the geographical distribution of samples tested varies between laboratories. Our findings make a strong case to change the nationally agreed case definition for RRV to not accept a single IgM positive test result as laboratory definitive evidence where the IgG is negative. Our study also identified a range of challenges in interpreting changes in seasonal patterns and geographical distribution of RRV. Any such observed changes should be investigated through further data analysis and/or mosquito trapping and testing in order to assess validity.
    Communicable diseases intelligence quarterly report. 01/2014; 38(2):E114-E121.
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    ABSTRACT: We describe the determinants of urinary oxygen tension (PO2) and the potential for use of urinary PO2 as a 'physiological biomarker' of the risk of acute kidney injury (AKI) in hospital settings. We also identify knowledge-gaps required for clinical translation of bedside monitoring of urinary PO2. Hypoxia in the renal medulla is a hallmark of AKI of diverse aetiology. Urine in the collecting ducts would be expected to equilibrate with the tissue PO2 of the inner medulla. Accordingly, the PO2 of urine in the renal pelvis changes in response to stimuli that would be expected to alter oxygenation of the renal medulla. Oxygen exchange across the walls of the ureter and bladder will confound measurement of the PO2 of bladder urine. Nevertheless, the PO2 of bladder urine also changes in response to stimuli that would be expected to alter renal medullary oxygenation. If confounding influences can be understood, urinary bladder PO2 may provide prognostically useful information, including for prediction of AKI after cardiopulmonary bypass surgery. To translate bedside monitoring of urinary PO2 into the clinical setting, we require (i) a more detailed knowledge of the relationship between renal medullary oxygenation and the PO2 of pelvic urine under physiological and pathophysiological conditions, (ii) a quantitative understanding of the impact of oxygen transport across the ureteric epithelium on urinary PO2 measured from the bladder, and (iii) a simple, robust medical device that can be introduced into the bladder via a standard catheter, to provide reliable and continuous measurement of urinary PO2.
    AJP Regulatory Integrative and Comparative Physiology 11/2013; · 3.28 Impact Factor
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    ABSTRACT: To ascertain the full mortality of influenza and other respiratory viruses, the testing of community autopsy specimens is essential. Respiratory virus PCR and culture were performed on 2418 fresh unfrozen respiratory samples collected from 1611 coronial cases where the death was either unknown or infection was suspected, from July 2007 to June 2011, to detect the common respiratory viruses in children and adults, using standardized microbiological testing. The respiratory virus positive rate was 8·3% (134 cases) with a peak of 28% (42 of 151 cases) in children under 10 years of age. Influenza virus was the commonest respiratory virus (50 cases, 3%), followed by respiratory syncytial virus (RSV) (30 cases, 2%). All tested respiratory viruses were found in children, most commonly adenovirus, enterovirus and RSV, and influenza A and RSV predominated in those over 60 years, but coinfection was uncommon. Almost all influenza cases occurred when influenza was widely circulating in the community but few were diagnosed pre-mortem. Influenza and RSV detection was associated with bronchitis or bronchiolitis in 7 (9%) of the 80 cases and caused pneumonia in 14 (0·8%) deaths overall. Our prospective review of respiratory viruses using standardized testing found a single lower respiratory tract autopsy specimen for respiratory virus PCR would detect most community infections at the time of death.
    Influenza and Other Respiratory Viruses 07/2013; · 1.47 Impact Factor
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    ABSTRACT: We propose a new non-linear poroelastic model that is suited to the analysis of soft tissues. In this paper the model is tailored to the analysis of cartilage and the engineering design of cartilage constructs. The proposed continuum formulation of the governing equations enables the strain of the individual material components within the extracellular matrix (ECM) to be followed over time, as the individual material components are synthesized, assembled and incorporated within the ECM or lost through passive transport or degradation. The material component analysis developed here naturally captures the effect of time-dependent changes of ECM composition on the deformation and internal stress states of the ECM. For example, it is shown that increased synthesis of aggrecan by chondrocytes embedded within a decellularized cartilage matrix initially devoid of aggrecan results in osmotic expansion of the newly synthesized proteoglycan matrix and tension within the structural collagen network. Specifically, we predict that the collagen network experiences a tensile strain, with a maximum of ~2% at the fixed base of the cartilage. The analysis of an example problem demonstrates the temporal and spatial evolution of the stresses and strains in each component of a self-equilibrating composite tissue construct, and the role played by the flux of water through the tissue. Copyright © 2013 John Wiley & Sons, Ltd.
    Journal of Tissue Engineering and Regenerative Medicine 06/2013; · 4.43 Impact Factor
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    ABSTRACT: Computational modeling of tendon lags the development of computational models for other tissues. A major bottleneck in the development of realistic computational models for Achilles tendon is the absence of detailed conceptual and theoretical models as to how the tissue actually functions. Without the conceptual models to provide a theoretical framework to guide the development and integration of multiscale computational models, modeling of the Achilles tendon to date has tended to be piecemeal and focused on specific mechanical or biochemical issues. In this paper, we present a new conceptual model of Achilles tendon tissue homeostasis, and discuss this model in terms of existing computational models of tendon. This approach has the benefits of structuring the research on relevant computational modeling to date, while allowing us to identify new computational models requiring development. The critically important functional issue for tendon is that it is continually damaged during use and so has to be repaired. From this follows the centrally important issue of homeostasis of the load carrying collagen fibrils within the collagen fibers of the Achilles tendon. Collagen fibrils may be damaged mechanically-by loading, or damaged biochemically-by proteases. Upon reviewing existing computational models within this conceptual framework of the Achilles tendon structure and function, we demonstrate that a great deal of theoretical and experimental research remains to be done before there are reliably predictive multiscale computational model of Achilles tendon in health and disease. WIREs Syst Biol Med 2013. doi: 10.1002/wsbm.1229 For further resources related to this article, please visit the WIREs website Conflict of interest: The authors have declared no conflicts of interest for this article.
    Wiley Interdisciplinary Reviews Systems Biology and Medicine 06/2013; · 3.68 Impact Factor
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    ABSTRACT: Bone remodelling is carried out by 'bone multicellular units' ([Formula: see text]s) in which active osteoclasts and active osteoblasts are spatially and temporally coupled. The refilling of new bone by osteoblasts towards the back of the [Formula: see text] occurs at a rate that depends both on the number of osteoblasts and on their secretory activity. In cortical bone, a linear phenomenological relationship between matrix apposition rate and [Formula: see text] cavity radius is found experimentally. How this relationship emerges from the combination of complex, nonlinear regulations of osteoblast number and secretory activity is unknown. Here, we extend our previous mathematical model of cell development within a single cortical [Formula: see text] to investigate how osteoblast number and osteoblast secretory activity vary along the [Formula: see text]'s closing cone. The mathematical model is based on biochemical coupling between osteoclasts and osteoblasts of various maturity and includes the differentiation of osteoblasts into osteocytes and bone lining cells, as well as the influence of [Formula: see text] cavity shrinkage on osteoblast development and activity. Matrix apposition rates predicted by the model are compared with data from tetracycline double labelling experiments. We find that the linear phenomenological relationship observed in these experiments between matrix apposition rate and [Formula: see text] cavity radius holds for most of the refilling phase simulated by our model, but not near the start and end of refilling. This suggests that at a particular bone site undergoing remodelling, bone formation starts and ends rapidly, supporting the hypothesis that osteoblasts behave synchronously. Our model also suggests that part of the observed cross-sectional variability in tetracycline data may be due to different bone sites being refilled by [Formula: see text]s at different stages of their lifetime. The different stages of a [Formula: see text]'s lifetime (such as initiation stage, progression stage, and termination stage) depend on whether the cell populations within the [Formula: see text] are still developing or have reached a quasi-steady state whilst travelling through bone. We find that due to their longer lifespan, active osteoblasts reach a quasi-steady distribution more slowly than active osteoclasts. We suggest that this fact may locally enlarge the Haversian canal diameter (due to a local lack of osteoblasts compared to osteoclasts) near the [Formula: see text]'s point of origin.
    Biomechanics and Modeling in Mechanobiology 04/2013; · 3.33 Impact Factor
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    ABSTRACT: BACKGROUND AND OBJECTIVE: Interferon alpha (IFNα) is a known antiviral agent. A double-blind, placebo-controlled clinical trial was conducted investigating the use of low-dose oral interferon alpha for preventing acute viral respiratory illnesses. METHODS: Two hundred healthy adults aged 18-75 years were enrolled and completed weekly health data questionnaires to monitor for symptoms and impact of respiratory illness. Serum samples were tested for antibodies against influenza and other common respiratory viruses. RESULTS: Low-dose oral IFNα prophylaxis did not reduce the incidence or impact of acute respiratory illness (ARI) or the impact of illness on daily activities. Post hoc analysis of participant subgroups, however, identified significant reductions in the incidence of ARI reported by males, those aged 50 years or more and those who received the 2009 seasonal influenza vaccine. Interferon alpha prophylaxis had a significant impact on the reporting of moderate-to-severe feverishness by the study population. Seropositive participants in the IFN group were more likely to report asymptomatic or mild symptoms compared with those in the placebo group who were more likely to report stronger symptoms. CONCLUSIONS: Low-dose oral IFNα prophylaxis was not effective in limiting the overall incidence of ARI in our study population. However, there was evidence that prophylaxis reduced the severity of symptoms and had a beneficial effect in some subpopulations, including those who received the 2009 seasonal trivalent influenza vaccination.
    Influenza and Other Respiratory Viruses 02/2013; · 1.47 Impact Factor
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    ABSTRACT: A review of the laboratory-confirmed cases of Murray Valley encephalitis (MVE) from Western Australia between 2009 and 2011 was conducted to describe the clinical, laboratory, and radiological features of the disease. The nine encephalitis patients presented with altered mental state and seizures, tremor, weakness, or paralysis. All patients developed a raised C-reactive protein, whereas most developed acute liver injury, neutrophilia, and thrombocytosis. All patients with encephalitis developed cerebral peduncle involvement on early magnetic resonance imaging (MRI). The absence of thalamic MRI hyperintensity during the acute illness, with or without leptomeningeal enhancement, predicted a better neurological outcome, whereas those patients with widespread abnormalities involving the thalamus, midbrain, and cerebral cortex or the cerebellum had devastating neurological outcomes. MRI scans repeated months after acute illness showed destruction of the thalamus and basal ganglia, cortex, or cerebellum. These findings may help clinicians predict the neurological outcome when evaluating patients with MVE.
    The American journal of tropical medicine and hygiene 01/2013; · 2.53 Impact Factor
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    ABSTRACT: IGF signaling is involved in cell proliferation, differentiation and apoptosis in a wide range of tissues, both normal and diseased, and so IGF-IR has been the focus of intense interest as a promising drug target. In this computational study on cartilage, we focus on two questions: (i) what are the key factors influencing IGF-IR complex formation, and (ii) how might cells regulate IGF-IR complex formation? We develop a reaction-diffusion computational model of the IGF system involving twenty three parameters. A series of parametric and sensitivity studies are used to identify the key factors influencing IGF signaling. From the model we predict the free IGF and IGF-IR complex concentrations throughout the tissue. We estimate the degradation half-lives of free IGF-I and IGFBPs in normal cartilage to be 20 and 100 mins respectively, and conclude that regulation of the IGF half-life, either directly or indirectly via extracellular matrix IGF-BP protease concentrations, are two critical factors governing the IGF-IR complex formation in the cartilage. Further we find that cellular regulation of IGF-II production, the IGF-IIR concentration and its clearance rate, all significantly influence IGF signaling. It is likely that negative feedback processes via regulation of these factors tune IGF signaling within a tissue, which may help explain the recent failures of single target drug therapies aimed at modifying IGF signaling.
    PLoS ONE 01/2013; 8(6):e66870. · 3.53 Impact Factor
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    ABSTRACT: The intestinal mucosa is a monolayer of rapidly self-renewing epithelial cells which is not only responsible for absorption of water and nutrients into the bloodstream but also acts as a protective barrier against harmful microbes entering the body. New functional epithelial cells are produced from stem cells, and their proliferating progeny. These stem cells are found within millions of crypts (tubular pits) spaced along the intestinal tract. The entire intestinal epithelium is replaced every 2-3 days in mice (3-5 days in humans) and hence cell production, differentiation, migration and turnover need to be tightly regulated. Malfunctions in this regulation are strongly linked to inflammatory bowel diseases and to the formation of adenomas and ultimately cancerous tumours. Despite a great deal of biological experimentation and observation, precisely how colonic crypts are regulated to produce mature colonocytes remains unclear. To assist in understanding how cell organisation in crypts is achieved, two very different conceptual models of cell behaviour are developed here, referred to as the 'pedigree' and the 'niche' models. The pedigree model proposes that crypt cells are largely preprogrammed and receive minimal prompting from the environment as they move through a routine of cell differentiation and proliferation to become mature colonocytes. The niche model proposes that crypt cells are primarily influenced by the local microenvironments along the crypt, and that predetermined cell behaviour plays a negligible role in their development. In this paper we present a computational model of colonic crypts in the mouse, which enables a comparison of the quality and controllability of mature coloncyte production by crypts operating under these two contrasting conceptual models of crypt regulation.
    PLoS ONE 01/2013; 8(9):e73204. · 3.53 Impact Factor

Publication Stats

975 Citations
251.43 Total Impact Points

Institutions

  • 2002–2014
    • University of Western Australia
      • • Faculty of Engineering, Computing and Mathematics
      • • School of Paediatrics and Child Health
      • • School of Computer Science and Software Engineering
      • • Centre for Health Services Research
      • • School of Chemistry and Biochemistry
      Perth City, Western Australia, Australia
  • 2013
    • Monash University (Australia)
      • School of Mathematical Sciences, Clayton
      Melbourne, Victoria, Australia
  • 2009–2013
    • University of Melbourne
      Melbourne, Victoria, Australia
  • 2006–2013
    • Victoria University Melbourne
      Melbourne, Victoria, Australia
  • 2012
    • Fremantle Hospital and Health Service
      Fremantle, Western Australia, Australia
    • Ludwig Institute for Cancer Research
      La Jolla, California, United States
  • 2009–2012
    • PathWest Laboratory Medicine
      Perth City, Western Australia, Australia
  • 2010
    • Western Australia Health
      Perth City, Western Australia, Australia
    • Sir Charles Gairdner Hospital
      Perth City, Western Australia, Australia
  • 2005–2010
    • Government of Western Australia
      Perth City, Western Australia, Australia
  • 1993–2009
    • University of Newcastle
      • • Mothers and Babies Research Centre
      • • Department of Civil Engineering
      • • School of Engineering
      • • Department of Environmental Engineering
      Newcastle, New South Wales, Australia