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1.  Risk Factors for Community-Based Reports of Gastrointestinal, Respiratory, and Dermal Symptoms: Findings From a Cohort Study in Australia 
Journal of Epidemiology  2014;24(1):39-46.
Although gastrointestinal (GI), respiratory, and dermal symptoms are common, few studies have conducted concurrent and comparative prospective analyses of risk factors for these 3 morbidity outcomes.
We used data from a community-based randomized controlled trial among 277 South Australian families to analyze GI (diarrhea, vomiting), respiratory (sore throat, runny nose, cough) and dermal (rash, generalized itch, dermal infection) symptoms.
Log-binomial regression analysis revealed similar risks of GI (adjusted risk ratio [RR], 1.65; 95% CI, 1.05–2.58) and respiratory (RR, 1.68; 95% CI, 1.31–2.15) symptoms among childcare/kindergarten attendees. Swimming in public pools/spas in the current or previous week was associated with all 3 symptom complexes, conferring similar risk for each (RR for GI: 1.33; 95% CI, 0.99–1.77; respiratory: 1.20; 95% CI, 1.04–1.38; dermal: 1.41; 95% CI, 1.08–1.85). Pet ownership was not associated with symptoms. Household clustering of GI and respiratory symptoms was common, and clustering of respiratory symptoms correlated with number of individuals per household.
This simultaneous examination of risk factors for 3 health outcomes yielded new comparative data that are useful for developing prevention strategies.
PMCID: PMC3872523  PMID: 24240632
risk factors; respiratory symptoms; gastrointestinal symptoms; dermal symptoms; swimming; swimming pools; household clustering
2.  Disease Mapping and Regression with Count Data in the Presence of Overdispersion and Spatial Autocorrelation: A Bayesian Model Averaging Approach 
This paper applies the generalised linear model for modelling geographical variation to esophageal cancer incidence data in the Caspian region of Iran. The data have a complex and hierarchical structure that makes them suitable for hierarchical analysis using Bayesian techniques, but with care required to deal with problems arising from counts of events observed in small geographical areas when overdispersion and residual spatial autocorrelation are present. These considerations lead to nine regression models derived from using three probability distributions for count data: Poisson, generalised Poisson and negative binomial, and three different autocorrelation structures. We employ the framework of Bayesian variable selection and a Gibbs sampling based technique to identify significant cancer risk factors. The framework deals with situations where the number of possible models based on different combinations of candidate explanatory variables is large enough such that calculation of posterior probabilities for all models is difficult or infeasible. The evidence from applying the modelling methodology suggests that modelling strategies based on the use of generalised Poisson and negative binomial with spatial autocorrelation work well and provide a robust basis for inference.
PMCID: PMC3924480  PMID: 24413702
Bayesian variable selection; cancer; disease mapping; ecologic studies; Gibbs sampling; spatial epidemiology
3.  Lungworm Infections in German Dairy Cattle Herds — Seroprevalence and GIS-Supported Risk Factor Analysis 
PLoS ONE  2013;8(9):e74429.
In November 2008, a total of 19,910 bulk tank milk (BTM) samples were obtained from dairy farms from all over Germany, corresponding to about 20% of all German dairy herds, and analysed for antibodies against the bovine lungworm Dictyocaulus viviparus by use of the recombinant MSP-ELISA. A total number of 3,397 (17.1%; n = 19,910) BTM samples tested seropositive. The prevalences in individual German federal states varied between 0.0% and 31.2% positive herds. A geospatial map was drawn to show the distribution of seropositive and seronegative herds per postal code area. ELISA results were further analysed for associations with land-use and climate data. Bivariate statistical analysis was used to identify potential spatial risk factors for dictyocaulosis. Statistically significant positive associations were found between lungworm seropositive herds and the proportion of water bodies and grassed area per postal code area. Variables that showed a statistically significant association with a positive BTM test were included in a logistic regression model, which was further refined by controlled stepwise selection of variables. The low Pseudo R2 values (0.08 for the full model and 0.06 for the final model) and further evaluation of the model by ROC analysis indicate that additional, unrecorded factors (e.g. management factors) or random effects may substantially contribute to lungworm infections in dairy cows. Veterinarians should include lungworms in the differential diagnosis of respiratory disease in dairy cattle, particularly those at pasture. Monitoring of herds through BTM screening for antibodies can help farmers and veterinarians plan and implement appropriate control measures.
PMCID: PMC3764042  PMID: 24040243
4.  Predicting future depression in adolescents using the Short Mood and Feelings Questionnaire: a two-nation study 
Journal of affective disorders  2011;134(0):151-159.
Adolescence is a key life period for the development of depression. Predicting the development of depression in adolescence through detecting specific early symptoms may aid in the development of timely screening and intervention programs.
We administered the Short Mood and Feelings Questionnaire (SMFQ) to 5,769 American and Australian students aged 10 to 15 years, at two time points, separated by 12 months. We attempted to predict high levels of depression symptoms at 12 months from symptoms at baseline, using statistical approaches based upon the quality, as well as the quantity, of depression symptoms present. These approaches included classification and regression trees (CART) and logistic regression.
A classification tree employing four SMFQ items, such as feelings of self-hatred and of being unloved, performed almost as well as all 13 SMFQ items at predicting subsequent depression symptomatology.
Depression was measured using a self-report instrument, rather than a criterion standard diagnostic interview.
Further validation on other populations of adolescents is required: however the results suggest that several symptoms of depression, especially feelings of self-hatred, and being unloved, are associated with increased levels of self-reported depression at 12 months. Although screening for depression can be problematic, symptoms such as the ones above should be considered for inclusion in screening tests for adolescents.
PMCID: PMC3734932  PMID: 21669461
depression; adolescents; screening; classification trees
5.  An empirical investigation of the potential impact of selective inclusion of results in systematic reviews of interventions: study protocol 
Systematic Reviews  2013;2:21.
Systematic reviewers may encounter a multiplicity of outcome data in the reports of randomised controlled trials included in the review (for example, multiple measurement instruments measuring the same outcome, multiple time points, and final and change from baseline values). The primary objectives of this study are to investigate in a cohort of systematic reviews of randomised controlled trials of interventions for rheumatoid arthritis, osteoarthritis, depressive disorders and anxiety disorders: (i) how often there is multiplicity of outcome data in trial reports; (ii) the association between selection of trial outcome data included in a meta-analysis and the magnitude and statistical significance of the trial result, and; (iii) the impact of the selection of outcome data on meta-analytic results.
Forty systematic reviews (20 Cochrane, 20 non-Cochrane) of RCTs published from January 2010 to January 2012 and indexed in the Cochrane Database of Systematic Reviews (CDSR) or PubMed will be randomly sampled. The first meta-analysis of a continuous outcome within each review will be included. From each review protocol (where available) and published review we will extract information regarding which types of outcome data were eligible for inclusion in the meta-analysis (for example, measurement instruments, time points, analyses). From the trial reports we will extract all outcome data that are compatible with the meta-analysis outcome as it is defined in the review and with the outcome data eligibility criteria and hierarchies in the review protocol. The association between selection of trial outcome data included in a meta-analysis and the magnitude and statistical significance of the trial result will be investigated. We will also investigate the impact of the selected trial result on the magnitude of the resulting meta-analytic effect estimates.
The strengths of this empirical study are that our objectives and methods are pre-specified and transparent. The results may inform methods guidance for systematic review conduct and reporting, particularly for dealing with multiplicity of randomised controlled trial outcome data.
PMCID: PMC3626625  PMID: 23575367
Systematic review; Randomised controlled trials; Reporting; Bias; Research methodology
6.  Addition of telephone coaching to a physiotherapist-delivered physical activity program in people with knee osteoarthritis: A randomised controlled trial protocol 
Knee osteoarthritis (OA) is one of the most common and costly chronic musculoskeletal conditions world-wide and is associated with substantial pain and disability. Many people with knee OA also experience co-morbidities that further add to the OA burden. Uptake of and adherence to physical activity recommendations is suboptimal in this patient population, leading to poorer OA outcomes and greater impact of associated co-morbidities. This pragmatic randomised controlled trial will investigate the clinical- and cost-effectiveness of adding telephone coaching to a physiotherapist-delivered physical activity intervention for people with knee OA.
168 people with clinically diagnosed knee OA will be recruited from the community in metropolitan and regional areas and randomly allocated to physiotherapy only, or physiotherapy plus nurse-delivered telephone coaching. Physiotherapy involves five treatment sessions over 6 months, incorporating a home exercise program of 4–6 exercises (targeting knee extensor and hip abductor strength) and advice to increase daily physical activity. Telephone coaching comprises 6–12 telephone calls over 6 months by health practitioners trained in applying the Health Change Australia (HCA) Model of Health Change to provide behaviour change support. The telephone coaching intervention aims to maximise adherence to the physiotherapy program, as well as facilitate increased levels of participation in general physical activity. The primary outcomes are pain measured by an 11-point numeric rating scale and self-reported physical function measured by the Western Ontario and McMaster Universities Osteoarthritis Index subscale after 6 months. Secondary outcomes include physical activity levels, quality-of-life, and potential moderators and mediators of outcomes including self-efficacy, pain coping and depression. Relative cost-effectiveness will be determined from health service usage and outcome data. Follow-up assessments will also occur at 12 and 18 months.
The findings will help determine whether the addition of telephone coaching sessions can improve sustainability of outcomes from a physiotherapist-delivered physical activity intervention in people with knee OA.
Trial Registration
Australian New Zealand Clinical Trials Registry reference: ACTRN12612000308897
PMCID: PMC3552972  PMID: 23231928
7.  Efficacy of acupuncture for chronic knee pain: protocol for a randomised controlled trial using a Zelen design 
Chronic knee pain is a common and disabling condition in people over 50 years of age, with knee joint osteoarthritis being a major cause. Acupuncture is a popular form of complementary and alternative medicine for treating pain and dysfunction associated with musculoskeletal conditions. This pragmatic Zelen-design randomised controlled trial is investigating the efficacy and cost-effectiveness of needle and laser acupuncture, administered by medical practitioners, in people with chronic knee pain.
Two hundred and eighty two people aged over 50 years with chronic knee pain have been recruited from metropolitan Melbourne and regional Victoria, Australia. Participants originally consented to participate in a longitudinal natural history study but were then covertly randomised into one of four treatment groups. One group continued as originally consented (ie natural history group) and received no acupuncture treatment. The other three were treatment groups: i) laser acupuncture, ii) sham laser or, iii) needle acupuncture. Acupuncture treatments used a combined Western and Traditional Chinese Medicine style, were delivered by general practitioners and comprised 8–12 visits over 12 weeks. Follow-up is currently ongoing. The primary outcomes are pain measured by an 11-point numeric rating scale (NRS) and self-reported physical function measured by the Western Ontario and McMaster (WOMAC) Universities Osteoarthritis Index subscale at the completion of treatment at 12 weeks. Secondary outcomes include quality of life, global rating of change scores and additional measures of pain (other NRS and WOMAC subscale) and physical function (NRS). Additional parameters include a range of psychosocial measures in order to evaluate potential relationships with acupuncture treatment outcomes. Relative cost-effectiveness will be determined from health service usage and outcome data. Follow-up assessments will also occur at 12 months.
The findings from this study will help determine whether laser and/or needle acupuncture is efficacious, and cost-effective, in the management of chronic knee pain in older people.
Trial registration
Australian New Zealand Clinical Trials Registry reference: ACTRN12609001001280
PMCID: PMC3493360  PMID: 22992309
8.  Randomised controlled trial of an automated, interactive telephone intervention (TLC Diabetes) to improve type 2 diabetes management: baseline findings and six-month outcomes 
BMC Public Health  2012;12:602.
Effective self-management of diabetes is essential for the reduction of diabetes-related complications, as global rates of diabetes escalate.
Randomised controlled trial. Adults with type 2 diabetes (n = 120), with HbA1c greater than or equal to 7.5 %, were randomly allocated (4 × 4 block randomised block design) to receive an automated, interactive telephone-delivered management intervention or usual routine care. Baseline sociodemographic, behavioural and medical history data were collected by self-administered questionnaires and biological data were obtained during hospital appointments. Health-related quality of life (HRQL) was measured using the SF-36.
The mean age of participants was 57.4 (SD 8.3), 63% of whom were male. There were no differences in demographic, socioeconomic and behavioural variables between the study arms at baseline. Over the six-month period from baseline, participants receiving the Australian TLC (Telephone-Linked Care) Diabetes program showed a 0.8% decrease in geometric mean HbA1c from 8.7% to 7.9%, compared with a 0.2% HbA1c reduction (8.9% to 8.7%) in the usual care arm (p = 0.002). There was also a significant improvement in mental HRQL, with a mean increase of 1.9 in the intervention arm, while the usual care arm decreased by 0.8 (p = 0.007). No significant improvements in physical HRQL were observed.
These analyses indicate the efficacy of the Australian TLC Diabetes program with clinically significant post-intervention improvements in both glycaemic control and mental HRQL. These observed improvements, if supported and maintained by an ongoing program such as this, could significantly reduce diabetes-related complications in the longer term. Given the accessibility and feasibility of this kind of program, it has strong potential for providing effective, ongoing support to many individuals with diabetes in the future.
PMCID: PMC3480918  PMID: 22857017
9.  A physiotherapist-delivered integrated exercise and pain coping skills training intervention for individuals with knee osteoarthritis: a randomised controlled trial protocol 
Knee osteoarthritis (OA) is a prevalent chronic musculoskeletal condition with no cure. Pain is the primary symptom and results from a complex interaction between structural changes, physical impairments and psychological factors. Much evidence supports the use of strengthening exercises to improve pain and physical function in this patient population. There is also a growing body of research examining the effects of psychologist-delivered pain coping skills training (PCST) particularly in other chronic pain conditions. Though typically provided separately, there are symptom, resource and personnel advantages of exercise and PCST being delivered together by a single healthcare professional. Physiotherapists are a logical choice to be trained to deliver a PCST intervention as they already have expertise in administering exercise for knee OA and are cognisant of the need for a biopsychosocial approach to management. No studies to date have examined the effects of an integrated exercise and PCST program delivered solely by physiotherapists in this population. The primary aim of this multisite randomised controlled trial is to investigate whether an integrated 12-week PCST and exercise treatment program delivered by physiotherapists is more efficacious than either program alone in treating pain and physical function in individuals with knee OA.
This will be an assessor-blinded, 3-arm randomised controlled trial of a 12-week intervention involving 10 physiotherapy visits together with home practice. Participants with symptomatic and radiographic knee OA will be recruited from the community in two cities in Australia and randomized into one of three groups: exercise alone, PCST alone, or integrated PCST and exercise. Randomisation will be stratified by city (Melbourne or Brisbane) and gender. Primary outcomes are overall average pain in the past week measured by a Visual Analogue Scale and physical function measured by the Western Ontario and McMaster Universities Osteoarthritis Index subscale. Secondary outcomes include global rating of change, muscle strength, functional performance, physical activity levels, health related quality of life and psychological factors. Measurements will be taken at baseline and immediately following the intervention (12 weeks) as well as at 32 weeks and 52 weeks to examine maintenance of any intervention effects. Specific assessment of adherence to the treatment program will also be made at weeks 22 and 42. Relative cost-effectiveness will be determined from health service usage and outcome data.
The findings from this randomised controlled trial will provide evidence for the efficacy of an integrated PCST and exercise program delivered by physiotherapists in the management of painful and functionally limiting knee OA compared to either program alone.
Trial registration
Australian New Zealand Clinical Trials Registry reference number: ACTRN12610000533099
PMCID: PMC3524463  PMID: 22828288
10.  Community based study to compare the incidence and health services utilization pyramid for gastrointestinal, respiratory and dermal symptoms 
Gastrointestinal (GI), respiratory and dermal symptoms are common and cause substantial morbidity, although the information on their exact incidence and comparative burden is limited. The aim of this study was to describe the epidemiology and rate these three major symptom complexes in order to improve our understanding of the health burden imposed by these symptoms.
We used data from a community based randomised control trial conducted from June 2007 to August 2008 among 277 South Australian families consuming rainwater. Using weekly health diaries, we prospectively collected information on GI (diarrhoea or vomiting), respiratory (sore throat, runny nose or cough) and dermal (rash, generalised itch or dermal infection) symptoms, as well as on relevant GP visits, time off work and/or hospitalisation due to these symptoms. Data were analysed using generalized estimating equations approach taking into account the variable number of weeks of follow-up of each individual and within-family clustering of responses.
Over one year, at least one episode of GI symptoms was reported by 54% of participants (95% CI 50%-58%), at least one respiratory episode by 91% (95% CI 88%-93%) and at least one episode of dermal symptoms by 27% (95% CI 24%-30%). The average number of weeks per year during which respiratory symptoms occurred was four times greater than for GI or dermal symptoms (4.9, 1.2 and 1.2 weeks, respectively, p<0.001), with an average number of GP visits per person per year being twice as frequent (0.48, 0.26, 0.19 respectively, p<0.001). However, on a per episode basis, a higher proportion of people saw a GP or were hospitalised for GI symptoms.
This first comparative study of three different symptom complexes showed that although respiratory symptoms are most common, GI symptoms cause a greater per episode burden on healthcare resources. Measuring and comparing the community based burden of these symptom complexes will assist evidence-based allocation of resources.
PMCID: PMC3411466  PMID: 22824457
Respiratory symptoms; Gastrointestinal symptoms; Dermal symptoms; Burden of illness; Healthcare utilization
11.  Synthesis and characterization of potential iron–platinum drugs and supplements by laser liquid photolysis 
Highly crystalline nanospherical iron–platinum systems were produced by 248 nm laser irradiation of a liquid precursor at different laser fluences, ranging from 100–375 mJ/cm2. The influence of laser intensity on particle size, iron composition, and structure was systematically investigated. Different nanostructures of iron–platinum alloy and chemically disordered iron–platinum L10 phase were obtained without annealing. The prepared precursor solution underwent deep photolysis to polycrystalline iron–platinum nanoalloys through Fe(III) acetylacetonate and Pt(II) acetylacetonate. Fe(II) and Pt(I) acetylacetone decomposed into Fe0 and Pt0 nanoparticles. We found that the (001) diffraction peak shifted linearly to a lower angle, with the last peak shifting in opposition to the others. This caused the face-centered cubic L10 structure to change its composition according to laser fluence. The nanostructures were shown to contain iron and platinum only by energy-dispersive spectroscopy at several spots. The response of these iron–platinum nanoparticles to infrared depends on their stoichiometric composition, which is controlled by laser fluence.
PMCID: PMC3781719  PMID: 24198494
nanostructures; iron; platinum; nanoparticles; laser liquid photolysis; composition
12.  Hospital-level associations with 30-day patient mortality after cardiac surgery: a tutorial on the application and interpretation of marginal and multilevel logistic regression 
Marginal and multilevel logistic regression methods can estimate associations between hospital-level factors and patient-level 30-day mortality outcomes after cardiac surgery. However, it is not widely understood how the interpretation of hospital-level effects differs between these methods.
The Australasian Society of Cardiac and Thoracic Surgeons (ASCTS) registry provided data on 32,354 patients undergoing cardiac surgery in 18 hospitals from 2001 to 2009. The logistic regression methods related 30-day mortality after surgery to hospital characteristics with concurrent adjustment for patient characteristics.
Hospital-level mortality rates varied from 1.0% to 4.1% of patients. Ordinary, marginal and multilevel regression methods differed with regard to point estimates and conclusions on statistical significance for hospital-level risk factors; ordinary logistic regression giving inappropriately narrow confidence intervals. The median odds ratio, MOR, from the multilevel model was 1.2 whereas ORs for most patient-level characteristics were of greater magnitude suggesting that unexplained between-hospital variation was not as relevant as patient-level characteristics for understanding mortality rates. For hospital-level characteristics in the multilevel model, 80% interval ORs, IOR-80%, supplemented the usual ORs from the logistic regression. The IOR-80% was (0.8 to 1.8) for academic affiliation and (0.6 to 1.3) for the median annual number of cardiac surgery procedures. The width of these intervals reflected the unexplained variation between hospitals in mortality rates; the inclusion of one in each interval suggested an inability to add meaningfully to explaining variation in mortality rates.
Marginal and multilevel models take different approaches to account for correlation between patients within hospitals and they lead to different interpretations for hospital-level odds ratios.
PMCID: PMC3366874  PMID: 22409732
13.  Efficacy of standardised manual therapy and home exercise programme for chronic rotator cuff disease: randomised placebo controlled trial 
Objective To investigate the efficacy of a programme of manual therapy and exercise treatment compared with placebo treatment delivered by physiotherapists for people with chronic rotator cuff disease.
Design Randomised, participant and single assessor blinded, placebo controlled trial.
Setting Metropolitan region of Melbourne, Victoria, Australia.
Participants 120 participants with chronic (>3 months) rotator cuff disease recruited through medical practitioners and from the community.
Interventions The active treatment comprised a manual therapy and home exercise programme; the placebo treatment comprised inactive ultrasound therapy and application of an inert gel. Participants in both groups received 10 sessions of individual standardised treatment over 10 weeks. For the following 12 weeks, the active group continued the home exercise programme and the placebo group received no treatment.
Main outcome measures The primary outcomes were pain and function measured by the shoulder pain and disability index, average pain on movement measured on an 11 point numerical rating scale, and participants’ perceived global rating of overall change.
Results 112 (93%) participants completed the 22 week trial. At 11 weeks no difference was found between groups for change in shoulder pain and disability index (3.6, 95% confidence interval −2.1 to 9.4) or change in pain (0.7, −0.1 to 1.5); both groups showed significant improvements. More participants in the active group reported a successful outcome (defined as “much better”), although the difference was not statistically significant: 42% (24/57) of active participants and 30% (18/61) of placebo participants (relative risk 1.43, 0.87 to 2.34). The active group showed a significantly greater improvement in shoulder pain and disability index than did the placebo group at 22 weeks (between group difference 7.1, 0.3 to 13.9), although no significant difference existed between groups for change in pain (0.9, −0.03 to 1.7) or for the percentage of participants reporting a successful treatment outcome (relative risk 1.39, 0.94 to 2.03). Several secondary outcomes favoured the active group, including shoulder pain and disability index function score, muscle strength, interference with activity, and quality of life.
Conclusion A standardised programme of manual therapy and home exercise did not confer additional immediate benefits for pain and function compared with a realistic placebo treatment that controlled for therapists’ contact in middle aged to older adults with chronic rotator cuff disease. However, greater improvements were apparent at follow-up, particularly in shoulder function and strength, suggesting that benefits with active treatment take longer to manifest.
Trial registration Clinical trials NCT00415441.
PMCID: PMC2882554  PMID: 20530557
14.  Semi-parametric risk prediction models for recurrent cardiovascular events in the LIPID study 
Traditional methods for analyzing clinical and epidemiological cohort study data have been focused on the first occurrence of a health outcome. However, in many situations, recurrent event data are frequently observed. It is inefficient to use methods for the analysis of first events to analyse recurrent event data.
We applied several semi-parametric proportional hazards models to analyze the risk of recurrent myocardial infarction (MI) events based on data from a very large randomized placebo-controlled trial of cholesterol-lowering drug. The backward selection procedure was used to select the significant risk factors in a model. The best fitting model was selected using the log-likelihood ratio test, Akaike Information and Bayesian Information Criteria.
A total of 8557 persons were included in the LIPID study. Risk factors such as age, smoking status, total cholesterol and high density lipoprotein cholesterol levels, qualifying event for the acute coronary syndrome, revascularization, history of stroke or diabetes, angina grade and treatment with pravastatin were significant for development of both first and subsequent MI events. No significant difference was found for the effects of these risk factors between the first and subsequent MI events. The significant risk factors selected in this study were the same as those selected by the parametric conditional frailty model. Estimates of the relative risks and 95% confidence intervals were also similar between these two methods.
Our study shows the usefulness and convenience of the semi-parametric proportional hazards models for the analysis of recurrent event data, especially in estimation of regression coefficients and cumulative risks.
PMCID: PMC2856584  PMID: 20356409
15.  Development of bone marrow lesions is associated with adverse effects on knee cartilage while resolution is associated with improvement - a potential target for prevention of knee osteoarthritis: a longitudinal study 
To examine the relationship between development or resolution of bone marrow lesions (BMLs) and knee cartilage properties in a 2 year prospective study of asymptomatic middle-aged adults.
271 adults recruited from the Melbourne Collaborative Cohort Study, underwent a magnetic resonance imaging scan (MRI) of their dominant knee at baseline and again approximately 2 years later. Cartilage volume, cartilage defects and BMLs were determined at both time points.
Among 234 subjects free of BMLs at baseline, 33 developed BMLs over 2 years. The incidence of BMLs was associated with progression of tibiofemoral cartilage defects (OR 2.63 (95% CI 0.93, 7.44), P = 0.07 for medial compartment; OR 3.13 (95% CI 1.01, 9.68), P = 0.048 for lateral compartment). Among 37 subjects with BMLs at baseline, 17 resolved. Resolution of BMLs was associated with reduced annual loss of medial tibial cartilage volume (regression coefficient -35.9 (95%CI -65, -6.82), P = 0.02) and a trend for reduced progression of medial tibiofemoral cartilage defects (OR 0.2 (95% CI 0.04, 1.09), P = 0.06).
In this cohort study of asymptomatic middle-aged adults the development of new BMLs was associated with progressive knee cartilage pathology while resolution of BMLs prevalent at baseline was associated with reduced progression of cartilage pathology. Further work examining the relationship between changes and BML and cartilage may provide another important target for the prevention of knee osteoarthritis.
PMCID: PMC2875638  PMID: 20085624
16.  Dietary fatty acid intake affects the risk of developing bone marrow lesions in healthy middle-aged adults without clinical knee osteoarthritis: a prospective cohort study 
Fatty acids have been implicated in osteoarthritis (OA), yet the mechanism by which fatty acids affect knee structure and consequently the risk of knee OA has not been fully elucidated. Higher intakes of fatty acids have been shown to be associated with the risk of bone marrow lesions (BMLs) in a healthy population. The aim of this study was to examine the association between fatty acid consumption and the incidence of BMLs in healthy middle-aged adults without clinical knee OA.
Two hundred ninety-seven middle-aged adults without clinical knee OA underwent magnetic resonance imaging (MRI) of their dominant knee at baseline. BMLs were assessed. Of the 251 participants with no BMLs in their knee at baseline, 230 underwent MRI of the same knee approximately 2 years later. Intakes of fatty acids were estimated from a food frequency questionnaire.
Increased consumption of saturated fatty acids was associated with an increased incidence of BMLs over 2 years after adjusting for energy intake, age, gender, and body mass index (odds ratio of 2.56 for each standard deviation increase in dietary intake, 95% confidence interval 1.03 to 6.37, P = 0.04). Intake of monounsaturated or polyunsaturated fatty acids was not significantly associated with the incidence of BMLs.
Increased fatty acid consumption may increase the risk of developing BMLs. As subchondral bone is important in maintaining joint integrity and the development of OA, this study suggests that dietary modification of fatty acid intake may be one strategy in the prevention of knee OA which warrants further investigation.
PMCID: PMC2714108  PMID: 19426478
17.  Neuropeptidomics of the Supraoptic Rat Nucleus 
Journal of Proteome Research  2008;7(11):4992-5003.
The mammalian supraoptic nucleus (SON) is a neuroendocrine center in the brain regulating a variety of physiological functions. Within the SON, peptidergic magnocellular neurons that project to the neurohypophysis (posterior pituitary) are involved in controlling osmotic balance, lactation, and parturition, partly through secretion of signaling peptides such as oxytocin and vasopressin into the blood. An improved understanding of SON activity and function requires identification and characterization of the peptides used by the SON. Here, small-volume sample preparation approaches are optimized for neuropeptidomic studies of isolated SON samples ranging from entire nuclei down to single magnocellular neurons. Unlike most previous mammalian peptidome studies, tissues are not immediately heated or microwaved. SON samples are obtained from ex vivo brain slice preparations via tissue punch and the samples processed through sequential steps of peptide extraction. Analyses of the samples via liquid chromatography mass spectrometry and tandem mass spectrometry result in the identification of 85 peptides, including 20 unique peptides from known prohormones. As the sample size is further reduced, the depth of peptide coverage decreases; however, even from individually isolated magnocellular neuroendocrine cells, vasopressin and several other peptides are detected.
Mammalian peptidome studies are extended to smaller, well-defined brain structures ranging from an individual brain nucleus to individual neurons. Specifically, we characterize the peptidome of the supraoptic nucleus and individual magnocellular neurons within the nucleus. With the use of a coronal brain slice preparation and optimized sample preparation strategies to reduce postmortem degradation, 85 peptides have been characterized, including 20 peptides previously not reported.
PMCID: PMC2646869  PMID: 18816085
supraoptic nuclei; peptidome; neuropeptides; peptide processing; prohormone; single cell; magnocellular neuron; sample preparation; MALDI-MS; ESI-MS/MS
18.  Negative beliefs about low back pain are associated with high pain intensity and high level disability in community-based women 
Although previous studies have investigated beliefs about back pain in clinical and employed populations, there is a paucity of data examining the beliefs of the broader community. We aimed to characterize the beliefs that community-dwelling women have about back pain and its consequences, and to determine whether those with varying levels of pain intensity and disability differ in their beliefs.
542 community-dwelling women, aged 24 to 80 years, were recruited from a research database. Participants completed a self-administered questionnaire that included detailed demographic information, the Chronic Pain Grade Questionnaire (CPG) and the Back Beliefs Questionnaire (BBQ). The CPG examined individuals' levels of pain intensity and disability, and the BBQ investigated their beliefs about back pain and its consequences.
506 (93.4%) women returned the study questionnaire. The mean (SD) BBQ score for the cohort was 30.7 (6.0), indicating generally positive beliefs about back pain. However, those women with high intensity pain and high level disability had a mean (SD) score of 28.5 (5.7) and 24.8 (5.7) respectively, which reflects greater negativity about back pain and its consequences. There was an association between negative beliefs and high pain intensity (OR = 0.94 (95% CI: 0.90, 0.99), p = 0.01) and high level disability (OR = 0.93 (95% CI: 0.89, 0.97), p = 0.001), after adjusting for confounders.
This study highlights that although women living in the community were generally positive about back pain, subgroups of women with high pain intensity and high level disability were identified who had more pessimistic views. While a causal relationship cannot be inferred from these cross-sectional data, the results suggest that negative beliefs individuals have about back pain may be predictive of chronic, disabling spinal pain.
PMCID: PMC2587466  PMID: 18983681
19.  Efficacy and safety of a subacromial continuous ropivacaine infusion for post-operative pain management following arthroscopic rotator cuff surgery: A protocol for a randomised double-blind placebo-controlled trial 
Major shoulder surgery often results in severe post-operative pain and a variety of interventions have been developed in an attempt to address this. The continuous slow infusion of a local anaesthetic directly into the operative site has recently gained popularity but it is expensive and as yet there is little conclusive evidence that it provides additional benefits over other methods of post-operative pain management.
This will be a randomised, placebo-controlled trial involving 158 participants. Following diagnostic arthroscopy, all participants will undergo arthroscopic subacromial decompression with or without rotator cuff repair, all operations performed by a single surgeon. Participants, the surgeon, nurses caring for the patients and outcome assessors will be blinded to treatment allocation. All participants will receive a pre-incision bolus injection of 20 mls of ropivacaine 1% into the shoulder and an intra-operative intravenous bolus of parecoxib 40 mg. Using concealed allocation participants will be randomly assigned to active treatment (local anaesthetic ropivacaine 0.75%) or placebo (normal saline) administered continuously into the subacromial space by an elastomeric pump at 5 mls per hour post-operatively. Patient controlled opioid analgesia and oral analgesics will be available for breakthrough pain. Outcome assessment will be at 15, 30 and 60 minutes, 2, 4, 8, 12, 18 and 24 hours, and 2 or 4 months for decompression or decompression plus repair respectively.
The primary end point will be average pain at rest over the first 12-hour post-operative period on a verbal analogue pain score. Secondary end points will be average pain at rest over the second 12-hour post-operative period, maximal pain at rest over the first and second 12-hour periods, amount of rescue medication used, length of inpatient stay and incidence of post-operative adhesive capsulitis.
The results of this trial will contribute to evidence-based recommendations for the effectiveness of pain management modalities following arthroscopic rotator cuff surgery. If the local anaesthetic pain-buster provides no additional benefits over placebo then valuable resources can be put to better use in other ways.
Trial registration
Australian Clinical Trials Register Number ACTR12606000195550
PMCID: PMC2386465  PMID: 18430210
20.  Precise and Parallel Characterization of Coding Polymorphisms, Alternative Splicing and Modifications in Human Proteins by Mass Spectrometry 
The human proteome is a highly complex extension of the genome wherein a single gene often produces distinct protein forms due to alternative splicing, RNA-editing, polymorphisms, and posttranslational modifications (PTMs). Such biological variation compounded by the high sequence identity within gene families currently overwhelms the complete and routine characterization of mammalian proteins by mass spectrometry (MS). A new database of human proteins (and their possible variants) was created and searched using tandem mass spectrometric data from intact proteins. This first application of Top Down MS/MS to wild-type human proteins demonstrates both gene-specific identification and the unambiguous characterization of multi-faceted mass shifts (Δm’s). Such Δm values found from the precise identification of 45 protein forms from HeLa cells reveal 34 coding SNPs, two protein forms from alternative splicing, and 12 diverse modifications (not including simple N-terminal processing), including a previously unknown phosphorylation at 10% occupancy. Automated protein identification was achieved with a median probability score of 10−13 and often occurred simultaneously with dissection of diverse sources of protein variability as they occur in combination. Top Down MS therefore has a bright future for enabling precise annotation of gene products expressed from the human genome by non-mass specrometrists.
PMCID: PMC1307493  PMID: 15863400
Proteomics; Top Down MS; modifications; single nucleotide polymorphisms; alternative splicing; PTM — posttranslational modification; MS — mass spectrometry; MS/MS — tandem mass spectrometry; Δm — mass discrepancy; MALDI — matrix-assisted laser desorption ionization; ESI — electrospray ionization; cSNP — nonsynonymous coding single nucleotide polymorphism; FTMS — Fourier transform mass spectrometry; ECD — electron capture dissociation; CAD — collisionally-activated dissociation; IRMPD — infrared multiphoton dissociation; BAF — barrier-to-autointegration factor; SWIFT — stored waveform inverse Fourier transform; THRASH — thorough high-resolution analysis of spectra by Horn
21.  Efficacy and cost-effectiveness of a physiotherapy program for chronic rotator cuff pathology: A protocol for a randomised, double-blind, placebo-controlled trial 
Chronic rotator cuff pathology (CRCP) is a common shoulder condition causing pain and disability. Physiotherapy is often the first line of management for CRCP yet there is little conclusive evidence to support or refute its effectiveness and no formal evaluation of its cost-effectiveness.
This randomised, double-blind, placebo-controlled trial will involve 200 participants with CRCP recruited from medical practices, outpatient departments and the community via print and radio media. Participants will be randomly allocated to a physiotherapy or placebo group using concealed allocation stratified by treating physiotherapist. Both groups will receive 10 sessions of individual standardised treatment over 10 weeks from one of 10 project physiotherapists. For the following 12 weeks, the physiotherapy group will continue a home exercise program and the placebo group will receive no treatment. The physiotherapy program will comprise shoulder joint and spinal mobilisation, soft tissue massage, postural taping, and home exercises for scapular control, posture and rotator cuff strengthening. The placebo group will receive inactive ultrasound and gentle application of an inert gel over the shoulder region. Blinded assessment will be conducted at baseline and at 10 weeks and 22 weeks after randomisation. The primary outcome measures are self reported questionnaires including the shoulder pain and disability index (SPADI), average pain on an 11-point numeric rating scale and participant perceived global rating of change. Secondary measures include Medical Outcomes Study 36-item short form (SF-36), Assessment of Quality of Life index, numeric rating scales for shoulder pain and stiffness, participant perceived rating of change for pain, strength and stiffness, and manual muscle testing for shoulder strength using a handheld dynamometer. To evaluate cost-effectiveness, participants will record the use of all health-related treatments in a log-book returned to the assessor monthly. To test the effect of the intervention using an intention-to-treat analysis, linear regression modelling will be applied adjusting for baseline outcome values and other demographic characteristics. Participant measures of perceived change will be compared between groups by calculating the relative risks and their 95% confidence intervals at each time point using log binomial regression.
Results from this trial will contribute to the evidence regarding the effectiveness of a physiotherapy program for the management of CRCP.
Trial registration
NIH Clinical Trials Registry # NCT00415441
PMCID: PMC2048959  PMID: 17761004
22.  Effect of antioxidants on knee cartilage and bone in healthy, middle-aged subjects: a cross-sectional study 
The aim of the present study is to examine the effect of dietary antioxidants on knee structure in a cohort of healthy, middle-aged subjects with no clinical knee osteoarthritis.
Two hundred and ninety-three healthy adults (mean age = 58.0 years, standard deviation = 5.5) without knee pain or knee injury were selected from an existing community-based cohort. The intake of antioxidant vitamins and food sources by these individuals was estimated from a food frequency questionnaire at baseline. The cartilage volume, bone area, cartilage defects and bone marrow lesions were assessed approximately 10 years later using magnetic resonance imaging.
In multivariate analyses, higher vitamin C intake was associated with a reduced risk of bone marrow lesions (odds ratio = 0.50, 95% confidence interval (CI) = 0.29–0.87, P = 0.01) and with a reduction in the tibial plateau bone area (β = -35.5, 95% CI = -68.8 to -2.3, P = 0.04). There was an inverse association between fruit intake and the tibial plateau bone area (β = -27.8, 95% CI = -54.9 to -0.7, P = 0.04) and between fruit intake and the risk of bone marrow lesions (odds ratio = 0.72, 95% CI = 0.52–0.99, P = 0.05). Neither fruit intake nor vitamin C intake was significantly associated with the cartilage volume or cartilage defects. Lutein and zeaxanthin intake was associated with a decreased risk of cartilage defects (odds ratio = 0.71, 95% CI = 0.51–0.99, P = 0.04), and vitamin E intake tended to be positively associated with the tibial plateau bone area (β = 33.7, 95% CI = -3.1 to 70.4, P = 0.07) only after adjusting for vitamin C intake. The β-cryptoxanthin intake was inversely associated with the tibial plateau bone area after adjusting for vitamin E intake (β = -33.2, 95% CI = -63.1 to -3.4, P = 0.03). Intake of vegetables and other carotenoids was not significantly associated with cartilage or bone measures.
The present study suggests a beneficial effect of fruit consumption and vitamin C intake as they are associated with a reduction in bone size and the number of bone marrow lesions, both of which are important in the pathogenesis of knee osteoarthritis. While our findings need to be confirmed by longitudinal studies, they highlight the potential of the diet to modify the risk of osteoarthritis.
PMCID: PMC2206367  PMID: 17617909
23.  Reproductive health of male Australian veterans of the 1991 Gulf War 
BMC Public Health  2007;7:79.
Since the 1991 Gulf War concerns have been raised about the effects of deployment to the Gulf War on veterans' health. Studies of the reproductive health of Gulf War veterans have reported varied findings.
We undertook a cross-sectional study of male Australian Gulf War veterans (n = 1,424) and a randomly sampled military comparison group (n = 1,548). The study was conducted from August 2000 to April 2002. A postal questionnaire included questions about difficulties achieving pregnancy, pregnancy outcomes including live births, stillbirths, miscarriages and terminations; and for all live births gestation, birth weight, sex, and any cancers, birth defects, chromosomal abnormalities or serious health problems.
Male Gulf War veterans reported slightly increased risk of fertility difficulties following the Gulf War (odds ratio [OR] 1.4; 95% confidence interval [CI] 1.0–1.8), but were more successful at subsequently fathering a child (OR 1.8; 95% CI 1.3–2.6). The study groups reported similar rates of pregnancies and live births. There was no increased risk in veterans of miscarriage, stillbirth, or terminations. Children of male Gulf War veterans born after the period of the Gulf War were not at greater risk of being born prematurely, having a low birth weight, or having a birth defect or chromosomal abnormality (OR 1.0; 95% CI 0.6–1.6). The numbers of cancers and deaths in children were too small to draw any firm conclusions.
The results of this study do not show an increased risk of adverse reproductive outcome in Australian male Gulf War veterans.
PMCID: PMC1885426  PMID: 17504542
24.  Knee cartilage loss in symptomatic knee osteoarthritis over 4.5 years 
The objective of this study was to describe the rate of change in knee cartilage volume over 4.5 years in subjects with symptomatic knee osteoarthritis (OA) and to determine factors associated with cartilage loss. One hundred and five subjects were eligible for this longitudinal study. Subjects' tibial cartilage volume was assessed by magnetic resonance imaging (MRI) at baseline, at 2 years and at 4.5 years. Of 105 subjects, 78 (74%) completed the study. The annual percentage losses of medial and lateral tibial cartilage over 4.5 years were 3.7 ± 4.7% (mean ± SD; 95% confidence interval 2.7 to 4.8%) and 4.4 ± 4.7% (mean ± SD; 95% confidence interval 3.4 to 5.5%), respectively. Cartilage volume in each individual seemed to track over the study period, relative to other study participants. After multivariate adjustment, annual medial tibial cartilage loss was predicted by lesser severity of baseline knee pain but was independent of age, body mass index and structural factors. No factors specified a priori were associated with lateral cartilage volume rates of change. Tibial cartilage declines at an average rate of 4% per year in subjects with symptomatic knee OA. There was evidence to support the concept that tracking occurs in OA. This may enable the prediction of cartilage change in an individual. The only significant factor affecting the loss of medial tibial cartilage was baseline knee pain, possibly through altered joint loading.
PMCID: PMC1779368  PMID: 16704746
25.  Risk of primary intracerebral haemorrhage associated with aspirin and non-steroidal anti-inflammatory drugs: case-control study 
BMJ : British Medical Journal  1999;318(7186):759-764.
To examine the association between use of aspirin or other non-steroidal anti-inflammatory drugs and intracerebral haemorrhage.
Case-control study.
13 major city hospitals in the Melbourne and metropolitan area.
331 consecutive cases of stroke verified by computed tomography or postmortem examination, and 331 age (± 5 years) and sex matched controls who were community based neighbours.
Questionnaire administered to all subjects either directly or by proxy with the next of kin. Drug use was validated by reviewing prescribing records held by the participants’ doctors.
Main outcome measures
Previous use of aspirin or other non-steroidal anti-inflammatory drugs.
Univariate analysis showed no increased risk of intracerebral haemorrhage with low dose aspirin use in the preceding 2 weeks. Using multiple logistic regression to control for possible confounding factors, the odds ratio associated with the use of aspirin was 1.00 (95% confidence interval 0.60 to 1.66, P=0.998) and the odds ratio associated with the use of other non-steroidal anti-inflammatory drugs was 0.85 (0.45 to 1.61, P=0.611) compared with respective non-users in the preceding fortnight. Moderate to high doses of aspirin (>1225 mg/week spread over at least three doses) yielded an odds ratio of 3.05 (1.02 to 9.14, P=0.047). There was no evidence of an increased risk among subgroups defined by age, sex, blood pressure status, alcohol intake, smoking, and the presence or absence of previous cardiovascular disease.
No increase in risk of intracerebral haemorrhage was found among aspirin users overall or among those who took low doses of the drug or other non-steroidal anti-inflammatory drugs. These data provide evidence that doses of aspirin usually used for prophylaxis against vascular disease produce no substantial increase in risk of intracerebral haemorrhage.
Key messagesLow to moderate dose aspirin treatment does not substantially increase the risk of intracerebral haemorrhageNo increase in risk of intracerebral haemorrhage was observed among users of non-steroidal anti-inflammatory drugsUsers of high doses of aspirin may have an increased risk of intracerebral haemorrhage, but numbers of cases in the group were small and the finding is therefore tentative
PMCID: PMC27788  PMID: 10082697

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