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1.  Relationship between Lifestyle and Health Factors and Severe Lower Urinary Tract Symptoms (LUTS) in 106,435 Middle-Aged and Older Australian Men: Population-Based Study 
PLoS ONE  2014;9(10):e109278.
Despite growing interest in prevention of lower urinary tract symptoms (LUTS) through better understanding of modifiable risk factors, large-scale population-based evidence is limited.
To describe risk factors associated with severe LUTS in the 45 and Up Study, a large cohort study.
Design, Setting, and Participants
A cross-sectional analysis of questionnaire data from 106,435 men aged ≥45 years, living in New South Wales, Australia.
Outcome Measures and Statistical Analysis
LUTS were measured by a modified version of the International Prostate Symptom Score (m-IPSS). The strength of association between severe LUTS and socio-demographic, lifestyle and health-related factors was estimated, using logistic regression to calculate odds ratios, adjusted for a range of confounding factors.
Overall, 18.3% reported moderate, and 3.6% severe, LUTS. Severe LUTS were more common among men reporting previous prostate cancer (7.6%), total prostatectomy (4.9%) or having part of the prostate removed (8.2%). After excluding men with prostate cancer or prostate surgery, the prevalence of moderate-severe LUTS in the cohort (n = 95,089) ranged from 10.6% to 35.4% for ages 45–49 to ≥80; the age-related increase was steeper for storage than voiding symptoms. The adjusted odds of severe LUTS decreased with increasing education (tertiary qualification versus no school certificate, odds ratio (OR = 0.78 (0.68–0.89))) and increasing physical activity (high versus low, OR = 0.83 (0.76–0.91)). Odds were elevated among current smokers versus never-smokers (OR = 1.64 (1.43–1.88)), obese versus healthy-weight men (OR = 1.27 (1.14–1.41)) and for comorbid conditions (e.g., heart disease versus no heart disease, OR = 1.36 (1.24–1.49)), and particularly for severe versus no physical functional limitation (OR = 5.17 (4.51–5.93)).
LUTS was associated with a number of factors, including modifiable risk factors, suggesting potential targets for prevention.
PMCID: PMC4198085  PMID: 25333345
2.  Age at diagnosis predicts deterioration in glycaemic control among children and adolescents with type 1 diabetes 
Poor glycemic control early in the course of type 1 diabetes mellitus (T1DM) increases the risk for microvascular complications. However, predictors of deteriorating control after diagnosis have not been described, making it difficult to identify high-risk patients and proactively provide aggressive interventions.
We examined whether diagnostic age, gender, and race were associated with deteriorating glycemic control during the first 5 years after diagnosis.
2218 pediatric patients with T1DM.
We conducted a longitudinal cohort study of pediatric patients with T1DM from the Midwest USA, 1993–2009, evaluating within-patient glycated hemoglobin (HbA1c) trajectories constructed from all available HbA1c values within 5 years of diagnosis.
52.6% of patients were male; 86.1% were non-Hispanic Caucasian. The mean diagnostic age was 9.0±4.1 years. The mean number of HbA1c values/year/participant was 2.4±0.9. HbA1c trajectories differed markedly across age groups, with older patients experiencing greater deterioration than their younger counterparts (p<0.001). HbA1c trajectories, stratified by age, varied markedly by race (p for race×diagnostic age <0.001). Non-Hispanic African-American patients experienced higher initial HbA1c (8.7% vs 7.6% (71.6 vs 59.6 mmol/mol); p<0.001), and greater deterioration in HbA1c than non-Hispanic Caucasian patients across diagnostic ages (rise of 2.04% vs 0.99% per year (22.3 vs 10.8 mmol/mol/year); p<0.0001).
Older diagnostic age and black race are major risk factors for deterioration in glycemic control early in the course of T1DM. These findings can inform efforts to explore the reasons behind these differences and develop preventive interventions for high-risk patients.
PMCID: PMC4212563  PMID: 25452876
Type 1; Adolescents / Children; Age of Diabetes Onset; Glycemic Control
3.  Average Daily Risk Range as a Measure for Clinical Research and Routine Care 
There is emerging evidence suggesting that glycemic variability may relate to risk for diabetes-related complications. This article provides a description of average daily risk range (ADRR), a diabetes-specific measure of risk for hyperglycemia and hypoglycemia, and provides a summary of research using ADRR and clinical applications of ADRR. Average daily risk range is a variability metric that is based on “risk” values obtained from glucose levels that are mathematically transformed to give equal weight to hyperglycemic and hypoglycemic excursions. It can be calculated using self-monitoring of blood glucose or continuous glucose monitoring (CGM) data. The ADRR is scored based on risk categories: low risk, 0–19; moderate risk, 20–40; and high risk, 40 and above. Research using ADRR has found it to be a reliable predictor of extreme blood glucose values regardless of diabetes type and patients’ age. Moreover, in treatment studies, ADRR presents as a very conservative measure of variability. Clinically, ADRR can provide meaningful data related to patients’ risk for hyperglycemia and hypoglycemia that is not available from glycated hemoglobin values. Average daily risk range scores may also help clinicians to identify patients who may be overtreating blood glucose levels, leading to very high or low values. To expand the utility of ADRR, future research should examine the validity of existing risk cutoff scores for pediatric patients, determine if ADRR cutoff scores need to be modified for CGM data, and investigate whether patients’ ADRR scores also relate to the development of long-term complications, including retinopathy and microalbuminuria.
PMCID: PMC3876383  PMID: 24124966
average daily risk range; continuous glucose monitoring; glycemic variability; measurement; self-monitoring of blood glucose
4.  Colon and rectal cancer incidence and water trihalomethane concentrations in New South Wales, Australia 
BMC Cancer  2014;14:445.
There is evidence, although inconsistent, that long term exposure to disinfection by products (DBPs) increases the risk of bowel cancer. No study has been conducted in Australia to examine this association and due to difference in the methods of disinfection the risk can vary across geographical regions and. This study was conducted to analyse the association of trihalomethanes (THMs) in water with colon and rectal cancer in NSW Australia.
Average yearly concentrations of total and individual species of THMs were obtained for 50 local government areas (LGAs). Indirectly-standardized incidence rates of colon and rectal cancers in LGAs for the period 1995 to 2001 were regressed against mean THM concentrations lagged five years, adjusting for socioeconomic status, high risk drinking, smoking status, usual source of water and year of diagnosis, including local and global random effects within a Bayesian framework. The incidence rate ratios (IRRs) for an interquartile range (IQR) increase in THMs were estimated.
Using five year lag of exposure there was a positive association between bromoform concentration and CRC in men (IRR = 1.025, 95% CI 1.010, 1.040) but not in women (IRR = 1.003, 95% CI 0.987, 1.018). The association in men was mainly found in colon cancer with bromoform (IRR = 1.035, 95% CI 1.017, 1.053). There was no appreciable association of colorectal cancer with other species of THMs. Sensitivity analyses did not materially change the associations observed.
A positive association was observed between colon cancer and water bromoform concentrations in men. Given the potential population impact of such an association, further research into the relationship between THMs, particularly brominated species, and colorectal cancer is warranted.
PMCID: PMC4088985  PMID: 24938491
Cancer; Colon; Rectal; Disinfection by-products; Chlorination; Ecological studies
5.  Spike Sorting by Joint Probabilistic Modeling of Neural Spike Trains and Waveforms 
This paper details a novel probabilistic method for automatic neural spike sorting which uses stochastic point process models of neural spike trains and parameterized action potential waveforms. A novel likelihood model for observed firing times as the aggregation of hidden neural spike trains is derived, as well as an iterative procedure for clustering the data and finding the parameters that maximize the likelihood. The method is executed and evaluated on both a fully labeled semiartificial dataset and a partially labeled real dataset of extracellular electric traces from rat hippocampus. In conditions of relatively high difficulty (i.e., with additive noise and with similar action potential waveform shapes for distinct neurons) the method achieves significant improvements in clustering performance over a baseline waveform-only Gaussian mixture model (GMM) clustering on the semiartificial set (1.98% reduction in error rate) and outperforms both the GMM and a state-of-the-art method on the real dataset (5.04% reduction in false positive + false negative errors). Finally, an empirical study of two free parameters for our method is performed on the semiartificial dataset.
PMCID: PMC4009224  PMID: 24829568
6.  Quantifying Phytogeographical Regions of Australia Using Geospatial Turnover in Species Composition 
PLoS ONE  2014;9(3):e92558.
The largest digitized dataset of land plant distributions in Australia assembled to date (750,741 georeferenced herbarium records; 6,043 species) was used to partition the Australian continent into phytogeographical regions. We used a set of six widely distributed vascular plant groups and three non-vascular plant groups which together occur in a variety of landscapes/habitats across Australia. Phytogeographical regions were identified using quantitative analyses of species turnover, the rate of change in species composition between sites, calculated as Simpson's beta. We propose six major phytogeographical regions for Australia: Northern, Northern Desert, Eremaean, Eastern Queensland, Euronotian and South-Western. Our new phytogeographical regions show a spatial agreement of 65% with respect to previously defined phytogeographical regions of Australia. We also confirm that these new regions are in general agreement with the biomes of Australia and other contemporary biogeographical classifications. To assess the meaningfulness of the proposed phytogeographical regions, we evaluated how they relate to broad scale environmental gradients. Physiographic factors such as geology do not have a strong correspondence with our proposed regions. Instead, we identified climate as the main environmental driver. The use of an unprecedentedly large dataset of multiple plant groups, coupled with an explicit quantitative analysis, makes this study novel and allows an improved historical bioregionalization scheme for Australian plants. Our analyses show that: (1) there is considerable overlap between our results and older biogeographic classifications; (2) phytogeographical regions based on species turnover can be a powerful tool to further partition the landscape into meaningful units; (3) further studies using phylogenetic turnover metrics are needed to test the taxonomic areas.
PMCID: PMC3962426  PMID: 24658356
7.  Frequency of Mealtime Insulin Bolus as a Proxy Measure of Adherence for Children and Youths with Type 1 Diabetes Mellitus 
Electronic measures of adherence can be superior to patient report. In type 1 diabetes, frequency of blood glucose monitoring (BGM), as measured by patients' home blood glucose meters, has already been identified as a valid proxy of adherence. We present methodology to calculate adherence using insulin pump records and evaluate the reliability and validity of this methodology.
Subjects and Methods
Blood glucose meter data, insulin pump records, and corresponding hemoglobin A1c (HbA1c) levels were randomly gathered from clinical and research databases for 100 children and youths (referred to hereafter as youths) with type 1 diabetes (mean±SD age, 12.7±4.6 years). Youths' mean frequency of daily BGM was calculated. Additionally, we calculated a mean mealtime insulin bolus score (BOLUS): youths received 1 point each for a bolus between 0600 and 1000 h, 1100 and 1500 h, and 1600 and 2200 h (maximum of 1 point/meal or 3 points/day).
Simple correlations between youths' HbA1c level, age, frequency of BGM, and insulin BOLUS scores were all significant. Partial correlations and multiple regression analyses revealed that insulin BOLUS scores better explain variations in HbA1c levels than the electronically recorded frequency of daily blood glucose measures.
Our procedures for calculating insulin BOLUS scores using insulin pump records demonstrate better concurrent validity with youths' HbA1c levels than that of the frequency of BGM with youths' HbA1c levels. Our analyses have shown that insulin bolus scoring was superior to the frequency of BGM in predicting youths' HbA1c levels.
PMCID: PMC3558673  PMID: 23317372
8.  Continuous Glucose Monitoring Versus Self-monitoring of Blood Glucose in Children with Type 1 Diabetes- Are there Pros and Cons for Both? 
US endocrinology  2012;8(1):27-29.
Glucose monitoring is essential for modern diabetes treatment and the achievement of near-normal glycemic control. Monitoring provides the data necessary for patients to make daily management decisions related to food intake, insulin dose, and physical exercise and can enable patients to avoid potentially dangerous episodes of hypo- and hyperglycemia. Additionally, monitoring can provide health care providers with the information needed to identify glycemic patterns, educate patients, and adjust insulin. Presently, youth with type 1 diabetes can self-monitor blood glucose via home blood glucose meters or monitor glucose concentrations nearly continuously using a continuous glucose monitor. There are advantages and disadvantages to the use of either of these technologies. This review describes the two technologies and the research supporting their use in the management of youth with type 1 diabetes in order to weigh their relative costs and benefits.
PMCID: PMC3848052  PMID: 24312136
diabetes; type 1; children; monitoring; glycemic control
9.  Cancer burden in China: a Bayesian approach 
BMC Cancer  2013;13:458.
Cancer is a serious health issue in China, but accurate national counts for cancer incidence are not currently available. Knowledge of the cancer burden is necessary for national cancer control planning. In this study, national death survey data and cancer registration data were used to calculate the cancer burden in China using a Bayesian approach.
Cancer mortality and incidence rates for 2004–2005 were obtained from the National Cancer Registration database. The third National Death Survey (NDS), 2004–2005 database provided nationally representative cancer mortality rates. Bayesian modeling methods were used to estimate mortality to incidence (MI) ratios from the registry data and national incidence from the NDS for specific cancer types by age, sex and urban or rural location.
The total estimated incident cancer cases in 2005 were 2,956,300 (1,762,000 males, 1,194,300 females). World age standardized incidence rates were 236.2 per 100,000 in males and 168.9 per 100,000 in females in urban areas and 203.7 per 100,000 and 121.8 per 100,000 in rural areas.
MI ratios are useful for estimating national cancer incidence in the absence of representative incidence or survival data. Bayesian methods provide a flexible framework for smoothing rates and representing statistical uncertainty in the MI ratios. Expansion of China’s cancer registration network to be more representative of the country would improve the accuracy of cancer burden estimates.
PMCID: PMC3850959  PMID: 24093796
Bayes Theorem; China; Incidence; Mortality; Neoplasm
10.  Expression and Regulation of Nampt in Human Islets 
PLoS ONE  2013;8(3):e58767.
Nicotinamide phosphoribosyltransferase (Nampt) is a rate-limiting enzyme in the mammalian NAD+ biosynthesis of a salvage pathway and exists in 2 known forms, intracellular Nampt (iNampt) and a secreted form, extracellular Nampt (eNampt). eNampt can generate an intermediate product, nicotinamide mononucleotide (NMN), which has been reported to support insulin secretion in pancreatic islets. Nampt has been reported to be expressed in the pancreas but islet specific expression has not been adequately defined. The aim of this study was to characterize Nampt expression, secretion and regulation by glucose in human islets. Gene and protein expression of Nampt was assessed in human pancreatic tissue and isolated islets by qRT-PCR and immunofluorescence/confocal imaging respectively. Variable amounts of Nampt mRNA were detected in pancreatic tissue and isolated islets. Immunofluorescence staining for Nampt was found in the exocrine and endocrine tissue of fetal pancreas. However, in adulthood, Nampt expression was localized predominantly in beta cells. Isolated human islets secreted increasing amounts of eNampt in response to high glucose (20 mM) in a static glucose-stimulated insulin secretion assay (GSIS). In addition to an increase in eNampt secretion, exposure to 20 mM glucose also increased Nampt mRNA levels but not protein content. The secretion of eNampt was attenuated by the addition of membrane depolarization inhibitors, diazoxide and nifedipine. Islet-secreted eNampt showed enzymatic activity in a reaction with increasing production of NAD+/NADH over time. In summary, we show that Nampt is expressed in both exocrine and endocrine tissue early in life but in adulthood expression is localized to endocrine tissue. Enzymatically active eNampt is secreted by human islets, is regulated by glucose and requires membrane depolarization.
PMCID: PMC3594147  PMID: 23536823
11.  Expenditure and resource utilisation for cervical screening in Australia 
The National Cervical Screening Program in Australia currently recommends that women aged 18–69 years are screened with conventional cytology every 2 years. Publicly funded HPV vaccination was introduced in 2007, and partly as a consequence, a renewal of the screening program that includes a review of screening recommendations has recently been announced. This study aimed to provide a baseline for such a review by quantifying screening program resource utilisation and costs in 2010.
A detailed model of current cervical screening practice in Australia was constructed and we used data from the Victorian Cervical Cytology Registry to model age-specific compliance with screening and follow-up. We applied model-derived rate estimates to the 2010 Australian female population to calculate costs and numbers of colposcopies, biopsies, treatments for precancer and cervical cancers in that year, assuming that the numbers of these procedures were not yet substantially impacted by vaccination.
The total cost of the screening program in 2010 (excluding administrative program overheads) was estimated to be A$194.8M. We estimated that a total of 1.7 million primary screening smears costing $96.7M were conducted, a further 188,900 smears costing $10.9M were conducted to follow-up low grade abnormalities, 70,900 colposcopy and 34,100 histological evaluations together costing $21.2M were conducted, and about 18,900 treatments for precancerous lesions were performed (including retreatments), associated with a cost of $45.5M for treatment and post-treatment follow-up. We also estimated that $20.5M was spent on work-up and treatment for approximately 761 women diagnosed with invasive cervical cancer. Overall, an estimated $23 was spent in 2010 for each adult woman in Australia on cervical screening program-related activities.
Approximately half of the total cost of the screening program is spent on delivery of primary screening tests; but the introduction of HPV vaccination, new technologies, increasing the interval and changing the age range of screening is expected to have a substantial impact on this expenditure, as well as having some impact on follow-up and management costs. These estimates provide a benchmark for future assessment of the impact of changes to screening program recommendations to the costs of cervical screening in Australia.
PMCID: PMC3548768  PMID: 23216968
12.  Development of biomarkers to optimize pediatric patient management: what makes children different? 
Biomarkers in Medicine  2011;5(6):781-794.
Despite the frequent utilization of biomarkers in medical practice, there is a relative paucity of information regarding validated pediatric biomarkers. Frequently, biomarkers found to be efficacious in adults are extrapolated to the pediatric clinical setting without considering that the pathogenesis of many diseases is distinctly different in children, and ontogeny directly influences disease evolution and therapeutic response in children. New and innovative approaches are necessary to provide reliable, validated biomarkers that can be used to improve and advance pediatric medical care.
PMCID: PMC3321646  PMID: 22103612
biomarker; children; development; genomics; ontogeny; pediatrics; pharmacogenomics
13.  Projecting prevalence by stage of care for prostate cancer and estimating future health service needs: protocol for a modelling study 
BMJ Open  2011;1(1):e000104.
Current strategies for the management of prostate cancer are inadequate in Australia. We will, in this study, estimate current service needs and project the future needs for prostate cancer patients in Australia.
Methods and analysis
First, we will project the future prevalence of prostate cancer for 2010–2018 using data for 1972–2008 from the New South Wales (NSW) Central Cancer Registry. These projections, based on modelled incidence and survival estimates, will be estimated using PIAMOD (Prevalence, Incidence, Analysis MODel) software. Then the total prevalence will be decomposed into five stages of care: initial care, continued monitoring, recurrence, last year of life and long-term survivor. Finally, data from the NSW Prostate Cancer Care and Outcomes Study, including data on patterns of treatment and associated quality of life, will be used to estimate the type and amount of services that will be needed by prostate cancer patients in each stage of care. In addition, Central Cancer Registry episode data will be used to estimate transition rates from localised or locally advanced prostate cancer to metastatic disease. Medicare and Pharmaceutical Benefits data, linked with Prostate Cancer Care and Outcomes Study data, will be used to complement the Cancer Registry episode data. The methods developed will be applied Australia-wide to obtain national estimates of the future prevalence of prostate cancer for different stages of clinical care.
Ethics and dissemination
This study was approved by the NSW Population and Health Services Research Ethics Committee. Results of the study will be disseminated widely to different interest groups and organisations through a report, conference presentations and peer-reviewed articles.
Article summary
Article focus
To describe the statistical models we will develop to obtain estimates of the future prevalence of prostate cancer in Australia for each stage of clinical care.
To describe how the methods developed will be used to determine:
i. How many prostate cancer patients will need medical attention in the near future, and
ii. What types of services they will need.
Key messages
This study will provide the first Australian estimates of current health service needs and projections of future needs for prostate cancer patients.
This information will be essential for ensuring that men with prostate cancer have adequate access to the different types of care they will require as they move through the disease trajectory.
Strengths and limitations of this study
Breakdown of prevalence according to health service needs by patient subgroup
Development and testing of validated statistical methods for use in other settings
Multiple population-based data sources: cancer registry, a patterns of care study and Medicare and Pharmaceutical Benefits data.
PIAMOD software has substantial data demands (requiring detailed specially-formatted input data including externally modelled survival estimates)
Numerous decisions are required regarding the best statistical models for incidence and survival
Several assumptions are needed regarding the future trends in incidence and survival.
PMCID: PMC3191396  PMID: 22021763
Organisation of health services; epidemiology; public health; statistics & research methods; urological tumours; health service research
14.  A duplicate gene rooting of seed plants and the phylogenetic position of flowering plants 
Flowering plants represent the most significant branch in the tree of land plants, with respect to the number of extant species, their impact on the shaping of modern ecosystems and their economic importance. However, unlike so many persistent phylogenetic problems that have yielded to insights from DNA sequence data, the mystery surrounding the origin of angiosperms has deepened with the advent and advance of molecular systematics. Strong statistical support for competing hypotheses and recent novel trees from molecular data suggest that the accuracy of current molecular trees requires further testing. Analyses of phytochrome amino acids using a duplicate gene-rooting approach yield trees that unite cycads and angiosperms in a clade that is sister to a clade in which Gingko and Cupressophyta are successive sister taxa to gnetophytes plus Pinaceae. Application of a cycads + angiosperms backbone constraint in analyses of a morphological dataset yields better resolved trees than do analyses in which extant gymnosperms are forced to be monophyletic. The results have implications both for our assessment of uncertainty in trees from sequence data and for our use of molecular constraints as a way to integrate insights from morphological and molecular evidence.
PMCID: PMC2838261  PMID: 20047866
seed plant rooting; phytochromes; amino acids; duplicate genes
15.  Cervical cancer screening in Australia: modelled evaluation of the impact of changing the recommended interval from two to three years 
BMC Public Health  2010;10:734.
The National Cervical Screening Program in Australia currently recommends that sexually active women between the ages of 18-70 years attend routine screening every 2 years. The publically funded National HPV Vaccination Program commenced in 2007, with catch-up in females aged 12-26 years conducted until 2009; and this may prompt consideration of whether the screening interval and other aspects of the organized screening program could be reviewed. The aim of the current evaluation was to assess the epidemiologic outcomes and cost implications of changing the recommended screening interval in Australia to 3 years.
We used a modelling approach to evaluate the effects of moving to a 3-yearly recommended screening interval. We used data from the Victorian Cervical Cytology Registry over the period 1997-2007 to model compliance with routine screening under current practice, and registry data from other countries with 3-yearly recommendations to inform assumptions about future screening behaviour under two alternative systems for screening organisation - retention of a reminder-based system (as in New Zealand), or a move to a call-and-recall system (as in England).
A 3-yearly recommendation is predicted to be of similar effectiveness to the current 2-yearly recommendation, resulting in no substantial change to the total number of incident cervical cancer cases or cancer deaths, or to the estimated 0.68% average cumulative lifetime risk of cervical cancer in unvaccinated Australian women. However, a 3-yearly screening policy would be associated with decreases in the annual number of colposcopy and biopsy procedures performed (by 4-10%) and decreases in the number of treatments for pre-invasive lesions (by 2-4%). The magnitude of the decrease in the number of diagnostic procedures and treatments would depend on the method of screening organization, with call-and-recall screening associated with the highest reductions. The cost savings are predicted to be of the order of A$10-18 M annually, equivalent to 6-11% of the total cost of the current program (excluding overheads), with call-and-recall being associated with the greatest savings.
Lengthening the recommended screening interval to 3 years in Australia is not predicted to result in increases in rates of cervical cancer and is predicted to decrease the number of women undergoing diagnostic and treatment procedures. These findings are consistent with a large body of international evidence showing that screening more frequently than every three years with cervical cytology does not result in substantial gains in screening effectiveness.
PMCID: PMC3001736  PMID: 21110881
16.  Projected mesothelioma incidence in men in New South Wales 
Based on observed numbers of incident mesotheliomas since 1972, to predict future numbers in men in New South Wales.
The incidence of mesothelioma was modelled in two ways. First by using an age/birth cohort model, and second by using a model based on potential exposure to asbestos in terms of age and calendar year. The latter model included a term for clearance of asbestos fibres from the lungs, and a term for diagnostic fraction. The age and calendar year model was based on the model introduced by Hodgson and colleagues but replaced piecewise effects by smooth functions represented by cubic splines.
The number of mesotheliomas between 2004 and 2060 was predicted as 6690 with the age‐cohort model and as 6779 by the age and calendar year model, with peak annual numbers of 187 in the year 2021 and 196 in the year 2014 with the two models respectively.
The pattern of parameter estimates in the two models was in accord with the known use of amphibole asbestos in Australia. The predicted peak year of 2014–21 is 30–35 years after the phasing out of amphibole use, and this period is in accord with predictions for the UK and the US; in the latter country the peak was 10–15 years earlier corresponding to a marked decline of amphibole use in and following the 1960s.
PMCID: PMC2078410  PMID: 17449562
17.  Hip fracture risk in relation to vitamin D supplementation and serum 25-hydroxyvitamin D levels: a systematic review and meta-analysis of randomised controlled trials and observational studies 
BMC Public Health  2010;10:331.
Vitamin D supplementation for fracture prevention is widespread despite conflicting interpretation of relevant randomised controlled trial (RCT) evidence. This study summarises quantitatively the current evidence from RCTs and observational studies regarding vitamin D, parathyroid hormone (PTH) and hip fracture risk.
We undertook separate meta-analyses of RCTs examining vitamin D supplementation and hip fracture, and observational studies of serum vitamin D status (25-hydroxyvitamin D (25(OH)D) level), PTH and hip fracture. Results from RCTs were combined using the reported hazard ratios/relative risks (RR). Results from case-control studies were combined using the ratio of 25(OH)D and PTH measurements of hip fracture cases compared with controls. Original published studies of vitamin D, PTH and hip fracture were identified through PubMed and Web of Science databases, searches of reference lists and forward citations of key papers.
The seven eligible RCTs identified showed no significant difference in hip fracture risk in those randomised to cholecalciferol or ergocalciferol supplementation versus placebo/control (RR = 1.13[95%CI 0.98-1.29]; 801 cases), with no significant difference between trials of <800 IU/day and ≥800 IU/day. The 17 identified case-control studies found 33% lower serum 25(OH)D levels in cases compared to controls, based on 1903 cases. This difference was significantly greater in studies with population-based compared to hospital-based controls (χ21 (heterogeneity) = 51.02, p < 0.001) and significant heterogeneity was present overall (χ216 (heterogeneity) = 137.9, p < 0.001). Serum PTH levels in hip fracture cases did not differ significantly from controls, based on ten case-control studies with 905 cases (χ29 (heterogeneity) = 149.68, p < 0.001).
Neither higher nor lower dose vitamin D supplementation prevented hip fracture. Randomised and observational data on vitamin D and hip fracture appear to differ. The reason for this is unclear; one possible explanation is uncontrolled confounding in observational studies. Post-fracture PTH levels are unrelated to hip fracture risk.
PMCID: PMC2906464  PMID: 20540727
18.  Investigation of relative risk estimates from studies of the same population with contrasting response rates and designs 
There is little empirical evidence regarding the generalisability of relative risk estimates from studies which have relatively low response rates or are of limited representativeness. The aim of this study was to investigate variation in exposure-outcome relationships in studies of the same population with different response rates and designs by comparing estimates from the 45 and Up Study, a population-based cohort study (self-administered postal questionnaire, response rate 18%), and the New South Wales Population Health Survey (PHS) (computer-assisted telephone interview, response rate ~60%).
Logistic regression analysis of questionnaire data from 45 and Up Study participants (n = 101,812) and 2006/2007 PHS participants (n = 14,796) was used to calculate prevalence estimates and odds ratios (ORs) for comparable variables, adjusting for age, sex and remoteness. ORs were compared using Wald tests modelling each study separately, with and without sampling weights.
Prevalence of some outcomes (smoking, private health insurance, diabetes, hypertension, asthma) varied between the two studies. For highly comparable questionnaire items, exposure-outcome relationship patterns were almost identical between the studies and ORs for eight of the ten relationships examined did not differ significantly. For questionnaire items that were only moderately comparable, the nature of the observed relationships did not differ materially between the two studies, although many ORs differed significantly.
These findings show that for a broad range of risk factors, two studies of the same population with varying response rate, sampling frame and mode of questionnaire administration yielded consistent estimates of exposure-outcome relationships. However, ORs varied between the studies where they did not use identical questionnaire items.
PMCID: PMC2868856  PMID: 20356408
19.  Are Current or Future Mesothelioma Epidemics in Hong Kong the Tragic Legacy of Uncontrolled Use of Asbestos in the Past? 
Environmental Health Perspectives  2009;118(3):382-386.
Because of the long latent period of asbestos-related mesothelioma, investigators suggest that the high incidence of this disease will continue in the coming decades.
We describe the time trends of mesothelioma incidence and its relationship to historical consumption of asbestos in Hong Kong and project future trends of mesothelioma incidence.
We obtained local annual consumption of total asbestos for 1960–2006 (converted to kilograms per person per year). Age-standardized incidence rates (ASIRs) of mesothelioma were computed and depicted on graphs using the centered moving average method. Indirectly standardized rates were regressed on a transformation of consumption data that assumed that the latency between asbestos exposure and mesothelioma diagnosis followed a normal distribution with a mean ± SD of 42 ± 10.5 years.
ASIRs for males started to increase substantially in 1994 and were highest in 2004; for females, ASIRs climbed in the 1980s and in the early 1990s but have fluctuated without obvious trends in recent years. The highest asbestos consumption level in Hong Kong was in 1960–1963 and then decreased sharply afterward. Using past asbestos consumption patterns, we predict that the mesothelioma incidence rate for males will peak in 2009, with the number of cases peaking in 2014, and then slowly decline in the coming decades.
Hong Kong experienced an epidemic of mesothelioma from 2000 to 2006 that corresponded with the peak of local asbestos consumption in the early 1960s assuming an average latent period of 42 years. The incidence is anticipated to decline in the coming decades but may not decrease back to the background risk level (the risk unrelated to asbestos exposure).
PMCID: PMC2854767  PMID: 20064790
asbestos; epidemic; incidence; mesothelioma; time trends
20.  Universal health care no guarantee of equity: Comparison of socioeconomic inequalities in the receipt of coronary procedures in patients with acute myocardial infarction and angina 
BMC Public Health  2009;9:460.
In Australia there is a socioeconomic gradient in morbidity and mortality favouring socioeconomically advantaged people, much of which is accounted for by ischaemic heart disease. This study examines if Australia's universal health care system, with its mixed public/private funding and delivery model, may actually perpetuate this inequity. We do this by quantifying and comparing socioeconomic inequalities in the receipt of coronary procedures in patients with acute myocardial infarction (AMI) and patients with angina.
Using linked hospital and mortality data, we followed patients admitted to Western Australian hospitals with a first admission for AMI (n = 5539) or angina (n = 7401) in 2001-2003. An outcome event was the receipt, within a year, of a coronary procedure—angiography, angioplasty and/or coronary artery bypass surgery (CABG). Socioeconomic status was assigned to each individual using an area-based measure, the SEIFA Index of Disadvantage. Multivariable proportional hazards regression was used to model the association between socioeconomic status and procedure rates, allowing for censoring and adjustment of multiple covariates. Mediating models examined the effect of private health insurance.
In the AMI patient cohort, socioeconomic gradients were not evident except that disadvantaged women were more likely than advantaged women to undergo CABG. In contrast, in the angina patient group there were clear socioeconomic gradients for all procedures, favouring more advantaged patients. Compared with patients in the most disadvantaged quintile of socioeconomic status, patients in the least disadvantaged quintile were 11% (1-21%) more likely to receive angiography, 52% (29-80%) more likely to undergo angioplasty and 30% (3-55%) more likely to undergo CABG. Private health insurance explained some of the socioeconomic variation in rates.
Australia's universal health care system does not guarantee equity in the receipt of high technology health care for patients with ischaemic heart disease. While such a system might ensure equity for patients with AMI, where guidelines for treatment are relatively well established, this is not the case for angina patients, where health care may be less urgent and more discretionary.
PMCID: PMC2807435  PMID: 20003401
21.  Etiology of Encephalitis in Australia, 1990–2007 
Emerging Infectious Diseases  2009;15(9):1359-1365.
Unexplained disease etiology in hospitalized patients highlights the importance of surveillance to detect emerging novel pathogens.
Encephalitis is a clinical syndrome commonly caused by emerging pathogens, which are not under surveillance in Australia. We reviewed rates of hospitalization for patients with encephalitis in Australia’s most populous state, New South Wales, from January 1990 through December 2007. Encephalitis was the primary discharge diagnosis for 5,926 hospital admissions; average annual hospitalization rate was 5.2/100,000 population. The most commonly identified pathogen was herpes simplex virus (n = 763, 12.9%). Toxoplasma encephalitis and subacute sclerosing panencephalitis showed notable declines. The average annual encephalitis case-fatality rate (4.6%) and the proportion of patients hospitalized with encephalitis with no identified pathogen (69.8%, range 61.5%–78.7%) were stable during the study period. The nonnotifiable status of encephalitis in Australia and the high proportion of this disease with no known etiology may conceal emergence of novel pathogens. Unexplained encephalitis should be investigated, and encephalitis hospitalizations should be subject to statutory notification in Australia.
PMCID: PMC2819877  PMID: 19788802
Encephalitis; viral encephalitis; infectious encephalitis; viruses; Australia; research
22.  Polynucleotide Phosphorylase Negatively Controls spv Virulence Gene Expression in Salmonella enterica †  
Infection and Immunity  2006;74(2):1243-1254.
Mutational inactivation of the cold-shock-associated exoribonuclease polynucleotide phosphorylase (PNPase; encoded by the pnp gene) in Salmonella enterica serovar Typhimurium was previously shown to enable the bacteria to cause chronic infection and to affect the bacterial replication in BALB/c mice (M. O. Clements et al., Proc. Natl. Acad. Sci. USA 99:8784-8789, 2002). Here, we report that PNPase deficiency results in increased expression of Salmonella plasmid virulence (spv) genes under in vitro growth conditions that allow induction of spv expression. Furthermore, whole-genome microarray-based transcriptome analyses of bacteria growing inside murine macrophage-like J774.A.1 cells revealed six genes as being significantly up-regulated in the PNPase-deficient background, which included spvABC, rtcB, entC, and STM2236. Mutational inactivation of the spvR regulator diminished the increased expression of spv observed in the pnp mutant background, implying that PNPase acts upstream of or at the level of SpvR. Finally, competition experiments revealed that the growth advantage of the pnp mutant in BALB/c mice was dependent on spvR as well. Combined, our results support the idea that in S. enterica PNPase, apart from being a regulator of the cold shock response, also functions in tuning the expression of virulence genes and bacterial fitness during infection.
PMCID: PMC1360324  PMID: 16428774
23.  PerR Controls Oxidative Stress Resistance and Iron Storage Proteins and Is Required for Virulence in Staphylococcus aureus 
Infection and Immunity  2001;69(6):3744-3754.
The Staphylococcus aureus genome encodes three ferric uptake regulator (Fur) homologues: Fur, PerR, and Zur. To determine the exact role of PerR, we inactivated the gene by allelic replacement using a kanamycin cassette, creating strain MJH001 (perR). PerR was found to control transcription of the genes encoding the oxidative stress resistance proteins catalase (KatA), alkyl hydroperoxide reductase (AhpCF), bacterioferritin comigratory protein (Bcp), and thioredoxin reductase (TrxB). Furthermore, PerR regulates transcription of the genes encoding the iron storage proteins ferritin (Ftn) and the ferritin-like Dps homologue, MrgA. Transcription of perR was autoregulated, and PerR repressed transcription of the iron homeostasis regulator Fur, which is a positive regulator of catalase expression. PerR functions as a manganese-dependent, transcriptional repressor of the identified regulon. Elevated iron concentrations produced induction of the PerR regulon. PerR may act as a peroxide sensor, since addition of external hydrogen peroxide to 8325-4 (wild type) resulted in increased transcription of most of the PerR regulon, except for fur and perR itself. The PerR-regulated katA gene encodes the sole catalase of S. aureus, which is an important starvation survival determinant but is surprisingly not required for pathogenicity in a murine skin abscess model of infection. In contrast, PerR is not necessary for starvation survival but is required for full virulence (P < 0.005) in this model of infection. PerR of S. aureus may act as a redox sentinel protein during infection, analogous to the in vitro activities of OxyR and PerR of Escherichia coli and Bacillus subtilis, respectively. However, it differs in its response to the metal balance within the cell and has the added capability of regulating iron uptake and storage.
PMCID: PMC98383  PMID: 11349039
24.  Characterization of the Major Superoxide Dismutase of Staphylococcus aureus and Its Role in Starvation Survival, Stress Resistance, and Pathogenicity 
Journal of Bacteriology  1999;181(13):3898-3903.
A Staphylococcus aureus mutant (SPW1) which is unable to survive long-term starvation was shown to have a transposon insertion within a gene homologous to the sodA family of manganese-dependent superoxide dismutases (SOD). Whole-cell lysates of the parental 8325-4 strain demonstrated three zones of SOD activity by nondenaturing gel electrophoresis. The activities of two of these zones were dependent on manganese for activity and were absent in SPW1. The levels of SOD activity and sodA expression were growth-phase dependent, occurring most during postexponential phase. This response was also dependent on the level of aeration of the culture, with highest activity and expression occurring only under high aeration. Expression of sodA and, consequently, SOD activity could be induced by methyl viologen but only during the transition from exponential- to postexponential-phase growth. SPW1 was less able to survive amino acid limitation and acid stress but showed no alteration in pathogenicity in a mouse abscess model of infection compared to the parental strain 8325-4.
PMCID: PMC93877  PMID: 10383955
25.  CtaA of Staphylococcus aureus Is Required for Starvation Survival, Recovery, and Cytochrome Biosynthesis 
Journal of Bacteriology  1999;181(2):501-507.
A Staphylococcus aureus mutant (SPW3) apparently unable to survive long-term starvation was shown to have a transposon insertion within a gene homologous to ctaA of Bacillus subtilis which encodes a heme A synthase. Analysis of the cytochrome profiles of SPW3 revealed the absence of heme A-containing cytochromes compared to the parental 8325-4 strain. SPW3 demonstrated a 100-fold reduction in the ability to survive starvation induced by glucose limitation, under aerated conditions, compared to 8325-4. Analysis of starved cultures revealed that greater than 90% of the cells which demonstrated metabolism (as shown by rhodamine 123 accumulation) were unable to recover and form colonies on agar. Analysis of the lag phase and initial growth kinetics of those cells which could recover also showed a defect. This recovery defect could be partially alleviated by the inclusion of catalase in the recovery medium, indicating the probable involvement of oxidative stress. SPW3 also exhibited reduced colony size similar to that of a small-colony variant, increased resistance to aminoglycoside antibiotics, and reduced hemolysin and toxic shock syndrome toxin 1 production, but no alteration in the ability to form lesions in a subcutaneous mouse infection model.
PMCID: PMC93404  PMID: 9882664

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