Background

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.

Methods

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.

Results

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.

Conclusions

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.

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.

Introduction

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

Strengths

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.

Limitations

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.

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.

Background

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.

Methods

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).

Results

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.

Conclusions

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.

Objectives

Based on observed numbers of incident mesotheliomas since 1972, to predict future numbers in men in New South Wales.

Methods

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.

Results

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.

Conclusions

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.

Background

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.

Methods

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.

Results

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).

Conclusions

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.

Background

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%).

Methods

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.

Results

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.

Conclusions

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.

Background

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.

Objectives

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.

Methods

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.

Results

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.

Conclusions

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).

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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.

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.

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.

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.

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.

Bacillus cereus 569 (ATCC 10876) germinates in response to inosine or to l-alanine, but the most rapid germination response is elicited by a combination of these germinants. Mutants defective in their germination response to either inosine or to l-alanine were isolated after Tn917-LTV1 mutagenesis and enrichment procedures; one class of mutant could not germinate in response to inosine as a sole germinant but still germinated in response to l-alanine, although at a reduced rate; another mutant germinated normally in response to inosine but was slowed in its germination response to l-alanine. These mutants demonstrated that at least two signal response pathways are involved in the triggering of germination. Stimulation of germination in l-alanine by limiting concentrations of inosine and stimulation of germination in inosine by low concentrations of l-alanine were still detectable in these mutants, suggesting that such stimulation is not dependent on complete functionality of both these germination loci. Two transposon insertions that affected inosine germination were found to be located 2.2 kb apart on the chromosome. This region was cloned and sequenced, revealing an operon of three open reading frames homologous to those in the gerA and related operons of Bacillus subtilis. The individual genes of this gerI operon have been named gerIA, gerIB, and gerIC. The GerIA protein is predicted to possess an unusually long, charged, N-terminal domain containing nine tandem copies of a 13-amino-acid glutamine- and serine-rich sequence.

The role of ςB, an alternative sigma factor of Staphylococcus aureus, has been characterized in response to environmental stress, starvation-survival and recovery, and pathogenicity. ςB was mainly expressed during the stationary phase of growth and was repressed by 1 M sodium chloride. A sigB insertionally inactivated mutant was created. In stress resistance studies, ςB was shown to be involved in recovery from heat shock at 54°C and in acid and hydrogen peroxide resistance but not in resistance to ethanol or osmotic shock. Interestingly, S. aureus acquired increased acid resistance when preincubated at a sublethal pH 4 prior to exposure to a lethal pH 2. This acid-adaptive response resulting in tolerance was mediated via sigB. However, ςB was not vital for the starvation-survival or recovery mechanisms. ςB does not have a major role in the expression of the global regulator of virulence determinant biosynthesis, staphylococcal accessory regulator (sarA), the production of a number of representative virulence factors, and pathogenicity in a mouse subcutaneous abscess model. However, SarA upregulates sigB expression in a growth-phase-dependent manner. Thus, ςB expression is linked to the processes controlling virulence determinant production. The role of ςB as a major regulator of the stress response, but not of starvation-survival, is discussed.

The starvation-survival response of Staphylococcus aureus as a result of glucose, amino acid, phosphate, or multiple-nutrient limitation was investigated. Glucose and multiple-nutrient limitation resulted in the loss of viability of about 99 to 99.9% of the population within 2 days. The remaining surviving cells developed increased survival potential, remaining viable for months. Amino acid or phosphate limitation did not lead to the development of a stable starvation-survival state, and cells became nonculturable within 7 days. For multiple-nutrient limitation, the development of the starvation-survival state was cell density dependent. Starvation survival was associated with a decrease in cell size and increase in resistance to acid shock and oxidative stress. There was no evidence for the formation of a viable but nonculturable state during starvation as demonstrated by flow cytometry. Long-term survival of cells was dependent on cell wall and protein biosynthesis. Analysis of [35S]methionine incorporation and labelled proteins demonstrated that differential protein synthesis occurred deep into starvation.