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© 2018 Author(s) (or their employer(s)). Objectives: The presence of asbestos in public buildings is a legacy of past asbestos use in many developed countries. Of particular concern is the amount and current condition in schools and the vulnerability of children to mesothelioma. Our aim was to compare the risk of mesothelioma between those exposed to blue asbestos as children and as adults at Wittenoom. Methods: Public sources were used to establish the Wittenoom residents' cohort. Mesothelioma incidence rates per 100 000 person-years at risk were derived for those first exposed to asbestos at Wittenoom as children (<15 years) or adults separately. Proportional hazards survival models examined the slope of the exposure-response relationship between asbestos exposure and incidence of mesothelioma in different sex and age groups. Results: The mesothelioma rate was lower among those first exposed as children (76.8 per 100 000) than those first exposed as adults (121.3 per 100 000). Adjusting for cumulative exposure to asbestos and sex, those exposed as adults had a greater risk of mesothelioma (adjusted HR 2.5, 95% CI 1.7 to 3.7). The slope of the exposure-response relationship did not differ between those exposed as children and those exposed as adults. Conclusion: We found no greater susceptibility to mesothelioma among those first exposed to asbestos as children than those first exposed as adults. However, given the long latency of mesothelioma, and the greater years of life yet to be lived by the Wittenoom children, it is likely that there will be more cases of mesothelioma in the future among those first exposed as children.

BACKGROUND: Malignant Pleural Mesothelioma (MPM) is an uncommon cancer with a poor prognosis and heterogeneous survival. Surgery for MPM is offered in some specialist centres to highly selected patients. A previously described classification and regression tree (CART) model stratified survival in unselected MPM patients using routinely collected clinical data. This study aimed to examine the performance of this CART model on a highly selected surgical population. METHODS: Data were collected from subjects undergoing cytoreductive surgery for MPM from specialist centres in Hyõgo, Japan and Sydney, Australia between 1991 and 2016. The CART model was applied using the combination of clinical variables to stratify subjects into risk groups (1-4); survival characteristics were then compared. RESULTS: 289 cases were included (205 from Australia, 84 from Japan). Overall median survival was 34.6 (IQR 17.5-56.1) months; median age 63.0 (IQR 57.0-67.8) years, 240/289 (83.0%) were male. There were no clinically meaningful differences between the two cohorts. Survival across the four risk groups was significantly different (p<0.0001); the model stratified survival well with a Harrell's c-statistic of 0.62 (96% CI 0.57-0.66) at 36 months. The group with the longest survival (median 82.5 months) had: no weight loss, Hb >153g/L and serum albumin >43g/L at time of referral to the surgical centre. CONCLUSION: Using routinely available clinical variables the CART model was able to stratify surgical patients into risk groups with statistically different survival characteristics with fair to good performance. Presence of weight loss, anaemia and low albumin should confer caution when considering surgical therapy for MPM.

Background: Rett syndrome is caused by a pathogenic mutation in the MECP2 gene with major consequences for motor and cognitive development. One of the effects of impaired MECP2 function is reduced production of Brain Derived Neurotrophic Factor (BDNF), a protein required for normal neuronal development. When housed in an enriched environment, MECP2 null mice improved motor abilities and increased levels of BDNF in the brain. We investigated the effects of environmental enrichment on gross motor skills and blood BDNF levels in girls with Rett syndrome. Methods: A genetically variable group of 12 girls with a MECP2 mutation and younger than 6 years participated in a modified individually randomised stepped wedge design study. Assessments were conducted on five occasions, two during the baseline period and three during the intervention period. Gross motor function was assessed using the Rett Syndrome Gross Motor Scale (maximum score of 45) on five occasions, two during the baseline period and three during the intervention period. Blood levels of BDNF were measured at the two baseline assessments and at the end of the intervention period. The intervention comprised motor learning and exercise supplemented with social, cognitive and other sensory experiences over a six-month period. Results: At the first assessment, the mean (SD) age of the children was 3 years (1 year 1 month) years ranging from 1 year 6 months to 5 years 2 months. Also at baseline, mean (SD) gross motor scores and blood BDNF levels were 22.7/45 (9.6) and 165.0 (28.8) ng/ml respectively. Adjusting for covariates, the enriched environment was associated with improved gross motor skills (coefficient 8.2, 95%CI 5.1, 11.2) and a 321.4 ng/ml (95%CI 272.0, 370.8) increase in blood BDNF levels after 6 months of treatment. Growth, sleep quality and mood were unaffected. Conclusions: Behavioural interventions such as environmental enrichment can reduce the functional deficit in Rett syndrome, contributing to the

Early identification of people at risk of developing COPD is crucial for implementing preventive strategies. We aimed to systematically review and assess the performance of all published models that predicted development of COPD. A search was conducted to identify studies that developed a prediction model for COPD development. The Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies was followed when extracting data and appraising the selected studies. Of the 4,481 records identified, 30 articles were selected for full-text review, and only four of these were eligible to be included in the review. The only consistent predictor across all four models was a measure of smoking. Sex and age were used in most models; however, other factors varied widely. Two of the models had good ability to discriminate between people who were correctly or incorrectly classified as at risk of developing COPD. Overall none of the models were particularly useful in accurately predicting future risk of COPD, nor were they good at ruling out future risk of COPD. Further studies are needed to develop new prediction models and robustly validate them in external cohorts.

© 2018 Wiley Periodicals, Inc. Background: Studies comparing different forms of asbestos are rare, and limited by the failure to compare results with unexposed populations. We compare autoimmune responses among former workers and residents of the crocidolite mining and milling town of Wittenoom, Western Australia, with an unexposed population. Methods: ANA testing using indirect immunofluorescence was performed on randomly selected serum samples from Wittenoom workers or residents and compared with those from participants of another unexposed cohort study. Results: ANA scores were higher in the Wittenoom participants compared with Busselton and the odds of being ANA positive was fivefold greater among Wittenoom participants than Busselton (OR 5.5, 95%CI 2.3-13.0). Conclusions: This study is the first to report increased ANA positivity among persons exposed exclusively to crocidolite. This finding of a high frequency of positive ANA tests among crocidolite-exposed subjects may be an indicator for an increased risk of systemic autoimmune diseases and needs further scrutiny.

© 2018 Reported infant vaccination coverage at age 12 months in Australia is > 90%. On-time coverage of the 2–4–6 month schedule and coverage in specific populations is rarely reported. We conducted a population-based cohort study of 1.9 million Australian births, 1996–2012, combining individual birth and perinatal records with immunisation records through probabilistic linkage. We assessed on-time coverage across 13 demographic and perinatal characteristics of diphtheria-tetanus-pertussis vaccines (DTP) defined as vaccination 14 days prior to the scheduled due date, to 30 days afterwards. On-time DTP vaccination coverage in non-Aboriginal infants was 88.1% for the 2-month dose, 82.0% for 4-month dose, and 76.7% for 6-month dose; 3-dose coverage was 91.3% when assessed at 12 months. On-time DTP coverage for Aboriginal infants was 77.0%, 66.5%, and 61.0% for the 2–4–6 month dose; 3-dose coverage at 12 months was 79.3%. Appreciable differences in on-time coverage were observed across population subgroups. On-time coverage in non-Aboriginal infants born to mothers with =3 previous pregnancies was 62.5% for the 6-month dose (47.9% for Aboriginal infants); up to 23.5 percentage points lower than for first-borns. Infants born to mothers who smoked during pregnancy had coverage 8.7–10.3 percentage points lower than infants born to non-smoking mothers for the 4- and 6-month dose. A linear relationship was apparent between increasing socio-economic disadvantage and decreasing on-time coverage. On-time coverage of the 2–4–6 month schedule is only 50–60% across specific population subgroups representing a significant avoidable public health risk. Aboriginal infants, multiparous mothers, and those who are socio-economically disadvantaged are key groups most likely to benefit from targeted programs addressing vaccine timeliness.

© 2017 European Cystic Fibrosis Society. Background: Staphylococcus aureus (S. aureus) may be related to more rapid progression of cystic fibrosis (CF) lung disease. Methods: In the AREST CF cohort study, children diagnosed with CF undergo annual bronchoscopies with bronchoalveolar lavage and ultra-low-dose, chest computed tomography (CT) up to 6-years-old. Spirometry was assessed 3-monthly from the age of 4. years. Associations between de novo S. aureus acquisition before school age and CT and lung function at ages 5-7. years were investigated. Models were adjusted for multiple markers of disease severity at baseline. Results: De novo S. aureus acquisition at 3-years-old (n/N=12/122) was associated with increased bronchiectasis score at age 5-6years. This association decreased but remained significant after adjustment for confounders. S. aureus at 3 was associated with significantly reduced FEF 25-75 at age 5-7years, but not with FEV 1 -%-predicted. Conclusion: De novo S. aureus acquisition at age 3 is associated with later bronchiectasis and FEF 25-75 in children with CF.

Nonalcoholic fatty liver disease (NAFLD) is a complex chronic liver disorder. Examination of parental pregnancy-related characteristics may provide insights into the origins of risk of NAFLD in offspring. We examined relationships between parental pregnancy-related characteristics and NAFLD in 1,170 adolescent offspring aged 17 years participating in the Western Australian Pregnancy (Raine) Cohort Study. Fatty liver was diagnosed using liver ultrasound. NAFLD was diagnosed in 15.2% of adolescents at age 17 years. In univariate analysis, maternal factors associated with NAFLD in female offspring were younger maternal age (P = 0.02), higher maternal prepregnancy BMI (P < 0.001), higher maternal weight gain by 18 weeks' gestation (P < 0.001), and maternal smoking during pregnancy (P = 0.04). Paternal age or body mass index (BMI) were not associated with NAFLD in female offspring. In contrast, higher paternal BMI (P < 0.001), maternal prepregnancy BMI (P < 0.001), and lower family socioeconomic status (SES) at time of birth (P = 0.001), but not parental age nor maternal gestational weight gain, were associated with NAFLD in male offspring. Using multivariate logistic regression, factors independently associated with NAFLD after adjusting for obesity in adolescent females included maternal obesity (odds ratio [OR], 3.46; 95% confidence interval [CI] , 1.49-8.05; P = 0.004) and maternal weight gain =6.0 kg by the 18th week of gestation (OR, 1.10; 95% CI, 1.04-1.15; P < 0.001). In adolescent males, family SES at the time of birth (OR, 9.07; 95% CI, 1.54-53.29; P = 0.02) remained significantly associated with NAFLD after multivariate modeling adjusted for adolescent obesity. Conclusion: Early-life contributors to NAFLD show considerable sexual dimorphism. Maternal obesity and higher early-mid gestational weight gain were associated with NAFLD in female offspring, whereas lower family SES at birth was associated with NAFLD in male offspring independent of adol

Background: Most studies use indirect cohort or case-control methods to estimate vaccine effectiveness (VE) of 7- and 13-valent pneumococcal conjugate vaccines (PCV7 and PCV13) against invasive pneumococcal disease (IPD). Neither method can measure the benefit vaccinationprograms afford the unvaccinated and many studies were unable to estimate dose-specific VE. We linked Australia’s national immunisation register with health data from two states to calculate IPD incidence by vaccination status and VE for a 3 + 0 PCV schedule (doses at 2, 4, 6 months, no booster) among a cohort of 1.4 million births. Methods: Births records for 2001–2012 were probabilistically linked to IPD notifications, hospitalisations, deaths, and vaccination history (available until December 2013). IPD rates in vaccinated and unvaccinated children <2 years old were compared using Cox proportional hazards models (adjusting for potential confounders), with VE = (1 − adjusted hazard ratio) × 100. Separate models were performed for all-cause, PCV7, PCV13 and PCV13-non-PCV7 serotype-specific IPD, and for Aboriginal and non-Aboriginal children. Results: Following introduction of universal PCV7 in 2005, rates of PCV7 serotype and all-cause IPD in unvaccinated children declined 89.5% and 61.4%, respectively, to be similar to rates in vaccinated children. Among non-Aboriginal children, VEs for 3 doses were 94.2% (95%CI: 81.9–98.1) for PCV7 serotype-specific IPD, 85.6% (95%CI: 60.5–94.8) for PCV13-non-PCV7 serotype-specific IPD and 80.1% (95%CI: 59.4–90.3) for all-cause IPD. There were no statistically significant differences between the VEs for 3 doses and for 1 or 2 doses against PCV13 and PCV13-non-PCV7 serotype-specific IPD, or between Aboriginal and non-Aboriginal children. Conclusion: Our population-based cohort study demonstrates that >90% coverage in the first year of a universal 3 + 0 PCV program provided high population-level protection, predominantly attributable to strong herd effects. The siz

OBJECTIVES: Three hundred and thirty thousand Italians arrived in Australia between 1945 and 1966, many on assisted passage schemes where the worker agreed to a 2-year unskilled employment contract. Italians were the largest of 52 migrant groups employed at the Wittenoom blue asbestos mining and milling operation. We compare mortality from asbestos-related diseases among Italian and Australian workers employed at Wittenoom. METHODS: A cohort of 6500 male workers was established from employment records and followed up at state and national mortality and cancer registries. SMRs were calculated to compare mortality with the Western Australian male population. Time-varying Cox proportional hazards models compared the risk of mesothelioma between Australian and Italian workers. RESULTS: 1031 Italians and 3465 Australians worked at Wittenoom between 1943 and 1966. Duration of employment was longer for the Italian workers, although the concentration of exposure was similar. The mesothelioma mortality rate per 100 000 was higher in Italians (184, 95% CI 148 to 229) than Australians (128, 95% CI 111 to 149). The risk of mesothelioma was greater than twofold (HR 2.27, 95% CI 1.43 to 3.60) in Italians at the lowest asbestos exposure category (<10 fibre years/per mL). CONCLUSIONS: A hierarchy in migration, isolation and a shortage of workers led to Italians at Wittenoom incurring higher cumulative exposure to blue asbestos and subsequently a greater rate of malignant mesothelioma than Australian workers. IMPACT: Poor working conditions and disparities between native and foreign-born workers has had a detrimental and differential impact on the long-term health of the workforce.

INTRODUCTION: Several countries have developed national immunisation registers, but only the Nordic countries have linked their registers to other health data in order to comprehensively evaluate the `real world' effectiveness of vaccines. Nordic countries can link datasets deterministically using the national person identifier, but most countries, including Australia, don't have such an identifier to enable this type of linkage. OBJECTIVES: To describe the process for assembling a linked study cohort that will enable the conduct of population-based studies related to immunisation and immunisation policy. METHODS: National death and immunisation databases along with state health data (notifications of vaccine preventable diseases, perinatal data, hospital admissions and emergency department presentations) up until December 2013 were probabilistically linked (using demographic details) for children born between 1996 and 2012 in two states: Western Australia and New South Wales (42% of Australia's population, combined). RESULTS: After exclusions there were 1.95 million children in the study cohort (live born children with both a birth and perinatal record which represents 97.5% of all live births in the state perinatal data collections - our source population) and 18.0 million person years of follow up (mean: 9.2 years per child). The characteristics of children in the cohort were generally similar to those only included in state perinatal databases and outcome measures were in keeping with expected figures from unlinked data sources. However, the lack of a dynamic national population register meant immigrants could not be included. CONCLUSIONS: We have been able to develop a similarly comprehensive system to the Nordic countries based on probabilistic linkage methods. Our experience should provide encouragement to other countries with national immunisation registers looking to establish similar systems.

Background: Vitamin D (25(OH)D) deficiency has been implicated as a possible risk factor for asthma development, but studies at selected time points measuring 25(OH)D levels during childhood have yielded conflicting findings. Prospective studies tracking 25(OH)D levels during the initiation phase of asthma in early childhood have not been reported. Objective: We sought to elucidate relationships between 25(OH)D levels from birth to age 10 years and susceptibility to allergic sensitization, respiratory tract infections, and asthma. Methods: Asthma-, allergy-, and respiratory tract infection-associated phenotypes (including pathogen identification) were characterized in a high-risk birth cohort. Plasma 25(OH)D concentrations were quantified at birth and at clinical follow-ups at the ages of 0.5, 1, 2, 3, 4, 5, and 10 years, and relationships with clinical outcomes were examined. Results: Cross-sectional analyses demonstrated inverse associations between 25(OH)D concentrations and the risk for concurrent sensitization at age 0.5, 2, and 3 years, and mixed-effects regression demonstrated inverse longitudinal associations of 25(OH)D levels with both sensitization and eczema. Multivariate regression modeling suggested that the number of 25(OH)D-deficient follow-ups was positively associated with risk for asthma/wheeze, eczema, and sensitization at 10 years; adjustment for sensitization (particularly by 2 years) in the asthma/wheeze models reduced 25(OH)D associations with these latter outcomes. 25(OH)D levels were also inversely associated with early nasopharyngeal colonization with . Streptococcus species and age of first febrile lower respiratory illness, both of which are known asthma risk factors. Conclusion: 25(OH)D deficiency in early childhood is associated with increased risk for persistent asthma, potentially through modulating susceptibility to early allergic sensitization, upper respiratory tract colonization with bacterial pathogens, or both. These relationshi

© 2017 AMPCo Pty Ltd. Produced with Elsevier B.V. All rights reserved. · The incidence of malignant mesothelioma in Australia is among the highest in the world as a result of widespread use of asbestos by industry and in construction throughout the 20th century. · The risk of developing malignant mesothelioma after asbestos exposure is dose-related; a transient, low dose exposure confers a correspondingly very low risk of disease. · Malignant mesothelioma is a heterogeneous disease, partly explaining the limited role of biomarkers in screening and diagnosis. · The prognosis remains poor, and early advice on medico-legal compensation and a collaborative team approach to managing malignant mesothelioma are both essential. · Chemotherapy can have a modest treatment effect in some people. New therapies, such as immunotherapy, do not yet have a defined role in the treatment of malignant mesothelioma. · As treatment options for malignant mesothelioma are limited and no cure is available, there is no established role for early detection or screening of at risk populations. · A multidisciplinary approach to caring for patients with malignant mesothelioma and their carers is vital.

Seasonal influenza can cause significant morbidity in pregnant women. Much of the existing epidemiological evidence on influenza during pregnancy has focused on the 2009 A/H1N1 pandemic. To measure the epidemiological characteristics of seasonal influenza infection among pregnant women and the impact on infant health, a cohort of 86 779 pregnancies during the influenza season (2012-2014) was established using probabilistic linkage of notifiable infectious disease, hospital admission, and birth information. A total of 192 laboratory-confirmed influenza infections were identified (2·2 per 1000 pregnancies), 14·6% of which were admitted to hospital. There was no difference in the proportion of infections admitted to hospital by trimester or subtype of infection. Influenza B infections were more likely to occur in second trimester compared with influenza A/H3N2 and influenza A/H1N1 infections (41·3%, 23·6%, and 33·3%, respectively), and on average, infants born to women with influenza B during pregnancy had 4·0% (95% CI 0·3-7·6%) lower birth weight relative to optimal compared with infants born to uninfected women (P = 0·03). Results from this linked population-based study suggest that there are differences in maternal infection by virus type and subtype and support the provision of seasonal influenza vaccine to pregnant women.

© 2017 Wiley Periodicals, Inc. Background: Respirable crystalline silica (RCS) has been associated with severe health risks. Exposures in Western Australia (WA) have been typically high in hard-rock mining and have reduced substantially since the mid-1900s. We described trends in RCS exposure in WA miners over the past 30 years. Methods: A total of 79 445 reported personal RCS exposure measurements, covering the years 1986-2014, were examined. Mixed-effects models were applied to estimate RCS exposure levels, including spline terms to estimate a time trend. Results: An overall downward trend of about -8% per year was observed for RCS exposures in WA mining. Highest RCS exposure levels were modeled for base metal mining and exploration settings. Drilling occupations were among the highest exposed jobs. Conclusion: RCS exposure levels have fallen considerably in the last three decades. However, there are still mining occupations that may need further attention to avoid adverse health effects in these workers.

Background and objective: Mannitol challenge testing is an established tool for clinical asthma diagnosis, and can be performed outside of specialized respiratory laboratories. Despite applicability in both clinical and non-clinical populations, with different pre-test asthma probabilities, differences in diagnostic properties have not been well explored. This study aimed to quantify the diagnostic utility of mannitol challenge testing for asthma in a community cohort and a symptomatic wheezing subset of this cohort. Methods: During the 22-year follow-up of the Western Australian Pregnancy (Raine) Cohort, 772 participants (384 males) completed mannitol challenge and skin prick testing and respiratory health questionnaires, of whom 148 reporting wheeze in the past 12 months were included in a wheezing subset. Results: Responsiveness to mannitol had low sensitivity (19%) and high specificity (97%) to identify current asthma in the complete cohort, with positive and negative predictive values (PPV and NPV) of 45% and 92%, respectively. Within the wheezing subset, sensitivity (19%) and specificity (94%) remained similar, but PPV increased to 79%, and NPV decreased to 52%. Conclusion: Our findings support previously reported high specificity and good PPV for mannitol challenge testing in symptomatic wheezing populations, and highlight the need for caution when interpreting mannitol test results in non-clinical populations.

Objectives: The correlation between ultra low dose computed tomography (ULDCT)-detected parenchymal lung changes and pulmonary function abnormalities is not well described. This study aimed to determine the relationship between ULDCT-detected interstitial lung disease (ILD) and measures of pulmonary function in an asbestos-exposed population. Methods: Two thoracic radiologists independently categorised prone ULDCT scans from 143 participants for ILD appearances as absent (score 0), probable (1) or definite (2) without knowledge of asbestos exposure or lung function. Pulmonary function measures included spirometry and diffusing capacity to carbon monoxide (DLCO). Results: Participants were 92% male with a median age of 73.0 years. CT dose index volume was between 0.6 and 1.8 mGy. Probable or definite ILD was reported in 63 (44.1%) participants. Inter-observer agreement was good (k = 0.613, p < 0.001). There was a statistically significant correlation between the ILD score and both forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) (r = -0.17, p = 0.04 and r = -0.20, p = 0.02). There was a strong correlation between ILD score and DLCO (r = -0.34, p < 0.0001). Conclusion: Changes consistent with ILD on ULDCT correlate well with corresponding reductions in gas transfer, similar to standard CT. In asbestos-exposed populations, ULDCT may be adequate to detect radiological changes consistent with asbestosis.

Background: Miners are frequently exposed to established and potential carcinogens. We aimed to assess cancer incidence in miners relative to the general population and identify high-risk subgroups. Methods: Incident cancers in Western Australian miners (n = 153,922; 86% male) during 1996–2013 were identified. Indirectly standardised incidence ratios (SIRs) were calculated and mixed-effects Poisson models were used to calculate Incidence Rate Ratios (IRRs) to identify high-risk within-cohort subgroups. Results: Compared with the general population, the overall cancer incidence in miners (n = 4194 cases) was lower for both females (SIR:0.83, 95%CI:0.74–0.92) and males (SIR:0.96, 95%CI:0.93–0.99). Overall, cancer incidence did not differ by employment duration or employment commencement time. Ever-underground work was associated with lung cancer (IRR:1.81, 95%CI:1.11–2.93). Relative to multi-ore miners, IRRs for specific cancers were significantly different when exclusively mining: iron (prostate:0.73, 95%CI:0.56–0.94); gold (lung:1.77, 95%CI:1.04–3.01 and colorectum:1.70, 95%CI:1.16–2.51); and other metals (urinary tract:1.85, 95%CI:1.03–3.31 and leukaemia:0.36, 95%CI:0.14–0.96). Conclusion: Working underground emerged as a significant determinant of lung cancer risk in our contemporary mining cohort. Increased risks of lung, prostate, colorectal and urinary tract cancers and leukaemia were identified in miners of specific ores. These findings underline the importance of continued surveillance of the health and exposures of this relatively young cohort of miners.

Objectives: Malignant mesothelioma (MM) is a rare and generally fatal cancer, usually caused by asbestos, although about 5-10% of cases report no asbestos exposure. This study aimed to identify sources whereby people in Western Australia (WA) may be unknowingly exposed to asbestos or to other exposures which may cause MM. Methods: Cases with no known asbestos exposure were selected from the WA Mesothelioma Register (WAMR). Matched controls were selected from hospital patients admitted for conditions unrelated to asbestos. Occupational histories were coded by an industrial hygienist. Data were analyzed using conditional logistic regression. Results: Thirty-eight MM participants and 134 controls were recruited. Risk of MM was increased (OR=3.1, 95%CI 1.0-9.6) after no known, but likely, exposure to asbestos at work. Conclusions: Because of its extensive use, few people in WA have never been exposed to asbestos. Unrecognized exposure may cause most MM cases initially regarded as "no exposure."

Background: Survival with the epithelioid subtype of malignant mesothelioma (MM) is longer than the biphasic or sarcomatoid subtypes. There is concern that cytology-diagnosed epithelioid MM may underdiagnose the biphasic subtype. This study examines survival differences between patients with epithelioid MM diagnosed by cytology only and other subtypes diagnosed by histology. Methods: Demographics, diagnosis method, MM subtype and survival were extracted from the Western Australia (WA) Mesothelioma Registry, which records details of all MM cases occurring in WA. Results: A total of 2024 MM cases were identified over 42 years. One thousand seven hundred forty-four (86.2%) were male, median (IQR) age was 68.6 (60.4–77.0) years. A total of 1212 (59.9%) cases were identified as epithelioid subtype of which 499 (41.2%) were diagnosed using fluid cytology only. Those with a cytology-only diagnosis were older than the histology group (median 70.2 vs 67.6 years, P<0.001), but median survival was similar (cytology 10.6 (5.5–19.2) vs histology 11.1 (4.8–19.8) months, P=0.727) and Cox regression modelling adjusting for age, sex, site and time since first exposure showed no difference in survival between the different diagnostic approaches. Conclusions: Survival of cytologically and histologically diagnosed epithelioid MM cases does not differ. A diagnostic tap should be considered adequate to diagnose epithelioid MM without need for further invasive testing.

Background & Aims: The pathway to non-alcoholic fatty liver disease (NAFLD) in adolescents may have its origins in adiposity gains, nutrition and sedentary lifestyle established during childhood. There is inadequate knowledge regarding the associations between infant nutrition and subsequent NAFLD. We examined the association of maternal factors and infant nutrition, with the subsequent diagnosis of NAFLD in adolescents. Methods: Adolescents aged 17 years in the Western Australian Pregnancy (Raine) Cohort study had fatty liver assessment using liver ultrasound. Prospectively recorded data on maternal pregnancy and infant feeding were examined against a NAFLD outcome during late adolescence. Results: NAFLD was diagnosed in 15.2% of the 1,170 adolescents examined. Ninety-four percent had been breastfed as infants. The duration of breastfeeding before starting supplementary milk was ⩾4 months in 54.4% and ⩾6 months in 40.6%. Breastfeeding without supplementary milk ⩾6 months (adjusted odds ratio [OR]: 0.64; 95% confidence interval [CI]: 0.43–0.94, p = 0.02), maternal pre-pregnancy obesity (adjusted OR: 2.29; 95% CI: 1.21–4.32, p = 0.01) and adolescent obesity (adjusted OR: 9.08; 95% CI: 6.26–13.17, p <0.001) were associated with NAFLD independent of a Western dietary pattern at 17 years of age. Adolescents with NAFLD who had been breastfed for ⩾6 months had a less adverse metabolic profile compared with adolescents breastfed for <6 months. Supplementary milk intake starting before 6 months was associated with a higher prevalence and ultrasound severity of NAFLD compared with intake starting after 6 months (17.7% vs. 11.2%, p = 0.003 and 7.8% vs. 3.4%, p = 0.005 respectively). Conclusion: Though NAFLD is generally mediated through adiposity gains, breastfeeding for at least 6 months, avoidance of early supplementary formula milk feeding, and normal maternal pre-pregnancy BMI may reduce the odds of a NAFLD diagnosis during adolescence. Lay summary: Non-alcoholic fatty li

Background Reduced gestational age and low birthweight are associated with an increased risk of neonatal infections. However, the long-term risk of infection, especially in late preterm infants or those at near-normal birthweight, is unknown. We estimated whether rates of infection-related admissions to hospital for children in Western Australia were associated with age, gestational age, birthweight, and birth length. Methods We did a population-based, data-linkage study using total-linked, registry data from the Western Australia Birth Register of all liveborn, non-Indigenous Australian singleton births recorded from Jan 1, 1980, to Dec 31, 2010. We followed up individuals from birth-related hospital discharge to age 18 years, death, or end of 2010, and linked to data about subsequent admissions to hospital or death registrations. Gestational age was assessed from both the last menstrual period and from estimates based on ultrasonography. We categorised birthweight by 500 g bands and birth length by 5 cm bands, and approximated the reference ranges for both to the 50th percentile. Because size at birth and gestational age are strongly associated, we calculated Z scores for gestational-specific and sex-specific birthweight, birth length, and ponderal index. Our primary outcomes were the number and type of infection-related admissions to hospital. We used multilevel negative binomial regression to generate rate ratios (RR) for such admissions, identified by codes from the International Classification of Diseases, versions 9 and 10-AM. We adjusted the RRs for maternal age at delivery, birth year, birth season, parity, sex, 5-min Apgar score, delivery method, socioeconomic status, and bronchopulmonary dysplasia. Findings Of 719 311 liveborn singletons included in the analysis and followed up for 8 824 093 person-years, 365 867 infection-related admissions to hospital occurred for 213 683 (30%) children. Of the 719 311 children included in the analysis, 137 124 (19%) ha

Objective: To describe the realities of conducting a cross-jurisdictional data linkage project involving state and Australian Government-based data collections to inform future national data linkage programs of work. Methods: We outline the processes involved in conducting a Proof of Concept data linkage project including the implementation of national data integration principles, data custodian and ethical approval requirements, and establishment of data flows. Results: The approval process involved nine approval and regulatory bodies and took more than two years. Data will be linked across 12 datasets involving three data linkage centres. A framework was established to allow data to flow between these centres while maintaining the separation principle that serves to protect the privacy of the individual. Conclusions: This will be the first project to link child immunisation records from an Australian Government dataset to other administrative health datasets for a population cohort covering 2 million births in two Australian states. Implications: Although the project experienced some delays, positive outcomes were realised, primarily the development of strong collaborations across key stakeholder groups including community engagement. We have identified several recommendations and enhancements to this now established framework to further streamline the process for data linkage studies involving Australian Government data.

It also covers related long-term conditions, such as asthma and COPD. This edition has been completely revised and brought up to date for all physicians dealing with pulmonary disorders caused by the environment or the workplace.

Objectives: To describe the incidence of malignant mesothelioma (MM) in Aboriginal people in Western Australia (WA) and determine the main routes of exposure to asbestos in this population. Methods: All MM cases in Western Australia, as well as the primary source of asbestos exposure, are recorded in the WA Mesothelioma Register. Aboriginal cases up to the end of 2013 were extracted from the register and compared with non-Aboriginal cases with respect to the primary means/source of exposure. Age-standardised incidence rates for each decade from 1980 were calculated for both Aboriginals and non-Aboriginals. Age-standardised mortality rates were calculated for the period 1994–2008 and compared with international rates. Results: There were 39 cases (77% male) of MM among WA Aboriginal people. Twenty-six (67%) were a direct result of the mining of crocidolite at Wittenoom and the subsequent contamination of the surrounding lands. Of the non-Aboriginal MM cases (n = 2070, 86.3% male), fewer than 25% can be attributed to Wittenoom. Aboriginals had consistently higher 10-year incidence rates than non-Aboriginals and, when compared to world populations, the highest mortality rate internationally. Conclusion: When incidence rates in Aboriginal people are compared with non-Aboriginal people, the Wittenoom mining operation has had a disproportionate effect on MM incidence in the local Aboriginal population.

Introduction/Aim: Asbestos exposure is associated with dose-dependent risk of benign pleural disease, lung cancer and mesothelioma. While an association between asbestosis and lung cancer (even after adjustment for asbestos exposure) is well established, the link between lung cancer and the presence of pleural plaque remains controversial with a recent report recent report containing small numbers of lung cancers (from death certificates) reporting an association. Methods: We followed 2218 subjects exposed to crocidolite asbestos as miners (n = 1286) or mine township residents, monitored with annual review, chest radiography (CXR) and outcome linkage to national cancer and mortality registry data over a 25-year period. Subjects were followed up from the date of their latest X-ray taken a year or more before the date of death, cancer incidence or end of follow-up. Hazard ratios for lung cancer were estimated by Cox regression, with age as the underlying matching time variable, for sex, tobacco smoking, asbestos exposure estimates (time since first exposure and fibre/mL years), International Labour Organisation CXR readings for asbestosis (defined as profusion score > 1/0) and presence (and extent) of pleural plaques.Results: Mean age at follow-up was 60.6 years; 1575 (71%) were male; 328 (14.8%) had any pleural plaque, and 359 (16.2%) had asbestosis. One hundred three (4.64%) lung cancers were recorded. One thousand five hundred sixty-eight (70.7%) were ever-smokers with a mean tobacco exposure of 39.3 pack years. Hazard ratios are presented in Table 1.Conclusions: In our population, the presence of pleural plaque is not associated with an increased risk of subsequent lung cancer. As we have demonstrated previously, the presence of asbestosis and cumulative asbestos exposure both contribute to increased subsequent lung cancer risk, although previous tobacco smoke exposure remains the strongest risk factor.

Objectives To estimate quantitative levels of exposure to diesel exhaust expressed by elemental carbon (EC) in the contemporary mining industry and to describe the excess risk of lung cancer that may result from those levels. Methods EC exposure has been monitored in Western Australian miners since 2003. Mixed-effects models were used to estimate EC levels for five surface and five underground occupation groups (as a fixed effect) and specific jobs within each group (as a random effect). Further fixed effects included sampling year and duration, and mineral mined. On the basis of published risk functions, we estimated excess lifetime risk of lung cancer mortality for several employment scenarios. Results Personal EC measurements (n=8614) were available for 146 different jobs at 124 mine sites. The mean estimated EC exposure level for surface occupations in 2011 was 14 mg/m3 for 12 hour shifts. Levels for underground occupation groups ranged from 18 to 44 mg/m3. Underground diesel loader operators had the highest exposed specific job: 59 mg/m3. A lifetime career (45 years) as a surface worker or underground miner, experiencing exposure levels as estimated for 2011 (14 and 44 mg/m3 EC), was associated with 5.5 and 38 extra lung cancer deaths per 1000 males, respectively. Conclusions EC exposure levels in the contemporary Australian mining industry are still substantial, particularly for underground workers. The estimated excess numbers of lung cancer deaths associated with these exposures support the need for implementation of stringent occupational exposure limits for diesel exhaust.

Objective: To investigate seizure outcomes and their relationships to genotype and functional abilities in individuals with the cyclin-dependent kinase-like-5 (CDKL5) disorder. Methods: Using the International CDKL5 Disorder Database, we identified 172 cases with a pathogenic CDKL5 mutation. We categorized individual mutations into 4 groups based on predicted structural and functional consequences. Negative binomial regression was used to model the linear association between current seizure rate and mutation group, current level of assistance required to walk 10 steps, and the highest level of expressive communication used to convey refusal or request. Results: All but 3 (169/172) patients had a history of epilepsy. The median age at seizure onset was 6 weeks (range 1 week-1.5 years) and the median seizure rate at ascertainment was 2 per day (range 0-20 per day). After adjusting for walking ability and confounders including use or otherwise of polytherapy, seizure rate was lower in those with truncating mutations between aa172 and aa781 compared to those with no functional protein (incidence rate ratio [IRR] 0.57; 95% confidence interval [CI] 0.35-0.93). Ability to walk and use of spoken language were associated with lower rates of current seizures when compared to those with the least ability after adjusting for genotype (walking: IRR 0.62; 95% CI 0.39-0.99, communication: IRR 0.48; 95% CI 0.23-1.02). At a median age at questionnaire completion of 5 years, those previously treated with corticosteroids had more frequent seizures than those who have never been treated, whether or not there was a history of infantile spasms. Conclusions: Epilepsy is pervasive but not mandatory for the CDKL5 disorder. Genotype and functional abilities were related to seizure frequency, which appears refractory to antiepileptic drugs.

Functional abilities in the CDKL5 disorder have been described as severely impaired, yet some individuals are able to run and use phrases for speech. Our study investigated gross motor, hand function, and expressive communication abilities in individuals with the CDKL5 disorder. Data for 108 females and 16 males registered with the International CDKL5 disorder database and with a pathogenic CDKL5 mutation were analyzed. Relationships between functional abilities, age, genotype, and gender were analyzed using regression models. Over half of the females could sit on the floor and nearly a quarter could walk 10 steps. Fewer males could complete these tasks although one boy was able to sit, walk, and run. Most females and few males were able to pick up a large object. Females mostly used gestures to communicate while males mostly used other forms of non-verbal communication. Compared to those with no functional CDKL5 protein, individuals with truncating variants after aa 781 were more likely to be able to stand (OR 5.7, 95%CI 1.2, 26.6) or walk independently (4.3, 95%CI 0.9, 20.5), and use more advanced communication methods such as words (OR 6.1, 95%CI 1.5–24.2). Although abilities were markedly impaired for the majority with the CDKL5 disorder, some females and a few males had better functional abilities. This variability may be related to underlying gene variants, with females with a late truncating variant having better levels of ability than those with no functional protein.

Background: Pregnant women are at risk of serious influenza infection. Although previous studies indicate maternal influenza vaccination can prevent hospitalisation in young infants, there is limited evidence of the effect in mothers. Methods: A cohort of 34,701 pregnant women delivering between 1 April 2012 and 31 December 2013 was created using birth records. Principal diagnosis codes from hospital emergency department (ED) and inpatient records were used to identify episodes of acute respiratory illness (ARI) during the 2012 and 2013 southern hemisphere influenza seasons. Cox regression models were used to calculate adjusted hazard ratios (aHRs) by maternal vaccination status, controlling for Indigenous status, socioeconomic level, medical conditions, and week of delivery. Results: 3,007 (8.7%) women received a seasonal influenza vaccine during pregnancy. Vaccinated women were less likely to visit an ED during pregnancy for an ARI (9.7 visits per 10,000 person-days vs. 35.5 visits per 10,000 person-days; aHR: 0.19, 95% CI: 0.05−0.68). Vaccinated women were also less likely to be hospitalised with an ARI compared to unvaccinated women (16.2 hospitalisations per 10,000 person-days vs. 34.0 hospitalisations per 10,000 person-days; aHR: 0.35, 95% CI: 0.13−0.97). Conclusions: Influenza vaccination during pregnancy was associated with significantly fewer hospital attendances for ARI in pregnant women.

BACKGROUND: Infants are at increased risk of hospitalization for influenza. Although vaccinating women during pregnancy has been shown to reduce the incidence of influenza infection among newborns, population-based data are limited. METHODS: A population-based cohort of 31,028 mothers and singleton infants were included in the analysis. Hospitalizations with a principal diagnosis or additional diagnoses consistent with severe respiratory illness occurring during the 2012 and 2013 southern hemisphere influenza seasons were identified using a state-wide hospital discharge database. Newborns were defined as "maternally vaccinated" if the mother received influenza vaccine ≥14 days before delivery. Cox regression models were used to estimate adjusted hazard ratios for hospitalization. RESULTS: A total of 3169 infants were maternally vaccinated and 27,859 were unvaccinated; 732 hospitalizations were identified, 528 (69%) of which were for bronchiolitis. There were 21.9 hospitalizations per 100,000 person days among maternally vaccinated infants and 30.2 hospitalizations per 100,000 person days among unvaccinated infants. Maternally vaccinated infants were 25% less likely to be hospitalized for an acute respiratory illness during influenza season compared with unvaccinated infants (adjusted hazard ratio: 0.75, 95% confidence interval: 0.56-0.99, P = 0.04). Vaccinations administered in the third trimester were associated with a 33% reduction in the risk of newborn hospitalization (adjusted hazard ratio: 0.67, 95% confidence interval: 0.47-0.95, P = 0.03). No such reduction was identified for vaccinations administered earlier in pregnancy. CONCLUSIONS: Maternal influenza vaccination was associated with a reduction in the incidence of hospital admission for acute respiratory illness among infants <6 months of age. These data suggest that vaccination during third trimester may provide optimal benefit to the newborn.

The Western Australian Data Linkage System is one of a few comprehensive, population-based data linkage systems worldwide, creating links between information from different sources relating to the same individual, family, place or event, while maintaining privacy. The Raine Study is an established cohort study with more than 2000 currently active participants. Individual consent was obtained from participants for information in publicly held databases to be linked to their study data. A waiver of consent was granted where it was impracticable to obtain consent. Approvals to link the datasets were obtained from relevant ethics committees and data custodians. The Raine Study dataset was subsequently linked to academic testing data collected by the Western Australian Department of Education. Examination of diet and academic performance showed that children who were predominantly breastfed for at least 6 months scored higher academically at age 10 than children who were breastfed for less than 6 months. A further study found that better diet quality at ages 1, 2 and 3 years was associated with higher academic scores at ages 10 and 12 years. Examination of nutritional intake at 14 years of age found that a better dietary pattern was associated with higher academic performance. The detailed longitudinal data collected in the Raine Study allowed for adjustment for multiple covariates and confounders. Data linkage reduces the burden on cohort participants by providing additional information without the need to contact participants. It can give information on participants who have been lost to follow-up; provide or complement missing data; give the opportunity for validation studies comparing recall of participants with administrative records; increase the population sample of studies by adding control participants from the general population; and allow for the adjustment of multiple covariates and confounders. The Raine Study dataset is extensive and detailed, and can be fu

Introduction: Malignant pleural mesothelioma (MPM) is a rare cancer with a heterogeneous prognosis. Prognostic models are not widely utilized clinically. Classification and regression tree (CART) analysis examines the interaction of multiple variables with a given outcome. Methods: Between 2005 and 2014, all cases with pathologically confirmed MPM had routinely available histological, clinical, and laboratory characteristics recorded. Classification and regression tree analysis was performed using 29 variables with 18-month survival as the dependent variable. Risk groups were refined according to survival and clinical characteristics. The model was then tested on an external international cohort. Results: A total of 482 cases were included in the derivation cohort; the median survival was 12.6 months, and the median age was 69 years. The model defined four risk groups with clear survival differences (p < 0.0001). The strongest predictive variable was the presence of weight loss. The group with the best survival at 18 months (86.7% alive, median survival 34.0 months, termed risk group 1) had no weight loss, a hemoglobin level greater than 153 g/L, and a serum albumin level greater than 43 g/L. The group with the worst survival (0% alive, median survival 7.5 months, termed risk group 4d) had weight loss, a performance score of 0 or 1, and sarcomatoid histological characteristics. The C-statistic for the model was 0.761, and the sensitivity was 94.5%. Validation on 174 external cases confirmed the model's ability to discriminate between risk groups in an alternative data set with fair performance (C-statistic 0.68). Conclusions: We have developed and validated a simple, clinically relevant model to reliably discriminate patients at high and lower risk of death using routinely available variables from the time of diagnosis in unselected populations of patients with MPM.

Background: Although antenatal influenza vaccination is an important public health intervention for preventing serious infection in pregnant women and newborns, reported vaccine coverage is often <50%. Concern for the safety to the fetus is a commonly cited reason for vaccine hesitancy and refusal. The incidence of stillbirth following pandemic vaccination has been previously studied; however, no population-based study has evaluated the incidence of stillbirth following seasonal trivalent influenza vaccination. Methods: We used probabilistic linking of perinatal and maternal vaccination records to establish a cohort of 58 008 births occurring between April 2012 and December 2013. Stillbirth was defined as birth ≥20 weeks’ gestation with an Apgar score of zero at 1 and 5 minutes following delivery. Cox regression models adjusted for maternal smoking, Indigenous status, and propensity for vaccination were used to calculate adjusted hazard ratios (aHRs) in vaccinated and unvaccinated mothers. Results: A total of 5076 (8.8%) pregnant women received trivalent influenza vaccine and 377 stillbirths occurred. There were 5.0 and 3.0 stillbirths per 100 000 pregnancy-days among unvaccinated and vaccinated women, respectively. After adjustment, stillbirth was 51% less likely among vaccinated vs unvaccinated mothers (aHR, 0.49; 95% confidence interval [CI], .29–.84). The largest relative reduction in stillbirths was observed for births occurring just after influenza season (aHR, 0.33; 95% CI, .12–.88). Conclusions: Mothers who received seasonal TIV during pregnancy were significantly less likely to experience stillbirth compared with unvaccinated mothers. These results support the safety of seasonal influenza immunization during pregnancy and suggest a protective effect.