Relative Risks of Adverse Perinatal Outcomes in Three Australian Communities Exposed to Per- and Polyfluoroalkyl Substances: Data Linkage Study.

INTRODUCTION: Firefighting foams containing per- and polyfluoroalkyl substances (PFAS) have caused environmental contamination in several Australian residential areas, including Katherine in the Northern Territory (NT), Oakey in Queensland (Qld), and Williamtown in New South Wales (NSW). We examined whether the risks of adverse perinatal outcomes were higher in mothers living in these exposure areas than in selected comparison areas without known contamination. METHODS: We linked residential addresses in exposure areas to addresses collected in the jurisdictional Perinatal Data Collections of the NT (1986-2017), Qld (2007-2018), and NSW (1994-2018) to select all pregnancies from mothers who gave birth while living in these areas. We also identified one comparison group for each exposure area by selecting pregnancies where the maternal address was in selected comparison areas. We examined 12 binary perinatal outcomes and three growth measurements. For each exposure area, we estimated relative risks (RRs) of adverse outcomes and differences in means of growth measures, adjusting for sociodemographic characteristics and other potential confounders. RESULTS: We included 16,970 pregnancies from the NT, 4654 from Qld, and 7475 from NSW. We observed elevated risks of stillbirth in Oakey (RR = 2.59, 95% confidence interval (CI) 1.25 to 5.39) and of postpartum haemorrhage (RR = 1.94, 95% CI 1.13 to 3.33) and pregnancy-induced hypertension (RR = 1.88, 95% CI 1.30 to 2.73) in Williamtown. The risks of other perinatal outcomes were not materially different from those in the relevant comparison areas or were uncertain due to small numbers of events. CONCLUSIONS: There was limited evidence for increased risks of adverse perinatal outcomes in mothers living in areas with PFAS contamination from firefighting foams. We found higher risks of some outcomes in individual areas, but these were not consistent across all areas under study and could have been due to chance, bias, or confounding.

Psychological distress in three Australian communities living with environmental per- and polyfluoroalkyl substances contamination.

BACKGROUND: Environmental chemical contamination is a recognised risk factor for psychological distress, but has been seldom studied in the context of per- and polyfluoroalkyl substances (PFAS) contamination. We examined psychological distress in a cross-sectional study of three Australian communities exposed to PFAS from the historical use of aqueous film-forming foam in firefighting activities, and three comparison communities without environmental contamination. METHODS: Participation was voluntary following recruitment from a PFAS blood-testing program (exposed) or random selection (comparison). Participants provided blood samples and completed a survey on their exposure history, sociodemographic characteristics, and four measures of psychological distress (Kessler-6, Distress Questionnaire-5, Patient Health Questionnaire-15, and Generalised Anxiety Disorder-7). We estimated prevalence ratios (PR) of clinically-significant psychological distress scores, and differences in mean scores: (1) between exposed and comparison communities; (2) per doubling in PFAS serum concentrations in exposed communities; (3) for factors that affect the perceived risk of living in a community exposed to PFAS; and (4) in relation to self-reported health concerns. RESULTS: We recruited 881 adults in exposed communities and 801 in comparison communities. We observed higher levels of self-reported psychological distress in exposed communities than in comparison communities (e.g., Katherine compared to Alice Springs, Northern Territory: clinically-significant anxiety scores, adjusted PR = 2.82, 95 % CI 1.16-6.89). We found little evidence to suggest that psychological distress was associated with PFAS serum concentrations (e.g., Katherine, PFOS and anxiety, adjusted PR = 0.85, 95 % CI 0.65-1.10). Psychological distress was higher among exposed participants who were occupationally exposed to firefighting foam, used bore water on their properties, or were concerned about their health. CONCLUSION: Psychological distress was substantially more prevalent in exposed communities than in comparison communities. Our findings suggest that the perception of risks to health, rather than PFAS exposure, contribute to psychological distress in communities with PFAS contamination.

Liver and cardiometabolic markers and conditions in a cross-sectional study of three Australian communities living with environmental per- and polyfluoroalkyl substances contamination.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) have been associated with higher cholesterol and liver function markers in some studies, but the evidence for specific cardiometabolic conditions has been inconclusive. OBJECTIVES: We quantified the associations of single and combined PFAS with cardiometabolic markers and conditions in a cross-sectional study of three Australian communities with PFAS-contaminated water from the historical use of aqueous film-forming foam in firefighting activities, and three comparison communities. METHODS: Participants gave blood samples for measurement of nine PFAS, four lipids, six liver function markers, and completed a survey on sociodemographic characteristics and eight cardiometabolic conditions. We estimated differences in mean biomarker concentrations per doubling in single PFAS concentrations (linear regression) and per interquartile range increase in the PFAS mixture (Bayesian kernel machine regression). We estimated prevalence ratios of biomarker concentrations outside reference limits and self-reported cardiometabolic conditions (Poisson regression). RESULTS: We recruited 881 adults in exposed communities and 801 in comparison communities. We observed higher mean total cholesterol with higher single and mixture PFAS concentrations in blood serum (e.g., 0.18 mmol/L, 95% credible interval -0.06 to 0.42, higher total cholesterol concentrations with an interquartile range increase in all PFAS concentrations in Williamtown, New South Wales), with varying certainty across communities and PFAS. There was less consistency in direction of associations for liver function markers. Serum perfluorooctanoic acid (PFOA) concentrations were positively associated with the prevalence of self-reported hypercholesterolemia in one of three communities, but PFAS concentrations were not associated with self-reported type II diabetes, liver disease, or cardiovascular disease. DISCUSSION: Our study is one of few that has simultaneously quantified the associations of blood PFAS concentrations with multiple biomarkers and cardiometabolic conditions in multiple communities. Our findings for total cholesterol were consistent with previous studies; however, substantial uncertainty in our estimates and the cross-sectional design limit causal inference.

Progressivity of out-of-pocket costs under Australia's universal health care system: A national linked data study.

BACKGROUND: In line with affordability and equity principles, Medicare-Australia's universal health care program-has measures to contain out-of-pocket (OOP) costs, particularly for lower income households. This study examined the distribution of OOP costs for Medicare-subsidised out-of-hospital services and prescription medicines in Australian households, according to their ability to pay. METHODS: OOP costs for out-of-hospital services and medicines in 2017-18 were estimated for each household, using 2016 Australian Census data linked to Medicare Benefits Schedule (MBS) and Pharmaceutical Benefit Scheme (PBS) claims. We derived household disposable income by combining income information from the Census linked to income tax and social security data. We quantified OOP costs as a proportion of equivalised household disposable income and calculated Kakwani progressivity indices (K). RESULTS: Using data from 82% (n = 6,830,365) of all Census private households, OOP costs as a percentage of equivalised household disposable income decreased from 1.16% in the poorest decile to 0.63% in the richest decile for MBS services, and from 1.35% to 0.35% for PBS medicines. The regressive trend was less pronounced for MBS services (K = -0.06), with percentage OOP cost relatively stable between the 2nd and 9th income deciles; while percentage OOP cost decreased with increasing income for PBS medicines (K = -0.24). CONCLUSION: OOP costs for out-of-hospital Medicare services were mildly regressive while those for prescription medicines were distinctly regressive. Actions to reduce inequity in OOP costs, particularly for medicines, should be considered.

Education-related inequalities in cause-specific mortality: first estimates for Australia using individual-level linked census and mortality data.

BACKGROUND: Socioeconomic inequalities in mortality are evident in all high-income countries, and ongoing monitoring is recommended using linked census-mortality data. Using such data, we provide the first estimates of education-related inequalities in cause-specific mortality in Australia, suitable for international comparisons. METHODS: We used Australian Census (2016) linked to 13 months of Death Registrations (2016-17). We estimated relative rates (RR) and rate differences (RD, per 100 000 person-years), comparing rates in low (no qualifications) and intermediate (secondary school) with high (tertiary) education for individual causes of death (among those aged 25-84 years) and grouped according to preventability (25-74 years), separately by sex and age group, adjusting for age, using negative binomial regression. RESULTS: Among 13.9 M people contributing 14 452 732 person-years, 84 743 deaths occurred. All-cause mortality rates among men and women aged 25-84 years with low education were 2.76 [95% confidence interval (CI): 2.61-2.91] and 2.13 (2.01-2.26) times the rates of those with high education, respectively. We observed inequalities in most causes of death in each age-sex group. Among men aged 25-44 years, relative and absolute inequalities were largest for injuries, e.g. transport accidents [RR = 10.1 (5.4-18.7), RD = 21.2 (14.5-27.9)]). Among those aged 45-64 years, inequalities were greatest for chronic diseases, e.g. lung cancer [men RR = 6.6 (4.9-8.9), RD = 57.7 (49.7-65.8)] and ischaemic heart disease [women RR = 5.8 (3.7-9.1), RD = 20.2 (15.8-24.6)], with similar patterns for people aged 65-84 years. When grouped according to preventability, inequalities were large for causes amenable to behaviour change and medical intervention for all ages and causes amenable to injury prevention among young men. CONCLUSIONS: Australian education-related inequalities in mortality are substantial, generally higher than international estimates, and related to preventability. Findings highlight opportunities to reduce them and the potential to improve the health of the population.

Real price of health-experiences of out-of-pocket costs in Australia: protocol for a systematic review.

INTRODUCTION: Australians have substantial out-of-pocket (OOP) health costs compared with other developed nations, even with universal health insurance coverage. This can significantly affect access to care and subsequent well-being, especially for priority populations including those on lower incomes or with multimorbidity and chronic illness. While it is known that high OOP healthcare costs may contribute to poorer health outcomes, it is not clear exactly how these expenses are experienced by people with chronic illnesses. Understanding this may provide critical insights into the burden of OOP costs among this population group and may highlight policy gaps. METHOD AND ANALYSIS: A systematic review of qualitative studies will be conducted using Pubmed, CINAHL Complete (EBSCO), Cochrane Library, PsycINFO (Ovid) and EconLit from date of inception to June 2022. Primary outcomes will include people's experiences of OOP costs such as their preferences, priorities, trade-offs and other decision-making considerations. Study selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and methodological appraisal of included studies will be assessed using the Critical Appraisal Skills Programme. A narrative synthesis will be conducted for all included studies. ETHICS AND DISSEMINATION: Ethics approval was not required given this is a systematic review that does not include human recruitment or participation. The study's findings will be disseminated through conferences and symposia and shared with consumers, policymakers and service providers, and published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42022337538.

The ATHENA COVID-19 Study: Cohort profile and first findings for people diagnosed with COVID-19 in Queensland, 1 January to 31 December 2020.

BACKGROUND: To date, there are limited Australian data on characteristics of people diagnosed with COVID-19 and on how these characteristics relate to outcomes. The ATHENA COVID-19 Study was established to describe health outcomes and investigate predictors of outcomes for all people diagnosed with COVID-19 in Queensland by linking COVID-19 notification, hospital, general practice and death registry data. This paper reports on the establishment and first findings for the ATHENA COVID-19 Study. METHODS: Part 1 of the ATHENA COVID-19 Study used Notifiable Conditions System data from 1 January 2020 to 31 December 2020, linked to: Emergency Department Collection data for the same period; Queensland Health Admitted Patient Data Collections (from 1 January 2010 to 30 January 2021); and Deaths Registrations data (from 1 January 2020 to 17 January 2021). RESULTS: To 31 December 2020, a total of 1,254 people had been diagnosed with SARS-CoV-2 infection in Queensland: half were female (49.8%); two-thirds (67.7%) were aged 20-59 years; and there was an over-representation of people living in less-disadvantaged areas. More than half of people diagnosed (57.6%) presented to an ED; 21.2% were admitted to hospital as an inpatient (median length of stay 11 days); 1.4% were admitted to an intensive care unit (82.4% of these required ventilation); and there were six deaths. Analysis of factors associated with these outcomes was limited due to small case numbers: people living in less-disadvantaged areas had a lower risk of being admitted to hospital (test for trend, p < 0.001), while those living in more remote areas were less likely than people living in major cities to present to an ED (test for trend: p=0.007), which may reflect differential health care access rather than health outcomes per se. Increasing age (test for trend, p < 0.001) and being a current/recent smoker (age-sex-adjusted relative risk: 1.61; 95% confidence interval: 1.00, 2.61) were associated with a higher risk of being admitted to hospital. CONCLUSION: Despite uncertainty in our estimates due to small numbers, our findings are consistent with what is known about COVID-19. Our findings reinforce the value of linking multiple data sources to enhance reporting of outcomes for people diagnosed with COVID-19 and provide a platform for longer term follow-up.

DOCK8 deficiency diminishes thymic T-regulatory cell development but not thymic deletion.

OBJECTIVE: To define the effect of DOCK8 deficiency on thymic tolerance in mice. METHODS: Thymocytes from wild-type (Dock8+/+ ) and DOCK8-deficient (Dock8pri/pri ) mice were examined by flow cytometry. Some mice had transgenic expression of the BCL2 anti-apoptotic protein in haemopoietic cells. Some mice expressed the transgenic 3A9 T-cell receptor (TCR), which triggers thymocyte deletion in mice also expressing hen egg lysozyme under the insulin promoter. RESULTS: In Dock8pr/pri mice, the proportion of thymocytes induced to acquire tolerance at the immature CCR7- stage was normal. Deletion of strongly self-reactive CD4+ thymocytes occurred efficiently in Dock8pri/pri mice in a TCR-transgenic model that requires self-antigen transfer from epithelial cells to bone marrow (BM)-derived antigen-presenting cells. Thymic Foxp3+ T-regulatory cells (TREG) and Helios+ Foxp3- TREG precursors were decreased in Dock8pri/pri mice, including when apoptosis was inhibited by BCL2 transgene expression. Dock8pri/pri thymic TREG expressed CD25 and CTLA-4 at normal levels. The results suggest that DOCK8 deficiency does not affect the function of BM-derived antigen-presenting cells in the thymus, the TCR self-reactivity threshold that activates tolerance mechanisms in thymocytes or the apoptotic deletion of these thymocytes. However, DOCK8 is required to prevent a subset of developing TREG cells from undergoing cell death via a mechanism that is distinct from apoptosis. CONCLUSION: DOCK8 deficiency diminishes TREG development in the thymus without compromising thymocyte deletion.

Protection from EAE in DOCK8 mutant mice occurs despite increased Th17 cell frequencies in the periphery.

Mutation of Dedicator of cytokinesis 8 (DOCK8) has previously been reported to provide resistance to the Th17 cell dependent EAE in mice. Contrary to expectation, we observed an elevation of Th17 cells in two different DOCK8 mutant mouse strains in the steady state. This was specific for Th17 cells with no change in Th1 or Th2 cell populations. In vitro Th cell differentiation assays revealed that the elevated Th17 cell population was not due to a T cell intrinsic differentiation bias. Challenging these mutant mice in the EAE model, we confirmed a resistance to this autoimmune disease with Th17 cells remaining elevated systemically while cellular infiltration in the CNS was reduced. Infiltrating T cells lost the bias toward Th17 cells indicating a relative reduction of Th17 cells in the CNS and a Th17 cell specific migration disadvantage. Adoptive transfers of Th1 and Th17 cells in EAE-affected mice further supported the Th17 cell-specific migration defect, however, DOCK8-deficient Th17 cells expressed normal Th17 cell-specific CCR6 levels and migrated toward chemokine gradients in transwell assays. This study shows that resistance to EAE in DOCK8 mutant mice is achieved despite a systemic Th17 bias.

The importance of including aliases in data linkage with vulnerable populations.

BACKGROUND: Records pertaining to individuals whose identity cannot be verified with legal documentation may contain errors, or be incorrect by intention of the individual. Probabilistic data linkage, especially in vulnerable populations where the incidence of such records may be higher, must be considerate of the usage of these records. METHODS: A data linkage was conducted between Queensland Youth Justice records and the Australian National Death Index. Links were assessed to determine how often they were made using the unverified (alias) records that would not have been made in their absence (i.e. links that were not also made using solely verified records). Anomalies in the linked records were investigated in order to make evaluations of the sensitivity and specificity of the linkage, compared to the links made using only verified records. RESULTS: From links made using verified records only, 1309 deaths were identified (2.6% of individuals). Using alias records in addition, the number of links increased by 16%. Links made using alias records only were more common in females, and those born after 1985. Different records belonging to the same individual in the justice dataset did not link to different death records, however there were instances of the same death record linking to multiple cohort individuals. CONCLUSIONS: The inclusion of aliases in data linkage in youths involved in the justice system increased mortality ascertainment without any discernible increase in false positive matches. We therefore conclude that alias records should be included in data linkage procedures in order to avoid biased attenuation of ascertainment in vulnerable populations, leading to the concealment of health inequality.

Risk of cancer associated with residential exposure to asbestos insulation: a whole-population cohort study.

BACKGROUND: The health risks associated with living in houses insulated with asbestos are unknown. Loose-fill asbestos was used to insulate some houses in the Australian Capital Territory (ACT). We compared the incidence of mesothelioma and other cancers in residents of the ACT who did and did not live in these houses. METHODS: Our cohort study included all ACT residents identified using Medicare enrolment data. These data were linked to addresses of affected residential properties in the ACT to ascertain exposure. We followed up residents by linking data to the Australian Cancer Database and National Death Index. Outcomes were diagnosis of mesothelioma and selected other cancers. Effects were estimated for males and females separately using standardised incidence ratios (SIRs), adjusting for age and calendar time of diagnosis. FINDINGS: Between Nov 1, 1983, and Dec 31, 2013, 1 035 578 ACT residents were identified from the Medicare database. Of these, 17 248 (2%) had lived in an affected property, including seven (2%) of 285 people diagnosed with mesothelioma. The adjusted incidence of mesothelioma in males who had lived at an affected property was 2·5 times that of unexposed males (SIR 2·54, 95% CI 1·02-5·24). No mesotheliomas were reported among females who had lived at an affected property. Among individuals who had lived at an affected property, there was an elevated incidence of colorectal cancer in women (SIR 1·73, 95% CI 1·29-2·26) and prostate cancer in men (1·29, 1·07-1·54); colorectal cancer was increased, although not significantly, in males (SIR 1·32, 95% CI 0·99-1·72), with no significant increase in the other cancers studied. INTERPRETATION: Residential asbestos insulation is likely to be unsafe. Our findings have important health, social, financial, and legal implications for governments and communities in which asbestos has been used to insulate houses. FUNDING: ACT Government.

Human lymphoma mutations reveal CARD11 as the switch between self-antigen-induced B cell death or proliferation and autoantibody production.

Self-tolerance and immunity are actively acquired in parallel through a poorly understood ability of antigen receptors to switch between signaling death or proliferation of antigen-binding lymphocytes in different contexts. It is not known whether this tolerance-immunity switch requires global rewiring of the signaling apparatus or if it can arise from a single molecular change. By introducing individual CARD11 mutations found in human lymphomas into antigen-activated mature B lymphocytes in mice, we find here that lymphoma-derived CARD11 mutations switch the effect of self-antigen from inducing B cell death into T cell-independent proliferation, Blimp1-mediated plasmablast differentiation, and autoantibody secretion. Our findings demonstrate that regulation of CARD11 signaling is a critical switch governing the decision between death and proliferation in antigen-stimulated mature B cells and that mutations in this switch represent a powerful initiator for aberrant B cell responses in vivo.