Excess Deaths Associated with Rheumatic Heart Disease, Australia, 2013-2017.

During 2013-2017, the mortality rate ratio for rheumatic heart disease among Indigenous versus non-Indigenous persons in Australia was 15.9, reflecting health inequity. Using excess mortality methods, we found that deaths associated with rheumatic heart disease among Indigenous Australians were probably substantially undercounted, affecting accuracy of calculations based solely on Australian Bureau of Statistics data.

Long-Term Pattern and Associated Costs of Re-hospitalisations in Patients After Index Atrial Fibrillation Admission in Western Australia, 2011-2017.

AIMS: This study aimed to determine total and cardiovascular-specific re-hospitalisation patterns and associated costs within 2 years of index atrial fibrillation (AF) admission in Western Australia (WA). METHOD: Patients aged 25-94 years, surviving an index (first-in-period) AF hospitalisation (principal diagnosis) from 2011 to 2015 were identified from WA-linked administrative data and followed for 2 years. Person-level hospitalisation costs ($ Australian dollar) were computed using the Australian Refined Diagnosis Related Groups and presented as median with first and third quartile costs. RESULTS: The cohort comprised 17,080 patients, 59.0% men, mean age 69.6±13.3 (standard deviation) years, and 59.0% had a CHA2DS2-VA (one point for congestive heart failure, hypertension, diabetes mellitus, vascular disease or age 65-74 years; two points for prior stroke/transient ischaemic attack or age ≥75 years) score of 2 or more. Within 2 years, 13,776 patients (80.6%) were readmitted with median of 2 (1-4) readmissions. Among total all-cause readmissions (n=54,240), 40.1% were emergent and 36.6% were cardiovascular-related, led by AF (19.5%), coronary events (5.8%), and heart failure (4.2%). The median index AF admission cost was $3,264 ($2,899-$7,649) while cardiovascular readmission costs were higher, particularly stroke ($10,732 [$4,179-23,390]), AF ablation ($7,884 [$5,283-$8,878]), and heart failure ($6,759 [$6,081-$13,146]). Average readmission costs over 2 years per person increased by $4,746 (95% confidence interval [CI] $4,459-$5,033) per unit increase in baseline CHA2DS2-VA score. The average 2-year hospitalisation costs per patient, including index admission, was $27,820 (95% CI $27,308-$28,333) and total WA costs were $475.2 million between 2011 and 2017. CONCLUSIONS: Patients after index AF hospitalisation have a high risk of cardiovascular and other readmissions with considerable healthcare cost implications. Readmission costs increased progressively with baseline CHA2DS2-VA score. Better integrated management of AF and coexistent comorbidities is likely key to reducing readmissions and associated costs.

High-coverage plasma lipidomics reveals novel sex-specific lipidomic fingerprints of age and BMI: Evidence from two large population cohort studies.

Obesity and related metabolic diseases show clear sex-related differences. The growing burden of these diseases calls for better understanding of the age- and sex-related metabolic consequences. High-throughput lipidomic analyses of population-based cohorts offer an opportunity to identify disease-risk-associated biomarkers and to improve our understanding of lipid metabolism and biology at a population level. Here, we comprehensively examined the relationship between lipid classes/subclasses and molecular species with age, sex, and body mass index (BMI). Furthermore, we evaluated sex specificity in the association of the plasma lipidome with age and BMI. Some 747 targeted lipid measures, representing 706 molecular lipid species across 36 classes/subclasses, were measured using a high-performance liquid chromatography coupled mass spectrometer on a total of 10,339 participants from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), with 563 lipid species being validated externally on 4,207 participants of the Busselton Health Study (BHS). Heat maps were constructed to visualise the relative differences in lipidomic profile between men and women. Multivariable linear regression analyses, including sex-interaction terms, were performed to assess the associations of lipid species with cardiometabolic phenotypes. Associations with age and sex were found for 472 (66.9%) and 583 (82.6%) lipid species, respectively. We further demonstrated that age-associated lipidomic fingerprints differed by sex. Specific classes of ether-phospholipids and lysophospholipids (calculated as the sum composition of the species within the class) were inversely associated with age in men only. In analyses with women alone, higher triacylglycerol and lower lysoalkylphosphatidylcholine species were observed among postmenopausal women compared with premenopausal women. We also identified sex-specific associations of lipid species with obesity. Lysophospholipids were negatively associated with BMI in both sexes (with a larger effect size in men), whilst acylcarnitine species showed opposing associations based on sex (positive association in women and negative association in men). Finally, by utilising specific lipid ratios as a proxy for enzymatic activity, we identified stearoyl CoA desaturase (SCD-1), fatty acid desaturase 3 (FADS3), and plasmanylethanolamine Δ1-desaturase activities, as well as the sphingolipid metabolic pathway, as constituent perturbations of cardiometabolic phenotypes. Our analyses elucidate the effect of age and sex on lipid metabolism by offering a comprehensive view of the lipidomic profiles associated with common cardiometabolic risk factors. These findings have implications for age- and sex-dependent lipid metabolism in health and disease and suggest the need for sex stratification during lipid biomarker discovery, establishing biological reference intervals for assessment of disease risk.

Correction: High-coverage plasma lipidomics reveals novel sex-specific lipidomic fingerprints of age and BMI: Evidence from two large population cohort studies.

[This corrects the article DOI: 10.1371/journal.pbio.3000870.].

Is it advisable to perform radiosurgery for EGFR-TKI-controlled brain metastases? A retrospective study of the role of radiosurgery in lung cancer treatment.

PURPOSE: Given the availability of TKIs with high central nervous system efficacy, the question arises as to whether upfront SRS provides additional clinical benefits. The goal of this study was to characterize the clinical outcomes of SRS as salvage therapy for TKI-uncontrolled BMs. METHODS: This retrospective study included EGFR-mutant NSCLC patients presenting BMs at the time of primary tumor diagnosis. BMs were categorized into three subgroups, referred to as "Nature of TKI-treated BMs", "TKI-controlled brain metastases ± SRS", and "SRS salvage therapy". The first subgroup analysis characterized the effects of TKIs on tumor behavior. In the second subgroup, we compared outcomes of TKI-controlled BMs treated with TKI alone versus those treated with combined TKI-SRS therapy. The third subgroup characterized the outcomes of TKI-uncontrolled BMs treated with SRS as salvage therapy Clinical outcomes include local and distant tumor control. RESULTS: This study included 106 patients with a total of 683 BMs. TKI treatment achieved control in 63% of local tumors at 24 months. Among the TKI-controlled BMs, local tumor control was significantly higher in the combined TKI-SRS group (93%) than in the TKI-alone group (65%) at 24 months (p < 0.001). No differences were observed between the two groups in terms of distant tumor control (p = 0.832). In dealing with TKI-uncontrolled BMs, salvage SRS achieved local tumor control in 58% of BMs at 24 months. CONCLUSIONS: While upfront TKI alone proved highly effective in BM control, this study also demonstrated the outcomes of SRS when implemented concurrently with TKI or as salvage therapy for TKI-uncontrolled BMs. This study also presents a strategy of the precise timing and targeting of SRS to lesions in progression.

Evidence-based medication adherence among seniors in the first year after heart failure hospitalisation and subsequent long-term outcomes: a restricted cubic spline analysis of adherence-outcome relationships.

PURPOSE: Non-adherence to heart failure (HF) medications is associated with poor outcomes. We used restricted cubic splines (RCS) to assess the continuous relationship between adherence to renin-angiotensin system inhibitors (RASI) and ß-blockers and long-term outcomes in senior HF patients. METHODS: We identified a population-based cohort of 4234 patients, aged 65-84 years, 56% male, who were hospitalised for HF in Western Australia between 2003 and 2008 and survived to 1-year post-discharge (landmark date). Adherence was calculated using the proportion of days covered (PDC) in the first year post-discharge. RCS Cox proportional-hazards models were applied to determine the relationship between adherence and all-cause death and death/HF readmission at 1 and 3 years after the landmark date. RESULTS: RCS analysis showed a curvilinear adherence-outcome relationship for both RASI and ß-blockers which was linear above PDC 60%. For each 10% increase in RASI and ß-blocker adherence above this level, the adjusted hazard ratio for 1-year all-cause death fell by an average of 6.6% and 4.8% respectively (trend p < 0.05) and risk of all-cause death/HF readmission fell by 5.4% and 5.8% respectively (trend p < 0.005). Linear reductions in adjusted risk for these outcomes at PDC ≥ 60% were also seen at 3 years after landmark date (all trend p < 0.05). CONCLUSION: RCS analysis showed that for RASI and ß-blockers, there was no upper adherence level (threshold) above 60% where risk reduction did not continue to occur. Therefore, interventions should maximise adherence to these disease-modifying HF pharmacotherapies to improve long-term outcomes after hospitalised HF.

Unplanned 30-day readmissions, comorbidity and impact on one-year mortality following incident heart failure hospitalisation in Western Australia, 2001-2015.

BACKGROUND: Readmissions within 30 days after heart failure (HF) hospitalisation is considered an important healthcare quality metric, but their impact on medium-term mortality is unclear within an Australian setting. We determined the frequency, risk predictors and relative mortality risk of 30-day unplanned readmission in patients following an incident HF hospitalisation. METHODS: From the Western Australian Hospitalisation Morbidity Data Collection we identified patients aged 25-94 years with an incident (first-ever) HF hospitalisation as a principal diagnosis between 2001 and 2015, and who survived to 30-days post discharge. Unplanned 30-day readmissions were categorised by principal diagnosis. Logistic and Cox regression analysis determined the independent predictors of unplanned readmissions in 30-day survivors and the multivariable-adjusted hazard ratio (HR) of readmission on mortality within the subsequent year. RESULTS: The cohort comprised 18,241 patients, mean age 74.3 ± 13.6 (SD) years, 53.5% males, and one-third had a modified Charlson Comorbidity Index score of ≥ 3. Among 30-day survivors, 15.5% experienced one or more unplanned 30-day readmission, of which 53.9% were due to cardiovascular causes; predominantly HF (31.4%). The unadjusted 1-year mortality was 15.9%, and the adjusted mortality HR in patients with 1 and ≥ 2 cardiovascular or non-cardiovascular readmissions (versus none) was 1.96 (95% confidence interval (CI) 1.80-2.14) and 3.04 (95% CI, 2.51-3.68) respectively. Coexistent comorbidities, including ischaemic heart disease/myocardial infarction, peripheral arterial disease, pneumonia, chronic kidney disease, and anaemia, were independent predictors of both 30-day unplanned readmission and 1-year mortality. CONCLUSION: Unplanned 30-day readmissions and medium-term mortality remain high among patients who survived to 30 days after incident HF hospitalisation. Any cardiovascular or non-cardiovascular readmission was associated with a two to three-fold higher adjusted HR for death over the following year, and various coexistent comorbidities were important associates of readmission and mortality risk. Our findings support the need to optimize multidisciplinary HF and multimorbidity management to potentially reduce repeat hospitalisation and improve survival.

Unplanned Readmissions and Long-Term Mortality Risk After Incident Heart Failure Hospitalisation in Western Australia, 2001-2015.

AIMS: To investigate the frequency and predictors of unplanned readmissions after incident heart failure (HF) hospitalisation and the association between readmissions and mortality over two years. METHODS: We performed a retrospective cohort study using Western Australian morbidity and mortality data to identify all patients, aged 25-94 years, who survived an incident (first-ever) HF hospitalisation (principal diagnosis) between 2001-2015. Ordinal logistic regression models determined the covariates independently associated with unplanned readmission(s). Cox proportional hazards models with time-varying exposures determined the hazard ratios (HR) of one or more readmissions for mortality over two years after incident HF. RESULTS: Of 18,693 patients, 53.4% male, mean age 74.4 (standard deviation [SD] 13.6) years, 61.3% experienced 32,431 unplanned readmissions (39.7% cardiovascular-related) within two years. Leading readmission causes were HF (19.1%), respiratory diseases (12.6%), and ischaemic heart disease (9.6%). All-cause death occurred in 27.2% of the cohort, and the multivariable-adjusted mortality HR of 1 (versus 0) readmission was 2.5 (95% confidence interval [CI], 2.3-2.7) increasing to 5.0 (95% CI, 4.7-5.4) for 2+ readmissions. The adjusted mortality HR of 1 and 2+ (versus 0) HF-specific readmission was 2.0 (95% CI, 1.8-2.1) and 3.6 (95% CI, 3.2-3.9), respectively. Coexistent cardiovascular and other comorbidities were independently associated with increased readmission and mortality risk. CONCLUSION: This study underlines the high burden of recurrent unplanned cardiovascular and other readmissions within two years after incident HF hospitalisation, and their additive adverse impact on mortality. Integrated multidisciplinary management of concomitant comorbidities, in addition to HF-targeted treatments, is necessary to improve long-term prognosis in HF patients.

DXA-Derived vs Standard Anthropometric Measures for Predicting Cardiometabolic Risk in Middle-Aged Australian Men and Women.

It is not clear if dual-energy X-ray absorptiometry (DXA) adiposity measures are superior to standard anthropometric measures for predicting cardiometabolic (CM) risk factors in a middle-aged general population. In the Busselton Healthy Ageing Study, we assessed a range of standard anthropometric and DXA-derived adiposity measures to predict metabolic syndrome (MetS) and CM risk factors in 4831 "baby boomers" aged 45-69 yr. Anthropometric and whole body DXA (GE Lunar Prodigy) measures were collected. Cross-sectional relationships of overall adiposity (BMI; DXA fat mass index, body fat %), central adiposity (waist circumference (WC); DXA trunk fat, android fat, abdominal visceral adipose tissue (VAT)) and ratio index (waist-to-hip ratio; DXA trunk/legs fat, android/gynoid ratio, VAT/total fat) with MetS and its components (as both continuous and binary outcomes) were evaluated using linear and logistic regression adjusting for age and lifestyle factors. Youden's Index was used to determine the optimal cut-points for predicting MetS. In linear regression analyses, central adiposity measures showed stronger associations with MetS score and CM risk factors than overall adiposity measures and fat ratio index, and DXA-VAT provided stronger associations than WC. Logistic regression models showed similar findings. For MetS diagnosis present in 35.9% of males and 24.4% of females, the highest odds ratio (95% CI) per SD change was observed for DXA-VAT (males: 5.02 [4.28, 5.88]; females: 3.91 [3.40, 4.49]), which remained significant (all p < 0.001) after further adjustment for BMI (males: 3.27 [2.65, 4.02]; females: 3.37 [2.79, 4.06]) or WC (males: 2.46 [1.95, 3.10]; females: 2.75 [2.21, 3.43]). The optimal DXA-VAT mass cut-point for predicting MetS was 1608 grams in males and 893 grams in females. DXA-VAT was superior to standard anthropometric and other DXA-derived adiposity measures for prediction of cardiometabolic risk factors, and has clinical utility for identifying middle-aged individuals at increased risk of MetS.

APOE ε2 resilience for Alzheimer's disease is mediated by plasma lipid species: Analysis of three independent cohort studies.

INTRODUCTION: The apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood. METHODS: We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087; the Alzheimer's Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species. RESULTS: A total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer's disease. Individual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively. DISCUSSION: Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer's disease and as such represent a potential therapeutic target.

Validation of ICD-10-AM Coding for Myocardial Infarction Subtype in Hospitalisation Data.

BACKGROUND: International Classification of Disease (ICD) codes are central for identifying myocardial infarction (MI) in administrative hospitalisation data, however validation of MI subtype codes is limited. We measured the sensitivity and specificity of ICD-10-AM (Australian Modification) codes for ST-elevation MI (STEMI) and non-STEMI (NSTEMI). METHODS: A sample of MI admissions was obtained from a dataset containing all MI hospitalisations in Western Australia (WA) for 2003, 2008 and 2013. Clinical data were collected from hospital medical records (n=799 patients). Cases were classified by ICD-10-AM codes for STEMI, NSTEMI and unspecified MI, and compared to clinical classification from review of available electrocardiographs (ECGs) and cardiac biomarkers (n=660). Sensitivity and specificity for ICD-10-AM coding versus clinical classification was measured, stratified by calendar year of discharge. RESULTS: The majority of classifiable cases had MI recorded in the principal diagnosis field (STEMI n=293, 84.2%; NSTEMI n=202, 74.3%; unspecified MI n=20, 50.0%). Overall sensitivity of the ICD-10-AM STEMI code was 86.3% (95% CI 81.7-90.0%) and was higher when restricted to MI as a principal versus secondary diagnosis (88.8% vs 66.7%). Comparable values for NSTEMI were 66.7% (95% CI 61.5-71.6%), and 68.8% vs 61.4% respectively. Between 2003 and 2013, sensitivity for both MI subtypes increased: 80.2-89.5% for STEMI, and 51.2-73.8% for NSTEMI. Specificity was high for NSTEMI throughout (88.2% 95% CI 84.1-91.6%), although improving over time for STEMI (68.1-76.4%). CONCLUSIONS: The sensitivity and specificity of ICD-10-AM codes for MI subtypes in hospitalisation data are generally high, particularly for principal diagnosis cases. However, the temporal improvement in sensitivity in coding of MI subtypes, particularly NSTEMI, may necessitate modification to trend studies using administrative hospitalisation data.

Can the CHA2 DS2 -VA schema be used to decide on anticoagulant therapy in Aboriginal and other Australians with non-valvular atrial fibrillation?

The Australasian guidelines recommend use of the CHA2 DS2 -VA schema to stratify ischaemic stroke risk in patients with non-valvular atrial fibrillation (N-VAF) and determine risk thresholds for recommending oral anticoagulant (OAC) therapy. However, the CHA2 DS2 -VA score has not been validated in a representative Australian population cohort with N-VAF, including in Aboriginal people who are known to have a higher age-adjusted stroke risk than other Australians. In a retrospective data-linkage study of 49 114 patients aged 24-84 years with N-VAF, 40.0% women and 2.5% Aboriginal, we found that patients with a CHA2 DS2 -VA score >2 had high annual stroke rates (>2%) that would justify OAC therapy. This occurred regardless of Aboriginal status. Non-Aboriginal patients with a CHA2 DS2 -VA score of 0 had a mean annual stroke rate of 0.4%, and hence were not likely to benefit from antithrombotic therapy. However, Aboriginal patients with a zero CHA2 DS2 -VA score had a significantly higher annual stroke rate of 0.9%, and could potentially obtain net clinical benefit from anticoagulation, primarily with the safer non-vitamin K antagonist OAC. We conclude that clinicians can confidently use the CHA2 DS2 -VA score to make decisions regarding anticoagulation in accordance with stroke risk in patients with N-VAF, except in Aboriginal people in whom the risk score was unable to identify those at truly low risk of stroke.

Prevalence and patterns of multimorbidity in Australian baby boomers: the Busselton healthy ageing study.

BACKGROUND AND OBJECTIVE: Chronic medical conditions accumulate within individuals with age. However, knowledge concerning the trends, patterns and determinants of multimorbidity remains limited. This study assessed the prevalence and patterns of multimorbidity using extensive individual phenotyping in a general population of Australian middle-aged adults. METHODS: Participants (n = 5029, 55% female), born between 1946 and 1964 and attending the cross-sectional phase of the Busselton Healthy Ageing Study (BHAS) between 2010 and 2015, were studied. Prevalence of 21 chronic conditions was estimated using clinical measurement, validated instrument scores and/or self-reported doctor-diagnosis. Non-random patterns of multimorbidity were explored using observed/expected (O/E) prevalence ratios and latent class analysis (LCA). Variables associated with numbers of conditions and class of multimorbidity were investigated. RESULTS: The individual prevalence of 21 chronic conditions ranged from 2 to 54% and multimorbidity was common with 73% of the cohort having 2 or more chronic conditions. (mean ± SD 2.75 ± 1.84, median = 2.00, range 0-13). The prevalence of multimorbidity increased with age, obesity, physical inactivity, tobacco smoking and family history of asthma, diabetes, myocardial infarct or cancer. There were 13 pairs and 27 triplets of conditions identified with a prevalence > 1.5% and O/E > 1.5. Of the triplets, arthritis (> 50%), bowel disease (> 33%) and depression-anxiety (> 33%) were observed most commonly. LCA modelling identified 4 statistically and clinically distinct classes of multimorbidity labelled as: 1) "Healthy" (70%) with average of 1.95 conditions; 2) "Respiratory and Atopy" (11%, 3.65 conditions); 3) "Non-cardiometabolic" (14%, 4.77 conditions), and 4) "Cardiometabolic" (5%, 6.32 conditions). Predictors of multimorbidity class membership differed between classes and differed from predictors of number of co-occurring conditions. CONCLUSION: Multimorbidity is common among middle-aged adults from a general population. Some conditions associated with ageing such as arthritis, bowel disease and depression-anxiety co-occur in clinically distinct patterns and at higher prevalence than expected by chance. These findings may inform further studies into shared biological and environmental causes of co-occurring conditions of ageing. Recognition of distinct patterns of multimorbidity may aid in a holistic approach to care management in individuals presenting with multiple chronic conditions, while also guiding health resource allocation in ageing populations.

Antithrombotic Therapy in Atrial Fibrillation Management in Western Australia: Temporal Trends and Evidence-Treatment Gaps.

OBJECTIVE: To describe temporal trends in appropriate antithrombotic therapy use in hospitalised atrial fibrillation (AF) patients and identify evidence-treatment gaps in clinical practice. DESIGN: Retrospective cohort study from January 2009-March 2016. SETTING: Tertiary and secondary teaching hospitals in Perth, Western Australia. PARTICIPANTS: Hospitalised adults with non-valvular AF. RESULTS: We identified 11,294 index AF admissions, with a mean age of 76.9 years, 45.8% women and 86.3% at high risk of stroke (CHA2DS2-VASc score ≥2 in men and ≥3 in women). In high risk subjects use of appropriate antithrombotic therapy improved over time with increasing oral anticoagulant (OAC) use and declining sole antiplatelet use (both trend p<0.001). However, by study end only 45.3% of high-risk patients were receiving OAC therapy. In low risk patients, receipt of OAC therapy was steady throughout the study at 40.5% (trend p=0.10). The gender gap in OAC use narrowed over time, with no significant difference between high risk men and women by study end. Use of OAC therapy in elderly patients (age ≥75 years) remained lower than younger patients (age <65 years) over the entire period, with only 31% of elderly patients receiving OAC therapy at study end. From 2012 onwards use of non-vitamin K oral anticoagulants (NOACs) doubled each year with declining warfarin use (both trend p<0.001). CONCLUSION: Despite substantial uptake of NOACs, OAC therapy in AF patients at high risk of stroke remains under-utilised in Western Australia and over-utilised in low risk patients. Further work is required to reduce treatment-risk mismatch for stroke prevention in AF patients.

Heritability of 596 lipid species and genetic correlation with cardiovascular traits in the Busselton Family Heart Study.

CVD is the leading cause of death worldwide, and genetic investigations into the human lipidome may provide insight into CVD risk. The aim of this study was to estimate the heritability of circulating lipid species and their genetic correlation with CVD traits. Targeted lipidomic profiling was performed on 4,492 participants from the Busselton Family Heart Study to quantify the major fatty acids of 596 lipid species from 33 classes. We estimated narrow-sense heritabilities of lipid species/classes and their genetic correlations with eight CVD traits: BMI, HDL-C, LDL-C, triglycerides, total cholesterol, waist-hip ratio, systolic blood pressure, and diastolic blood pressure. We report heritabilities and genetic correlations of new lipid species/subclasses, including acylcarnitine (AC), ubiquinone, sulfatide, and oxidized cholesteryl esters. Over 99% of lipid species were significantly heritable (h2: 0.06-0.50) and all lipid classes were significantly heritable (h2: 0.14-0.50). The monohexosylceramide and AC classes had the highest median heritabilities (h2 = 0.43). The largest genetic correlation was between clinical triglycerides and total diacylglycerol (rg = 0.88). We observed novel positive genetic correlations between clinical triglycerides and phosphatidylglycerol species (rg: 0.64-0.82), and HDL-C and alkenylphosphatidylcholine species (rg: 0.45-0.74). Overall, 51% of the 4,768 lipid species-CVD trait genetic correlations were statistically significant after correction for multiple comparisons. This is the largest lipidomic study to address the heritability of lipids and their genetic correlation with CVD traits. Future work includes identifying putative causal genetic variants for lipid species and CVD using genome-wide SNP and whole-genome sequencing data.

Differences in stroke risk and cardiovascular mortality for Aboriginal and other Australian patients with atrial fibrillation.

OBJECTIVES: To assess the risks of stroke and cardiovascular mortality for Aboriginal and non-Aboriginal Australians with atrial fibrillation. DESIGN: Retrospective data linkage cohort study. SETTING, PARTICIPANTS: All people aged 20-84 years hospitalised with atrial fibrillation in Western Australia during 2000-2012. MAIN OUTCOME MEASURES: Stroke incidence rates and mortality after hospitalisation for atrial fibrillation, and 10-year risks of stroke and of cardiovascular and all-cause mortality. RESULTS: Among 55 482 index admissions with atrial fibrillation, 7.7% of 20-59-year-old patients and 1.3% of 60-84-year-old patients were Aboriginal Australians. A larger proportion of Aboriginal patients aged 20-59 years had CHA2 DS2 -VASc scores of 2 or more (59.8% v 21.8%). In 20-59-year-old Aboriginal patients, the incidence during follow-up (maximum, 10 years; median, 7.1 years) of stroke (incidence rate ratio [IRR], 3.2; 95% CI, 2.5-4.1) and fatal stroke (IRR, 5.7; 95% CI, 3.9-8.9) were markedly higher than for non-Aboriginal patients. Stroke incidence was higher for 60-84-year-old patients, but the difference between Aboriginal and non-Aboriginal patients was smaller (IRR, 1.6; 95% CI, 1.3-2.0). Cardiovascular mortality during follow-up was also higher for 20-59-year-old Aboriginal patients (IRR, 4.4; 95% CI, 4.3-5.9). The hazards of stroke (adjusted HR [aHR], 1.67; 95% CI, 1.22-2.28) and cardiovascular mortality (aHR, 1.47; 95% CI, 1.18-1.83) in younger Aboriginal patients remained significantly higher after multivariable adjustment; age/sex, principal diagnosis of atrial fibrillation, and CHA2 DS2 -VASc score were the most influential factors. CONCLUSION: Stroke risk and cardiovascular mortality are markedly higher for Aboriginal than non-Aboriginal patients with atrial fibrillation, particularly for patients under 60. Strategies for providing evidence-based therapies and cardiovascular prevention to Aboriginal people with atrial fibrillation must be improved.

Comparison of medication adherence measures derived from linked administrative data and associations with mortality using restricted cubic splines in heart failure patients.

PURPOSE: There is no gold standard method to calculate medication adherence using administrative drug data. We compared three common methods and their ability to predict subsequent mortality in patients with heart failure (HF). METHODS: Person-linked population-based datasets were used to identify 4234 patients (56% male, mean age of 76), who survived 1 year (landmark period) following hospitalization for HF in Western Australia from 2003 to 2008. Adherence was estimated by the medication possession ratio (MPR), MPR modified (MPRm), and proportion of days covered (PDC) in patients dispensed a renin-angiotensin system inhibitor (RASI) and/or ß-blocker within the landmark period. Adjusted Cox regression models that fitted restricted cubic splines (RCS) assessed the relationship between medication adherence and 1-year all-cause death postlandmark period. RESULTS: In the landmark period, 87% and 68% of the HF cohort were dispensed RASI and ß-blockers, respectively. Mean adherence estimates for RASI and ß-blockers were 90% and 79% for MPR, 96% and 86% for MPRm, and 82% and 73% for PDC, respectively. In RCS models, MPRm was not associated with subsequent 1-year death in either the RASI or ß-blocker group, while MPR was independently associated with death in the RASI group only (P ≤ .01). However, PDC as a binary variable (PDC <80% or ≥80%) or continuous variable was independently associated with 1-year death in both RASI and ß-blocker groups (all P ≤ .02). CONCLUSION: Proportion of days covered calculated from administrative drug data provides a more conservative estimate of adherence than MPR or MPRm and was the most consistent predictor of subsequent mortality in an HF cohort using RCS analysis.

A Validation Study: How Predictive Is a Diagnostic Coding Algorithm at Identifying Rheumatic Heart Disease in Western Australian Hospital Data?

BACKGROUND: International Classification of Diseases codes for rheumatic heart disease (RHD) (ICD-10 I05-I08) include valvular heart disease of unspecified origin, limiting their usefulness for estimating RHD burden. An expert opinion-based algorithm was developed to increase their accuracy for epidemiological case ascertainment. The algorithm included codes not defaulting to RHD ('probable') plus selected codes pertaining to mitral valve involvement in patients <60 years ('possible'). We aimed to determine the positive predictive value (PPV) for RHD of algorithm-selected hospital admissions. METHODS: Chart reviews of RHD-coded admissions (n=368) to Western Australian tertiary hospitals (2009-2016) authenticated RHD diagnosis. We selected all cases with algorithm-positive codes from populations at high-risk of RHD and an age-stratified random sample from low-risk groups. RHD status was determined from echocardiographic reports or clinical diagnosis in charts. PPVs were compared by population risk status (high-risk/low-risk), age group, gender, principal/secondary diagnosis and probable/possible codes. RESULTS: High-risk patients had higher PPVs than low-risk patients (83.8% vs 54.9%, p<0.0001). PPVs were 91.5% and 51.5% respectively for algorithm-defined 'probable RHD' and 'possible' codes (p<0.0001). The PPVs in low-risk patients were higher for principal diagnoses than secondary diagnoses (84.5% vs 44.8%, weighted p<0.0001) but were similar in high-risk patients (92.5% vs 81.7%, p=0.096). CONCLUSION: The algorithm performs well for RHD coded as a principal diagnosis, 'probable' codes or in populations at high risk of RHD. Refinement is needed for identifying true RHD in low-risk groups.

A 5α-reductase (SRD5A2) polymorphism is associated with serum testosterone and sex hormone-binding globulin in men, while aromatase (CYP19A1) polymorphisms are associated with oestradiol and luteinizing hormone reciprocally.

CONTEXT: Pituitary luteinizing hormone (LH) stimulates testicular production of testosterone (T) which is metabolized to dihydrotestosterone (DHT) by 5α-reductase and to oestradiol (E2) by aromatase. How the activity of population variants in these enzymes impacts on gonadal function is unclear. We examined whether polymorphisms in 5α-reductase (SRD5A2) and aromatase (CYP19A1) genes predict circulating sex hormone concentrations. DESIGN: Cross-sectional analysis of 1865 community-dwelling men aged 50.4 ± 16.8 years. MEASUREMENTS: Early morning sera assayed for T, DHT and E2 (mass spectrometry), and SHBG and LH (immunoassay). Two SRD5A2 and eleven CYP19A1 polymorphisms were analysed by PCR. Regression models were adjusted for age and cardiometabolic risk factors. RESULTS: SRD5A2 polymorphism rs9282858 GA vs. GG was associated with higher serum T (+1.5 nmol/L, P < 0.001) and higher SHBG (+3.3 nmol/L, P = 0.001). CYP19A1 polymorphisms were associated with higher serum E2 and lower LH in reciprocal fashion, from which the two-copy haplotype rs10046 = T/rs2899470 = G/rs11575899 = I/rs700518 = G/rs17703883 = T was associated with higher E2 (63.4 vs. 56.5 pmol/L, P = 0.001) and lower LH (3.9 vs. 4.5 IU/L, P = 0.001) compared to null copies. Conversely, rs10046 = C/rs2899470 = T/rs11575899 = D/rs700518 = A/rs17703883 = C was associated with lower E2 (51.8 vs. 62.0 pmol/L, P = 0.001) and higher LH (5.7 vs. 3.9 IU/L, P < 0.001). These haplotypes were associated primarily with differences in E2 in men <65 years and LH in men ≥65 years. CONCLUSIONS: A 5α-reductase polymorphism predicts circulating T and SHBG, while aromatase polymorphisms predict E2 and LH in reciprocal fashion. Age and aromatase polymorphisms interact to affect E2 and LH. How these functional polymorphisms impact on male reproductive and general health outcomes requires further study.

Evaluating recruitment strategies for AUSPICE, a large Australian community-based randomised controlled trial.

OBJECTIVES: To examine the effectiveness of different strategies for recruiting participants for a large Australian randomised controlled trial (RCT), the Australian Study for the Prevention through Immunisation of Cardiovascular Events (AUSPICE). DESIGN, SETTING, PARTICIPANTS: Men and women aged 55-60 years with at least two cardiovascular risk factors (hypertension, hypercholesterolaemia, overweight/obesity) were recruited for a multicentre placebo-controlled RCT assessing the effectiveness of 23-valent pneumococcal polysaccharide vaccine (23vPPV) for preventing cardiovascular events. METHODS: Invitations were mailed by the Australian Department of Human Services to people in the Medicare database aged 55-60 years; reminders were sent 2 weeks later. Invitees could respond in hard copy or electronically. Direct recruitment was supplemented by asking invitees to extend the invitation to friends and family (snowball sampling) and by Facebook advertising. MAIN OUTCOME: Proportions of invitees completing screening questionnaire and recruited for participation in the RCT. RESULTS: 21 526 of 154 992 invited people (14%) responded by completing the screening questionnaire, of whom 4725 people were eligible and recruited for the study. Despite the minimal study burden (one questionnaire, one clinic visit), the overall participation rate was 3%, or an estimated 10% of eligible persons. Only 16% of eventual participants had responded within 2 weeks of the initial invitation letter (early responders); early and late responders did not differ in their demographic or medical characteristics. Socio-economic disadvantage did not markedly influence response rates. Facebook advertising and snowball sampling did not increase recruitment. CONCLUSIONS: Trial participation rates are low, and multiple concurrent methods are needed to maximise recruitment. Social media strategies may not be successful in older age groups. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12615000536561.