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.

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.

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.

U-shaped association of vigorous physical activity with risk of metabolic syndrome in men with low lean mass, and no interaction of physical activity and serum 25-hydroxyvitamin D with metabolic syndrome risk.

BACKGROUND: There is uncertainty over how lean mass, physical activity (PA) and 25-hydroxyvitamin D (25-OH-D) status interact on metabolic syndrome (MetS) risk in adults. AIMS: To test the hypothesis that these factors additively influence MetS risk. METHODS: Four thousand eight hundred and fifty-eight adults (54.6% female) mean ± SD age 58.0 ± 5.8 years, body mass index 28.1 ± 4.8 kg/m2 , resident in Busselton, Western Australia. PA assessed by questionnaire (all/total and vigorous), lean mass using dual energy X-ray absorptiometry (% total body mass), serum 25-OH-D via immunoassay, analysed using multivariable logistic regression. RESULTS: In men, lower total PA was associated with MetS (no vs >24 h/week odds ratio (OR) = 3.1; ≤8 vs >24 h/week OR = 1.8, both P < 0.001), as was lower lean mass (low vs high OR = 20.4; medium vs high OR = 7.4, both P < 0.001). Men with low lean mass exhibited a U-shaped relationship of vigorous PA with MetS risk (covariate-adjusted: 0 vs 4-8 h/week OR = 2.1, P = 0.037; >12 vs 4-8 h/week OR = 4.3, P = 0.002; interaction P = 0.039). In women, low PA (0 vs >24 h/week OR = 2.1, P = 0.003) and lean mass (low vs high OR = 13.1; medium vs high OR = 7.2, both P < 0.001) were associated with MetS risk. Low 25-OH-D status was associated with MetS in men (low vs high OR = 4.1; medium vs high OR = 2.3, both P < 0.001) and women (OR = 3.5 and 2.1 respectively, both P < 0.001) with no PA interaction. CONCLUSIONS: Men and women with high lean mass have low risk of MetS regardless of PA. Low lean mass identifies men who may benefit most from increasing PA, with an optimal level associated with lowest risk. 25-OH-D and PA do not interact on MetS risk.

Equalization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies.

AIMS: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied. METHODS AND RESULTS: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms. CONCLUSION: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.

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.

Higher circulating androgens and higher physical activity levels are associated with less central adiposity and lower risk of cardiovascular death in older men.

OBJECTIVE: Low endogenous sex hormones and low physical activity (PA) levels have been associated with CVD risk. Whether these interact to influence CVD outcomes remains unclear. We assessed whether sex hormone concentrations and PA were additively associated with lower central adiposity and CVD risk. PATIENTS: 3351 community-dwelling men, mean age 77 years. MEASUREMENTS: Baseline testosterone (T), dihydrotestosterone (DHT) and oestradiol (E2) were assayed. Levels of PA were ascertained by questionnaire. Men were stratified using median splits into high hormone + high PA (H/H), high hormone + low PA (H/L); low hormone + high PA (L/H) and low hormone + low PA (L/L) groups. RESULTS: A total of 865 CVD events and 499 CVD deaths occurred during 10-year mean follow-up. Men with higher T, DHT or SHBG and higher PA had the lowest BMI, waist circumference and risk of metabolic syndrome. Men with higher T had the lowest risk of incident CVD events, irrespective of PA level. Men with higher T or DHT and higher PA had the lowest risk of dying from CVD (eg, hazard ratios for T/PA H/H 0.76 P = 0.031; H/L 0.85 P = 0.222; L/H 0.80 P = 0.075; L/L 1.00). CONCLUSION: Higher circulating androgens and higher PA were associated with less central adiposity at baseline and fewer CVD deaths during follow-up. These findings are consistent with a potential additive effect of androgens and PA on cardiometabolic outcomes in older men.

Cross-sectional associations of sex hormones with leucocyte telomere length, a marker of biological age, in a community-based cohort of older men.

CONTEXT: Telomeres protect chromosomes from damage, and shorter leucocyte telomere length (LTL) is a marker of advancing biological age. The association between testosterone (T) and its bioactive metabolites, dihydrotestosterone (DHT) and oestradiol (E2) with telomere length, particularly in older men, is uncertain. The study aimed to clarify associations of sex hormones with LTL in older men. PARTICIPANTS AND METHODS: We used cross-sectional data from 2913 men aged 76.7 ± 3.2 years with morning blood samples assayed for T, DHT, E2 (mass spectrometry), and sex hormone-binding globulin (SHBG, immunoassay), to correlate sex hormones with LTL measured using PCR and expressed as T/S ratio in multivariable linear regression models adjusted for age, cardiometabolic risk factors and cardiovascular disease history. RESULTS: Average difference per decade of age was T -0.46 nmol/L, DHT -0.11 nmol/L, E2 -7.5 pmol/L, SHBG +10.2 nmol/L and LTL (T/S ratio) -0.065. E2 correlated with T/S ratio (r = 0.038, P = 0.039) and SHBG was inversely correlated (r = -0.053, P = 0.004). After multivariable adjustment, E2 was associated with T/S ratio (per 1 SD increase E2: coefficient 0.011, P = 0.043), T and DHT were not associated. When E2 and SHBG were simultaneously included, E2 remained positively (coefficient 0.014, P = 0.014) and SHBG inversely (coefficient -0.013, P = 0.037) associated with T/S ratio. CONCLUSIONS: In older men, neither T nor DHT is associated with LTL while E2 is independently associated with LTL and SHBG is inversely associated, thus relating sex hormone exposure to lower biological age. Further research is needed to determine causality and clarify the role of sex hormones in male ageing.

Obstructive airway disease in 46-65-year-old people in Busselton, Western Australia, 1966-2015.

OBJECTIVE: To document the changing levels of tobacco smoking, respiratory symptoms, doctor-diagnosed asthma, and lung function in Busselton adults aged 46-65 years over the past 50 years. DESIGN, SETTING, PARTICIPANTS: Repeated cross-sectional population surveys (1966 to 2010-2015) of adults registered to vote in the Busselton shire, Western Australia, including a modified version of the British Medical Research Council questionnaire on respiratory symptoms. MAIN OUTCOME MEASURES: History of doctor-diagnosed asthma and chronic obstructive pulmonary disease (COPD), tobacco smoking history, respiratory medications used, spirometry parameters (forced expiratory volume in one second [FEV1], forced vital capacity [FVC]). RESULTS: The prevalence of tobacco smoking among men declined from 53% in 1966 to 12% in 2010-2015, and from 26% to 9% among women. The prevalence of ever-smoking (ie, smokers and ex-smokers) decreased from 80% to 57% for men but increased from 33% to 50% for women. The prevalence of doctor-diagnosed asthma increased, as did the use of long-acting bronchodilator aerosol medications by people with asthma and COPD. There have been no consistent changes in the prevalence of specific respiratory symptoms, but measures of lung function have significantly improved. CONCLUSIONS: Smoking rates declined as a result of changes in pricing, prohibitions on smoking and the feedback of survey results to Busselton participants. Significant improvements in lung function were measured, and it can be anticipated that the prevalence of other smoking-related diseases will also decline.

Greater physical activity and higher androgen concentrations are independently associated with lower cardiometabolic risk in men.

CONTEXT: Male ageing is associated with lower circulating testosterone (T) and increased incidence of cardiovascular disease (CVD). Whether physical activity (PA) interacts with hormones to modify CVD risk is unclear. OBJECTIVE: We assessed whether PA and sex hormone concentrations were independently associated with measures of CVD risk. PARTICIPANTS: A total of 1649 men. METHODS: Leisure, home, work and total PA were ascertained. At baseline, serum T, dihydrotestosterone (DHT) and oestradiol (E2) were assayed. Men were stratified into high PA+high hormone (H/H); low PA+high hormone (L/H); high PA+low hormone (H/L); and low PA+low hormone (L/L). RESULTS: Mean age was 49.8 years at outset with 415 CVD events and 127 CVD deaths occurring during 20-year follow-up. Men with higher PA and higher T or DHT had lower odds of metabolic syndrome (eg leisure H/H vs L/L odds ratio [OR] 0.17 P<.001 for T, 0.26 P<.001 for DHT). Men with higher PA and E2 had lower risk of metabolic syndrome (eg leisure PA H/H vs L/L OR 0.51, P=.001). Men with higher leisure, work or total PA and higher DHT had the lowest risk of CVD death (eg leisure H/H hazard ratio [HR] 0.55 vs L/L, P=.033). Men with lower leisure, home or work PA and higher E2 were at greater risk of CVD death (eg leisure L/H HR 1.60 vs L/L, P=.039). CONCLUSIONS: Considering T, DHT and E2 in the context of PA better informs consideration of cardiovascular risk. A 2×2 factorial RCT assessing PA and androgens would illuminate the scope for preventing CVD in men.

Neutral associations of testosterone, dihydrotestosterone and estradiol with fatal and non-fatal cardiovascular events, and mortality in men aged 17-97 years.

CONTEXT: Lower testosterone (T) is associated with poorer health outcomes in older men, however, the relationship between T, dihydrotestosterone (DHT) and estradiol (E2) with cardiovascular disease (CVD) in younger to middle-aged men remains unclear. OBJECTIVES: We assessed associations between endogenous sex hormones with mortality (all-cause and CVD) and CVD events, in a cohort of men aged 17-97 years. PARTICIPANTS AND METHODS: Sex hormones were assayed using mass spectrometry in 2143 men from the 1994/5 Busselton Health Survey. Outcomes to December 2010 were analysed. RESULTS: Of the 1804 men included in the analysis, mean age was 50·3 ± 16·8 years and 68·9% of men were aged <60. Mean follow-up period was 14·9 years. There were 319 deaths, 141 CVD deaths and 399 CVD events. Compared to the full cohort, men who died had lower baseline T (12·0 ± 4·4 vs 13·6 ± 4·9 nmol/l), free T (181·9 ± 52·9 vs 218·3 ± 63·8 pmol/l) and DHT (1·65 ± 0·64 vs 1·70 ± 0·72 nmol/l), but higher E2 (64·0 ± 32 vs 60·1 ± 30·2 pmol/l). After adjustment for risk factors, T was not associated with mortality (adjusted HR = 0·90, 95% CI 0·79-1·04; P = 0·164 for every increase in 1 SD of T), CVD deaths (adjusted HR = 1·04, 95% CI 0·84-1·29; P = 0·708) or CVD events (adjusted HR = 1·03, 95% CI 0·92-1·15, P = 0·661). No associations were found for free T, DHT or E2. Results were similar for men older and younger than 60 years. CONCLUSIONS: In predominantly middle-aged men, T, DHT and E2 do not influence mortality or CVD outcomes. This neutral association of hormones with CVD contrasts with prior studies of older men.

Estimating eligibility for lung cancer screening in an Australian cohort, including the effect of spirometry.

OBJECTIVES: To estimate the proportion of ever-smokers who are eligible for lung cancer screening in an Australian cohort, and to evaluate the effect of spirometry in defining chronic obstructive pulmonary disease (COPD) when assessing screening eligibility. DESIGN: Cross-sectional study of 3586 individuals aged 50-68 years who live in the Busselton Shire of Western Australia. OUTCOMES: Proportion of ever-smokers eligible for lung cancer screening based on United States Preventive Services Task Force (USPSTF) criteria, and PLCOm2012 lung cancer risk > 1.5%. The effect of using self-reported COPD, symptoms consistent with COPD, or spirometry to define COPD for screening eligibility according to the PLCOm2012 criteria. RESULTS: Of ever-smokers aged 55-68 years, 254 (20.1%) would be eligible for screening according to USPSTF criteria; fewer would be eligible according to PLCOm2012 criteria (225, 17.9%; P = 0.004). This is equivalent to 8.9-10.0% of the total population aged 55-68 years, which suggests about 450 000 individuals in Australia may be eligible for lung cancer screening. The proportions of eligible participants were not significantly different whether spirometry results or symptoms consistent with COPD were used to determine PLCOm2012 risk. CONCLUSIONS: The proportion of ever-smokers in this population who were eligible for lung cancer screening was 17.9-20.1%. Using symptoms to define COPD is an appropriate surrogate measure for spirometry when determining the presence of COPD in this population. There are significant challenges for policy makers on how to identify and recruit these eligible individuals from the wider population.

Higher ferritin levels, but not serum iron or transferrin saturation, are associated with Type 2 diabetes mellitus in adult men and women free of genetic haemochromatosis.

CONTEXT: Iron overload predisposes to diabetes and higher ferritin levels have been associated with diabetes. However, it is unclear whether ferritin reflects differences in iron-related parameters between diabetic and nondiabetic persons. We examined associations of serum ferritin, iron and transferrin saturation with Type 2 diabetes in adults without genetic predisposition to iron overload. DESIGN, PARTICIPANTS AND MEASUREMENTS: Cross-sectional analysis of community-dwelling men and women aged 17-97 years from the Busselton Health Survey, Western Australia. Men and women carrying genotypes associated with haemochromatosis (C282Y/C282Y or C282Y/H63D) were excluded. Serum ferritin, iron and transferrin saturation were assayed. RESULTS: There were 1834 men (122 with diabetes, 6·6%) and 2351 women (141 with diabetes, 6%). In men, higher serum ferritin was associated with diabetes after adjusting for age, smoking, alcohol, cardiovascular history, body mass index (BMI), waist, blood pressure, lipids, C-reactive protein (CRP), adiponectin, alanine transaminase (ALT) and gamma-glutamyl transpeptidase (GGT) [odds ratio (OR): 1·29 per 1 unit increase log ferritin, 95% confidence interval (CI) = 1·01-1·65, P = 0·043]. In women, higher serum ferritin was associated with diabetes [fully adjusted OR: 1·31 per 1 unit increase log ferritin, 95% CI = 1·04-1·63, P = 0·020; 1·84 for tertile (T) 3 vs T1, 95% CI = 1·09-3·11]. Neither iron levels nor transferrin saturation were associated with diabetes risk in men or women. Higher ferritin was not associated with insulin resistance in nondiabetic adults. CONCLUSIONS: In adults, higher ferritin levels are independently associated with prevalent diabetes while iron and transferrin saturation are not. Ferritin is a robust biomarker for diabetes risk, but further investigation is needed to clarify whether this relationship is mediated via iron metabolism.

Higher serum testosterone and dihydrotestosterone, but not oestradiol, are independently associated with favourable indices of lung function in community-dwelling men.

OBJECTIVES: Lower circulating androgens and poorer lung function are associated with increased cardiovascular risk and mortality in men. The association between androgens and lung function is unclear. We tested the hypothesis that circulating testosterone (T) and its metabolites dihydrotestosterone (DHT) and oestradiol (E2) are differentially associated with lung function in men. METHODS: Early-morning serum T, DHT and E2 were assayed using mass spectrometry in 1768 community-dwelling men from Busselton, Western Australia. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were measured using spirometry. Linear regression models adjusting for age, height, smoking, exercise, body mass index, respiratory conditions and cardiovascular risk factors were used. RESULTS: Mean age was 50.1 ± 16·8 years. 16·0% were current smokers, 14·1% reported a history of asthma and 2·7% reported chronic obstructive pulmonary disease. Current smokers had higher T compared with never smokers (age-adjusted mean 14·5 vs 13·5 nmol/l, P = 0·002) and higher E2 (65·3 vs 60·1 pmol/l, P = 0·017). In fully adjusted analyses, T was associated with FEV1 (51 ml per 1 SD increase, P < 0·001) as was DHT (62 ml, P < 0·001), E2 was not (P = 0·926). Similar results were seen for FVC (T: 76 ml, P < 0·001; DHT: 65 ml, P < 0·001; E2 P = 0·664). Higher DHT was marginally associated with the ratio FEV1/FVC (0·3% per 1 SD increase, P = 0·047). CONCLUSIONS: Both T and DHT were independently associated with higher FEV1 and FVC in predominantly middle-aged community-dwelling men. Androgens may contribute to, or be biomarkers for, better lung function in men. Further research is needed to clarify whether androgens preserve lung function in ageing men.

Testosterone, dihydrotestosterone and estradiol are differentially associated with carotid intima-media thickness and the presence of carotid plaque in men with and without coronary artery disease.

Clarifying the relationship of sex hormones to preclinical atherosclerosis could illuminate pathways by which androgens are associated with cardiovascular events and mortality. Our aim was to determine hormone profiles associated with carotid intima-media thickness (CIMT) and carotid atheroma, in men with and without known coronary artery disease (CAD). We included 492 community-based men aged 20-70 years (Group A) and 426 men with angiographically proven CAD aged <60 years (Group B). Fasting early morning sera were assayed for testosterone (T), dihydrotestosterone (DHT) and estradiol (E2) using mass spectrometry. CIMT and carotid plaque were assessed ultrasonographically. Mean (±SD) age was Group A: 53.8±12.6 and Group B: 49.6±5.1 years. Higher T was associated with reduced CIMT (-0.011 mm per 1-SD increase, p=0.042) and lower prevalence of carotid plaque (odds ratio [OR] per 1-SD increase, 0.68, p=0.012) in Group A, but not B. E2 was associated with increased CIMT in Group A (0.013 mm, p=0.011) but not B. Higher DHT and E2 were associated with reduced carotid plaque in Group B (DHT: OR=0.77, p=0.024; E2: OR=0.75, p=0.008), but not A. In community-dwelling men, higher T is associated with favourable CIMT and lower prevalence of carotid plaque, while higher E2 is associated with worse CIMT. In men with CAD, higher DHT or E2 are associated with less carotid plaque. T, DHT and E2 are differentially associated with preclinical carotid atherosclerosis in a cardiovascular phenotype-specific manner. Interventional studies are needed to examine effects of exogenous T and its metabolites DHT and E2, on atherogenesis.

Association of Cardiometabolic Multimorbidity With Mortality.

IMPORTANCE: The prevalence of cardiometabolic multimorbidity is increasing. OBJECTIVE: To estimate reductions in life expectancy associated with cardiometabolic multimorbidity. DESIGN, SETTING, AND PARTICIPANTS: Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES: A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI). MAIN OUTCOMES AND MEASURES: All-cause mortality and estimated reductions in life expectancy. RESULTS: In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy. CONCLUSIONS AND RELEVANCE: Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

A longitudinal analysis of the influence of the neighborhood built environment on walking for transportation: the RESIDE study.

The purpose of the present analysis was to use longitudinal data collected over 7 years (from 4 surveys) in the Residential Environments (RESIDE) Study (Perth, Australia, 2003-2012) to more carefully examine the relationship of neighborhood walkability and destination accessibility with walking for transportation that has been seen in many cross-sectional studies. We compared effect estimates from 3 types of logistic regression models: 2 that utilize all available data (a population marginal model and a subject-level mixed model) and a third subject-level conditional model that exclusively uses within-person longitudinal evidence. The results support the evidence that neighborhood walkability (especially land-use mix and street connectivity), local access to public transit stops, and variety in the types of local destinations are important determinants of walking for transportation. The similarity of subject-level effect estimates from logistic mixed models and those from conditional logistic models indicates that there is little or no bias from uncontrolled time-constant residential preference (self-selection) factors; however, confounding by uncontrolled time-varying factors, such as health status, remains a possibility. These findings provide policy makers and urban planners with further evidence that certain features of the built environment may be important in the design of neighborhoods to increase walking for transportation and meet the health needs of residents.

Differential associations of testosterone, dihydrotestosterone and oestradiol with physical, metabolic and health-related factors in community-dwelling men aged 17-97 years from the Busselton Health Survey.

OBJECTIVES: Lower testosterone (T) levels are associated with poorer health outcomes in older men, but associations in younger or middle-aged men are uncertain, and data for dihydrotestosterone (DHT) and oestradiol (E2) are limited. We assessed the associations of circulating T, DHT and E2 with physical and health-related factors in a cohort comprising men aged 17-97 years. PARTICIPANTS AND METHODS: Serum from 2143 community-dwelling men from the 1994/95 Busselton Health Survey was assayed for T, DHT and E2 using liquid chromatography-tandem mass spectrometry. Men receiving hormonal therapy or reporting the use of testosterone, or with prostate cancer or orchidectomy were excluded. RESULTS: Of the men, 43% had never smoked, 6·1% had diabetes and 16·8% cardiovascular disease (CVD). Mean (±SD) age was 50·3 ± 17·0 years. Total T was moderately correlated with DHT (r = 0·56), E2 (r = 0·35) and sex hormone-binding globulin (r = 0·53). In age-, smoking-, body mass index (BMI)- and sex hormone-binding globulin (SHBG)-adjusted analyses, T was inversely associated with metabolic syndrome score, while DHT and E2 were not associated. In multivariable models, higher total T was associated with lower age, BMI and C-reactive protein, and with higher creatinine and haemoglobin, independently of SHBG. Higher DHT was associated with lower age, BMI and glucose level, and higher creatinine and haemoglobin. E2 was positively associated with age, BMI and haemoglobin. CONCLUSIONS: In men spanning younger, middle and older ages, circulating androgens are more related to age and metabolic factors than CVD or chronic disease. Further investigation is required to clarify whether androgens and oestrogens have contrasting roles as risk predictors for CVD.

Disparities experienced by Aboriginal compared to non-Aboriginal metropolitan Western Australians in receiving coronary angiography following acute ischaemic heart disease: the impact of age and comorbidities.

INTRODUCTION: Aboriginal Australians have a substantially higher frequency of ischaemic heart disease (IHD) events than their non-Aboriginal counterparts, together with a higher prevalence of comorbidities. The pattern of health service provision for IHD suggests inequitable delivery of important diagnostic procedures. Published data on disparities in IHD management among Aboriginal Australians are conflicting, and the role of comorbidities has not been adequately delineated. We compared the profiles of Aboriginal and non-Aboriginal patients in the metropolitan area undergoing emergency IHD admissions at Western Australian metropolitan hospitals, and investigated the determinants of receiving coronary angiography. METHODS: Person-linked administrative hospital and mortality records were used to identify 28-day survivors of IHD emergency admission events (n =20,816) commencing at metropolitan hospitals in 2005-09. The outcome measure was receipt of angiography. The Aboriginal to non-Aboriginal risk ratio (RR) was estimated from a multivariable Poisson log-linear regression model with allowance for multiple IHD events in individuals. The subgroup of myocardial infarction (MI) events was modelled separately. RESULTS: Compared with their non-Aboriginal counterparts, Aboriginal IHD patients were younger and more likely to have comorbidities. In the age- and sex-adjusted model, Aboriginal patients were less likely than others to receive angiography (RRIHD 0.77, 95% CI 0.72-0.83; RRMI 0.81, 95% CI 0.75-0.87) but in the full multivariable model this disparity was accounted for by comorbidities as well as IHD category and MI subtype, and private health insurance (RRIHD 0.95, 95% CI 0.89-1.01; RRMI 0.94, 95% CI 0.88-1.01). When stratified by age groups, this disparity was not significant in the 25-54 year age group (RRMI 0.95, 95% CI 0.88-1.02) but was significant in the 55-84 year age group (RRMI 0.88, 95% CI 0.77-0.99). CONCLUSIONS: The disproportionate under-management of older Aboriginal IHD patients is of particular concern. Regardless of age, the disparity between Aboriginal and non-Aboriginal Australians in receiving angiography for acute IHD in a metropolitan setting is mediated substantially by comorbidities. This constellation of health problems is a 'double-whammy' for Aboriginal people, predisposing them to IHD and also adversely impacting on their receipt of angiography. Further research should investigate how older age and comorbidities influence clinical decision making in this context.

Leisure time physical activity and long-term cardiovascular and cancer outcomes: the Busselton Health Study.

The study aimed to investigate whether meeting leisure time physical activity recommendations was associated with reduced incident and fatal cancer or cardiovascular disease (CVD) in a community-based cohort of middle- to late-aged adults with long-term follow-up. At baseline, 2,320 individuals were assessed on a large number of lifestyle and clinical parameters including their level of physical activity per week, other risk factors (e.g. smoking and alcohol use) various anthropometric measures, blood tests and medical history. Individuals were linked to hospital and mortality registry data to identify future cancer and cardiovascular events (fatal and non-fatal) out to 15 years of follow-up. Cox regression analyses adjusted for relevant confounders identified a priori were used to estimate risk for all-cause, cancer-specific and CVD-specific mortality. In the full cohort an estimated 21 % decreased risk for all-cause mortality (HR 0.79; 95 % CI 0.66-0.96) and 22 % decreased risk for fatal/non-fatal CVD events (HR 0.78; 95 % CI 0.66-0.92) was associated with baseline self-reported physical activity levels of 150 min or more. After exclusion of those with chronic co-morbidities (CVD, cancer, diabetes, chronic obstructive pulmonary disease, hypertension treatment) at baseline, lower risk for fatal/non-fatal CVD events remained significantly associated with 150 min or more of physical activity (HR 0.77; 95 % CI 0.62-0.96). Results from this well established prospective community-based cohort study support the role of leisure time physical activity in reducing all-cause mortality and CVD events (fatal/nonfatal) in the broader population studied. The data also suggest that physical activity associated reductions in risk for CVD events (fatal/nonfatal) were not overly impacted by prevalent key non-communicable diseases.