Clinical outcomes and health care costs of transferring rural Western Australians for invasive coronary angiography, and a cost-effective alternative care model: a retrospective cross-sectional study.

OBJECTIVES: To examine the severity of coronary artery disease (CAD) in people from rural or remote Western Australia referred for invasive coronary angiography (ICA) in Perth and their subsequent management; to estimate the cost savings were computed tomography coronary angiography (CTCA) offered in rural centres as a first line investigation for people with suspected CAD. DESIGN: Retrospective cohort study. SETTING, PARTICIPANTS: Adults with stable symptoms in rural and remote WA referred to Perth public tertiary hospitals for ICA evaluation during the 2019 calendar year. MAIN OUTCOME MEASURES: Severity and management of CAD (medical management or revascularisation); health care costs by care model (standard care or a proposed alternative model with local CTCA assessment). RESULTS: The mean age of the 1017 people from rural and remote WA who underwent ICA in Perth was 62 years (standard deviation, 13 years); 680 were men (66.9%), 245 were Indigenous people (24.1%). Indications for referral were non-ST elevation myocardial infarction (438, 43.1%), chest pain with normal troponin level (394, 38.7%), and other (185, 18.2%). After ICA assessment, 619 people were medically managed (60.9%) and 398 underwent revascularisation (39.1%). None of the 365 patients (35.9%) without obstructed coronaries (< 50% stenosis) underwent revascularisation; nine patients with moderate CAD (50-69% stenosis; 7%) and 389 with severe CAD (≥ 70% stenosis or occluded vessel; 75.5%) underwent revascularisation. Were CTCA used locally to determine the need for referral, 527 referrals could have been averted (53%), the ICA:revascularisation ratio would have improved from 2.6 to 1.6, and 1757 metropolitan hospital bed-days (43% reduction) and $7.3 million in health care costs (36% reduction) would have been saved. CONCLUSION: Many rural and remote Western Australians transferred for ICA in Perth have non-obstructive CAD and are medically managed. Providing CTCA as a first line investigation in rural centres could avert half of these transfers and be a cost-effective strategy for risk stratification of people with suspected CAD.

Prehospital continuous positive airway pressure (CPAP) for acute respiratory distress: a randomised controlled trial.

OBJECTIVE: To compare the efficacy of continuous positive airway pressure (CPAP) versus usual care for prehospital patients with severe respiratory distress. METHODS: We conducted a parallel group, individual patient, non-blinded randomised controlled trial in Western Australia between March 2016 and December 2018. Eligible patients were aged ≥40 years with acute severe respiratory distress of non-traumatic origin and unresponsive to initial treatments by emergency medical service (EMS) paramedics. Patients were randomised (1:1) to usual care or usual care plus CPAP. The primary outcomes were change in dyspnoea score and change in RR at ED arrival, and hospital length of stay. RESULTS: 708 patients were randomly assigned (opaque sealed envelope) to usual care (n=346) or CPAP (n=362). Compared with usual care, patients randomised to CPAP had a greater reduction in dyspnoea scores (usual care -1.0, IQR -3.0 to 0.0 vs CPAP -3.5, IQR -5.2 to -2.0), median difference -2.0 (95% CI -2.5 to -1.6); and RR (usual care -4.0, IQR -9.0 to 0.0 min-1 vs CPAP -8.0, IQR -14.0 to -4.0 min-1), median difference -4.0 (95% CI -5.0 to -4.0) min-1. There was no difference in hospital length of stay (usual care 4.2, IQR 2.1 to 7.8 days vs CPAP 4.8, IQR 2.5 to 7.9 days) for the n=624 cases admitted to hospital, median difference 0.36 (95% CI -0.17 to 0.90). CONCLUSIONS: The use of prehospital CPAP by EMS paramedics reduced dyspnoea and tachypnoea in patients with acute respiratory distress but did not impact hospital length of stay. TRIAL REGISTRATION NUMBER: ACTRN12615001180505.

Impact of Pre-Hospital Activation of STEMI on False Positive Activation Rate and Door to Balloon Time.

BACKGROUND: Pre-hospital identification of ST-segment elevation myocardial infarction (STEMI) by paramedical staff reduces reperfusion time. However, the impact of this approach on the rate of unnecessary activation of coronary catheterisation lab (CCL) remains unclear. METHODS: The study reviewed consecutive STEMI patients over 3 years (July 2015 to June 2018) from all primary percutaneous coronary intervention (PPCI) centres and inter-hospital transfers (IHT) from non-PPCI capable centres in Western Australia. Out-of-hospital cardiac arrests (OOHCA) and STEMI calls for in-patients receiving treatment for other medical reasons were excluded. RESULTS: During the 3 years study period, 1,736 STEMI cases were recorded. Pre-hospital (PH) activation occurred in 799 (46%) cases. Median door to balloon time (D2BT) was 68 minutes (IQR 63 mins). D2BT for PH activation (40 min [IQR 25 min]) was significantly lower than both the PPCI centre emergency department (ED) activation (86 min [IQR 55 min]) and IHT activation groups (108 min [IQR 55 min]), p-value <0.00001. In PH activation group 98% patients received primary PCI in less than 90 minutes compared to 54% and 26% patients in the ED and the IHT activation groups, respectively. False positive STEMI activation rate was lower in the PH activation group (2.75%) compared to ED activation (5.4%) and IHT group (6%), p-value 0.0115. The false positive rate did not vary significantly between working hours and out-of-hour calls (5% vs 4%, p-value=0.304). Pericarditis, coronary artery disease other than STEMI, atypical chest pain, and stress induced cardiomyopathy were the common diagnoses in false positive activations. CONCLUSION: Pre-hospital activation of STEMI leads to reduced door to balloon times without a significant increase in inappropriate procedures, though false positive activation rates are unclear. The majority of STEMI patients transferred from non-PPCI centres failed to receive reperfusion therapy within 90 minutes of initial hospital presentation. Further studies are required to assess the benefits of thrombolysis in selected patients in inter-hospital transfer group.

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.

Cardiac Complications in Patients Hospitalised With COVID-19 in Australia.

OBJECTIVES: Describe the incidence of cardiac complications in patients admitted to hospital with COVID-19 in Australia. DESIGN: Observational cohort study. SETTING: Twenty-one (21) Australian hospitals. PARTICIPANTS: Consecutive patients aged ≥18 years admitted to hospital with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. MAIN OUTCOME MEASURES: Incidence of cardiac complications. RESULTS: Six-hundred-and-forty-four (644) hospitalised patients (62.5±20.1 yo, 51.1% male) with COVID-19 were enrolled in the study. Overall in-hospital mortality was 14.3%. Twenty (20) (3.6%) patients developed new atrial fibrillation or flutter during admission and 9 (1.6%) patients were diagnosed with new heart failure or cardiomyopathy. Three (3) (0.5%) patients developed high grade atrioventricular (AV) block. Two (2) (0.3%) patients were clinically diagnosed with pericarditis or myopericarditis. Among the 295 (45.8%) patients with at least one troponin measurement, 99 (33.6%) had a peak troponin above the upper limit of normal (ULN). In-hospital mortality was higher in patients with raised troponin (32.3% vs 6.1%, p<0.001). New onset atrial fibrillation or flutter (6.4% vs 1.0%, p=0.001) and troponin elevation above the ULN (50.3% vs 16.4%, p<0.001) were more common in patients 65 years and older. There was no significant difference in the rate of cardiac complications between males and females. CONCLUSIONS: Among patients with COVID-19 requiring hospitalisation in Australia, troponin elevation was common but clinical cardiac sequelae were uncommon. The incidence of atrial arrhythmias and troponin elevation was greatest in patients 65 years and older.

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.

Ischaemic Stroke and the Echocardiographic "Bubble Study": Are We Screening the Right Patients?

BACKGROUND: Patent foramen ovale (PFO) is a potential mechanism for paradoxical embolism in cryptogenic ischaemic stroke or transient ischaemic attack (TIA). PFO is typically demonstrated with agitated saline ("bubble study", BS) during echocardiography. We hypothesised that the BS is frequently requested in patients that have a readily identifiable cause of stroke, that any PFO detected is likely incidental, and its detection often does not alter management. METHODS: This was a retrospective observational study of patients with recent ischaemic stroke/TIA referred for a BS. Patient demographics, stroke risk factors, vascular/cerebral imaging results and transoesophageal echocardiogram (TOE) reports were recorded. A "modified" Risk of Paradoxical Embolism (RoPE) score was calculated. Change in management was defined as antiplatelet/anticoagulant therapy alteration or referral for PFO closure. Bubble Study complications were recorded. RESULTS: Among 715 patients with ischaemic stroke/TIA referred for a BS, 8.7% had atrial fibrillation and 9.2% had carotid stenosis ≥70%. At least three stroke risk factors were present in 39.3% and only 47.1% of patients screened had a "modified" RoPE score of >5. A PFO was detected in 248 patients of whom only 31% (77/248) had a subsequent change in management. Of BS performed, 1/924 patients (0.1%) suffered a TIA as a complication. CONCLUSIONS: The echocardiographic BS is frequently performed in patients that have a readily identifiable cause of stroke and whose PFO unlikely relates to the stroke/TIA. Bubble Study findings resulted in a change in management in the minority. The procedure is safe but the complication rate warrants informed consent.

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.

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.

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.

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.

A cohort study examination of established and emerging risk factors for atrial fibrillation: the Busselton Health Study.

Atrial fibrillation (AF) is the most common chronic arrhythmia in adults and its prevalence is increasing. Due to its serious cardiovascular complications there is a strong need to understand predisposing risk factors to develop effective prevention strategies. There are a few established risk factors but a number of further risk factors have been suggested including obesity, metabolic syndrome, sleep-disordered breathing, and inflammation. The aim of this study was to investigate established and emerging risk factors for AF in a cohort study of 4,267 adults in Busselton, Western Australia, without a history of AF at baseline in 1994/95 who were followed for 15 years for incident AF events. Baseline measurement included questionnaire, clinical assessment and blood sample. A total of 343 (8%) experienced AF during follow-up. Cox regression analysis confirmed advancing age, male sex, taller height, being on hypertension treatment and higher body mass index (BMI) as the major common risk factors (all p < 0.001). However, further modelling showed the effect of being on hypertension treatment may be stronger in women (p = 0.001) and the effect of BMI stronger in men (p = 0.004). After adjustment for these factors, no other factors were strongly related (p < 0.001) although short PR interval, history of valvular heart disease, stroke, chronic obstructive pulmonary disease, lung function and adiponectin level were marginally related (p < 0.05). This cohort study of predictors for incident AF has confirmed the major established risk factors. However, recently suggested potential novel risk factors for AF (inflammation, sleep-disordered breathing, glucose/metabolic disorders) were not confirmed in this study.

Management of acute coronary syndrome in special subgroups: female, older, diabetic and Indigenous patients.

While the evidence base for management of acute coronary syndrome (ACS) is extensive, some subgroups have been underrepresented or excluded from relevant clinical trials. These subgroups - such as women, older people, diabetic patients and Indigenous Australians - present clinical challenges for which there is limited evidence to guide optimal therapy. Women may have a different pattern of presentation, with potential for delays in diagnosis and worse outcomes in ST-elevation myocardial infarction, but there is no evidence that treatments affect them differently from men. Older people suffer from a high-risk, low-treatment paradox. This may be due to under-appreciation of the benefits of treatments for older people, or to good clinical judgement in avoiding harm from worsening age-related comorbidities. Patients with diabetes have a high risk of ACS and suffer worse outcomes. Moderate glycaemic control with close monitoring and avoidance of hypoglycaemia are recommended. Coronary artery bypass grafting is preferred to percutaneous coronary intervention for patients with diabetes and multivessel disease, although the latter is reasonable in single-vessel disease. Indigenous patients have a high prevalence of coronary disease, with more frequent coronary events at a young age, a heavy load of risk factors and poor outcomes after ACS. The complex sociocultural barriers to treatment are yet to be addressed adequately.

Predicting multifaceted risks using machine learning in atrial fibrillation: insights from GLORIA-AF study.

Aims: Patients with atrial fibrillation (AF) have a higher risk of ischaemic stroke and death. While anticoagulants are effective at reducing these risks, they increase the risk of bleeding. Current clinical risk scores only perform modestly in predicting adverse outcomes, especially for the outcome of death. We aimed to test the multi-label gradient boosting decision tree (ML-GBDT) model in predicting risks for adverse outcomes in a prospective global AF registry. Methods and results: We studied patients from phase II/III of the Global Registry on Long-Term Oral Anti-Thrombotic Treatment in Patients with Atrial Fibrillation registry between 2011 and 2020. The outcomes were all-cause death, ischaemic stroke, and major bleeding within 1 year following the AF. We trained the ML-GBDT model and compared its discrimination with the clinical scores in predicting patient outcomes. A total of 25 656 patients were included [mean age 70.3 years (SD 10.3); 44.8% female]. Within 1 year after AF, ischaemic stroke occurred in 215 (0.8%), major bleeding in 405 (1.6%), and death in 897 (3.5%) patients. Our model achieved an optimized area under the curve in predicting death (0.785, 95% CI: 0.757-0.813) compared with the Charlson Comorbidity Index (0.747, P = 0.007), ischaemic stroke (0.691, 0.626-0.756) compared with CHA2DS2-VASc (0.613, P = 0.028), and major bleeding (0.698, 0.651-0.745) as opposed to HAS-BLED (0.607, P = 0.002), with improvement in net reclassification index (10.0, 12.5, and 23.6%, respectively). Conclusion: The ML-GBDT model outperformed clinical risk scores in predicting the risks in patients with AF. This approach could be used as a single multifaceted holistic tool to optimize patient risk assessment and mitigate adverse outcomes when managing AF.

A comprehensive investigation of variants in genes encoding adiponectin (ADIPOQ) and its receptors (ADIPOR1/R2), and their association with serum adiponectin, type 2 diabetes, insulin resistance and the metabolic syndrome.

BACKGROUND: Low levels of serum adiponectin have been linked to central obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. Variants in ADIPOQ, the gene encoding adiponectin, have been shown to influence serum adiponectin concentration, and along with variants in the adiponectin receptors (ADIPOR1 and ADIPOR2) have been implicated in metabolic syndrome and type 2 diabetes. This study aimed to comprehensively investigate the association of common variants in ADIPOQ, ADIPOR1 and ADIPOR2 with serum adiponectin and insulin resistance syndromes in a large cohort of European-Australian individuals. METHODS: Sixty-four tagging single nucleotide polymorphisms in ADIPOQ, ADIPOR1 and ADIPOR2 were genotyped in two general population cohorts consisting of 2,355 subjects, and one cohort of 967 subjects with type 2 diabetes. The association of tagSNPs with outcomes were evaluated using linear or logistic modelling. Meta-analysis of the three cohorts was performed by random-effects modelling. RESULTS: Meta-analysis revealed nine genotyped tagSNPs in ADIPOQ significantly associated with serum adiponectin across all cohorts after adjustment for age, gender and BMI, including rs10937273, rs12637534, rs1648707, rs16861209, rs822395, rs17366568, rs3774261, rs6444175 and rs17373414. The results of haplotype-based analyses were also consistent. Overall, the variants in the ADIPOQ gene explained <5% of the variance in serum adiponectin concentration. None of the ADIPOR1/R2 tagSNPs were associated with serum adiponectin. There was no association between any of the genetic variants and insulin resistance or metabolic syndrome. A multi-SNP genotypic risk score for ADIPOQ alleles revealed an association with 3 independent SNPs, rs12637534, rs16861209, rs17366568 and type 2 diabetes after adjusting for adiponectin levels (OR=0.86, 95% CI=(0.75, 0.99), P=0.0134). CONCLUSIONS: Genetic variation in ADIPOQ, but not its receptors, was associated with altered serum adiponectin. However, genetic variation in ADIPOQ and its receptors does not appear to contribute to the risk of insulin resistance or metabolic syndrome but did for type 2 diabetes in a European-Australian population.

Body mass index and waist circumference: relationship to cardiometabolic risk factors in children--Busselton Health Study 2005-2007.

AIM: This study aims to analyse the continuous relationship of each cardiometabolic risk factor with body mass index (BMI) and waist circumference percentiles in a population-based sample of children. METHODS: A cross-sectional sample of 996 school children aged 6-16.9 years in Busselton, Western Australia, (2005-2007) had anthropometry and fasting blood tests for total cholesterol, high density lipoprotein, low density lipoprotein, triglycerides, glucose, insulin, high-sensitive C-reactive protein, liver function tests and adiponectin. Age- and menarche (for girls)-adjusted means of each risk factor were related to BMI and waist circumference centiles across the full normal-overweight-obese range. RESULTS: The correlations between BMI and waist circumference (boys 0.91 and girls 0.91) and between BMI z-score and waist z-score (boys 0.80 and girls 0.82) were high. An increase in insulin across all centile groups (for BMI and waist circumference) was found in both sexes. An increase was found for diastolic blood pressure and systolic blood pressure z-score, high density lipoprotein, high-sensitive C-reactive protein, alanine transaminase and gamma-glutamyltransferase in only the centile groups >85% for BMI and waist circumference for both sexes. Mixed and sex-discordant results were found for triglycerides, adiponectin and glucose. CONCLUSION: There are important differences in the relationships between increasing BMI/adiposity, and each comorbidity and these relationships can differ between boys and girls. This information has implications for screening and management of adiposity-related cardiometabolic risk factors in children and for public health initiatives to reduce future burden of cardiovascular disease.

Alcohol Consumption and Cardiovascular Outcomes in Patients With Nonalcoholic Fatty Liver Disease: A Population-Based Cohort Study.

Low-level alcohol consumption is associated with reduced cardiovascular disease (CVD) in the general population. It is unclear whether this association is seen in patients with nonalcoholic fatty liver disease (NAFLD) who have an increased risk of CVD. We examined the association between alcohol consumption and CVD-related outcomes in subjects with NAFLD from a general population cohort. Subjects participating in the 1994-1995 Busselton Health survey underwent clinical and biochemical assessment. NAFLD was identified using the Fatty Liver Index of >60, and alcohol consumption quantified using a validated questionnaire. CVD hospitalizations and death during the ensuing 20 years were ascertained using the Western Australian data linkage system. A total of 659 of 4,843 patients were diagnosed with NAFLD. The average standard drinks per week was 8.0 for men and 4.0 for women. Men consuming 8-21 drinks per week had a 38% (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.43-0.90) lower risk of CVD hospitalization as compared with men consuming 1-7 drinks per week. With both men and women combined, consumption of 8-21 drinks per week was associated with a 32% (HR 0.68, 95% CI 0.49-0.93) reduction in CVD hospitalization in minimally adjusted and 29% (HR 0.71, 95% CI 0.51-0.99) in fully adjusted models. No protective association was observed with binge drinking. There was no association between alcohol consumption and CVD death. Conclusion: Low to moderate alcohol consumption is associated with fewer CVD hospitalizations but not CVD death in subjects with NAFLD.

Performance of multilabel machine learning models and risk stratification schemas for predicting stroke and bleeding risk in patients with non-valvular atrial fibrillation.

BACKGROUND: Appropriate anticoagulant therapy for patients with atrial fibrillation (AF) requires assessment of stroke and bleeding risks. However, risk stratification schemas such as CHA2DS2-VASc and HAS-BLED have modest predictive capacity for patients with AF. Multilabel machine learning (ML) techniques may improve predictive performance and support decision-making for anticoagulant therapy. We compared the performance of multilabel ML models with the currently used risk scores for predicting outcomes in AF patients. METHODS: This was a retrospective cohort study of 9670 patients, mean age 76.9 years, 46% women, who were hospitalized with non-valvular AF, and had 1-year follow-up. The outcomes were ischemic stroke (167), major bleeding (430) admissions, all-cause death (1912) and event-free survival (7387). Discrimination and calibration of ML models were compared with clinical risk scores by area under the curve (AUC). Risk stratification was assessed using net reclassification index (NRI). RESULTS: Multilabel gradient boosting classifier chain provided the best AUCs for stroke (0.685 95% CI 0.676, 0.694), major bleeding (0.709 95% CI 0.703, 0.716) and death (0.765 95% CI 0.763, 0.768) compared to multi-layer neural networks and classifier chain using support vector machine. It provided modest performance improvement for stroke compared to AUC of CHA2DS2-VASc (0.652, NRI = 3.2%, p-value = 0.1), but significantly improved major bleeding prediction compared to AUC of HAS-BLED (0.522, NRI = 22.8%, p-value < 0.05). It also achieved greater discriminant power for death compared with AUC of CHA2DS2-VASc (0.606, p-value < 0.05). ML models identified additional risk features such as hemoglobin level, renal function. CONCLUSIONS: Multilabel ML models can outperform clinical risk stratification scores for predicting the risk of major bleeding and death in non-valvular AF patients.