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Abstract High‐quality randomized trial evidence is lacking on whether low‐dose aspirin exerts significant effects on blood pressure (BP) in older adults. The authors assessed longitudinal BP changes in participants enrolled in ASPirin in Reducing Events in the Elderly (ASPREE), a randomized, placebo‐controlled trial of 100 mg daily aspirin in 19 114 community‐dwelling Australian and U.S. adults without cardiovascular disease (CVD), dementia, or independence‐limiting physical disability. Participants’ BP was recorded at baseline and annual study visits, and managed by their usual care provider. BP trajectories for aspirin versus placebo during 4.7 years of follow‐up were examined for systolic and diastolic BP separately, using linear mixed models to account for between and within‐individual variability in BP. Analyses by subgroups were also explored with inclusion of interaction terms in the models. The difference in mean change in systolic BP between aspirin and placebo during study follow‐up was −0.03 mm Hg (95% confidence interval [CI]: −0.13, 0.07; p = .541) (aspirin minus placebo), while the mean difference for change in diastolic BP was −0.05 mm Hg (95% CI: –0.11, 0.01; p = .094). These small, non‐significant differences in BP change between the aspirin and placebo groups were consistent across baseline levels of BP and antihypertensive treatment status (treated/untreated). Likewise, subgroups of age, sex, chronic kidney disease, diabetes, and frailty revealed no interaction effect between the subgroup, aspirin treatment, and time. Interval‐censored Cox proportional hazards regression showed no difference in rates of incident treated hypertension between aspirin and placebo‐treated participants. The authors conclude that daily low‐dose aspirin does not significantly affect BP in older adults when managed by usual care.

Abstract Male sex, early life chemical exposure and the brain aromatase enzyme have been implicated in autism spectrum disorder (ASD). In the Barwon Infant Study birth cohort (n = 1074), higher prenatal maternal bisphenol A (BPA) levels are associated with higher ASD symptoms at age 2 and diagnosis at age 9 only in males with low aromatase genetic pathway activity scores. Higher prenatal BPA levels are predictive of higher cord blood methylation across the CYP19A1 brain promoter I.f region (P = 0.009) and aromatase gene methylation mediates (P = 0.01) the link between higher prenatal BPA and brain-derived neurotrophic factor methylation, with independent cohort replication. BPA suppressed aromatase expression in vitro and in vivo. Male mice exposed to mid-gestation BPA or with aromatase knockout have ASD-like behaviors with structural and functional brain changes. 10-hydroxy-2-decenoic acid (10HDA), an estrogenic fatty acid alleviated these features and reversed detrimental neurodevelopmental gene expression. Here we demonstrate that prenatal BPA exposure is associated with impaired brain aromatase function and ASD-related behaviors and brain abnormalities in males that may be reversible through postnatal 10HDA intervention.

Abstract Background The net benefit of aspirin cessation in older adults remains uncertain. This study aimed to use observational data to emulate a randomized trial of aspirin cessation versus continuation in older adults without cardiovascular disease (CVD). Methods Post hoc analysis using a target trial emulation framework applied to the immediate post-trial period (2017–2021) of a study of low-dose aspirin initiation in adults aged ≥ 70 years (ASPREE; NCT01038583). Participants from Australia and the USA were included if they were free of CVD at the start of the post-trial intervention period (time zero, T0) and had been taking open-label or randomized aspirin immediately before T0. The two groups in the target trial were as follows: aspirin cessation (participants who were taking randomized aspirin immediately before T0; assumed to have stopped at T0 as instructed) versus aspirin continuation (participants on open-label aspirin at T0 regardless of their randomized treatment; assumed to have continued at T0). The outcomes after T0 were incident CVD, major adverse cardiovascular events (MACE), all-cause mortality, and major bleeding during 3, 6, and 12 months (short-term) and 48 months (long-term) follow-up. Hazard ratios (HRs) comparing aspirin cessation to continuation were estimated from propensity-score (PS) adjusted Cox proportional-hazards regression models. Results We included 6103 CVD-free participants (cessation: 5427, continuation: 676). Over both short- and long-term follow-up, aspirin cessation versus continuation was not associated with elevated risk of CVD, MACE, and all-cause mortality (HRs, at 3 and 48 months respectively, were 1.23 and 0.73 for CVD, 1.11 and 0.84 for MACE, and 0.23 and 0.79 for all-cause mortality, p > 0.05), but cessation had a reduced risk of incident major bleeding events (HRs at 3 and 48 months, 0.16 and 0.63, p

Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is an important cause of drug-resistant epilepsy. A significant subset of individuals diagnosed with MOGHE display somatic mosaicism for loss-of-function variants in SLC35A2, which encodes the UDP-galactose transporter. We developed a mouse model to investigate how disruption of this transporter leads to a malformation of cortical development. We used in utero electroporation and CRISPR/Cas9 to knockout Slc35a2 in a subset of layer 2/3 cortical neuronal progenitors in the developing brains of male and female fetal mice to model mosaic expression. Mosaic Slc35a2 knockout was verified through next-generation sequencing and immunohistochemistry of GFP-labelled transfected cells. Histology of brain tissue in mosaic Slc35a2 knockout mice revealed the presence of upper layer-derived cortical neurons in the white matter. Reconstruction of single filled neurons identified altered dendritic arborisation with Slc35a2 knockout neurons having increased complexity. Whole-cell electrophysiological recordings revealed that Slc35a2 knockout neurons display reduced action potential firing, increased afterhyperpolarisation duration and reduced burst-firing when compared with control neurons. Mosaic Slc35a2 knockout mice also exhibited significantly increased epileptiform spiking and increased locomotor activity. We successfully generated a mouse model of mosaic Slc35a2 deficiency, which recapitulates features of the human phenotype, including impaired neuronal migration. We show that knockout in layer 2/3 cortical neuron progenitors is sufficient to disrupt neuronal excitability, increase epileptiform activity and cause hyperactivity in mosaic mice. Our mouse model provides an opportunity to further investigate the disease mechanisms that contribute to MOGHE and facilitate the development of precision therapies.

Abstract Background Cognitive impairment is common after stroke, and a large proportion of stroke patients will develop dementia. However, there have been few large prospective studies which have assessed cognition both prior to and after stroke. This study aims to determine the extent to which incident stroke impacts different domains of cognitive function in a longitudinal cohort of older community-dwelling individuals. Methods 19,114 older individuals without cardiovascular disease or major cognitive impairment were recruited and followed over a maximum 11 years. Stroke included ischaemic and haemorrhagic stroke and was adjudicated by experts. Cognitive function was assessed regularly using Modified Mini-Mental State Examination (3MS), Hopkins Verbal Learning Test–Revised (HVLT-R), Symbol Digit Modalities Test (SDMT), and Controlled Oral Word Association Test (COWAT). Linear mixed models were used to investigate the change in cognition at the time of stroke and decline in cognitive trajectories following incident stroke. Results During a median follow-up period of 8.4 [IQR: 7.2, 9.6] years, 815 (4.3%) participants experienced a stroke. Over this time, there was a general decline observed in 3MS, HVLT-R delayed recall, and SDMT scores across participants. However, for individuals who experienced a stroke, there was a significantly greater decline across all cognitive domains immediately after the event immediately after the event (3MS: -1.03 [95%CI: -1.45, -0.60]; HVLT-R: -0.47 [-0.70, -0.24]; SDMT: -2.82 [-3.57, -2.08]; COWAT: -0.67 [-1.04, -0.29]) and a steeper long-term decline for three of these domains (3MS -0.62 [-0.88, -0.35]; COWAT: -0.30 [-0.46, -0.14]); HVLT-R: -0.12 [95%CI, -0.70, -0.24]). However individuals with stroke experienced no longer-term decline in SDMT compared to the rest of the participants. Conclusions These findings highlight the need for comprehensive neuropsychology assessments for ongoing monitoring of cognition following incident stroke; and potential early intervention.

Abstract Background Multimorbidity is strongly associated with disability or functional decline, poor quality of life and high consumption of health care services. This study aimed (1) To identify patterns of multimorbidity among patients undergoing first recorded percutaneous coronary intervention (PCI); (2) To explore the association between the identified patterns of multimorbidity on length of hospital stay, 30-day and 12- month risk of major adverse cardiac and cerebrovascular events (MACCE) after PCI. Methods A retrospective cohort study of the Melbourne Interventional Group (MIG) registry. This study included 14,025 participants who underwent their first PCI from 2005 to 2015 in Victoria, Australia. Based on a probabilistic modelling approach, Latent class analysis was adopted to classify clusters of people who shared similar combinations and magnitude of the comorbidity of interest. Logistic regression models were used to estimate odd ratios and 95% confidence interval (CI) for the 30-day and 12-month MACCE. Results More than two-thirds of patients had multimorbidity, with the most prevalent conditions being hypertension (59%) and dyslipidaemia (60%). Four distinctive multimorbidity clusters were identified each with significant associations for higher risk of 30-day and 12-month MACCE. The cluster B had the highest risk of 30-day MACCE event that was characterised by a high prevalence of reduced estimated glomerular filtration rate (92%), hypertension (73%) and reduced ejection fraction (EF) (57%). The cluster C, characterised by a high prevalence of hypertension (94%), dyslipidaemia (88%), reduced eGFR (87%), diabetes (73%) and reduced EF (65%) had the highest risk of 12-month MACCE and highest length of hospital stay. Conclusion Hypertension and dyslipidaemia are prevalent in at least four in ten patients undergoing coronary angioplasty. This study showed that clusters of patients with multimorbidity had significantly different risk of 30-day and 12-month MACCE after PCI. This suggests the necessity for treatment approaches that are more personalised and customised to enhance patient outcomes and the quality of care delivered to patients in various comorbidity clusters. These results should be validated in a prospective cohort and to evaluate the potential impacts of these clusters on the prevention of MACCE after PCI.

Cardiovascular diseases (CVD) are one of the leading causes of death globally, and a major contributor to CVD mortality is ambient air pollution (AAP). This study aimed to evaluate associations between AAP and mortality from CVD, including ischemic heart diseases (IHD) and strokes. Data on daily mortality records, six criteria AAP and meteorology in the capital city of Mongolia were collected between 1 January 2016 and 31 December 2022. A time-stratified case-crossover design was analysed with distributed lag conditional Poisson regression to estimate the relative risk of CVD mortality. We found that for each interquartile range increase in PM2.5, PM10, SO2 and NO2 pollutants, the risk of CVD mortality increased by 1.5% (RR = 1.015; 95% CI: 1.005, 1.025), 4.4% (RR = 1.044; 95% CI: 1.029, 1.059), 3.1% (RR = 1.033; 95% CI: 1.015, 1.047) and 4.8% (RR = 1.048; 95% CI: 1.013, 1.085) at lag01, respectively. The association between all pollutants, except O3, and CVD mortality was higher in subgroups ≥ 65 years and male, during the cold season and after using a new type of coal briquettes. Despite using the new type of coal briquettes, Ulaanbaatar’s ambient air pollution remained higher than the WHO’s guidelines. Based on our findings, we recommend that efforts should be focused on adopting more efficient strategies to reduce the current pollution level.

Introduction Calcium channel blockers (CCB), a commonly prescribed antihypertensive (AHT) medicine, may be associated with increased risk of breast cancer. The proposed study aims to examine whether long-term CCB use is associated with the development of breast cancer and to characterise the dose–response nature of any identified association, to inform future hypertension management.Methods and analysis The study will use data from 2 of Australia’s largest cohort studies; the Australian Longitudinal Study on Women’s Health, and the 45 and Up Study, combined with the Rotterdam Study. Eligible women will be those with diagnosed hypertension, no history of breast cancer and no prior CCB use at start of follow-up (2004–2009). Cumulative dose-duration exposure to CCB and other AHT medicines will be captured at the earliest date of: the outcome (a diagnosis of invasive breast cancer); a competing risk event (eg, bilateral mastectomy without a diagnosis of breast cancer, death prior to any diagnosis of breast cancer) or end of follow-up (censoring event). Fine and Gray competing risks regression will be used to assess the association between CCB use and development of breast cancer using a generalised propensity score to adjust for baseline covariates. Time-varying covariates related to interaction with health services will also be included in the model. Data will be harmonised across cohorts to achieve identical protocols and a two-step random effects individual patient-level meta-analysis will be used.Ethics and dissemination Ethical approval was obtained from the following Human research Ethics Committees: Curtin University (ref No. HRE2022-0335), NSW Population and Health Services Research Ethics Committee (2022/ETH01392/2022.31), ACT Research Ethics and Governance Office approval under National Mutual Acceptance for multijurisdictional data linkage research (2022.STE.00208). Results of the proposed study will be published in high-impact journals and presented at key scientific meetings.Trial registration number NCT05972785.

Abstract Background Unhealthy lifestyle behaviours such as smoking, high alcohol consumption, poor diet or low physical activity are associated with morbidity and mortality. Public health guidelines provide recommendations for adherence to these four factors, however, their relationship to the health of older people is less certain. Methods The study involved 11,340 Australian participants (median age 7.39 [Interquartile Range (IQR) 71.7, 77.3]) from the ASPirin in Reducing Events in the Elderly study, followed for a median of 6.8 years (IQR: 5.7, 7.9). We investigated whether a point-based lifestyle score based on adherence to guidelines for a healthy diet, physical activity, non-smoking and moderate alcohol consumption was associated with subsequent all-cause and cause-specific mortality. Results In multivariable adjusted models, compared to those in the unfavourable lifestyle group, individuals in the moderate lifestyle group (Hazard Ratio (HR) 0.73 [95% CI 0.61, 0.88]) and favourable lifestyle group (HR 0.68 [95% CI 0.56, 0.83]) had lower risk of all-cause mortality. A similar pattern was observed for cardiovascular related mortality and non-cancer/non-cardiovascular related mortality. There was no association of lifestyle with cancer-related mortality. Conclusions In a large cohort of initially healthy older people, reported adherence to a healthy lifestyle is associated with reduced risk of all-cause and cause-specific mortality. Adherence to all four lifestyle factors resulted in the strongest protection.

Abstract Background Coronavirus disease of 2019 (COVID-19) is associated with venous thromboembolism (VTE), not only during hospitalization but also after discharge, raising concerns about anticoagulant (AC) use for post-discharge COVID-19 patients. We aimed to systematically review the current literature on the possible benefits or risks regarding extended thromboprophylaxis. Main body We searched related databases from December 1, 2019, to October 6, 2022, including studies on the necessity, duration, and selection of the ideal AC regarding extended thromboprophylaxis for post-discharge COVID-19 patients. The screening of the selected databases led to 18 studies and 19 reviews and guidelines. Studies included 52,927 hospitalized COVID-19 patients, with 19.25% receiving extended thromboprophylaxis. VTE events ranging from 0 to 8.19% (median of 0.7%) occurred in a median follow-up of 49.5 days. All included studies and guidelines, except four studies, recommended post-discharge prophylaxis after an individual risk assessment indicating high thrombotic and low bleeding risk. Studies used risk assessment models (RAMs), clinical evaluation, and laboratory data to identify COVID-19 patients with a high risk of VTE. IMPROVE-DD was the most recommended RAM. Direct oral anticoagulants (DOACs) and low molecular weight heparins (LMWHs) were the most used AC classes. Conclusions Post-discharge prophylaxis for COVID-19 patients is recommended after an individual assessment. The IMPROVE-DD model can help predict VTE risk. After distinguishing patients who need post-discharge AC therapy, DOACs for 30–35 days and LMWHs for 40–45 days can be the drug of choice. Further studies, particularly the results of the ongoing randomized controlled trials (RCTs), are required. Also, to properly handle such patients, every physician should consider lifestyle modification in addition to pharmacological treatment for post-discharge VTE prophylaxis.

Background There is increasing awareness that patients without standard modifiable risk factors (SMuRFs; diabetes, hypercholesterolaemia, hypertension and smoking) may represent a unique subset of patients with acute coronary syndrome (ACS). We aimed to investigate the prevalence and outcomes of patients with SMuRF-less ACS undergoing percutaneous coronary intervention (PCI) compared with those with SMuRFs.Methods We analysed data from the Melbourne Interventional Group PCI Registry. Patients with coronary artery disease were excluded. The primary outcome was 30-day mortality. Secondary outcomes included in-hospital and 30-day events. Long-term mortality was investigated using Cox-proportional hazards regression.Results From 1 January 2005 to 31 December 2020, 2727/18 988 (14.4%) patients were SMuRF less, with the proportion increasing over time. Mean age was similar for patients with and without SMuRFs (63 years), and fewer females were SMuRF-less (19.8% vs 25.4%, p

BackgroundThis study evaluates primary care practices' engagement with various features of a quality improvement (QI) intervention for patients with coronary heart disease (CHD) in four Australian states.MethodsTwenty-seven practices participated in the QI intervention from November 2019 -November 2020. A combination of surveys, semi-structured interviews and other materials within the QUality improvement in primary care to prevent hospitalisations and improve Effectiveness and efficiency of care for people Living with heart disease (QUEL) study were used in the process evaluation. Data were summarised using descriptive statistical and thematic analyses for 26 practices.ResultsSixty-four practice team members and Primary Health Networks staff provided feedback, and nine of the 63 participants participated in the interviews. Seventy-eight percent (40/54) were either general practitioners or practice managers. Although 69% of the practices self-reported improvement in their management of heart disease, engagement with the intervention varied. Forty-two percent (11/26) of the practices attended five or more learning workshops, 69% (18/26) used Plan-Do-Study-Act cycles, and the median (Interquartile intervals) visits per practice to the online SharePoint site were 170 (146-252) visits. Qualitative data identified learning workshops and monthly feedback reports as the key features of the intervention.ConclusionPractice engagement in a multi-featured data-driven QI intervention was common, with learning workshops and monthly feedback reports identified as the most useful features. A better understanding of these features will help influence future implementation of similar interventions.Trial registrationAustralian New Zealand Clinical Trials Registry (ANZCTR) number ACTRN12619001790134.

ASPirin in Reducing Events in the Elderly (ASPREE), a placebo-controlled prevention trial of low dose aspirin, provided the opportunity to establish a biospecimen biobank from initially healthy persons aged 70+ years for future research. The ASPREE Healthy Ageing Biobank (ASPREE Biobank) collected, processed and stored blood and urine samples at -80degC or under nitrogen vapour at two timepoints, three years apart, from a willing subset of Australian ASPREE participants. Written informed consent included separate opt-in questions for biomarker and genetic testing. Fractionated blood and urine were aliquoted into multiple low-volume, barcoded cryotubes for frozen storage within 4 hours of collection. Specially designed and outfitted mobile laboratories provided opportunities for participation by people in regional and rural areas. Detailed, high quality demographic, physiological and clinical data were collected annually through the ASPREE trial. 12,219 participants contributed blood/urine at the first timepoint, 10,617 of these older adults provided 3-year follow-up samples, and an additional 1,712 provided saliva for DNA. The mean participant age was 74 years, 54% were female and 46% lived outside major cities. Despite geographical and logistical challenges, nearly 100% of blood/urine specimens were processed and frozen within 4 hours of collection into >1.4 million aliquots. After a median of 4.7 years, major clinical events among ASPREE Biobank participants included 332 with dementia, 613 with cardiovascular disease events, 1259 with cancer, 357 with major bleeds and 615 had died. The ASPREE Biobank houses and curates a large number of biospecimens collected prior to the clinical manifestations of major disease, and 3-year follow-up samples, all linked to high quality, extensive phenotypic information. This provides the opportunity to identify or validate diagnostic, prognostic and predictive biomarkers, and potentially study biological effectors, of ageing-related diseases or maintenance of older-age good health.

BackgroundPlatelets (PLTS) and fresh frozen plasma (FFP) are often transfused in cardiac surgery patients for perioperative bleeding. Their relative effectiveness is unknown.MethodsWe conducted an entropy-weighted retrospective cohort study using the Australian and New Zealand Society of Cardiac and Thoracic Surgeons National Cardiac Surgery Database. All adults undergoing cardiac surgery between 2005-2021 across 58 sites were included. The primary outcome was operative mortality.ResultsOf 174,796 eligible patients, 15,360 (8.79%) received PLTS in the absence of FFP and 6,189 (3.54%) patients received FFP in the absence of PLTS. The median cumulative dose was 1 unit of pooled platelets (IQR 1 to 3) and 2 units of FFP (IQR 0 to 4) respectively. After entropy weighting to achieve balanced cohorts, FFP was associated with increased perioperative (Risk Ratio [RR], 1.63; 95% Confidence Interval [CI], 1.40 to 1.91; PConclusionIn perioperative bleeding in cardiac surgery patient, platelets are associated with a relative mortality benefit over FFP. This information can be used by clinicians in their choice of procoagulant therapy in this setting.

Abstract In the general population, body mass index (BMI) and waist circumference are recognized risk factors for several chronic diseases and all-cause mortality. However, whether these associations are the same for older adults is less clear. The association of baseline BMI and waist circumference with all-cause and cause-specific mortality was investigated in 18,209 Australian and US participants (mean age: 75.1 ± 4.5 years) from the ASPirin in Reducing Events in the Elderly (ASPREE) study, followed up for a median of 6.9 years (IQR: 5.7, 8.0). There were substantially different relationships observed in men and women. In men, the lowest risk of all-cause and cardiovascular mortality was observed with a BMI in the range 25.0–29.9 kg/m2 [HR25-29.9 vs 21–24.9 kg/m 2: 0.85; 95% CI, 0.73–1.00] while the highest risk was in those who were underweight [HRBMI

BackgroundInsufficient data exists regarding the relationship between body mass index (BMI) and the prognosis of chronic heart failure (CHF) specifically within low- and middle-income Asian countries. The objective of this study was to evaluate the impact of BMI on adverse outcomes of ambulatory patients with CHF in Vietnam.MethodsBetween 2018 and 2020, we prospectively enrolled consecutive outpatients with clinically stable CHF in an observational cohort, single-center study. The participants were stratified according to Asian-specific BMI thresholds. The relationships between BMI and adverse outcomes (all-cause death and all-cause hospitalization) were analyzed by Kaplan–Meier survival curves and Cox proportional-hazards model.ResultsAmong 320 participants (age 63.5 ± 13.3 years, 57.9% male), the median BMI was 21.4 kg/m2 (IQR 19.5–23.6), and 10.9% were underweight (BMI 0.05).ConclusionIn ambulatory patients with CHF in Vietnam, lower BMI, especially underweight status (BMI

Background It is unknown if the presence of saphenous vein grafting (SVG) adversely affects late survival following coronary surgery with multiple arterial grafting (MAG) versus single arterial grafting. Methods and Results A retrospective, observational, multicenter cohort study from 2001 to 2020 was conducted using the Australian and New Zealand Society of Cardiac and Thoracic Surgeons Database linked to the National Death Index. Patients undergoing primary isolated coronary artery bypass grafting with ≥2 grafts were included, and exclusions were patients aged

Background:. This study compares the arthroscopic shaver and liposuction with other established methods for treatment of adolescent gynecomastia. Methods:. Surgical management was via four operative techniques: open excision, open excision/liposuction, arthroscopic shaver/liposuction, or open excision and free nipple graft. Data were collected and compared using independent t tests, linear regression models, and one-way analysis of variance. Results:. Patients were stratified by Rohrich grades I -II (low) (N = 47) or III -IV (high) (N = 13). The groups were similar in age (P = 0.662) with lower BMI in the low-grade group (x̄ = 25.36 ± 2.1) vs. high-grade group (x̄ = 27.62 ± 4.0; P < 0.001). The low-grade group showed no significant difference in operative time across surgical techniques with decreased mean operative time in the high-grade group using the arthroscopic shaver technique (x̄ = 55.8 ± 7.56) compared with open excision (x̄ = 70.83 ± 11.02, P = 0.04), open excision plus liposuction (x̄ = 89.5 ± 24.93, P = 24.93), and open excision plus free nipple graft (x̄ = 81.67 ± 19.11, P = 0.05). There was no significant difference in complication (P = 0.84) or reoperation (P = 0.68) rates across surgical techniques regardless of grade. Conclusions:. These findings suggest that the arthroscopic shaver is safe and effective for treatment of both low- and high-grade gynecomastia in adolescents. The results yielded a similar incidence of complications and reoperation across surgical techniques, and the arthroscopic shaver approach demonstrated a shorter operative time compared with other techniques for high-grade gynecomastia.

Abstract Aims Prescribed opioids are commonly used in the older community‐dwelling population for the treatment of chronic pain. Although the harmful effects of opioid abuse and overdose are well understood, little is known about the long‐term cardiovascular (CV) effects of prescribed opioids. The aim of this study was to investigate the CV effects associated with prescribed opioid use. Methods and results A post hoc analysis of participants in the Aspirin in Reducing Events in the Elderly (ASPREE) trial was conducted. Participants in the ASPREE trial included community‐dwelling older adults without a prior history of CV disease (CVD). Prescribed opioid use was defined as opioid use at baseline and/or at the first annual visit (AV1). Cox proportional hazards regression was used to calculate hazard ratios and 95% confidence intervals (95% CI) for associations between opioid use and CVD events following AV1. Of the 17 701 participants included (mean age 75.2 years, 58.2% female), 813 took opioids either at baseline or at AV1. Over a median follow‐up period of 3.58 years (IQR 2.50–4.62), CVD events, most notably heart failure hospitalization, occurred in 7% (n = 57) amongst opioid users and 4% (n = 680) amongst non‐opioid users. After adjustment for multiple covariates, opiate use was associated with a 1.67‐fold (CI 1.26–2.23, P

A well-tolerated rAAV vector-mediated gene therapy in normotensive Brown Norway rats is used to reduce intraocular pressure in a dose dependent manner, encouraging further evaluations on pre-clinical models of glaucoma.

Current evidence on benefits of night-time blood pressure (BP) lowering drug treatment on cardiovascular disease (CVD) prevention attributable to the Ambulatory Blood Pressure Monitoring in the Prediction of Cardiovascular Events and Effects of Chronotherapy (MAPEC) trial and Bedtime hypertension treatment improves cardiovascular risk reduction (Hygia) trials has raised concern on their validity and methodology. In this commentary, the authors have updated the progress of the ongoing trials that were planned to examine the effect of night-time BP lowering drug treatment on CVD prevention. As compared to MAPEC and Hygia trials, three pragmatic trials the Blood Pressure Medication Timing (BPMedtime) trial (US), the Treatment In Morning versus Evening (TIME) trial (UK), Bedmed and Bedmed-frail (Canada) were planned without ambulatory BP monitoring. The BPMedtime trial was stopped after the pilot phase due to underestimated sample size and insufficient funds. TIME trial (UK) had a similar issue when changing the sample size from 10,269 to more than 20,000 participants. The TIME trial was completed and the initial results showing that protection against heart attack, stroke and vascular death is not affected by whether antihypertensive medications are taken in the morning or evening. The full study of the TIME trial is published in December 2022. Bedmed and Bedmed-frail trials are ongoing and will be completed in 2023. Time of taking BP lowering drug should be determined by patients at their convenience to improve the adherence. There was no difference in adverse effects of taking BP lowering drugs at night or morning. Evidence on the effect of night-time treatment on CVD events is inconsistent. The results from ongoing trials in Canada will contribute evidence to the use of BP lowering drug treatment for the prevention of CVD.

ObjectivesMachine learning (ML) classification tools are known to accurately predict many cardiac surgical outcomes. A novel approach, ML-based survival analysis, remains unstudied for predicting mortality after cardiac surgery. We aimed to benchmark performance, as measured by the concordance index (C-index), of tree-based survival models against Cox proportional hazards (CPH) modeling and explore risk factors using the best-performing model.Methods144,536 patients with 147,301 surgery events from the Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) national database were used to train and validate models. Univariate analysis was performed using Student's T-test for continuous variables, Chi-squared test for categorical variables, and stratified Kaplan-Meier estimation of the survival function. Three ML models were tested, a decision tree (DT), random forest (RF), and gradient boosting machine (GBM). Hyperparameter tuning was performed using a Bayesian search strategy. Performance was assessed using 2-fold cross-validation repeated 5 times.ResultsThe highest performing model was the GBM with a C-index of 0.803 (0.002), followed by RF with 0.791 (0.003), DT with 0.729 (0.014), and finally CPH with 0.596 (0.042). The 5 most predictive features were age, type of procedure, length of hospital stay, drain output in the first 4 h (ml), and inotrope use greater than 4 h postoperatively.ConclusionTree-based learning for survival analysis is a non-parametric and performant alternative to CPH modeling. GBMs offer interpretable modeling of non-linear relationships, promising to expose the most relevant risk factors and uncover new questions to guide future research.

Changes in Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) channel function have been linked to depressive-like traits, making them potential drug targets. However, there is currently no peer-reviewed data supporting the use of a small molecule modulator of HCN channels in depression treatment. Org 34167, a benzisoxazole derivative, has been patented for the treatment of depression and progressed to Phase I trials. In the current study, we analysed the biophysical effects of Org 34167 on HCN channels in stably transfected human embryonic kidney 293 (HEK293) cells and mouse layer V neurons using patch-clamp electrophysiology, and we utilised three high-throughput screens for depressive-like behaviour to assess the activity of Org 34167 in mice. The impact of Org 34167 on locomotion and coordination were measured by performing rotarod and ledged beam tests. Org 34167 is a broad-spectrum inhibitor of HCN channels, slowing activation and causing a hyperpolarising shift in voltage-dependence of activation. It also reduced Ih-mediated sag in mouse neurons. Org 34167 (0.5 mg/kg) reduced marble burying and increased the time spent mobile in the Porsolt swim and tail suspension tests in both male and female BALB/c mice, suggesting reduced depressive-like behaviour. Although no adverse effects were seen at 0.5 mg/kg, an increase in dose to 1 mg/kg resulted in visible tremors and impaired locomotion and coordination. These data support the premise that HCN channels are valid targets for anti-depressive drugs albeit with a narrow therapeutic index. Drugs with higher HCN subtype selectivity are needed to establish if a wider therapeutic window can be obtained.

Objectives We sought to establish the minimum level of clinical benefit attributable to the Victorian Cardiac Outcomes Registry (VCOR) for the registry to be cost-effective.Design A modelled cost-effectiveness study of VCOR was conducted from the Australian healthcare system and societal perspectives.Setting Observed deaths and costs attributed to coronary heart disease (CHD) over a 5-year period (2014–2018) were compared with deaths and costs arising from a hypothetical situation which assumed that VCOR did not exist. Data from the Australian Bureau of Statistics and published sources were used to construct a decision analytic life table model to simulate the follow-up of Victorians aged ≥25 years for 5 years, or until death. The assumed contribution of VCOR to the proportional change in CHD mortality trend observed over the study period was varied to quantify the minimum level of clinical benefits required for the registry to be cost-effective. The marginal costs of VCOR operation and years of life saved (YoLS) were estimated.Primary outcome measures The return on investment (ROI) ratio and the incremental cost-effectiveness ratio (ICER).Results The minimum proportional change in CHD mortality attributed to VCOR required for the registry to be considered cost-effective was 0.125%. Assuming this clinical benefit, a net return of $A4.30 for every dollar invested in VCOR was estimated (ROI ratio over 5 years: 4.3 (95% CI 3.6 to 5.0)). The ICER estimated for VCOR was $A49 616 (95% CI $A42 228 to $A59 608) per YoLS. Sensitivity analyses found that the model was sensitive to the time horizon assumed and the extent of registry contribution to CHD mortality trends.Conclusions VCOR is likely cost-effective and represents a sound investment for the Victorian healthcare system. Our evaluation highlights the value of clinical quality registries in Australia.

Introduction The world is undergoing a demographic transition to an older population. Preventive healthcare has reduced the burden of chronic illness at younger ages but there is limited evidence that these advances can improve health at older ages. Statins are one class of drug with the potential to prevent or delay the onset of several causes of incapacity in older age, particularly major cardiovascular disease (CVD). This paper presents the protocol for the STAtins in Reducing Events in the Elderly (STAREE) trial, a randomised double-blind placebo-controlled trial examining the effects of statins in community dwelling older people without CVD, diabetes or dementia.Methods and analysis We will conduct a double-blind, randomised placebo-controlled trial among people aged 70 years and over, recruited through Australian general practice and with no history of clinical CVD, diabetes or dementia. Participants will be randomly assigned to oral atorvastatin (40 mg daily) or matching placebo (1:1 ratio). The co-primary endpoints are disability-free survival defined as survival-free of dementia and persistent physical disability, and major cardiovascular events (cardiovascular death or non-fatal myocardial infarction or stroke). Secondary endpoints are all-cause death, dementia and other cognitive decline, persistent physical disability, fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, heart failure, atrial fibrillation, fatal and non-fatal cancer, all-cause hospitalisation, need for permanent residential care and quality of life. Comparisons between assigned treatment arms will be on an intention-to-treat basis with each of the co-primary endpoints analysed separately in time-to-first-event analyses using Cox proportional hazards regression models.Ethics and dissemination STAREE will address uncertainties about the preventive effects of statins on a range of clinical outcomes important to older people. Institutional ethics approval has been obtained. All research outputs will be disseminated to general practitioner co-investigators and participants, published in peer-reviewed journals and presented at national and international conferences.Trial registration number NCT02099123.

Study objective: This study examined the association between frailty and incident cardiovascular disease (CVD) events, major adverse cardiovascular events (MACE), and CVD-related mortality. Design: Longitudinal cohort study. Setting: The ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial in Australia and the United States. Participants: 19,114 community-dwelling older adults (median age 74.0 years; 56.4 % females). Interventions: Pre-frailty and frailty were assessed using a modified Fried phenotype and a deficit accumulation Frailty Index (FI) at baseline. Main outcome measures: CVD was defined as a composite of CVD death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for heart failure; MACE included all except heart failure. Cox proportional hazards regression was used to analyze the association between frailty and CVD outcomes over a median follow-up of 4.7 years. Results: Baseline pre-frail and frail groups had a higher risk of incident CVD events (Hazard Ratio (HR): 1.31; 95 % Confidence Interval (CI): 1.14–1.50 for pre-frail and HR: 1.63; 95 % CI: 1.15–2.32 for frail) and MACE (pre-frail HR: 1.26; 95 % CI: 1.08–1.47 and frail HR: 1.51; 95 % CI: 1.00–2.29) than non-frail participants according to Fried phenotype after adjusting for traditional CVD risk factors. Effect sizes were similar or larger when frailty was assessed with FI; similar results for men and women. Conclusion: Frailty increases the likelihood of developing CVD, including MACE, in community-dwelling older men and women without prior CVD events. Screening for frailty using Fried or FI method could help identify community-dwelling older adults without prior CVD events who are more likely to develop CVD, including MACE, and may facilitate targeted preventive measures to reduce their risk.

Background and aimsFatty streaks initiating the formation of atheromatous plaque appear in the tunica intima. The tunica media is not known to be a nidus for lipid accumulation initiating atherogenesis. We assessed changes to the tunica media in response to a micro-injury produced in the pig aorta. In addition, we assessed human carotid endarterectomy plaques for indication of atheroma initiation in the tunica media.MethodsThree healthy landrace female pigs underwent laparotomy to inject autologous blood and create micro-hematomas at 6 sites within the tunica media of the infrarenal abdominal aorta. These pigs were fed a high-fat diet (HFD) for 4–12 weeks. Post-mortem aortas from all pigs, including a control group of healthy pigs, were serially stained to detect lipid deposits, vasa vasora (VV), immune cell infiltration and inflammatory markers, as well as changes to the vascular smooth muscle cell (vSMC) compartment. Moreover, 25 human carotid endarterectomy (CEA) specimens were evaluated for their lipid composition in the tunica media and intima.ResultsHigh lipid clusters, VV density, and immune cell infiltrates were consistently observed at 5 out of 6 injection sites under prolonged hyperlipidemia. The hyperlipidemic diet also affected the vSMC compartment in the tunica media adjacent to the tunica adventitia, which correlated with VV invasion and immune cell infiltration. Analysis of human carotid specimens post-CEA indicated that 32% of patients had significantly greater atheroma in the tunica media than in the arterial intima.ConclusionThe arterial intima is not the only site for atherosclerosis initiation. We show that injury to the media can trigger atherogenesis.

Introduction General practitioners (GPs) routinely provide care for patients with heart failure (HF); however, adherence to management guidelines, including titrating medication to optimal dose, can be challenging in this setting. This study will evaluate the effectiveness of a multifaceted intervention to support adherence to HF management guidelines in primary care.Methods and analysis We will undertake a multicentre, parallel-group, randomised controlled trial of 200 participants with HF with reduced ejection fraction. Participants will be recruited during a hospital admission due to HF. Following hospital discharge, the intervention group will have follow-up with their GP scheduled at 1 week, 4 weeks and 3 months with the provision of a medication titration plan approved by a specialist HF cardiologist. The control group will receive usual care. The primary endpoint, assessed at 6 months, will be the difference between groups in the proportion of participants being prescribed five guideline-recommended treatments; (1) ACE inhibitor/angiotensin receptor blocker/angiotensin receptor neprilysin inhibitor at least 50% of target dose, (2) beta-blocker at least 50% of target dose, (3) mineralocorticoid receptor antagonist at any dose, (4) anticoagulation for patients diagnosed with atrial fibrillation, (5) referral to cardiac rehabilitation. Secondary outcomes will include functional capacity (6-minute walk test); quality of life (Kansas City Cardiomyopathy Questionnaire); depressive symptoms (Patient Health Questionnaire-2); self-care behaviour (Self-Care of Heart Failure Index). Resource utilisation will also be assessed.Ethics and dissemination Ethical approval was granted by the South Metropolitan Health Service Ethics Committee (RGS3531), with reciprocal approval at Curtin University (HRE2020-0322). Results will be disseminated via peer-reviewed publications and conferences.Trial registration number ACTRN12620001069943.

Registry randomised clinical trials (RRCTs) have the potential to provide pragmatic answers to important clinical questions. RRCTs can be embedded into large population-based registries or smaller single site registries to provide timely answers at a reduced cost compared with traditional randomised controlled trials. RRCTs can take a number of forms in addition to the traditional individual-level randomised trial, including parallel group trials, platform or adaptive trials, cluster randomised trials and cluster randomised stepped-wedge trials. From an implementation perspective, initially it is advantageous to embed RRCT into well-established registries as these have typically already overcome any issues with end point validation and adjudication. With advances in data linkage and data quality, RRCTs can play an important role in answering clinical questions in a pragmatic, cost-effective way.

Abstract Aims Risk factors for asymptomatic echocardiographic abnormalities that predict symptomatic heart failure (HF) may provide insight into early mechanisms of HF pathogenesis. We examined risk factors associated with asymptomatic echocardiographic structural, systolic, and diastolic abnormalities, separately and in combination, and interactions between risk factors, in the prospective community‐based SCReening Evaluation of the Evolution of New HF (SCREEN‐HF) Study cohort of 3190 participants at increased risk of cardiovascular disease. Methods and results Inclusion criteria were age ≥ 60 years with one or more of hypertension, diabetes, ischaemic heart disease, valvular heart disease, abnormal heart rhythm, cerebrovascular disease, or renal impairment. Exclusion criteria were known HF, ejection fraction mild valve abnormality. Structural, systolic, and diastolic echocardiographic abnormalities were defined according to the Atherosclerosis Risk in Communities study criteria, and risk factors for asymptomatic structural, systolic, and diastolic abnormalities were identified using logistic regression analysis. In multivariable analysis, increased body mass index (BMI), non‐steroidal anti‐inflammatory drug therapy, and alcohol intake were risk factors for isolated structural abnormality, whereas male gender, increased heart rate, atrial fibrillation (AF), angiotensin‐converting enzyme inhibitor therapy, and obstructive sleep apnoea were associated with a lower risk. Moreover, male gender, smoking, increased systolic blood pressure, and physical inactivity were risk factors for isolated systolic abnormality, whereas increased pulse pressure and antihypertensive therapy were associated with a lower risk. Furthermore, increased age, blood pressure, amino‐terminal pro‐B‐type natriuretic peptide level, and warfarin therapy (associated with AF) were risk factors for isolated diastolic abnormality, whereas increased heart rate and triglyceride level (associated with BMI) were associated with a lower risk. The association of increased heart rate with lower risk of structural and diastolic abnormalities was independent of β‐blocker therapy. Interactions between risk factors differed for structural, systolic, and diastolic abnormalities. Conclusions The different risk factors for asymptomatic structural, systolic, and diastolic abnormalities that predict symptomatic HF, and the interactions between risk factors, illustrate how these structural, systolic, and diastolic abnormalities represent unique trajectories that lead to symptomatic HF. Improved understanding of these trajectories may assist in the design of HF prevention strategies.

Abstract Clinical Trial Networks in which trialists work collaboratively enable multi-site, large-scale, high-quality clinical trials to be efficiently run. Although the benefits of Clinical Trial Networks are largely known, establishing a Clinical Trial Network can be complex. There are many factors for clinicians and researchers to consider, and there is currently a paucity of information on how to form a Clinical Trial Network. This article provides a suggested roadmap on how to establish a Clinical Trial Network. The Australian Clinical Trials Alliance (ACTA) is the peak body for Clinical Trial Networks, Coordinating Centres and Registries in Australia, and has produced several resources to support the effective and efficient running of clinical trials. This guide has come about through discussions with members of the ACTA Clinical Trial Network Sector Expansion Reference Group consisting of clinical trialists, clinicians, researchers, and consumers.

Rationale & Objective: Variability in estimated glomerular filtration rate (eGFR) over time is often observed, but it is unknown whether this variation is clinically important. We investigated the association between eGFR variability and survival free of dementia or persistent physical disability (disability-free survival) and cardiovascular disease (CVD) events (myocardial infarction, stroke, hospitalization for heart failure, or CVD death). Study Design: Post hoc analysis. Setting & Participants: 12,549 participants of the ASPirin in Reducing Events in the Elderly trial. Participants were without documented dementia, major physical disability, previous CVD, and major life-limiting illness at enrollment. Predictors: eGFR variability. Outcomes: Disability-free survival and CVD events. Analytical Approach: eGFR variability was estimated using the standard deviation of eGFR measurements obtained from participants’ baseline, first, and second annual visits. Associations between tertiles of eGFR variability with disability-free survival and CVD events occurring after the eGFR variability estimation period were examined. Results: During median follow-up of 2.7 years after the second annual visit, 838 participants died, developed dementia, or acquired a persistent physical disability; 379 had a CVD event. The highest tertile of eGFR variability had an increased risk of death/dementia/disability (HR, 1.35; 95% CI, 1.14-1.59) and CVD events (HR, 1.37; 95% CI, 1.06-1.77) compared with the lowest tertile after covariate adjustment. These associations were present in patients with and without chronic kidney disease at baseline. Limitations: Limited representation of diverse demographics. Conclusions: In older, generally healthy adults, higher variability in eGFR over time predicts increased risk of future death/dementia/disability and CVD events.

Machine learning (ML) is increasingly applied to predict adverse postoperative outcomes in cardiac surgery. Commonly used ML models fail to translate to clinical practice due to absent model explainability, limited uncertainty quantification, and no flexibility to missing data. We aimed to develop and benchmark a novel ML approach, the uncertainty-aware attention network (UAN), to overcome these common limitations. Two Bayesian uncertainty quantification methods were tested, generalized variational inference (GVI) or a posterior network (PN). The UAN models were compared with an ensemble of XGBoost models and a Bayesian logistic regression model (LR) with imputation. The derivation datasets consisted of 153,932 surgery events from the Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) Cardiac Surgery Database. An external validation consisted of 7343 surgery events which were extracted from the Medical Information Mart for Intensive Care (MIMIC) III critical care dataset. The highest performing model on the external validation dataset was a UAN-GVI with an area under the receiver operating characteristic curve (AUC) of 0.78 (0.01). Model performance improved on high confidence samples with an AUC of 0.81 (0.01). Confidence calibration for aleatoric uncertainty was excellent for all models. Calibration for epistemic uncertainty was more variable, with an ensemble of XGBoost models performing the best with an AUC of 0.84 (0.08). Epistemic uncertainty was improved using the PN approach, compared to GVI. UAN is able to use an interpretable and flexible deep learning approach to provide estimates of model uncertainty alongside state-of-the-art predictions. The model has been made freely available as an easy-to-use web application demonstrating that by designing uncertainty-aware models with innately explainable predictions deep learning may become more suitable for routine clinical use.

Abstract Background Poor social health is associated with increased risk of cardiovascular disease (CVD). Recent research suggests that different social health domains should be considered separately as the implications for health and possible interventions may differ. Aim To assess social isolation, low social support and loneliness as predictors of CVD. Methods Secondary analysis of 11,486 community-dwelling, Australians, aged 70 years and over, free of CVD, dementia, or significant physical disability, from the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Social isolation, social support (Revised Lubben Social Network Scale), and loneliness were assessed as predictors of CVD using Cox proportional-hazard regression. CVD events included fatal CVD, heart failure hospitalization, myocardial infarction and stroke. Analyses were adjusted for established CVD risk factors. Results Individuals with poor social health were 42 % more likely to develop CVD (p = 0.01) and twice as likely to die from CVD (p = 0.02) over a median 4.5 years follow-up. Interaction effects indicated that poorer social health more strongly predicted CVD in smokers (HR 4.83, p = 0.001, p-interaction = 0.01), major city dwellers (HR 1.94, p

Developmental and epileptic encephalopathies (DEEs) are characterized by pharmaco-resistant seizures with concomitant intellectual disability. Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe of these syndromes. De novo variants in ion channels, including gain-of-function variants in KCNT1, which encodes for sodium activated potassium channel protein KNa1.1, have been found to play a major role in the etiology of EIMFS. Here, we test a potential precision therapeutic approach in KCNT1-associated DEE using a gene-silencing antisense oligonucleotide (ASO) approach. We generated a mouse model carrying the KCNT1 p.P924L pathogenic variant; only the homozygous animals presented with the frequent, debilitating seizures and developmental compromise that are seen in patients. After a single intracerebroventricular bolus injection of a Kcnt1 gapmer ASO in symptomatic mice at postnatal day 40, seizure frequency was significantly reduced, behavioral abnormalities improved, and overall survival was extended compared with mice treated with a control ASO (nonhybridizing sequence). ASO administration at neonatal age was also well tolerated and effective in controlling seizures and extending the life span of treated animals. The data presented here provide proof of concept for ASO-based gene silencing as a promising therapeutic approach in KCNT1-associated epilepsies.

BackgroundStatins are the most widely prescribed medication to lower low-density lipoprotein cholesterol (LDL-c). However, a significant portion of patients are unable to tolerate them due to side effects, most commonly muscle related. Nutraceuticals, natural plant derivatives with lipid-lowering properties, may provide an alternative to lower LDL-c in these patients.AimsTo investigate whether a nutraceutical regimen, either alone or in combination with ezetimibe, can lower LDL-c in patients with hypercholesterolemia who are intolerant to statins.MethodsParticipants were recruited into a double-blind, randomized, placebo-controlled intervention study. Treatments were (i) placebo, (ii) nutraceutical (500 mg berberine, 200 mg red yeast rice (RYR), 2 g plant sterols)/daily, (iii) ezetimibe (10 mg)/daily, or (iv) the combination of nutraceutical and ezetimibe/daily. At baseline and week 8, all participants provide a fasting blood sample for assessment of lipid profile and safety bloods.ResultsFifty participants were randomized, with 44 completing the treatment period. Following adjustment for baseline levels and compared with placebo, LDL-c was significantly reduced (all p < 0.0001) with ezetimibe (−1.02 mmol/L), nutraceutical (−1.15 mmol/L) and the nutraceutical and ezetimibe combination (−1.92 mmol/L). Non-HDL cholesterol was significantly reduced (all p < 0.0001) with ezetimibe (−1.29 mmol/L), nutraceutical (−1.37 mmol/L) and the nutraceutical and ezetimibe combination (−2.18 mmol/L). Remnant cholesterol and triglycerides was significantly reduced with the nutraceutical and ezetimibe combination (p = 0.018).ConclusionA nutraceutical regimen (berberine, RYR and plant sterols) and ezetimibe independently and additively lower LDL-c in patients with hypercholesterolemia who are intolerant to statins.

Abstract Objective To compare the frequency and impact on the channel function of KCNH2 variants in SUDEP patients with epilepsy controls comprising patients older than 50 years, a group with low SUDEP risk, and establish loss‐of‐function KCNH2 variants as predictive biomarkers of SUDEP risk. Methods We searched for KCNH2 variants with a minor allele frequency of 20% reduction in maximal amplitude, were observed in 8.9% (8/90) SUDEP patients compared to 3.3% (11/332) epilepsy controls suggesting about threefold enrichment (nominal p = 0.04). KCNH2 variants that did not change channel function occurred at a similar frequency in SUDEP (2.2%; 2/90) and epilepsy control (2.7%; 9/332) cohorts (p > 0.99). Rare KCNH2 variants (

Abstract Genetic testing is used to optimise the management of inherited cardiovascular disorders that can cause sudden cardiac death. Yet more genotype–phenotype correlation studies from populations not ascertained on clinical symptoms or family history of disease are required to improve understanding of gene penetrance. We performed targeted sequencing of 25 genes used routinely in clinical genetic testing for inherited cardiovascular disorders in a population of 13,131 asymptomatic older individuals (mean age 75 years) enrolled in the ASPREE trial. Participants had no prior history of cardiovascular disease events, dementia or physical disability at enrolment. Variants were classified following ACMG/AMP standards. Sudden and rapid cardiac deaths were clinically adjudicated as ASPREE trial endpoints, and assessed during mean 4.7 years of follow-up. In total, 119 participants had pathogenic/deleterious variants in one of the 25 genes analysed (carrier rate of 1 in 110 or 0.9%). Participants carried variants associated with hypertrophic cardiomyopathy (N = 24), dilated cardiomyopathy (N = 29), arrhythmogenic right-ventricular cardiomyopathy (N = 22), catecholaminergic polymorphic ventricular tachycardia (N = 4), aortopathies (N = 1), and long-QT syndrome (N = 39). Among 119 carriers, two died from presumed sudden/rapid cardiac deaths during follow-up (1.7%); both with pathogenic variants in long-QT syndrome genes (KCNQ1, SCN5A). Among non-carriers, the rate of sudden/rapid cardiac deaths was significantly lower (0.08%, 11/12936, p

Background Renal impairment post-percutaneous coronary intervention (post-PCI) is a well-described adverse effect following the administration of contrast media. Within a large cohort of registry patients, we aimed to explore the incidence, predictors and clinical outcomes of renal impairment post-PCI.Methods The Victorian Cardiac Outcomes Registry is an Australian state-based clinical quality registry focusing on collecting data from all PCI capable centres. Data from 36 970 consecutive PCI cases performed between 2014 and 2018 were analysed. Patients were separated into three groups based on post-procedure creatinine levels (new renal impairment (NRI), defined as an absolute rise in serum creatinine>44.2 µmol/L or>25% of baseline creatinine; new renal impairment requiring dialysis (NDR), defined as worsening renal failure that necessitated a new requirement for renal dialysis; no NRI). Multivariate logistic regression analysis was performed to investigate the impact of NRI and NDR on clinical outcomes.Results 3.1% (n=1134) of patients developed NRI, with an additional 0.6% (n=225) requiring dialysis. 96.3% (n=35 611) of patients did not develop NRI. Those who developed renal impairment were more comorbid, with higher rates of diabetes (22% vs 38% vs 38%, p

Abstract Background Given the age-related decline in glomerular filtration rate (GFR) in healthy individuals, we examined the association of all-cause death or cardiovascular event with the Kidney age - Chronological age Difference (KCD) score, whereby an individual’s kidney age is estimated from their estimated GFR (eGFR) and the age-dependent eGFR decline reported for healthy living potential kidney donors. Methods We examined the association between death or cardiovascular event and KCD score, age-dependent stepped eGFR criteria (eGFRstep), and eGFR

ObjectivesWomen have a worse prognosis after coronary artery bypass grafting (CABG) surgery compared to men. We sought to quantify to what extent this difference in post-CABG survival could be attributed to sex itself, or whether this was mediated by difference between men and women at the time of intervention. Additionally, we explored to what extent these effects were homogenous across patient subgroups.MethodsTime to all-cause mortality was available for 102,263 CABG patients, including 20,988 (21%) women, sourced through an individual participant data meta-analysis of five cohort studies. Difference between men and women in survival duration was assessed using Kaplan–Meier estimates, and Cox’s proportional hazards model.ResultsDuring a median follow-up of 5 years, 13,598 (13%) patients died, with women more likely to die than men: female HR 1.20 (95%CI 1.16; 1.25). We found that differences in patient characteristics at the time of CABG procedure mediated this sex effect, and accounting for these resulted in a neutral female HR 0.98 (95%CI 0.94; 1.02). Next we performed a priori defined subgroup analyses of the five most prominent mediators: age, creatinine, peripheral vascular disease, type 2 diabetes, and heart failure. We found that women without peripheral vascular disease (PVD) or women aged 70+, survived longer than men (interaction p-values 0.04 and 6 × 10–5, respectively), with an effect reversal in younger women.ConclusionSex differences in post-CABG survival were readily explained by difference in patient characteristics and comorbidities. Pre-planned analyses revealed patient subgroups (aged 70+, or without PVD) of women that survived longer than men, and a subgroup of younger women with comparatively poorer survival.

Genetic variation in voltage-gated sodium (NaV) channels is a significant contributor to neurodevelopmental disorders. NaV channel alpha subunits are encoded by the SCNxA family and four are predominately expressed in the brain: SCN1A, SCN2A, SCN3A, and SCN8A. Gene expression is developmentally regulated, and they are known to express functionally distinct transcript variants. Precision therapies targeting these genes and their transcript variants are currently in preclinical development, yet the developmental expression of these transcripts in the human brain is yet to be fully understood. Additionally, the functional consequences of some mutations differ depending on the studied channel isoform, suggesting differential transcript variant expression can affect disease prognoses. We characterise the expression of the four SCNxAs and their transcript variants in human, Rhesus monkey and mouse brain using publicly available RNA-sequencing data and analysis tools, demonstrating that this approach can be used to answer important biological questions of gene and transcript developmental regulation. We find that gene expression and transcript variant regulation are conserved across species at similar developmental stages and determine the developmental milestones for transcript variant expression. Our study provides a guide to researchers testing therapies and clinicians advising prognoses based on the expression of channel isoforms.

Variants in HCN1 are associated with a range of epilepsy syndromes including developmental and epileptic encephalopathies. Here we describe a child harboring a novel de novo HCN1 variant, E246A, in a child with epilepsy and mild developmental delay. By parental report, the child had difficulty in discriminating between colors implicating a visual deficit. This interesting observation may relate to the high expression of HCN1 channels in rod and cone photoreceptors where they play an integral role in shaping the light response. Functional analysis of the HCN1 E246A variant revealed a right shift in the voltage dependence of activation and slowing of the rates of activation and deactivation. The changes in the biophysical properties are consistent with a gain-of-function supporting the role of HCN1 E246A in disease causation. This case suggests that visual function, including color discrimination, should be carefully monitored in patients with diseases due to HCN1 pathogenic variants.

Abstract Aim Heart failure (HF) incidence increases markedly with age. We examined age‐associated longitudinal change in cardiac structure and function, and their prediction by age and cardiovascular disease (CVD) risk factors, in a community‐based cohort aged ≥60 years at increased CVD risk but without HF. Methods and results CVD risk factors were recorded in 3065 participants who underwent a baseline echocardiographic examination, of whom 2358 attended a follow‐up examination 3.8 [median, inter‐quartile range (IQR) 3.5, 4.2] years later. Median age was 71 (IQR 67, 76) years and 55% of participants were male. Age was associated with longitudinal increase in left ventricular (LV) mass index (LVMI); decrease in LV volumes; increase in LV ejection fraction; decrease in mitral annular systolic velocity; decrease in diastolic function (decreased mitral early diastolic annular velocity (e′); and increase in left atrial volume index, mitral peak early diastolic flow velocity (E)/e′ ratio, and tricuspid regurgitant velocity (TRVmax) in men and women, except for TRVmax in men). In multivariable analysis, longitudinal increase in LVMI was explained by CVD risk factors alone, whereas age, together with CVD risk factors, independently predicted longitudinal change in all other echocardiographic parameters. CVD risk factors were differentially associated with longitudinal change in different echocardiographic parameters. Conclusions Whereas the increase in LVMI with age was explained by CVD risk factors alone, age, together with risk factors, independently predicted longitudinal change in all other echocardiographic parameters, providing evidence for age‐specific mechanisms of change in cardiac structure and function as people age. Age‐associated change in LVMI, LV volumes, and diastolic function resembled what might be expected for the evolution of HF with preserved ejection fraction. Given the differential association of different CVD risk factors with longitudinal change in different echocardiographic parameters, therapies aimed at attenuation of age‐associated change in cardiac structure and function, and HF evolution, will likely need to address multiple CVD risk factors.

Healthspan and healthy aging are areas of research with potential socioeconomic impact. Here, the authors present the Medical Genome Reference Bank (MGRB) which consist of over 4,000 individuals aged 70 years and older without a history of the major age-related diseases and report on results from whole-genome sequencing and association analyses.

Study objective: The aim of this study was to identify whether physical component score (PCS) of health-related quality of life trajectories over 4.7-years predicted subsequent risk of incident fatal and non-fatal CVD events, and all-cause mortality. Methods: This study included 16,871 community-dwelling people aged ≥65 years enrolled in the ASPREE (ASPirin in Reducing Events in the Elderly) trial. PCS was assessed annually using the SF-12 (version-2) over a median 4.7-years (i.e. from baseline (2010–2014) till June 2017). Incident CVD events and all-cause mortality occurring after June 2017 until the second-year after the end of the trial were considered. Growth mixture and logistic regression modelling were used. Results: Four PCS trajectories were identified: high (66.5%), intermediate (13.3%), decline (13.8%), and low (6.5%), and there was subsequently a total of 406 (2.50%) incident CVD events, 197 (1.17%) fatal CVD, and 751 (4.45%) deaths. The declining PCS trajectory group had the highest risk of incident CVD (adjusted OR, 1.51; 95%CI 1.14, 1.99), while the low PCS trajectory group had the greatest risk of fatal CVD (adjusted OR, 1.74; 95%CI 1.06, 2.85) and all-cause mortality (adjusted OR, 1.83; 95%CI 1.40, 2.40). After further adjustment for the baseline PCS score, only the association between declining PCS trajectory and incident CVD (adjusted OR, 1.51; 95%CI 1.11, 2.07) remained. Conclusion: Our study strengthens the importance of PCS as a predictive measure of CVD and all-cause mortality in older people and also highlights that a declining PCS trajectory could be considered an early predictor of future CVD events.

BackgroundFly-In-Fly-Out (FIFO) workers travel to work at isolated locations, and rotate continuous workdays with leave periods at home, and such work practice is common in the offshore oil and gas and onshore mining industry worldwide. The COVID-19 pandemic and accompanying public health actions appear to have had a negative impact on several health-related behaviours among the general population. However, little is known about the impact of the COVID-19 pandemic on the health behaviours of FIFO workers, who have shown higher pre-pandemic rates of risky behaviours than the general population in Australia. This study examined the health-related behaviours of FIFO workers in the mining industry during the COVID-19 pandemic.MethodsA descriptive cross-sectional study was conducted. FIFO workers from an Australian mining company who underwent COVID-19 screening between May and November 2020 completed an online survey about their regular health-related behaviours. The independent sample t-test and Pearson's chi-square test where appropriate were conducted to examine the differences between males and females for the behavioural outcomes.ResultsA total of 768 FIFO workers (633 males and 135 females) participated in the study. Prevalence of smoking was high (32%). Males smoked more cigarettes per day than females (15.2±7.0 vs 13.1±7.1, p = .174). Most participants (74.7%) drank alcohol on more than two days per week. Compared to females, more males (20.2% vs 8.0%) consumed alcohol at short-term harmful levels (p = .010). About a third (34.4%) of the workers (33.5% of males and 38.5% of females, p = .264) engaged in inadequate moderate-vigorous exercises/physical activity. About a third (33.1%) of workers (33.7% of males and 30.4% of females; p = .699) had multiple risk behaviours.ConclusionsPrevalence of multiple risk behaviours was high. Interventions aimed at the prevention of risky health-related behaviours should target the different behavioural patterns and may require emphasis on gender-informed techniques particularly when addressing alcohol consumption.