Publications by authors named "Christopher M Reid"

355 Publications

Outcomes following the percutaneous coronary intervention in contemporary Vietnamese practice: Insight from a single centre prospective cohort.

Heart Lung 2021 Jun 3;50(5):634-639. Epub 2021 Jun 3.

School of Public Health, Curtin University, Perth, Australia. Electronic address:

Background: Evidence regarding the outcomes of percutaneous coronary intervention (PCI) in low-and-middle incomes countries remains limited.

Objectives: To report the outcomes post PCI at discharge, 30 days and 12 months in Vietnam and identify the key factors associated with adverse outcomes at 12 months.

Methods: We used data from a single centre prospective cohort in Vietnam. Data regarding demographics, clinical presentation, procedural information, and outcomes of patients were collected and analysed. Primary outcomes were mortality and major adverse cardiac and cerebrovascular events.

Results: In total, 926 patients were included. Poor outcomes were relatively low in those undergoing PCI. Predictors of mortality and major adverse cardiac and cerebrovascular events at 12 months post-PCI included being older than 75, being male, having acute myocardial infarction, left ventricular ejection fraction ≤ 40%, prior cerebral vascular disease and having an unsuccessful PCI.

Conclusions: Adverse outcomes of patients undergoing PCI in Vietnam are relatively low in comparison with those reported in other countries across the Asia Pacific region. Identification of factors associated with poor outcomes is beneficial for improving the quality of cardiac care and developing the prediction model of outcomes post-PCI in Vietnam.
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http://dx.doi.org/10.1016/j.hrtlng.2021.04.017DOI Listing
June 2021

Predictive Performance of a Polygenic Risk Score for Incident Ischemic Stroke in a Healthy Older Population.

Stroke 2021 May 27:STROKEAHA120033670. Epub 2021 May 27.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia. (J.T.N., M.R., A. Bakshi, G.P., L.T.P.T., M.R.N., R.L.W., C.M.R., A.M.T., J.J.M., P.L.).

Background And Purpose: Polygenic risk scores (PRSs) can be used to predict ischemic stroke (IS). However, further validation of PRS performance is required in independent populations, particularly older adults in whom the majority of strokes occur.

Methods: We predicted risk of incident IS events in a population of 12 792 healthy older individuals enrolled in the ASPREE trial (Aspirin in Reducing Events in the Elderly). The PRS was calculated using 3.6 million genetic variants. Participants had no previous history of cardiovascular events, dementia, or persistent physical disability at enrollment. The primary outcome was IS over 5 years, with stroke subtypes as secondary outcomes. A multivariable model including conventional risk factors was applied and reevaluated after adding PRS. Area under the curve and net reclassification were evaluated.

Results: At baseline, mean population age was 75 years. In total, 173 incident IS events occurred over a median follow-up of 4.7 years. When PRS was added to the multivariable model as a continuous variable, it was independently associated with IS (hazard ratio, 1.41 [95% CI, 1.20-1.65] per SD of the PRS; <0.001). The PRS alone was a better discriminator for IS events than most conventional risk factors. PRS as a categorical variable was a significant predictor in the highest tertile (hazard ratio, 1.74; =0.004) compared with the lowest. The area under the curve of the conventional model was 66.6% (95% CI, 62.2-71.1) and after inclusion of the PRS, improved to 68.5 ([95% CI, 64.0-73.0] =0.095). In subgroup analysis, the continuous PRS remained an independent predictor for large vessel and cardioembolic stroke subtypes but not for small vessel stroke. Reclassification was improved, as the continuous net reclassification index after adding PRS to the conventional model was 0.25 (95% CI, 0.17-0.43).

Conclusions: PRS predicts incident IS in a healthy older population but only moderately improves prediction over conventional risk factors. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583.
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http://dx.doi.org/10.1161/STROKEAHA.120.033670DOI Listing
May 2021

Antihypertensives and Statin Therapy for Primary Stroke Prevention: A Secondary Analysis of the HOPE-3 Trial.

Stroke 2021 May 14:STROKEAHA120030790. Epub 2021 May 14.

Population Health Research Institute, Hamilton Health Sciences, ON, Canada (J.B., E.M.L., P.G., R.G.H., S.Y.).

Background And Purpose: The HOPE-3 trial (Heart Outcomes Prevention Evaluation-3) found that antihypertensive therapy combined with a statin reduced first stroke among people at intermediate cardiovascular risk. We report secondary analyses of stroke outcomes by stroke subtype, predictors, treatment effects in key subgroups.

Methods: Using a 2-by-2 factorial design, 12 705 participants from 21 countries with vascular risk factors but without overt cardiovascular disease were randomized to candesartan 16 mg plus hydrochlorothiazide 12.5 mg daily or placebo and to rosuvastatin 10 mg daily or placebo. The effect of the interventions on stroke subtypes was assessed.

Results: Participants were 66 years old and 46% were women. Baseline blood pressure (138/82 mm Hg) was reduced by 6.0/3.0 mm Hg and LDL-C (low-density lipoprotein cholesterol; 3.3 mmol/L) was reduced by 0.90 mmol/L on active treatment. During 5.6 years of follow-up, 169 strokes occurred (117 ischemic, 29 hemorrhagic, 23 undetermined). Blood pressure lowering did not significantly reduce stroke (hazard ratio [HR], 0.80 [95% CI, 0.59-1.08]), ischemic stroke (HR, 0.80 [95% CI, 0.55-1.15]), hemorrhagic stroke (HR, 0.71 [95% CI, 0.34-1.48]), or strokes of undetermined origin (HR, 0.92 [95% CI, 0.41-2.08]). Rosuvastatin significantly reduced strokes (HR, 0.70 [95% CI, 0.52-0.95]), with reductions mainly in ischemic stroke (HR, 0.53 [95% CI, 0.37-0.78]) but did not significantly affect hemorrhagic (HR, 1.22 [95% CI, 0.59-2.54]) or strokes of undetermined origin (HR, 1.29 [95% CI, 0.57-2.95]). The combination of both interventions compared with double placebo substantially and significantly reduced strokes (HR, 0.56 [95% CI, 0.36-0.87]) and ischemic strokes (HR, 0.41 [95% CI, 0.23-0.72]).

Conclusions: Among people at intermediate cardiovascular risk but without overt cardiovascular disease, rosuvastatin 10 mg daily significantly reduced first stroke. Blood pressure lowering combined with rosuvastatin reduced ischemic stroke by 59%. Both therapies are safe and generally well tolerated.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00468923.
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http://dx.doi.org/10.1161/STROKEAHA.120.030790DOI Listing
May 2021

Mis-reporting of energy intake among older Australian adults: Prevalence, characteristics, and associations with quality of life.

Nutrition 2021 Apr 6;90:111259. Epub 2021 Apr 6.

Monash University, School of Public Health & Preventive Medicine, Melbourne, Australia. Electronic address:

Objectives: Mis-reporting is common in dietary assessment, leading to misinterpretation of disease risk and could be important in older adults with increased chronic disease risk. This study investigated the prevalence and characteristics of mis-reporting among older adults and its association with health outcomes including quality of life (QoL).

Methods: The study was conducted in 335 community-dwelling older adults at increased risk for cardiovascular disease, participating in the SCReening Evaluation of the Evolution of New Heart Failure Study dietary substudy. Diet was assessed using 4-day weighed food diaries, QoL measured through Short Form 36, and physical activity assessed using the European Prospective Investigation into Cancer and Nutrition physical activity questionnaire. Dietary mis-reporting was defined based on Goldberg cutoffs, using individual physical activity levels. Odds ratios were determined to establish associations between mis-reporting and health outcomes.

Results: The prevalence of mis-reporting among older adults was 49.3%, with 44.5% of women mis-reporting their energy intake. The study found under-reporting of energy to be associated with body mass index, specifically being overweight (odds ratio: 3.08; 95% confidence interval [CI], 1.54-6.15) and obese (odds ratio: 6.60; 95% CI, 3.05-4.26), as well as physical inactivity (odds ratio: 0.24; 95% CI, 0.14-0.43). Only physical inactivity predicted over-reporting of dietary intake (odds ratio: 7.52; 95% CI, 1.57-36.0).

Conclusions: Dietary under-reporting was associated with being overweight, obese, and physically inactive in addition to the absence of comorbidities, reinforcing the need for further research in older adults to factor in dietary mis-reporting for meaningful diet-disease relationship analyses.
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http://dx.doi.org/10.1016/j.nut.2021.111259DOI Listing
April 2021

The Influence of Academic Pedigree on Integrated Plastic Surgery Resident Training Location.

J Surg Educ 2021 May 5. Epub 2021 May 5.

Division of Plastic Surgery, Department of Surgery, UC San Diego Health Center, San Diego, California. Electronic address:

Introduction: Plastic surgery residencies are among the most competitive programs for graduate medical education. While board scores and research output are well-studied indicators of match success, no studies describe the association between an applicant's medical school ranking and subsequent residency ranking.

Methods: A cross-sectional study of integrated plastic surgery residents for the 2019 to 2020 academic year was performed. Integrated plastic surgery residency programs were ranked according to 2020 Doximity Residency Navigator. AAMC-affiliated allopathic medical schools were ranked according to US News & World Report 2020 Best Medical Schools. Multiple regression analysis was used to determine if academic pedigree predicted placement at highly competitive plastic surgery residency programs.

Results: A total of 914 residents across 69 integrated plastic surgery residency programs were included. Ten medical schools accounted for 169 (18.4%) of all trainees. 159 (16.5%) matched at their home program for residency. Medical school ranking and medical school-affiliated integrated plastic surgery program ranking were significant predictors of match success and future residency competitiveness. The presence of an affiliated plastic surgery residency program predicted total number of medical school graduates who matriculated into plastic surgery residency (p < 0.0005). Graduates of top-ranked schools represented a disproportionate number of current plastic surgery residents (Top 10 program: 12.5%, Top 20: 24.1%, Top 40: 40.9%, Top 50: 49.1%).

Conclusions: Both medical school ranking and home plastic surgery program ranking appeared to influence match success and future residency training program competitiveness. This is the first study to demonstrate these associations.
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http://dx.doi.org/10.1016/j.jsurg.2021.03.021DOI Listing
May 2021

Lowering cholesterol, blood pressure, or both to prevent cardiovascular events: results of 8.7 years of follow-up of Heart Outcomes Evaluation Prevention (HOPE)-3 study participants.

Eur Heart J 2021 May 8. Epub 2021 May 8.

The Population Health Research Institute, Hamilton Health Sciences, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.

Aims: Rosuvastatin (10 mg per day) compared with placebo reduced major adverse cardiovascular (CV) events by 24% in 12 705 participants at intermediate CV risk after 5.6 years. There was no benefit of blood pressure (BP) lowering treatment in the overall group, but a reduction in events in the third of participants with elevated systolic BP. After cessation of all the trial medications, we examined whether the benefits observed during the active treatment phase were sustained, enhanced, or attenuated.

Methods And Results: After the randomized treatment period (5.6 years), participants were invited to participate in 3.1 further years of observation (total 8.7 years). The first co-primary outcome for the entire length of follow-up was the composite of myocardial infarction, stroke, or CV death [major adverse cardiovascular event (MACE)-1], and the second was MACE-1 plus resuscitated cardiac arrest, heart failure, or coronary revascularization (MACE-2). In total, 9326 (78%) of 11 994 surviving Heart Outcomes Prevention Evaluation (HOPE)-3 subjects consented to participate in extended follow-up. During 3.1 years of post-trial observation (total follow-up of 8.7 years), participants originally randomized to rosuvastatin compared with placebo had a 20% additional reduction in MACE-1 [95% confidence interval (CI), 0.64-0.99] and a 17% additional reduction in MACE-2 (95% CI 0.68-1.01). Therefore, over the 8.7 years of follow-up, there was a 21% reduction in MACE-1 (95% CI 0.69-0.90, P = 0.005) and 21% reduction in MACE-2 (95% CI 0.69-0.89, P = 0.002). There was no benefit of BP lowering in the overall study either during the active or post-trial observation period, however, a 24% reduction in MACE-1 was observed over 8.7 years.

Conclusion: The CV benefits of rosuvastatin, and BP lowering in those with elevated systolic BP, compared with placebo continue to accrue for at least 3 years after cessation of randomized treatment in individuals without cardiovascular disease indicating a legacy effect.

Trial Registration Number: NCT00468923.
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http://dx.doi.org/10.1093/eurheartj/ehab225DOI Listing
May 2021

Receipt of Government-Funded Health Services and Medication Prescriptions in the Management of Patients With Cardiovascular Disease.

Heart Lung Circ 2021 Apr 28. Epub 2021 Apr 28.

School of Health Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; The George Institute for Global Health, Sydney, NSW, Australia. Electronic address:

Background: Cardiovascular disease (CVD) and risk factors remains a major burden in terms of disease, disability, and death in the Australian population and mental health is considered as an important risk factor affecting cardiovascular disease. A multidisciplinary collaborative approach in primary care is required to ensure an optimal outcome for managing cardiovascular patients with mental health issues. Medicare introduced numerous primary care health services and medications that are subsidised by the Australian government in order to provide a more structured approach to reduce and manage CVD. However, the utilisation of these services nor gender comparison for CVD management in primary care has been explored. Therefore, the aim is to compare the provision of subsidised chronic disease management plans (CDMPs), mental health care and prescription of guideline-indicated medications to men and women with CVD in primary care practices for secondary prevention.

Methods: De-identified data for all active patients with CVD were extracted from 50 Australian primary care practices. Outcomes included the frequency of receipt of CDMPs, mental health care and prescription of evidence-based medications. Analyses adjusted for demography and clinical characteristics, stratified by gender, were performed using logistic regression and accounted for clustering effects by practices.

Results: Data for 14,601 patients with CVD (39.4% women) were collected. The odds of receiving the CDMPs was significantly greater amongst women than men (preparation of general practice management plan [GPMP]: (46% vs 43%; adjusted OR [95% CI]: 1.22 [1.12, 1.34]). Women were more likely to have diagnosed with mental health issues (32% vs 20%, p<0.0001), however, the adjusted odds of men and women receiving any government-subsidised mental health care were similar. Women were less often prescribed blood pressure, lipid-lowering and antiplatelet medications. After adjustment, only an antiplatelet medication or agent was less likely to be prescribed to women than men (44% vs 51%; adjusted OR [95% CI]: 0.84 [0.76, 0.94]).

Conclusion: Women were more likely to receive CDMPs but less likely to receive antiplatelet medications than men, no gender difference was observed in the receipt of mental health care. However, the receipt of the CDMPs and the mental health treatment consultations were suboptimal and better use of these existing services could improve ongoing CVD management.
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http://dx.doi.org/10.1016/j.hlc.2021.04.005DOI Listing
April 2021

Kidney age - chronological age difference (KCD) score provides an age-adapted measure of kidney function.

BMC Nephrol 2021 Apr 26;22(1):152. Epub 2021 Apr 26.

University of Melbourne, Parkville, Victoria, Australia.

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 < 60 ml/min/1.73 m (eGFR60) in a community-based high cardiovascular risk cohort of 3837 individuals aged ≥60 (median 70, interquartile range 65, 75) years, followed for a median of 5.6 years.

Results: In proportional hazards analysis, KCD score ≥ 20 years (KCD20) was associated with increased risk of death or cardiovascular event in unadjusted analysis and after adjustment for age, sex and cardiovascular risk factors. Addition of KCD20, eGFRstep or eGFR60 to a cardiovascular risk factor model did not improve area under the curve for identification of individuals who experienced death or cardiovascular event in receiver operating characteristic curve analysis. However, addition of KCD20 or eGFR60, but not eGFRstep, to a cardiovascular risk factor model improved net reclassification and integrated discrimination. KCD20 identified individuals who experienced death or cardiovascular event with greater sensitivity than eGFRstep for all participants, and with greater sensitivity than eGFR60 for participants aged 60-69 years, with similar sensitivities for men and women.

Conclusions: In this high cardiovascular risk cohort aged ≥60 years, the KCD score provided an age-adapted measure of kidney function that may assist patient education, and KCD20 provided an age-adapted criterion of eGFR-related increased risk of death or cardiovascular event. Further studies that include the full age spectrum are required to examine the optimal KCD score cut point that identifies increased risk of death or cardiovascular event, and kidney events, associated with impaired kidney function, and whether the optimal KCD score cut point is similar for men and women.

Trial Registration: ClinicalTrials.gov NCT00400257 , NCT00604006 , and NCT01581827 .
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http://dx.doi.org/10.1186/s12882-021-02324-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077774PMC
April 2021

Rescue PCI in the management of STEMI: Contemporary results from the Melbourne Interventional Group registry.

Int J Cardiol Heart Vasc 2021 Apr 15;33:100745. Epub 2021 Mar 15.

Department of Cardiology, Ballarat Health Services, Ballarat, Victoria, Australia.

Background: Fibrinolysis is an important reperfusion strategy in the management of ST-elevation myocardial infarction (STEMI) when timely access to primary percutaneous coronary intervention (PPCI) is unavailable. Rescue PCI is generally thought to have worse outcomes than PPCI in STEMI. We aimed to determine short- and long-term outcomes of patients with rescue PCI versus PPCI for treatment of STEMI.

Methods And Results: Patients admitted with STEMI (excluding out-of-hospital cardiac arrest) within the Melbourne Interventional Group (MIG) registry between 2005 and 2018 treated with either rescue PCI or PPCI were included in this retrospective cohort analysis. Comparison of 30-day major adverse cardiac events (MACE) and long-term mortality between the two groups was performed. There were 558 patients (7.1%) with rescue PCI and 7271 with PPCI. 30-day all-cause mortality (rescue PCI 6% vs. PPCI 5%, p = 0.47) and MACE (rescue PCI 10.3% vs. PPCI 8.9%, p = 0.26) rates were similar between the two groups. Rates of in-hospital major bleeding (rescue PCI 6% vs. PPCI 3.4%, p = 0.002) and 30-day stroke (rescue PCI 2.2% vs. PPCI 0.8%, p < 0.001) were higher following rescue PCI. The odds ratio for haemorrhagic stroke in the rescue PCI group was 10.3. Long-term mortality was not significantly different between the groups (rescue PCI 20% vs. PPCI 19%, p = 0.33).

Conclusions: With contemporary interventional techniques and medical therapy, rescue PCI remains a valuable strategy for treating patients with failed fibrinolysis where PPCI is unavailable and it has been suggested in extenuating circumstances where alternative revascularisation strategies are considered.
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http://dx.doi.org/10.1016/j.ijcha.2021.100745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988313PMC
April 2021

A Cohort Study of Anticholinergic Medication Burden and Incident Dementia and Stroke in Older Adults.

J Gen Intern Med 2021 Jun 22;36(6):1629-1637. Epub 2021 Mar 22.

Department of Pharmacy Practice and Science, College of Pharmacy and Department of Family Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA.

Background: Anticholinergic medications may increase risk of dementia and stroke, but prospective studies in healthy older people are lacking.

Objective: Compare risk of incident dementia and stroke by anticholinergic burden among initially healthy older people.

Design: Prospective cohort study.

Setting: Primary care (Australia and USA).

Participants: 19,114 community-dwelling participants recruited for the ASPREE trial, aged 70+ years (65+ if US minorities) without major cardiovascular disease, dementia diagnosis, or Modified Mini-Mental State Examination score below 78/100.

Measurements: Baseline anticholinergic exposure was calculated using the Anticholinergic Cognitive Burden (ACB) score. Dementia was adjudicated using Diagnostic and Statistical Manual of Mental Disorders volume IV criteria, and stroke using the World Health Organization definition.

Results: At baseline, 15,000 participants (79%) had an ACB score of zero, 2930 (15%) a score of 1-2, and 1184 (6%) a score of ≥ 3 (indicating higher burden). After a median follow-up of 4.7 years and adjusting for baseline covariates, a baseline ACB score of ≥ 3 was associated with increased risk of ischemic stroke (adjusted HR 1.58, 95% CI 1.06, 2.35), or dementia (adjusted HR 1.36, 95% CI 1.01, 1.82), especially of mixed etiology (adjusted HR 1.53, 95% CI 1.06, 2.21). Results were similar for those exposed to moderate/highly anticholinergic medications.

Limitations: Residual confounding and reverse causality are possible. Assessment of dose or duration was not possible.

Conclusions: High anticholinergic burden in initially healthy older people was associated with increased risk of incident dementia and ischemic stroke. A vascular effect may underlie this association. These findings highlight the importance of minimizing anticholinergic exposure in healthy older people.
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http://dx.doi.org/10.1007/s11606-020-06550-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175463PMC
June 2021

Comparison of Long-Term Outcomes After Percutaneous Coronary Intervention in Patients With Insulin-Treated Versus Non-Insulin Treated Diabetes Mellitus.

Am J Cardiol 2021 Jun 3;148:36-43. Epub 2021 Mar 3.

School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia; Department of Cardiology, Royal Melbourne Hospital, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia. Electronic address:

There are conflicting data on whether patients with insulin-treated diabetes mellitus (ITDM) have poorer outcomes compared with non-insulin treated diabetic (non-ITDM) patients following percutaneous coronary intervention (PCI). We therefore compared clinical outcomes following PCI in ITDM versus non-ITDM patients. We prospectively collected data on 4,579 patients with diabetes underwent PCI between 2005 and 2014 in a large multicenter registry and dichotomized them as having ITDM (n = 1,111) or non-ITDM (n = 3,468). The non-ITDM group was further divided into diet control only (diet-DM; n = 786) and those taking oral hypoglycemic agents (OHG-DM; n = 2,639), and clinical outcomes were compared with ITDM patients. Median follow-up for long-term mortality was 4.2 years (IQR 2.0 to 6.6 years). ITDM patients were more likely to be female, obese, and have severe renal impairment (all p <0.001). Procedural characteristics were similar other than a greater use of drug-eluting stents in ITDM patients. On multivariable analysis, ITDM was an independent predictor of 12-month major adverse cardiovascular and cerebrovascular events (MACCE; OR 1.26, 95% CI 1.02 to1.55, p = 0.03). Dividing the non-ITDM group further by treatment, a progressively higher rate of 12-month MACCE across the 3 groups was observed (13.5% vs 17.9% vs 21.8%; p <0.001). Long-term mortality was similar in the diet-DM and OHG-DM groups, but significantly higher in the ITDM group on Kaplan-Meier analysis (log-rank p <0.001). In conclusion, there is a clear gradient of adverse outcomes with escalation of therapy from diet control to OHGs to insulin.
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http://dx.doi.org/10.1016/j.amjcard.2021.02.025DOI Listing
June 2021

Effects of aspirin on the long-term management of depression in older people: a double-blind randomised placebo-controlled trial.

Mol Psychiatry 2021 Jan 27. Epub 2021 Jan 27.

School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, 3004, Australia.

Late-life depression is common and often inadequately managed using existing therapies. Depression is also associated with increased markers of inflammation, suggesting a potential role for anti-inflammatory agents. ASPREE-D is a sub-study of ASPREE, a large multi-centre, population-based, double-blind, placebo-controlled trial of aspirin vs placebo in older Australian and American adults (median follow-up: 4.7 years) of whom 1879 were depressed at baseline. Participants were given 100 mg daily dose of aspirin or placebo. Depressive symptoms were assessed annually using the validated, self-rated short version of the Center for Epidemiological Studies Depression scale. There was a significant increase in depressive scores (0.6; 95% CI 0.2 to 0.9; χ (1) = 10.37; p = 0.001) and a decreased score in the mental health component of a quality of life scale (-0.7; 95% CI -1.4 to -0.1; χ (1) = 4.74; p = 0.029) in the aspirin group compared to the placebo group. These effects were greater in the first year of follow-up and persisted throughout the study, albeit with small to very small effect sizes. This study failed to demonstrate any benefit of aspirin in the long-term course of depression in this community-dwelling sample of older adults over a 5-year period, and identified an adverse effect of aspirin in the course of depression in those with pre-existing depressive symptoms.
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http://dx.doi.org/10.1038/s41380-021-01020-5DOI Listing
January 2021

Effect of Age on Clinical Outcomes in Elderly Patients (>80 Years) Undergoing Percutaneous Coronary Intervention: Insights From a Multi-Centre Australian PCI Registry.

Heart Lung Circ 2021 Jul 19;30(7):1002-1013. Epub 2021 Jan 19.

Alfred Health, Melbourne, Vic, Australia; The University of Melbourne, Melbourne, Vic, Australia. Electronic address:

Objectives: To evaluate the effect of age in an all-comers population undergoing percutaneous coronary intervention (PCI).

Background: Age is an important consideration in determining appropriateness for invasive cardiac assessment and perceived clinical outcomes.

Methods: We analysed data from 29,012 consecutive patients undergoing PCI in the Melbourne Interventional Group (MIG) registry between 2005 and 2017. 25,730 patients <80 year old (78% male, mean age 62±10 years; non-elderly cohort) were compared to 3,282 patients ≥80 year old (61% male, mean age 84±3 years; elderly cohort).

Results: The elderly cohort had greater prevalence of hypertension, diabetes and previous myocardial infarction (all p<0.001). Elderly patients were more likely to present with acute coronary syndromes, left ventricular ejection fraction <45% and chronic kidney disease (p<0.0001). In-hospital, 30-day and long-term all-cause mortality (over a median of 3.6 and 5.1 years for elderly and non-elderly cohorts, respectively) were higher in the elderly cohort (5.2% vs. 1.9%; 6.4% vs. 2.2%; and 43% vs. 14% respectively, all p<0.0001). In multivariate Cox regression analysis, estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m (HR 3.8, 95% CI: 3.4-4.3), cardiogenic shock (HR 3.0, 95% CI: 2.6-3.4), ejection fraction <30% (HR 2.5, 95% CI: 2.1-2.9); and age ≥80 years (HR 2.8, 95% CI: 2.6-3.1) were independent predictors of long-term all-cause mortality (all p<0.0001).

Conclusion: The elderly cohort is a high-risk group of patients with increasing age being associated with poorer long-term mortality. Age, thus, should be an important consideration when individualising treatment in elderly patients.
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http://dx.doi.org/10.1016/j.hlc.2020.12.003DOI Listing
July 2021

The Eya1 Phosphatase Mediates Shh-Driven Symmetric Cell Division of Cerebellar Granule Cell Precursors.

Dev Neurosci 2020 20;42(5-6):170-186. Epub 2021 Jan 20.

Department of Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

During neural development, stem and precursor cells can divide either symmetrically or asymmetrically. The transition between symmetric and asymmetric cell divisions is a major determinant of precursor cell expansion and neural differentiation, but the underlying mechanisms that regulate this transition are not well understood. Here, we identify the Sonic hedgehog (Shh) pathway as a critical determinant regulating the mode of division of cerebellar granule cell precursors (GCPs). Using partial gain and loss of function mutations within the Shh pathway, we show that pathway activation determines spindle orientation of GCPs, and that mitotic spindle orientation correlates with the mode of division. Mechanistically, we show that the phosphatase Eya1 is essential for implementing Shh-dependent GCP spindle orientation. We identify atypical protein kinase C (aPKC) as a direct target of Eya1 activity and show that Eya1 dephosphorylates a critical threonine (T410) in the activation loop. Thus, Eya1 inactivates aPKC, resulting in reduced phosphorylation of Numb and other components that regulate the mode of division. This Eya1-dependent cascade is critical in linking spindle orientation, cell cycle exit and terminal differentiation. Together these findings demonstrate that a Shh-Eya1 regulatory axis selectively promotes symmetric cell divisions during cerebellar development by coordinating spindle orientation and cell fate determinants.
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http://dx.doi.org/10.1159/000512976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118085PMC
January 2021

The effect of taking blood pressure lowering medication at night on cardiovascular disease risk. A systematic review.

J Hum Hypertens 2021 Apr 18;35(4):308-314. Epub 2021 Jan 18.

School of Public Health, Curtin University, Perth, WA, Australia.

To investigate the effect of night-time BP-lowering drug treatment on the risk of major CVD and mortality, we systematically reviewed randomized controlled trials comparing night-time versus morning dosing. Two studies were found relevant to the clinical question (the MAPEC and Hygia trials). They were similar in study design and population and were conducted by the same study group. As the Hygia trial had more power with a significantly larger sample size, we did not perform a meta-analysis. Both studies reported a reduction of ~50% in major CVD events and all-cause mortality with night-time dosing and a reduction of 60% in CVD mortality. The results from these studies support the implementation of night-time BP-lowering drug treatment in the prevention of CVD and mortality. However there is an on-going discussion on the validity and methodology of MAPEC and Hygia trials, the interpretation of the results should be cautious. Stronger evidence is needed prior to changing clinical practice. Questions that remain to be answered relate to the generalisability of the results across different populations at different levels of BP related risk and the importance of morning versus evening timing of medication on CVD prevention as determined though a well-designed randomised controlled trial.
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http://dx.doi.org/10.1038/s41371-020-00469-1DOI Listing
April 2021

Temporal trends in patient risk profile and clinical outcomes following percutaneous coronary intervention.

Cardiovasc Revasc Med 2020 Dec 17. Epub 2020 Dec 17.

Department of Cardiology, Royal Melbourne Hospital, Melbourne, Victoria, Australia; Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, Victoria, Australia; Melbourne University, Melbourne, Victoria, Australia. Electronic address:

Background: Patient selection and procedural characteristics continue to evolve in percutaneous coronary intervention (PCI). Australian data on long-term trends and outcomes are limited. This study aimed to identify long-term temporal trends in patient characteristics and outcomes in a large Australian PCI cohort.

Methods: We analysed data from 41,146 PCI procedures included in the multi-centre Melbourne Interventional Group registry to determine trends in patient characteristics, procedural practices and outcomes from 2005 to 2018. Procedures were divided into 2-yearly periods for trends analysis.

Results: Temporal trends in patient characteristics showed increases in age, proportion of males, rates of obesity, insulin-requiring diabetes mellitus, current smoking, obstructive sleep apnoea and prior PCI (all P < 0.01). Increases in the proportion of ST-elevation myocardial infarction, cardiogenic shock or out-of-hospital cardiac arrest (OHCA) were observed, and CathPCI National Cardiovascular Data Registry mortality risk scores increased over time (all P < 0.01). Use of radial access and drug-eluting stents increased, and lesions treated were more frequently ostial, left main or ACC/AHA type B2/C in recent years (all P < 0.01). In contrast, major bleeding and no reflow rates declined, however 30-day mortality, 12-month mortality and rates of stroke increased (all P < 0.01). Rates of vascular complications and 30-day target vessel revascularisation remained similar. In multivariable analysis, 2-yearly time periods were not independently associated with risk of 30-day mortality or 30-day MACE.

Conclusions: Over the last 14 years, Australian PCI procedural complexity and patient risk profiles have increased. Higher mortality rates appear to relate to increased patient risk profile rather than procedural factors.
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http://dx.doi.org/10.1016/j.carrev.2020.12.019DOI Listing
December 2020

The role of CHA2DS2-VASc score in evaluating patients with atrial fibrillation undergoing percutaneous coronary intervention.

Coron Artery Dis 2021 Jun;32(4):288-294

Department of Cardiology, Box Hill Hospital.

Objective: The aim of the review was to assess whether CHA2DS2-VASc score is predictive of mortality in patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI).

Background: The CHA2DS2-VASc score is validated in predicting stroke risk in atrial fibrillation. The optimum management strategy for these patients undergoing PCI is still debated.

Methods: The CHA2DS2-VASc score was calculated in consecutive patients with atrial fibrillation undergoing PCI in a large Australian registry between 2007 and 2013. Patients were divided into low (1-2), intermediate (3-4) and high (≥5) groups. Clinical and procedural data, 30-day, 1-year and long-term outcomes were compared between the groups.

Results: A total of 564 patients were included in our analysis. Patients with high CHA2DS2-VASc scores had higher mortality rates at 1-year (2, 8, 15; P = 0.002) and long-term (6, 20, 37; P < 0.001). High-risk patients were more likely to have renal impairment and multivessel disease. Increasing CHA2DS2-VASc score was associated with increased risk of stroke (0, 2, 6; P = 0.03). However, only 41.9% received anticoagulation, with no difference across the risk groups. When compared to low-risk, intermediate [HR 3.57; 95% confidence interval (CI), 1.28-9.92; P = 0.015] and high (hazard ratio 7.82; 95% CI, 2.88-21.24; P < 0.001) CHA2DS2-VASc scores were significant predictors of long-term mortality.

Conclusions: Higher CHA2DS2-VASc scores in patients with atrial fibrillation undergoing PCI are associated with significantly worse outcomes. Despite being high-risk, the patients in this cohort are likely undertreated with anticoagulation. Close clinical follow-up with greater utilization of anticoagulation and optimal medical therapy has the potential to improve long-term outcomes.
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http://dx.doi.org/10.1097/MCA.0000000000000987DOI Listing
June 2021

Health-related quality of life and all-cause mortality among older healthy individuals in Australia and the United States: a prospective cohort study.

Qual Life Res 2021 Apr 3;30(4):1037-1048. Epub 2021 Jan 3.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, 553 St Kilda Road, Melbourne, VIC, 3004, Australia.

Purpose: Previous research has demonstrated that lower health-related quality of life (HRQoL) is associated with higher morbidity and mortality, especially in-patient groups. The association of HRQoL with all-cause mortality in community samples requires further investigation. This study aimed to examine whether HRQoL predicts all-cause mortality in older healthy community-dwelling people from Australia and the United States (U.S.) enrolled in the Aspirin in Reducing Events in the Elderly (ASPREE) trial. We also explored whether this association varies by gender or country.

Method: A prospective cohort of 19,106 individuals aged 65-98 years, who were without a dementia diagnosis or a known major life-limiting disease, and completed the 12-item short-form-HRQoL at recruitment (2010-2014). They were followed until June 2017. Cox proportional-hazard models were used to determine the association between the physical (PCS) and mental component scores (MCS) of HRQoL and all-cause mortality, adjusting for sociodemographic factors, health-related behaviours and clinical measures. Hazards ratios were estimated for every 10-unit increase in PCS or MCS.

Results: There were 1052 deaths over a median 4.7-years (interquartile range 3.6-5.7) of follow-up, with 11.9 events per 1000 person-years. Higher PCS was associated with lower all-cause mortality (HR 0.83, 95% CI 0.77, 0.89) in the entire sample, while higher MCS was associated with lower mortality among U.S. participants only (HR 0.78, 95% CI 0.63, 0.95). Gender differences in the association of either PCS or MCS with mortality were not observed.

Conclusion: Our large study provides evidence that HRQoL is inversely associated with all-cause mortality among initially healthy older people.
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http://dx.doi.org/10.1007/s11136-020-02723-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005489PMC
April 2021

Effect of Aspirin on Activities of Daily Living Disability in Community-Dwelling Older Adults.

J Gerontol A Biol Sci Med Sci 2020 Dec 26. Epub 2020 Dec 26.

Center for Aging and Population Health, University of Pittsburgh, Pittsburgh, PA, U.S.

Background: Cerebrovascular events, dementia and cancer can contribute to physical disability with activities of daily living (ADL). It is unclear whether low-dose aspirin reduces this burden in aging populations. In a secondary analysis, we now examine aspirin's effects on incident and persistent ADL disability within a primary prevention aspirin trial in community-dwelling older adults.

Methods: The ASPREE (ASPirin in Reducing Events in the Elderly) trial of daily 100mg aspirin versus placebo recruited 19,114 healthy adults aged 70+ years (65+ years if U.S. minority) in Australia and the U.S. Six basic ADLs were assessed every six months. Incident ADL disability was defined as inability or severe difficulty with ≥1 ADL; persistence was confirmed if the same ADL disability remained after six months. Proportional hazards modelling compared time to incident or persistent ADL disability for aspirin versus placebo; death without prior disability was a competing risk.

Results: Over a median 4.7 years, incident ADL disability was similar in those receiving aspirin (776/9525) and placebo (787/9589) with walking, bathing, dressing and transferring the most commonly reported. Only 24% of incident ADL disability progressed to persistent. Persistent ADL disability was lower in the aspirin group (4.3 versus 5.3 events/1000py; HR=0.81, 95% CI:0.66-1.00), with bathing and dressing the most common ADL disabilities in both groups. Following persistent ADL disability there were more deaths in the aspirin group (24 versus 12).

Discussion: Low-dose aspirin in initially healthy older people did not reduce risk of incident ADL disability, although there was evidence of reduced persistent ADL disability.
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http://dx.doi.org/10.1093/gerona/glaa316DOI Listing
December 2020

Comparison of Long-Term Mortality in Patients With Single Coronary Narrowing and Diabetes Mellitus to That of Patients With Multivessel Coronary Narrowing Without Diabetes Mellitus.

Am J Cardiol 2021 03 5;142:1-4. Epub 2020 Dec 5.

Department of Cardiology, Austin Health, Melbourne, Australia; The University of Melbourne, Parkville, Victoria, Australia. Electronic address:

It is well recognized that patients with diabetes mellitus (DM) and multivessel coronary artery disease (MVD) undergoing percutaneous coronary intervention (PCI) have poorer long-term outcomes compared with those undergoing coronary artery bypass grafting. However, the relative impact of DM status and extent of coronary artery disease on long term mortality in patients undergoing PCI is unknown. We sought to compare patients with DM undergoing PCI for single and multivessel disease to their non-DM counterparts. Overall, 34,690 consecutive patients undergoing PCI from the Melbourne Interventional Group registry (2005 to 2017) were included (mean age 64.5 ± 12 years, 76.6% male). Our cohort was stratified by the presence of DM and extent of CAD (DM-SVD [single-vessel disease] [n = 2,669], DM-MVD [n = 6,118], no-DM-SVD [n = 10,993], no-DM-MVD [n = 14,910]). DM-SVD and no-DM-MVD cohorts demonstrated comparable baseline cardiovascular risk profiles, although the no-DM-MVD cohort had higher rates of prior myocardial infarction, while the DM-SVD cohort had a higher proportion of patients with renal impairment. Over a median follow-up of 4.8 (IQR 2.0 to 8.2) years, 6,031 (17.5%) patients died. Using the no-DM-SVD group as the reference category, adjusted risk of mortality was highest in the MVD-DM cohort (HR 1.90; 95% CI 1.71 to 2.09). Similar adjusted risk of long-term mortality was observed in the DM-SVD (HR 1.32, 95%CI 1.15 to 1.51) and no-DM-MVD (HR 1.30, 95%CI 1.20 to 1.40) groups. In conclusion, we found that the long-term mortality of patients with DM and SVD undergoing PCI was the risk equivalent of non-DM patients with MVD.
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http://dx.doi.org/10.1016/j.amjcard.2020.11.036DOI Listing
March 2021

Baseline characteristics and age-related macular degeneration in participants of the "ASPirin in Reducing Events in the Elderly" (ASPREE)-AMD trial.

Contemp Clin Trials Commun 2020 Dec 11;20:100667. Epub 2020 Oct 11.

Department of Epidemiology and Preventive Medicine, Monash University, The Alfred Centre 99 Commercial Road, Melbourne, VIC, 3004, Australia.

Purpose: To describe the baseline participant characteristics in the ASPREE-AMD study, investigating the effect of aspirin on AMD incidence and progression.

Methods: Australian participants from the ASPirin in Reducing Events in the Elderly (ASPREE) trial, randomized to 100 mg aspirin daily or placebo, had non-mydriatic, digital color fundus images graded according to the Beckman AMD classification. Associations with AMD were determined for baseline characteristics and genetic risk variants.

Results: ASPREE-AMD sub-study enrolled 4993 participants with gradable macular images. Median age was 73.4 years (IQR, 71.5, 76.6), 52% were female, 10% had diabetes mellitus, 73% had hypertension, and 44% were former/current smokers. Early, intermediate and late AMD (detected in 20.6%, 16.1%, 1.1%, respectively), significantly associated with age, were also associated with increasing HDL levels: OR = 1.52 (95%CI, 1.26, 1.84), OR = 1.43 (1.17, 1.77) and OR = 1.96 (1.02, 3.76), respectively. Female sex was associated with early [OR = 1.37 (1.16, 1.62)], and intermediate [OR = 1.35 (1.12, 1.63)] AMD, as was previous regular use of aspirin, with OR = 1.46 (1.11, 1.92) and OR = 1.37 (1.01, 1.85), respectively. Current smoking had increased odds for late AMD, OR = 4.02 (1.42, 11.36). Genetic risk variant rs3750846 () was associated with each AMD stage ( < 0.001), risk variants rs570618 and rs10922109 ( with intermediate and late AMD ( < 0.001), and rare variant rs147859257 () with late AMD ( < 0.001). The randomized groups were well balanced for all analyzed AMD risk factors.

Conclusions: Observed associations are typical of AMD. The ASPREE-AMD clinical trial provides a unique opportunity to determine the risks and benefits of low-dose aspirin for AMD incidence and progression in elderly population.

Trial Registration: Australian New Zealand Clinical Trial Registry: ACTRN 12613000755730.
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http://dx.doi.org/10.1016/j.conctc.2020.100667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658662PMC
December 2020

Fatal and non-fatal events within 14 days after early, intensive mobilization post stroke.

Neurology 2020 Nov 3. Epub 2020 Nov 3.

University of Melbourne, Melbourne Brain Centre, Parkville, Australia.

Objective: This tertiary analysis from AVERT examined fatal and non-fatal Serious Adverse Events (SAEs) at 14 days.

Method: AVERT was a prospective, parallel group, assessor blinded, randomized international clinical trial comparing mobility training commenced <24 hours post stroke, termed very early mobilization (VEM) to usual care (UC). Primary outcome was assessed at 3 months. Included: Patients with ischaemic and haemorrhagic stroke within 24 hours of onset. Treatment with thrombolytics allowed. Excluded: Patients with severe premorbid disability and/or comorbidities. Interventions continued for 14 days or hospital discharge if less. The primary early safety outcome was fatal SAEs within 14 days. Secondary outcomes were non-fatal SAEs classified as neurologic, immobility-related, and other. Mortality influences were assessed using binary logistic regression adjusted for baseline stroke severity (NIHSS) and age.

Results: 2,104 participants were randomized to VEM (n = 1,054) or UC (n = 1,050) with a median age of 72 years (IQR 63-80) and NIHSS 7 (IQR 4-12). By 14 days, 48 had died in VEM, 32 in UC, age and stroke severity adjusted Odds Ratio of 1.76 (95% CI 1.06-2.92, = 0.029). Stroke progression was more common in VEM. Exploratory subgroup analyses showed higher odds of death in intracerebral haemorrhage and >80 years subgroups, but there was no significant treatment by subgroup interaction. No difference in non-fatal SAEs found.

Conclusion: While the overall case fatality at 14 days post-stroke was only 3.8%, mortality adjusted for age and stroke severity was increased with high dose, intensive training compared to usual care. Stroke progression was more common in VEM.

Classification Of Evidence: This study provides Class I evidence that very early mobilization increases mortality at 14 days post stroke.

Trial Registration: Australian New Zealand Clinical Trials Registry, ACTRN12606000185561.
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http://dx.doi.org/10.1212/WNL.0000000000011106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055346PMC
November 2020

Outcomes of Percutaneous Coronary Intervention in Patients With Rheumatoid Arthritis.

Am J Cardiol 2021 02 2;140:39-46. Epub 2020 Nov 2.

Department of Cardiology, Royal Melbourne Hospital, Melbourne, Victoria, Australia; Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, Victoria, Australia; Department of Medicine, Melbourne University, Victoria, Australia. Electronic address:

Rheumatoid arthritis (RA) is the most common inflammatory arthritis and is associated with increased risk of cardiovascular events and mortality. Evidence regarding outcomes following PCI is limited. This study aimed to assess differences in outcomes following percutaneous coronary intervention (PCI) between patients with and without RA. The Melbourne Interventional Group PCI registry (2005 to 2018) was used to identify 756 patients with RA. Outcomes were compared with the remaining cohort (n = 38,579). Patients with RA were older, more often female, with higher rates of hypertension, previous stroke, peripheral vascular disease, obstructive sleep apnea, chronic lung disease, myocardial infarction, and renal impairment, whereas rates of dyslipidemia and current smoking were lower, all p <0.05. Lesions in patients with RA were more frequently complex (ACC/AHA type B2/C), requiring longer stents, with higher rates of no reflow, all p <0.05. Risk of long-term mortality, adjusted for potential confounders, was higher for patients with RA (hazard ratio 1.53, 95% confidence interval 1.30 to 1.80; median follow-up 5.0 years), whereas 30-day outcomes including mortality, major adverse cardiovascular events, bleeding, stroke, myocardial infarction, coronary artery bypass surgery, and target vessel revascularization were similar. In subgroup analysis, patients with RA and lower BMI (P < 0.001) and/or acute coronary syndromes (P = 0.05) had disproportionately higher risk of long-term mortality compared with patients without RA. In conclusion, patients with RA who underwent PCI had more co-morbidities and longer, complex coronary lesions. Risk of short-term adverse outcomes was similar, whereas risk of long-term mortality was higher, especially among patients with acute coronary syndromes and lower body mass index.
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http://dx.doi.org/10.1016/j.amjcard.2020.10.048DOI Listing
February 2021

Long-Term Blood Pressure Variability and Risk of Cardiovascular Disease Events Among Community-Dwelling Elderly.

Hypertension 2020 12 2;76(6):1945-1952. Epub 2020 Nov 2.

Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia (E.K.C., R.W., A.M.T., J.R., R.L.W., J.J.M., C.M.R.).

High office blood pressure variability (OBPV) in midlife increases the risk of cardiovascular disease (CVD), but the impact of OBPV in older adults without previous CVD is unknown. We conducted a post hoc analysis of ASPREE trial (Aspirin in Reducing Events in the Elderly) participants aged 70-years and older (65 for US minorities) without history of CVD events at baseline, to examine risk of incident CVD associated with long-term, visit-to-visit OBPV. CVD was a prespecified, adjudicated secondary end point in ASPREE. We estimated OBPV using within-individual SD of mean systolic BP from baseline and first 2 annual visits. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% CI for associations with CVD events. In 16 475 participants who survived to year 2 without events, those in the highest tertile of OBPV had increased risk of CVD events after adjustment for multiple covariates, when compared with participants in the lowest tertile (HR, 1.36 [95% CI, 1.08-1.70]; =0.01). Similar increased risk was observed for ischemic stroke (HR, 1.56 [95% CI, 1.04-2.33]; =0.03), heart failure hospitalization, or death (HR, 1.73 [95% CI, 1.07-2.79]; =0.02), and all-cause mortality (HR, 1.27 [95% CI, 1.04-1.54]; =0.02). Findings were consistent when stratifying participants by use of antihypertensive drugs, while sensitivity analyses suggested the increased risk was especially for individuals whose BP was uncontrolled during the OBPV estimation period. Our findings support increased OBPV as a risk factor for CVD events in healthy older adults with, or without hypertension, who have not had such events previously. Registration- URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01038583; URL: https://www.isrctn.com; Unique identifiers: ISRCTN83772183.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666049PMC
December 2020

Effect of Testosterone Treatment on Cardiovascular Events in Men: Protocol for a Systematic Literature Review and Meta-Analysis.

JMIR Res Protoc 2020 Oct 29;9(10):e15163. Epub 2020 Oct 29.

Medical School, University of Western Australia, Perth, Australia.

Background: Testosterone prescriptions have increased dramatically in recent decades, with increasing usage in men. Despite epidemiological associations reported high circulating concentrations of endogenous androgens and low risk of cardiovascular events and mortality, the effects of exogenous androgens in the form of testosterone therapy for maintaining physiological circulating androgen concentrations on the cardiovascular system remain uncertain with no published meta-analysis on this topic.

Objective: The aim of this study was to investigate the effects of prescribed testosterone treatment, in all forms and durations, from well-developed randomized controlled trials, on cardiovascular events in men aged 18 years or older.

Methods: Peer-reviewed journal articles published from 1980 to 2019 will be searched from databases (ie CINAHL [Cumulated Index to Nursing and Allied Health Literature], Embase, Medline, Scopus, Cochrane Controlled Register of Trials as well as the Clinical Trial Registry). Randomized controlled trials or cluster randomized controlled trials with at least one intervention arm of testosterone and a control group of usual care or no testosterone treatment will be included in this review and meta-analysis. Studies on men with previous cardiovascular events or cardiac vascularization (coronary bypass surgery or percutaneous coronary intervention) will be excluded. Data related to primary outcomes such as clinical events of any type of stroke or transient ischemic attack, nonfatal myocardial infarction or acute coronary syndrome, emergency coronary artery revascularization, carotid surgery, cardiac mortality, and all-cause mortality will be extracted for analysis. The criteria for PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) will be followed in the evaluation of evidence.

Results: Search terms have been piloted and finalized. This study will be completed by the end of 2020.

Conclusions: This protocol will guide a systematic literature review of the evidence around prescribed testosterone and its effect on cardiovascular events in men aged 18 years or older. The findings will inform clinical management of hypogonadal men.

Trial Registration: PROSPERO International Prospective Register of Systematic Reviews CRD42019134278; https://tinyurl.com/y6t7ggge.

International Registered Report Identifier (irrid): PRR1-10.2196/15163.
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http://dx.doi.org/10.2196/15163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661242PMC
October 2020

Prescription Medication Use in Older Adults Without Major Cardiovascular Disease Enrolled in the Aspirin in Reducing Events in the Elderly (ASPREE) Clinical Trial.

Pharmacotherapy 2020 10;40(10):1042-1053

Department of Epidemiology & Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

Background: Efforts to minimize medication risks among older adults include avoidance of potentially inappropriate medications. Contemporary analysis of medication use in community-dwelling older people compared with the general population is lacking.

Participants: A total of 19,114 community-dwelling adults in Australia and the United States aged 70 years or older (65 years or older for U.S. minorities) without histories of major cardiovascular disease, cognitive impairment, or disability participated in a randomized, placebo-controlled trial of aspirin: ASPirin in Reducing Events in the Elderly study. Measurements Prescribed baseline medications obtained by self-report and medical record review were grouped by World Health Organization Anatomic and Therapeutic Chemical category. Potentially inappropriate medications were defined using a modified American Geriatrics Society Beers Criteria. Polypharmacy was defined as 5 or more medications, and hyperpolypharmacy defined as 10 or more medications. Cross-sectional descriptive statistics and adjusted odds ratios were computed.

Results: The median number of prescription medications per participant was three, regardless of age. Women had a higher medication prevalence. Cardiovascular drugs (primarily antihypertensives) were the most commonly reported (64%). Overall, 39% of the cohort reported taking at least one potentially inappropriate medication, with proton-pump inhibitors being the most commonly reported (21.2% of cohort). Of the cohort, 27% had polypharmacy, and 2% hyperpolypharmacy. Age 75 years or older, less than 12 years of education, hypertension, diabetes mellitus, chronic kidney disease, frailty, gastrointestinal complaint, and depressive symptoms were associated with an increased likelihood of potentially inappropriate medications and polypharmacy. For almost all medication classes, prevalence was equivalent or lower than the general older population.

Conclusion: Overall medication burden and polypharmacy are low in older adults free of major cardiovascular disease, disability, and cognitive impairment. The prevalence of potentially inappropriate medications is higher than previously reported and similar to more vulnerable populations as a result of the introduction of proton-pump inhibitors to the American Geriatrics Society Beers Criteria. Longitudinal follow-up is required to further understand the balance of benefits and risks for potentially inappropriate medications and polypharmacy in community-dwelling older people.
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http://dx.doi.org/10.1002/phar.2461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957955PMC
October 2020

Transcriptional regulation of MGE progenitor proliferation by PRDM16 controls cortical GABAergic interneuron production.

Development 2020 11 16;147(22). Epub 2020 Nov 16.

Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA

The mammalian cortex is populated by neurons derived from neural progenitors located throughout the embryonic telencephalon. Excitatory neurons are derived from the dorsal telencephalon, whereas inhibitory interneurons are generated in its ventral portion. The transcriptional regulator PRDM16 is expressed by radial glia, neural progenitors present in both regions; however, its mechanisms of action are still not fully understood. It is unclear whether PRDM16 plays a similar role in neurogenesis in both dorsal and ventral progenitor lineages and, if so, whether it regulates common or unique networks of genes. Here, we show that expression in mouse medial ganglionic eminence (MGE) progenitors is required for maintaining their proliferative capacity and for the production of proper numbers of forebrain GABAergic interneurons. PRDM16 binds to cis-regulatory elements and represses the expression of region-specific neuronal differentiation genes, thereby controlling the timing of neuronal maturation. PRDM16 regulates convergent developmental gene expression programs in the cortex and MGE, which utilize both common and region-specific sets of genes to control the proliferative capacity of neural progenitors, ensuring the generation of correct numbers of cortical neurons.
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http://dx.doi.org/10.1242/dev.187526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687860PMC
November 2020

Serum Testosterone is Inversely and Sex Hormone-binding Globulin is Directly Associated with All-cause Mortality in Men.

J Clin Endocrinol Metab 2021 Jan;106(2):e625-e637

School of Population and Global Health, University of Western Australia, Perth, Australia.

Context: Serum testosterone concentrations decline with age, while serum sex hormone-binding globulin (SHBG) concentrations increase.

Objective: To analyze associations of baseline serum testosterone and SHBG concentrations, and calculated free testosterone (cFT) values, with all-cause and cause-specific mortality in men.

Design, Setting, And Participants: The UK Biobank prospective cohort study of community-dwelling men aged 40-69 years old, followed for 11 years.

Main Outcome Measures: All-cause, atherosclerotic cardiovascular disease (CVD) and cancer-related mortality. Cox proportional hazards regression was performed, adjusting for age, waist circumference, medical conditions, and other covariates. Models for testosterone included SHBG and vice versa.

Results: In a complete case analysis of 149 436 men with 10 053 deaths (1925 CVD and 4927 cancer-related), men with lower testosterone had a higher mortality rate from any cause (lowest vs highest quintile, Q1 vs Q5, fully-adjusted hazard ratio [HR] = 1.14, 95% confidence interval [CI] = 1.06-1.22, overall trend P < 0.001), and cancer (HR = 1.20, CI = 1.09-1.33, P < 0.001), with no association for CVD deaths. Similar results were seen for cFT. Men with lower SHBG had a lower mortality rate from any cause (Q1 vs Q5, HR = 0.68, CI = 0.63-0.73, P < 0.001), CVD (HR = 0.70, CI = 0.59-0.83, P < 0.001), and cancer (HR = 0.80, CI = 0.72-0.89, P < 0.001). A multiply imputed dataset (N = 208 425, 15 914 deaths, 3128 CVD-related and 7468 cancer-related) and analysis excluding deaths within the first 2 years (9261, 1734, and 4534 events) yielded similar results.

Conclusions: Lower serum testosterone is independently associated with higher all-cause and cancer-related, but not CVD-related, mortality in middle-aged to older men. Lower SHBG is independently associated with lower all-cause, CVD-related, and cancer-related mortality. Confirmation and determination of causality requires mechanistic studies and prospective trials.
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http://dx.doi.org/10.1210/clinem/dgaa743DOI Listing
January 2021

Incidence and Predictors of Unplanned Hospital Readmission after Percutaneous Coronary Intervention.

J Clin Med 2020 Oct 10;9(10). Epub 2020 Oct 10.

School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia.

Unplanned readmissions to hospital after percutaneous coronary intervention (PCI) pose a significant burden to the healthcare system and are potentially preventable. In this study, we sought to determine the incidence of, and risk factors for, unplanned hospital readmissions within 30 days following PCI. We prospectively collected data on 28,488 patients undergoing PCI between 2013 and 2019, who were enrolled in the state-wide multi-centre Victorian Cardiac Outcomes Registry. Patients' data were then linked to data from the Victorian Department of Health administrative database that records statewide hospital admissions. Disease diagnosis codes were used to identify cause of readmission. Patients who had an unplanned readmission were further divided into those who had a cardiac vs. non-cardiac cause for readmission. Overall, 3059 patients (10.7%) had an unplanned hospital readmission within 30 days of PCI, of which 1848 patients (60.4%) were readmitted for primarily cardiac diagnoses. Independent predictors of both 30-day unplanned cardiac and non-cardiac readmissions post-PCI were female sex, having ≥1 admission in the 12 months prior to PCI, acute coronary syndrome presentation, having any in-hospital complication and being discharged on an oral anticoagulant (all < 0.05). A stepwise increase in readmission risk was observed with increasing number of admissions from 1 to ≥4 admissions in the 12 months prior to PCI. In conclusion, a substantial proportion of patients undergoing PCI have unexpected readmissions to hospital in the 30 days following PCI. Targeted strategies for patients with risk factors for readmission may be useful to reduce this significant burden to the healthcare system.
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http://dx.doi.org/10.3390/jcm9103242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600497PMC
October 2020