Publications by authors named "Mark Woodward"

632 Publications

Gender Equity in Leadership and Conferences of the Stroke Society of Australasia.

Cerebrovasc Dis 2021 Jul 15:1-6. Epub 2021 Jul 15.

Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.

Introduction And Aim: Internationally, women are underrepresented as leaders in major scientific organizations and conferences. We aimed to determine gender differences in leadership roles and annual scientific conferences of the Stroke Society of Australasia (SSA).

Methods: In a retrospective review of SSA data (2014-2019), committee members were obtained through the SSA Web site, and moderators, speakers, and award recipients were identified from SSA annual scientific conference programs. Gender was determined by name inspection and Web search. Absolute numbers and proportions of women and men were recorded for all roles examined, overall and per year. Associations between representation of women in conferences and percentage of women in speaking roles were tested using multinomial regression.

Results: Presidential leadership of the SSA was held by men in 2014-2016 and 2019 and women in 2017-2018. SSA committee membership was predominantly women (55%), being lowest (47%) in 2014 and 2019 and highest (65%) in 2017. There was a wide gender variation at scientific conferences, with 41% of keynote speakers being women overall, from 20% in 2016 to 75% in 2015. From 2014 to 2019, 55% of all speakers were women, ranging from 32% (in 2016) to 71% (in 2015). A higher percentage of women as speakers or moderators was associated with a program committee with over a third of its members composed of women (p ≤ 0.044).

Conclusions: Representation of women varied from 2014 to 2019 in the SSA organization and its conferences, although men are more often elected president in the organization and women are less often keynote speakers. When more women were included in the program committee, the representation of women as speakers increased.
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http://dx.doi.org/10.1159/000517453DOI Listing
July 2021

The association of energy and macronutrient intake with all-cause mortality, cardiovascular disease, and dementia: findings from 120,963 women and men in the UK Biobank.

Br J Nutr 2021 Jul 14:1-24. Epub 2021 Jul 14.

The George Institute for Global Health, University of New South Wales, Sydney, Australia.

This study aimed to investigate the association between individual, and combinations of, macronutrients with premature death, cardiovascular disease (CVD) and dementia. Sex differences were investigated. Data were utilised from a prospective cohort of 120,963 individuals (57% female) within the UK Biobank, who completed ≥two 24-hour diet recalls. The associations of macronutrients, as percentages of total energy intake, with outcomes were investigated. Combinations of macronutrients were defined using k-means cluster analysis, with clusters explored in association with outcomes. There was a higher risk of death with high carbohydrate intake (Hazard ratios (HRs), 95% confidence intervals (95% CI) upper v lowest third 1.13 (1.03, 1.23)), yet a lower risk with higher intakes of protein (upper v lowest third 0.82 (0.76, 0.89)). There was a lower risk of CVD with moderate intakes (middle v lowest third) of energy and protein (sub distribution HRs (SHR), 0.87 (0.79, 0.97) and (0.87 (0.79, 0.96)) respectively). There was a lower risk of dementia with moderate energy intake (SHR 0.71 (0.52, 0.96)). Sex differences were identified. The dietary cluster characterised by low carbohydrate, low fat and high protein was associated with a lower risk of death (HR 0.84 (0.76, 0.93)) compared to the reference cluster, and a lower risk of CVD for men (SHR 0.83 (0.71, 0.97)). Given that associations were evident, both as single macronutrients and for combinations with other macronutrients for death, and for CVD in men, we suggest that the biggest benefit from diet-related policy and interventions will be when combinations of macronutrients are targeted.
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http://dx.doi.org/10.1017/S000711452100266XDOI Listing
July 2021

Polygenic risk scores predict diabetes complications and their response to intensive blood pressure and glucose control.

Diabetologia 2021 Jul 6. Epub 2021 Jul 6.

Ontario Institute for Cancer Research, Toronto, ON, Canada.

Aims/hypothesis: Type 2 diabetes increases the risk of cardiovascular and renal complications, but early risk prediction could lead to timely intervention and better outcomes. Genetic information can be used to enable early detection of risk.

Methods: We developed a multi-polygenic risk score (multiPRS) that combines ten weighted PRSs (10 wPRS) composed of 598 SNPs associated with main risk factors and outcomes of type 2 diabetes, derived from summary statistics data of genome-wide association studies. The 10 wPRS, first principal component of ethnicity, sex, age at onset and diabetes duration were included into one logistic regression model to predict micro- and macrovascular outcomes in 4098 participants in the ADVANCE study and 17,604 individuals with type 2 diabetes in the UK Biobank study.

Results: The model showed a similar predictive performance for cardiovascular and renal complications in different cohorts. It identified the top 30% of ADVANCE participants with a mean of 3.1-fold increased risk of major micro- and macrovascular events (p = 6.3 × 10 and p = 9.6 × 10, respectively) and a 4.4-fold (p = 6.8 × 10) higher risk of cardiovascular death. While in ADVANCE overall, combined intensive blood pressure and glucose control decreased cardiovascular death by 24%, the model identified a high-risk group in whom it decreased the mortality rate by 47%, and a low-risk group in whom it had no discernible effect. High-risk individuals had the greatest absolute risk reduction with a number needed to treat of 12 to prevent one cardiovascular death over 5 years.

Conclusions/interpretation: This novel multiPRS model stratified individuals with type 2 diabetes according to risk of complications and helped to target earlier those who would receive greater benefit from intensive therapy.
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http://dx.doi.org/10.1007/s00125-021-05491-7DOI Listing
July 2021

Strengthening Knowledge to Practice on Effective Salt Reduction Interventions in Low- and Middle-Income Countries.

Curr Nutr Rep 2021 Jul 5. Epub 2021 Jul 5.

The George Institute for Global Health, University of New South Wales, Level 5, 1 King St, Newtown, Sydney, NSW, 2042, Australia.

Purpose Of Review: The objective of this review was to consolidate available published information on the implementation and evaluation of salt reduction interventions in low- and middle-income countries (LMICs).

Recent Findings: The Science of Salt database (made up of studies identified in a weekly Medline search) was used to retrieve articles related to the implementation of salt reduction interventions from June 2013 to February 2020. Studies that measured the effects of the interventions in LMICs, based on four outcome measures-salt intake; sodium levels in foods; knowledge, attitudes, and behaviours (KABs) towards salt; and blood pressure-were included. Results were summarised overall and according to subgroups of intervention type, duration, sample size, country's income class, and regional classification. The review identified 32 studies, representing 13 upper middle-income and four lower middle-income countries. The main salt reduction interventions were education, food reformulation, and salt substitution; and many interventions were multi-faceted. More studies reported a positive effect of the interventions (decreased salt intake (12/17); lower sodium levels in foods or compliance with agreed targets (6/6); improved KAB (17/19); and decreased blood pressure (10/14)) than a null effect, and no study reported a negative effect of the intervention. However, many studies were of small scale and targeted specific groups, and none was from low-income countries. Consumer education, food reformulation, and salt substitution, either alone or in combination, were effective in their target populations. Supporting scale-up of salt reduction interventions in LMICs is essential to cover broader populations and to increase their public health impact.
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http://dx.doi.org/10.1007/s13668-021-00365-1DOI Listing
July 2021

Derivation and Validation of a 10-Year Risk Score for Symptomatic Abdominal Aortic Aneurysm: A Cohort Study of Nearly 500,000 Individuals.

Circulation 2021 Jun 25. Epub 2021 Jun 25.

Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK.

Abdominal aortic aneurysm (AAA) can occur in patients who are ineligible for routine ultrasound screening. A simple AAA risk score was derived and compared to current guidelines used for ultrasound screening of AAA. UK Biobank participants without previous AAA were split into a derivation cohort (n=401,820, 54.6% women, mean age 56.4 years, 95.5% white race) and validation cohort (n=83,816). Incident AAA was defined as first hospital inpatient diagnosis of AAA, death from AAA, or an AAA-related surgical procedure. A multivariable Cox model was developed in the derivation cohort into an AAA risk score that did not require blood biomarkers. To illustrate the sensitivity and specificity of the risk score for AAA, a theoretical threshold to refer patients for ultrasound at 0.25% 10-year risk was modelled. Discrimination of the risk score was compared to a model of US Preventive Services Task Force (USPSTF) AAA screening guidelines. In the derivation cohort there were 1,570 (0.40%) cases of AAA over a median 11.3 years of follow-up. Components of the AAA risk score were age (stratified by smoking status), weight (stratified by smoking status), antihypertensive and cholesterol lowering medication use, height, diastolic blood pressure, baseline cardiovascular disease, and diabetes. In the validation cohort, over ten years of follow-up, the C-index for the model of the USPSTF guidelines was 0.705 (95% CI 0.678, 0.733). The C-index of the risk score as a continuous variable was 0.856 (95%CI 0.837-0.878). In the validation cohort, the USPSTF model yielded sensitivity 63.9% and specificity 71.3%. At the 0.25% 10-year risk threshold, the risk score yielded sensitivity 82.1% and specificity 70.7%, while also improving the net reclassification index (NRI) compared to the USPSTF model +0.176 (95%CI 0.120, 0.232). A combined model, whereby risk scoring was combined with the USPSTF model, also improved prediction compared to USPSTF alone (NRI +0.101, 95%CI 0.055, 0.147). In an asymptomatic general population, a risk score based on patient age, height, weight and medical history may improve identification of asymptomatic patients at risk for clinical events from AAA. Further development and validation of risk scores to detect asymptomatic AAA is needed.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.053022DOI Listing
June 2021

Salt reduction to prevent hypertension: the reasons of the controversy.

Eur Heart J 2021 Jul;42(25):2501-2505

Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.

There is a causal relationship between dietary salt intake and blood pressure. A reduction in salt intake from the current world average of ∼10 g/day to the WHO recommended level of <5 g/day, lowers blood pressure and reduces the risk of cardiovascular disease and all-cause mortality. However, a few cohort studies have claimed that there is a J-shaped relationship between salt intake and cardiovascular risk, i.e. both high and low salt intakes are associated with an increased risk. These cohort studies have several methodological problems, including reverse causality, and inaccurate and biased estimation of salt intake, e.g. from a single spot urine sample with formulas. Recent studies have shown that the formulas used to estimate salt intake from spot urine cause a spurious J-curve. Research with inappropriate methodology should not be used to refute the robust evidence on the enormous benefits of population-wide reduction in salt intake. Several countries, e.g. Finland, the UK, have successfully reduced salt intake, which has resulted in falls in population blood pressure and deaths from stroke and ischaemic heart disease. Every country should develop and implement a coherent, workable strategy to reduce salt intake. Even a modest reduction in salt intake across the whole population will lead to a major improvement in public health, along with huge cost-savings to the healthcare service.
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http://dx.doi.org/10.1093/eurheartj/ehab274DOI Listing
July 2021

Clinical risk factors associated with radiographic osteoarthritis progression among people with knee pain: a longitudinal study.

Arthritis Res Ther 2021 06 4;23(1):160. Epub 2021 Jun 4.

Faculty of Medicine and Health, Discipline of Physiotherapy, The University of Sydney, Sydney, Australia.

Background: The aim of this study was to identify modifiable clinical factors associated with radiographic osteoarthritis progression over 1 to 2 years in people with painful medial knee osteoarthritis.

Methods: A longitudinal study was conducted within a randomised controlled trial, the "Long-term Evaluation of Glucosamine Sulfate" (LEGS study). Recruitment occurred in 2007-2009, with 1- and 2-year follow-up assessments by blinded assessors. Community-dwelling people with chronic knee pain (≥4/10) and medial tibiofemoral narrowing (but retaining >2mm medial joint space width) on radiographs were recruited. From 605 participants, follow-up data were available for 498 (82%, mean [sd] age 60 [8] years). Risk factors evaluated at baseline were pain, physical function, use of non-steroidal anti-inflammatory drugs (NSAIDs), statin use, not meeting physical activity guidelines, presence of Heberden's nodes, history of knee surgery/trauma, and manual occupation. Multivariable logistic regression analysis was conducted adjusting for age, sex, obesity, high blood pressure, allocation to glucosamine and chondroitin treatment, and baseline structural disease severity (Kellgren and Lawrence grade, joint space width, and varus alignment). Radiographic osteoarthritis progression was defined as joint space narrowing ≥0.5mm over 1 to 2 years (latest follow-up used where available).

Results: Radiographic osteoarthritis progression occurred in 58 participants (12%). Clinical factors independently associated with radiographic progression were the use of NSAIDs, adjusted odds ratios (OR) and 95% confidence intervals (CI) 2.05 (95% CI 1.1 to 3.8), and not meeting physical activity guidelines, OR 2.07 (95% CI 0.9 to 4.7).

Conclusions: Among people with mild radiographic knee osteoarthritis, people who use NSAIDs and/or do not meet physical activity guidelines have a greater risk of radiographic osteoarthritis progression.

Trial Registration: ClinicalTrials.gov , NCT00513422 . This original study trial was registered a priori, on August 8, 2007. The current study hypothesis arose before inspection of the data.
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http://dx.doi.org/10.1186/s13075-021-02540-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176608PMC
June 2021

Blood pressure-lowering treatment for the prevention of cardiovascular events in patients with atrial fibrillation: An individual participant data meta-analysis.

PLoS Med 2021 Jun 1;18(6):e1003599. Epub 2021 Jun 1.

Deep Medicine, Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom.

Background: Randomised evidence on the efficacy of blood pressure (BP)-lowering treatment to reduce cardiovascular risk in patients with atrial fibrillation (AF) is limited. Therefore, this study aimed to compare the effects of BP-lowering drugs in patients with and without AF at baseline.

Methods And Findings: The study was based on the resource provided by the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC), in which individual participant data (IPD) were extracted from trials with over 1,000 patient-years of follow-up in each arm, and that had randomly assigned patients to different classes of BP-lowering drugs, BP-lowering drugs versus placebo, or more versus less intensive BP-lowering regimens. For this study, only trials that had collected information on AF status at baseline were included. The effects of BP-lowering treatment on a composite endpoint of major cardiovascular events (stroke, ischaemic heart disease or heart failure) according to AF status at baseline were estimated using fixed-effect one-stage IPD meta-analyses based on Cox proportional hazards models stratified by trial. Furthermore, to assess whether the associations between the intensity of BP reduction and cardiovascular outcomes are similar in those with and without AF at baseline, we used a meta-regression. From the full BPLTTC database, 28 trials (145,653 participants) were excluded because AF status at baseline was uncertain or unavailable. A total of 22 trials were included with 188,570 patients, of whom 13,266 (7%) had AF at baseline. Risk of bias assessment showed that 20 trials were at low risk of bias and 2 trials at moderate risk. Meta-regression showed that relative risk reductions were proportional to trial-level intensity of BP lowering in patients with and without AF at baseline. Over 4.5 years of median follow-up, a 5-mm Hg systolic BP (SBP) reduction lowered the risk of major cardiovascular events both in patients with AF (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.83 to 1.00) and in patients without AF at baseline (HR 0.91, 95% CI 0.88 to 0.93), with no difference between subgroups. There was no evidence for heterogeneity of treatment effects by baseline SBP or drug class in patients with AF at baseline. The findings of this study need to be interpreted in light of its potential limitations, such as the limited number of trials, limitation in ascertaining AF cases due to the nature of the arrhythmia and measuring BP in patients with AF.

Conclusions: In this meta-analysis, we found that BP-lowering treatment reduces the risk of major cardiovascular events similarly in individuals with and without AF. Pharmacological BP lowering for prevention of cardiovascular events should be recommended in patients with AF.
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http://dx.doi.org/10.1371/journal.pmed.1003599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168843PMC
June 2021

Are there sex differences in crash and crash-related injury between men and women? A 13-year cohort study of young drivers in Australia.

SSM Popul Health 2021 Jun 12;14:100816. Epub 2021 May 12.

School of Population Health, UNSW, Sydney, Australia.

Background: Young men have long been known to be disproportionately impacted by road crash and crash-related injury compared to young women and older drivers. However, there is limited insight into how sex differences in crash and crash-related injury changes over time as men and women get older and gain more driving experience. To explore sex differences in crash and crash-related injury, we undertook a sex disaggregated analysis in a large longitudinal cohort of over 20,000 young drivers in New South Wales, Australia, for up to 13 years after they first attained their independent car driver licence.

Methods: DRIVE Study survey data from 2003-04 were linked with police, hospital and deaths data up to 2016. Sex differences were analysed using cumulative incidence curves investigating time to first crash and in negative binominal regression models adjusted for driver demographics and crash risk factors.

Results: After adjusting for demographics and driving exposure, compared with women, men had 1.25 (95% CI 1.18-1.33), 2.07 (1.75-2.45), 1.28 (95% CI 1.13-1.46), 1.32 (95% CI 1.17-1.50) and 1.59 (95% CI 1.43-1.78) times higher rates of any crash, single vehicle crash, crash on streets with a speed limit of 80 km/h or above, crash in wet conditions and crash in the dark, respectively. By contrast, men were less likely to be involved in crashes that resulted in hospitalisation compared to women 0.73 (95% CI 0.55-0.96).

Conclusions: Young men are at increased risk of crash, and this risk persists as they get older and gain more driving experience. Despite lower risk of crash, women are at higher risk of crash related injury requiring hospitalisation. These differences in men's and women's risk of crash and injury signal the need for better understanding of how sex and/or gender may contribute to risk of crash and injury across the life-course.
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http://dx.doi.org/10.1016/j.ssmph.2021.100816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141461PMC
June 2021

The Impact of Frailty on the Effectiveness and Safety of Intensive Glucose Control and Blood Pressure-Lowering Therapy for People With Type 2 Diabetes: Results From the ADVANCE Trial.

Diabetes Care 2021 May 25. Epub 2021 May 25.

Westmead Applied Research Centre, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia

Objective: To develop a frailty index (FI) and explore the relationship of frailty to subsequent adverse outcomes on the effectiveness and safety of more intensive control of both blood glucose and blood pressure (BP), among participants with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial.

Research Design And Methods: Cox proportional hazard models were used to estimate the effectiveness and safety of intensive glucose control and BP intervention according to frailty (defined as FI >0.21) status. The primary outcomes were macro- and microvascular events. The secondary outcomes were all-cause mortality, cardiovascular mortality, severe hypoglycemia, and discontinuation of BP treatment due to hypotension/dizziness.

Results: There were 11,140 participants (mean age, 65.8 years; 42.5% women, 25.7% frail). Frailty was an independent predictor of all primary outcomes and secondary outcomes. The effect of intensive glucose treatment on primary outcomes showed some evidence of attenuation in the frail: hazard ratios for combined major macro- and microvascular events 1.03 (95% CI 0.90-1.19) in the frail versus 0.84 (95% CI 0.74-0.94) in the nonfrail ( = 0.02). A similar trend was observed with BP intervention. Severe hypoglycemia rates (per 1,000 person-years) were higher in the frail: 8.39 (6.15-10.63) vs. 4.80 (3.84-5.76) in nonfrail ( < 0.001). There was no significant difference in discontinuation of BP treatment between frailty groups.

Conclusions: It was possible to retrospectively estimate frailty in a trial population, and this FI identified those at higher risk of poor outcomes. Participants with frailty had some attenuation of benefit from intensive glucose-lowering and BP-lowering treatments.
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http://dx.doi.org/10.2337/dc20-2664DOI Listing
May 2021

Sex differences in the association between major cardiovascular risk factors in midlife and dementia: a cohort study using data from the UK Biobank.

BMC Med 2021 May 19;19(1):110. Epub 2021 May 19.

The George Institute for Global Health, University of New South Wales, Level 5, 1 King St, Newtown, NSW, 2042, Australia.

Background: Sex differences in major cardiovascular risk factors for incident (fatal or non-fatal) all-cause dementia were assessed in the UK Biobank. The effects of these risk factors on all-cause dementia were explored by age and socioeconomic status (SES).

Methods: Cox proportional hazards models were used to estimate hazard ratios (HRs) and women-to-men ratio of HRs (RHR) with 95% confidence intervals (CIs) for systolic blood pressure (SBP) and diastolic blood pressure (DBP), smoking, diabetes, adiposity, stroke, SES and lipids with dementia. Poisson regression was used to estimate the sex-specific incidence rate of dementia for these risk factors.

Results: 502,226 individuals in midlife (54.4% women, mean age 56.5 years) with no prevalent dementia were included in the analyses. Over 11.8 years (median), 4068 participants (45.9% women) developed dementia. The crude incidence rates were 5.88 [95% CI 5.62-6.16] for women and 8.42 [8.07-8.78] for men, per 10,000 person-years. Sex was associated with the risk of dementia, where the risk was lower in women than men (HR = 0.83 [0.77-0.89]). Current smoking, diabetes, high adiposity, prior stroke and low SES were associated with a greater risk of dementia, similarly in women and men. The relationship between blood pressure (BP) and dementia was U-shaped in men but had a dose-response relationship in women: the HR for SBP per 20 mmHg was 1.08 [1.02-1.13] in women and 0.98 [0.93-1.03] in men. This sex difference was not affected by the use of antihypertensive medication at baseline. The sex difference in the effect of raised BP was consistent for dementia subtypes (vascular dementia and Alzheimer's disease).

Conclusions: Several mid-life cardiovascular risk factors were associated with dementia similarly in women and men, but not raised BP. Future bespoke BP-lowering trials are necessary to understand its role in restricting cognitive decline and to clarify any sex difference.
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http://dx.doi.org/10.1186/s12916-021-01980-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132382PMC
May 2021

Socioeconomic disparities in the management of coronary heart disease in 438 general practices in Australia.

Eur J Prev Cardiol 2021 May;28(4):400-407

The George Institute for Global Health, University of New South Wales, Australia.

Background: This population-based cross-stional and panel study investigated disparities in the management of coronary heart disease (CHD) by level of socioeconomic status.

Methods: CHD patients (aged ≥18 years), treated in 438 general practices in Australia, with ≥3 recent encounters with their general practitioners, with last encounter being during 2016-2018, were included. Secondary prevention prescriptions and number of treatment targets achieved were each modelled using a Poisson regression adjusting for demographics, socioeconomic indicators, remoteness of patient's residence, comorbidities, lifetime follow-up, number of patient-general practitioner encounters and cluster effect within the general practices. The latter model was constructed using the Generalised Estimating Equations approach. Sensitivity analysis was run by comorbidity.

Results: Of 137,408 patients (47% women), approximately 48% were prescribed ≥3 secondary prevention medications. However, only 44% were screened for CHD-associated risk factors. Of the latter, 45% achieved ≥5 treatment targets. Compared with patients from the highest socioeconomic status fifth, those from the lowest socioeconomic status fifth were 8% more likely to be prescribed more medications for secondary prevention (incidence rate ratio (95% confidence interval): 1.08 (1.04-1.12)) but 4% less likely to achieve treatment targets (incidence rate ratio: 0.96 (0.95-0.98)). These disparities were also observed when stratified by comorbidities.

Conclusion: Despite being more likely to be prescribed medications for secondary prevention, those who are most socioeconomically disadvantaged are less likely to achieve treatment targets. It remains to be determined whether barriers such as low adherence to treatment, failure to fill prescriptions, low income, low level of education or other barriers may explain these findings.
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http://dx.doi.org/10.1177/2047487320912087DOI 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

Association of lactation with maternal risk of type 2 diabetes: A systematic review and meta-analysis of observational studies.

Diabetes Obes Metab 2021 Aug 20;23(8):1902-1916. Epub 2021 May 20.

The George Institute for Global Health, Imperial College London, London, UK.

Aim: To investigate the association between lactation and maternal risk of type 2 diabetes, including a potential graded association according to lactation duration.

Methods: A systematic review and meta-analysis of observational studies that investigated the reported association between lactation (irrespective of duration, intensity or mode) and maternal risk of type 2 diabetes was conducted.

Results: A total of 22 studies (17 cohort studies and five cross-sectional studies) were included in this systematic review, and 16 contributed to the meta-analysis. Studies that investigated the association of lactation with risk of type 2 diabetes in the first months after birth in women with gestational diabetes reported conflicting results. Studies with a longer follow-up showed a graded protective association for lactation and the risk of type 2 diabetes, with a potentially larger risk reduction in women with gestational diabetes than in those without gestational diabetes. Overall, ever versus never lactation was associated with a 27% lower risk of type 2 diabetes (RR 0.73, 95% CI [0.65, 0.83]). Each additional month of lactation was associated with a 1% lower risk of type 2 diabetes (RR 0.99, 95% CI [0.98, 0.99]). However, the overall quality of the studies was modest.

Conclusions: Lactation is associated with a significantly reduced risk of maternal type 2 diabetes over the life course, particularly in women with gestational diabetes. The protective effect seems to increase with longer duration of lactation. Further research is warranted to understand whether this association is modified by exposure to other risk factors.
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http://dx.doi.org/10.1111/dom.14417DOI Listing
August 2021

Social deprivation as a risk factor for COVID-19 mortality among women and men in the UK Biobank: nature of risk and context suggests that social interventions are essential to mitigate the effects of future pandemics.

J Epidemiol Community Health 2021 Apr 27. Epub 2021 Apr 27.

The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.

Objectives: To investigate sex differences in the effects of social deprivation on COVID-19 mortality and to place these effects in context with other diseases.

Design: Prospective population-based study.

Setting: UK Biobank.

Participants: 501 865 participants (54% women).

Main Outcome Measure: COVID-19 as the underlying cause of death.

Results: Of 472 946 participants alive when COVID-19 was first apparent in the UK (taken as 1 February 2020), 217 (34% women) died from COVID-19 over the next 10 months, resulting in an incidence, per 100 000 person years, of 100.65 (95% CI 79.47 to 121.84) for women and 228.59 (95% CI 194.88 to 262.30) for men. Greater social deprivation, quantified using the Townsend Deprivation Score, was associated with greater risk of fatal COVD-19. Adjusted for age and ethnicity, HRs for women and men, comparing those in the most with the least deprived national fifths, were 3.66 (2.82 to 4.75) for women and 3.00 (2.46 to 3.66) for men. Adjustments for key baseline lifestyle factors attenuated these HRs to 2.20 (1.63 to 2.96) and 2.62 (2.12 to 3.24), respectively. There was evidence of a log-linear trend in the deprivation-fatal COVID-19 association, of similar magnitude to the equivalent trends for the associations between deprivation and fatal influenza or pneumonia and fatal cardiovascular disease. For all three causes of death, there was no evidence of a sex difference in the associations.

Conclusions: Higher social deprivation is a risk factor for death from COVID-19 on a continuous scale, with two to three times the risk in the most disadvantaged 20% compared with the least. Similarities between the social gradients in COVID-19, influenza/pneumonia and cardiovascular disease mortality, the lack of sex differences in these effects, and the partial mediation of lifestyle factors suggest that better social policies are crucial to alleviate the general medical burden, including from the current, and potential future, viral pandemics.
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http://dx.doi.org/10.1136/jech-2020-215810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098299PMC
April 2021

Atherosclerosis inflammation and burden in young adult smokers and vapers measured by PET/MR.

Atherosclerosis 2021 05 30;325:110-116. Epub 2021 Mar 30.

BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, USA. Electronic address:

Background And Aims: Electronic cigarette (EC) use is popular among youth, touted as a safer alternative to smoking and promoted as a tool to aid in smoking cessation. EC cardiovascular safety however is not well established. The aim of this study was to examine cardiovascular consequences of EC use by evaluating their effect on the entire atherosclerotic cascade in young adults using noninvasive combined positron emission tomography (PET)/magnetic resonance imaging (MR) and comparing EC use with age matched smokers of traditional cigarettes and nonsmoking controls.

Methods: Carotid PET/MR was applied to look at vascular inflammation (18-fluorodeoxyglucose (FDG)-PET) and plaque burden (multi-contrast MR of vessel wall) from 60 18-30 year-old subjects (20 electronic cigarette users, 20 traditional smokers and 20 nonsmokers).

Results: Groups were reasonably well balanced in terms of age, gender, demographics, cardiovascular risk and most biomarkers. There were no differences in vascular inflammation as measured by 18-FDG-PET target to background ratios (TBR) between EC users, traditional cigarette smokers and nonsmokers. However, measures of carotid plaque burden - wall area, normalized wall index, and wall thickness - measured from MR were significantly higher in both traditional smokers and EC users than in nonsmokers.

Conclusions: Young adult EC users, smokers and nonsmokers in our study did not exhibit vascular inflammation as defined by 18-F-FDG-PET TBR max, but smokers and EC users had significantly more carotid plaque burden compared to matched nonsmokers. Results could indicate that vaping does not cause an increase in vascular inflammation as measured by FDG-PET.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.03.021DOI Listing
May 2021

Changes in GFR and Albuminuria in Routine Clinical Practice and the Risk of Kidney Disease Progression.

Am J Kidney Dis 2021 Apr 23. Epub 2021 Apr 23.

George Institute for Global Health, University of New South Wales, Newtown, New South Wales, Australia; Department of Epidemiology and Biostatistics, School of Public Health, The George Institute for Global Health, Imperial College London, London; Department of Epidemiology, John Hopkins University, Baltimore, MD.

Rationale & Objective: Changes in urinary albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) have been used separately as alternative kidney disease outcomes in randomized trials. We tested the hypothesis that combined changes in UACR and eGFR predict advanced kidney disease better than either alone.

Study Design: Observational cohort study.

Setting & Participants: 91,319 primary care patients assembled from the Clinical Practice Research Datalink in the United Kingdom between 2000 and 2015.

Exposures: Changes in UACR and eGFR (categorized as ≥30% increase, stable, or ≥30% decrease), alone and in combination, over a 3-year period.

Outcomes: The primary outcome was advanced CKD (sustained eGFR <30 mL/min/1.73 m); secondary outcomes included kidney failure, cardiovascular disease, and all-cause mortality.

Analytical Approach: Multivariable Cox regression with bias from missing values assessed using multiple imputation; discrimination statistics compared across exposure groups.

Results: 91,319 individuals were studied, with a mean eGFR of 72.6 mL/min/1.73 m and median UACR of 9.7 mg/g; 70,957 (77.7%) had diabetes. During a median follow-up of 2.9 years, 2,541 people progressed to advanced CKD. Compared with stable values, hazard ratios for a ≥30% increase in UACR and ≥30% decrease in eGFR were 1.78 (95% CI, 1.59-1.98) and 7.53 (95% CI, 6.70-8.45), respectively, for the outcome of advanced CKD. Compared with stable values of both, the hazard ratio for the combination of an increase in UACR and a decrease in eGFR was 15.15 (95% CI, 12.43-18.46) for the outcome of advanced CKD. The combination of changes in UACR and eGFR predicted kidney outcomes better than either alone.

Limitations: Selection bias, relatively small proportion of individuals without diabetes, and very few kidney failure events.

Conclusions: In a large-scale general population, the combination of an increase in UACR and a decrease in eGFR was strongly associated with the risk of advanced CKD. Further assessment of combined changes in UACR and eGFR as an alternative outcome for kidney failure in trials of CKD progression is warranted.
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http://dx.doi.org/10.1053/j.ajkd.2021.02.335DOI Listing
April 2021

Combination blood pressure lowering in the presence or absence of background statin and aspirin therapy: a combined analysis of PROGRESS and ADVANCE Trials.

J Hypertens 2021 Aug;39(8):1689-1696

The George Institute for Global Health, University of New South Wales.

Objectives: To assess the effects of combination BP lowering on cardiovascular events and mortality in the presence of aspirin and/or statin therapy in a combined analysis of the ADVANCE and PROGRESS trials.

Methods: We conducted an analysis of 14 682 participants allocated combination therapy with perindopril and indapamide or placebo followed up for a mean of 4.2 years. Participants were stratified into four groups defined by background use of medications at baseline: statin, aspirin, both or neither. Linear mixed effect models were used to assess differences in BP and Cox proportional hazard models were used to estimate the risks of major cardiovascular events, all-cause mortality and treatment discontinuation.

Results: At baseline, 14% of patients were on both aspirin and statin, 35% on aspirin, 9% on statins and 42% on neither aspirin/statins. Compared with placebo, combination BP therapy reduced mean SBP by 5.7 mmHg in ADVANCE and 12.1 mmHg in PROGRESS, with no difference (P > 0.447) between patients by baseline use of aspirin/statin. Combination BP therapy reduced the risk of major cardiovascular events (hazard ratio 0.78, 95% CI 0.71-0.86), with no significant difference (P = 0.600) between aspirin/statin subgroups. Rates of treatment discontinuation were similar with combination BP therapy compared with placebo (18.4 versus 18%), with no evidence of difference across the subgroups (P = 0.340).

Conclusion: BP lowering with perindopril and indapamide reduces the risk of major cardiovascular events independent of baseline use of aspirin and/or statins.
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http://dx.doi.org/10.1097/HJH.0000000000002862DOI Listing
August 2021

Sex Disparities in Cardiovascular Risk Factor Assessment and Screening for Diabetes-Related Complications in Individuals With Diabetes: A Systematic Review.

Front Endocrinol (Lausanne) 2021 30;12:617902. Epub 2021 Mar 30.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.

Background: Insight in sex disparities in the detection of cardiovascular risk factors and diabetes-related complications may improve diabetes care. The aim of this systematic review is to study whether sex disparities exist in the assessment of cardiovascular risk factors and screening for diabetes-related complications.

Methods: PubMed was systematically searched up to April 2020, followed by manual reference screening and citations checks (snowballing) using Google Scholar. Observational studies were included if they reported on the assessment of cardiovascular risk factors (HbA1c, lipids, blood pressure, smoking status, or BMI) and/or screening for nephropathy, retinopathy, or performance of feet examinations, in men and women with diabetes separately. Studies adjusting their analyses for at least age, or when age was considered as a covariable but left out from the final analyses for various reasons (i.e. backward selection), were included for qualitative analyses. No meta-analyses were planned because substantial heterogeneity between studies was expected. A modified Newcastle-Ottawa Quality Assessment Scale for cohort studies was used to assess risk of bias.

Results: Overall, 81 studies were included. The majority of the included studies were from Europe or North America (84%).The number of individuals per study ranged from 200 to 3,135,019 and data were extracted from various data sources in a variety of settings. Screening rates varied considerably across studies. For example, screening rates for retinopathy ranged from 13% to 90%, with half the studies reporting screening rates less than 50%. Mixed findings were found regarding the presence, magnitude, and direction of sex disparities with regard to the assessment of cardiovascular risk factors and screening for diabetes-related complications, with some evidence suggesting that women, compared with men, may be more likely to receive retinopathy screening and less likely to receive foot exams.

Conclusion: Overall, no consistent pattern favoring men or women was found with regard to the assessment of cardiovascular risk factors and screening for diabetes-related complications, and screening rates can be improved for both sexes.
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http://dx.doi.org/10.3389/fendo.2021.617902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043152PMC
March 2021

Antihypertensive treatment and risk of cancer: an individual participant data meta-analysis.

Lancet Oncol 2021 04;22(4):558-570

Deep Medicine, Oxford Martin School, University of Oxford, Oxford, UK; Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. Electronic address:

Background: Some studies have suggested a link between antihypertensive medication and cancer, but the evidence is so far inconclusive. Thus, we aimed to investigate this association in a large individual patient data meta-analysis of randomised clinical trials.

Methods: We searched PubMed, MEDLINE, The Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from Jan 1, 1966, to Sept 1, 2019, to identify potentially eligible randomised controlled trials. Eligible studies were randomised controlled trials comparing one blood pressure lowering drug class with a placebo, inactive control, or other blood pressure lowering drug. We also required that trials had at least 1000 participant years of follow-up in each treatment group. Trials without cancer event information were excluded. We requested individual participant data from the authors of eligible trials. We pooled individual participant-level data from eligible trials and assessed the effects of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), β blockers, calcium channel blockers, and thiazide diuretics on cancer risk in one-stage individual participant data and network meta-analyses. Cause-specific fixed-effects Cox regression models, stratified by trial, were used to calculate hazard ratios (HRs). The primary outcome was any cancer event, defined as the first occurrence of any cancer diagnosed after randomisation. This study is registered with PROSPERO (CRD42018099283).

Findings: 33 trials met the inclusion criteria, and included 260 447 participants with 15 012 cancer events. Median follow-up of included participants was 4·2 years (IQR 3·0-5·0). In the individual participant data meta-analysis comparing each drug class with all other comparators, no associations were identified between any antihypertensive drug class and risk of any cancer (HR 0·99 [95% CI 0·95-1·04] for ACEIs; 0·96 [0·92-1·01] for ARBs; 0·98 [0·89-1·07] for β blockers; 1·01 [0·95-1·07] for thiazides), with the exception of calcium channel blockers (1·06 [1·01-1·11]). In the network meta-analysis comparing drug classes against placebo, we found no excess cancer risk with any drug class (HR 1·00 [95% CI 0·93-1·09] for ACEIs; 0·99 [0·92-1·06] for ARBs; 0·99 [0·89-1·11] for β blockers; 1·04 [0·96-1·13] for calcium channel blockers; 1·00 [0·90-1·10] for thiazides).

Interpretation: We found no consistent evidence that antihypertensive medication use had any effect on cancer risk. Although such findings are reassuring, evidence for some comparisons was insufficient to entirely rule out excess risk, in particular for calcium channel blockers.

Funding: British Heart Foundation, National Institute for Health Research, Oxford Martin School.
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http://dx.doi.org/10.1016/S1470-2045(21)00033-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024901PMC
April 2021

Sex Differences in Disease Profiles, Management, and Outcomes Among People with Atrial Fibrillation After Ischemic Stroke: Aggregated and Individual Participant Data Meta-Analyses.

Womens Health Rep (New Rochelle) 2020 30;1(1):190-202. Epub 2020 Jun 30.

Menzies Institute for Medical Research Tasmania, University of Tasmania, Hobart, Australia.

To examine sex differences in disease profiles, management, and survival at 1 and 5 years after ischemic stroke (IS) among people with atrial fibrillation (AF). We performed a systematic literature search of reports of AF at IS onset according to sex. We undertook an individual participant data meta-analysis (IPDMA) of nine population-based stroke incidence studies conducted in Australasia, Europe, and South America (1993-2014). Poisson regression was used to estimate women:men mortality rate ratios (MRRs). Study-specific MRRs were combined using random effects meta-analysis. In our meta-analysis based on aggregated data from 101 studies, the pooled AF prevalence was 23% (95% confidence interval [CI]: 22%-25%) in women and 17% (15%-18%) in men. Our IPDMA is of 1,862 IS-AF cases, with women (79.2 ± 9.1, years) being older than men (76.5 ± 9.5, years). Crude pooled mortality rate was greater for women than for men (1-year MRR 1.24; 1.01-1.51; 5-year 1.12; 1.03-1.22). However, the sex difference was greatly attenuated after accounting for age, prestroke function, and stroke severity (1-year 1.09; 0.97-1.22; 5-year 0.98; 0.84-1.16). Women were less likely to have anticoagulant prescription at discharge (odds ratio [OR] 0.94; 95% CI: 0.89-0.98) than men when pooling IPDMA and aggregated data. AF was more prevalent after IS among women than among men. Among IS-AF cases, women were less likely to receive anticoagulant agents at discharge; however, greater mortality rate in women was mostly attributable to prestroke factors. Further information needs to be collected in population-based studies to understand the reasons for lower treatment of AF in women.
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http://dx.doi.org/10.1089/whr.2020.0029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784810PMC
June 2020

Sex differences in risk factors for cognitive decline and dementia, including death as a competing risk, in individuals with diabetes: Results from the ADVANCE trial.

Diabetes Obes Metab 2021 Aug 4;23(8):1775-1785. Epub 2021 May 4.

The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.

Aim: To estimate the associations between risk factors and cognitive decline (CD)/dementia, and the sex differences in these risk factors in individuals with type 2 diabetes, while accounting for the competing risk of death.

Materials And Methods: The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial of 11,140 individuals with type 2 diabetes was used to estimate the odds of CD/dementia using multinomial logistic regression.

Results: During a median 5-year follow-up, 1827 participants (43.2% women) had CD/dementia (1718 with CD only; 21 with dementia only; 88 with CD and dementia), and 929 (31.0% women) died without CD/dementia. Women had lower odds of CD/dementia than men (odds ratio [OR] [95% confidence interval], 0.88 [0.77, 1.00]); older age, higher total cholesterol, HbA1c, waist circumference, waist-to-height ratio, moderately increased albumin-creatinine ratio, stroke/transient ischaemic attack and retinal disease were each associated with greater odds of CD/dementia; higher years at education completion, baseline cognitive function, taller stature and current alcohol use were inversely associated. Higher waist circumference (women-to-men ratio of ORs [ROR], 1.05 [1.00, 1.10] per 5 cm) and presence of anxiety/depression (ROR, 1.28 [1.01, 1.63]) were associated with greater ORs for CD/dementia in women than men.

Conclusions: Several risk factors were associated with CD/dementia. Higher waist circumference and mental health symptoms were more strongly associated with CD/dementia in women than men. Further studies should examine the mechanisms that underlie these sex differences.
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http://dx.doi.org/10.1111/dom.14391DOI Listing
August 2021

Oestradiol and the risk of myocardial infarction in women: a cohort study of UK Biobank participants.

Int J Epidemiol 2021 Jan 17. Epub 2021 Jan 17.

George Institute for Global Health, Department of Epidemiology and Biostatistics, Imperial College London, London, UK.

Background: It is commonly assumed that high oestradiol levels in women are cardioprotective. We assessed the association between oestradiol and the risk of incident myocardial infarction (MI) in women.

Methods: We used data from 263 295 female UK Biobank participants [mean age 56.2; standard deviation (SD) 8.0 years] without previous cardiovascular disease (CVD). Associations of oestradiol with age and other cardiovascular risk factors were assessed. Cox proportional hazards models estimated crude, ag- and multiple-adjusted hazard ratios (HR) for MI associated with oestradiol levels.

Results: After a mean follow-up of 9 years, 2206 incident cases of MI had been recorded, including 230 events among the 57 204 women (mean age 48) with detectable oestradiol levels. In the unadjusted analyses, a unit higher in log-transformed oestradiol was associated with an HR [95% confidence interval (CI) for MI of 0.73 (0.58; 0.92)]. After adjusting for age, this HR became 0.94 (0.75; 1.17), and after further adjusting for classical CVD risk factors, it was 1.05 (0.83; 1.31. Results were similar in subgroup analyses defined by age, menopausal status, socioeconomic status, contraceptive pill use and the use of hormone replacement therapy. The multivariable-adjusted HR for the 171 431 women (mean age 59) with undetectable levels of oestradiol, compared with those with detectable levels, was 0.97 (0.92; 1.02).

Conclusions: Higher levels of oestradiol were not associated with a decreased risk of MI. The presumed cardioprotective effects of oestradiol seem to be largely confounded by age and further confounded by other cardiovascular risk factors.
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http://dx.doi.org/10.1093/ije/dyaa284DOI Listing
January 2021

Risk for recurrent cardiovascular disease events among patients with diabetes and chronic kidney disease.

Cardiovasc Diabetol 2021 03 1;20(1):58. Epub 2021 Mar 1.

Department of Epidemiology, University of Alabama At Birmingham, 1665 University Blvd, RPHB 140J, Birmingham, AL, 35233-0013, USA.

Background: Adults who have experienced multiple cardiovascular disease (CVD) events have a very high risk for additional events. Diabetes and chronic kidney disease (CKD) are each associated with an increased risk for recurrent CVD events following a myocardial infarction (MI).

Methods: We compared the risk for recurrent CVD events among US adults with health insurance who were hospitalized for an MI between 2014 and 2017 and had (1) CVD prior to their MI but were free from diabetes or CKD (prior CVD), and those without CVD prior to their MI who had (2) diabetes only, (3) CKD only and (4) both diabetes and CKD. We followed patients from hospital discharge through December 31, 2018 for recurrent CVD events including coronary, stroke, and peripheral artery events.

Results: Among 162,730 patients, 55.2% had prior CVD, and 28.3%, 8.3%, and 8.2% had diabetes only, CKD only, and both diabetes and CKD, respectively. The rate for recurrent CVD events per 1000 person-years was 135 among patients with prior CVD and 110, 124 and 171 among those with diabetes only, CKD only and both diabetes and CKD, respectively. Compared to patients with prior CVD, the multivariable-adjusted hazard ratio for recurrent CVD events was 0.92 (95%CI 0.90-0.95), 0.89 (95%CI: 0.85-0.93), and 1.18 (95%CI: 1.14-1.22) among those with diabetes only, CKD only, and both diabetes and CKD, respectively.

Conclusion: Following MI, adults with both diabetes and CKD had a higher risk for recurrent CVD events compared to those with prior CVD without diabetes or CKD.
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http://dx.doi.org/10.1186/s12933-021-01247-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923492PMC
March 2021

The probability of receiving a kidney transplantation in end-stage kidney disease patients who are treated with haemodiafiltration or haemodialysis: a pooled individual participant data from four randomised controlled trials.

BMC Nephrol 2021 02 25;22(1):70. Epub 2021 Feb 25.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

Background: Due to a critical shortage of available kidney grafts, most patients with Stage 5 Chronic Kidney Disease (CKD5) require bridging dialysis support. It remains unclear whether treatment by different dialysis modalities changes the selection and/or preparation of a potential transplant candidate. Therefore, we assessed whether the likelihood of receiving kidney transplant (both living or deceased kidney donors) differs between haemodialysis (HD) and online haemodiafiltration (HDF) in patients with CKD5D.

Methods: Individual participant data from four randomised controlled trials comparing online HDF with HD were used. Information on kidney transplant was obtained during follow-up. The likelihood of receiving a kidney transplant was compared between HD and HDF, and evaluated across different subgroups: age, sex, diabetes, history of cardiovascular disease, albumin, dialysis vintage, fistula, and level of convection volume standardized to body surface area. Hazard ratios (HRs), with corresponding 95% confidence intervals (95% CI), comparing the effect of online HDF versus HD on the likelihood of receiving a kidney transplant, were estimated using Cox proportional hazards models with a random effect for study.

Results: After a median follow-up of 2.5 years (Q1 to Q3: 1.9-3.0), 331 of the 1620 (20.4%) patients with CKD5D received a kidney transplant. This concerned 22% (n = 179) of patients who were treated with online HDF compared with 19% (n = 152) of patients who were treated with HD. No differences in the likelihood of undergoing a kidney transplant were found between the two dialysis modalities in both the crude analyse (HR: 1.07, 95% CI: 0.86-1.33) and adjusted analysis for age, sex, diabetes, cardiovascular history, albumin, and creatinine (HR: 1.15, 95%-CI: 0.92-1.44). There was no evidence for a differential effect across subgroups based on patient- and disease-characteristics nor in different categories of convection volumes.

Conclusions: Treatment with HD and HDF does not affect the selection and/or preparation of CKD5D patients for kidney transplant given that the likelihood of receiving a kidney transplant does not differ between the dialysis modalities. These finding persisted across a variety of subgroups differing in patient and disease characteristics and is not affected by the level of convection volume delivered during HDF treatment sessions.
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http://dx.doi.org/10.1186/s12882-021-02265-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905891PMC
February 2021

Comparison of Circulating Biomarkers in Predicting Diabetic Kidney Disease Progression With Autoantibodies to Erythropoietin Receptor.

Kidney Int Rep 2021 Feb 10;6(2):284-295. Epub 2020 Nov 10.

Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan.

Introduction: Several circulating markers, including autoantibodies to erythropoietin receptor (anti-EPOR antibodies), have been identified as useful biomarkers in predicting diabetic kidney disease progression. However, a direct comparison of their utility is lacking. We aimed to validate and to compare the prognostic value of anti-EPOR antibodies with that of other known biomarkers, using the ADVANCE trial and its long-term follow-up, ADVANCE-ON, cohorts.

Methods: In this nested case-control study from the ADVANCE trial cohort, we included 165 case participants who had the composite kidney outcome (renal replacement therapy, renal death, or doubling of serum creatinine to ≥200 μmol/l) and 330 matched controls. We compared the associations of baseline plasma levels of anti-EPOR antibodies, tumor necrosis factor receptor (TNFR)-1 and -2, and bone morphogenetic protein (BMP)-7 with kidney outcomes.

Results: Cases had higher baseline plasma levels of anti-EPOR antibodies than controls (median 1.7 vs. 0.6 enzyme-linked immunosorbent assay unit,  < 0.001). Higher levels of anti-EPOR antibodies were associated with an increased risk of kidney outcome (odds ratio 2.16 [95% confidence interval 1.51, 3.08], per 1 SD of log-transformed levels) after adjusting for conventional markers. Elevated circulating TNFR1 and TNFR2 levels, and lower BMP-7 levels at baseline, were associated with poor kidney outcome (odds ratios 2.06 [1.29, 3.30], 1.66 [1.13, 2.43], and 0.45 [0.32, 0.65], respectively). The addition of anti-EPOR antibodies into the model improved the prediction of kidney outcome, regardless of other biomarkers.

Conclusion: Anti-EPOR antibodies provide a promising biomarker, as with TNFR1, TNFR2, and BMP-7, in predicting kidney disease progression in people with type 2 diabetes mellitus.
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http://dx.doi.org/10.1016/j.ekir.2020.10.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879109PMC
February 2021

Variability in estimated glomerular filtration rate and the risk of major clinical outcomes in diabetes: Post hoc analysis from the ADVANCE trial.

Diabetes Obes Metab 2021 06 4;23(6):1420-1425. Epub 2021 Mar 4.

The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.

There are limited data on whether estimated glomerular filtration rate (eGFR) variability modifies the risk of future clinical outcomes in type 2 diabetes (T2D). We assessed the association between 20-month eGFR variability and the risk of major clinical outcomes in T2D among 8241 participants in the ADVANCE trial. Variability in eGFR (coefficient of variation [CV ]) was calculated from three serum creatinine measurements over 20 months. Participants were classified into three groups by thirds of CV : low (≤6.4; reference), moderate (>6.4 to ≤12.1) and high (>12.1). The primary outcome was the composite of major macrovascular events, new or worsening nephropathy and all-cause mortality. Cox regression models were used to estimate hazard ratios (HRs). Over a median follow-up of 2.9 years following the 20-month period, 932 (11.3%) primary outcomes were recorded. Compared with low variability, greater 20-month eGFR variability was independently associated with higher risk of the primary outcome (HR for moderate and high variability: 1.07, 95% CI: 0.91-1.27 and 1.22, 95% CI: 1.03-1.45, respectively) with evidence of a positive linear trend (p = .015). These data indicate that eGFR variability predict changes in the risk of major clinical outcomes in T2D.
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http://dx.doi.org/10.1111/dom.14351DOI Listing
June 2021

Sex differences in treatment, radiological features and outcome after intracerebral haemorrhage: Pooled analysis of Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage trials 1 and 2.

Eur Stroke J 2020 Dec 20;5(4):345-350. Epub 2020 Sep 20.

The George Institute for Global Health, University of New South Wales, Sydney, Australia.

Introduction: Reports vary on how sex influences the management and outcome from acute intracerebral haemorrhage. We aimed to quantify sex disparities in clinical characteristics, management, including response to blood pressure lowering treatment, and outcomes in patients with acute intracerebral haemorrhage, through interrogation of two large clinical trial databases.

Patients And Methods: Post-hoc pooled analysis of the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage trials 1 and 2, where patients with a hypertensive response (systolic, 150-220 mmHg) after spontaneous intracerebral haemorrhage (<6 h) were randomised to intensive (target <140 mmHg <1 h) or guideline-recommended (<180 mmHg) blood pressure lowering treatment. The interaction of sex on early haematoma growth (24 h), death or major disability (modified Rankin scale scores 3-6 at 90 days), and effect of randomised treatment were determined in multivariable logistic regression models adjusted for baseline confounding variables.

Results: In 3233 participants, 1191 (37%) were women who were significantly older, had higher baseline National Institutes of Health Stroke Scale scores and smaller haematoma volumes compared to men. Men had higher three-month mortality (odds ratio 1.48, 95% confidence interval 1.10-2.00); however, there was no difference between women and men in the combined endpoint of death or major disability. There were no significant sex differences on mean haematoma growth or effect of randomised blood pressure lowering treatment.

Discussion: Men included in the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage trials had more comorbidities, larger baseline haematoma volumes and higher mortality after adjustment for age, as compared with women.

Conclusion: Men included in the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage trials had a greater odds of dying after intracerebral haemorrhage than women, which could not be readily explained by differing casemix or patterns of blood pressure management.

Clinical Trial Registration: The Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage trials studies are registered with ClinicalTrials.gov (NCT00226096 and NCT00716079).
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http://dx.doi.org/10.1177/2396987320957513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856581PMC
December 2020