Compliance-Adjusted Estimates of Aspirin Effects Among Older Persons in the ASPREE Randomized Trial.

The Aspirin in Reducing Events in the Elderly (ASPREE) Trial recruited 19,114 participants across Australia and the United States during 2010-2014. Participants were randomized to receive either 100 mg of aspirin daily or matching placebo, with disability-free survival as the primary outcome. During a median 4.7 years of follow-up, 37% of participants in the aspirin group permanently ceased taking their study medication and 10% commenced open-label aspirin use. In the placebo group, 35% and 11% ceased using study medication and commenced open-label aspirin use, respectively. In order to estimate compliance-adjusted effects of aspirin, we applied rank-preserving structural failure time models. The results for disability-free survival and most secondary endpoints were similar in intention-to-treat and compliance-adjusted analyses. For major hemorrhage, cancer mortality, and all-cause mortality, compliance-adjusted effects of aspirin indicated greater risks than were seen in intention-to-treat analyses. These findings were robust in a range of sensitivity analyses. In accordance with the original trial analyses, compliance-adjusted results showed an absence of benefit with aspirin for primary prevention in older people, along with an elevated risk of clinically significant bleeding.

Self-Reported Early and Later Life Weight and the Risk of All-Cause Mortality in Older Adults.

OBJECTIVES: The extent to which body weight in early adulthood is associated with late-life mortality risk is unclear. This study aimed to determine the association between body mass index (BMI) in early adulthood (at 18 years of age) and older age (70 years and over), and the risk of mortality in later life. DESIGN: Secondary analysis of the ASPREE Longitudinal Study of Older Persons (ALSOP). SETTING, PARTICIPANTS: Data were from 14,853 relatively healthy community-dwelling Australians aged ≥ 70 years when enrolled in the study. MEASUREMENTS: Self-reported weight at age ≥ 70 years and recalled weight at age 18 years were collected at ALSOP study baseline. Height was measured with a stadiometer and was used for calculation of BMI at both timepoints. BMI at each timepoint was defined as: underweight, normal weight, overweight and obese. Individuals were categorised into one of five 'lifetime' BMI groups: normal weight (BMI between 18.5 and 24.9 at both times), overweight (25.0-29.9 at either or both times), obesity to non-obese (≥30.0 at age 18 and <30.0 ≥ 70 years), non-obese to obesity (<30.0 at age 18 and ≥30.0 at age ≥ 70 years), and early and later life obesity (≥30.0 at both times). RESULTS: During a median 4.7 years follow-up, 715 deaths occurred. Obesity at 18 years, but not in older age (p=0.44), was significantly associated with the risk of mortality in later life, even after accounting for current health status (HR: 2.35, 95% CI: 1.53-3.58, p<0.001). Compared with participants with normal BMI at both time points, being obese at both time points was associated with increased mortality risk (HR=1.99, 95% CI: 1.04-3.81, p=0.03), and the risk was even greater for individuals who were obese at 18 years but were no longer obese in older age (HR=2.92, 95% CI: 1.65-5.16, p<0.001), in fully adjusted models. Participants who were normal weight at 18 years and were obese in later life, did not have an increased mortality risk (p=0.78). CONCLUSIONS: Obesity in early adulthood, and obesity in both early and later life, were associated with increased mortality risk in later life. This highlights the importance of preventing obesity in early adulthood and maintaining a normal weight over an adult lifespan.

Content and delivery preferences for information to support the management of high blood pressure.

Blood pressure(BP) management interventions have been shown to be more effective when accompanied by appropriate patient education. As high BP remains poorly controlled, there may be gaps in patient knowledge and education. Therefore, this study aimed to identify specific content and delivery preferences for information to support BP management among Australian adults from the general public. Given that BP management is predominantly undertaken by general practitioners(GPs), information preferences to support BP management were also ascertained from a small sample of Australian GPs. An online survey of adults was conducted to identify areas of concern for BP management to inform content preferences and preferred format for information delivery. A separate online survey was also delivered to GPs to determine preferred information sources to support BP management. Participants were recruited via social media. General public participants (n = 465) were mostly female (68%), >60 years (57%) and 49% were taking BP-lowering medications. The management of BP without medications, and role of lifestyle in BP management were of concern among 30% and 26% of adults respectively. Most adults (73%) preferred to access BP management information from their GP. 57% of GPs (total n = 23) preferred information for supporting BP management to be delivered via one-page summaries. This study identified that Australian adults would prefer more information about the management of BP without medications and via lifestyle delivered by their GP. This could be achieved by providing GPs with one-page summaries on relevant topics to support patient education and ultimately improve BP management.

Mechanisms and Points of Control in the Spread of Inflammation: A Mathematical Investigation.

Understanding the mechanisms that control the body's response to inflammation is of key importance, due to its involvement in myriad medical conditions, including cancer, arthritis, Alzheimer's disease and asthma. While resolving inflammation has historically been considered a passive process, since the turn of the century the hunt for novel therapeutic interventions has begun to focus upon active manipulation of constituent mechanisms, particularly involving the roles of apoptosing neutrophils, phagocytosing macrophages and anti-inflammatory mediators. Moreover, there is growing interest in how inflammatory damage can spread spatially due to the motility of inflammatory mediators and immune cells. For example, impaired neutrophil chemotaxis is implicated in causing chronic inflammation under trauma and in ageing, while neutrophil migration is an attractive therapeutic target in ailments such as chronic obstructive pulmonary disease. We extend an existing homogeneous model that captures interactions between inflammatory mediators, neutrophils and macrophages to incorporate spatial behaviour. Through bifurcation analysis and numerical simulation, we show that spatially inhomogeneous outcomes can present close to the switch from bistability to guaranteed resolution in the corresponding homogeneous model. Finally, we show how aberrant spatial mechanisms can play a role in the failure of inflammation to resolve and discuss our results within the broader context of seeking novel inflammatory treatments.

Effectiveness of a shared team approach between nurses and doctors for improved risk factor management in survivors of stroke: a cluster randomized controlled trial.

BACKGROUND AND PURPOSE: Limited evidence exists on the benefits of organized care for improving risk factor control in patients with stroke or transient ischaemic attack. The effectiveness of an individualized management programme in reducing absolute cardiovascular disease risk in this high-risk population was determined. METHODS: This was a prospective, multicentre, cluster-randomized controlled trial with blinded assessment of outcomes and intention-to-treat analysis. Patients hospitalized for stroke/transient ischaemic attack and aged ≥18 years were recruited from four hospitals. General practices treating recruited patients were randomized to provide either usual care or an individualized management programme comprising nurse-led education and review of care plans by stroke specialists in addition to usual care. The primary outcome was a change in cardiovascular Framingham Risk Score between baseline and 12 months. RESULTS: From January 2010 to November 2013, 156 general practices (280 patients) were randomly assigned to usual care (control) and 159 (283 patients) to the intervention. The median age was 70.1 years; 65% were male. Overall, >80% of participants were prescribed recommended secondary prevention therapies at baseline. The primary efficacy analysis comprised 533 participants, with 30 either dying or lost to follow-up. In adjusted analyses, no significant between-group difference was found in the cardiovascular risk score at 12 months (0.04, 95% confidence interval -1.7, 1.8). CONCLUSIONS: The effectiveness of an organized secondary prevention programme for stroke may be limited in patients from high-performing hospitals with regular post-discharge follow-up and communication with general practices.

ASPREE-D: Aspirin for the prevention of depression in the elderly.

BACKGROUND: Not only is depression associated with increased inflammation but inflammation is a risk factor for the genesis of depression. Many of the environmental risk factors for depression are transduced through inflammatory signaling. Anti-inflammatory agents show promise for the management of depression in preclinical, epidemiological, and early clinical studies. This opens the door to the potential for anti-inflammatory agents to treat and prevent depression. There are no evidence-based pharmacotherapies for depression prevention. METHOD: ASPREE-D, aspirin in the prevention of depression in the elderly, is a sub study of ASPREE, which explores the potential of aspirin to prevent a range of inflammation related disorders in the elderly. With a sample size of 19,114, and a duration of 5 years, this placebo controlled study will be one of the largest randomized controlled trials in psychiatry and will provide definitive evidence on the ability of aspirin to prevent depression. RESULTS: This paper presents the rationale for the study and presents a summary of the study design. CONCLUSIONS: ASPREE-D may not only define novel therapy but will provide mechanistic proof of concept of the role of inflammation in depression.

Comprehensive genome-wide evaluation of lapatinib-induced liver injury yields a single genetic signal centered on known risk allele HLA-DRB1*07:01.

Lapatinib is associated with a low incidence of serious liver injury. Previous investigations have identified and confirmed the Class II allele HLA-DRB1*07:01 to be strongly associated with lapatinib-induced liver injury; however, the moderate positive predictive value limits its clinical utility. To assess whether additional genetic variants located within the major histocompatibility complex locus or elsewhere in the genome may influence lapatinib-induced liver injury risk, and potentially lead to a genetic association with improved predictive qualities, we have taken two approaches: a genome-wide association study and a whole-genome sequencing study. This evaluation did not reveal additional associations other than the previously identified association for HLA-DRB1*07:01. The present study represents the most comprehensive genetic evaluation of drug-induced liver injury (DILI) or hypersensitivity, and suggests that investigation of possible human leukocyte antigen associations with DILI and other hypersensitivities represents an important first step in understanding the mechanism of these events.

Slowing the progression of age-related hearing loss: Rationale and study design of the ASPIRIN in HEARING, retinal vessels imaging and neurocognition in older generations (ASPREE-HEARING) trial.

BACKGROUND: Age-related hearing loss (ARHL) is a leading cause of disability in the elderly. Low-grade inflammation and microvessel pathology may be responsible for initiating or exacerbating some of the hearing loss associated with aging. A growing body of evidence demonstrates an association of hearing loss with cognitive decline. A shared etiological pathway may include a role of inflammation, alongside vascular determinants. The ASPREE-HEARING study aims to determine whether low-dose aspirin decreases the progression of ARHL, and if so, whether this decrease in progression is also associated with retinal microvascular changes and/or greater preservation of cognitive function. DESIGN AND METHODS: A three year double-blind, randomized controlled trial of oral 100mg enteric-coated aspirin or matching placebo, enrolling 1262 Australians aged ≥70years with normal cognitive function and no overt cardiovascular disease. The primary outcome is the change in mean pure tone average hearing threshold (decibels) in the better ear, over a 3-year period. Secondary outcomes consist of changes in retinal microvascular indicators, and changes in cognitive function. Participants are recruited from a larger trial, ASPirin in Reducing Events in the Elderly (ASPREE), which is designed to assess whether daily low dose aspirin will extend disability-free life. DISCUSSION: ASPREE-HEARING will determine whether aspirin slows development or progression of ARHL, and will interrogate the relationship between inflammatory and microvascular mechanisms that may underlie the effects of aspirin on ARHL. This study will improve understanding of the patterns of comorbidity with, and the relationships between, aging and ARHL, alongside modeling the impacts of ARHL.