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Objective: Both grip strength and gait speed can be used as markers of muscle function, however, no previous study has examined them in the same population with respect to risk of falls. Methods: In this prospective cohort study, utilising data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial and ASPREE-Fracture substudy, we analysed the association of grip strength and gait speed and serious falls in healthy older adults. Grip strength was measured using a handheld dynamometer and gait speed from 3-metre timed walks. Serious falls were confined to those involving hospital presentation. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for associations with falls. Results: Over an average of 4.0±1.3 years, amongst 16,445 participants, 1,533 had at least one serious fall. After adjustment for age, sex, physical activity, body mass index, Short Form 12 (state of health), chronic kidney disease, polypharmacy and aspirin, each standard deviation (SD) lower grip strength was associated with 27% (HR 1.27, 95% CI 1.17–1.38) higher risk of falls. The results remained the same for males and females. There was a dose-response relationship in the association between grip strength and falls risk. The higher risk of falls was observed in males in all body mass index (BMI) categories, but only in obese females. The association between gait speed and falls risk was weaker than the association between grip strength and falls risk. Conclusions: All males and only obese females with low grip strength appear to be at the greatest risk of serious falls. These findings may assist in early identification of falls. [ABSTRACT FROM AUTHOR]

Background: ASPirin in Reducing Events in the Elderly, a randomized, double-blind, placebo-controlled trial of daily low-dose aspirin (100 mg) in older adults, showed an increase in all-cause mortality, primarily due to cancer. In contrast, prior randomized controlled trials, mainly involving younger individuals, demonstrated a delayed cancer benefit with aspirin. We now report a detailed analysis of cancer incidence and mortality.Methods: 19 114 Australian and US community-dwelling participants aged 70 years and older (US minorities 65 years and older) without cardiovascular disease, dementia, or physical disability were randomly assigned and followed for a median of 4.7 years. Fatal and nonfatal cancer events, a prespecified secondary endpoint, were adjudicated based on clinical records.Results: 981 cancer events occurred in the aspirin and 952 in the placebo groups. There was no statistically significant difference between groups for all incident cancers (hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 0.95 to 1.14), hematological cancer (HR = 0.98, 95% CI = 0.73 to 1.30), or all solid cancers (HR = 1.05, 95% CI = 0.95 to 1.15), including by specific tumor type. However, aspirin was associated with an increased risk of incident cancer that had metastasized (HR = 1.19, 95% CI = 1.00 to 1.43) or was stage 4 at diagnosis (HR = 1.22, 95% CI = 1.02 to 1.45), and with higher risk of death for cancers that presented at stages 3 (HR = 2.11, 95% CI = 1.03 to 4.33) or 4 (HR = 1.31, 95% CI = 1.04 to 1.64).Conclusions: In older adults, aspirin treatment had an adverse effect on later stages of cancer evolution. These findings suggest that in older persons, aspirin may accelerate the progression of cancer and, thus, suggest caution with its use in this age group. [ABSTRACT FROM AUTHOR]

Background: There are no primary prevention trials of aspirin with relevant geriatric outcomes in elderly people. ASPirin in Reducing Events in the Elderly (ASPREE) is a placebo-controlled trial of low-dose aspirin that will determine whether 5 years of daily 100-mg enteric-coated aspirin extends disability-free and dementia-free life in a healthy elderly population and whether these benefits outweigh the risks.Methods: Set in primary care, this randomized double-blind placebo-controlled trial has a composite primary endpoint of death, incident dementia or persistent physical disability. Participants aged 70+ years (non-minorities) or 65+ years (U.S. minorities) were free of cardiovascular disease, dementia, or physical disability and without a contraindication to, or indication for, aspirin. Baseline data include physical and lifestyle, personal and family medical history, hemoglobin, fasting glucose, creatinine, lipid panel, urinary albumin:creatinine ratio, cognition (3MS, HVLT-R, COWAT, SDMT), mood (CES-D-10), physical function (gait speed, grip strength), Katz activities of daily living and quality of life (SF-12).Results: Recruitment ended in December 2014 with 16,703 Australian and 2,411 U.S. participants, a median age of 74 (range 65-98) years and 56% women. Approximately 55% of the U.S. cohort were from minority groups; 9% of the total cohort. Proportions with hypertension, overweight, and chronic kidney disease were similar to age-matched populations from both countries although lower percentages had diabetes, dyslipidemia, and osteoarthritis.Discussion: Findings from ASPREE will be generalizable to a healthier older population in both countries and will assess whether the broad benefits of daily low-dose aspirin in prolonging independent life outweigh the risks. [ABSTRACT FROM AUTHOR]

Background: We aimed to describe the self‐reported level of eyesight amongst a cohort of relatively healthy older Australian adults, and to investigate associations between poorer self‐rated eyesight and demographic, health, and functional characteristics Methods: The ASPirin in Reducing Events in the Elderly (ASPREE) Longitudinal Study of Older Persons (ALSOP) study was embedded in a multisite trial which recruited independently living Australians from general practices (2010–2014). Self‐rated eyesight was recorded on a paper‐based questionnaire as Excellent, Good, Fair, Poor, Very poor, or Completely blind at the baseline study wave Results: Data from 14 592 participants (aged 70–95 years, 54.61% female) were included in this cross‐sectional analysis. Eighty percent of participants reported excellent or good eyesight (n = 11 677). People with complete blindness were precluded from enrolling but 299 participants (2.0%) reported poor or very poor eyesight, and 2616 rated their eyesight as fair (17.9%). Lower levels of eyesight were associated with being older, female, fewer years of formal education, a primary language other than English, smoking, and self‐reported macular degeneration, glaucoma, retinopathy, cataracts, and hearing problems (each p ≤ 0.021). People with lower levels of eyesight had a higher number of falls, frailty characteristics, and depressive symptoms, and lower mental and physical health functioning scores (each p < 0.001) Conclusions: Whilst most of these healthy older Australians reported good or excellent eyesight, a notable minority reported poor or very poor eyesight, and this was associated with a range of poorer health measures. These findings support the need for additional resources to prevent vision loss and associated sequelae [ABSTRACT FROM AUTHOR]

Background Development of chronic disease risk prediction models has become a growing area of research in recent years. The internal validity of such models is sometimes lower than estimated from the development sample. Overfitting or overoptimism of the developed model and/or differences between the samples are likely causes for this. For modelling of an uncommon outcome, bootstrapping for overoptimism is the preferred method for afterwards shrinking of regression coefficients and the model's discrimination and calibration for overoptimism. However, computer programs for different types of bootstrap validation are not readily available. We developed two SAS macro programs - one for the simple bootstrap that compares the discriminatory performance of the Cox proportional hazards model from the original sample in bootstrap samples; and another (which is more efficient), known as stepwise bootstrap validation, that makes the same comparison but from models developed by variable selection from bootstrap samples in the original sample. These are illustrated through an example from cardiovascular disease (CVD) risk prediction. Methods Two SAS macro programs for Cox proportional hazards model using Proc PHREG were developed for estimating overoptimism in Harrell's C and Somers' D statistics. The computer programs were applied to data on CVD incidence for a Framingham cohort that combined both the original and offspring exams. The risk factors considered were current smoking, diabetes, age, sex, systolic blood pressure, diastolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, triglycerides and body mass index. Results The degree of overoptimism in both Harrell's C and Somers' D statistics were low. Both these statistics were corrected for overoptimism by subtracting overoptimism from their observed values. Between the two bootstrap validation algorithms, the degree of overoptimism was estimated to be higher for stepwise bootstrap validation. Conclusion The programs are very useful for evaluating the 'overoptimism corrected' predictive performance of Cox proportional hazards model. [ABSTRACT FROM AUTHOR]

Abstract: Objective: At the time of licensing by regulatory agencies, the full range of risks and possible adverse drug reactions associated with a medication is rarely fully realized. This commentary aims to describe the role of registries as useful components of postmarketing pharmacovigilance systems for monitoring highly specialized medications associated with significant financial costs. Study Design and Setting: We consider the limitations of traditional pharmacovigilance programs and discuss the strengths, limitations, and uses of registries in postmarketing pharmacovigilance systems. Results: Registries have become increasingly appealing in postmarketing surveillance of medications; however, their exact role continues to evolve. Key registry projects, including the Prospective Immunogenicity Surveillance Registry, British Society for Rheumatology Biologics Register, Australian Rheumatology Association Database, the Haemostasis Registry, and the Bosentan Patient Registry highlight the value of registries for monitoring the incidence of rare adverse events. Conclusion: Although often limited by lack of a control group and the need for complete case ascertainment to maintain data integrity, registries are a useful component of postmarketing pharmacovigilance systems for monitoring highly specialized medications associated with significant financial costs. [Copyright &y& Elsevier]

In the past, postmarketing surveillance of drugs relied mainly on the spontaneous reporting of adverse drug reactions. There are now several other approaches used, including databases with individual prescription data (or prescription event monitoring systems), electronic health records and record linkage between health databases. The recent drug withdrawals have continued to highlight the inadequacies of current postmarketing surveillance and the need for better strategies to monitor the safety of new drugs. One such strategy is the use of drug registries. Drug registries facilitate a special form of prospective observational cohort study of patients exposed to a particular drug. They are particularly useful in establishing the safety of orphan drugs and ascertaining the safety of drugs in specific populations. To minimize bias, patient eligibility is defined and data capture is standardized. All patients are followed up systematically over a pre-defined time period, either manually or using electronic record linkage to other health databases. To establish the incidence of any adverse events using a drug registry, there should be complete follow-up of all patients. Drug registries may play an important role in postmarketing surveillance of new drugs. Unlike spontaneous reporting systems they have the benefit of being able to determine the incidence of one or more outcomes in the patient population. Drug registries do, however, have some limitations, including a potential for bias and confounding, long periods of follow-up and high cost. [ABSTRACT FROM AUTHOR]

Objective To investigate workforce participation patterns among Australian medical graduates and the extent of cohort differences in these patterns. Design We carried out a retrospective longitudinal cohort study, with data collected by postal survey on current occupation, location, absences from the workforce and occupation since graduation. Participants Graduates who had completed their basic medical training at Monash University, Melbourne, Australia, in 1980, 1985, 1990 and 1995 were invited to participate ( n = 546); 368 took part in the study (69%). Outcome measures The proportion of graduates in the Australian medical workforce, the equivalent full-time contribution to the Australian medical workforce, and the proportion taking temporary absences from the workforce were determined. Results The rate of participation in the Australian medical workforce was 96% 2 years after graduation. It then declined to reach 85% by 10 years and regained slightly to reach 88% by 15 years after graduation. There was no indication that the 1995 cohort made a lower contribution to the Australian medical workforce than the earlier cohorts in their first 7 years after graduation. Conclusion Although there are few indications of differences between these cohorts during the first 7 years after graduation, the main contributing factors to losses from the Australian medical workforce – medical work overseas and parental leave – do not exert their maximum influence until a later timepoint. Longitudinal cohort data are essential for monitoring trends in medical workforce participation and hence for effective workforce planning. [ABSTRACT FROM AUTHOR]

: ObjectiveTo determine whether treatment with vitamin E (500 IU daily) reduces either the incidence or rate of progression of age-related cataracts.: DesignA prospective, randomized, double-masked, placebo-controlled clinical trial entitled the Vitamin E, Cataract and Age-Related Maculopathy Trial.: ParticipantsOf 1906 screened volunteers, 1193 eligible subjects with early or no cataract, aged 55 to 80 years, were enrolled and followed up for 4 years.: InterventionSubjects were assigned randomly to receive either 500 IU of natural vitamin E in soybean oil encapsulated in gelatin or a placebo with an identical appearance.: Main outcome measuresThe incidence and progression rates of age-related cataract were assessed annually with both clinical lens opacity gradings and computerized analysis of Scheimpflug and retroillumination digital lens images obtained with a Nidek EAS-1000 lens camera. The analysis was undertaken using data from the eye with the more advanced opacity for each type of cataract separately and for any cataract changes in each individual.: ResultsOverall, 87% of the study population completed the 4 years of follow-up, with 74% of the vitamin E group and 76% of the placebo group continuing on their randomized treatment allocation throughout this time. For cortical cataract, the 4-year cumulative incidence rate was 4.5% among those randomized to vitamin E and 4.8% among those randomized to placebo (P = 0.87). For nuclear cataract, the corresponding rates were 12.9% and 12.1% (P = 0.77). For posterior subcapsular cataract, the rates were 1.7% and 3.5% (P = 0.08), whereas for any of these forms of cataract, they were 17.1% and 16.7%, respectively. Progression of cortical cataract was seen in 16.7% of the vitamin E group and 18.4% of the placebo group (P = 0.76). Corresponding rates for nuclear cataract were 11.4% and 11.9% (P = 0.84), whereas those of any cataract were 16.5% and 16.7%, respectively. There was no difference in the rate of cataract extraction between the 2 groups (P = 0.87). Lens characteristics of the participants withdrawn from the randomized medications were not different from those who continued.: ConclusionsVitamin E given for 4 years at a dose of 500 IU daily did not reduce the incidence of or progression of nuclear, cortical, or posterior subcapsular cataracts. These findings do not support the use of vitamin E to prevent the development or to slow the progression of age-related cataracts. [Copyright &y& Elsevier]

As thyroid disorders are common amongst the elderly, this study aims to evaluate the reference interval (RI) for thyroid stimulating hormone (TSH) in healthy adults aged 70 years and over.A proposed RI was determined from the Australian participants of the ASPirin in Reducing Events in the Elderly (ASPREE) randomised trial. Participants had no history of cardiovascular disease, thyroid cancer, dementia, or life-threatening illnesses. Participants prescribed with any thyroid-related medication at baseline were excluded. TSH levels were measured using a commercial chemiluminescence microparticle immunoassay. The RI was determined using the middle 95th percentile of the logarithmic transformed data of baseline TSH. Cox proportional hazard regression models were used to validate the RI by assessing disease incidence over time.A total of 10,995 participants had baseline TSH measures. Median (IQR) age was 73.9 (71.8–77.3) years. We propose a RI of 0.34–3.75 mU/L. TSH levels did not differ by age or sex. At baseline, there was no association between symptoms associated with thyroid disease and levels of TSH. Over the follow-up period of up to 11 years, no association was seen between baseline TSH levels and relevant disease outcomes for participants within the RI.From a group of initially healthy, community-dwelling adults aged >=70 years, we propose a RI of TSH to best represent euthyroidism. This concentration was not associated with an increased risk of thyroid related symptoms or outcomes, confirming its appropriateness for clinical use. [ABSTRACT FROM AUTHOR]

A recent genome-wide association study of age-related macular degeneration (AMD) identified new AMD-associated risk variants. These variants now can be incorporated into an updated polygenic risk score (PRS). This study aimed to assess the performance of an updated PRS, PRS2023, in an independent cohort of older individuals with retinal imaging data and to compare performance with an older PRS, PRS2016. Cross-sectional study. A total of 4175 participants of European ancestry, 70 years of age or older, with genotype and retinal imaging data. We used logistic regression models and area under the receiver operating characteristic curve (AUC) to assess the performance of PRS2023 compared with PRS2016. AMD status and severity were graded using color fundus photography. Association of PRS2023 and PRS2016 with AMD risk at baseline. At enrollment among 4175 participants, 2605 participants (62.4%) had no AMD and 853 participants (20.4%), 671 participants (16.1%), and 46 participants (1.1%) had early, intermediate, and late-stage AMD, respectively. More than 27% of the participants with a high PRS2023 (top quartile) had intermediate or late-stage AMD, compared with < 15% for those in the middle 2 quartiles and less than 13% for those in the lowest quartile. Both PRS2023 and PRS2016 were associated significantly with AMD after adjustment for age, sex, smoking status, and lipid levels, with increasing odds ratios (ORs) for worsening AMD grades. PRS2023 outperformed PRS2016 (P = 0.03 for all AMD and P = 0.03 for late AMD, DeLong test comparing AUC). PRS2023 was associated with late-stage AMD with an adjusted OR of 5.05 (95% confidence interval [CI], 3.41–7.47) per standard deviation. The AUC of a model containing conventional or nongenetic risk factors and PRS2023 was 91% (95% CI, 87%–95%) for predicting late-stage AMD, which improved 12% over the model without the PRS (AUC, 79%; P < 0.001 for difference). A new PRS, PRS2023, for AMD outperforms a previous PRS and predicts increasing risk for late-stage AMD (with stronger association for more severe imaging-confirmed AMD grades). Our findings have clinical implications for the improved prediction and risk stratification of AMD. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

Background: In randomized clinical trials, treatment effects may vary, and this possibility is referred to as heterogeneity of treatment effect (HTE). One way to quantify HTE is to partition participants into subgroups based on individual's risk of experiencing an outcome, then measuring treatment effect by subgroup. Given the limited availability of externally validated outcome risk prediction models, internal models (created using the same dataset in which heterogeneity of treatment analyses also will be performed) are commonly developed for subgroup identification. We aim to compare different methods for generating internally developed outcome risk prediction models for subject partitioning in HTE analysis. Methods: Three approaches were selected for generating subgroups for the 2,441 participants from the United States enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) randomized controlled trial. An extant proportional hazards-based outcomes predictive risk model developed on the overall ASPREE cohort of 19,114 participants was identified and was used to partition United States' participants by risk of experiencing a composite outcome of death, dementia, or persistent physical disability. Next, two supervised non-parametric machine learning outcome classifiers, decision trees and random forests, were used to develop multivariable risk prediction models and partition participants into subgroups with varied risks of experiencing the composite outcome. Then, we assessed how the partitioning from the proportional hazard model compared to those generated by the machine learning models in an HTE analysis of the 5-year absolute risk reduction (ARR) and hazard ratio for aspirin vs. placebo in each subgroup. Cochran's Q test was used to detect if ARR varied significantly by subgroup. Results: The proportional hazard model was used to generate 5 subgroups using the quintiles of the estimated risk scores; the decision tree model was used to generate 6 subgroups (6 automatically determined tree leaves); and the random forest model was used to generate 5 subgroups using the quintiles of the prediction probability as risk scores. Using the semi-parametric proportional hazards model, the ARR at 5 years was 15.1% (95% CI 4.0–26.3%) for participants with the highest 20% of predicted risk. Using the random forest model, the ARR at 5 years was 13.7% (95% CI 3.1–24.4%) for participants with the highest 20% of predicted risk. The highest outcome risk group in the decision tree model also exhibited a risk reduction, but the confidence interval was wider (5-year ARR = 17.0%, 95% CI= -5.4–39.4%). Cochran's Q test indicated ARR varied significantly only by subgroups created using the proportional hazards model. The hazard ratio for aspirin vs. placebo therapy did not significantly vary by subgroup in any of the models. The highest risk groups for the proportional hazards model and random forest model contained 230 participants each, while the highest risk group in the decision tree model contained 41 participants. Conclusions: The choice of technique for internally developed models for outcome risk subgroups influences HTE analyses. The rationale for the use of a particular subgroup determination model in HTE analyses needs to be explicitly defined based on desired levels of explainability (with features importance), uncertainty of prediction, chances of overfitting, and assumptions regarding the underlying data structure. Replication of these analyses using data from other mid-size clinical trials may help to establish guidance for selecting an outcomes risk prediction modelling technique for HTE analyses. [ABSTRACT FROM AUTHOR]

Examines the risk factors for the development of flucloxacillin associated with jaundice. Influence of prolong duration of flucloxacillin treatment in the development of jaundice; Consideration of risk-benefit ratio; Detection of liver damage due to flucloxacillin.

A correction is presented to the article "Baseline Characteristics of Participants in the ASPREE (Aspirin in Reducing Events in the Elderly) Study", which appeared in an earlier issue.

Background: This study examined the associations of body mass index (BMI) and waist circumference (WC), as well as their short‐ and long‐term changes over time, with incident dementia in older individuals. Methods: Data came from 18,837 community‐dwelling individuals aged 65+ years from Australia and the United States, who were relatively healthy without major cognitive impairment at enrolment. Anthropometric measures were prospectively assessed at baseline, as well as change and variability from baseline to year two (three time‐points). In a subgroup (n = 11,176), self‐reported weight at age 18 and 70+ years was investigated. Dementia cases satisfied DSM‐IV criteria. Cox regression was used to examine the associations between anthropometric measures and incident risk of dementia. Results: Compared to normal weight, an overweight (HR: 0.67, 95%CI: 0.57–0.79, p < 0.001) or obese BMI (HR: 0.73, 95%CI: 0.60–0.89, p = 0.002), or a larger WC (elevated, HR: 0.71, 95%CI: 0.58–0.86, p < 0.001; highly elevated, HR: 0.65, 95%CI: 0.55–0.78, p < 0.001; relative to low) at baseline was associated with lower dementia risk. In contrast, substantial increases in BMI (>5%) over 2 years after baseline were associated with higher dementia risk (HR: 1.49, 95% CI: 1.17–1.91, p = 0.001). Increased dementia risk was also seen with an underweight BMI at baseline and a 2‐year BMI decrease (>5%), but these associations appeared only in the first 4 years of follow‐up. Compared to normal weight at both age 18 and 70+ years, being obese at both times was associated with increased dementia risk (HR: 2.27, 95%CI: 1.22–4.24, p = 0.01), while obesity only at age 70+ years was associated with decreased risk (HR: 0.70, 95%CI: 0.51–0.95, p = 0.02). Conclusions: Our findings suggest that long‐term obesity and weight gain in later life may be risk factors for dementia. Being underweight or having substantial weight loss in old age may be early markers of pre‐clinical dementia. [ABSTRACT FROM AUTHOR]

Background The burden of metabolic dysfunction-associated steatotic liver disease (MASLD) is growing rapidly, including among older adults. The number of older adults is also rising with concomitantly increasing rates of age-related physical and cognitive dysfunction. However, data on whether MASLD affects physical and cognitive function in older adults is limited. As such, we aimed to identify whether prevalent MASLD influences the risk of incident physical disability or dementia in initially healthy older adults. Methods A post-hoc analysis of participants from the ASPREE-XT cohort study, which recruited community-dwelling older adults without a history of cardiovascular disease, dementia, or independence-limiting functional impairment. The Fatty Liver Index (to identify MASLD) was calculated in those with complete data. Cox proportional-hazards models were used to investigate the outcomes of dementia and persistent physical disability in participants with MASLD vs those without. Results Of the 9 097 individuals included (mean age 75.1 ± 4.2 years; 45.0% men), 341 (3.7%) developed persistent physical disability and 370 (4.1%) developed dementia over a median follow-up of 6.4 years (IQR 5.3–7.5 years). When adjusting for known contributors including age, gender, education, comorbidity, and functional measures, MASLD was associated with an increased risk of persistent physical disability (HR 1.41 [95% CI: 1.07–1.87]) and reduced risk of incident dementia (HR 0.63 [95% CI: 0.48–0.83]). Conclusions Prevalent MASLD is associated with reduced rates of incident dementia but increased risk of persistent physical disability in initially relatively healthy older adults. Understanding the mechanisms underlying these divergent results to allow appropriate risk stratification and counseling is important. [ABSTRACT FROM AUTHOR]

Background Blood concentrations of testosterone and estrone tend to increase in women aged ≥70 years, whereas concentrations of their precursor hormone dehydroepiandrosterone decline. It is unknown whether these changes influence physical function. We investigated whether concentrations of these hormones were associated with grip strength and self-reported physical function in community-dwelling older women. Methods A total of 9 179 Australian women, aged ≥70 years, were recruited to the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Sex hormones were measured in Sex Hormones in Older Women, an ASPREE substudy, by liquid chromatography–tandem mass spectrometry in 6 358 women. The associations between hormone concentrations and physical function (handgrip strength and self-reported physical function assessed by SF-12v2 physical component summary [PCS]) were examined using multiple linear regression. Results The median age of the 5,447 participants was 74.0 (interquartile range 71.7–77.6) years. Testosterone concentrations above the lowest quartile were associated with less decline in grip strength (mean –1.39 [95% CI –1.54 to –1.24] vs –1.75 [–2.00 to –1.50] kg, p  = .02), and dehydroepiandrosterone concentrations above the lowest quartile were associated with less decline in grip strength (–1.39 [–1.54 to –1.25] vs –1.82 [–2.11 to –1.55] kg, p  = .007) and PCS scores (–1.49 [–1.80 to –1.17] vs –2.33 [–2.93 to –1.72], p  = .02) over 4 years, compared with those in the respective lowest quartile. Conclusions Low endogenous concentrations of testosterone and dehydroepiandrosterone were associated the greatest likelihood of physical function decline in community-based women aged ≥70 years. Further studies are warranted to determine whether testosterone and dehydroepiandrosterone therapy prevent functional decline in this at-risk group using sensitive measures of muscle strength and performance. [ABSTRACT FROM AUTHOR]

Background The prognostic implication of cholesterol levels in older adults remains uncertain. This study aimed to examine the relationship between low-density-lipoprotein cholesterol (LDL-c) and mortality outcomes in older individuals. Methods This post hoc analysis examined the associations of LDL-c levels with mortality risks from all-cause, cardiovascular disease (CVD), cancer, and combined non-CVD/noncancer conditions in a cohort of individuals aged ≥65 years from the ASPirin in Reducing Events in the Elderly trial (NCT01038583). At baseline, participants had no diagnosed dementia, physical disability, or CVD, and were not taking lipid-lowering agents. Outcome analyses were performed using multivariable Cox models. Results We analyzed 12 334 participants (mean age: 75.2 years). Over a median 7-year follow-up, 1 250 died. Restricted cubic splines found a U-shaped relation for LDL-c and all-cause mortality, cancer mortality, and noncancer/non-CVE mortality (nadir: 3.3–3.4 mmol/L); the risk of CVD mortality was similar at LDL-c below 3.3 mmol/L and increased above 3.3 mmol/L. Similar trends were observed in analyses modeling LDL-c by quartiles. When modeling LDL-c as a continuous variable, the risk of all-cause mortality, cancer mortality, and noncancer/non-CVD mortality was decreased by 9%, 16%, and 18%, respectively, per 1-mmol/L higher LDL-c, and the risk of CVD mortality was increased by 19% per 1-mmol/L higher LDL-c. Reduced all-cause and non-CVD/noncancer mortality risks were only significant in males but not females (p interaction < .05). Conclusions There were U-shaped relationships between LDL-c and all-cause mortality, cancer mortality, and noncancer/non-CVD mortality in healthy older adults. Higher LDL-c levels were associated with an increased risk of CVD mortality. Future studies are warranted to confirm our results. [ABSTRACT FROM AUTHOR]

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

Background & Aims: The burden of metabolic dysfunction‐associated steatotic liver disease (MASLD) is growing rapidly, as is the number of older adults globally. However, relatively few studies have been performed evaluating the prevalence and risk factors for MASLD in older adults. As such, we aimed to identify the prevalence of MASLD in older adults, as well as sociodemographic, clinical, functional and biochemical associations. Methods: The study population included older adults without a history of cardiovascular disease, dementia or independence‐limiting functional impairment who had participated in the ASPirin in Reducing Events in the Elderly (ASPREE) randomised trial. MASLD was defined using the Fatty Liver Index (FLI). Associations were identified using Poisson regression with robust variance for FLI ≥ 60 vs FLI < 30. Results: 9097 Australian participants aged ≥70 years had complete biochemical and anthropometric data to identify MASLD. The study population had a mean age of 75.1 ± 4.3 years and was 45.0% male. Almost one‐third (33.0%) had prevalent MASLD, and the prevalence decreased with increasing age (adjusted RR [aRR] 0.96, 95% CI: 0.96–0.97). MASLD was also negatively associated with social advantage (aRR 0.94, 95% CI: 0.90–0.99) and exercise tolerance and was positively associated with diabetes mellitus (aRR: 1.22, 95% CI: 1.16–1.29), hypertension (aRR: 1.31, 95% CI: 1.22–1.41), male sex (aRR: 1.66, 95% CI: 1.57–1.74), pre‐frailty (aRR: 1.99, 95% CI: 1.82–2.12) and frailty (aRR: 2.36, 95% CI: 2.16–2.56). MASLD and nonalcoholic fatty liver disease (NAFLD) results were 100% concordant. Conclusion: This study in a large cohort of relatively healthy community‐dwelling older adults shows that MASLD is common, decreases with age and is associated with poorer metabolic health, social disadvantage and frailty. [ABSTRACT FROM AUTHOR]

The article offers information regarding monitoring outcomes in spine surgery. It mentions that the aim of the Australian Spine Registry (ASR) is to enhance the quality of care for spine surgery patients by providing a tool for individual surgeons to complete audits of their surgery and monitoring trends in surgical approach and outcomes for spine surgery. It presents information on development of clinical quality registries (CQRs) in Australia.

Background The 10-item Center for the Epidemiological Studies of Depression Short Form (CES-D-10) is a widely used self-report measure of depression symptomatology. The aim of this study is to investigate the psychometric properties of the CES-D-10 in healthy community dwelling older adults. Methods The sample consists of 19,114 community-based individuals residing in Australia and the United States who participated in the ASPREE trial baseline assessment. All individuals were free of any major illness at the time. We evaluated construct validity by performing confirmatory factor analysis, examined measurement invariance across country and gender followed by evaluating item discrimination bias in age, gender, race, ethnicity and education level, and assessing internal consistency. Results High item–total correlations and Cronbach's alpha indicated high internal consistency. The factor analyses suggested a unidimensional factor structure. Construct validity was supported in the overall sample, and by country and gender sub-groups. The CES-D-10 was invariant across countries, and although evidence of marginal gender non-invariance was observed there was no evidence of notable gender specific item discrimination bias. No notable differences in discrimination parameters or group membership measurement non-invariance were detected by gender, age, race, ethnicity, and education level. Conclusion These findings suggest the CES-D-10 is a reliable and valid measure of depression in a volunteer sample. No noteworthy evidence of invariance and/or item discrimination bias is observed across gender, age, race, language and ethnic groups. [ABSTRACT FROM AUTHOR]

In this large primary prevention trial in community-dwelling persons aged 70 years or older, daily low-dose aspirin increased the risk for incident anemia by approximately 20%. These findings question preventive use of aspirin in older patients and suggest caution with this practice. Visual Abstract. Effect of Low-Dose Aspirin Versus Placebo on Incidence of Anemia in the Elderly: In this large primary prevention trial of aspirin in community-dwelling persons aged 70 years or older, daily low-dose aspirin increased the risk of incident anemia by approximately 20%. These findings question preventive use of aspirin in older patients and suggest caution with this practice. Background: Daily low-dose aspirin increases major bleeding; however, few studies have investigated its effect on iron deficiency and anemia. Objective: To investigate the effect of low-dose aspirin on incident anemia, hemoglobin, and serum ferritin concentrations. Design: Post hoc analysis of the ASPREE (ASPirin in Reducing Events in the Elderly) randomized controlled trial. (ClinicalTrials.gov: NCT01038583) Setting: Primary/community care in Australia and the United States. Participants: Community-dwelling persons aged 70 years or older (≥65 years for Black persons and Hispanic persons). Intervention: 100 mg of aspirin daily or placebo. Measurements: Hemoglobin concentration was measured annually in all participants. Ferritin was measured at baseline and 3 years after random assignment in a large subset. Results: 19 114 persons were randomly assigned. Anemia incidence in the aspirin and placebo groups was 51.2 events and 42.9 events per 1000 person-years, respectively (hazard ratio, 1.20 [95% CI, 1.12 to 1.29]). Hemoglobin concentrations declined by 3.6 g/L per 5 years in the placebo group and the aspirin group experienced a steeper decline by 0.6 g/L per 5 years (CI, 0.3 to 1.0 g/L). In 7139 participants with ferritin measures at baseline and year 3, the aspirin group had greater prevalence than placebo of ferritin levels less than 45 µg/L at year 3 (465 [13%] vs. 350 [9.8%]) and greater overall decline in ferritin by 11.5% (CI, 9.3% to 13.7%) compared with placebo. A sensitivity analysis quantifying the effect of aspirin in the absence of major bleeding produced similar results. Limitations: Hemoglobin was measured annually. No data were available on causes of anemia. Conclusion: Low-dose aspirin increased incident anemia and decline in ferritin in otherwise healthy older adults, independent of major bleeding. Periodic monitoring of hemoglobin should be considered in older persons on aspirin. Primary Funding Source: National Institutes of Health and Australian National Health and Medical Research Council. [ABSTRACT FROM AUTHOR]

Objective: The role of circulating sex hormones on structural brain ageing is yet to be established. This study explored whether concentrations of circulating sex hormones in older women are associated with the baseline and longitudinal changes in structural brain ageing, defined by the brain‐predicted age difference (brain‐PAD). Design: Prospective cohort study using data from NEURO and Sex Hormones in Older Women; substudies of the ASPirin in Reducing Events in the Elderly clinical trial. Patients: Community‐dwelling older women (aged 70+ years). Measurements: Oestrone, testosterone, dehydroepiandrosterone (DHEA), and sex‐hormone binding globulin (SHBG) were quantified from plasma samples collected at baseline. T1‐weighted magnetic resonance imaging was performed at baseline, 1 and 3 years. Brain age was derived from whole brain volume using a validated algorithm. Results: The sample comprised of 207 women not taking medications known to influence sex hormone concentrations. A statistically higher baseline brain‐PAD (older brain age relative to chronological age) was seen for women in the highest DHEA tertile compared with the lowest in the unadjusted analysis (p =.04). This was not significant when adjusted for chronological age, and potential confounding health and behavioural factors. Oestrone, testosterone and SHBG were not associated with brain‐PAD cross‐sectionally, nor were any of the examined sex hormones or SHBG associated with brain‐PAD longitudinally. Conclusion: No strong evidence of an association between circulating sex hormones and brain‐PAD. Given there is prior evidence to suggests sex hormones may be important for brain ageing, further studies of circulating sex hormones and brain health in postmenopausal women are warranted. [ABSTRACT FROM AUTHOR]

Introduction: Frailty is a common geriatric syndrome that adversely impacts health outcomes. This study examined correlates of physical frailty in healthy community-dwelling older adults and studied the effect of frailty on disability-free survival (DFS), defined as survival free of independence-limiting physical disability or dementia. Methods: This is a post hoc analysis of 19,114 community-dwelling older adults (median age: 74.0 years, interquartile range or IQR: 6.1 years) from Australia and the USA enrolled in the "ASPirin in Reducing Events in the Elderly (ASPREE)" clinical trial. Frailty was assessed using a modified Fried phenotype and a deficit accumulation frailty index (FI) utilizing a ratio score derived from 66 items. Multinomial logistic regression was used to examine the correlates of frailty and Cox regression to analyze the association between frailty and DFS (and its components). Results: At study enrollment, 39.0% were prefrail, and 2.2% of participants were frail, according to Fried phenotype. Older age, higher waist circumference, lower education, ethnoracial origin, current smoking, depression, and polypharmacy were associated with prefrailty and frailty according to Fried phenotype and FI. Fried phenotype defined prefrailty and frailty predicted reduced DFS (prefrail: HR: 1.67; 95% CI: 1.50–1.86 and frail: HR: 2.80; 95% CI: 2.27–3.46), affecting each component of DFS including dementia, physical disability, and mortality. Effect sizes were larger, according to FI. Conclusion: Our study showed that prefrailty is common in community-dwelling older adults initially free of cardiovascular disease, dementia, or independence-limiting physical disability. Prefrailty and frailty significantly reduced disability-free survival. Addressing modifiable correlates, like depression and polypharmacy, might reduce the adverse impact of frailty on dementia-free and physical disability-free survival. [ABSTRACT FROM AUTHOR]

Background: The Maintain Your Brain (MYB) trial aims to prevent cognitive decline and dementia through multidomain, web-based risk-reduction. To facilitate translation, it is important to understand drivers of participation. Objective: To describe characteristics associated with participation in MYB. Methods: This was an observational ancillary study of MYB, a randomized controlled trial nested within the 45 and Up Study in New South Wales, Australia. We linked 45 and Up Study survey and MYB participation data. The study cohort comprised 45 and Up Study participants, aged 55–77 years at 1 January 2018, who were invited to participate in MYB. 45 and Up Study participant characteristics and subsequent MYB consent and participation were examined. Results: Of 98,836 invited, 13,882 (14%) consented to participate and 6,190 participated (6%). Adjusting for age and sex, a wide range of factors were related to participation. Higher educational attainment had the strongest relationship with increased MYB participation (university versus school non-completion; AdjOR = 5.15; 95% CI:4.70–5.64) and lower self-rated quality of life with reduced participation (Poor versus Excellent: AdjOR = 0.19; 95% CI:0.11–0.32). A family history of Alzheimer's disease was related to increased participation but most other dementia risk factors such as diabetes, obesity, stroke, high blood pressure, and current smoking were associated with reduced participation. Conclusion: Higher socio-economic status, particularly educational attainment, is strongly associated with engagement in online dementia prevention research. Increasing population awareness of dementia risk factors, and better understanding the participation barriers in at-risk groups, is necessary to ensure online interventions are optimally designed to promote maximum participation. [ABSTRACT FROM AUTHOR]

In the general population, body mass index (BMI) and waist circumference are recognized risk factors for several chronic diseases and all-cause mortality. However, whether these associations are the same for older adults is less clear. The association of baseline BMI and waist circumference with all-cause and cause-specific mortality was investigated in 18,209 Australian and US participants (mean age: 75.1 ± 4.5 years) from the ASPirin in Reducing Events in the Elderly (ASPREE) study, followed up for a median of 6.9 years (IQR: 5.7, 8.0). There were substantially different relationships observed in men and women. In men, the lowest risk of all-cause and cardiovascular mortality was observed with a BMI in the range 25.0–29.9 kg/m2 [HR25-29.9 vs 21–24.9 kg/m2: 0.85; 95% CI, 0.73–1.00] while the highest risk was in those who were underweight [HRBMI <21 kg/m2 vs BMI 21–24.9 kg/m2: 1.82; 95% CI 1.30–2.55], leading to a clear U-shaped relationship. In women, all-cause mortality was highest in those with the lowest BMI leading to a J-shaped relationship (HRBMI <21 kg/m2 vs BMI 21–24.9 kg/m2: 1.64; 95% CI 1.26–2.14). Waist circumference showed a weaker relationship with all-cause mortality in both men and women. There was little evidence of a relationship between either index of body size and subsequent cancer mortality in men or women, while non-cardiovascular non-cancer mortality was higher in underweight participants. For older men, being overweight was found to be associated with a lower risk of all-cause mortality, while among both men and women, a BMI in the underweight category was associated with a higher risk. Waist circumference alone had little association with all-cause or cause-specific mortality risk. Trial registration ASPREE https://ClinicalTrials.gov number NCT01038583. [ABSTRACT FROM AUTHOR]

Simple Summary: Planning and delivering cancer treatment in older adults with cancer is complex, given the difficulty in balancing the benefits of treatment on survival and quality of life, and the risk of harmful side effects. As a result, treatment rates in older adults with cancer tend to differ from younger patients, and there are few reports describing treatment rates in older adults. In a group of healthy older patients with cancer, we looked at rates of treatment classed as surgery, drug therapies such a chemotherapy or immunotherapy, and radiotherapy, and found that the vast majority received some form of treatment (81%), most commonly, surgery. Those with breast cancers were most likely to receive treatment (98%), in contrast to blood cancers, where patients were least likely to receive treatment (only 60% received treatment). Older patients, those residing in the US, current smokers, and those with diabetes were also less likely to receive treatment. Introduction: Cancer treatment planning in older adults is complex and requires careful balancing of survival, quality of life benefits, and risk of treatment-related morbidity and toxicity. As a result, treatment selection in this cohort tends to differ from that for younger patients. However, there are very few studies describing cancer treatment patterns in older cohorts. Methods: We used data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial and the ASPREE Cancer Treatment Substudy (ACTS) to describe cancer treatment patterns in older adults. We used a multivariate logistic regression model to identify factors affecting receipt of treatment. Results: Of 1893 eligible Australian and United States (US) participants with incident cancer, 1569 (81%) received some form of cancer treatment. Non-metastatic breast cancers most frequently received treatment (98%), while haematological malignancy received the lowest rates of treatment (60%). Factors associated with not receiving treatment were older age (OR 0.94, 95% CI 0.91–0.96), residence in the US (OR 0.34, 95% CI 0.22–0.54), smoking (OR 0.57, 95% CI 0.40–0.81), and diabetes (OR 0.56, 95% CI 0.39–0.80). After adjustment for treatment patterns in sex-specific cancers, sex did not impact receipt of treatment. Conclusions: This study is one of the first describing cancer treatment patterns and factors affecting receipt of treatment across common cancer types in older adults. We found that most older adults with cancer received some form of cancer treatment, typically surgery or systemic therapy, although this varied by factors such as cancer type, age, sex, and country of residence. [ABSTRACT FROM AUTHOR]

Presents a response by John J. McNeil etal to a letter to the editor about his article "Fernitrothion: Toxicokinetics and Toxicologic Evaluation in Human Volunteers," published in the March 2003 issue of "Environmental Health Perspectives".

Frailty and chronic kidney disease (CKD) both increase with age and are prevalent in older adults. However, studies in older adults examining the relationship between frailty and milder impairments of kidney function are relatively sparse. We examined the cross‐sectional association of baseline estimated glomerular filtration rate (eGFR), albuminuria and CKD ([eGFR <60 ml/min/1.73 m2] and/or albuminuria [>3.0 mg/mmol]) with prefrailty and frailty in the ASPirin in Reducing Events in the Elderly (ASPREE) trial cohort of healthy older participants. Univariate logistic regression models measured the unadjusted odds ratios (OR) and 95% confidence intervals (CI) for prevalent combined prefrailty and frailty (respectively defined as presence of 1–2 or 3+ of 5 modified fried criteria) for the association between CKD, eGFR, albuminuria and other potential risk factors. Multivariable models calculated OR for prefrailty‐frailty adjusted for potential confounders and either CKD, (i) eGFR and albuminuria measured as either continuous variables; (ii) or categorical variables; (iii). Of 17 759 eligible participants, 6934 were classified as prefrail, 389 were frail. CKD, eGFR and albuminuria were all associated with combined prefrailty‐frailty on univariate analysis. In the multivariable modelling, neither CKD (reduced eGFR and/or albuminuria), nor eGFR (either continuous or categorical variables) were associated with prefrailty‐frailty. However, albuminuria, either as a continuous variable (OR [95% CI] 1.07 [1.04–1.10]; p <.001), or categorical variable (OR 1.21 [1.08–1.36]; p =.001) was consistently associated with prefrailty‐frailty. The complex relationship between albuminuria (which may be a biomarker for vascular inflammation), ageing, progressive CKD and frailty requires further investigation. Summary at a glance: Albuminuria, but not estimated glomerular filtration rated (eGFR), was consistently associated with prevalent prefrailty‐frailty, after covariate adjustment in a well population of older adults with chronic kidney disease (CKD). The complex relationship between albuminuria (a possible biomarker for vascular inflammation), ageing, progressive CKD and development of frailty requires further investigation. [ABSTRACT FROM AUTHOR]

Background: For the design and analysis of clinical trials with time-to-event outcomes, the Cox proportional hazards model and the logrank test have been the cornerstone methods for many decades. Increasingly, the key assumption of proportionality-or time-fixed effects-that underpins these methods has been called into question. The availability of novel therapies with new mechanisms of action and clinical trials of longer duration mean that non-proportional hazards are now more frequently encountered.Methods: We compared several regression-based methods to model time-dependent treatment effects. For illustration purposes, we used selected endpoints from a large, community-based clinical trial of low dose daily aspirin in older persons. Relative and absolute estimands were defined, and analyses were conducted in all participants. Additional exploratory analyses were undertaken by selected subgroups of interest using interaction terms in the regression models.Discussion: In the trial with median 4.7 years follow-up, we found evidence for non-proportionality and a time-dependent treatment effect of aspirin on cancer mortality not previously reported in trial findings. We also found some evidence of time-dependence to an aspirin by age interaction for major adverse cardiovascular events. For other endpoints, time-fixed treatment effect estimates were confirmed as appropriate.Conclusions: The consideration of treatment effects using both absolute and relative estimands enhanced clinical insights into potential dynamic treatment effects. We recommend these analytical approaches as an adjunct to primary analyses to fully explore findings from clinical trials. [ABSTRACT FROM AUTHOR]

Background: The role of aspirin in reducing lipoprotein(a)-mediated atherothrombotic events in primary prevention is not established.Objectives: This study sought to assess whether low-dose aspirin benefits individuals with elevated plasma lipoprotein(a)-associated genotypes in the setting of primary prevention.Methods: The study analyzed 12,815 genotyped individuals ≥70 years of age of European ancestry and without prior cardiovascular disease events enrolled in the ASPREE (ASPirin in Reducing Events in the Elderly) randomized controlled trial of 100 mg/d aspirin. We defined lipoprotein(a)-associated genotypes using rs3798220-C carrier status and quintiles of a lipoprotein(a) genomic risk score (LPA-GRS). We tested for interaction between genotypes and aspirin allocation in Cox proportional hazards models for incidence of major adverse cardiovascular events (MACE) and clinically significant bleeding. We also examined associations in the aspirin and placebo arms of the trial separately.Results: During a median 4.7 years (IQR: 3.6-5.7 years) of follow-up, 435 MACE occurred, with an interaction observed between rs3798220-C and aspirin allocation (P = 0.049). rs3798220-C carrier status was associated with increased MACE risk in the placebo group (HR: 1.90; 95% CI: 1.11-3.24) but not in the aspirin group (HR: 0.54; 95% CI: 0.17-1.70). High LPA-GRS (vs low) was associated with increased MACE risk in the placebo group (HR: 1.70; 95% CI: 1.14-2.55), with risk attenuated in the aspirin group (HR: 1.41; 95% CI: 0.90-2.23), but the interaction was not statistically significant. In all participants, aspirin reduced MACE by 1.7 events per 1,000 person-years and increased clinically significant bleeding by 1.7 events per 1,000 person-years. However, in the rs3798220-C and high LPA-GRS subgroups, aspirin reduced MACE by 11.4 and 3.3 events per 1,000 person-years respectively, without significantly increased bleeding risk.Conclusions: Aspirin may benefit older individuals with elevated lipoprotein(a) genotypes in primary prevention. [ABSTRACT FROM AUTHOR]

Background: Frailty is associated with chronic inflammation, which may be modified by aspirin. The purpose of this study was to determine whether low-dose aspirin reduces incident frailty in healthy older adult participants of the ASPirin in Reducing Events in the Elderly (ASPREE) trial.Methods: In the United States and Australia, 19 114 community-dwelling individuals aged ≥70 and older (U.S. minorities ≥65 years) and free of overt cardiovascular disease, persistent physical disability, and dementia were enrolled in ASPREE, a double-blind, placebo-controlled trial of 100-mg daily aspirin versus placebo. Frailty, a prespecified study end point, was defined according to a modified Fried frailty definition (Fried frailty) and the frailty index based on the deficit accumulation model (frailty index). Competing risk Cox proportional hazard models were used to compare time to incident frailty by aspirin versus placebo. Sensitivity analysis was conducted to include frailty data with and without imputation of missing data.Results: Over a median 4.7 years, 2 252 participants developed incident Fried frailty, and 4 451 had incident frailty according to the frailty index. Compared with placebo, aspirin treatment did not alter the risk of incident frailty (Fried frailty hazard ratio [HR]: 1.04, 95% confidence interval [CI] 0.96-1.13; frailty index HR: 1.03, 95% CI 0.97-1.09). The proportion of individuals classified as frail, and the trajectory in continuous frailty scores over time, were not different between the aspirin and placebo treatment groups. The results were consistent across a series of subgroups.Conclusions: Low-dose aspirin use in healthy older adults when initiated in older ages does not reduce risk of incident frailty or the trajectory of frailty. [ABSTRACT FROM AUTHOR]

Uncertainty remains regarding the benefit of hip replacement in older adults in the context of age-related decline in physical function. This study aimed to examine the effect of hip replacement on functional outcomes and identify factors associated with clinically important improvement in physical function postoperatively in community-dwelling older adults. This cohort study was performed within the ASPREE trial, with 698 participants receiving hip replacement and 677 age- and sex-matched controls without knee or hip replacement during the trial drawn from 16,703 Australian participants aged ≥70 years. Health status (physical and mental component summary [PCS and MCS]) was assessed annually using the SF-12. Participants receiving hip replacement had significantly lower pre- and post-replacement PCS scores compared with controls (p < 0.0001). There was significant improvement in PCS score following hip replacement (mean change 4.9, 95%CI 4.0–5.7) but no change in controls (0.01, 95%CI −0.7–0.7). Following hip replacement, 46.7% of participants experienced clinically important improvement in PCS score, while 15.5% experienced worsened PCS score. Participants experiencing improved postoperative PCS score had significantly lower PCS and higher MCS scores preoperatively. The degree of preoperative physical function impairment was a significant indicator of older people most likely to benefit from hip replacement surgery. [ABSTRACT FROM AUTHOR]

Background and objective: The clinical significance of sleep‐disordered breathing (SDB) in older age is uncertain. This study determined the prevalence and associations of SDB with mood, daytime sleepiness, quality of life (QOL) and cognition in a relatively healthy older Australian cohort. Methods: A cross‐sectional analysis was conducted from the Study of Neurocognitive Outcomes, Radiological and retinal Effects of Aspirin in Sleep Apnoea. Participants completed an unattended limited channel sleep study to measure the oxygen desaturation index (ODI) to define mild (ODI 5–15) and moderate/severe (ODI ≥ 15) SDB, the Centre for Epidemiological Studies Scale, the Epworth Sleepiness Scale, the 12‐item Short‐Form for QOL and neuropsychological tests. Results: Of the 1399 participants (mean age 74.0 years), 36% (273 of 753) of men and 25% (164 of 646) of women had moderate/severe SDB. SDB was associated with lower physical health‐related QOL (mild SDB: beta coefficient [β] −2.5, 95% CI −3.6 to −1.3, p < 0.001; moderate/severe SDB: β −1.8, 95% CI −3.0 to −0.6, p = 0.005) and with lower global composite cognition (mild SDB: β −0.1, 95% CI −0.2 to 0.0, p = 0.022; moderate/severe SDB: β −0.1, 95% CI −0.2 to 0.0, p = 0.032) compared to no SDB. SDB was not associated with daytime sleepiness nor depression. Conclusion: SDB was associated with lower physical health‐related quality of life and cognitive function. Given the high prevalence of SDB in older age, assessing QOL and cognition may better delineate subgroups requiring further management, and provide useful treatment target measures for this age group. The clinical implications for sleep‐disordered breathing (SDB) in older age remain uncertain. This study of healthy community‐dwelling older Australians reports significant associations between SDB and a lower physical health‐related quality of life, in contrast to other studies of SDB in older age, and between SDB and lower cognitive function. See relatededitorial [ABSTRACT FROM AUTHOR]

Purpose: Recent epidemiological evidence has suggested that use of lipid-lowering medications, particularly statins, was associated with reduced cardiovascular disease (CVD) events and persistent physical disability in healthy older adults. However, the comparative efficacy of different statins in this group remains unclear. This study aimed to compare different forms of statins in their associations with CVD and physical disability in healthy older adults. Methods: This post hoc analysis included data from 5981 participants aged ≥ 70 years (≥ 65 if US minorities; median age:74.0) followed for a median of 4.7 years, who had no prior CVD events or physical disability and reported using a statin at baseline. The incidence of the composite and components of major adverse cardiovascular events and persistent physical disability were compared across different statins according to their type, potency, and lipophilicity using multivariable Cox proportional-hazards models. Results: Atorvastatin was the most used statin type at baseline (37.9%), followed by simvastatin (29.6%), rosuvastatin (25.5%), and other statins (7.0%, predominantly pravastatin). In comparisons of specific statins according to type and lipophilicity (lipophilic vs. hydrophilic statin), observed differences in all outcomes were small and not statistically significant (all p values > 0.05). High-potency statin use (atorvastatin and rosuvastatin) was marginally associated with lower risk of fatal CVD events compared with low-/moderate-potency statin use (hazard ratio: 0.59; 95% confidence interval: 0.35, 1.00). Conclusion: There were minimal differences in CVD outcomes and no significant difference in persistent physical disability between various forms of statins in healthy older adults. Future investigations are needed to confirm our results. [ABSTRACT FROM AUTHOR]

Objectives To describe the trends in emergency admissions over 10 years in terms of volume, age-specific rates, hospital length of stay ( LOS) and clinical reasons. Methods A retrospective analysis of population-based linked Department of Health ED and hospital admission data for metropolitan Melbourne 1999/2000 to 2008/2009 was conducted. Outcome measures included: hospital admission numbers (total, single day/overnight, ≥2 days LOS); admission rates per 1000 person-years (total, single day/overnight, ≥2 days LOS); hospital LOS. Results The volume of patients admitted to hospital through EDs rose by 56% over the 10 years to June 2009. The number of same day/overnight admissions rose by 60%, equating to a 6.1% average annual increase beyond that accounted for by demographic change (95% CI 5.7-6.5%). The volume of patients admitted for ≥2 days also increased; however, the admission rate per 1000 persons for these longer-stay patients declined over the decade by 9% (95% CI 5-12%). The most frequent discharge diagnoses were injury or poisoning, and disorders of the circulatory, respiratory or digestive systems. The numbers and mortality rate for ED admissions declined over the decade. Conclusion Emergency hospital admissions have risen over the last decade even after adjustment for population changes. There was a disproportionate rise in same day/overnight admissions, with overrepresentation of the elderly. This is possibly related to changes in ED models of care, including introduction of short-stay units, improved diagnostic and therapeutic capability, and risk-averse management to optimise safe discharge, within the context of time-based performance targets. [ABSTRACT FROM AUTHOR]

Objective Assessing the reliability of clinical registries is important for ensuring the availability of credible data. Therefore, this study aimed to investigate the reliability of data collected by the Australian and New Zealand Haemostasis Registry (the registry). Design Data from 5% of randomly selected registry cases were re-abstracted by an independent data auditor who was blinded to the results of the original data abstraction. Categorical data were investigated for agreement between original and re-abstracted data. The mean difference and standard deviations (SD) of differences were calculated for continuous variables. We estimated a ‘prediction interval’ as the mean difference ± twice the SD of differences. We computed a coefficient of variation as the SD of differences. Setting The registry records all cases of off-licence use of recombinant activated factor VII (rFVIIa) at participating institutions (on-licence use of rFVIIa is not recorded). Results Data on 76 registry cases (6% of registry) were re-abstracted. Various parameters demonstrated high levels of inter-rater reliability, including age, gender and intensive care unit admission (88, 99 and 99% agreement, respectively). Other variables were highly unreliable, including crystalloid infusion volumes (coefficient of variation 123.01%), red blood cell units (92.05%) and time from bleeding onset to administration of rFVIIa (153.06%). Conclusions Registry audits are useful for identifying variables with poor reliability. Repeated audits will not improve data reliability; however, they can assist in identifying and evaluating the impact of modified data collection processes on improving data reliability. [ABSTRACT FROM AUTHOR]

Past therapies for the treatment of obesity have typically involved pharmacological agents usually in combination with a calorie- controlled diet. This paper reviews the efficacy and safety of pharmacotherapies for obesity focusing on drugs approved for long-term therapy (orlistat), drugs approved for short-term use (amfepramone [diethylpropion], phentermine), recently withdrawn therapies (rimonabant, sibutamine) and drugs evaluated in Phase III studies (taranabant, pramlintide, lorcaserin and tesofensine and combination therapies of topiramate plus phentermine, bupropion plus naltrexone, and bupropion plus zonisamide). No current pharmacotherapy possesses the efficacy needed to produce substantial weight loss in morbidly obese patients. Meta-analyses support a significant though modest loss in bodyweight with a mean weight difference of 4.7kg (95% CI 4.1 to 5.3 kg) for rimonabant, 4.2 kg (95% CI 3.6 to 4.8 kg) for sibutramine and 2.9 kg (95% CI 2.5 to 3.2 kg) for orlistat compared to placebo at ≥12 months. Of the Phase III pharmacotherapies, lorcaserin, taranabant, topiramate and bupropion with naltrexone have demonstrated significant weight loss compared to placebo at ≥12 months. Some pharmacotherapies have also demonstrated clinical benefits. Further studies are required in some populations such as younger and older people whilst the long term safety continues to be a major consideration and has led to the withdrawal of several drugs. [ABSTRACT FROM AUTHOR]

Abstract: A number of previous investigators have demonstrated that arterial augmentation index (AIx), a measure of apparent arterial stiffness, reflects in part vascular endothelial function, and that AIx is modulated by nitric oxide (NO) responses. We evaluated AIx in a population of 253 ageing subjects (mean age 63.4±6 (standard deviation, SD) years) and its relationship to (i) plasma levels of asymmetric dimethylarginine (ADMA), a marker and mediator of vascular endothelial dysfunction and (ii) the ratio of ADMA to its non-metabolised enantiomer symmetric dimethylarginine (SDMA), an inverse index of ADMA metabolic clearance. Evaluation was performed by univariate followed by multivariate analyses. On multivariate analyses, both ADMA (β =0.16, p =0.01) and ADMA:SDMA (β =0.21, p <0.001) ratio were significant direct correlates of AIx. Other significant correlates of AIx on multivariate analysis were: use of angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (ACEi/ARB) (β =−0.24, p =0.004), smoking history (β =0.15, p =0.007), male gender (β =−0.38, p <0.001), creatinine clearance (CrCL) (β =−0.25, p <0.001), and history of hypertension (β =0.17, p =0.04). We conclude that (1) endothelial dysfunction engendered by impairment of NO synthesis may represent the basis for increased arterial stiffness in ageing individuals and (2) the fundamental biochemical anomaly may be impairment of ADMA clearance. These pathophysiological factors are likely to be relevant to optimize therapy to ameliorate disorders of arterial compliance in the ageing population. [Copyright &y& Elsevier]

Summary: Risk-adjusted survival rates have been the principle mode of comparison between trauma systems. In mature trauma systems, it is possible that there will be further improvements in survival but these are likely to be small. In the future, the largest gains will come from quality of life and improved function of the survivors. The issues related to measuring quality of survival for trauma systems are reviewed, including feasibility, ethical considerations, risk adjustment of outcomes of survivors, and challenges for selection of instruments and administration. In addition, the preliminary experiences of measuring outcomes in survivors through the Victorian State Trauma Registry are discussed. Although function and quality of life have been identified as important factors to measure in trauma populations, a standardised protocol has not been established. The experience in Victoria suggests that monitoring of population-based outcomes in survivors is feasible and may create the basis for benchmarking the level of morbidity in survivors. [Copyright &y& Elsevier]

Pharmacotherapy for the management of obesity is primarily aimed at weight loss, weight loss maintenance and risk reduction, and has included thyroid hormone, amphetamines, phentermine, amfepramone (diethylpropion), phenylpropanolamine, mazindol, fenfluramines and, more recently, sibutramine and orlistat. These agents decrease appetite, reduce absorption of fat or increase energy expenditure. Primary endpoints used to evaluate anti-obesity drugs most frequently include mean weight loss, percentage weight loss and proportion of patients losing ≥5% and ≥10% of initial bodyweight. Secondary endpoints may include reduction in body fat, risk factors for cardiovascular disease and the incidences of diseases such as diabetes mellitus. Most pharmacotherapies have demonstrated significantly greater weight loss in patients on active treatment than those receiving placebo in short-term (≤1 year) randomised controlled trials of pharmacological treatment in conjunction with a calorie-controlled diet or lifestyle intervention. The evidence of long-term efficacy is limited to sibutramine (2 years) and orlistat (4 years). These are the only drugs currently approved for the long-term management of obesity in adults. Sibutramine recipients randomised following 6 months’ treatment to either sibutramine or placebo demonstrated significantly better weight maintenance at 2 years than those taking placebo (p < 0.001), with ≥10% loss of initial bodyweight in 46% of patients. For patients taking orlistat, weight loss was 2.2kg greater than those on placebo at 4 years (p < 0.001), with significantly more patients achieving ≥10% loss of initial bodyweight (26.2% and 15.6%, respectively; p < 0.001). Other drugs that have been evaluated for weight loss include ephedrine, the antidepressants fluoxetine and bupropion, and the antiepileptics topiramate and zonisamide. Two clinical trials with fluoxetine both reported no significant difference in weight loss compared with placebo at 52 weeks. Clinical trials evaluating ephedrine, bupropion, topiramate and zonisamide have demonstrated significantly greater weight loss than placebo but have been limited to 16–26 weeks’ treatment. A major obstacle to the evaluation of the clinical trials is the potential bias resulting from low study completion rates. Completion rates varied from 52.8% of phentermine recipients in a 9-month study, to 40% of fenfluramine recipients in a 24-week comparative study with phentermine and 18% of amfepramone recipients in a 24-week study. One-year completion rates range from 51% to 73% for sibutramine and from 66% to 85% for orlistat. Other potential sources of bias include run-in periods and subsequent patient selection based on compliance or initial weight loss. Several potential new therapies targeting weight loss and obesity through the CNS pathways or peripheral adiposity signals are in early phase clinical trials. Over the next decade the drug treatment of obesity is likely to change significantly because of the availability of new pharmacotherapies to regulate eating behaviours, nutrient partitioning and/or energy expenditure. [ABSTRACT FROM AUTHOR]

Frailty is a state of heightened vulnerability and susceptibility to physiologic stressors that increases with age. It has shown increasing utility in predicting a range of adverse health outcomes. Here, we characterize a 67-item deficit-accumulation frailty index (FI) in 19 110 community-dwelling individuals in the ASPirin in Reducing Events in the Elderly clinical trial. Participants aged 65-98 years were recruited from the United States and Australia and were without diagnosed dementia and cardiovascular disease, and major physical disability. The median FI score was .10 (interquartile range: .07-.14) at baseline, and the prevalence of frailty (FI > .21) increased from 8.1% to 17.4% after 6 years. FI was positively associated with age, and women had significantly higher scores than men at all ages. The FI was negatively correlated with gait speed (r = -.31) and grip strength (r = -.46), and strongly associated with a modified Fried's frailty phenotype (p < .0001, for all comparisons). Frailty was associated with the primary composite outcome capturing independent life lived free of major disability and dementia, and increased the rate of persistent physical disability (hazard ratio: 21.3, 95% confidence interval: 15.6-28.9). It added significantly to the predictive capacity of these outcomes above age, sex, and ethnicity alone. The FI is thus a useful biomarker of aging even among relatively healthy older individuals and provides important information about an individual's vulnerability to and risk of disease. [ABSTRACT FROM AUTHOR]