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To assess the internal consistency, latent structure and convergent validity of the Depression, Anxiety and Stress Scale-21 (DASS-21) among adolescents in Vietnam. An anonymous, self-completed questionnaire was conducted among 1,745 high school students in Hanoi, Vietnam between October, 2013 and January, 2014. Confirmatory factor analyses were performed to assess the latent structure of the DASS-21. Factorial invariance between girls and boys was examined. Cronbach alphas and correlation coefficients between DASS-21 factor scores and the domain scores of the Duke Health Profile Adolescent Vietnamese validated version (ADHP-V) were calculated to assess DASS-21 internal consistency and convergent validity. A total of 1,606/ 1,745 (92.6%) students returned the questionnaire. Of those, 1,387 students provided complete DASS-21 data. The scale demonstrated adequate internal consistency (Cronbach α: 0.761 to 0.906). A four-factor model showed the best fit to the data. Items loaded significantly on a common general distress factor, the depression, and the anxiety factors, but few on the stress factor (p<0.05). DASS-21 convergent validity was confirmed with moderate correlation coefficients (-0.47 to -0.66) between its factor scores and the ADHP-V mental health related domains. The DASS-21 is reliable and suitable for use to assess symptoms of common mental health problems, especially depression and anxiety among Vietnamese adolescents. However, its ability in detecting stress among these adolescents may be limited. Further research is warrant to explore these results.

In a trial comparing 100 mg of aspirin with placebo in nearly 20,000 community-dwelling persons 70 years of age or older in Australia and the United States, aspirin use had no effect on the rate of survival free from dementia or physical disability.

Background Most clinical trials with time-to-event primary outcomes are designed assuming constant event rates and proportional hazards over time. Non-constant event rates and non-proportional hazards are seen increasingly frequently in trials. The objectives of this review were firstly to identify whether non-constant event rates and time-dependent treatment effects were allowed for in sample size calculations of trials, and secondly to assess the methods used for the analysis and reporting of time-to-event outcomes including how researchers accounted for non-proportional treatment effects. Methods We reviewed all original reports published between January and June 2017 in four high impact medical journals for trials for which the primary outcome involved time-to-event analysis. We recorded the methods used to analyse and present the main outcomes of the trial and assessed the reporting of assumptions underlying these methods. The sample size calculation was reviewed to see if the effect of either non-constant hazard rates or anticipated non-proportionality of the treatment effect was allowed for during the trial design. Results From 446 original reports we identified 66 trials with a time-to-event primary outcome encompassing trial start dates from July 1995 to November 2014. The majority of these trials (73%) had sample size calculations that used standard formulae with a minority of trials (11%) using simulation for anticipated changing event rates and/or non-proportional hazards. Well-established analytical methods, Kaplan-Meier curves (98%), the log rank test (88%) and the Cox proportional hazards model (97%), were used almost exclusively for the main outcome. Parametric regression models were considered in 11% of the reports. Of the trials reporting inference from the Cox model, only 11% reported any results of testing the assumption of proportional hazards. Conclusions Our review confirmed that when designing trials with time-to-event primary outcomes, methodologies assuming constant event rates and proportional hazards were predominantly used despite potential efficiencies in sample size needed or power achieved using alternative methods. The Cox proportional hazards model was used almost exclusively to present inferential results, yet testing and reporting of the pivotal assumption underpinning this estimation method was lacking.

The major efficacy trials on diabetes prevention have used resource-intensive approaches to identify high-risk individuals and deliver lifestyle interventions. Such strategies are not feasible for wider implementation in low- and middle-income countries (LMICs). We aimed to evaluate the effectiveness of a peer-support lifestyle intervention in preventing type 2 diabetes among high-risk individuals identified on the basis of a simple diabetes risk score. The Kerala Diabetes Prevention Program was a cluster-randomized controlled trial conducted in 60 polling areas (clusters) of Neyyattinkara taluk (subdistrict) in Trivandrum district, Kerala state, India. Participants (age 30-60 years) were those with an Indian Diabetes Risk Score (IDRS) ≥60 and were free of diabetes on an oral glucose tolerance test (OGTT). A total of 1,007 participants (47.2% female) were enrolled (507 in the control group and 500 in the intervention group). Participants from intervention clusters participated in a 12-month community-based peer-support program comprising 15 group sessions (12 of which were led by trained lay peer leaders) and a range of community activities to support lifestyle change. Participants from control clusters received an education booklet with lifestyle change advice. The primary outcome was the incidence of diabetes at 24 months, diagnosed by an annual OGTT. Secondary outcomes were behavioral, clinical, and biochemical characteristics and health-related quality of life (HRQoL). A total of 964 (95.7%) participants were followed up at 24 months. Baseline characteristics of clusters and participants were similar between the study groups. After a median follow-up of 24 months, diabetes developed in 17.1% (79/463) of control participants and 14.9% (68/456) of intervention participants (relative risk [RR] 0.88, 95% CI 0.66-1.16, p = 0.36). At 24 months, compared with the control group, intervention participants had a greater reduction in IDRS score (mean difference: -1.50 points, p = 0.022) and alcohol use (RR 0.77, p = 0.018) and a greater increase in fruit and vegetable intake (≥5 servings/day) (RR 1.83, p = 0.008) and physical functioning score of the HRQoL scale (mean difference: 3.9 score, p = 0.016). The cost of delivering the peer-support intervention was US$22.5 per participant. There were no adverse events related to the intervention. We did not adjust for multiple comparisons, which may have increased the overall type I error rate. A low-cost community-based peer-support lifestyle intervention resulted in a nonsignificant reduction in diabetes incidence in this high-risk population at 24 months. However, there were significant improvements in some cardiovascular risk factors and physical functioning score of the HRQoL scale. Australia and New Zealand Clinical Trials Registry ACTRN12611000262909.

Background Non-proportional hazards are common with time-to-event data but the majority of randomised clinical trials (RCTs) are designed and analysed using approaches which assume the treatment effect follows proportional hazards (PH). Recent advances in oncology treatments have identified two forms of non-PH of particular importance - a time lag until treatment becomes effective, and an early effect of treatment that ceases after a period of time. In sample size calculations for treatment effects on time-to-event outcomes where information is based on the number of events rather than the number of participants, there is crucial importance in correct specification of the baseline hazard rate amongst other considerations. Under PH, the shape of the baseline hazard has no effect on the resultant power and magnitude of treatment effects using standard analytical approaches. However, in a non-PH context the appropriateness of analytical approaches can depend on the shape of the underlying hazard. Methods A simulation study was undertaken to assess the impact of clinically plausible non-constant baseline hazard rates on the power, magnitude and coverage of commonly utilized regression-based measures of treatment effect and tests of survival curve difference for these two forms of non-PH used in RCTs with time-to-event outcomes. Results In the presence of even mild departures from PH, the power, average treatment effect size and coverage were adversely affected. Depending on the nature of the non-proportionality, non-constant event rates could further exacerbate or somewhat ameliorate the losses in power, treatment effect magnitude and coverage observed. No single summary measure of treatment effect was able to adequately describe the full extent of a potentially time-limited treatment benefit whilst maintaining power at nominal levels. Conclusions Our results show the increased importance of considering plausible potentially non-constant event rates when non-proportionality of treatment effects could be anticipated. In planning clinical trials with the potential for non-PH, even modest departures from an assumed constant baseline hazard could appreciably impact the power to detect treatment effects depending on the nature of the non-PH. Comprehensive analysis plans may be required to accommodate the description of time-dependent treatment effects.

There is a lack of understanding of what is normal in terms of sex steroid levels in older women. To determine whether sex steroid levels vary with age in and establish reference ranges for women >70 years of age. Cross-sectional, community-based study. Included 6392 women ≥70 years of age. Sex steroids measured by liquid chromatography-tandem mass spectrometry. A reference group, to establish sex steroid age-specific reference ranges, excluded women using systemic or topical sex steroid, antiandrogen or glucocorticoid therapy, or an antiglycemic agent. The reference group of 5326 women had a mean age of 75.1 (±4.2) years, range of 70 to 94.7 years. Median values (range) were 181.2 pmol/L (3.7 to 5768.9) for estrone (E1), 0.38 nmol/L (0.035 to 8.56) for testosterone (T), 2.60 nmol/L (0.07 to 46.85) for dehydroepiandrosterone (DHEA), and 41.6 nmol/L (2.4 to 176.6) for SHBG. Estradiol and DHT were below method sensitivity in 66.1% and 72.7% of the samples, respectively. Compared with women aged 70 to 74 years, women aged ≥85 years had higher median levels of E1 (11.7%, P = 0.01), T (11.3%, P = 0.02), and SHBG (22.7%, P < 0.001) and lower DHEA (30% less, P < 0.001). Women with overweight and obesity had higher E1 (P < 0.001) and T (P < 0.03) and lower SHBG (P < 0.001) than did women with normal body mass index. Smokers had 17.2% higher median T levels (P = 0.005). From the age of 70 years, T and E1 increase with age, despite a steady decline in DHEA. Whether E1 and T are biomarkers for longevity or contribute to healthy aging merits investigation.

IntroductionThe world is undergoing a demographic transition to an older population. Preventive healthcare has reduced the burden of chronic illness at younger ages but there is limited evidence that these advances can improve health at older ages. Statins are one class of drug with the potential to prevent or delay the onset of several causes of incapacity in older age, particularly major cardiovascular disease (CVD). This paper presents the protocol for the STAtins in Reducing Events in the Elderly (STAREE) trial, a randomised double-blind placebo-controlled trial examining the effects of statins in community dwelling older people without CVD, diabetes or dementia.Methods and analysisWe will conduct a double-blind, randomised placebo-controlled trial among people aged 70 years and over, recruited through Australian general practice and with no history of clinical CVD, diabetes or dementia. Participants will be randomly assigned to oral atorvastatin (40 mg daily) or matching placebo (1:1 ratio). The co-primary endpoints are disability-free survival defined as survival-free of dementia and persistent physical disability, and major cardiovascular events (cardiovascular death or non-fatal myocardial infarction or stroke). Secondary endpoints are all-cause death, dementia and other cognitive decline, persistent physical disability, fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, heart failure, atrial fibrillation, fatal and non-fatal cancer, all-cause hospitalisation, need for permanent residential care and quality of life. Comparisons between assigned treatment arms will be on an intention-to-treat basis with each of the co-primary endpoints analysed separately in time-to-first-event analyses using Cox proportional hazards regression models.Ethics and disseminationSTAREE will address uncertainties about the preventive effects of statins on a range of clinical outcomes important to older people. Institutional ethics approval has been obtained. All research outputs will be disseminated to general practitioner co-investigators and participants, published in peer-reviewed journals and presented at national and international conferences.Trial registration numberNCT02099123.

Although melanoma is initiated by acquisition of point mutations and limited focal copy number alterations in melanocytes-of-origin, the nature of genetic changes that characterise lethal metastatic disease is poorly understood. Here, we analyze the evolution of human melanoma progressing from early to late disease in 13 patients by sampling their tumours at multiple sites and times. Whole exome and genome sequencing data from 88 tumour samples reveals only limited gain of point mutations generally, with net mutational loss in some metastases. In contrast, melanoma evolution is dominated by whole genome doubling and large-scale aneuploidy, in which widespread loss of heterozygosity sculpts the burden of point mutations, neoantigens and structural variants even in treatment-naïve and primary cutaneous melanomas in some patients. These results imply that dysregulation of genomic integrity is a key driver of selective clonal advantage during melanoma progression. The genetic changes that occur in late stage metastatic melanoma are not well delineated. Here, the authors use rapid autopsy samples from metastatic melanoma patients and show that the late stage in the disease is characterised by whole genome doubling and aneuploidy.

BackgroundWe examined whether impaired kidney function, identified through elevated levels of urine albumin to creatinine ratio (UACR) or reduced estimated glomerular filtration rate (eGFR), is associated with hospitalisation or death due to heart failure (HF) in a large community-based cohort of older adults.MethodsWe included 17 834 participants from the ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial and follow-up ASPREE eXTension observational study with complete baseline data on albuminuria and eGFR. HRs for hospitalisation due to HF (HHF), HF death, a composite outcome of HHF and HF death, and HF re-admission were calculated using Cox models adjusting for potential confounders.ResultsOver a median follow-up of 8.6 years, 354 (1.98%) participants had a first hospitalisation for HF and 147 (0.82%) died due to HF. Participants with albuminuria (UACR ≥3.0 mg/mmol; 11.3%) had higher risk for HHF, HF death and the combined HF outcome compared with those with no albuminuria (HRs 1.47 (95% CI 1.12 to 1.92), 1.55 (95% CI 1.04 to 2.33) and 1.33 (95% CI, 1.05 to 1.70), respectively). In participants with albuminuria, there was also an increased risk for re-admission due to HF (HR 1.30 (95% CI 1.03 to 1.65)), although there was no difference in risk of HF death. For eGFR, a U-shaped relationship was observed with increased risk of HHF, HF death and the HF composite outcome at both low (eg, <60 mL/min/1.73 m²) and high (eg, >90 mL/min/1.73 m²) eGFR levels. However, the association at high eGFR was not statistically significant and may reflect residual confounding. No association was observed between eGFR and HF re-admission.ConclusionsIn this large cohort of older adults, albuminuria was associated with increased risk of HF outcomes, supporting its role in HF risk assessment. Low eGFR was also linked to higher risk of HHF, HF death and the HF composite outcome. Associations with high eGFR were not conclusive and should be considered hypothesis-generating.

Purpose To explore the relationship between sociodemographic and lifestyle variables with health-related quality of life (HRQoL) of a large cohort of ‘healthy’ older individuals. Methods The sample included individuals aged 65+ years from Australia ( N  = 16,703) and the USA ( N  = 2411) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) multicentre placebo-controlled trial study and free of cardiovascular disease, dementia, serious physical disabilities or ‘fatal’ illnesses. The associations with the physical (PCS) and mental component scores (MCS) of HRQoL (SF-12 questionnaire) were explored using multiple linear regression models from data collected at baseline (2010–2014). Results The adjusted PCS mean was slightly higher in the USA (49.5 ± 9.1) than Australia (48.2 ± 11.6; p  < 0.001), but MCS was similar in both samples (55.7 ± 7.5 and 55.7 ± 9.6, respectively; p = 0.603). Males, younger participants, better educated, more active individuals, or those currently drinking 1–2 alcoholic drinks/day showed a better HRQoL (results more evident for PCS than MCS), while current heavy smokers had the lowest physical HRQoL in both countries. Neither age, walking time, nor alcohol intake was associated with MCS in either cohort. Conclusions Baseline HRQoL of ASPREE participants was higher than that reported in population-based studies of older individuals, but the associations between sociodemographic and lifestyle variables were consistent with the published literature. As the cohort ages and develops chronic diseases, ASPREE will be able to document HRQoL changes.