[Special issue PRO] Considering endpoints for comparative tolerability of cancer treatments using patient report given the estimand framework.

Regulatory agencies are advancing the use of systematic approaches to collect patient experience data, including patient-reported outcomes (PROs), in cancer clinical trials to inform regulatory decision-making. Due in part to clinician under-reporting of symptomatic adverse events, there is a growing recognition that evaluation of cancer treatment tolerability should include the patient experience, both in terms of the overall side effect impact and symptomatic adverse events. Methodologies around implementation, analysis, and interpretation of "patient" reported tolerability are under development, and current approaches are largely descriptive. There is robust guidance for use of PROs as efficacy endpoints to compare cancer treatments, but it is unclear to what extent this can be relied-upon to develop tolerability endpoints. An important consideration when developing endpoints to compare tolerability between treatments is the linkage of trial design, objectives, and statistical analysis. Despite interest in and frequent collection of PRO data in oncology trials, heterogeneity in analyses and unclear PRO objectives mean that design, objectives, and analysis may not be aligned, posing substantial challenges for the interpretation of results. The recent ICH E9 (R1) estimand framework represents an opportunity to help address these challenges. Efforts to apply the estimand framework in the context of PROs have primarily focused on efficacy outcomes. In this paper, we discuss considerations for comparing the patient-reported tolerability of different treatments in an oncology trial context.

Modelling the replacement of red and processed meat with plant-based alternatives and the estimated effect on insulin sensitivity in a cohort of Australian adults.

Dietary guidelines are increasingly promoting mostly plant-based diets, limits on red meat consumption, and plant-based sources of protein for health and environmental reasons. It is unclear how the resulting food substitutions associate with insulin resistance, a risk factor for type 2 diabetes. We modelled the replacement of red and processed meat with plant-based alternatives and the estimated effect on insulin sensitivity. We included 783 participants (55 % female) from the Childhood Determinants of Adult Health study, a population-based cohort of Australians. In adulthood, diet was assessed at three time points using FFQ: 2004­2006, 2009­2011 and 2017­2019. We calculated the average daily intake of each food group in standard serves. Insulin sensitivity was estimated from fasting glucose and insulin concentrations in 2017­2019 (aged 39­49 years) using homoeostasis model assessment. Replacing red meat with a combination of plant-based alternatives was associated with higher insulin sensitivity (ß = 10·5 percentage points, 95 % CI (4·1, 17·4)). Adjustment for waist circumference attenuated this association by 61·7 %. Replacing red meat with either legumes, nuts/seeds or wholegrains was likewise associated with higher insulin sensitivity. Point estimates were similar but less precise when replacing processed meat with plant-based alternatives. Our modelling suggests that regularly replacing red meat, and possibly processed meat, with plant-based alternatives may associate with higher insulin sensitivity. Further, abdominal adiposity may be an important mediator in this relationship. Our findings support advice to prioritise plant-based sources of protein at the expense of red meat consumption.

A Healthful Plant-Based Eating Pattern Is Longitudinally Associated with Higher Insulin Sensitivity in Australian Adults.

BACKGROUND: A healthful plant-based eating pattern is associated with lower type 2 diabetes risk; however, the association with its preceding state, impaired insulin sensitivity, is less well established, particularly in younger populations with repeated measures of diet over time. OBJECTIVE: We aimed to examine the longitudinal relationship between a healthful plant-based eating pattern and insulin sensitivity in young to middle-aged adults. METHODS: We included 667 participants from the Childhood Determinants of Adult Health (CDAH) study, a population-based cohort in Australia. Healthful plant-based diet index (hPDI) scores were derived from food frequency questionnaire data. Plant foods considered "healthful" were scored positively (e.g., whole grains, fruit, vegetables), with all remaining foods scored reversely (e.g., refined grains, soft drinks, meat). Updated homeostatic model assessment (HOMA2) estimated insulin sensitivity from fasting insulin and glucose concentrations. We used linear mixed-effects regression to analyze data from 2 time points: CDAH-1 (2004-2006, 26-36 y of age) and CDAH-3 (2017-2019, 36-49 y of age). hPDI scores were modeled as between- and within-person effects (i.e., a participant's overall mean and their deviation from said mean at each time point, respectively). RESULTS: The median follow-up duration was 13 y. In our primary analysis, each 10-unit difference in hPDI score was associated with higher log-HOMA2 insulin sensitivity [95% confidence interval], with between-person (ß = 0.11 [0.05, 0.17], P < 0.001) and within-person effects (ß = 0.10 [0.04, 0.16], P = 0.001). The within-person effect persisted despite accounting for compliance with dietary guidelines. Adjustment for waist circumference attenuated the between-person effect by 70% (P = 0.26) and the within-person effect by 40% (P = 0.04). CONCLUSIONS: In young to middle-aged Australian adults, a healthful plant-based eating pattern (determined using hPDI scores) was longitudinally associated with higher insulin sensitivity, and therefore, potentially lower type 2 diabetes risk later in life.

The Association Between PCSK9 Inhibitor Use and Sepsis: A Systematic Review and Meta-Analysis of 20 Double-Blind, Randomized, Placebo-Controlled Trials.

OBJECTIVE: The aim of this study was to determine the impact of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor use on incident sepsis and other severe infections. METHODS: We searched PubMed, EMBASE, CENTRAL, and ClinicalTrial.gov up to September 14, 2021, for double-blind, placebo-controlled randomized trials of alirocumab, evolocumab, or inclisiran with >100 participants in each arm and report of serious adverse events related to infection. Data were synthesized with the fixed-effect Mantel-Haenszel model to generate risk ratios (RRs) with 95% confidence intervals (CIs) of each outcome for PCSK9 inhibitor versus placebo. Main outcome was sepsis. Other outcomes were total severe infections, severe bacterial and viral infections, and severe organ system-specific infections including respiratory tract, gastrointestinal, and genitourinary tract infections. RESULTS: A total of 20 studies of 64,984 participants were included (alirocumab: n = 7; evolocumab: n = 9; inclisiran: n = 4). Sepsis was reported in 292 (0.51%) participants from 11 trials (PCSK9 inhibitor 0.47%; placebo 0.56%). PCSK9 inhibitor use was not associated with risk of sepsis compared with placebo (Summary RR: 0.85, 95% CI: 0.67-1.07, P = .16); nor was it associated with any severe infection (0.96, 95% CI: 0.89-1.03), severe bacterial (0.96, 95% CI: 0.81-1.14) and viral infections (1.01, 95% CI: 0.77-1.33); nor with any severe organ system-specific infection (all P values >.05). The between-study heterogeneity in all analyses was small. CONCLUSION: There was neither a beneficial nor a harmful association between PCSK9 inhibitors and risk of sepsis or severe infections. These findings provide reassurance regarding the safety of PCSK9 inhibitors in patients who are concerned about potential drug side effects related to infections.

Age-related changes in gait domains: Results from the LonGenity study.

BACKGROUND: Impairment in gait domains such as pace, rhythm, and variability are associated with falls, cognitive decline, and dementia. However, the longitudinal changes in these gait domains are poorly understood. The aim of this study was to examine age-related changes in gait domains overall and in those with cognitive impairment and mobility disability. METHODS: Participants were from the LonGenity study (n = 797; M Age=75.1 SD 6.5 years; 58.2% female) and were followed up to 12 years (Median=3.3; IQR: 1.1; 6.3). Gait speed and absolute values of step length, step time, cadence and, variability (standard deviation) of step length and step time during usual pace walking were assessed. Principal components analysis was used to obtain weighted combinations of three gait domains: pace (velocity, step length), variability (step length variability, step time variability) and rhythm (step time). Linear mixed effect models were used to examine age-related changes in gait domains overall, and in those with cognitive impairment and mobility disability at baseline. RESULTS: Pace declined, and rhythm increased (worsened) in an accelerating non-linear fashion. Variability gradually increased with age. Those with cognitive impairment had faster rates of change in pace and rhythm. Those with mobility disability had faster increases in rhythm. CONCLUSIONS: Age-related changes in gait domains are not uniform. Individuals with cognitive and mobility impairments are particularly vulnerable to accelerated change in pace and or rhythm.

Impact of Blood Lipids on 10-Year Cardiovascular Risk in Individuals Without Dyslipidemia and With Low Risk Factor Burden.

OBJECTIVE: To determine the association of plasma lipids with the prevalence of subclinical atherosclerosis and 10-year risk of incident cardiovascular (CV) events among healthy individuals without dyslipidemia and with low risk factor burden. PATIENTS AND METHODS: The analysis (June 24, 2020, through June 12, 2021) included 1204 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) study who were current nonsmokers and did not have CV disease, hypertension (blood pressure ≥130/80 mm Hg or antihypertensive use), diabetes (fasting glucose ≥126 mg/dL or glucose-lowering medication use), and dyslipidemia (low-density-lipoprotein-cholesterol [LDL-C] ≥160 mg/dL, high-density-lipoprotein-cholesterol [HDL-C] <40 mg/dL, total cholesterol [TC] ≥240 mg/dL, triglycerides [TGs] ≥150 mg/dL, or lipid-lowering medication use) at baseline. Associations of lipids with baseline atherosclerosis (presence of carotid plaque and/or coronary calcification) and incident CV events over 10 years were examined using multivariable relative risk regression and Cox regression, respectively. RESULTS: At baseline, participants' median age was 54 (IQR, 49 to 62) years, and 10-year CV risk was 2.7% (IQR, 1.0% to 6.6%); 43.4% had subclinical atherosclerosis. A 1-SD higher LDL-C (23.4 mg/dL), TC (24.7 mg/dL), non-HDL-C (25.3 mg/dL), TC/HDL-C (0.75), and LDL-C/HDL-C (0.66) was associated with a higher prevalence of atherosclerosis of between 6% and 9% (P<.05). For every 1-SD higher LDL-C, non-HDL-C, TC/HDL-C, LDL-C/HDL-C, and TG/HDL-C (0.49), the 10-year incidence of CV events was significantly increased by 40%, 44%, 51%, 49%, and 39%, respectively. For every 1-SD lower HDL-C (13.5 mg/dL), CV risk was increased by 37%. Triglycerides had no association with either outcome. CONCLUSION: Except for TGs, all lipid variables were associated with atherosclerosis and future risk of CV disease among persons without dyslipidemia and with low risk factor burden.

Cognitive inhibition tasks interfere with dual-task walking and increase prefrontal cortical activity more than working memory tasks in young and older adults

BACKGROUND: Prior work suggests there may be greater reliance on executive function for walking in older people. The pre-frontal cortex (PFC), which controls aspects of executive function, is known to be active during dual-task walking (DTW). However, there is debate on how PFC activity during DTW is impacted by ageing and the requirements of the cognitive task. RESEARCH QUESTION: Functional near infrared spectroscopy, was used to investigate how PFC activity during walking was affected by (i) healthy ageing; and (ii) dual-tasks that utilise inhibition or working memory aspects of executive function. METHODS: Young (n = 26, 16 females, mean 20.9 years) and older (n = 26, 16 females, mean 70.3 years) adults performed five conditions: normal walking; Reciting Alternate Letters of the alphabet (RAL, requiring cognitive inhibition and working memory) during standing and walking; and serial subtraction by threes (SS3, requiring working memory alone) during standing and walking. Walking speed, cognitive performance, the PFC haemodynamic response, and fear of falling ratings were analysed using linear mixed-effects modelling. RESULTS: Compared to quiet standing, PFC activity increased during normal walking for older adults but decreased for young adults (p < 0.01). Across both groups, fear of falling contributed to higher PFC activity levels when walking (p < 0.01). PFC activity increased during DTW, and this increase was greater when performing RAL compared to the SS3 task (p < 0.01). Although the rate of correct responses was higher for RAL, walking speed reduced more with RAL than SS3 in the young group (p = 0.01), and the rate of correct responses reduced more when walking with RAL than SS3 in the older group (p < 0.01). SIGNIFICANCE: Older adults have increased levels of PFC activation during walking compared to younger adults and fear of falling is a cofounding factor. The interference between gait and a concurrent cognitive task is higher when the cognitive task requires inhibition.

Longitudinal associations between falls and future risk of cognitive decline, the Motoric Cognitive Risk syndrome and dementia: the Einstein Ageing Study.

BACKGROUND: falls share risk factors with cognitive decline but whether falls predict cognitive decline, pre-dementia syndromes and dementia is poorly understood. OBJECTIVES: this study aimed to examine if falls are associated with cognitive decline in specific domains and the risk of Motoric Cognitive Risk (MCR) syndrome and dementia. DESIGN: cross-sectional study. METHODS: in older people (age 80.6 ± 5.3 years) free of dementia at baseline, the number of falls (none, one or multiple) during the year before enrolment and the first year of follow-up (exposure) were recorded. Decline in specific cognitive functions (global cognition, episodic verbal memory, verbal fluency, working memory, response inhibition and processing speed-attention), incident MCR and incident dementia were outcome measures. Linear mixed effects models were used to examine the associations between falls and cognitive decline, adjusting for confounders. Cox proportional hazards models were used to determine if falls predicted risk of incident MCR or dementia. RESULTS: of 522 eligible participants, 140 had a single fall and 70 had multiple falls. Multiple falls were associated with a greater decline in global cognition, episodic memory, verbal fluency and processing speed-attention compared to those with no falls (P < 0.05). Over a median follow-up of 1.0 years 36 participants developed MCR and 43 participants developed dementia. Those with multiple falls had a two-fold increased risk of MCR compared to those with no falls, but no increased risk of developing dementia. CONCLUSIONS: multiple falls may be an important marker to identify older people at greater risk of future cognitive decline and incident MCR.

Health-related quality of life in people with psychotic disorders: The role of loneliness and its contributors.

BACKGROUND: Perception of loneliness has been identified as the strongest predictor of health-related quality of life assessed with the Assessment of Quality of Life-4D in people with psychotic disorders. We aimed to establish contributors to perceived loneliness, and ascertain the mediating role of loneliness in the relationship between identified contributors to loneliness and other known predictors of health-related quality of life with health-related quality of life. METHODS: Data for 1642 people collected as part of the 2010 Australian National Survey of Psychosis were analysed. Health-related quality of life was assessed using the Assessment of Quality of Life-4D, and loneliness through a single-item five-level categorical variable. To identify independent contributors to loneliness, a statistical model was constructed with reference to a theoretical model comprising 23 variables. A predictive model with health-related quality of life as the dependent variable was then developed and tested to assess the mediating role of loneliness. RESULTS: Nine contributors to loneliness were found (social dysfunction, experienced stigma, contact with friends, diagnosis, depressive symptoms, anxiety, mental health service utilisation, arthritis and traumatic events in childhood), with social dysfunction the strongest. In the prediction of health-related quality of life, all contributors to loneliness were partially mediated through loneliness (except service utilisation) as were negative symptoms and use of psychotropic/anticholinergic medications. CONCLUSION: Assuming a plausible causal model of mediation, loneliness was found to have direct and indirect effects on health-related quality of life in people with psychotic disorders. Findings add impetus to efforts to develop and trial strategies aimed at reducing loneliness in this population, and, in turn, improving their health-related quality of life.

"Factors influencing sedentary time and physical activity early after stroke: a qualitative study".

PURPOSE: We aimed to understand from the perspective of stroke survivors and their carers (1) factors contributing to sedentary time and physical activity during inpatient rehabilitation and the transition home, and (2) actual and perceived opportunities to reduce sedentary time and increase physical activity. MATERIAL AND METHODS: Qualitative study with 7 stroke survivor/carer dyads and 8 stroke survivors. Semi-structured interviews were conducted 2-4 weeks after hospital discharge, audio recorded and transcribed prior to thematic analysis. RESULTS: Stroke survivors were mean age 69 [SD15] years (53% male). Carers were mean age 62 [SD15] years (86% were female). Five themes were identified: (1) Education and guidance about physical activity and sedentary behaviour after stroke is important to build understanding of recovery and secondary prevention, (2) Stroke survivors need clear communication about safety and risk, (3) Return to life participation supports motivation for and engagement in physical activity, 4) Social and professional influences and 5) Opportunities to be physically active. CONCLUSION: Stroke survivors and their carers need a clearer understanding of the role of physical activity and risks of sedentary time during stroke recovery. Physical activity enablers included consistent communication, building confidence and skills to self-manage activity before discharge.Implications for RehabilitationInpatient rehabilitation and early after discharge may be an important time-point to support stroke survivors to establish long term physical activity behaviours before contact with healthcare professionals reduces.To reduce sedentary behaviour, people need to understand the health benefits of breaking up sedentary time and people who need physical support to stand up will need greater support from health professionals.Being able to imagine a future post-stroke self is important motivation to get up and move. Rehabilitation should help develop a person's vision of their post-stroke self.Managing potential risks in hospital without overly restricting physical activity is important and requires consistent communication from the multi-disciplinary team.Building a person's confidence and skills to self-manage physical activity in the community prior to discharge home may be another key enabler for activity.

Relative Trajectories of Gait and Cognitive Decline in Aging.

BACKGROUND: Gait and cognition decline with advancing age, and presage the onset of dementia. Yet, the relative trajectories of gait and cognitive decline in aging are poorly understood-particularly among those with the motoric cognitive risk (MCR) syndrome. This study compared changes in simple and complex gait performance and cognition, as a function of age and MCR. METHODS: We examined gait and cognitive functions of 1 095 LonGenity study participants (mean age = 75.4 ± 6.7 years) with up to 12 years of annual follow-up. Participants were of Ashkenazi Jewish descent, free of dementia, ambulatory, and had a 12.2% MCR prevalence at baseline. Gait speed was measured at usual pace walking (single-task walking, STW-speed) and walking while talking (WWT-speed). Eleven neuropsychological test scores were examined separately, and as a global cognition composite. Linear mixed-effects models adjusted for baseline sex, education, parental longevity, cognitive impairment, and global health were used to estimate changes in gait and cognition, as a function of age and MCR. RESULTS: STW-speed, WWT-speed, and cognitive tests performance declined in a nonlinear (accelerating) fashion with age. STW-speed declined faster than WWT-speed and cognitive test scores. People with MCR showed faster rates of decline on figure copy and phonemic fluency. CONCLUSIONS: Gait declines at a faster rate than cognition in aging. People with MCR are susceptible to faster decline in visuospatial, executive, and language functions. This study adds important knowledge of trajectories of gait and cognitive decline in aging, and identifies MCR as a risk factor for accelerated cognitive decline.

Case-Fatality and Functional Outcome after Subarachnoid Hemorrhage (SAH) in INternational STRoke oUtComes sTudy (INSTRUCT).

BACKGROUND: There are few large population-based studies of outcomes after subarachnoid hemorrhage (SAH) than other stroke types. METHODS: We pooled data from 13 population-based stroke incidence studies (10 studies from the INternational STRroke oUtComes sTudy (INSTRUCT) and 3 new studies; N=657). Primary outcomes were case-fatality and functional outcome (modified Rankin scale score 3-5 [poor] vs. 0-2 [good]). Harmonized patient-level factors included age, sex, health behaviours (e.g. current smoking at baseline), comorbidities (e.g.history of hypertension), baseline stroke severity (e.g. NIHSS >7) and year of stroke. We estimated predictors of case-fatality and functional outcome using Poisson regression and generalized estimating equations using log-binomial models respectively at multiple timepoints. RESULTS: Case-fatality rate was 33% at 1 month, 43% at 1 year, and 47% at 5 years. Poor functional outcome was present in 27% of survivors at 1 month and 15% at 1 year. In multivariable analysis, predictors of death at 1-month were age (per decade increase MRR 1.14 [1.07-1.22]) and SAH severity (MRR 1.87 [1.50-2.33]); at 1 year were age (MRR 1.53 [1.34-1.56]), current smoking (MRR 1.82 [1.20-2.72]) and SAH severity (MRR 3.00 [2.06-4.33]) and; at 5 years were age (MRR 1.63 [1.45-1.84]), current smoking (MRR 2.29 [1.54-3.46]) and severity of SAH (MRR 2.10 [1.44-3.05]). Predictors of poor functional outcome at 1 month were age (per decade increase RR 1.32 [1.11-1.56]) and SAH severity (RR 1.85 [1.06-3.23]), and SAH severity (RR 7.09 [3.17-15.85]) at 1 year. CONCLUSION: Although age is a non-modifiable risk factor for poor outcomes after SAH, however, severity of SAH and smoking are potential targets to improve the outcomes.

Antihypertensive drug class in combination with lipid lowering treatment for primary prevention of cardiovascular disease in the elderly.

BACKGROUND: Antihypertensives and lipid-lowering therapy (LLT) are often used concurrently. OBJECTIVES: To determine whether there was a difference in clinical outcomes when older patients with LLT were prescribed angiotensin-converting-enzyme-inhibitors (ACE-Is) compared with diuretics. METHODS: This analysis included 648 LLT older users free of cardiovascular disease (CVD) from a trial comparing ACE-I versus diuretic-based therapy. Comparisons were made between LLT+ACE-I (n = 335) and LLT+diuretic groups (n = 313) using multivariable Cox proportional-hazard models. Primary endpoints were all-cause and CVD mortality (in-trial [4.1-year]+post-trial [6.9-year]) and secondary endpoints (in-trial) were the composite of all-cause mortality and first CVD events and its components, CVD mortality and incident diabetes. RESULTS: There were no significant differences between the two groups for the primary endpoints over the in-trial plus post-trial follow-up, nor was there a difference for any secondary outcomes over the in-trial follow-up. CONCLUSIONS: The LLT+ACE-I and LLT+diuretic combinations showed similar effects in CVD-free older individuals. Randomised trials are needed to provide conclusive evidence.

The association between simple reaction time variability and gait variability: The Tasmanian Study of Cognition and Gait.

INTRODUCTION: Greater double support time (DST) variability is associated with falls and memory decline. The underlying neurophysiological mechanisms of DST variability are poorly understood. Simple reaction time (SRT) variability, a measure of attention-processing speed is associated with falls and dementia and, may underlie greater DST variability. The aims of this study were to examine the association between SRT and DST variability and if SRT variability mediates the associations between poorer cognition/brain structure and DST variability. METHODS: Participants (n = 408) were community-dwelling older people without dementia (mean age 72.0 ± 7.0). DST variability was the standard deviation (SD) of DST, assessed with a walkway and averaged across steps of 6 walks. SRT variability was the SD of a button pressing task in response to a visual stimulus. Executive function and processing speed were assessed with neuropsychological tests. Magnetic Resonance Imaging was used to obtain cortical thickness (total and in frontal regions) and cerebral small vessel disease (cSVD). Multivariable linear regression models were used to examine the association between SRT and DST variability and if SRT variability mediated any associations of cognition/brain structure with DST variability. RESULTS: Greater SRT variability was associated with greater DST variability (p = 0.002). SRT variability partially mediated the association between poorer executive function and greater DST variability. Smaller mean thickness in orbitofrontal regions and greater cSVD burden were only associated with DST variability (p < 0.05), not with SRT variability (p > 0.05). CONCLUSIONS: Greater SRT variability, which may occur due to inefficient executive functioning, could be an underlying neurophysiological mechanism of greater DST variability.

Adherence to evidence-based processes of care reduces one-year mortality after aneurysmal subarachnoid hemorrhage (aSAH).

BACKGROUND: There is limited research on the provision of evidence-based care and its association with outcomes after aneurysmal subarachnoid hemorrhage (aSAH). AIMS: We examined adherence to evidence-based care after aSAH and associations with survival and discharge destination. Also, factors associated with evidence-based care including age, sex, Charlson comorbidity index, severity scores, and delayed cerebral ischemia and infarction were examined for association with survival and discharge destination. METHODS: In a retrospective cohort (2010-2016) of all aSAH cases across two comprehensive cerebrovascular centres, we extracted 3 indicators of evidence-based aSAH care from medical records: (1) antihypertensives prior to aneurysm treatment, (2) nimodipine, and (3) aneurysm treatment (coiling/clipping). We defined 'optimal care' as receiving all eligible processes of care. Survival at 1 year was obtained by data linkage. We estimated (1) proportion of patients and characteristics associated with receiving processes of care, (2) associations between processes of care with 1-year mortality using cox-proportional hazard model and discharge destination with log binomial regression adjusting for age, sex, severity of aSAH, delayed cerebral ischemia and/or cerebral infarction and comorbidities. Sensitivity analyses explored effect modification of the association between processes of care and outcome by management type (active versus comfort measures). RESULTS: Among 549 patients (69% women), 59% were managed according to the guidelines. Individual indicators were associated with lower 1-year mortality but not discharge destination. Optimal care reduced mortality at 1 year in univariable (HR 0.24 95% CI 0.17-0.35) and multivariable analyses (HR 0.51 95% CI 0.34-0.77) independent of age, sex, severity, comorbidities, and hospital network. CONCLUSION: Adherence to processes of care reduced 1-year mortality after aSAH. Many patients with aSAH do not receive evidence-based care and this must be addressed to improve outcomes.

Proposing a causal pathway for health-related quality of life in people with psychotic disorders.

This study aimed to establish independent predictors for health-related quality of life (HRQoL) in people with psychotic disorders, and the mediating role of global functioning in those relationships. Data for 1642 people collected as part of the second Australian National Survey of Psychosis were analyzed. The Assessment of Quality of Life (AQoL)-4D and the Personal and Social Performance scale were used for assessing HRQoL and global functioning respectively. The study commenced with a theoretical model comprised of 26 sociodemographic and clinical variables. A predictive model for HRQoL was built up using a purposeful selection strategy to arrive at a set of clinically meaningful, independent predictors. The mediating effect of global functioning was then assessed. Seven variables were found to have an independent effect on HRQoL: perception of loneliness, number of negative symptoms, use of psychotropic and anticholinergic medications, course of disorder, lifetime histories of chronic pain and cardiovascular disease and living arrangements at the time of the interview. All variables except perceived loneliness and chronic pain were partially mediated through global functioning. This final model explained 46% of the variance in HRQoL, with loneliness and number of negative symptoms the strongest predictors. Evidence in support of a credible causal pathway for HRQoL in people with psychotic disorders, mediated by global functioning was presented. The importance of the quality of social relationships was highlighted, and potential targets for improving the HRQoL of this population identified.

Retrospectively Estimating Energy Intake and Misreporting From a Qualitative Food Frequency Questionnaire: An Example Using Australian Cohort and National Survey Data.

Qualitative food frequency questionnaires (Q-FFQ) omit portion size information from dietary assessment. This restricts researchers to consumption frequency data, limiting investigations of dietary composition (i.e., energy-adjusted intakes) and misreporting. To support such researchers, we provide an instructive example of Q-FFQ energy intake estimation that derives typical portion size information from a reference survey population and evaluates misreporting. A sample of 1,919 Childhood Determinants of Adult Health Study (CDAH) participants aged 26-36 years completed a 127-item Q-FFQ. We assumed sex-specific portion sizes for Q-FFQ items using 24-h dietary recall data from the 2011-2012 Australian National Nutrition and Physical Activity Survey (NNPAS) and compiled energy density values primarily using the Australian Food Composition Database. Total energy intake estimation was daily equivalent frequency × portion size (g) × energy density (kJ/g) for each Q-FFQ item, summed. We benchmarked energy intake estimates against a weighted sample of age-matched NNPAS respondents (n = 1,383). Median (interquartile range) energy intake was 9,400 (7,580-11,969) kJ/day in CDAH and 9,055 (6,916-11,825) kJ/day in weighted NNPAS. Median energy intake to basal metabolic rate ratios were 1.43 (1.15-1.78) in CDAH and 1.35 (1.03-1.74) in weighted NNPAS, indicating notable underreporting in both samples, with increased levels of underreporting among the overweight and obese. Using the Goldberg and predicted total energy expenditure methods for classifying misreporting, 65 and 41% of CDAH participants had acceptable/plausible energy intake estimates, respectively. Excluding suspected CDAH misreporters improved the plausibility of energy intake estimates, concordant with expected body weight associations. This process can assist researchers wanting an estimate of energy intake from a Q-FFQ and to evaluate misreporting, broadening the scope of diet-disease investigations that depend on consumption frequency data.

The Associations Between Grey Matter Volume Covariance Patterns and Gait Variability-The Tasmanian Study of Cognition and Gait.

Greater gait variability predicts dementia. However, little is known about the neural correlates of gait variability. The aims of this study were to determine (1) grey matter volume covariance patterns associated with gait variability and (2) whether these patterns were associated with specific cognitive domains. Participants (n = 351; mean age 71.9 ± 7.1) were randomly selected from the Southern Tasmanian electoral roll. Step time, step length, step width and double support time were measured using an electronic walkway. Gait variability was calculated as the standard deviation of all steps for each gait measure. Voxel-based morphometry and multivariate covariance-based analyses were used to identify grey matter patterns associated with each gait variability measure. The individual expressions of grey matter patterns were correlated with processing speed, memory, executive and visuospatial functions. The grey matter covariance pattern of double support time variability included frontal, medial temporal, anterior cingulate, insula, cerebellar and striatal regions. Greater expression of this pattern was correlated with poorer performance in all cognitive functions (p < 0.001). The covariance pattern of step length variability included frontal, temporal, insula, occipital and cerebellar regions and was correlated with all cognitive functions (p < 0.05), except memory (p = 0.76). The covariance pattern of step width variability was limited to the cerebellum and correlated only with memory (p = 0.047). No significant pattern was identified for step time variability. In conclusion, different grey matter covariance patterns were associated with individual gait variability measures. These patterns were also correlated with specific cognitive functions, suggesting common neural networks may underlie both gait and cognition.

The Association Between Physical Activity Intensity, Cognition, and Brain Structure in People With Type 2 Diabetes.

BACKGROUND: Physical inactivity is a risk factor for type 2 diabetes (T2D) and dementia. However, it is unknown if physical activity (PA) intensity is associated with brain health in people with T2D. Therefore, this study aimed to determine (i) associations between PA intensity and step count with both cognition and brain structure and (ii) if apolipoprotein E-ε4 or insulin therapy modifies any associations. METHODS: Participants were people with T2D (n = 220; aged 55-86 years). An accelerometer worn over the right hip was used to obtain step count and moderate-to-vigorous PA (MVPA) averaged over 7 days. Cognition in 7 domains was obtained using a battery of neuropsychological tests. Brain structure was measured by Magnetic Resonance Imaging. Linear regression models were used to examine associations between step count, MVPA and each cognitive and Magnetic Resonance Imaging measure. Apolipoprotein E-ε4 × PA and insulin therapy × PA product terms were added to the models to examine effect modification. RESULTS: The mean age of participants was 67.9 (SD = 6.3). Higher step count was associated with greater hippocampal volume (ß = 0.028, 95% CI = 0.005, 0.051). Insulin therapy modified the association between MVPA and attention-processing speed, such that associations were significant in people receiving insulin therapy (p for interaction = .019). There were no other significant associations. CONCLUSIONS: Higher step count and greater time spent in MVPA may be associated with better hippocampal volume and attention-processing speed, respectively, in people with T2D. People with greater diabetes severity (receiving insulin therapy) may get more cognitive benefit from MVPA.

Older participant perspectives on permanent study drug discontinuation in an ongoing primary prevention trial of statins.

PURPOSE: Study drug discontinuation is commonplace in clinical trials of older populations. Little is known about why older participants discontinue the study drug. This qualitative study aimed to understand factors contributing to permanent study drug discontinuation among participants aged ≥ 70 years within an ongoing primary prevention trial of statins by exploring their experiences and perceptions. METHODS: Trial participants who had permanently discontinued the study drug within 2 years of randomisation were purposively sampled by age (< 75 and ≥ 75 years) and sex to participate in semi-structured phone interviews between March 2019 and February 2020. Interviews were audio-recorded, transcribed and analysed thematically. RESULTS: Thirty participants were interviewed (21 females; mean age, 77 years), and three themes were identified from the data. Perceived adverse events (AEs) and their effect on daily living (mobility, functional capacity, quality of life) were identified as the major factors leading to the participants permanently discontinuing their study drug, despite an ambiguity about the cause of the AE. For some, concurrent challenging life circumstances further lowered their tolerance to perceived AEs thus making discontinuation more likely. A few discontinuations were attributed to other factors (e.g. GP advice, unrelated illness). CONCLUSION: Among healthy older participants enrolled in a statin trial, perceived AEs and their related impact were key factors contributing to the permanent study drug discontinuation. Addressing anticipated participant-reported AEs and their concerns about drug-related side effects at trial entry, as well as offering timely medical assistance and support when AEs occur, may be useful to reduce drug discontinuation rates.