Background Poor sleep is common in people with multiple sclerosis (PwMS). Previous systematic reviews have evaluated intervention effectiveness to improve sleep in PwMS using questionnaires, but no review has comprehensively examined whether sleep interventions improve activity monitor measured sleep outcomes in PwMS. Methods Adhering to the PRISMA guidelines, we searched PubMed, EMBASE, and PsycINFO databases to identify randomized controlled trials, quasi-experimental and cohort studies published from inception to October 2025. A random-effects model was used to estimate the pooled intervention effects of sleep interventions on objective sleep outcomes. Results Ten studies were included in the review for narrative synthesis, with five eligible for quantitative meta-analysis. Six sleep parameters were assessed via activity monitors: total sleep time, sleep efficiency, total time in bed, sleep onset latency, wake after sleep onset, and frequency of awakenings. Sleep interventions utilised included physical activity, mindfulness, cognitive behavioral therapy (CBT), melatonin, eszopiclone and transcranial direct current stimulation (tDCS). Only sleep efficiency improved following mindfulness interventions. The median length of actigraph wear time was 7 days (range 4 nights to 16 weeks). Study quality appraisal scores ranged from moderate to high, suggesting a low risk of bias. Conclusion Activity monitors have been used to assess sleep intervention effectiveness in PwMS in studies assessing physical activity, mindfulness and CBT. Objective improvements in sleep were reported following mindfulness and only using one measure (sleep efficiency). However, the small number of included studies limits definitive conclusions. Future trials should consider a wider range of outcome measures and longer time horizons.

There is widespread interest among patients, clinicians, regulators and other constituents in post-treatment patient-reported cancer data. Side effect bother is a patient-reported outcome (PRO) that can capture an important aspect of tolerability. In this study, we examined side effect bother at cancer treatment discontinuation and post-discontinuation in commercial cancer trials. We sought to understand completion rates, the extent of bother and its association with other PROs. Data were evaluated from three trials in patients with solid tumours (renal cell carcinoma and breast cancer). Side effect bother was measured with the Functional Assessment of Chronic Illness Therapy (FACIT) GP5 item. Symptom items were drawn from FACIT and function items were drawn from the EQ-5D-3L. FACIT items, including the GP5, are on a 0–4 scale (higher = worse symptoms/bother), and were dichotomised as 0–1 (“low”) vs 2–4 (“moderate”). EQ-5D-3L items were characterised as no problems (1) and some problems (2–3). Descriptive and correlation analyses were conducted separately for each trial. Among patients who received treatment, completion rates at discontinuation for most items were at least 70

BACKGROUND:Cardiovascular disease is a leading cause of global mortality. Carotid-femoral pulse wave velocity (cfPWV) is the gold-standard noninvasive measure of arterial stiffness and is commonly used to assess early vascular aging, as it predicts future cardiovascular events. Although the influence of cardiovascular risk factors on cfPWV is well studied in adults, evidence in youth is limited. This study aimed to identify common cardiovascular risk factors that best explain variation in cfPWV among young people. METHODS:This study included 6763 participants aged 5 to 40 years with cfPWV measured using the SphygmoCor device, drawn from the Youth Vascular Consortium. Analyses were conducted across 5 subsets based on data completeness. Multiple linear regression models, stratified by sex and age (≤19 and >19 years), were developed to identify cardiovascular risk factors explaining cfPWV variation. Model selection was guided by Akaike information criterion and adjusted R2. RESULTS:Age and systolic blood pressure were consistent predictors, explaining <40% of cfPWV variance in cfPWV. Heart rate and waist circumference also emerged as key predictors of cfPWV, although lipids contributed modestly only in young adults. Waist circumference was the strongest anthropometric predictor in most groups. CONCLUSIONS:Age, systolic blood pressure, and heart rate were the strong contributors among traditional risk factors, yet explained <40% of variance in cfPWV in most groups. These findings highlight the role of hemodynamic load in shaping arterial stiffness even in childhood and adolescence, when structural changes are evolving. A large proportion of variance remains unexplained, suggesting that genetic, prenatal, environmental, and behavioral factors warrant investigation.

BACKGROUND:There is growing recognition of the importance of patient-reported tolerability in complementing traditional clinician-reported safety evaluation of cancer therapies. Recent regulatory guidance listed the evaluation of overall side effect impact as a core patient-reported outcome in oncology clinical trials. A single item ('GP5') that asks about side effect bother is included in the Functional Assessment of Chronic Illness Therapy and has been used to capture overall side effect impact. This paper sought to expand the evidence base for GP5 by examining its association with clinician-reported treatment-emergent adverse events and patient-reported global health. METHODS:We examined six commercial cancer clinical trials that collected GP5. The patient population was drawn from the safety population and the analysis focused on the first on-treatment assessment. Clinician-reported adverse events were classified as symptomatic if such adverse events were considered amenable to patient self-reporting (e.g. nausea). Chi-square tests and Pearson's correlation were used to examine associations. We considered adverse event grade and frequency, both for symptomatic adverse events and any type of adverse events. Global health was measured using the visual analogue scale of the EuroQol-5 Dimensions-3 Levels measure. 'Moderate-severe' bother was characterised as scores of 2-4 on a 0-4 point scale for GP5, and 'severe' bother was characterised as scores of 3-4. Analyses were conducted separately for each trial. RESULTS:Data from 3,557 patients were included. Across the trials, most (71.7%-94.2%) patients had an adverse event of some kind, but fewer (17.1%-44.4%) had an adverse event of grade 3 or higher. In general, fewer than 50% of patients (20.6%-44.2%) reported moderate-severe bother and 5.8%-17.% reported severe bother. There were consistent, albeit not always statistically significant, associations between GP5 and adverse events, and GP5/global health correlations ranged from -0.17 to -0.41. DISCUSSION:GP5 is associated with both clinician- and patient-reported symptoms, suggesting its validity and usefulness as part of comprehensive tolerability assessment of cancer trials.

BACKGROUND:Dual decline in gait and cognition is associated with an increased risk of dementia, with the strongest association seen between gait speed and delayed memory. However, the underlying brain correlates remain unknown. This study aimed to explore the associations between regional brain volumes and dual decline in gait speed and delayed memory. METHOD:Participants over 60 years were randomly selected from the Southern Tasmanian electoral roll (Australia). Baseline brain MRI and three serial gait speed and delayed memory assessments were performed on average 2.5 years apart. Participants were classified into four groups depending on tertiles of annual decline in gait speed and memory: non-decline, gait only, cognition only, and dual decline. Twenty-one regional brain volumes (in frontal, parietal, temporal, subcortical, brain stem and cerebellar areas) were preselected based on previous studies of gait and memory. Multinomial logistic regression was used to examine the associations between baseline regional brain volumes and the four groups. RESULT:The mean age of participants was 70.9 ± SD 6.7 years (n = 266). Lower volume in six brain regions (superior frontal gyrus, anterior cingulate cortex, middle frontal gyrus, thalamus, orbitofrontal cortex, hippocampus) were associated with a higher risk of dual decline. Lower volumes in the thalamus and cerebellum were associated with a higher risk of gait only and cognitive only decline respectively. However, these associations did not remain significant after correction for multiple comparisons. CONCLUSION:In this exploratory study regions related to memory, executive function, motor, and sensory motor integration were found to have associations with dual decline. Larger studies investigating a wider range of brain pathologies are required to fully understand the mechanisms underlying dual decline.

BACKGROUND: Aortic pulse wave velocity (PWV) is an indicator of vascular aging and has proven to be effective in adult cardiovascular risk assessment. To use it in young people to identify those who may be at increased cardiovascular disease risk, reference values need to be determined. The Youth Vascular Consortium is a large, international database which was established to investigate vascular aging in youth. Using data from the Youth Vascular Consortium, this study aimed to develop reference values for aortic PWV in healthy young people. METHODS: This is a retrospective, multicenter study. Data on demographics, anthropometric, biochemical, and vascular aging measures from participants aged 1 year to 40 years were harmonized. Generalized additive models were used to derive percentile curves for PWV and predicted percentiles at years of age were reported by sex, continent, and device. RESULTS: Data from 19 930 participants (mean age=17 years, 51% female, 71% European), classified as healthy based on blood pressure, body mass index, serum glucose, and cholesterol levels, were included to construct the reference values. Six devices were used to assess aortic PWV (29% SphygmoCor). Device-specific percentile curves for aortic PWV were constructed, and an increasing trend was identified for both sexes with age. CONCLUSIONS: This study provided reference values for aortic PWV assessed with 6 devices for healthy young people by age and sex. These percentiles may be applied clinically to identify youth with impaired vascular aging and, thus, those who may be at risk of developing overt cardiovascular disease in the future.

Dual decline in gait and cognition is associated with an increased risk of dementia, with the strongest association seen between gait speed and delayed memory. However, the underlying brain correlates remain unknown. This study aimed to explore the associations between regional brain volumes and dual decline in gait speed and delayed memory. Participants over 60 years were randomly selected from the Southern Tasmanian electoral roll (Australia). Baseline brain MRI and three serial gait speed and delayed memory assessments were performed on average 2.5 years apart. Participants were classified into four groups depending on tertiles of annual decline in gait speed and memory: non-decline, gait only, cognition only, and dual decline. Twenty-one regional brain volumes (in frontal, parietal, temporal, subcortical, brain stem and cerebellar areas) were preselected based on previous studies of gait and memory. Multinomial logistic regression was used to examine the associations between baseline regional brain volumes and the four groups. The mean age of participants was 70.9 ± SD 6.7 years ( n  = 266). Lower volume in six brain regions (superior frontal gyrus, anterior cingulate cortex, middle frontal gyrus, thalamus, orbitofrontal cortex, hippocampus) were associated with a higher risk of dual decline. Lower volumes in the thalamus and cerebellum were associated with a higher risk of gait only and cognitive only decline respectively. However, these associations did not remain significant after correction for multiple comparisons. In this exploratory study regions related to memory, executive function, motor, and sensory motor integration were found to have associations with dual decline. Larger studies investigating a wider range of brain pathologies are required to fully understand the mechanisms underlying dual decline.

Patient-perceived treatment tolerability can affect patient ability and willingness to remain on therapy. We sought to examine completion rates for a single item of overall side effect bother at baseline and at the first on-treatment assessment, the association between this item with other patient-reported outcomes (PROs) and the odds of early discontinuation due to clinician-assessed adverse events or reasons other than disease progression. Data were from three commercial cancer trials in solid tumours, focusing on the safety population. The GP5 item from the Functional Assessment of Cancer Therapy (FACT) was used for side effect bother. Other PROs included items on specific symptoms, functional impacts and global health status, all drawn from validated measures. Descriptive statistics were used for completion rates, and correlation and logistic regression analyses were used to examine associations. GP5 was dichotomised as 0–1 (‘low’) versus 2–4 (‘high’). Completion rates were at or above 90

BACKGROUND:Strategies used by people living with MS to get to sleep and stay asleep, and whether they impact sleep quality and daytime sleepiness is not clear. METHODS:Australian MS Longitudinal Study participants (n = 1590) self-reported treatments used for sleep, sleep quality and daytime sleepiness. Prescription medications that could influence sleep were identified from administrative data collected <3 months prior to self-reports. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI); daytime sleepiness using the Epworth Sleepiness Scale (ESS). Effects of prescription medications on sleep outcomes were examined using inverse probability weighted regression adjustment (IPWRA), to account for confounding by indication. RESULTS:Using treatment strategies to improve sleep was common, with 72 % utilising ≥1 and 47 % utilising ≥3 treatments. Poor sleepers were more likely to use any strategy (80 % vs 52 %), multiple strategies (50 % vs 33 %), sleep hygiene behaviours (62 % vs 42 %), and medications (51 % vs 13 %), vs good sleepers. Benzodiazepine users had worse sleep quality, selective serotonin reuptake inhibitors users had worse daytime sleepiness, even after adjusting for the reasons for medication use and factors associated with sleep quality or daytime sleepiness. CONCLUSION:Using treatment strategies to get to sleep or stay asleep was common. As expected, those with sleep in the clinically poor range were most likely to use any strategies, and multiple strategies. Most prescription medications had no impact on sleep after adjusting for confounding; but participants using benzodiazepines had poorer sleep quality, and selective serotonin reuptake inhibitors users had poorer daytime sleepiness.

BACKGROUND:Aortic pulse wave velocity (PWV) is an indicator of vascular aging and has proven to be effective in adult cardiovascular risk assessment. To use it in young people to identify those who may be at increased cardiovascular disease risk, reference values need to be determined. The Youth Vascular Consortium is a large, international database which was established to investigate vascular aging in youth. Using data from the Youth Vascular Consortium, this study aimed to develop reference values for aortic PWV in healthy young people. METHODS:This is a retrospective, multicenter study. Data on demographics, anthropometric, biochemical, and vascular aging measures from participants aged 1 year to 40 years were harmonized. Generalized additive models were used to derive percentile curves for PWV and predicted percentiles at years of age were reported by sex, continent, and device. RESULTS:Data from 19 930 participants (mean age=17 years, 51% women, 71% European), classified as healthy based on blood pressure, body mass index, serum glucose, and cholesterol levels, were included to construct the reference values. Six devices were used to assess aortic PWV (29% SphygmoCor). Device-specific percentile curves for aortic PWV were constructed, and an increasing trend was identified for both sexes with age. CONCLUSIONS:This study provided reference values for aortic PWV assessed with 6 devices for healthy young people by age and sex. These percentiles may be applied clinically to identify youth with impaired vascular aging and, thus, those who may be at risk of developing overt cardiovascular disease in the future.

The gut microbiome is associated with bone mass acquisition, yet evidence in childhood remains limited. Given that lower peak bone mass predicts osteoporosis in later life, understanding early influences is important. This analysis explores the association between the early life gut microbiome and bone health in later childhood. Data were obtained from 700 children recruited in pregnancy and followed prospectively within the Copenhagen Prospective Studies on Asthma in Childhood2010 cohort, a population-based mother-child cohort. The infant gut microbiome was measured at 1 wk (n = 445), 1 mo (n = 492), 1 yr (n = 508), 4 yr (n = 350), and 6 yr (n = 327) of age by 16S ribosomal ribonucleic acid amplicon sequencing targeting the fourth variable region. Total body less head BMD and area-adjusted BMC were measured by DXA at 6 yr of age. Associations were investigated by multiple linear regression, permutational analysis of variance, differential abundance analysis, and Random Forest machine learning. There were few associations between the early-life gut microbiome and bone health outcomes at age 6. We found negative associations between alpha (within-sample) diversity and area-adjusted BMC at 4 yr. Beta (between-sample) diversity of the gut microbiome at 6 yr was associated with concurrent BMD. Escherichia-Shigella abundance at 1 mo of age was associated with lower BMD. Sutterella abundance at 1 yr was associated with lower BMD and area-adjusted BMC at 6 yr. There were no other associations between the gut microbiome and bone outcome measures at any time point. In a well-powered unselected cohort study with longitudinal sampling of the gut microbiome, there were some suggestive but no consistent associations between the early gut microbiome and bone health outcomes at 6 yr of age.

BACKGROUND:Dual decline in gait and memory is associated with a higher risk of dementia. However, little is known about specific brain regions and their association with dual decline. Therefore, this study examined the strength of associations between baseline regional brain volumes and dual decline in gait speed and memory. METHODS:Participants aged over 60 years were randomly selected from the Southern Tasmanian electoral roll. Participants (n = 266) were classified into four groups depending on tertiles of annual decline in gait speed and delayed memory recall: non-decline, gait-only decline, cognitive-only decline, and dual decline. Multinomial logistic regression was used to examine the strength of associations between baseline regional brain volumes and the four groups. RESULTS:The mean age of participants was 70.9 ± SD 6.7 years. For the dual decline group, eight regions (in order of strength - orbitofrontal cortex, middle frontal gyrus, superior frontal gyrus, thalamus, anterior cingulate cortex, brainstem, inferior temporal gyrus and hippocampus) had relative risk ratios below 0.60 for a 1 SD increase in volume. For gait-only and cognitive-only decline, only the thalamus and cerebellum respectively, had relative risk ratios below 0.60. CONCLUSIONS:In this study, we observed that smaller volumes in regions related to memory, executive function, motor, and sensory-motor integration had the strongest associations with dual decline.

Risk factors for cardiovascular disease (CVD) begin to develop in childhood. Measures of vascular ageing that capture vascular structural and functional degeneration, such as carotid-to-femoral pulse wave velocity (cfPWV), are independent predictors of CVD. Importantly, exposure to modifiable factors is known to be associated with early vascular ageing; however, this has not been thoroughly assessed in youth. This review aimed to identify modifiable factors of cfPWV in youth (≤19 years). Medline, Scopus and Embase online databases were searched from inception to March 2025. Seven thousand five hundred and sixty-seven articles were identified; 51 studies were included. Most studies investigated the relationship between adiposity factors (n = 31). In a meta-analysis, there was a significant association between BMI and cfPWV (0.013 m/s per kg/m2, P < 0.0001). This review identified various modifiable factors that are adversely associated with cfPWV in youth. Lifestyle interventions targeting these factors are likely to be beneficial for vascular health in youth.

Background: Cardiovascular disease (CVD) primary prevention guidelines classify people at high risk and recommended for pharmacological treatment based on clinical criteria and absolute CVD risk estimation. Despite relying on similar evidence, recommendations vary between international guidelines, which may impact who is recommended to receive treatment for CVD prevention. Objective: To determine the agreement in treatment recommendations according to guidelines from Australia, England and the United States. Methods: Cross-sectional analysis of the National Health and Nutrition Examination Survey (n = 2647). Adults ≥ 40 years were classified as high-risk and recommended for treatment according to Australia, England and United States CVD prevention guidelines. Agreement in high-risk classification and recommendation for treatment was assessed by Kappa statistic. Results: Participants were middle aged, 49% were male and 38% were white. The proportion recommended for treatment was highest using the United States guidelines (n = 1318, 49.8%) followed by the English guidelines (n = 1276, 48.2%). In comparison, only 26.6% (n = 705) of participants were classified as recommended for treatment according to the Australian guidelines. There was moderate agreement in the recommendation for treatment between the English and United States guidelines (κ = 0.69 [0.64–0.74]). In comparison, agreement in recommendation for treatment was minimal between the Australian and United States guidelines (κ = 0.47 [0.43–0.52]) and weak between the Australian and English guidelines (κ = 0.50 [0.45–0.55]). Conclusions: Despite similar evidence underpinning guidelines, there is little agreement between guidelines regarding the people recommended to receive treatment for CVD prevention. These findings suggest greater consistency in high-risk classification between CVD prevention guidelines may be required.

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: 2004–2006, 2009–2011 and 2017–2019. We calculated the average daily intake of each food group in standard serves. Insulin sensitivity was estimated from fasting glucose and insulin concentrations in 2017–2019 (aged 39–49 years) using homoeostasis model assessment. Replacing red meat with a combination of plant-based alternatives was associated with higher insulin sensitivity (β = 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.

Background: A high prevalence of cardiovascular disease (CVD) globally prompts the necessity of a surrogate marker to identify CVD development at the subclinical stage. Observation of early alterations to the vasculature has proven to be beneficial in identifying adults who have an increased risk of CVD. Hence, utilizing vascular ageing as an effective, non-invasive, subclinical marker in assessing cardiovascular risk in young people could be promising for the reduction of CVD incidence. Pulse wave velocity (PWV) is a marker of vascular ageing, and even though the importance of PWV in cardiovascular health assessment in adults has been established, to use it routinely to evaluate young people at risk, normal values need to be determined. The Youth Vascular Consortium (YVC) is an international collaborative that was established to comprehensively investigate vascular ageing with a range of measures among young people. This study aimed to develop normal values for PWV measured by commonly used devices among healthy young people using data from the YVC. Methods: This retrospective study included data on demographics, anthropometric, biochemical and vascular ageing measures collected from participants aged 1 to 40 years. Generalised additive models were used to derive percentile curves for the PWV data by age. Observed and predicted percentiles at years of age were reported by sex, geographical region and device. Results: The YVC collected data on 36,973 participants from 24 countries across five different regions. Of these, 19,018 participants (mean age = 17 years, 51% female, 71% European) were classified as healthy based on their systolic and diastolic blood pressure, serum glucose, serum cholesterol and body mass index. Six devices were used to measure PWV (30% SphygmoCor). Device-specific percentile curves for PWV against age were constructed and an increasing trend in PWV was identified with age for both males and females. Conclusion: This study provided normal values for PWV measured with six different devices for young people as age and sex-specific percentile curves. These curves may be applied clinically to identify young people with impaired vascular ageing and thus, those who may be at risk of overt CVD.