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Background: The literature investigating the relationship between social media use, mental health, and sleep has produced inconsistent findings. Younger people spend more time on social media than other age groups, and are more likely to be impacted by social media use. This systematic review with meta-analysis aimed to synthesise the evidence on the associations between social media use, mental health, and sleep of young individuals., Methods: Electronic databases PubMed, Scopus and PsycINFO were searched using an established methodology and pre-determined search terms for studies that reported the association between social media use, mental health, and sleep., Results: The search yielded 6108 articles, of which 182 (n = 1,169,396) were eligible for the systematic review, and 98 (n = 102,683) could be included in the meta-analyses. The systematic review identified a high level of heterogeneity in the study results. Meta-analyses found small but significant positive associations between social media use, depression, and anxiety. In addition, problematic social media use was positively associated with depression, anxiety, and sleep problems, and negatively associated with wellbeing. Geographical location, anxiety measure type, study design, age, and gender were identified as potential moderators., Limitations: Associations for specific social media platforms as well as some moderator effects were not examined due to an insufficient number of studies., Conclusions: This study provides important evidence of an association between social media use/ problematic social media use, mental health, and sleep. The findings support future longitudinal research to identify the directions and underlying mechanisms of the inter-relationship between these variables., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

High blood pressure (BP) is a significant contributor to the disease burden globally and is emerging as an important cause of morbidity and mortality in the young as well as the old. The well-established impact of high BP on neurodegeneration, cognitive impairment, and dementia is widely acknowledged. However, the influence of BP across its full range remains unclear. This review aims to explore in more detail the effects of BP levels on neurodegeneration, cognitive function, and dementia. Moreover, given the pressing need to identify strategies to reduce BP levels, particular attention is placed on reviewing the role of magnesium (Mg) in ageing and its capacity to lower BP levels, and therefore potentially promote brain health. Overall, the review aims to provide a comprehensive synthesis of the evidence linking BP, Mg and brain health. It is hoped that these insights will inform the development of cost-effective and scalable interventions to protect brain health in the ageing population.

Background: Consistent evidence shows that magnesium (Mg) intake is associated with lower blood pressure (BP), and that lower BP is associated with improved cerebral health. However, recent findings indicate that the positive effect of dietary Mg intake on cerebral health is not mediated by a decrease in BP. As Mg's anti-inflammatory action is a plausible alternative mechanism, the objective of this study was to investigate the associations between Mg intake and inflammation to determine whether it mediates any neuroprotective effect., Methods: Participants from the UK Biobank (n = 5775, aged 40-73 years, 54.7% female) were assessed for dietary magnesium using an online food questionnaire, brain and white matter lesion (WML) volumes were segmented with FreeSurfer software, and inflammation markers including high-sensitivity C-reactive protein (hs-CRP), leukocyte, erythrocyte count, and Glycoprotein acetylation (GlycA) were measured using specific laboratory techniques such as immunoturbidimetry, automated cell counting, and nuclear magnetic resonance. Hierarchical linear regression models were performed to investigate the association between dietary Mg, and inflammatory markers and between dietary Mg, brain and WMLs volumes. Mediation analysis was performed to test a possible mediation role of inflammation on the association between dietary Mg and brain and WMLs volumes., Results: Higher dietary Mg intake was associated with lower inflammation: hs-CRP level (- 0.0497%; 95% confidence interval [CI] - 0.0497%,  - 0.0199%) leukocytes count (- 0.0015%; 95%CI - 0.00151%,  - 0.0011%), and GlycA (- 0.0519%; 95%CI - 0.1298%,  - 0.0129%). Moreover, higher dietary Mg intake was associated with larger grey matter volume (0.010%; 95%CI 0.004%, 0.017%), white matter volume (0.012%; 95%CI 0.003,  0.022) and right hippocampal volume (0.002%; 95%CI 0.0007, -0.0025%). Lower hs-CRP levels mediated the positive association between higher dietary Mg intake and larger grey matter volume., Conclusions: The anti-inflammatory effects of dietary Mg intake in the general population, appears to mediate its neuroprotective effect., (© 2024. The Author(s).)

The health promotion literature that considers how scientific evidence can be effectively communicated tends to focus on evaluating the effectiveness of communication materials. This has resulted in a knowledge gap regarding effective knowledge translation processes. This study explores the process, reasoning and practices for developing books for children that incorporate evidence-based information to aid understanding of scientific evidence about health and environmental or natural disasters. This study is informed by a systematic review of the literature combined with responses to an email interview with authors of books for children. Nine published studies were included in the systematic review. Twenty-two authors responded to the email survey (25% response rate, following 86 invitations). We report seven key findings to guide the development of health-promoting books for children: (i) understand the needs and expectations of the audience, (ii) articulate the topic and research evidence, (iii) assemble a team with a mix of content knowledge and creative expertise, (iv) format should be chosen to suit the user group and guided by the creative team, (v) early testing with children and their support system is crucial, (vi) develop a dissemination strategy to reach the user group and (vii) engage in reflexivity through evaluation of effectiveness of messaging. The current investigation can guide the process, reasoning and practice of developing books for children that incorporate evidence about health and environmental disasters., (© The Author(s) 2024. Published by Oxford University Press.)

Importance: The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) reported no effect of prostate-specific antigen (PSA) screening on prostate cancer mortality at a median 10-year follow-up (primary outcome), but the long-term effects of PSA screening on prostate cancer mortality remain unclear., Objective: To evaluate the effect of a single invitation for PSA screening on prostate cancer-specific mortality at a median 15-year follow-up compared with no invitation for screening., Design, Setting, and Participants: This secondary analysis of the CAP randomized clinical trial included men aged 50 to 69 years identified at 573 primary care practices in England and Wales. Primary care practices were randomized between September 25, 2001, and August 24, 2007, and men were enrolled between January 8, 2002, and January 20, 2009. Follow-up was completed on March 31, 2021., Intervention: Men received a single invitation for a PSA screening test with subsequent diagnostic tests if the PSA level was 3.0 ng/mL or higher. The control group received standard practice (no invitation)., Main Outcomes and Measures: The primary outcome was reported previously. Of 8 prespecified secondary outcomes, results of 4 were reported previously. The 4 remaining prespecified secondary outcomes at 15-year follow-up were prostate cancer-specific mortality, all-cause mortality, and prostate cancer stage and Gleason grade at diagnosis., Results: Of 415 357 eligible men (mean [SD] age, 59.0 [5.6] years), 98% were included in these analyses. Overall, 12 013 and 12 958 men with a prostate cancer diagnosis were in the intervention and control groups, respectively (15-year cumulative risk, 7.08% [95% CI, 6.95%-7.21%] and 6.94% [95% CI, 6.82%-7.06%], respectively). At a median 15-year follow-up, 1199 men in the intervention group (0.69% [95% CI, 0.65%-0.73%]) and 1451 men in the control group (0.78% [95% CI, 0.73%-0.82%]) died of prostate cancer (rate ratio [RR], 0.92 [95% CI, 0.85-0.99]; P = .03). Compared with the control, the PSA screening intervention increased detection of low-grade (Gleason score [GS] ≤6: 2.2% vs 1.6%; P < .001) and localized (T1/T2: 3.6% vs 3.1%; P < .001) disease but not intermediate (GS of 7), high-grade (GS ≥8), locally advanced (T3), or distally advanced (T4/N1/M1) tumors. There were 45 084 all-cause deaths in the intervention group (23.2% [95% CI, 23.0%-23.4%]) and 50 336 deaths in the control group (23.3% [95% CI, 23.1%-23.5%]) (RR, 0.97 [95% CI, 0.94-1.01]; P = .11). Eight of the prostate cancer deaths in the intervention group (0.7%) and 7 deaths in the control group (0.5%) were related to a diagnostic biopsy or prostate cancer treatment., Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, a single invitation for PSA screening compared with standard practice without routine screening reduced prostate cancer deaths at a median follow-up of 15 years. However, the absolute reduction in deaths was small., Trial Registration: isrctn.org Identifier: ISRCTN92187251.

Several modifiable risk factors for neurodegeneration and dementia have been identified, although individuals vary in their vulnerability despite a similar risk of exposure. This difference in vulnerability could be explained at least in part by the variability in DNA repair mechanisms' efficiency between individuals. Therefore, the aim of this study was to test associations between documented, prevalent genetic variation (single nucleotide polymorphism, SNP) in DNA repair genes, cognitive function, and brain structure. Community-living participants ( n = 488,159; 56.54 years (8.09); 54.2% female) taking part in the UK Biobank study and for whom cognitive and genetic measures were available were included. SNPs in base excision repair (BER) genes of the bifunctional DNA glycosylases OGG1 (rs1052133, rs104893751), NEIL1 (rs7402844, rs5745906), NEIL2 (rs6601606), NEIL3 (rs10013040, rs13112390, rs13112358, rs1395479), MUTYH (rs34612342, rs200165598), NTHL1 (rs150766139, rs2516739) were considered. Cognitive measures included fluid intelligence, the symbol-digit matching task, visual matching, and trail-making. Hierarchical regression and latent class analyses were used to test the associations between SNPs and cognitive measures. Associations between SNPs and brain measures were also tested in a subset of 39,060 participants. Statistically significant associations with cognition were detected for 12 out of the 13 SNPs analyzed. The strongest effects amounted to a 1-6% difference in cognitive function detected for NEIL1 (rs7402844), NEIL2 (rs6601606), and NTHL1 (rs2516739). Associations varied by age and sex, with stronger effects detected in middle-aged women. Weaker associations with brain measures were also detected. Variability in some BER genes is associated with cognitive function and brain structure and may explain variability in the risk for neurodegeneration and dementia.

Introduction: Although various studies have examined availability, access barriers and patient experiences of rural health services for the ageing population, no synthesis of this literature exists in Australia., Objective: The objective of this study was to examine the current literature surrounding rural service provision and to evaluate the barriers to access for older individuals and to recognise gaps in the literature., Design: A systematic scoping review of peer-reviewed literature from three online databases (PUBMED, SCOPUS and Web of Science)., Findings: Thirty-two papers were included in analysis. The most prominent types of health service discussed were residential aged care (n = 12) and community health care (n = 10). More studies explored the perspectives of health personnel than the service end users. Qualitative synthesis revealed three themes associated with health service and rural ageing: access to services, health workforce experiences and end user experiences., Discussion: Access to health services for the elderly population is a complex issue. Promoting positive experiences for both health providers and patients is critical to assisting in healthy ageing for people living in rural and remote areas. This requires intervention on a social and institutional level. Key research gaps in the literature include the effectiveness of an integrated approach to institutional interventions, utilisation of preventative measures such as screening programs for cancer and greater identification of the health needs and perceptions among culturally diverse elderly residents. These studies are critical to promote appropriate and patient-centred care for elderly populations in rural and remote areas., Conclusion: The review highlights the need to address availability, retention and service innovations across health services to improve access to care and health outcomes of rural elderly residents., (© 2023 The Authors. Australian Journal of Rural Health published by John Wiley & Sons Australia, Ltd on behalf of National Rural Health Alliance Ltd.)

Purpose: To examine the association between dietary magnesium (Mg) intake and brain volumes and white matter lesions (WMLs) in middle to early old age., Methods: Participants (aged 40-73 years) from UK Biobank (n = 6001) were included and stratified by sex. Dietary Mg was measured using an online computerised 24 h recall questionnaire to estimate daily Mg intake. Latent class analysis and hierarchical linear regression models were performed to investigate the association between baseline dietary Mg, Mg trajectories, and brain volumes and WMLs. Associations between baseline Mg, and baseline blood pressure (BP) measures, and baseline Mg, Mg trajectories and BP changes (between baseline and wave 2) were also investigated to assess whether BP mediates the link between Mg intake and brain health. All analyses controlled for health and socio-demographic covariates. Possible interactions between menopausal status and Mg trajectories in predicting brain volumes and WMLs were also investigated., Results: On average, higher baseline dietary Mg intake was associated with larger brain volumes (gray matter [GM]: 0.001% [SE = 0.0003]; left hippocampus [LHC]: 0.0013% [SE = 0.0006]; and right hippocampus [RHC]: 0.0023% [SE = 0.0006]) in both men and women. Latent class analysis of Mg intake revealed three classes: "high-decreasing" (men = 3.2%, women = 1.9%), "low-increasing" (men = 1.09%, women = 1.62%), and "stable normal" (men = 95.71%, women = 96.51%). In women, only the "high-decreasing" trajectory was significantly associated with larger brain volumes (GM: 1.17%, [SE = 0.58]; and RHC: 2.79% [SE = 1.11]) compared to the "normal-stable", the "low-increasing" trajectory was associated with smaller brain volumes (GM: - 1.67%, [SE = 0.30]; white matter [WM]: - 0.85% [SE = 0.42]; LHC: - 2.43% [SE = 0.59]; and RHC: - 1.50% [SE = 0.57]) and larger WMLs (1.6% [SE = 0.53]). Associations between Mg and BP measures were mostly non-significant. Furthermore, the observed neuroprotective effect of higher dietary Mg intake in the "high-decreasing" trajectory appears to be greater in post-menopausal than pre-menopausal women., Conclusions: Higher dietary Mg intake is related to better brain health in the general population, and particularly in women., (© 2023. The Author(s).)

Background: Screening men for prostate cancer using prostate-specific antigen (PSA) testing remains controversial. We aimed to estimate the likely budgetary impact on secondary care in England and Wales to inform screening decision makers., Methods: The Cluster randomised triAl of PSA testing for Prostate cancer study (CAP) compared a single invitation to men aged 50-69 for a PSA test with usual care (no screening). Routinely collected hospital care data were obtained for all men in CAP, and NHS reference costs were mapped to each event via Healthcare Resource Group (HRG) codes. Secondary-care costs per man per year were calculated, and cost differences (and population-level estimates) between arms were derived annually for the first five years following randomisation., Results: In the first year post-randomisation, secondary-care costs averaged across all men (irrespective of a prostate cancer diagnosis) in the intervention arm (n = 189279) were £44.80 (95% confidence interval: £18.30-£71.30) higher than for men in the control arm (n = 219357). Extrapolated to a population level, the introduction of a single PSA screening invitation could lead to additional secondary care costs of £314 million., Conclusions: Introducing a single PSA screening test for men aged 50-69 across England and Wales could lead to very high initial secondary-care costs., (© 2023. The Author(s).)

BACKGROUND: Long-term patient-reported outcomes are needed to inform treatment decisions for localized prostate cancer. METHODS: Patient-reported outcomes of 1643 randomly assigned participants in the ProtecT (Prostate Testing for Cancer and Treatment) trial were evaluated to assess the functional and quality-of-life impacts of prostatectomy, radiotherapy with neoadjuvant androgen deprivation, and active monitoring. This article focuses on the outcomes of the randomly assigned participants from 7 to 12 years using mixed effects linear and logistic models. RESULTS: Response rates exceeded 80% for most measures. Among the randomized groups over 7 to 12 years, generic quality-of-life scores were similar. Among those in the prostatectomy group, urinary leakage requiring pads occurred in 18 to 24% of patients over 7 to 12 years, compared with 9 to 11% in the active monitoring group and 3 to 8% in the radiotherapy group. In the prostatectomy group, 18% reported erections sufficient for intercourse at 7 years, compared with 30% in the active monitoring and 27% in the radiotherapy groups; all converged to low levels of potency by year 12. Nocturia (voiding at least twice per night) occurred in 34% in the prostatectomy group compared with 48% in the radiotherapy group and 47% in the active monitoring group at 12 years. Fecal leakage affected 12% in the radiotherapy group compared with 6% in the other groups by year 12. The active monitoring group experienced gradual age-related declines in sexual and urinary function, avoiding radical treatment effects unless they changed management. CONCLUSIONS: ProtecT provides robust evidence about continued impacts of treatments in the long term. These data allow patients newly diagnosed with localized prostate cancer and their clinicians to assess the trade-offs between treatment harms and benefits and enable better informed and prudent treatment decisions. (Funded by the UK National Institute for Health and Care Research Health Technology Assessment Programme projects 96/20/06 and 96/20/99; ISRCTN number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.)

Background and Objective: Most guidelines in the UK, Europe and North America do not recommend organised population-wide screening for prostate cancer. Prostate-specific antigen-based screening can reduce prostate cancer-specific mortality, but there are concerns about overdiagnosis, overtreatment and economic value. The aim was therefore to assess the cost effectiveness of eight potential screening strategies in the UK., Methods: We used a cost-utility analysis with an individual-based simulation model. The model was calibrated to data from the 10-year follow-up of the Cluster Randomised Trial of PSA Testing for Prostate Cancer (CAP). Treatment effects were modelled using data from the Prostate Testing for Cancer and Treatment (ProtecT) trial. The participants were a hypothetical population of 10 million men in the UK followed from age 30 years to death. The strategies were: no screening; five age-based screening strategies; adaptive screening, where men with an initial prostate-specific antigen level of < 1.5 ng/mL are screened every 6 years and those above this level are screened every 4 years; and two polygenic risk-stratified screening strategies. We assumed the use of pre-biopsy multi-parametric magnetic resonance imaging for men with prostate-specific antigen ≥ 3 ng/mL and combined transrectal ultrasound-guided and targeted biopsies. The main outcome measures were projected lifetime costs and quality-adjusted life-years from a National Health Service perspective., Results: All screening strategies increased costs compared with no screening, with the majority also increasing quality-adjusted life-years. At willingness-to-pay thresholds of £20,000 or £30,000 per quality-adjusted life-year gained, a once-off screening at age 50 years was optimal, although this was sensitive to the utility estimates used. Although the polygenic risk-stratified screening strategies were not on the cost-effectiveness frontier, there was evidence to suggest that they were less cost ineffective than the alternative age-based strategies., Conclusions: Of the prostate-specific antigen-based strategies compared, only a once-off screening at age 50 years was potentially cost effective at current UK willingness-to-pay thresholds. An additional follow-up of CAP to 15 years may reduce uncertainty about the cost effectiveness of the screening strategies., (© 2022. The Author(s).)

Multiple sclerosis (MS) is a chronic neurological disease of the central nervous system that is currently incurable. Diet may influence the onset and progression of MS. A variety of literature reviews have been conducted in the field of diet and MS. However, conventional reviews mostly focus on specific topics rather than delivering a holistic view of the literature landscape. Using a data-driven approach, we aimed to provide an overview of the literature on diet and MS, revealing gaps in knowledge. We conducted citation network analysis to identify clusters of all available publications about diet and MS over the past 50 years. We also conducted topic analysis of each cluster and illustrated them in word clouds. Four main clusters were identified from 1626 publications: MS risk and symptom management; mouse models of MS; gluten sensitivity; and dysphagia. Citation network analysis revealed that in this emerging field, articles published after 1991 were more likely to be highly cited. Relatively few studies focused on MS disease progression compared to risk factors, and limited evidence was available for many foods and nutrients in relation to MS. Future studies could focus on filling these identified knowledge gaps., Competing Interests: The authors declare no conflicts of interest.

The "Black Summer" bushfires of 2019/2020 in Australia generated smoke that persisted for over three months, mainly affecting Eastern Australia. Most communication strategies focused on the fire itself, revealing a knowledge gap in effective communication of the impact of bushfire smoke on health, especially for children and those living in non-English speaking minority groups. To address this, semi-structured qualitative interviews were undertaken with sixteen adults with caring ( n = 11) or educational ( n = 5) responsibilities for primary-school aged children (5-12 years, with some also having children up to 16 years) who had direct experience of the "Black Summer" bushfires. Overall, 43% ( n = 7) of the sample spoke English as a first language, 25% ( n = 4) spoke Turkish, with the remainder speaking Persian, Arabic, and Spanish. Thematic inductive qualitative content analysis revealed predominant themes of the role of parents and caregivers as conduits and curators of information. Air quality apps were the most common source of information. Language barriers and the lack of child-friendly methods of communication were highlighted as particular challenges. This qualitative study provides evidence for future development of communication strategies to better serve culturally and linguistically diverse individuals and the children in their care.

Objective: To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making., Patients and Methods: Men aged 50-69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores., Results: Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL., Conclusion: Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes., (© 2022 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

The objectives of this study were to investigate the long-term associations between changes in physical activity levels and hippocampal volumes over time, while considering the influence of age, sex, and APOE-ε4 genotype. We investigated the effects of change in physical activity on hippocampal volumes in 411 middle age (mean age = 47.2 years) and 375 older age (mean age = 63.1 years) adults followed up to 12 years. An annual volume decrease was observed in the left (middle age: 0.46%; older age: 0.51%) but not in the right hippocampus. Each additional 10 metabolic equivalents (METs, ~2 h of moderate exercise) increase in weekly physical activity was associated with 0.33% larger hippocampal volume in middle age (equivalent to ~1 year of typical aging). In older age, each additional MET was associated with 0.05% larger hippocampal volume; however, the effects declined with time by 0.005% per year. For older age APOE-ε4 carriers, each additional MET was associated with a 0.10% increase in hippocampal volume. No sex effects of physical activity change were found. Increasing physical activity has long-term positive effects on hippocampal volumes and appears especially beneficial for older APOE-ε4 carriers. To optimize healthy brain aging, physical activity programs should focus on creating long-term exercise habits., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: To quantify the association between blood pressure (BP) across its full range, brain volumes and white matter lesions (WMLs) while investigating the effects of age, sex, body mass index (BMI), and antihypertensive medication., Methods: UK Biobank participants ( n = 36,260) aged (40-70) years were included and stratified by sex and four age groups (age ≤ 45, 46-55, 56-65 and &gt; 65 years). Multi-level regression analyses were used to assess the association between mean arterial pressure (MAP), systolic BP (SBP), diastolic BP (DBP), and brain volumes segmented using the FreeSufer software (gray matter volume [GMV], white matter volume [WMV], left [LHCV] and right hippocampal volume [RHCV]) and WMLs. Interaction effects between body mass index (BMI), antihypertensive medication and BP in predicting brain volumes and WMLs were also investigated., Results: Every 10 mmHg higher DBP was associated with lower brain volumes (GMV: -0.19%--0.40%) [SE = 47.7-62.4]; WMV: -0.20--0.23% [SE = 34.66-53.03]; LHCV: -0.40--0.59% [SE = 0.44-0.57]; RHCV: -0.17--0.57% [SE = 0.32-0.95]) across all age groups. A similar pattern was detected in both sexes, although it was weaker in men. Every 10 mmHg higher MAP was associated with larger WMLs across all age groups but peaked &gt;65 years (1.19-1.23% [SE = 0.002]). Both lower BMI and anti-hypertensive medication appeared to afford a protective effect., Conclusion: Higher BP is associated with worse cerebral health across the full BP range from middle adulthood and into old age.

Neuroinflammation and oxidative stress (OS) are implicated in the pathophysiology of Alzheimer's disease (AD). However, it is unclear at what stage of the disease process inflammation first becomes manifest. The aim of this study was to investigate the associations between specific plasma markers of inflammation and OS, tau, and Amyloid-β 38, 40, and 42 levels in cognitively unimpaired middle-age and older individuals. Associations between inflammatory states identified through principal component analysis and AD biomarkers were investigated in middle-age (52-56 years, n = 335, 52% female) and older-age (72-76 years, n = 351, 46% female) participants without dementia. In middle-age, a component reflecting variation in OS was most strongly associated with tau and to a lesser extent amyloid-β levels. In older-age, a similar component to that observed in middle-age was only associated with tau, while another component reflecting heightened inflammation independent of OS, was associated with all AD biomarkers. In middle and older-age, inflammation and OS states are associated with plasma AD biomarkers.

The 2019-20 bushfires that raged in eastern Australia were an overwhelming natural disaster leading to lives lost or upended, and communities destroyed. For almost a month, Canberra, Australia's capital city in the Australian Capital Territory (ACT), was obscured by smoke from fires which threatened the outer suburbs. While smoke itself is experientially different from many natural disasters, it nevertheless poses a significant public health threat. As the impact of extended bushfire smoke in an urban setting is relatively unexplored we aimed to capture the individual and community-level experiences of the event and their importance for community and social functioning. We responded rapidly by conducting semi-structured interviews with a range of Canberra residents who, due to their personal or social circumstances, were potentially vulnerable to the effects of the smoke. Three major themes emerging from the narratives depicted disruption to daily life, physical and psychological effects, and shifting social connectedness. This study highlighted the ambiguous yet impactful nature of a bushfire smoke event, and identified four simple key messages that may be critically relevant to policy making in preparation for similar smoke events in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Williamson, Banwell, Calear, LaBond, Leach, Olsen, Walsh, Zulfiqar, Sutherland and Phillips.)

Background : Elevated blood pressure (BP) is a major health risk factor and the leading global cause of premature death. Hypertension is also a risk factor for cognitive decline and dementia. However, when elevated blood pressure starts impacting cerebral health is less clear. We addressed this gap by estimating how a validated measure of brain health relates to changes in BP over a period of 12 years. Methods : Middle-age (44-46 years at baseline, n = 335, 52% female) and older-age (60-64 years, n = 351, 46% female) cognitively intact individuals underwent up to four brain scans. Brain health was assessed using a machine learning approach to produce an estimate of "observed" age (BrainAGE), which can be contrasted with chronological age. Longitudinal associations between blood pressures and BrainAGE were assessed with linear mixed-effects models. Results : A progressive increase in BP was observed over the follow up (MAP = 0.8 mmHg/year, SD = 0.92; SBP = 1.41 mmHg/year, SD = 1.49; DBP = 0.61 mmHg/year, SD = 0.78). In fully adjusted models, every additional 10 mmHg increase in blood pressure (above 90 for mean, 114 for systolic, and 74 for diastolic blood pressure) was associated with a higher BrainAGE by 65.7 days for mean, and 51.1 days for systolic/diastolic blood pressure. These effects occurred across the blood pressure range and were not exclusively driven by hypertension. Conclusion : Increasing blood pressure is associated with poorer brain health. Compared to a person becoming hypertensive, somebody with an ideal BP is predicted to have a brain that appears more than 6 months younger at midlife., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cherbuin, Walsh, Shaw, Luders, Anstey, Sachdev, Abhayaratna and Gaser.)

Background: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46)., Materials and Method: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy., Results: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer., Conclusions: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

Purpose: To investigate men's experiences of receiving external-beam radiotherapy (EBRT) with neoadjuvant Androgen Deprivation Therapy (ADT) for localized prostate cancer (LPCa) in the ProtecT trial., Methods: A longitudinal qualitative interview study was embedded in the ProtecT RCT. Sixteen men with clinically LPCa who underwent EBRT in ProtecT were purposively sampled to include a range of socio-demographic and clinical characteristics. They participated in serial in-depth qualitative interviews for up to 8 years post-treatment, exploring experiences of treatment and its side effects over time., Results: Men experienced bowel, sexual, and urinary side effects, mostly in the short term but some persisted and were bothersome. Most men downplayed the impacts, voicing expectations of age-related decline, and normalizing these changes. There was some reticence to seek help, with men prioritizing their relationships and overall health and well-being over returning to pretreatment levels of function. Some unmet needs with regard to information about treatment schedules and side effects were reported, particularly among men with continuing functional symptoms., Conclusions: These findings reinforce the importance of providing universal clear, concise, and timely information and supportive resources in the short term, and more targeted and detailed information and care in the longer term to maintain and improve treatment experiences for men undergoing EBRT.

Background: To summarise and quantify the evidence on the association between Blood pressure (BP), white matter lesions (WMLs), and brain volumes., Method: Electronic databases PubMed, Scopus, and Clarivate were searched in February 2020 using an established methodology and pre-determined search terms. Studies were eligible for inclusion if they reported on the association between BP and WMLs or brain volume in cognitively healthy individuals, while adjusting for age and intra-cranial volume., Results: Searches yielded 7509 articles, of which 52 (26 longitudinal and 33 cross-sectional), were eligible and had a combined sample size of 343,794 individuals. Analyses found that 93.7% of studies reported that higher BP was associated with poorer cerebral health (higher WMLs and lower brain volumes). Meta-analysis of compatible results indicated a dose-dependent relationship with every one standard deviation increase in systolic BP (SBP) above 120 mmHg being associated with a 11.2% (95% CI 2.3, 19.9, p = 0.0128) increase in WMLs and -0.13% (95% CI -0.25, -0.023, p = 0.0183) smaller hippocampal volume., Conclusion: The association between BP and brain volumes appears across the full range of BP measurements and is not limited to hypertensive individuals. Higher BP in community-residing individuals is associated with poorer cerebral health.

Understanding heterogeneity in brain aging trajectories is important to estimate the extent to which aging outcomes can be optimized. Although brain changes in late life are well-characterized, brain changes in middle age are not well understood. In this study, we investigated hippocampal change in a generally healthy community-living population of middle (n = 421, mean age 47.2 years) and older age (n = 411, mean age 63.0 years) individuals, over a follow-up of up to 12 years. Manually traced hippocampal volumes were analyzed using multilevel models and latent class analysis to investigate longitudinal aging trajectories and laterality and sex effects, and to identify subgroups that follow different aging trajectories. Hippocampal volumes decreased on average by 0.18%/year in middle age and 0.3%/year in older age. Men tended to experience steeper declines than women in middle age only. Three subgroups of individuals following different trajectories were identified in middle age and 2 in older age. Contrary to expectations, the subgroup containing two-thirds of older age participants maintained stable hippocampal volumes across the follow-up., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Type 2 diabetes mellitus (T2D) prevalence continues to increase, and age of incidence continues to decrease. More information is needed to target interventions to the ages where they can be most effective. The objective of this study was to explore the degree to which the association between diet and T2D incidence changes through adulthood., Methods: Participants were a large number (N = 2818) of community living adults in Canberra and Queanbeyan, Australia across three cohorts; young (20-24 followed to 32-36), mid-life (40-44 followed to 52-56) and late-life (60-64 followed to 72-76). Self-report dietary pattern scores at baseline and diabetes incidence across 12 years follow-up were measured, alongside confounders of caloric intake, sex, smoking status, years of education, hypertension, BMI and physical activity., Results: Cox proportional hazards indicated that neither Western nor Prudent dietary pattern scores were significantly associated with T2D incidence when confounders were included in the model. Unadjusted estimates suggested a positive association between Western dietary pattern scores and subsequent diabetes incidence (HR = 1.40, 95% CI [1.18, 1.64]). Compared with the mid-life cohort, a higher Western dietary pattern score posed a lower risk for incident T2D in the young cohort (unadjusted HR = 0.46, 95% CI [0.22, 0.96]), who also had significantly lower BMI and higher physical activity. No such significant effects were found for the late-life cohort., Conclusions: Our findings indicate that mid-life may be a period of heightened vulnerability to the effects of an unhealthy diet on diabetes risk, but this effect is attenuated when risk factors related to diet, such as adiposity, are taken into account.

Background: There is limited evidence relating to the cost-effectiveness of treatments for localised prostate cancer., Methods: The cost-effectiveness of active monitoring, surgery, and radiotherapy was evaluated within the Prostate Testing for Cancer and Treatment (ProtecT) randomised controlled trial from a UK NHS perspective at 10 years' median follow-up. Prostate cancer resource-use collected from hospital records and trial participants was valued using UK reference-costs. QALYs (quality-adjusted-life-years) were calculated from patient-reported EQ-5D-3L measurements. Adjusted mean costs, QALYs, and incremental cost-effectiveness ratios were calculated; cost-effectiveness acceptability curves and sensitivity analyses addressed uncertainty; subgroup analyses considered age and disease-risk., Results: Adjusted mean QALYs were similar between groups: 6.89 (active monitoring), 7.09 (radiotherapy), and 6.91 (surgery). Active monitoring had lower adjusted mean costs (£5913) than radiotherapy (£7361) and surgery (£7519). Radiotherapy was the most likely (58% probability) cost-effective option at the UK NICE willingness-to-pay threshold (£20,000 per QALY). Subgroup analyses confirmed radiotherapy was cost-effective for older men and intermediate/high-risk disease groups; active monitoring was more likely to be the cost-effective option for younger men and low-risk groups., Conclusions: Longer follow-up and modelling are required to determine the most cost-effective treatment for localised prostate cancer over a man's lifetime., Trial Registration: Current Controlled Trials number, ISRCTN20141297: http://isrctn.org (14/10/2002); ClinicalTrials.gov number, NCT02044172: http://www.clinicaltrials.gov (23/01/2014).

Background: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening., Methods: United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups., Results: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age., Conclusions: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS., Impact: Personalized genetic risk assessments could inform prostate cancer screening decisions., (©2020 American Association for Cancer Research.)

Physical activity has received substantial research attention due to its beneficial impact on cognition in ageing, particularly via the action of brain-derived neurotrophic factor (BDNF). It is well established that physical activity can elevate circulating levels of BDNF, and that BDNF has neurotrophic, neuroprotective and cognitively beneficial properties. Yet, practical implementation of this knowledge is limited by a lack of clarity on context and dose-effect. Against a shifting backdrop of gradually diminishing physical and cognitive capacity in normal ageing, the type, intensity, and duration of physical activity required to elicit elevations in BDNF, and more importantly, the magnitude of BDNF elevation required for detectable neuroprotection remains poorly characterised. The purpose of this review is to provide an overview of the association between physical activity, BDNF, and cognition, with a focus on clarifying the magnitude of these effects in the context of normative ageing. We discuss the implications of the available evidence for the design of physical activity interventions intended to promote healthy cognitive ageing., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Health experts including planners and policy-makers face complex decisions in diverse and constantly changing healthcare systems. Visual analytics may play a critical role in supporting analysis of complex healthcare data and decision-making. The purpose of this study was to examine the real-world experience that experts in mental healthcare planning have with visual analytics tools, investigate how well current visualisation techniques meet their needs, and suggest priorities for the future development of visual analytics tools of practical benefit to mental healthcare policy and decision-making., Methods: Health expert experience was assessed by an online exploratory survey consisting of a mix of multiple choice and open-ended questions. Health experts were sampled from an international pool of policy-makers, health agency directors, and researchers with extensive and direct experience of using visual analytics tools for complex mental healthcare systems planning. We invited them to the survey, and the experts' responses were analysed using statistical and text mining approaches., Results: The forty respondents who took part in the study recognised the complexity of healthcare systems data, but had most experience with and preference for relatively simple and familiar visualisations such as bar charts, scatter plots, and geographical maps. Sixty-five percent rated visual analytics as important to their field for evidence-informed decision-making processes. Fifty-five percent indicated that more advanced visual analytics tools were needed for their data analysis, and 67.5% stated their willingness to learn new tools. This was reflected in text mining and qualitative synthesis of open-ended responses., Conclusions: This exploratory research provides readers with the first self-report insight into expert experience with visual analytics in mental healthcare systems research and policy. In spite of the awareness of their importance for complex healthcare planning, the majority of experts use simple, readily available visualisation tools. We conclude that co-creation and co-development strategies will be required to support advanced visual analytics tools and skills, which will become essential in the future of healthcare.

Background: The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer (PCa) randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy., Objective: To determine report outcomes according to treatment received in men in randomised and treatment choice cohorts., Design, Setting, and Participants: This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy., Intervention: Two cohorts included 1643 men who agreed to be randomised; 997 declined randomisation and chose treatment., Outcome Measurements and Statistical Analysis: Health-related quality of life impacts on urinary, bowel, and sexual function were assessed using patient-reported outcome measures. Analysis was carried out based on treatment received for each cohort and on pooled estimates using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores., Results and Limitations: According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p=0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p=0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6mo) and urinary incontinence (55% at 6mo) after surgery, and of sexual dysfunction (88% at 6mo) and bowel dysfunction (5% at 6mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and outdating of the interventions being evaluated during the lengthy follow-up required in trials of screen-detected PCa., Conclusions: Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group., Patient Summary: More than 90 out of every 100 men with localised prostate cancer do not die of prostate cancer within 10yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are much better after active monitoring, but the risks of spreading of prostate cancer are more common., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Local shape complexity can be biologically meaningful as a marker of disease, trauma, or change in brain structure over time. Fractal dimensionality (FD) is currently the dominant measure of local shape complexity used in neuroimaging but its limitations are not well understood., New Method: Elliptical Fourier harmonic power requirement (HPR) may provide complementary information to FD. We benchmarked the performance of FD and HPR on a series of simulated shapes, systematically manipulating aspects of local shape complexity, and a series of clinical contours (glioma tumour cores and stroke lesions from the BRATS and ATLAS datasets). HPR was calculated as the point of 99.9% harmonic power. FD was calculated at six resolutions (8 × 8, 16 × 16, 32 × 32, 64 × 64, 128 × 128, and 256 × 256), by using an approach which computationally indexes the complexity of the shape boundary (i.e. the number of cells defining the contour) relative to the total grid size., Results and Comparison With Existing Methods: PR and FD were moderately positively correlated (r ≈ 0.2 to 0.8 depending on shape properties), and both were sensitive to the frequency and amplitude of local complexity. FD was most biased by rotation, while HPR was more biased by global shape features such as deep invaginations. FD indicated an aggregate measure of complexity across the whole contour, while HPR indicated the point of highest complexity., Conclusions: The HPR index provides conceptually distinct local complexity information from the current FD standard. Future research will benefit from using these complementary measures., (Copyright © 2019. Published by Elsevier B.V.)

It is widely recognised that type 2 diabetes (T2D) represents a major disease burden but it is only recently that its role in neurodegeneration has attracted more attention. This research has shown that T2D is associated with impaired cerebral health, cognitive decline and dementia. However, the impact on the brain of progressive metabolic changes associated with the pre-clinical development of the disease is less clear. The aim of this review is to comprehensively summarise how the emergence of risk factors and co-morbid conditions linked to the development of T2D impact cerebral health. Particular attention is directed at characterising how normal but elevated blood glucose levels in individuals without T2D contribute to neurodegenerative processes, and how the main risk factors for T2D including obesity, physical activity and diet modulate these effects. Where available, evidence from the animal and human literature is contrasted, and sex differences in risk and outcomes are highlighted., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Body mass index (BMI), hyperglycaemia and type 2 diabetes and their interactive effects are associated with brain volume atrophy in ageing. It remains to be established if these risk factors are particularly concerning in individuals with high or low brain volumes., Methods: Demographics, venous blood and magnetic resonance imaging data were collected for 494 healthy community-living adults aged 53-78 (mean 65) years, as part of the Personality and Total Health Through Life study. Associations between BMI, blood glucose, diabetes status and brain volume (whole brain, grey matter, white matter and subcortical structures) were investigated using quantile regression., Results: Quantile regression revealed vulnerability to BMI × glucose interactions particularly in lower volumes and significant main effects for type 2 diabetes particularly in higher volumes. Diabetes was most strongly associated with brain volumes. The association between BMI, blood glucose and diabetes was not consistent across the full range of brain volumes., Conclusion: Explicit investigation of the upper and lower boundaries of brain volume distributions was valuable. We found evidence of protective reserve from higher brain volumes and that a combination of high BMI and higher blood glucose was particularly concerning for individuals with lower brain volumes., (© 2018 EAN.)

Background: Chronic obstructive pulmonary disease (COPD) is a major disease burden which accounts for 5% of all deaths globally, with most of those (>90%) occurring in lower to middle income countries (LMIC). It is also emerging as an important modifiable dementia risk factor., Objective: To address the knowledge gap surrounding the nature of the associations between COPD, dementia, and mortality, and the geographical variation of those associations in LMIC., Methods: Data from the 10/66 study surveying 15,394 participants (mean age 74 years, 62% female) across 8 countries was used to estimate the prevalence of self-reported COPD and its association with incident dementia and premature death. Proportional sub-hazards models using a cumulative incidence function were applied to identify the probability of incident dementia onset given the risk of premature death, with estimates pooled across countries via random effect meta-analysis., Results: Over the 3-year follow-up, almost 10% of participants developed dementia and 14% were deceased. COPD was not significantly associated with dementia incidence except in Cuba. However, fully adjusted models indicated that individuals with COPD were at a 28% increased risk of premature death, a trend present across most countries when analyzed individually., Conclusion: The link between COPD and dementia is currently somewhat different and weaker in LMIC than in developed countries. This may be because premature death in the populations studied mask the development of clinical dementia. Given the global trend toward increased life expectancy, it is critical that the disease burden associated with COPD be addressed without delay if a further rise in dementia prevalence associated with COPD is to be avoided in LMIC.

Manual review of the extensive literature covering nutrition-based lifestyle interventions to promote healthy cognitive ageing has proved educational, however, data-driven techniques can better account for the large size of the literature (tens of thousands of potentially relevant publications to date) and interdisciplinary nature, where relevant publications may be found. In this study, we present a new way to map the literature landscape, focusing on nutrition-based lifestyle interventions to promote healthy cognitive ageing. We applied a combination of citation network analysis and text mining to map out the existing literature on nutritional interventions and cognitive health. Results indicated five overarching clusters of publications, which could be further deconstructed into a total of 35 clusters. These could be broadly distinguished by the focus on lifespan stages (e.g., infancy versus older age), and specificity regarding nutrition (e.g., a narrow focus on iodine deficiency versus a broad focus on weight gain). Rather than concentrating into a single cluster, interventions were present throughout the majority of the research. We conclude that a data-driven map of the nutritional intervention literature can benefit the design of future interventions, by highlighting topics and themes that could be synthesized across currently disconnected clusters of publications.

Background: There is a growing research focus on temporal cognition, due to its importance in memory and planning, and links with psychological wellbeing. Researchers are increasingly using diary studies, experience sampling and social media data to study temporal thought. However, it remains unclear whether such reports can be accurately interpreted for temporal orientation. In this study, temporal orientation judgements about text reports of thoughts were compared across human coding, automatic text mining, and participant self-report. Methods: 214 participants responded to randomly timed text message prompts, categorically reporting the temporal direction of their thoughts and describing the content of their thoughts, producing a corpus of 2505 brief (1-358, M = 43 characters) descriptions. Two researchers independently, blindly coded temporal orientation of the descriptions. Four approaches to automated coding used tense to establish temporal category for each description. Concordance between temporal orientation assessments by self-report, human coding, and automatic text mining was evaluated. Results: Human coding more closely matched self-reported coding than automated methods. Accuracy for human (79.93% correct) and automated (57.44% correct) coding was diminished when multiple guesses at ambiguous temporal categories (ties) were allowed in coding (reduction to 74.95% correct for human, 49.05% automated). Conclusion: Ambiguous tense poses a challenge for both human and automated coding protocols that attempt to infer temporal orientation from text describing momentary thought. While methods can be applied to minimize bias, this study demonstrates that researchers need to be wary about attributing temporal orientation to text-reported thought processes, and emphasize the importance of eliciting self-reported judgements.

Previous studies have demonstrated associations between higher blood glucose and brain atrophy and functional deficits, however, little is known about the association between blood glucose, striatal volume and striatal function despite sensori-motor deficits being reported in diabetes. This study investigated the relationship between blood glucose levels, striatal volume and fine motor skills in a longitudinal cohort of cognitively healthy individuals living in the community with normal or impaired fasting glucose or type 2 diabetes. Participants were 271 cognitively healthy individuals (mean age 63 years at inclusion) with normal fasting glucose levels (<5.6 mmol/L) (n=173), impaired fasting glucose (5.6-6.9 mmol/L) (n=57), or with type 2 diabetes (≥7.0 mmol/L) (n=41). Fasting glucose, Purdue Pegboard scores as measurement of fine motor skills, and brain scans were collected at wave 1, 2 and 4, over a total follow-up of twelve years. Striatal volumes were measured using FreeSurfer after controlling for age, sex and intracranial volume. Results showed that type 2 diabetes was associated with smaller right putamen volume and lower Purdue Pegboard scores after controlling for age, sex and intracranial volume. These findings add to the evidence suggesting that higher blood glucose levels, especially type 2 diabetes, may impair brain structure and function., (Copyright © 2018. Published by Elsevier B.V.)

Objectives: Randomized controlled trials (RCTs) deliver robust internally valid evidence but generalizability is often neglected. Design features built into the Prostate testing for cancer and Treatment (ProtecT) RCT of treatments for localized prostate cancer (PCa) provided insights into its generalizability., Study Design and Setting: Population-based cluster randomization created a prospective study of prostate-specific antigen (PSA) testing and a comprehensive-cohort study including groups choosing treatment or excluded from the RCT, as well as those randomized. Baseline information assessed selection and response during RCT conduct., Results: The prospective study (82,430 PSA-tested men) represented healthy men likely to respond to a screening invitation. The extended comprehensive cohort comprised 1,643 randomized, 997 choosing treatment, and 557 excluded with advanced cancer/comorbidities. Men choosing treatment were very similar to randomized men except for having more professional/managerial occupations. Excluded men were similar to the randomized socio-demographically but different clinically, representing less healthy men with more advanced PCa., Conclusion: The design features of the ProtecT RCT provided data to assess the representativeness of the prospective cohort and generalizability of the findings of the RCT. Greater attention to collecting data at the design stage of pragmatic trials would better support later judgments by clinicians/policy-makers about the generalizability of RCT findings in clinical practice., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Prostate cancer screening remains controversial because potential mortality or quality-of-life benefits may be outweighed by harms from overdetection and overtreatment., Objective: To evaluate the effect of a single prostate-specific antigen (PSA) screening intervention and standardized diagnostic pathway on prostate cancer-specific mortality., Design, Setting, and Participants: The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) included 419 582 men aged 50 to 69 years and was conducted at 573 primary care practices across the United Kingdom. Randomization and recruitment of the practices occurred between 2001 and 2009; patient follow-up ended on March 31, 2016., Intervention: An invitation to attend a PSA testing clinic and receive a single PSA test vs standard (unscreened) practice., Main Outcomes and Measures: Primary outcome: prostate cancer-specific mortality at a median follow-up of 10 years. Prespecified secondary outcomes: diagnostic cancer stage and Gleason grade (range, 2-10; higher scores indicate a poorer prognosis) of prostate cancers identified, all-cause mortality, and an instrumental variable analysis estimating the causal effect of attending the PSA screening clinic., Results: Among 415 357 randomized men (mean [SD] age, 59.0 [5.6] years), 189 386 in the intervention group and 219 439 in the control group were included in the analysis (n = 408 825; 98%). In the intervention group, 75 707 (40%) attended the PSA testing clinic and 67 313 (36%) underwent PSA testing. Of 64 436 with a valid PSA test result, 6857 (11%) had a PSA level between 3 ng/mL and 19.9 ng/mL, of whom 5850 (85%) had a prostate biopsy. After a median follow-up of 10 years, 549 (0.30 per 1000 person-years) died of prostate cancer in the intervention group vs 647 (0.31 per 1000 person-years) in the control group (rate difference, -0.013 per 1000 person-years [95% CI, -0.047 to 0.022]; rate ratio [RR], 0.96 [95% CI, 0.85 to 1.08]; P = .50). The number diagnosed with prostate cancer was higher in the intervention group (n = 8054; 4.3%) than in the control group (n = 7853; 3.6%) (RR, 1.19 [95% CI, 1.14 to 1.25]; P < .001). More prostate cancer tumors with a Gleason grade of 6 or lower were identified in the intervention group (n = 3263/189 386 [1.7%]) than in the control group (n = 2440/219 439 [1.1%]) (difference per 1000 men, 6.11 [95% CI, 5.38 to 6.84]; P < .001). In the analysis of all-cause mortality, there were 25 459 deaths in the intervention group vs 28 306 deaths in the control group (RR, 0.99 [95% CI, 0.94 to 1.03]; P = .49). In the instrumental variable analysis for prostate cancer mortality, the adherence-adjusted causal RR was 0.93 (95% CI, 0.67 to 1.29; P = .66)., Conclusions and Relevance: Among practices randomized to a single PSA screening intervention vs standard practice without screening, there was no significant difference in prostate cancer mortality after a median follow-up of 10 years but the detection of low-risk prostate cancer cases increased. Although longer-term follow-up is under way, the findings do not support single PSA testing for population-based screening., Trial Registration: ISRCTN Identifier: ISRCTN92187251.