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The development of dementia is a devastating aspect of Parkinson's disease (PD), affecting nearly half of patients within 10 years post-diagnosis. For effective therapies to prevent and slow progression to PD dementia (PDD), the key mechanisms that determine why some people with PD develop early dementia, while others remain cognitively unaffected, need to be understood. Neuroinflammation and tau protein accumulation have been demonstrated in post-mortem PD brains, and in many other neurodegenerative disorders leading to dementia. However, whether these processes mediate dementia risk early on in the PD disease course is not established. To this end, we used PET neuroimaging with 11C-PK11195 to index neuroinflammation and 18F-AV-1451 for misfolded tau in early PD patients, stratified according to dementia risk in our 'Neuroinflammation and Tau Accumulation in Parkinson's Disease Dementia' (NET-PDD) study. The NET-PDD study longitudinally assesses newly-diagnosed PD patients in two subgroups at low and high dementia risk (stratified based on pentagon copying, semantic fluency, MAPT genotype), with comparison to age- and sex-matched controls. Non-displaceable binding potential (BPND) in 43 brain regions (Hammers' parcellation) was compared between groups (pairwise t-tests), and associations between BPND of the tracers tested (linear-mixed-effect models). We hypothesized that people with higher dementia risk have greater inflammation and/or tau accumulation in advance of significant cognitive decline. We found significantly elevated neuroinflammation (11C-PK11195 BPND) in multiple subcortical and restricted cortical regions in the high dementia risk group compared with controls, while in the low-risk group this was limited to two cortical areas. The high dementia risk group also showed significantly greater neuroinflammation than the low-risk group concentrated on subcortical and basal ganglia regions. Neuroinflammation in most of these regions was associated with worse cognitive performance (Addenbrooke's Cognitive Examination-III score). Overall neuroinflammation burden also correlated with serum levels of pro-inflammatory cytokines. In contrast, increases in 18F-AV-1451 (tau) BPND in PD versus controls were restricted to subcortical regions where off-target binding is typically seen, with no relationship to cognition found. Whole-brain 18F-AV-1451 burden correlated with serum phosphorylated tau181 levels. Although there was minimal regional tau accumulation in PD, regional neuroinflammation and tau burden correlated in PD participants, with the strongest association in the high dementia risk group, suggesting possible co-localization of these pathologies. In conclusion, our findings suggest that significant regional neuroinflammation in early PD might underpin higher risk for PDD development, indicating neuroinflammation as a putative early modifiable aetiopathological disease factor to prevent or slow dementia development using immunomodulatory strategies., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: The relationship between multimorbidity (i.e. ≥ 2 chronic conditions) and incontinence (i.e. urinary and/or faecal incontinence) is underexplored. This study investigated the association between multimorbidity and incident incontinence in Chinese adults aged ≥50 years., Methods: Data from the 2011 and 2015 waves of the China Health and Retirement Longitudinal Study were used. The association between 12 chronic conditions, multimorbidity and new-onset incontinence was analysed using weighted logistic regression models. Mediation analysis was conducted to explore the potential mediators (self-reported health, subjective memory, depressive symptoms, disability, cognitive function, handgrip strength, mobility limitations, medications and frailty status) between multimorbidity and incontinence., Findings: Among 9,986 individuals aged ≥50 years who were continent at baseline, 5.3% (n = 521) were newly incontinent 4 years later (incident cases). The risk of incident incontinence increased with physical multimorbidity (OR 2.04, 95% CI 1.62-2.57). Compared to no chronic condition, having 1, 2, 3 and ≥ 4 chronic conditions were associated with incident incontinence with OR (95% CI): 1.41 (1.01-1.97), 1.74 (1.24-2.44), 2.82 (1.93-4.12) and 3.99 (2.29-6.95), respectively. The association between multimorbidity and incontinence was mediated by self-reported health (41.2%), medications (26.6%), mobility limitations (20.9%), depressive symptoms (12.8%), disability (11.6%), subjective memory (8.7%) and frailty status (8.3%)., Conclusion: This longitudinal study found that physical multimorbidity and specific chronic conditions may increase the risk of new-onset incontinence among Chinese adults aged ≥50 years. Self-reported health, medications and mobility limitations seemed to be important intermediate conditions between multimorbidity and incident incontinence., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Previous Mendelian randomization (MR) studies on obesity and risk of breast cancer adopted a small number of instrumental variables and focused mainly on the crude total effect. We aim to investigate the independent causal effect of obesity on breast cancer susceptibility, considering the distribution of fat, covering both early and late life., Methods: Using an enlarged set of female-specific genetic variants associated with adult general [body mass index (BMI)] and abdominal obesity [waist-to-hip ratio (WHR) with and without adjustment for BMI, WHR and WHRadjBMI] as well as using sex-combined genetic variants of childhood obesity (childhood BMI), we performed a two-sample univariable MR to re-evaluate the total effect of each obesity-related exposure on overall breast cancer (Ncase = 133 384, Ncontrol = 113 789). We further looked into its oestrogen receptor (ER)-defined subtypes (NER+ = 69 501, NER- = 21 468, Ncontrol = 105 974). Multivariable MR was applied to estimate the independent causal effect of each obesity-related exposure on breast cancer taking into account confounders as well as to investigate the independent effect of adult and childhood obesity considering their inter-correlation., Results: In univariable MR, the protective effects of both adult BMI [odds ratio (OR) = 0.89, 95% CI = 0.83-0.96, P = 2.06 × 10-3] and childhood BMI (OR = 0.78, 95% CI = 0.70-0.87, P = 4.58 × 10-6) were observed for breast cancer overall. Comparable effects were found in ER+ and ER- subtypes. Similarly, genetically predicted adult WHR was also associated with a decreased risk of breast cancer overall (OR = 0.87, 95% CI = 0.80-0.96, P = 3.77 × 10-3), restricting to ER+ subtype (OR = 0.88, 95% CI = 0.80-0.98, P = 1.84 × 10-2). Conditional on childhood BMI, the effect of adult general obesity on breast cancer overall attenuated to null (BMI: OR = 1.00, 95% CI = 0.90-1.10, P = 0.96), whereas the effect of adult abdominal obesity attenuated to some extent (WHR: OR = 0.90, 95% CI = 0.82-0.98, P = 1.49 × 10-2; WHRadjBMI: OR = 0.92, 95% CI = 0.86-0.99, P = 1.98 × 10-2). On the contrary, an independent protective effect of childhood BMI was observed in breast cancer overall, irrespective of adult measures (adjusted for adult BMI: OR = 0.84, 95% CI = 0.77-0.93, P = 3.93 × 10-4; adjusted for adult WHR: OR = 0.84, 95% CI = 0.76-0.91, P = 6.57 × 10-5; adjusted for adult WHRadjBMI: OR = 0.80, 95% CI = 0.74-0.87, P = 1.24 × 10-7)., Conclusion: Although successfully replicating the inverse causal relationship between adult obesity-related exposures and risk of breast cancer, our study demonstrated such effects to be largely (adult BMI) or partly (adult WHR or WHRadjBMI) attributed to childhood obesity. Our findings highlighted an independent role of childhood obesity in affecting the risk of breast cancer as well as the importance of taking into account the complex interplay underlying correlated exposures., (© The Author(s) 2022; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Sex hormone-binding globulin (SHBG), testosterone and oestradiol have been associated with many diseases in observational studies; however, the causality of associations remains unestablished., Methods: A phenome-wide Mendelian randomization (MR) association study was performed to explore disease outcomes associated with genetically proxied circulating SHBG, testosterone and oestradiol levels by using updated genetic instruments in 339 197 unrelated White British individuals (54% female) in the UK Biobank. Two-sample MR analyses with data from large genetic studies were conducted to replicate identified associations in phenome-wide MR analyses. Multivariable MR analyses were performed to investigate mediation effects of hormone-related biomarkers in observed associations with diseases., Results: Phenome-wide MR analyses examined associations of genetically predicted SHBG, testosterone and oestradiol levels with 1211 disease outcomes, and identified 28 and 13 distinct phenotypes associated with genetically predicted SHBG and testosterone, respectively; 22 out of 28 associations for SHBG and 10 out of 13 associations for testosterone were replicated in two-sample MR analyses. Higher genetically predicted SHBG levels were associated with a reduced risk of hypertension, type 2 diabetes, diabetic complications, coronary atherosclerotic outcomes, gout and benign and malignant neoplasm of uterus, but an increased risk of varicose veins and fracture (mainly in females). Higher genetically predicted testosterone levels were associated with a lower risk of type 2 diabetes, coronary atherosclerotic outcomes, gout and coeliac disease mainly in males, but an increased risk of cholelithiasis in females., Conclusions: These findings suggest that sex hormones may causally affect risk of several health outcomes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Cardiovascular disease (CVD) risk prediction models for individuals with type 2 diabetes are important tools to guide intensification of interventions for CVD prevention. We aimed to assess the added value of incorporating risk factors variability in CVD risk prediction for people with type 2 diabetes., Methods: We used electronic health records (EHRs) data from 83 910 adults with type 2 diabetes but without pre-existing CVD from the UK Clinical Practice Research Datalink for 2004-2017. Using a landmark-modelling approach, we developed and validated sex-specific Cox models, incorporating conventional predictors and trajectories plus variability of systolic blood pressure (SBP), total and high-density lipoprotein (HDL) cholesterol, and glycated haemoglobin (HbA1c). Such models were compared against simpler models using single last observed values or means., Results: The standard deviations (SDs) of SBP, HDL cholesterol and HbA1c were associated with higher CVD risk (P < 0.05). Models incorporating trajectories and variability of continuous predictors demonstrated improvement in risk discrimination (C-index = 0.659, 95% CI: 0.654-0.663) as compared with using last observed values (C-index = 0.651, 95% CI: 0.646-0.656) or means (C-index = 0.650, 95% CI: 0.645-0.655). Inclusion of SDs of SBP yielded the greatest improvement in discrimination (C-index increase = 0.005, 95% CI: 0.004-0.007) in comparison to incorporating SDs of total cholesterol (C-index increase = 0.002, 95% CI: 0.000-0.003), HbA1c (C-index increase = 0.002, 95% CI: 0.000-0.003) or HDL cholesterol (C-index increase= 0.003, 95% CI: 0.002-0.005)., Conclusion: Incorporating variability of predictors from EHRs provides a modest improvement in CVD risk discrimination for individuals with type 2 diabetes. Given that repeat measures are readily available in EHRs especially for regularly monitored patients with diabetes, this improvement could easily be achieved., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Identifying linked cases of infection is a critical component of the public health response to viral infectious diseases. In a clinical context, there is a need to make rapid assessments of whether cases of infection have arrived independently onto a ward, or are potentially linked via direct transmission. Viral genome sequence data are of great value in making these assessments, but are often not the only form of data available. Here, we describe A2B-COVID, a method for the rapid identification of potentially linked cases of COVID-19 infection designed for clinical settings. Our method combines knowledge about infection dynamics, data describing the movements of individuals, and evolutionary analysis of genome sequences to assess whether data collected from cases of infection are consistent or inconsistent with linkage via direct transmission. A retrospective analysis of data from two wards at Cambridge University Hospitals NHS Foundation Trust during the first wave of the pandemic showed qualitatively different patterns of linkage between cases on designated COVID-19 and non-COVID-19 wards. The subsequent real-time application of our method to data from the second epidemic wave highlights its value for monitoring cases of infection in a clinical context., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Background: This study was to systematically test whether previously reported risk factors for chronic kidney disease (CKD) are causally related to CKD in European and East Asian ancestries using Mendelian randomization., Methods: A total of 45 risk factors with genetic data in European ancestry and 17 risk factors in East Asian participants were identified as exposures from PubMed. We defined the CKD by clinical diagnosis or by estimated glomerular filtration rate of <60 ml/min/1.73 m2. Ultimately, 51 672 CKD cases and 958 102 controls of European ancestry from CKDGen, UK Biobank and HUNT, and 13 093 CKD cases and 238 118 controls of East Asian ancestry from Biobank Japan, China Kadoorie Biobank and Japan-Kidney-Biobank/ToMMo were included., Results: Eight risk factors showed reliable evidence of causal effects on CKD in Europeans, including genetically predicted body mass index (BMI), hypertension, systolic blood pressure, high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein(a), type 2 diabetes (T2D) and nephrolithiasis. In East Asians, BMI, T2D and nephrolithiasis showed evidence of causality on CKD. In two independent replication analyses, we observed that increased hypertension risk showed reliable evidence of a causal effect on increasing CKD risk in Europeans but in contrast showed a null effect in East Asians. Although liability to T2D showed consistent effects on CKD, the effects of glycaemic phenotypes on CKD were weak. Non-linear Mendelian randomization indicated a threshold relationship between genetically predicted BMI and CKD, with increased risk at BMI of >25 kg/m2., Conclusions: Eight cardiometabolic risk factors showed causal effects on CKD in Europeans and three of them showed causality in East Asians, providing insights into the design of future interventions to reduce the burden of CKD., (© The Author(s) 2021. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background and Objectives: With the emergence of healthy aging as a key societal issue in recent decades, technology has often been proposed as a solution to the challenges faced by aging societies. From a public health perspective, however, aging-related technologies have been inconsistently conceptualized and ill-defined. By examining how relevant concepts in "technology for aging" have been developed to date, we hope to identify gaps and begin clarifying the topic., Research Design and Methods: We conducted a scoping review according to PRISMA-ScR, drawing on PubMed and Embase. We selected articles that directly reported concepts of technology for aging, or from which such concepts could be inferred., Results: We identified 43 articles, most of which were narrative reviews (n = 31). Concepts of technology for aging were presented in diverse ways with some overlap. Most studies provided some terminology (n = 36), but with little conceptual uniformity. Conceptual discourse was often focused on the aging agenda; while technological aspects were poorly defined. A conceptual framework from a public health perspective was derived from 8 articles-it showed that technology strategies do not take a population approach., Discussion and Implications: While the potential of "technology for aging" is vast, its real capacity to deliver a desirable life for older people remains underdeveloped. Clearer concepts and realistic goals at population level are lacking. Efficient investment must be made throughout the social system, and technology needs to be integrated via macro-level practices., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Rationale: chronic obstructive pulmonary disease (COPD) is a leading cause of mortality and common in older adults. The BODE Index is the most recognised mortality risk score in COPD but includes a 6-minute walk test (6MWT) that is seldom available in practise; the BODE Index may be better adopted if the 6MWT was replaced., Objectives: we investigated whether a modified BODE Index in which 6MWT was replaced by an alternative measure of physical capacity, specifically the short physical performance battery (SPPB) or components, retained its predictive ability for mortality in individuals with COPD., Methods: we analysed 630 COPD patients from the ERICA cohort study for whom UK Office for National Statistics verified mortality data were available. Variables tested at baseline included spirometry, 6MWT, SPPB and its components (4-m gait speed test [4MGS], chair stand and balance). Predictive models were developed using stratified multivariable Cox regression, and assessed by C-indices and calibration plots with 10-fold cross-validation and replication., Results: during median 2 years of follow-up, 60 (10%) individuals died. There was no significant difference between the discriminative ability of BODE6MWT (C-index 0.709, 95% confidence interval [CI], 0.680-0.737), BODESPPB (C-index 0.683, 95% CI, 0.647-0.712), BODE4MGS (C-index 0.676, 95% CI, 0.643-0.700) and BODEBALANCE (C-index 0.686, 95% CI, 0.651-0.713) for predicting mortality., Conclusions: the SPPB, and its 4MGS and balance components, can potentially be used as an alternative to the 6MWT in the BODE Index without significant loss of predictive ability in all-cause mortality., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Background: Delirium is common, distressing and associated with poor outcomes. Previous studies investigating the impact of delirium on cognitive outcomes have been limited by incomplete ascertainment of baseline cognition or lack of prospective delirium assessments. This study quantified the association between delirium and cognitive function over time by prospectively ascertaining delirium in a cohort aged ≥ 65 years in whom baseline cognition had previously been established., Methods: For 12 months, we assessed participants from the Cognitive Function and Ageing Study II-Newcastle for delirium daily during hospital admissions. At 1-year, we assessed cognitive decline and dementia in those with and without delirium. We evaluated the effect of delirium (including its duration and number of episodes) on cognitive function over time, independently of baseline cognition and illness severity., Results: Eighty two of 205 participants recruited developed delirium in hospital (40%). One-year outcome data were available for 173 participants: 18 had a new dementia diagnosis, 38 had died. Delirium was associated with cognitive decline (-1.8 Mini-Mental State Examination points [95% CI -3.5 to -0.2]) and an increased risk of new dementia diagnosis at follow up (OR 8.8 [95% CI 1.9-41.4]). More than one episode and more days with delirium (>5 days) were associated with worse cognitive outcomes., Conclusions: Delirium increases risk of future cognitive decline and dementia, independent of illness severity and baseline cognition, with more episodes associated with worse cognitive outcomes. Given that delirium has been shown to be preventable in some cases, we propose that delirium is a potentially modifiable risk factor for dementia., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Background and Objectives: A 2008 European consensus on research outcome measures in dementia care concluded that measurement of carer quality of life (QoL) was limited. Three systematic reviews (2012, 2017, and 2018) of dementia carer outcome measures found existing instruments wanting. In 2017, recommendations were published for developing reliable measurement tools of carers' needs for research and clinical application. The aim of this study was to develop a new instrument to measure the QoL of dementia carers (family/friends)., Methods: Items were generated directly from carers following an inductive needs-led approach. Carers (n = 566) from 22 English and Welsh locations then completed the items and comparator measures at three time points. Rasch, factor, and psychometric (reliability, validity, responsiveness, and minimally important differences [MIDs]) analyses were undertaken., Results: Following factor analysis, the pool of 70 items was refined to three independent scales: primary SIDECAR-D (direct impact of caring upon carer QOL, 18 items), secondary SIDECAR-I (indirect impact, 10 items), and SIDECAR-S (support and information, 11 items). All three scales satisfy Rasch model assumptions. SIDECAR-D, I, S psychometrics: reliability (internal ≥ .70; test-retest ≥ .85); convergent validity (as hypothesized); responsiveness (effect sizes: D: moderate; I and S: small); MIDs (D = 9/100, I = 10/100, S = 11/100)., Discussion and Implications: SIDECAR scales demonstrate robust measurement properties, meeting COSMIN quality standards for study design and psychometrics. SIDECAR provides a theoretically based needs-led QoL profile specifically for dementia carers. SIDECAR is free for use in public health, social care, and voluntary sector services, and not-for-profit organizations., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Epidemiological evidence indicates that diets rich in plant foods are associated with a lower risk of ischaemic heart disease (IHD), but there is sparse information on fruit and vegetable subtypes and sources of dietary fibre. This study examined the associations of major plant foods, their subtypes and dietary fibre with risk of IHD in the European Prospective Investigation into Cancer and Nutrition (EPIC)., Methods: We conducted a prospective analysis of 490 311 men and women without a history of myocardial infarction or stroke at recruitment (12.6 years of follow-up, n cases = 8504), in 10 European countries. Dietary intake was assessed using validated questionnaires, calibrated with 24-h recalls. Multivariable Cox regressions were used to estimate hazard ratios (HR) of IHD., Results: There was a lower risk of IHD with a higher intake of fruit and vegetables combined [HR per 200 g/day higher intake 0.94, 95% confidence interval (CI): 0.90-0.99, P-trend = 0.009], and with total fruits (per 100 g/day 0.97, 0.95-1.00, P-trend = 0.021). There was no evidence for a reduced risk for fruit subtypes, except for bananas. Risk was lower with higher intakes of nuts and seeds (per 10 g/day 0.90, 0.82-0.98, P-trend = 0.020), total fibre (per 10 g/day 0.91, 0.85-0.98, P-trend = 0.015), fruit and vegetable fibre (per 4 g/day 0.95, 0.91-0.99, P-trend = 0.022) and fruit fibre (per 2 g/day 0.97, 0.95-1.00, P-trend = 0.045). No associations were observed between vegetables, vegetables subtypes, legumes, cereals and IHD risk., Conclusions: In this large prospective study, we found some small inverse associations between plant foods and IHD risk, with fruit and vegetables combined being the most strongly inversely associated with risk. Whether these small associations are causal remains unclear., (© The Author(s) 2020. Published by Oxford University Press on behalf of the International Epidemiological Association.)

The highly abundant N6-methyladenosine (m6A) RNA modification affects most aspects of mRNA function, yet the precise function of the rarer 5-methylcytidine (m5C) remains largely unknown. Here, we map m5C in the human transcriptome using methylation-dependent individual-nucleotide resolution cross-linking and immunoprecipitation (miCLIP) combined with RNA bisulfite sequencing. We identify NSUN6 as a methyltransferase with strong substrate specificity towards mRNA. NSUN6 primarily targeted three prime untranslated regions (3'UTR) at the consensus sequence motif CTCCA, located in loops of hairpin structures. Knockout and rescue experiments revealed enhanced mRNA and translation levels when NSUN6-targeted mRNAs were methylated. Ribosome profiling further demonstrated that NSUN6-specific methylation correlated with translation termination. While NSUN6 was dispensable for mouse embryonic development, it was down-regulated in human tumours and high expression of NSUN6 indicated better patient outcome of certain cancer types. In summary, our study identifies NSUN6 as a methyltransferase targeting mRNA, potentially as part of a quality control mechanism involved in translation termination fidelity., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

We propose a novel model for hierarchical time-to-event data, for example, healthcare data in which patients are grouped by their healthcare provider. The most common model for this kind of data is the Cox proportional hazard model, with frailties that are common to patients in the same group and given a parametric distribution. We relax the parametric frailty assumption in this class of models by using a non-parametric discrete distribution. This improves the flexibility of the model by allowing very general frailty distributions and enables the data to be clustered into groups of healthcare providers with a similar frailty. A tailored Expectation-Maximization algorithm is proposed for estimating the model parameters, methods of model selection are compared, and the code is assessed in simulation studies. This model is particularly useful for administrative data in which there are a limited number of covariates available to explain the heterogeneity associated with the risk of the event. We apply the model to a clinical administrative database recording times to hospital readmission, and related covariates, for patients previously admitted once to hospital for heart failure, and we explore latent clustering structures among healthcare providers., (© The Author 2018. Published by Oxford University Press.)

Introduction: There is an absence of evidence regarding the impact of treating tobacco smoking and vaping equivalently in workplace policies. We aimed to describe and compare smoking and vaping policies in acute nonspecialist NHS Trusts (n = 131) and Higher Education Institutions (HEIs) (n = 131) in England., Methods: We conducted a census of smoking and vaping policies through organizational websites searches and direct requests for information. We recorded whether and where smoking and vaping were permitted., Results: Smoking was prohibited indoors in all organizations. No NHS Trust permitted smoking freely outdoors, in contrast with 60% of HEIs. In 27% of NHS Trusts and 33% of HEIs smoking was permitted in designated areas, while in 73% of NHS Trusts and 8% of HEIs smoking was prohibited anywhere on site. Vaping was prohibited indoors in all NHS Trusts and all but one HEI, but permitted freely outdoors in 18% of NHS Trusts and 75% of HEIs. Vaping was permitted in designated outdoor spaces in 23% of NHS Trusts: 21% had areas shared with smokers; 2% had separate vaping areas. Vaping was permitted in designated outdoor areas in 18% of HEIs, all of which were shared with smokers. Vaping was prohibited anywhere on site in 54% of NHS Trusts and 6% of HEIs., Conclusions: Policies vary considerably in whether vaping and smoking are treated equivalently. Smoking policies in most HEIs should be reviewed to include more effective tobacco control approaches. Evidence is needed on the impact of imposing shared or separate spaces on vapers and smokers., Implications: This report provides a comprehensive review of smoking and vaping policies in two types of organization across England. It highlights key discrepancies between current public health recommendations for vaping and existing workplace policies, which often lead to smokers and vapers sharing spaces. The report identifies the need for evidence on the impact of imposing shared spaces on smokers and vapers to inform workplace policies that maximize public health benefit., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco.)

Objectives: Because the mortality rate is very low in thoracic surgery, its use as a quality discriminator is limited. Acute kidney injury (AKI) is a candidate measure because it is associated with increased rates of morbidity and mortality and is partly preventable. The incidence of AKI after thoracic surgery is not well documented. We conducted an audit to determine the incidence and outcomes of AKI. This audit became a pilot project, and the results indicate the feasibility of a larger study., Methods: Retrospective data on renal function post-thoracic surgery were collected at a tertiary cardiothoracic unit over 12 months. Renal impairment was classified according to the Kidney Disease Improving Global Outcomes criteria., Results: Of 568 patients (mean = 59  ±  SD 18; 38% women), AKI was diagnosed in 86 (15.1%) within 72 h post-thoracic surgery based on the Kidney Disease Improving Global Outcomes staging system (stage 1, n = 55; stage 2, n = 25; stage 3, n = 6). Significant differences were found in postoperative length of stay (3 vs 5 days; P < 0.001) of patients with and without AKI. There was a significant difference between the age groups of patients with and without AKI (P < 0.05) in the open surgical group but not in the group having video-assisted thoracoscopic surgery (VATS). There was no significant difference in the mortality rates between patients with and without AKI., Conclusions: The incidence of AKI after thoracic surgery was 15.1%. AKI was associated with longer hospital stays and was more likely in ≥60-year-old patients after open surgery than after VATS. Reducing AKI could improve patient outcomes. We propose that AKI may be a useful quality measure in thoracic surgery. We are developing a multicentre audit based on this approach., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: It can be challenging for general practitioners to support their oldest old patients through the complex process of relocation., Objective: To provide a typology of the experiences of moving in very old age that is clinically useful for practitioners navigating very old people's relocation., Methods: Qualitative analysis of data from a mixed-methods UK population-based longitudinal study, Cambridge City over-75s Cohort (CC75C), from Year 21 follow-up onwards. Interviews with participants aged ≥95 years old and proxy informants (Year 21: 44/48, 92%, subsequent attrition all deaths). Thematic analysis of qualitative data available from 26/32 participants who moved before they died., Results: Individuals who moved voluntarily in with family experienced gratitude, and those who moved into sheltered house or care homes voluntarily had no regrets. One voluntary move into care was experienced with regret, loss and increased isolation as it severed life-long community ties. Regret and loss were key experiences for those making involuntary moves into care, but acceptance, relief and appreciation of increased company were also observed. The key experience of family members was trauma. Establishing connections with people or place ahead of moving, for example through previous respite care, eased moving. A checklist for practitioners based on the resulting typology of relocation is proposed., Conclusions: Most of the sample moved into residential care. This study highlights the importance of connections to locality, people and place along with good family relationships as the key facilitators of a healthy transition into care for the oldest old. The proposed checklist may have clinical utility., (© The Author(s) 2019. Published by Oxford University Press.)

Background and Objectives: Older people are likely to transition to a new home closer to family who can provide assistance or to long-term residential care as their health declines and their care needs increase. A minority choose to move to "age-friendly" housing before the onset of disability, but the majority prefer to "age in place" and defer moving until health crises compel a transition. Older people living with dementia are likely to move into residential care, but not much is known about the role they play in decision making around these moves. This qualitative study addresses this gap in knowledge by examining how a rare cohort of "older old" people, most with some level of cognitive impairment, were involved in decisions surrounding assistance seeking and moving to a care home., Research Design and Methods: Thematic analysis of qualitative interview data from Cambridge City over-75s Cohort (CC75C) study participants aged 95 years and older, who had moved in later life, and their proxy informants ( n = 26)., Results: Moves at such an old age were made due to a complexity of push and pull factors which had layered dynamics of decision making. In most cases ( n = 22), decision making involved other people with varying degrees of decision ownership. Only four older people, who moved voluntarily, had full ownership of the decision to move. Many relatives reported being traumatized by events leading up to the move., Discussion and Implications: "Older old" people are sometimes unable to make their own decisions about moving due to the urgency of health crisis and cognitive decline. There is a need to support relatives to discuss moving and housing options at timely junctures before health crises intervene in an effort to optimize older people's participation in decision making., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Previous estimates of whether long-term exposure to benzodiazepines increases dementia risk are conflicting and are compromised by the difficulty of controlling for confounders and by reverse causation. We investigated how estimates for the association between benzodiazepine use and later dementia incidence varied based on study design choices, using a case-control study nested within the United Kingdom's Clinical Practice Research Datalink. A total of 40,770 dementia cases diagnosed between April 2006 and July 2015 were matched on age, sex, available data history, and deprivation to 283,933 control subjects. Benzodiazepines and Z-drug prescriptions were ascertained in a drug-exposure period 4-20 years before dementia diagnosis. Estimates varied with the inclusion of new or prevalent users, with the timing of covariate ascertainment, and with varying time between exposure and outcome. There was no association between any new prescription of benzodiazepines and dementia (adjusted odds ratio (OR) = 1.03, 95% confidence interval (CI): 1.00, 1.07), whereas an inverse association was observed among prevalent users (adjusted OR = 0.91, 95% CI: 0.87, 0.95), although this was likely induced by unintentional adjustment for colliders. By considering the choice of confounders and timing of exposure and covariate measurement, our findings overall are consistent with no causal effect of benzodiazepines or Z-drugs on dementia incidence., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Motivation: Methods for analysis of GWAS summary statistics have encouraged data sharing and democratized the analysis of different diseases. Ideal validation for such methods is application to simulated data, where some 'truth' is known. As GWAS increase in size, so does the computational complexity of such evaluations; standard practice repeatedly simulates and analyses genotype data for all individuals in an example study., Results: We have developed a novel method based on an alternative approach, directly simulating GWAS summary data, without individual data as an intermediate step. We mathematically derive the expected statistics for any set of causal variants and their effect sizes, conditional upon control haplotype frequencies (available from public reference datasets). Simulation of GWAS summary output can be conducted independently of sample size by simulating random variates about these expected values. Across a range of scenarios, our method, produces very similar output to that from simulating individual genotypes with a substantial gain in speed even for modest sample sizes. Fast simulation of GWAS summary statistics will enable more complete and rapid evaluation of summary statistic methods as well as opening new potential avenues of research in fine mapping and gene set enrichment analysis., Availability and Implementation: Our method is available under a GPL license as an R package from http://github.com/chr1swallace/simGWAS., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2018. Published by Oxford University Press.)

Aims: Increases in fat-free mass and fat mass have been associated with higher risk of atrial fibrillation (AF) in observational studies. It is not known whether these associations reflect independent causal processes. Our aim was to evaluate independent causal roles of fat-free mass and fat mass on AF., Methods and Results: We conducted a large observational study to estimate the associations between fat-free mass and fat mass on incident AF in the UK Biobank (N = 487 404, N events = 10 365). Genome-wide association analysis was performed to obtain genetic instruments for Mendelian randomization (MR). We evaluated the causal effects of fat-free mass and fat mass on AF with two-sample method by using genetic associations from AFGen consortium as outcome. Finally, we evaluated independent causal effects of fat-free mass and fat mass with multivariate MR. Both fat-free mass and fat mass had observational associations with incident AF [hazard ratio (HR) = 1.77, 95% confidence interval (CI) 1.72-1.83; HR = 1.40, 95% CI 1.37-1.43 per standard deviation increase in fat-free and fat mass, respectively]. The causal effects using the inverse-variance weighted method were 1.55 (95% CI 1.38-1.75) for fat-free mass and 1.30 (95% CI 1.17-1.45) for fat mass. Weighted median, Egger regression, and penalized methods showed similar estimates. The multivariate MR analysis suggested that the causal effects of fat-free and fat mass were independent of each other (causal risk ratios: 1.37, 95% CI 1.06-1.75; 1.28, 95% CI 1.03-1.58)., Conclusion: Genetically programmed increases in fat-free mass and fat mass independently cause an increased risk of AF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Seminal human brain histology work has demonstrated developmental waves of myelination. Here, using a micro-structural magnetic resonance imaging (MRI) marker linked to myelin, we studied fine-grained age differences to deduce waves of growth, stability, and decline of cortical myelination over the life-cycle. In 484 participants, aged 8-85 years, we fitted smooth growth curves to T1- to T2-weighted ratio in each of 360 regions from one of seven cytoarchitectonic classes. From the first derivatives of these generally inverted-U trajectories, we defined three milestones: the age at peak growth; the age at onset of a stable plateau; and the age at the onset of decline. Age at peak growth had a bimodal distribution comprising an early (pre-pubertal) wave of primary sensory and motor cortices and a later (post-pubertal) wave of association, insular and limbic cortices. Most regions reached stability in the 30-s but there was a second wave reaching stability in the 50-s. Age at onset of decline was also bimodal: in some right hemisphere regions, the curve declined from the 60-s, but in other left hemisphere regions, there was no significant decline from the stable plateau. These results are consistent with regionally heterogeneous waves of intracortical myelinogenesis and age-related demyelination.

Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied., Methods and Results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms., Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Small area ecological studies are commonly used in epidemiology to assess the impact of area level risk factors on health outcomes when data are only available in an aggregated form. However, the resulting estimates are often biased due to unmeasured confounders, which typically are not available from the standard administrative registries used for these studies. Extra information on confounders can be provided through external data sets such as surveys or cohorts, where the data are available at the individual level rather than at the area level; however, such data typically lack the geographical coverage of administrative registries. We develop a framework of analysis which combines ecological and individual level data from different sources to provide an adjusted estimate of area level risk factors which is less biased. Our method (i) summarizes all available individual level confounders into an area level scalar variable, which we call ecological propensity score (EPS), (ii) implements a hierarchical structured approach to impute the values of EPS whenever they are missing, and (iii) includes the estimated and imputed EPS into the ecological regression linking the risk factors to the health outcome. Through a simulation study, we show that integrating individual level data into small area analyses via EPS is a promising method to reduce the bias intrinsic in ecological studies due to unmeasured confounders; we also apply the method to a real case study to evaluate the effect of air pollution on coronary heart disease hospital admissions in Greater London.

Motivation: The use of single nucleotide polymorphism (SNP) interactions to predict complex diseases is getting more attention during the past decade, but related statistical methods are still immature. We previously proposed the SNP Interaction Pattern Identifier (SIPI) approach to evaluate 45 SNP interaction patterns/patterns. SIPI is statistically powerful but suffers from a large computation burden. For large-scale studies, it is necessary to use a powerful and computation-efficient method. The objective of this study is to develop an evidence-based mini-version of SIPI as the screening tool or solitary use and to evaluate the impact of inheritance mode and model structure on detecting SNP-SNP interactions., Results: We tested two candidate approaches: the 'Five-Full' and 'AA9int' method. The Five-Full approach is composed of the five full interaction models considering three inheritance modes (additive, dominant and recessive). The AA9int approach is composed of nine interaction models by considering non-hierarchical model structure and the additive mode. Our simulation results show that AA9int has similar statistical power compared to SIPI and is superior to the Five-Full approach, and the impact of the non-hierarchical model structure is greater than that of the inheritance mode in detecting SNP-SNP interactions. In summary, it is recommended that AA9int is a powerful tool to be used either alone or as the screening stage of a two-stage approach (AA9int+SIPI) for detecting SNP-SNP interactions in large-scale studies., Availability and Implementation: The 'AA9int' and 'parAA9int' functions (standard and parallel computing version) are added in the SIPI R package, which is freely available at https://linhuiyi.github.io/LinHY&#95;Software/., Supplementary Information: Supplementary data are available at Bioinformatics online.

Background: Diabetes is a common co-morbidity for patients with heart failure. Diabetes as a co-morbidity means that inpatient care should focus on both conditions to maximize the treatment regimen. However, this pressing issue is not widely researched and so it is unclear whether the acute care management needs of these patients are being met., Aims: (1) To assess the differences in the number of hospital readmissions between patients with heart failure and patients with heart failure-diabetes; (2) to assess the use of integrated care approach for patients with heart failure-diabetes during the index heart failure-related admission; (3) to explore patient experiences of admissions., Methods: A mixed methods design was used: we identified heart failure-related admissions between 1 April 2011 and 31 March 2012 in two hospitals, then reviewed medical records and interviewed 14 patients., Results: Over a 12 month period patients with heart failure-diabetes ( n=172) had more heart failure-related Accident and Emergency attendance episodes (incident rate ratio 1.24, p<0.01) and hospital readmissions (incident rate ratio 1.23, p=0.01) than patients with heart failure ( n=370). We reviewed 72 medical records which met inclusion criteria (adults with heart failure-diabetes, ejection fraction <45%): during admission most of them were reviewed by heart failure specialists but less than one-third were reviewed by diabetes specialists. The interview respondents addressed the need for better integration and co-ordination of care., Conclusions: This is one of the first UK studies to assess the integration of inpatient care for those with heart failure and multi-morbidities. The findings suggest that maximal care management during admission should be explored as a way of reducing the frequent readmissions and improving patient outcomes.

Background: A strong focus on individual choice and behaviour informs interventions designed to reduce health inequalities in the UK. We review evidence for wider mechanisms from a range of disciplines, demonstrate that they are not yet impacting on programmes, and argue for their systematic inclusion in policy and research., Methods: We identified potential mechanisms relevant to health inequalities and their amelioration from different disciplines and analysed six policy documents published between 1976 and 2010 using Bacchi's 'What's the problem represented to be?' framework for policy analysis., Results: We found substantial evidence of supra-individualistic and relational mechanisms relevant to health inequalities from sociology, history, biology, neuroscience, philosophy and psychology. Policy documents sometimes expressed these mechanisms in policy rhetoric but rarely in policy recommendations, which continue to focus on individual behaviour., Discussion: Current evidence points to the potential of systematically applying broader thinking about causal mechanisms, beyond individual choice and responsibility, to the design, implementation and evaluation of policies to reduce health inequalities. We provide a set of questions designed to enable critique of policy discussions and programmes to ensure that these wider mechanisms are considered.

Motivation: A common class of behaviour encountered in the biological sciences involves branching and recombination. During branching, a statistical process bifurcates resulting in two or more potentially correlated processes that may undergo further branching; the contrary is true during recombination, where two or more statistical processes converge. A key objective is to identify the time of this bifurcation (branch or recombination time) from time series measurements, e.g. by comparing a control time series with perturbed time series. Gaussian processes (GPs) represent an ideal framework for such analysis, allowing for nonlinear regression that includes a rigorous treatment of uncertainty. Currently, however, GP models only exist for two-branch systems. Here, we highlight how arbitrarily complex branching processes can be built using the correct composition of covariance functions within a GP framework, thus outlining a general framework for the treatment of branching and recombination in the form of branch-recombinant Gaussian processes (B-RGPs)., Results: We first benchmark the performance of B-RGPs compared to a variety of existing regression approaches, and demonstrate robustness to model misspecification. B-RGPs are then used to investigate the branching patterns of Arabidopsis thaliana gene expression following inoculation with the hemibotrophic bacteria, Pseudomonas syringae DC3000, and a disarmed mutant strain, hrpA. By grouping genes according to the number of branches, we could naturally separate out genes involved in basal immune response from those subverted by the virulent strain, and show enrichment for targets of pathogen protein effectors. Finally, we identify two early branching genes WRKY11 and WRKY17, and show that genes that branched at similar times to WRKY11/17 were enriched for W-box binding motifs, and overrepresented for genes differentially expressed in WRKY11/17 knockouts, suggesting that branch time could be used for identifying direct and indirect binding targets of key transcription factors., Availability and Implementation: https://github.com/cap76/BranchingGPs., Supplementary Information: Supplementary data are available at Bioinformatics online.

Background: age-specific mortality reduction has been accompanied by a decrease in the prevalence of some diseases and an increase in others. Whether populations are becoming 'healthier' depends on which aspect of health is being considered. Frailty has been proposed as an integrative measure to quantify health status., Objective: to investigate changes in the near-term lethality of frailty before and after a 20-year interval using the frailty index (FI), a summary of age-related health deficit accumulation., Design: baseline data from the Cognitive Function and Ageing Studies (CFAS) in 1991 (n = 7,635) and 2011 (n = 7,762)., Setting: three geographically distinct UK centres (Newcastle, Cambridgeshire and Nottingham)., Subjects: individuals aged 65 and over (both institutionalised and community-living)., Methods: a 30-item frailty score was used, which includes morbidities, risk factors and subjective measures of disability. Missing items were imputed using multiple imputations by chained equations. Binomial regression was used to investigate the relationship between frailty, age, sex and cohort. Two-year mortality was modelled using logistic regression., Results: mean frailty was slightly higher in CFAS II (0.19, 95% confidence interval (CI): 0.19-0.20) than CFAS I (0.18, 95% CI: 0.17-0.18). Two-year mortality in CFAS I was higher than in CFAS II (odds ratio (OR) = 1.16, 95% CI: 1.03-1.30). The association between frailty and 2-year mortality was non-linear with an OR of ~1.6 for each 0.10 increment in the FI., Conclusions: the relationship between frailty and mortality did not significantly differ across the studies. Severe frailty as an indicator of mortality is shown to be a stable construct.

Background: death certification data are routinely collected in most developed countries. Coded causes of death are a readily accessible source and have the potential advantage of providing complete follow-up, but with limitations., Objective: to investigate the reliability of using death certificates for surveillance of dementia, the time trend of recording dementia on death certificates and predictive factors of recording of dementia., Subjects: individuals aged 65 and over in six areas across England and Wales were randomly selected for the Medical Research Council Cognitive Function and Ageing Study (CFAS) and CFAS II with mortality follow-up., Methods: prevalence of dementia recorded on death certificates were calculated by year. Reporting of dementia on death certificates compared with the study diagnosis of dementia, with sensitivity, specificity and Cohen's κ were estimated. Multivariable logistic regression models explored the impact of potential factors on the reporting of dementia on the death certificate., Results: the overall unadjusted prevalence of dementia on death certificates rose from 5.3% to 25.9% over the last 26 years. Dementia reported on death certificates was poor with sensitivity 21.0% in earlier cohort CFAS, but it had increased to 45.2% in CFAS II. Dementia was more likely to be recorded on death certificates in individuals with severe dementia, or those living in an institution, yet less likely reported if individuals died in hospital., Conclusion: recording dementia on death certificate has improved significantly in the England and Wales. However, such information is still an underestimate and should be used alongside epidemiological estimations., (© The Author(s) 2018.)

Background: harmful alcohol consumption is reported to be increasing in older people. To intervene and reduce associated risks, evidence currently available needs to be identified., Methods: two systematic reviews in older populations (55+ years): (1) Interventions to prevent or reduce excessive alcohol consumption; (2) Interventions as (1) also reporting cognitive and dementia outcomes. Comprehensive database searches from 2000 to November 2016 for studies in English, from OECD countries. Alcohol dependence treatment excluded. Data were synthesised narratively and using meta-analysis. Risk of bias was assessed using NICE methodology. Reviews are reported according to PRISMA., Results: thirteen studies were identified, but none with cognition or dementia outcomes. Three related to primary prevention; 10 targeted harmful or hazardous older drinkers. A complex range of interventions, intensity and delivery was found. There was an overall intervention effect for 3- and 6-month outcomes combined (8 studies; 3,591 participants; pooled standard mean difference (SMD) -0.18 (95% CI -0.28, -0.07) and 12 months (6 studies; 2,788 participants SMD -0.16 (95% CI -0.32, -0.01) but risk of bias for most studies was unclear with significant heterogeneity. Limited evidence (three studies) suggested more intensive interventions with personalised feedback, physician advice, educational materials, follow-up could be most effective. However, simple interventions including brief interventions, leaflets, alcohol assessments with advice to reduce drinking could also have a positive effect., Conclusions: alcohol interventions in older people may be effective but studies were at unclear or high risk of bias. Evidence gaps include primary prevention, cost-effectiveness, impact on cognitive and dementia outcomes., (© The Author 2017. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Background: medical practice has changed over the last decades reflecting the ageing population, when multi-morbidity requiring multiple medications is more common., Objective: describe and quantify self-reported medicine use including both prescription and over the counter medicines in two comparable population-based studies of older people (65+) in England and to assess the nature and scale of polypharmacy., Methods: data used were from two separate population-based studies; the Cognitive Function Ageing Study I and II. Descriptive analyses were performed to summarise and quantify general medicine use. Negative binomial regression models were fitted to determine factors associated with the number of medicines used., Results: medication use, including both prescribed medicines and over the counter products has increased dramatically over the last 2 decades. The number of people taking five or more items quadrupled from 12 to 49%, while the proportion of people who did not take any medication has decreased from around 1 in 5 to 1 in 13. Cardiovascular drugs were the most frequently taken medication. Polypharmacy is associated with increases in the number of diagnosed long-term conditions., Conclusions: comparison between CFAS I and II reveals marked increases in medication usage and polypharmacy in the older population. The influence of healthcare organisation, introduction of new guidelines and technology changes leading to diagnosis of earlier, milder chronic diseases and treatment may be contributing to this changing pattern. Further research is needed to develop practical solutions to optimise medication management in older people, reducing the harming associated with medication., (© The Author 2017. Published by Oxford University Press on behalf of the British Geriatrics Society.All rights reserved. For permissions, please email: journals.permissions@oup.com)

Background: vascular cognitive impairment no dementia (VCI-ND) defines a preclinical phase of cognitive decline associated with vascular disorders. The neuropsychological profile of VCI-ND may vary according to different vascular conditions., Objective: to determine the neuropsychological profile of individuals with no dementia and vascular disorders, including hypertension, peripheral vascular disease (PVD), coronary heart disease (CHD), diabetes and stroke. Risk of 2-year incident dementia in individuals with disease and cognitive impairment was also tested., Methods: participants were from the Cognitive Function and Ageing Study. At baseline, 13,004 individuals aged ≥65 years were enrolled into the study. Individuals were grouped by baseline disorder status (present, absent) for each condition. Cognitive performance was assessed using the Mini Mental State Examination (MMSE) and the Cambridge Cognitive Examination (CAMCOG). Dementia was assessed at 2 years., Results: in the cross-sectional analysis, hypertension, PVD and CHD were not associated with cognitive impairment. Stroke was associated with impaired global (MMSE) and CAMCOG sub-scale (including memory and non-memory) scores. Diabetes was associated with impairments in global cognitive function (MMSE) and abstract thinking. In the longitudinal analysis, cognitive impairments were associated with incident dementia in all groups., Conclusion: the neuropsychological profile in individuals with vascular disorders depends on the specific condition investigated. In all conditions cognitive impairment is a risk factor for dementia. A better understanding of which cognitive domains are affected in different disease groups could help improve operationalisation of the neuropsychological criteria for VCI-ND and could also aid with the development of dementia risk prediction models in persons with vascular disease., (© The Author 2017. Published by Oxford University Press on behalf of the British Geriatrics Society.)

DNA methylation is a key epigenetic modification involved in gene regulation whose contribution to disease susceptibility remains to be fully understood. Here, we present a novel Bayesian smoothing approach (called ABBA) to detect differentially methylated regions (DMRs) from whole-genome bisulfite sequencing (WGBS). We also show how this approach can be leveraged to identify disease-associated changes in DNA methylation, suggesting mechanisms through which these alterations might affect disease. From a data modeling perspective, ABBA has the distinctive feature of automatically adapting to different correlation structures in CpG methylation levels across the genome while taking into account the distance between CpG sites as a covariate. Our simulation study shows that ABBA has greater power to detect DMRs than existing methods, providing an accurate identification of DMRs in the large majority of simulated cases. To empirically demonstrate the method's efficacy in generating biological hypotheses, we performed WGBS of primary macrophages derived from an experimental rat system of glomerulonephritis and used ABBA to identify >1000 disease-associated DMRs. Investigation of these DMRs revealed differential DNA methylation localized to a 600 bp region in the promoter of the Ifitm3 gene. This was confirmed by ChIP-seq and RNA-seq analyses, showing differential transcription factor binding at the Ifitm3 promoter by JunD (an established determinant of glomerulonephritis), and a consistent change in Ifitm3 expression. Our ABBA analysis allowed us to propose a new role for Ifitm3 in the pathogenesis of glomerulonephritis via a mechanism involving promoter hypermethylation that is associated with Ifitm3 repression in the rat strain susceptible to glomerulonephritis., (Copyright © 2017 Rackham et al.)

Summary: Ontologies are widely used constructs for encoding and analyzing biomedical data, but the absence of simple and consistent tools has made exploratory and systematic analysis of such data unnecessarily difficult. Here we present three packages which aim to simplify such procedures. The ontologyIndex package enables arbitrary ontologies to be read into R, supports representation of ontological objects by native R types, and provides a parsimonius set of performant functions for querying ontologies. ontologySimilarity and ontologyPlot extend ontologyIndex with functionality for straightforward visualization and semantic similarity calculations, including statistical routines., Availability and Implementation: ontologyIndex , ontologyPlot and ontologySimilarity are all available on the Comprehensive R Archive Network website under https://cran.r-project.org/web/packages/ ., Contact: Daniel Greene dg333@cam.ac.uk., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2016. Published by Oxford University Press.)

Motivation: Testing SNP-SNP interactions is considered as a key for overcoming bottlenecks of genetic association studies. However, related statistical methods for testing SNP-SNP interactions are underdeveloped., Results: We propose the SNP Interaction Pattern Identifier (SIPI), which tests 45 biologically meaningful interaction patterns for a binary outcome. SIPI takes non-hierarchical models, inheritance modes and mode coding direction into consideration. The simulation results show that SIPI has higher power than MDR (Multifactor Dimensionality Reduction), AA&#95;Full, Geno&#95;Full (full interaction model with additive or genotypic mode) and SNPassoc in detecting interactions. Applying SIPI to the prostate cancer PRACTICAL consortium data with approximately 21 000 patients, the four SNP pairs in EGFR-EGFR , EGFR-MMP16 and EGFR-CSF1 were found to be associated with prostate cancer aggressiveness with the exact or similar pattern in the discovery and validation sets. A similar match for external validation of SNP-SNP interaction studies is suggested. We demonstrated that SIPI not only searches for more meaningful interaction patterns but can also overcome the unstable nature of interaction patterns., Availability and Implementation: The SIPI software is freely available at http://publichealth.lsuhsc.edu/LinSoftware/ ., Contact: hlin1@lsuhsc.edu., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

Multiple imputation with delta adjustment provides a flexible and transparent means to impute univariate missing data under general missing-not-at-random mechanisms. This facilitates the conduct of analyses assessing sensitivity to the missing-at-random (MAR) assumption. We review the delta-adjustment procedure and demonstrate how it can be used to assess sensitivity to departures from MAR, both when estimating the prevalence of a partially observed outcome and when performing parametric causal mediation analyses with a partially observed mediator. We illustrate the approach using data from 34,446 respondents to a tuberculosis and human immunodeficiency virus (HIV) prevalence survey that was conducted as part of the Zambia-South Africa TB and AIDS Reduction Study (2006-2010). In this study, information on partially observed HIV serological values was supplemented by additional information on self-reported HIV status. We present results from 2 types of sensitivity analysis: The first assumed that the degree of departure from MAR was the same for all individuals with missing HIV serological values; the second assumed that the degree of departure from MAR varied according to an individual's self-reported HIV status. Our analyses demonstrate that multiple imputation offers a principled approach by which to incorporate auxiliary information on self-reported HIV status into analyses based on partially observed HIV serological values., (© The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology., (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Motivation: Analysing the joint association between a large set of responses and predictors is a fundamental statistical task in integrative genomics, exemplified by numerous expression Quantitative Trait Loci (eQTL) studies. Of particular interest are the so-called ': hotspots ': , important genetic variants that regulate the expression of many genes. Recently, attention has focussed on whether eQTLs are common to several tissues, cell-types or, more generally, conditions or whether they are specific to a particular condition., Results: We have implemented MT-HESS, a Bayesian hierarchical model that analyses the association between a large set of predictors, e.g. SNPs, and many responses, e.g. gene expression, in multiple tissues, cells or conditions. Our Bayesian sparse regression algorithm goes beyond ': one-at-a-time ': association tests between SNPs and responses and uses a fully multivariate model search across all linear combinations of SNPs, coupled with a model of the correlation between condition/tissue-specific responses. In addition, we use a hierarchical structure to leverage shared information across different genes, thus improving the detection of hotspots. We show the increase of power resulting from our new approach in an extensive simulation study. Our analysis of two case studies highlights new hotspots that would remain undetected by standard approaches and shows how greater prediction power can be achieved when several tissues are jointly considered., Availability and Implementation: C[Formula: see text] source code and documentation including compilation instructions are available under GNU licence at http://www.mrc-bsu.cam.ac.uk/software/., (© The Author 2015. Published by Oxford University Press.)

Purpose: The aim of this paper is to assess the frequency of identification as well as the inter-coder and test-retest reliability of identification of behavior change techniques (BCTs) in written intervention descriptions., Methods: Forty trained coders applied the "Behavior Change Technique Taxonomy version 1" (BCTTv1) to 40 intervention descriptions published in protocols and repeated this 1 month later., Results: Eighty of 93 defined BCTs were identified by at least one trained coder, and 22 BCTs were identified in 16 (40 %) or more of 40 descriptions. Good inter-coder reliability was observed across 80 BCTs identified in the protocols: 66 (80 %) achieved mean prevalence and bias-adjusted kappa (PABAK) scores of 0.70 or greater, and 59 (74 %) achieved mean scores of 0.80 or greater. There was good within-coder agreement between baseline and 1 month, demonstrating good test-retest reliability., Conclusions: BCTTv1 can be used by trained coders to identify BCTs in intervention descriptions reliably. However, some frequently occurring BCT definitions require further clarification.

Background: Few studies have investigated the impact of the community environment, as distinct from area deprivation, on cognition in later life. This study explores cross-sectional associations between cognitive impairment and dementia and environmental features at the community level in older people., Method: The postcodes of the 2,424 participants in the year-10 interview of the Cognitive Function and Ageing Study in England were mapped into small area level geographical units (Lower-layer Super Output Areas) and linked to environmental data in government statistics. Multilevel logistic regression was conducted to investigate associations between cognitive impairment (defined as MMSE ≤ 25), dementia (organicity level ≥3 in GMS-AGECAT) and community level measurements including area deprivation, natural environment, land use mix and crime. Sensitivity analyses tested the impact of people moving residence within the last two years., Results: Higher levels of area deprivation and crime were not significantly associated with cognitive impairment and dementia after accounting for individual level factors. Living in areas with high land use mix was significantly associated with a nearly 60% reduced odds of dementia (OR: 0.4; 95% CI: 0.2, 0.8) after adjusting for individual level factors and area deprivation, but there was no linear trend for cognitive impairment. Increased odds of dementia (OR: 2.2, 95% CI: 1.2, 4.2) and cognitive impairment (OR: 1.4, 95% CI: 1.0, 2.0) were found in the highest quartile of natural environment availability. Findings were robust to exclusion of the recently relocated., Conclusion: Features of land use have complex associations with cognitive impairment and dementia. Further investigations should focus on environmental influences on cognition to inform health and social policies., (© The Author 2015. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Background: Limited and dated evidence shows ethnic inequalities in health status and health care in respiratory diseases., Methods: This retrospective, cohort study linked Scotland's hospitalization/death records on respiratory disorders to 4.65 million people in the 2001 census (providing ethnic group). For all-respiratory diseases and chronic obstructive pulmonary disease (COPD) from April 2001 to 2010 we calculated age, country of birth and Scottish Index of Multiple Deprivation (SIMD) adjusted risk ratios (RRs), by sex. We calculated hazard ratios (HRs) for death following hospitalization and for readmission. We multiplied ratios and confidence intervals (CIs) by 100, so the reference Scottish White population's RR/HR = 100., Results: RRs were comparatively low for all-respiratory diseases in Other White British (84.0, 95% CI 79.6, 88.6) and Chinese (67.4, 95% CI 55.2, 82.3) men and high in Pakistani men (138.1, 95% CI 125.5, 151.9) and women (132.7, 95% CI 108.8, 161.8). For COPD, White Irish men (142.5, 95% CI 125.3, 162.1) and women (141.9, CI 124.8, 161.3) and any Mixed Background men (161, CI 127.1, 203.9) and women (215.4, CI 158.2, 293.3) had high RRs, while Indian men (54.5, CI 41.9, 70.9) and Chinese women (50.5, CI 31.4, 81.1) had low RRs. In most non-White groups, mortality following hospitalization and readmission was similar or lower than the reference., Conclusions: The pattern of ethnic variations in these respiratory disorders was complex and did not merely reflect smoking patterns. Readmission and death after hospitalization data did not signal inequity in services for ethnic minority groups., (© The Author 2015. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

Background: non-participation in epidemiological studies threatens the generalisability of findings., Objective: to investigate the change in non-participation between the Medical Research Council Cognitive Function and Ageing Study (CFAS) I and II., Design: a comparison of two epidemiological studies of older people using identical methods., Setting: three geographical areas of the United Kingdom., Subjects: older people aged 65 years and over., Methods: the two studies were conducted approximately two decades apart between 1989 and 1994 (CFAS I) and between 2008 and 2011 (CFAS II). Random samples were drawn from primary care lists. We compared demographic factors associated with non-participation., Results: non-participation in CFAS II was higher than in CFAS I (45.3 versus 18.3%). After adjustment for confounders, in both CFAS I and CFAS II, women were more likely to decline to take part (CFAS I: odds ratio (OR) 1.3 95% confidence interval (CI) 1.2 to 1.4; CFAS II: 1.1 95% CI 1.1 to 1.2). Deprivation was associated with non-participation in both studies (highest versus lowest Townsend deprivation quintile, CFAS I: OR 1.4 95% CI 1.2 to 1.6; CFAS II: 2.0 95% CI 1.8 to 2.2). Age was not associated with non-participation in either study (CFAS I, P = 0.21; CFAS II, P = 0.47)., Conclusions: non-participation in epidemiological studies of older people has increased substantially in the past two decades and public willingness to take part in studies of this kind would appear to be declining. As communities become more diverse and older people have increasing commitments on their time, new ways to engage prospective participants are urgently needed., (© The Author 2015. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Background: The number of Mendelian randomization analyses including large numbers of genetic variants is rapidly increasing. This is due to the proliferation of genome-wide association studies, and the desire to obtain more precise estimates of causal effects. However, some genetic variants may not be valid instrumental variables, in particular due to them having more than one proximal phenotypic correlate (pleiotropy)., Methods: We view Mendelian randomization with multiple instruments as a meta-analysis, and show that bias caused by pleiotropy can be regarded as analogous to small study bias. Causal estimates using each instrument can be displayed visually by a funnel plot to assess potential asymmetry. Egger regression, a tool to detect small study bias in meta-analysis, can be adapted to test for bias from pleiotropy, and the slope coefficient from Egger regression provides an estimate of the causal effect. Under the assumption that the association of each genetic variant with the exposure is independent of the pleiotropic effect of the variant (not via the exposure), Egger's test gives a valid test of the null causal hypothesis and a consistent causal effect estimate even when all the genetic variants are invalid instrumental variables., Results: We illustrate the use of this approach by re-analysing two published Mendelian randomization studies of the causal effect of height on lung function, and the causal effect of blood pressure on coronary artery disease risk. The conservative nature of this approach is illustrated with these examples., Conclusions: An adaption of Egger regression (which we call MR-Egger) can detect some violations of the standard instrumental variable assumptions, and provide an effect estimate which is not subject to these violations. The approach provides a sensitivity analysis for the robustness of the findings from a Mendelian randomization investigation., (© The Author 2015; Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: delirium is common and serious, yet frequently missed by medical staff. It is known that delirium is widely taught and examined in UK medical schools; however, what is taught, and how such teaching is delivered, remains unknown. The primary aim of this study was to determine the content of UK undergraduate medical education about delirium and establish how it is delivered. A secondary aim was to highlight and share examples of gold-standard teaching on delirium., Methods: all UK undergraduate medical schools were invited to complete a survey. Schools were asked to describe how delirium was taught and to provide delirium-related learning outcomes. Learning outcomes were mapped to the three overarching themes outlined in Tomorrow's Doctors (knowledge, skills and attitudes)., Results: 24/31 schools (77%) provided responses. In line with previous work, delirium was widely taught and examined. 18/24 schools reported at least one learning outcome that mapped to the knowledge domain, 19/24 for the skills domain and 2/24 for the attitudes domain. 4/24 evaluated the impact of sessions and 3/24 involved patients and the public in teaching. 13/24 schools were confident that exposure to delirium was guaranteed. Innovative teaching methods were reported by a number of schools; weblinks to examples are provided., Discussion: there was widespread failure to address attitudes on delirium within teaching, to evaluate the impact of sessions, to involve patients and the public in teaching and to guarantee exposure to delirium. Future teaching interventions should be directed at attitudinal outcomes, using a synthesis of clinical experience with multidisciplinary interaction and supportive technologies., (© The Author 2014. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: criteria for mild cognitive impairment (MCI) capture an intermediate cognitive state between normal ageing and dementia, associated with increased dementia risk. Whether criteria for MCI are applicable in the context of stroke and can be used to predict dementia in stroke cases is not known., Objectives: to determine the prevalence of MCI in individuals with stroke and identify predictors of 2-year incident dementia in stroke cases., Methods: individuals were from the Medical Research Council Cognitive Function and Ageing Study. MCI prevalence in individuals with stroke was determined. Logistic regression, with receiver operating characteristic curve analysis, was used to identify variables associated with risk of dementia in stroke cases including MCI criteria, demographic, health and lifestyle variables., Findings: of 2,640 individuals seen at the first assessment, 199 reported stroke with no dementia. In individuals with stroke, criteria for MCI are not appropriate, with less than 1% of stroke cases being classified as having MCI. However, in individuals with stroke two components of the MCI definition, subjective memory complaint and cognitive function (memory and praxis scores) predicted 2-year incident dementia (area under the curve = 0.85, 95% CI: 0.77-0.94, n = 113)., Conclusion: criteria for MCI do not appear to capture risk of dementia in the context of stroke in the population. In stroke cases, subjective and objective cognitive performance predicts dementia and these variables could possibly be incorporated into dementia risk models for stroke cases. Identifying individuals with stroke at greatest risk of dementia has important implications for treatment and intervention., (© The Author 2014. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)