Folic acid in pregnancy and mortality from cancer and cardiovascular disease : further follow-up of the Aberdeen folic acid supplementation trial

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions. Acknowledgements The authors wish to acknowledge Professor Marion Hall, who set up the original randomised trial of folic acid supplementation. The authors also thank Ms Katie Wilde and the Data Management Team, University of Aberdeen, for their help with the extraction and linking of data and the data analysts from ISD Scotland.Peer reviewedPublisher PD

Quality of life, cognitive, physical and emotional function at diagnosis predicts head and neck cancer survival: analysis of cases from the Head and Neck 5000 study.

Purpose: The aim of this paper is to determine whether health-related quality of life (HRQOL) at diagnosis of head and neck cancer (HNC) is associated with overall survival following treatment with curative intent after adjusting for other factors.Methods: Data were collected from 5,511 participants of the Head and Neck 5000 study (HN5000). HRQOL was measured using the EORTC QLQ-C30. Questionnaire and covariate data were available from 2,171 participants diagnosed as follows: oral cavity (655), oropharynx HPV+ (723) and HPV- (277), and larynx (516). On average, participants were followed up 3.2 years (sd 1.2) after diagnosis. Data were adjusted for age, gender, co-morbidity, intended treatment, education level, income from benefits, smoking status and alcohol consumption.Results: There was a clinically meaningful difference between Global HRQOL scores at diagnosis and survival in an unadjusted and adjusted model: (HR=0.86, CI=0.82-0.89, p<0.001 (unadjusted) and HR=0.90, CI=0.86-0.94, p<0.001 (adjusted)). In analyses stratified by tumour site and HPV status this association was similarly noted before adjustment and persisted after. There were some tumour sub-site variations: improved survival for people with laryngeal cancer reporting higher levels of physical role or social functioning and people with oral cancer reporting higher levels of role or social functioning.Conclusion: As survival is the main priority for most people diagnosed with cancer, pre-treatment HRQOL is an additional factor to be included in risk stratification and case-mix adjustments. There is merit in incorporating HRQOL into routine clinical care as this is a useful facet in patient-clinician decision making, prognostication and recovery

Spinal Manipulation vs Sham Manipulation for Nonspecific Low Back Pain:A Systematic Review and Meta-Analysis

OBJECTIVE: The purpose of this systematic review was to identify and critically evaluate randomized controlled trials of spinal manipulation (SM) vs sham manipulation in the treatment of nonspecific low back pain. METHODS: Four electronic databases were searched from their inception to March 2015 to identify all relevant trials. Reference lists of retrieved articles were hand-searched. All data were extracted by 2 independent reviewers, and risk of bias was assessed using the Cochrane Back Review Group Risk of Bias tool. RESULTS: Nine randomized controlled trials were included in the systematic review, and 4 were found to be eligible for inclusion in a meta-analysis. Participants in the SM group had improved symptoms compared with participants receiving sham treatment (standardized mean difference = − 0.36; 95% confidence interval, − 0.59 to − 0.12). The majority of studies were of low risk of bias; however, several of the studies were small, the practitioner could not be blinded, and some studies did not conduct intention-to-treat analysis and had a high level of dropouts. CONCLUSION: There is some evidence that SM has specific treatment effects and is more effective at reducing nonspecific low back pain when compared with an effective sham intervention. However, given the small number of studies included in this analysis, we should be cautious of making strong inferences based on these results

IV. Discours

Abstract Background The Enhanced Recovery After Surgery (ERAS) programme is an approach to the perioperative care of patients which aims to improve outcomes and speed up recovery after surgery. Although the evidence base appears strong for this programme, the implementation of ERAS has been slow. This study aimed to gain an understanding of the facilitating factors and challenges of implementing the programme with a view to providing additional contextual information to aid implementation. The study had a particular focus on the nutritional elements as these have been highlighted as important. Methods The study employed qualitative research methods, guided by the Normalisation Process Theory (NPT) to explore the experiences and opinions of 26 healthcare professionals from a range of disciplines implementing the programme. Results This study identified facilitating factors to the implementation of ERAS: alignment with evidence based practice, standardising practice, drawing on the evidence base of other specialties, leadership, teamwork, ERAS meetings, patient involvement and education, a pre-operative assessment unit, staff education, resources attached to obtaining The Commissioning for Quality and Innovation (CQUIN) money, the ward layout, data collection and feedback, and adapting the care pathway. A number of implementation challenges were also identified: resistance to change, standardisation affecting personalised patient care, the buy-in of relevant stakeholders, keeping ERAS visible, information provision to patients, resources, palatability of nutritional drinks, aligning different ward cultures, patients going to non-ERAS departments, spreading the programme within the hospital, differences in health issue, and utilising a segmental approach.  Conclusions The findings presented here provide useful contextual information from diverse surgical specialties to inform healthcare providers when implementing ERAS in practice. Addressing the challenges and utilising the facilitating factors identified in this study, could speed up the rate at which ERAS is adopted, implemented and embedded

Assessing Causality in the Association between Child Adiposity and Physical Activity Levels:A Mendelian Randomization Analysis

BackgroundCross-sectional studies have shown that objectively measured physical activity is associated with childhood adiposity, and a strong inverse dose-response association with body mass index (BMI) has been found. However, few studies have explored the extent to which this association reflects reverse causation. We aimed to determine whether childhood adiposity causally influences levels of physical activity using genetic variants reliably associated with adiposity to estimate causal effects.Methods and FindingsThe Avon Longitudinal Study of Parents and Children collected data on objectively assessed activity levels of 4,296 children at age 11 y with recorded BMI and genotypic data. We used 32 established genetic correlates of BMI combined in a weighted allelic score as an instrumental variable for adiposity to estimate the causal effect of adiposity on activity.In observational analysis, a 3.3 kg/m(2) (one standard deviation) higher BMI was associated with 22.3 (95% CI, 17.0, 27.6) movement counts/min less total physical activity (p = 1.6x10(-16)), 2.6 (2.1, 3.1) min/d less moderate-to-vigorous-intensity activity (p = 3.7x10(-29)), and 3.5 (1.5, 5.5) min/d more sedentary time (p = 5.0x10(-4)). In Mendelian randomization analyses, the same difference in BMI was associated with 32.4 (0.9, 63.9) movement counts/min less total physical activity (p = 0.04) (similar to 5.3% of the mean counts/minute), 2.8 (0.1, 5.5) min/d less moderate-to-vigorous-intensity activity (p = 0.04), and 13.2 (1.3, 25.2) min/d more sedentary time (p = 0.03). There was no strong evidence for a difference between variable estimates from observational estimates. Similar results were obtained using fat mass index. Low power and poor instrumentation of activity limited causal analysis of the influence of physical activity on BMI.ConclusionsOur results suggest that increased adiposity causes a reduction in physical activity in children and support research into the targeting of BMI in efforts to increase childhood activity levels. Importantly, this does not exclude lower physical activity also leading to increased adiposity, i.e., bidirectional causation.Please see later in the article for theEditors' SummaryEditors' SummaryBackgroundThe World Health Organization estimates that globally at least 42 million children under the age of five are obese. The World Health Organization recommends that all children undertake at least one hour of physical activity daily, on the basis that increased physical activity will reduce or prevent excessive weight gain in children and adolescents. In practice, while numerous studies have shown that body mass index (BMI) shows a strong inverse correlation with physical activity (i.e., active children are thinner than sedentary ones), exercise programs specifically targeted at obese children have had only very limited success in reducing weight. The reasons for this are not clear, although environmental factors such as watching television and lack of exercise facilities are traditionally blamed.Why Was This Study Done? ?One of the reasons why obese children do not lose weight through exercise might be that being fat in itself leads to a decrease in physical activity. This is termed reverse causation, i.e., obesity causes sedentary behavior, rather than the other way around. The potential influence of environmental factors (e.g., lack of opportunity to exercise) makes it difficult to prove this argument. Recent research has demonstrated that specific genotypes are related to obesity in children. Specific variations within the DNA of individual genes (single nucleotide polymorphisms, or SNPs) are more common in obese individuals and predispose to greater adiposity across the weight distribution. While adiposity itself can be influenced by many environmental factors that complicate the interpretation of observed associations, at the population level, genetic variation is not related to the same factors, and over the life course cannot be changed. Investigations that exploit these properties of genetic associations to inform the interpretation of observed associations are termed Mendelian randomization studies. This research technique is used to reduce the influence of confounding environmental factors on an observed clinical condition. The authors of this study use Mendelian randomization to determine whether a genetic tendency towards high BMI and fat mass is correlated with reduced levels of physical activity in a large cohort of children.What Did the Researchers Do and Find? ?The researchers looked at a cohort of children from a large long-term health research project (the Avon Longitudinal Study of Parents and Children). BMI and total body fat were recorded. Total daily activity was measured via a small movement-counting device. In addition, the participants underwent genotyping to detect the presence of several SNPs known to be linked to obesity. For each child a total BMI allelic score was determined based on the number of obesity-related genetic variants carried by that individual. The association between obesity and reduced physical activity was then studied in two ways. Direct correlation between actual BMI and physical activity was measured (observational data). Separately, the link between BMI allelic score and physical activity was also determined (Mendelian randomization or instrumental variable analysis). The observational data showed that boys were more active than girls and had lower BMI. Across both sexes, a higher-than-average BMI was associated with lower daily activity. In genetic analyses, allelic score had a positive correlation with BMI, with one particular SNP being most strongly linked to high BMI and total fat mass. A high allelic score for BMI was also correlated with lower levels of daily physical activity. The authors conclude that children who are obese and have an inherent predisposition to high BMI also have a propensity to reduced levels of physical activity, which may compound their weight gain.What Do These Findings Mean? ?This study provides evidence that being fat is in itself a risk factor for low activity levels, separately from external environmental influences. This may be an example of "reverse causation," i.e., high BMI causes a reduction in physical activity. Alternatively, there may be a bidirectional causality, so that those with a genetic predisposition to high fat mass exercise less, leading to higher BMI, and so on, in a vicious circle. A significant limitation of the study is that validated allelic scores for physical activity are not available. Thus, it is not possible to determine whether individuals with a high allelic score for BMI also have a propensity to exercise less, or whether it is simply the circumstance of being overweight that discourages activity.This study does suggest that trying to persuade obese children to lose weight by exercising more is likely to be ineffective unless additional strategies to reduce BMI, such as strict diet control, are also implemented.Additional InformationPlease access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001618.The US Centers for Disease Control and Prevention provides obesity-related statistics, details of prevention programs, and an overview on public health strategy in the United StatesA more worldwide view is given by the World Health OrganizationThe UK National Health Service website gives information on physical activity guidelines for different age groupsThe International Obesity Task Force is a network of organizations that seeks to alert the world to the growing health crisis threatened by soaring levels of obesityMedlinePlus-which brings together authoritative information from the US National Library of Medicine, National Institutes of Health, and other government agencies and health-related organizations-has a page on obesityAdditional information on the Avon Longitudinal Study of Parents and Children is availableThe British Medical Journal has an article that describes Mendelian randomization</p

The long-term impact of folic acid in pregnancy on offspring DNA methylation : follow-up of the Aberdeen folic acid supplementation trial (AFAST)

Funding This work was supported by the NIHR Bristol Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. R.C.R., G.C.S., N.K., T.G., G.D.S. and C.L.R. work in a unit that receives funds from the University of Bristol and the UK Medical Research Council (MC_UU_12013/1, MC_UU_12013/2 and MC_UU_12013/8). This work was also supported by CRUK (grant number C18281/A19169) and the ESRC (grant number ES/N000498/1). C.M.T. is supported by a Wellcome Trust Career Re-entry Fellowship (grant number 104077/Z/14/Z).Peer reviewedPublisher PD

Objectively measured physical activity and fat mass in a large cohort of children

Background Previous studies have been unable to characterise the association between physical activity and obesity, possibly because most relied on inaccurate measures of physical activity and obesity. Methods and Findings We carried out a cross sectional analysis on 5,500 12-year-old children enrolled in the Avon Longitudinal Study of Parents and Children. Total physical activity and minutes of moderate and vigorous physical activity (MVPA) were measured using the Actigraph accelerometer. Fat mass and obesity (defined as the top decile of fat mass) were measured using the Lunar Prodigy dual x-ray emission absorptiometry scanner. We found strong negative associations between MVPA and fat mass that were unaltered after adjustment for total physical activity. We found a strong negative dose-response association between MVPA and obesity. The odds ratio for obesity in adjusted models between top and the bottom quintiles of minutes of MVPA was 0.03 (95% confidence interval [CI] 0.01-0.13, p-value for trend &lt; 0.0001) in boys and 0.36 (95% CI 0.17-0.74, p-value for trend = 0.006) in girls. Conclusions We demonstrated a strong graded inverse association between physical activity and obesity that was stronger in boys. Our data suggest that higher intensity physical activity may be more important than total activity

No effect of n - 3 long-chain polyunsaturated fatty acid (EPA and DHA) supplementation on depressed mood and cognitive function : a randomised controlled trial

Low dietary intakes of the n-3 long-chain PUFA (LCPUFA) EPA and DHA are thought to be associated with increased risk for a variety of adverse&nbsp; outcomes, including some psychiatric disorders. Evidence from&nbsp; observational and intervention studies for a role of n-3 LCPUFA in depression is mixed, with some support for a benefit of EPA and/or DHA in major depressive illness. The present study was a double-blind randomised controlled trial that evaluated the effects of EPA+DHA supplementation (1.5 g/d) on mood and cognitive function in mild to moderately depressed&nbsp; individuals. Of 218 participants who entered the trial, 190 completed the planned 12 weeks intervention. Compliance, confirmed by plasma fatty acid concentrations, was good, but there was no evidence of a difference between supplemented and placebo groups in the primary outcome - namely, the depression subscale of the Depression Anxiety and Stress Scales at 12 weeks. Mean depression score was 8.4 for the EPA+DHA group and 9.6 for the placebo group, with an adjusted difference of - 1.0 (95 % CI - 2.8, 0.8; P = 0.27). Other measures of mood, mental health and cognitive function, including Beck Depression Inventory score and attentional bias toward threat words, were similarly little affected by the intervention. In conclusion, substantially increasing EPA+DHA intake for 3 months was found not to have beneficial or harmful effects on mood in mild to moderate depression. Adding the present result to a meta-analysis of previous relevant randomised controlled trial results confirmed an overall negligible benefit of n-3 LCPUFA supplementation for depressed mood.<br /