No Effect of Folic Acid Supplementation on Global DNA Methylation in Men and Women with Moderately Elevated Homocysteine

A global loss of cytosine methylation in DNA has been implicated in a wide range of diseases. There is growing evidence that modifications in DNA methylation can be brought about by altering the intake of methyl donors such as folate. We examined whether long-term daily supplementation with 0.8 mg of folic acid would increase global DNA methylation compared with placebo in individuals with elevated plasma homocysteine. We also investigated if these effects were modified by MTHFR C677T genotype. Two hundred sixteen participants out of 818 subjects who had participated in a randomized double-blind placebo-controlled trial were selected, pre-stratified on MTHFR C677T genotype and matched on age and smoking status. They were allocated to receive either folic acid (0.8 mg/d; n = 105) or placebo treatment (n = 111) for three years. Peripheral blood leukocyte DNA methylation and serum and erythrocyte folate were assessed. Global DNA methylation was measured using liquid chromatography-tandem mass spectrometry and expressed as a percentage of 5-methylcytosines versus the total number of cytosine. There was no difference in global DNA methylation between those randomized to folic acid and those in the placebo group (difference = 0.008, 95%CI = −0.05,0.07, P = 0.79). There was also no difference between treatment groups when we stratified for MTHFR C677T genotype (CC, n = 76; CT, n = 70; TT, n = 70), baseline erythrocyte folate status or baseline DNA methylation levels. In moderately hyperhomocysteinemic men and women, long-term folic acid supplementation does not increase global DNA methylation in peripheral blood leukocytes

An analysis of the control hierarchy modeling of the CMS detector control system

The supervisory level of the Detector Control System (DCS) of the CMS experiment is implemented using Finite State Machines (FSM), which model the behaviours and control the operations of all the sub-detectors and support services. The FSM tree of the whole CMS experiment consists of more than 30.000 nodes. An analysis of a system of such size is a complex task but is a crucial step towards the improvement of the overall performance of the FSM system. This paper presents the analysis of the CMS FSM system using the micro Common Representation Language 2 (mcrl2) methodology. Individual mCRL2 models are obtained for the FSM systems of the CMS sub-detectors using the ASF+SDF automated translation tool. Different mCRL2 operations are applied to the mCRL2 models. A mCRL2 simulation tool is used to closer examine the system. Visualization of a system based on the exploration of its state space is enabled with a mCRL2 tool. Requirements such as command and state propagation are expressed using modal mu-calculus and checked using a model checking algorithm. For checking local requirements such as endless loop freedom, the Bounded Model Checking technique is applied. This paper discusses these analysis techniques and presents the results of their application on the CMS FSM system

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk

Cost-utility and cost-effectiveness analysis of a clinical medication review focused on personal goals in older persons with polypharmacy compared to usual care: Economic evaluation of the DREAMeR study

AIMS: The ageing society may lead to increasing healthcare expenditure. A clinical medication review (CMR) could potentially reduce costs. The aim of this study is to perform a cost-utility and cost-effectiveness analysis from a societal perspective of a patient-centred CMR. METHODS: A trial-based cost-utility and cost-effectiveness analysis was performed as part of the DREAMeR study, a pragmatic controlled trial that randomised patients aged ≥70 years using at least seven drugs to either CMR or usual care. Over six months, healthcare consumption and drug use were collected to estimate costs, and effects were collected in terms of quality-adjusted life years (QALYs) measured with EQ-5D-5 L and EQ-VAS and as reduced health-related complaints with impact on patients' daily lives. RESULTS: The total mean costs per patient (n = 588) over six months were €4,189 ± 6,596 for the control group (n = 294) and €4,008 ± 6,678 for the intervention group (n = 294), including estimated intervention costs of €199 ± 67, which resulted in a mean incremental total cost savings of €181 for the intervention group compared to the control group. Compared to the control group, for the intervention group, the mean incremental QALYs over six months were: -0.00217 measured with EQ-5D and 0.003 measured with EQ-VAS. The incremental effect of reduced health-related complaints with impact was -0.34. There was a likelihood of >90% that the intervention was cost-saving. CONCLUSIONS: The benefits of a patient-centred CMR were inconsistent with no benefits on HR-QoL measured with EQ-5D-5 L and small benefits on HR-QoL measured with EQ-VAS and health-related complaints with impact on patients' daily lives. Additionally, a CMR could potentially be cost saving from a societal perspective

YEARS clinical decision rule for diagnosing pulmonary embolism: a prospective diagnostic cohort follow-up study in primary care

Objectives The Wells rule is often used in primary care to rule out pulmonary embolism (PE), but its efficiency is low as many referred patients do not have PE. In this study, we evaluated in primary care an alternative and potentially more efficient diagnostic strategy—the YEARS algorithm; a simplified three-item version of the Wells rule combined with a pretest probability adjusted D-dimer interpretation. Design In this comprehensive prospective diagnostic validation study, primary care patients suspected of PE were enrolled by their general practitioner. All three YEARS items were collected in addition to D-dimer results, and patients were followed for 3 months to establish the final diagnosis. Setting Primary care in the Netherlands. Participants 753 patients with suspected acute PE were included. Five patients (0.7%) were lost to followup. Main outcome measures Failure rate (number of PE cases among patients classified by the algorithm as ‘PE ruled-out’) and efficiency (fraction of patients classified as ‘PE probable/further imaging needed’). Results Prevalence of PE was 5.5% (41/748 patients). In total, 603 patients were classified as ‘PE ruled-out’ by the YEARS algorithm (532 with zero YEARS items and a D-dimer<1000 ng/mL and 71 with≥1 positive YEARS item and a D-dimer<500 ng/mL), resulting in an efficiency of 80.6% (603/748 patients, 95% CI 77.6% to 83.4%). Of these patients, three patients had a diagnosis of nonfatal PE during 3 months follow-up, all three with zero YEARS items and D-dimer between 500 and 1000 ng/ mL, resulting in an overall diagnostic failure rate of 0.50% (3/603 patients, 95% CI 0.13% to 1.57%). In the patients categorised as ‘imaging needed’ (n=145), a total of 38 (26.2%) were indeed diagnosed with PE. Conclusions Our study suggests that acute PE can be safely ruled out in 80% of patients by the YEARS algorithm in a primary care setting, while only 20% of patients required referral to hospital care for imaging tests. In those classified as ‘imaging needed’, PE was present in about one in every four patients, demonstrating a high detection proportion

Accuracy of physicians' intuitive risk estimation in the diagnostic management of pulmonary embolism: An Individual Patient Data Meta-Analysis

BACKGROUND: In patients clinically suspected of having pulmonary embolism (PE), physicians often rely on intuitive estimation ("gestalt") of PE presence. Although shown to be predictive, gestalt is criticized for its assumed variation across physicians and lack of standardization. OBJECTIVES: To assess the diagnostic accuracy of gestalt in the diagnosis of PE and gain insight into its possible variation. METHODS: We performed an individual patient data meta-analysis including patients suspected of having PE. The primary outcome was diagnostic accuracy of gestalt for the diagnosis of PE, quantified as risk ratio (RR) between gestalt and PE based on 2-stage random-effect log-binomial meta-analysis regression as well as gestalts' sensitivity and specificity. The variability of these measures was explored across different health care settings, publication period, PE prevalence, patient subgroups (sex, heart failure, chronic lung disease, and items of the Wells score other than gestalt), and age. RESULTS: We analyzed 20 770 patients suspected of having PE from 16 original studies. The prevalence of PE in patients with and without a positive gestalt was 28.8% vs 9.1%, respectively. The overall RR was 3.02 (95% CI, 2.35-3.87), and the overall sensitivity and specificity were 74% (95% CI, 68%-79%) and 61% (95% CI, 53%-68%), respectively. Although variation was observed across individual studies (I 2, 90.63%), the diagnostic accuracy was consistent across all subgroups and health care settings. CONCLUSION: A positive gestalt was associated with a 3-fold increased risk of PE in suspected patients. Although variation was observed across studies, the RR of gestalt was similar across prespecified subgroups and health care settings, exemplifying its diagnostic value for all patients suspected of having PE

The Early Royal Society and Visual Culture

Recent studies have fruitfully examined the intersection between early modern science and visual culture by elucidating the functions of images in shaping and disseminating scientific knowledge. Given its rich archival sources, it is possible to extend this line of research in the case of the Royal Society to an examination of attitudes towards images as artefacts –manufactured objects worth commissioning, collecting and studying. Drawing on existing scholarship and material from the Royal Society Archives, I discuss Fellows’ interests in prints, drawings, varnishes, colorants, images made out of unusual materials, and methods of identifying the painter from a painting. Knowledge of production processes of images was important to members of the Royal Society, not only as connoisseurs and collectors, but also as those interested in a Baconian mastery of material processes, including a “history of trades”. Their antiquarian interests led to discussion of painters’ styles, and they gradually developed a visual memorial to an institution through portraits and other visual records.AH/M001938/1 (AHRC