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Background: DNA methylation arrays are widely used in epigenome-wide association studies and methylation quantitative trait locus (mQTL) studies. Here, we performed the first genome-wide analysis of monozygotic (MZ) twin correlations and mQTLs on data obtained with the Illumina MethylationEPIC BeadChip (EPIC array) and compared the performance of the EPIC array to the Illumina HumanMethylation450 BeadChip (HM450 array) for buccal-derived DNA.Results: Good-quality EPIC data were obtained for 102 buccal-derived DNA samples from 49 MZ twin pairs (mean age = 7.5 years, range = 1–10). Differences between MZ twins in the cellular content of buccal swabs were a major driver for differences in their DNA methylation profiles, highlighting the importance to adjust for cellular composition in DNA methylation studies of buccal-derived DNA. After adjusting for cellular composition, the genome-wide mean correlation (r) between MZ twins was 0.21 for the EPIC array, and cis mQTL analysis in 84 twins identified 1,296,323 significant associations (FDR 5%), encompassing 33,749 methylation sites and 616,029 genetic variants. MZ twin correlations were slightly larger (p −16) for novel EPIC probes (N = 383,066, mean r = 0.22) compared to probes that are also present on HM450 (N = 406,822, mean r = 0.20). In line with this observation, a larger percentage of novel EPIC probes was associated with genetic variants (novel EPIC probes with significant mQTL 4.7%, HM450 probes with mQTL 3.9%, p −16). Methylation sites with a large MZ correlation and sites associated with mQTLs were most strongly enriched in epithelial cell DNase I hypersensitive sites (DHSs), enhancers, and histone mark H3K4me3.Conclusions: We conclude that the contribution of familial factors to individual differences in DNA methylation and the effect of mQTLs are larger for novel EPIC probes, especially those within regulatory elements connected to active regions specific to the investigated tissue.

Contains fulltext : 70810.pdf (Publisher’s version ) (Closed access) INTRODUCTION: Several studies have shown the usefulness of positron emission tomography (PET) quantification using standardised uptake values (SUV) for diagnosis and staging, prognosis and response monitoring. Many factors affect SUV, such as patient preparation procedures, scan acquisition, image reconstruction and data analysis settings, and the variability in methodology across centres prohibits exchange of SUV data. Therefore, standardisation of 2-[(18)F] fluoro-2-deoxy-D-glucose (FDG) PET whole body procedures is required in multi-centre trials. METHODS: A protocol for standardisation of quantitative FDG whole body PET studies in the Netherlands (NL) was defined. This protocol is based on standardisation of: (1) patient preparation; (2) matching of scan statistics by prescribing dosage as function of patient weight, scan time per bed position, percentage of bed overlap and image acquisition mode (2D or 3D); (3) matching of image resolution by prescribing reconstruction settings for each type of scanner; (4) matching of data analysis procedure by defining volume of interest methods and SUV calculations and; (5) finally, a multi-centre QC procedure is defined using a 20-cm diameter phantom for verification of scanner calibration and the NEMA NU 2 2001 Image Quality phantom for verification of activity concentration recoveries (i.e., verification of image resolution and reconstruction convergence). DISCUSSION: This paper describes a protocol for standardization of quantitative FDG whole body multi-centre PET studies. CONCLUSION: The protocol was successfully implemented in the Netherlands and has been approved by the Netherlands Society of Nuclear Medicine.

Nursing home physicians are bound to be confronted more often with patients that have an advance directive concerning a request for euthanasia in the case of dementia. Despite the fact that in the Netherlands euthanasia in dementia, under certain conditions, is justified when a written request is present, these requests are rarely carried out.This article provides insight into the medical ethical problems that physicians may encounter when treating a patient with dementia in the posession of a written request for euthanasia. Dilemma's with respect to the patient's (in)competence, personal identity and unbearable suffering, are adressed successively. It appears that insight into the way that physicians in daily practice deal with these dilemma's is limited. More research into the issues around advance directives in dementia is recommended.

Background Pain is highly prevalent in nursing homes (NH) in several countries. Data about pain in Dutch NH's, where medical care is delivered by specifically trained NH-physicians, are not available. The aim of the present study is to determine prevalence, course, correlates, recognition and treatment of pain among Dutch NH-patients and to make a comparison with international data. Methods The study-population consisted of 350 elderly NH-patients from 14 Dutch NH's. Pain (pain-subscale Nottingham Health Profile) and clinical characteristics (gender, age, cognition, depression, anxiety, sleeping problems, morbidity and functional status) were measured at baseline and at six months. Association of pain (baseline and six months) with clinical characteristics was assessed with chi-square and multiple logistic regression analyses. Results Pain-prevalence was 68.0% (40.5% mild pain symptoms, 27.5% serious pain symptoms). 80% of the patients with pain at baseline still experienced pain at six months. Serious pain at baseline was significantly associated with depression (OR: 2.56; 95% CI: 1.34-4.89) and anxiety (OR 2.47; 95% CI: 1.22-4.99). Serious pain at six months was associated with pain at baseline (OR 18.55; 95% CI: 5.19-66.31) and depression at baseline (OR: 2.63; 95% CI:1.10-6.29). Recognition of pain by NH-physicians varied (35% to 69.7%) depending on measurement instrument and severity of pain. Analgesics were received by 64.5% (paracetamol (acetaminophen), NSAIDs, opioids). Paracetamol (acetaminophen) and opioids frequently were prescribed below daily defined doses. Conclusion Pain occurred frequently also among Dutch NH-patients and was associated with depression and anxiety. Recognition and treatment by NH-physicians proved sub-optimal. Future studies should focus on interventions to improve recognition and treatment of pain.

Changes in scores on health status questionnaires are difficult to interpret. Several methods to determine minimally important changes (MICs) have been proposed which can broadly be divided in distribution-based and anchor-based methods. Comparisons of these methods have led to insight into essential differences between these approaches. Some authors have tried to come to a uniform measure for the MIC, such as 0.5 standard deviation and the value of one standard error of measurement (SEM). Others have emphasized the diversity of MIC values, depending on the type of anchor, the definition of minimal importance on the anchor, and characteristics of the disease under study. A closer look makes clear that some distribution-based methods have been merely focused on minimally detectable changes. For assessing minimally important changes, anchor-based methods are preferred, as they include a definition of what is minimally important. Acknowledging the distinction between minimally detectable and minimally important changes is useful, not only to avoid confusion among MIC methods, but also to gain information on two important benchmarks on the scale of a health status measurement instrument. Appreciating the distinction, it becomes possible to judge whether the minimally detectable change of a measurement instrument is sufficiently small to detect minimally important changes.