Aims Carotid–femoral pulse wave velocity (PWV), a direct measure of aortic stiffness, has become increasingly important for total cardiovascular (CV) risk estimation. Its application as a routine tool for clinical patient evaluation has been hampered by the absence of reference values. The aim of the present study is to establish reference and normal values for PWV based on a large European population. Methods and results We gathered data from 16 867 subjects and patients from 13 different centres across eight European countries, in which PWV and basic clinical parameters were measured. Of these, 11 092 individuals were free from overt CV disease, non-diabetic and untreated by either anti-hypertensive or lipid-lowering drugs and constituted the reference value population, of which the subset with optimal/normal blood pressures (BPs) (n = 1455) is the normal value population. Prior to data pooling, PWV values were converted to a common standard using established conversion formulae. Subjects were categorized by age decade and further subdivided according to BP categories. Pulse wave velocity increased with age and BP category; the increase with age being more pronounced for higher BP categories and the increase with BP being more important for older subjects. The distribution of PWV with age and BP category is described and reference values for PWV are established. Normal values are proposed based on the PWV values observed in the non-hypertensive subpopulation who had no additional CV risk factors. Conclusion The present study is the first to establish reference and normal values for PWV, combining a sizeable European population after standardizing results for different methods of PWV measurement.

Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors

Cancer Epigenetics: Tumor Heterogeneity, Plasticity of Stem-like States, and Drug Resistance

Environmental factors such as tobacco smoking may have long-lasting effects on DNA methylation patterns, which might lead to changes in gene expression and in a broader context to the development or progression of various diseases. We conducted an epigenome-wide association study (EWAs) comparing current, former and never smokers from 1793 participants of the population-based KORA F4 panel, with replication in 479 participants from the KORA F3 panel, carried out by the 450K BeadChip with genomic DNA obtained from whole blood. We observed wide-spread differences in the degree of site-specific methylation (with p-values ranging from 9.31E-08 to 2.54E-182) as a function of tobacco smoking in each of the 22 autosomes, with the percent of variance explained by smoking ranging from 1.31 to 41.02. Depending on cessation time and pack-years, methylation levels in former smokers were found to be close to the ones seen in never smokers. In addition, methylation-specific protein binding patterns were observed for cg05575921 within AHRR, which had the highest level of detectable changes in DNA methylation associated with tobacco smoking (-24.40% methylation; p = 2.54E-182), suggesting a regulatory role for gene expression. The results of our study confirm the broad effect of tobacco smoking on the human organism, but also show that quitting tobacco smoking presumably allows regaining the DNA methylation state of never smokers.

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Tobacco smoking leads to extensive genome-wide changes in DNA methylation.

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.

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DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis

For some time now councils with social services responsibilities (CSSRs) have been required to conduct surveys of user’s experience of social services. These have taken place nationally in three-yearly cycles. In 2002/03 the survey was for older people, in 2003/04 it was for younger adults with physical and sensory impairments, and in 2004/05 it was for children. 2005/06 marked the beginning of the second wave of the cycle. The mandate for conducting surveys of user’s experiences and satisfaction with services was first given in the white paper Modern Local Government: in Touch with the People (Department for the Environment, Trade and the Regions, 1998). In 2002 the Office of National Statistics (ONS) and SPRU developed a set of questionnaires for this purpose (Qureshi and Rowlands, 2004). Subsequent national surveys have drawn on this work to identify a set of compulsory questions for each round. User experience surveys (UESs) are regarded as an important part of the overall performance framework for social care and, providing councils with information about how they might improve services locally. Local authorities are required to submit their results to government bodies so that the relative performance of the CSSRs can be judged. This report is composed of five sections. The aims and objectives of the report are outlined in the second section and the method used to gather the data is outlined in section 3. In section 4 we report on the findings from the fieldwork and draw some conclusions and recommendations for the national survey in section 5. The topic guides for the focus groups and interviews are included in the appendices along with a brief discussion of the findings from the focus groups and a copy of the final extended questionnaire.

Younger Adults' Understanding of Questions for a Service User Experience Survey. Funded/commissioned by: The Health and Social Care Information Centre

A single cytosine-guanine dinucleotide (CpG) site within coagulation factor II (thrombin) receptor-like 3 (F2RL3) was recently found to be hypomethylated in peripheral blood genomic DNA from smokers compared with former and non-smokers. We performed two epigenome-wide association studies (EWAS) nested in a prospective healthy cohort using the Illumina 450K Methylation Beadchip. The two populations consisted of matched pairs of healthy individuals (n = 374), of which half went on to develop breast or colon cancer. The association was analysed between methylation and smoking status, as well as cancer risk. In addition to the same locus in F2RL3, we report several loci that are hypomethylated in smokers compared with former and non-smokers, including an intragenic region of the aryl hydrocarbon receptor repressor gene (AHRR; cg05575921, P = 2.31 × 10(-15); effect size = 14-17%), an intergenic CpG island on 2q37.1 (cg21566642, P = 3.73 × 10(-13); effect size = 12%) and a further intergenic region at 6p21.33 (cg06126421, P = 4.96 × 10(-11), effect size = 7-8%). Bisulphite pyrosequencing validated six loci in a further independent population of healthy individuals (n = 180). Methylation levels in AHRR were also significantly decreased (P < 0.001) and expression increased (P = 0.0047) in the lung tissue of current smokers compared with non-smokers. This was further validated in a mouse model of smoke exposure. We observed an association with breast cancer risk for the 2q37.1 locus (P = 0.003, adjusted for the smoking status), but not for the other loci associated with smoking. These data show that smoking has a direct effect on the epigenome in lung tissue, which is also detectable in peripheral blood DNA and may contribute to cancer risk.

/pdf/epigenome-wide-association-study-in-the-european-prospective-3rljsyu8g6.pdf

Epigenome-wide association study in the European Prospective Investigation into Cancer and Nutrition (EPIC-Turin) identifies novel genetic loci associated with smoking

The COVID-19 pandemic and subsequent lockdown and social distancing led to changes to breastfeeding support available to women in the United Kingdom. Face-to-face professional support was reduced, and face-to-face peer support was cancelled. Anecdotal media accounts highlighted practices separating some mothers and babies in hospitals, alongside inaccurate stories of the safety of breastfeeding circulating. Meanwhile, new families were confined to their homes, separated from families and support networks. Given that we know breastfeeding is best supported by practices that keep mother and baby together, high-quality professional and peer-to-peer support, and positive maternal well-being, it is important to understand the impact of the pandemic upon the ability to breastfeed. To explore this, we conducted an online survey with 1219 breastfeeding mothers in the United Kingdom with a baby 0-12 months old to understand the impact of the pandemic upon breastfeeding duration, experiences and support. The results highlighted two very different experiences: 41.8% of mothers felt that breastfeeding was protected due to lockdown, but 27.0% of mothers struggled to get support and had numerous barriers stemming from lockdown with some stopped breastfeeding before they were ready. Mothers with a lower education, with more challenging living circumstances and from Black and minority ethnic backgrounds were more likely to find the impact of lockdown challenging and stop breastfeeding. The findings are vital in understanding how we now support those women who may be grieving their loss of breastfeeding and are affected by their negative experiences and how we can learn from those with a positive experience to make sure all breastfeeding women are better supported if similar future events arise.

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Experiences of breastfeeding during COVID-19: Lessons for future practical and emotional support

Epigenetics is the study of all mechanisms that regulate gene transcription and genome stability that are maintained throughout the cell division, but do not include the DNA sequence itself. The best-studied epigenetic mechanism to date is DNA methylation, where methyl groups are added to the cytosine base within cytosine–guanine dinucleotides (CpG sites). CpGs are frequently clustered in high density (CpG islands (CGIs)) at the promoter of over half of all genes. Current knowledge of transcriptional regulation by DNA methylation centres on its role at the promoter where unmethylated CGIs are present at most actively transcribed genes, whereas hypermethylation of the promoter results in gene repression. Over the last 5 years, research has gradually incorporated a broader understanding that methylation patterns across the gene (so-called intragenic or gene body methylation) may have a role in transcriptional regulation and efficiency. Numerous genome-wide DNA methylation profiling studies now support this notion, although whether DNA methylation patterns are a cause or consequence of other regulatory mechanisms is not yet clear. This review will examine the evidence for the function of intragenic methylation in gene transcription, and discuss the significance of this in carcinogenesis and for the future use of therapies targeted against DNA methylation.

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Intragenic DNA methylation: implications of this epigenetic mechanism for cancer research

Background Most biomarkers of exposure tend to have short half-lives. This includes cotinine, a metabolite of nicotine widely used to assess smoke exposure. Cotinine is thus unsuitable as a determinant of past exposure to cigarette smoke. Methods We used bisulphite pyrosequencing of a set of four genomic loci (AHRR, 6p21, and two at 2q37) that had differential DNA methylation levels in peripheral blood DNA dependent on tobacco exposure to create a predictive model of smoking status. Results Combining four gene loci into a single methylation index provided high positive predictive and sensitivity values for predicting former smoking status in both test (n = 81) and validation (n = 180) sample sets. Conclusions This study provides a direct molecular measure of prior exposure to tobacco that can be performed using the quantitative approach of bisulphite pyrosequencing. Epigenetic changes that are detectable in blood may more generally act as molecular biomarkers for other exposures that are also difficult to quantify in epidemiological studies.

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DNA methylation as a long-term biomarker of exposure to tobacco smoke.

Background:

Reports on the management and outcome of rare conditions, such as oesophageal atresia, are frequently limited to case series reporting single-centre experience over many years. The aim of this study was to identify all infants born with oesophageal atresia in the UK and Ireland to describe current clinical practice and outcomes.



Methods:

This was a prospective multicentre cohort study of all infants born with oesophageal atresia and/or tracheo-oesophageal fistula in 2008–2009 in the UK and Ireland to record current clinical management and early outcomes.



Results:

A total of 151 infants admitted to 28 paediatric surgical units were identified. Some aspects of perioperative management were universal, including oesophageal decompression, operative technique and the use of transanastomotic tubes. However, there were a number of areas where clinical practice varied considerably, including the routine use of perioperative chest drains, postoperative contrast studies and antireflux medication, with each of these being employed in 30–50 per cent of patients. There was a trend towards routine postoperative ventilation.



Conclusion:

The prospective methodology used in this study can help identify practices that all surgeons employ and also those that few surgeons use. Areas of clinical equipoise can be recognized and avenues for further research identified. Copyright © 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Natalie S. Shenker

Papers

Epigenome-wide association study in the European Prospective Investigation into Cancer and Nutrition (EPIC-Turin) identifies novel genetic loci associated with smoking

Experiences of breastfeeding during COVID-19: Lessons for future practical and emotional support

Intragenic DNA methylation: implications of this epigenetic mechanism for cancer research

DNA methylation as a long-term biomarker of exposure to tobacco smoke.

Contemporary management and outcomes for infants born with oesophageal atresia