Alternative COVID-19 mitigation measures in school classrooms: analysis using an agent-based model of SARS-CoV-2 transmission.

The SARS-CoV-2 epidemic has impacted children's education, with schools required to implement infection control measures that have led to periods of absence and classroom closures. We developed an agent-based epidemiological model of SARS-CoV-2 transmission in a school classroom that allows us to quantify projected infection patterns within primary school classrooms, and related uncertainties. Our approach is based on a contact model constructed using random networks, informed by structured expert judgement. The effectiveness of mitigation strategies in suppressing infection outbreaks and limiting pupil absence are considered. COVID-19 infections in primary schools in England in autumn 2020 were re-examined and the model was then used to estimate infection levels in autumn 2021, as the Delta variant was emerging and it was thought likely that school transmission would play a major role in an incipient new wave of the epidemic. Our results were in good agreement with available data. These findings indicate that testing-based surveillance is more effective than bubble quarantine, both for reducing transmission and avoiding pupil absence, even accounting for insensitivity of self-administered tests. Bubble quarantine entails large numbers of absences, with only modest impact on classroom infections. However, maintaining reduced contact rates within the classroom can have a major benefit for managing COVID-19 in school settings.

Fresh street: the development and feasibility of a place-based, subsidy for fresh fruit and vegetables.

BACKGROUND: Many UK communities experience food insecurity, and consume diets high in energy-dense, nutrient poor, processed foods and low in fruit and vegetables (FV). We explored a novel area-based approach to promote FV consumption and healthy eating in one such community. METHODS: We developed a weekly subsidy scheme for fresh FV with key local stakeholders in an area of socioeconomic deprivation in Northern England. The scheme (Fresh Street) offered five £1 vouchers to every household, regardless of income or household type. Vouchers were redeemable with local suppliers of fresh FV (not supermarkets). The feasibility of the scheme was assessed in four streets using rapid ethnographic assessment and voucher redemption information. RESULTS: Local councillors and public health teams were supportive of the scheme. Most eligible households joined the scheme (n = 80/97, 83%), and 89.3% (17 849/19 982) of vouchers issued were redeemed. Householders reported that the scheme made them think about what they were eating, and prompted them to buy and eat more FV. CONCLUSIONS: This feasibility study reported high levels of acceptance for a place-based, household-level weekly FV subsidy scheme. Further research is required to evaluate the effectiveness of this approach to creating healthy diets, eating behaviours and food systems.

Novel DNA methylation signatures of tobacco smoking with trans-ethnic effects.

BACKGROUND: Smoking remains one of the leading preventable causes of death. Smoking leaves a strong signature on the blood methylome as shown in multiple studies using the Infinium HumanMethylation450 BeadChip. Here, we explore novel blood methylation smoking signals on the Illumina MethylationEPIC BeadChip (EPIC) array, which also targets novel CpG-sites in enhancers. METHOD: A smoking-methylation meta-analysis was carried out using EPIC DNA methylation profiles in 1407 blood samples from four UK population-based cohorts, including the MRC National Survey for Health and Development (NSHD) or 1946 British birth cohort, the National Child Development Study (NCDS) or 1958 birth cohort, the 1970 British Cohort Study (BCS70), and the TwinsUK cohort (TwinsUK). The overall discovery sample included 269 current, 497 former, and 643 never smokers. Replication was pursued in 3425 trans-ethnic samples, including 2325 American Indian individuals participating in the Strong Heart Study (SHS) in 1989-1991 and 1100 African-American participants in the Genetic Epidemiology Network of Arteriopathy Study (GENOA). RESULTS: Altogether 952 CpG-sites in 500 genes were differentially methylated between smokers and never smokers after Bonferroni correction. There were 526 novel smoking-associated CpG-sites only profiled by the EPIC array, of which 486 (92%) replicated in a meta-analysis of the American Indian and African-American samples. Novel CpG sites mapped both to genes containing previously identified smoking-methylation signals and to 80 novel genes not previously linked to smoking, with the strongest novel signal in SLAMF7. Comparison of former versus never smokers identified that 37 of these sites were persistently differentially methylated after cessation, where 16 represented novel signals only profiled by the EPIC array. We observed a depletion of smoking-associated signals in CpG islands and an enrichment in enhancer regions, consistent with previous results. CONCLUSION: This study identified novel smoking-associated signals as possible biomarkers of exposure to smoking and may help improve our understanding of smoking-related disease risk.

Childhood DNA methylation as a marker of early life rapid weight gain and subsequent overweight.

BACKGROUND: High early postnatal weight gain has been associated with childhood adiposity; however, the mechanism remains unknown. DNA methylation is a hypothesised mechanism linking early life exposures and subsequent disease. However, epigenetic changes associated with high early weight gain have not previously been investigated. Our aim was to investigate the associations between early weight gain, peripheral blood DNA methylation, and subsequent overweight/obese. Data from the UK Avon Longitudinal study of Parents and Children (ALSPAC) cohort were used to estimate associations between early postnatal weight gain and epigenome-wide DNA CpG site methylation (Illumina 450 K Methylation Beadchip) in blood in childhood (n = 125) and late adolescence (n = 96). High weight gain in the first year (a change in weight z-scores > 0.67), both unconditional (rapid weight gain) and conditional on birthweight (rapid thrive), was related to individual CpG site methylation and across regions using the meffil pipeline, with and without adjustment for cell type proportions, and with 5% false discovery rate correction. Variation in methylation at high weight gain-associated CpG sites was then examined with regard to body composition measures in childhood and adolescence. Replication of the differentially methylated CpG sites was sought using whole-blood DNA samples from 104 children from the UK Southampton Women's Survey. RESULTS: Rapid infant weight gain was associated with small (+ 1% change) increases in childhood methylation (age 7) for two distinct CpG sites (cg01379158 (NT5M) and cg11531579 (CHFR)). Childhood methylation at one of these CpGs (cg11531579) was also higher in those who experienced rapid weight gain and were subsequently overweight/obese in adolescence (age 17). Rapid weight gain was not associated with differential DNA methylation in adolescence. Childhood methylation at the cg11531579 site was also suggestively associated with rapid weight gain in the replication cohort. CONCLUSIONS: This study identified associations between rapid weight gain in infancy and small increases in childhood methylation at two CpG sites, one of which was replicated and was also associated with subsequent overweight/obese. It will be important to determine whether loci are markers of early rapid weight gain across different, larger populations. The mechanistic relevance of these differentially methylated sites requires further investigation.

Testing for causality between systematically identified risk factors and glioma: a Mendelian randomization study.

BACKGROUND: Whilst epidemiological studies have provided evidence of associations between certain risk factors and glioma onset, inferring causality has proven challenging. Using Mendelian randomization (MR), we assessed whether associations of 36 reported glioma risk factors showed evidence of a causal relationship. METHODS: We performed a systematic search of MEDLINE from inception to October 2018 to identify candidate risk factors and conducted a meta-analysis of two glioma genome-wide association studies (5739 cases and 5501 controls) to form our exposure and outcome datasets. MR analyses were performed using genetic variants to proxy for candidate risk factors. We investigated whether risk factors differed by subtype diagnosis (either glioblastoma (n = 3112) or non-glioblastoma (n = 2411)). MR estimates for each risk factor were determined using multiplicative random effects inverse-variance weighting (IVW). Sensitivity analyses investigated potential pleiotropy using MR-Egger regression, the weighted median estimator, and the mode-based estimator. To increase power, trait-specific polygenic risk scores were used to test the association of a genetically predicated increase in each risk factor with glioma onset. RESULTS: Our systematic search identified 36 risk factors that could be proxied using genetic variants. Using MR, we found evidence that four genetically predicted traits increased risk of glioma, glioblastoma or non-glioblastoma: longer leukocyte telomere length, liability to allergic disease, increased alcohol consumption and liability to childhood extreme obesity (> 3 standard deviations from the mean). Two traits decreased risk of non-glioblastoma cancers: increased low-density lipoprotein cholesterol (LDLc) and triglyceride levels. Our findings were similar across sensitivity analyses that made allowance for pleiotropy (genetic confounding). CONCLUSIONS: Our comprehensive investigation provides evidence of a causal link between both genetically predicted leukocyte telomere length, allergic disease, alcohol consumption, childhood extreme obesity, and LDLc and triglyceride levels, and glioma. The findings from our study warrant further research to uncover mechanisms that implicate these traits in glioma onset.

Vitamin B6 catabolism and lung cancer risk: results from the Lung Cancer Cohort Consortium (LC3).

BACKGROUND: Increased vitamin B6 catabolism related to inflammation, as measured by the PAr index (the ratio of 4-pyridoxic acid over the sum of pyridoxal and pyridoxal-5'-phosphate), has been positively associated with lung cancer risk in two prospective European studies. However, the extent to which this association translates to more diverse populations is not known. MATERIALS AND METHODS: For this study, we included 5323 incident lung cancer cases and 5323 controls individually matched by age, sex, and smoking status within each of 20 prospective cohorts from the Lung Cancer Cohort Consortium. Cohort-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between PAr and lung cancer risk were calculated using conditional logistic regression and pooled using random-effects models. RESULTS: PAr was positively associated with lung cancer risk in a dose-response fashion. Comparing the fourth versus first quartiles of PAr resulted in an OR of 1.38 (95% CI: 1.19-1.59) for overall lung cancer risk. The association between PAr and lung cancer risk was most prominent in former smokers (OR: 1.69, 95% CI: 1.36-2.10), men (OR: 1.60, 95% CI: 1.28-2.00), and for cancers diagnosed within 3 years of blood draw (OR: 1.73, 95% CI: 1.34-2.23). CONCLUSION: Based on pre-diagnostic data from 20 cohorts across 4 continents, this study confirms that increased vitamin B6 catabolism related to inflammation and immune activation is associated with a higher risk of developing lung cancer. Moreover, PAr may be a pre-diagnostic marker of lung cancer rather than a causal factor.

Childhood adversity and DNA methylation in two population-based cohorts.

Childhood adversity affects later health, but the underlying molecular mechanisms are unclear. Although there is some evidence from animal models and case-control studies of a role for DNA methylation, evidence from human population-based studies is limited. In two cohorts (mothers from the Avon Longitudinal Study of Parents and Children, ALSPAC, n = 780 and women from the MRC National Survey of Health and Development, NSHD, n = 552), we assessed the association of seven adverse childhood experiences (ACEs: parental physical illness, parental mental illness, parental death, parental separation, suboptimal maternal bonding, childhood illness and child maltreatment) as well as their combination (ACE score) with genome-wide DNA methylation levels measured using the Illumina Infinium HumanMethylation450 BeadChip in peripheral blood at mean age 47 years (ALSPAC) and in buccal cells at age 53 years (NSHD). CpG sites with a genome-wide false discovery rate (FDR) below 0.05 and differentially methylated regions (DMRs) with one-step Sidák correction p-values below 0.05 in each cohort were examined in the other cohort. No individual CpG sites replicated across cohorts. However, nine DMRs replicated across cohorts respectively associated with the ACE score (one region), parental mental illness (two regions), parental physical illness (three regions) and parental death (three regions). These observations indicate that some adverse childhood experiences, notably those related to parental health, may leave imprints on peripheral DNA methylation that persist to mid-life.

Maternal depression during pregnancy and cord blood DNA methylation: findings from the Avon Longitudinal Study of Parents and Children.

Up to 13% of women may experience symptoms of depression during pregnancy or in the postpartum period. Depression during pregnancy has been associated with an increased risk of adverse neurodevelopmental outcomes in the child and epigenetic mechanisms could be one of the biological pathways to explain this association. In 844 mother-child pairs from the Avon Longitudinal Study of Parents and Children, we carried out an epigenome-wide association study (EWAS) to investigate associations between prospectively collected data on maternal depression ascertained by the Edinburgh Postnatal Depression Scale in pregnancy and DNA methylation in the cord blood of newborn offspring. In individual site analysis, we identified two CpG sites associated with maternal depression in the middle part of pregnancy. In our regional analysis, we identified 39 differentially methylated regions (DMRs). Seven DMRs were associated with depression at any time point during pregnancy, 7 associated with depression in mid-pregnancy, 23 were associated with depression in late pregnancy, and 2 DMRs were associated with depression throughout pregnancy. Several of these map to genes associated with psychiatric disease and brain development. We attempted replication in The Generation R Study and could not replicate our results. Although our findings in ALSPAC suggest that maternal depression could be associated with cord blood DNA methylation the results should be viewed as preliminary and hypothesis generating until further replicated in a larger sample.

Meffil: efficient normalization and analysis of very large DNA methylation datasets.

Motivation: DNA methylation datasets are growing ever larger both in sample size and genome coverage. Novel computational solutions are required to efficiently handle these data. Results: We have developed meffil, an R package designed for efficient quality control, normalization and epigenome-wide association studies of large samples of Illumina Methylation BeadChip microarrays. A complete re-implementation of functional normalization minimizes computational memory without increasing running time. Incorporating fixed and random effects within functional normalization, and automated estimation of functional normalization parameters reduces technical variation in DNA methylation levels, thus reducing false positive rates and improving power. Support for normalization of datasets distributed across physically different locations without needing to share biologically-based individual-level data means that meffil can be used to reduce heterogeneity in meta-analyses of epigenome-wide association studies. Availability and implementation: https://github.com/perishky/meffil/. Supplementary information: Supplementary data are available at Bioinformatics online.

DNA methylation from birth to late adolescence and development of multiple-risk behaviours.

BACKGROUND: Risk behaviours in adolescence are linked to poor educational attainment and health and other outcomes in young adulthood. We explored whether there are molecular mechanisms associated with the development, or the result, of multiple risk behaviours (MRBs). METHODS: MRBs (antisocial behaviour and delinquency, traffic-related risk behaviour, risky sexual behaviour, lack of exercise) and their sumscore were characterized based on self-reported questions at age 7 and 17 within the ARIES subsample of the ALSPAC birth cohort, and were linked to DNA methylation at over 485,000 CpG sites at ages 0,7 and 17. Associations were determined for participants with complete data (n = 227-575). RESULTS: There was weak evidence of associations between cumulative MRBs and methylation at cg01783492 and cg16720578 at age 17. DNA methylation at age 17 was associated with risky sexual behaviour (cg22883332), lack of exercise (cg03152353, cg20056908, cg20571116) and substance use (cg02188400, cg13906377). No associations between DNA methylation and individual risk behaviours at age 7 were observed. DNA methylation at age 7 might predispose for traffic-related risk behaviour (cg24683561) and substance use (cg08761410) at age 17. LIMITATIONS: Main limitations are absence of information on directly measured blood cell type proportions and tissue specificity, and a modest sample size. CONCLUSIONS: Cumulative MRB in late adolescence was associated with effects on DNA methylation. More specifically, risky sexual behaviour and sedentary behaviour are associated with changes in DNA methylation, while DNA methylation in childhood may predict later traffic-related risky behaviour. For substance use effects in both temporal directions were observed.

Epigenetic profiling of ADHD symptoms trajectories: a prospective, methylome-wide study.

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent developmental disorder, associated with a range of long-term impairments. Variation in DNA methylation, an epigenetic mechanism, is implicated in both neurobiological functioning and psychiatric health. However, the potential role of DNA methylation in ADHD symptoms is currently unclear. In this study, we examined data from the Avon Longitudinal Study of Parents and Children (ALSPAC)-specifically the subsample forming the Accessible Resource for Integrated Epigenomics Studies (ARIES)-that includes (1) peripheral measures of DNA methylation (Illumina 450k) at birth (n=817, 49% male) and age 7 (n=892, 50% male) and (2) trajectories of ADHD symptoms (7-15 years). We first employed a genome-wide analysis to test whether DNA methylation at birth associates with later ADHD trajectories; and then followed up at age 7 to investigate the stability of associations across early childhood. We found that DNA methylation at birth differentiated ADHD trajectories across multiple genomic locations, including probes annotated to SKI (involved in neural tube development), ZNF544 (previously implicated in ADHD), ST3GAL3 (linked to intellectual disability) and PEX2 (related to perixosomal processes). None of these probes maintained an association with ADHD trajectories at age 7. Findings lend novel insights into the epigenetic landscape of ADHD symptoms, highlighting the potential importance of DNA methylation variation in genes related to neurodevelopmental and peroxisomal processes that play a key role in the maturation and stability of cortical circuits.

DNA methylation and substance-use risk: a prospective, genome-wide study spanning gestation to adolescence.

Epigenetic processes have been implicated in addiction; yet, it remains unclear whether these represent a risk factor and/or a consequence of substance use. Here, we believe we conducted the first genome-wide, longitudinal study to investigate whether DNA methylation patterns in early life prospectively associate with substance use in adolescence. The sample comprised of 244 youth (51% female) from the Avon Longitudinal Study of Parents and Children (ALSPAC), with repeated assessments of DNA methylation (Illumina 450k array; cord blood at birth, whole blood at age 7) and substance use (tobacco, alcohol and cannabis use; age 14-18). We found that, at birth, epigenetic variation across a tightly interconnected genetic network (n=65 loci; q<0.05) associated with greater levels of substance use during adolescence, as well as an earlier age of onset amongst users. Associations were specific to the neonatal period and not observed at age 7. Key annotated genes included PACSIN1, NEUROD4 and NTRK2, implicated in neurodevelopmental processes. Several of the identified loci were associated with known methylation quantitative trait loci, and consequently likely to be under significant genetic control. Collectively, these 65 loci were also found to partially mediate the effect of prenatal maternal tobacco smoking on adolescent substance use. Together, findings lend novel insights into epigenetic correlates of substance use, highlight birth as a potentially sensitive window of biological vulnerability and provide preliminary evidence of an indirect epigenetic pathway linking prenatal tobacco exposure and adolescent substance use.

Challenges and novel approaches for investigating molecular mediation.

Understanding mediation is useful for identifying intermediates lying between an exposure and an outcome which, when intervened upon, will block (some or all of) the causal pathway between the exposure and outcome. Mediation approaches used in conventional epidemiology have been adapted to understanding the role of molecular intermediates in situations of high-dimensional omics data with varying degrees of success. In particular, the limitations of observational epidemiological study including confounding, reverse causation and measurement error can afflict conventional mediation approaches and may lead to incorrect conclusions regarding causal effects. Solutions to analysing mediation which overcome these problems include the use of instrumental variable methods such as Mendelian randomization, which may be applied to evaluate causality in increasingly complex networks of omics data.

25-Hydroxyvitamin D in pregnancy and genome wide cord blood DNA methylation in two pregnancy cohorts (MoBa and ALSPAC).

The aim of the study was to investigate whether maternal mid-pregnancy 25-hydroxyvitamin D concentrations are associated with cord blood DNA methylation. DNA methylation was assessed using the Illumina HumanMethylation450 BeadChip, and maternal plasma 25-hydroxyvitamin D was measured in 819 mothers/newborn pairs participating in the Norwegian Mother and Child Cohort (MoBa) and 597 mothers/newborn pairs participating in the Avon Longitudinal Study of Parents and Children (ALSPAC). Across 473,731CpG DNA methylation sites in cord blood DNA, none were strongly associated with maternal 25-hydroxyvitamin D after adjusting for multiple tests (false discovery rate (FDR)>0.5; 473,731 tests). A meta-analysis of the results from both cohorts, using the Fisher method for combining p-values, also did not strengthen findings (FDR>0.2). Further exploration of a set of CpG sites in the proximity of four a priori defined candidate genes (CYP24A1, CYP27B1, CYP27A1 and CYP2R1) did not result in any associations with FDR<0.05 (56 tests). In this large genome wide assessment of the potential influence of maternal vitamin D status on DNA methylation, we did not find any convincing associations in 1416 newborns. If true associations do exist, their identification might require much larger consortium studies, expanded genomic coverage, investigation of alternative cell types or measurements of 25-hydroxyvitamin D at different gestational time points.

Who are the obese? A cluster analysis exploring subgroups of the obese.

BACKGROUND: Body mass index (BMI) can be used to group individuals in terms of their height and weight as obese. However, such a distinction fails to account for the variation within this group across other factors such as health, demographic and behavioural characteristics. The study aims to examine the existence of subgroups of obese individuals. METHODS: Data were taken from the Yorkshire Health Study (2010-12) including information on demographic, health and behavioural characteristics. Individuals with a BMI of ≥30 were included. A two-step cluster analysis was used to define groups of individuals who shared common characteristics. RESULTS: The cluster analysis found six distinct groups of individuals whose BMI was ≥30. These subgroups were heavy drinking males, young healthy females; the affluent and healthy elderly; the physically sick but happy elderly; the unhappy and anxious middle aged and a cluster with the poorest health. CONCLUSIONS: It is important to account for the important heterogeneity within individuals who are obese. Interventions introduced by clinicians and policymakers should not target obese individuals as a whole but tailor strategies depending upon the subgroups that individuals belong to.

Environmental risk, Oxytocin Receptor Gene (OXTR) methylation and youth callous-unemotional traits: a 13-year longitudinal study.

Youth with high callous-unemotional traits (CU) are at risk for early-onset and persistent conduct problems. Research suggests that there may be different developmental pathways to CU (genetic/constitutional vs environmental), and that the absence or presence of co-occurring internalizing problems is a key marker. However, it is unclear whether such a distinction is valid. Intermediate phenotypes such as DNA methylation, an epigenetic modification regulating gene expression, may help to clarify etiological pathways. This is the first study to examine prospective inter-relationships between environmental risk (prenatal/postnatal) and DNA methylation (birth, age 7 and 9) in the prediction of CU (age 13), for youth low vs high in internalizing problems. We focused on DNA methylation in the vicinity of the oxytocin receptor (OXTR) gene as it has been previously implicated in CU. Participants were 84 youth with early-onset and persistent conduct problems drawn from the Avon Longitudinal Study of Parents and Children. For youth with low internalizing problems (46%), we found that (i) OXTR methylation at birth associated with higher CU (age 13) as well as decreased experience of victimization during childhood (evocative epigenetic-environment correlation; birth-age 7), (ii) higher prenatal parental risks (maternal psychopathology, criminal behaviors, substance use) associated with higher OXTR methylation at birth and (iii) OXTR methylation levels were more stable across time (birth-age 9). In contrast, for youth with high internalizing problems, CU were associated with prenatal risks of an interpersonal nature (that is, intimate partner violence, family conflict) but not OXTR methylation. Findings support the existence of distinct developmental pathways to CU.

The Making Cases Count intiative.

Given the challenges faced, how can homeopaths communicate the power and scope of the therapeutic system of homeopathy? Homeopaths need to communicate to patients, the public and media, other healthcare professionals, healthcare researchers, and funders of healthcare (healthcare insurers, those who commission healthcare services either in publicly funded healthcare systems such as the NHS or charities). Effective communication with these stakeholders requires information that is: (a) easily understood, (b) credible, and (c) relevant. The patient's voice is the trusted, indisputable and easily understood common ground in homeopathy. Yet, the experiences of patients are rarely heard outside the profession of homeopathy. Homeopaths are in a unique position to make these voices heard by disseminating the results of their routine practice cases incorporating their patients' voices. The 'Making Cases Count' initiative has been created in order to bring about a culture where easily understood, trusted and salient information is regularly made available to all stakeholders in homeopathy. The Making Cases Count initiative supports, guides and incentives homeopaths to collect routine data with the aim of bringing about a culture where a significant proportion of homeopaths collect routine data from their patients in a format which will then be able to be transformed (i.e. anonymised, summarised and counted). This routine data requires numbers and categories to report the behavior and the perspective of patients receiving homeopathic treatment. This can be strengthened through the use of validated outcome measures in hearing patients' voices. When transformed, this routine data will then be able to inform homeopaths and more importantly other key stakeholders. It is now time to make patient cases count.

Prevalence of complementary and alternative medicine (CAM) use by the general population: a systematic review and update.

OBJECTIVES: To update previous systematic reviews of 12-month prevalence of complementary and alternative medicine (CAM) use by general populations; to explore trends in CAM use by national populations; to develop and apply a brief tool for assessing methodological quality of published CAM-use prevalence surveys. DESIGN: Nine databases were searched for published studies from 1998 onwards. Studies prior to 1998 were identified from two previous systematic reviews. A six-item literature-based tool was devised to assess robustness and interpretability of CAM-use estimates. RESULTS: Fifty-one reports from 49 surveys conducted in 15 countries met the inclusion criteria. We extracted 32 estimates of 12-month prevalence of use of any CAM (range 9.8-76%) and 33 estimates of 12-month prevalence of visits to CAM practitioners (range 1.8-48.7%). Quality of methodological reporting was variable; 30/51 survey reports (59%) met four or more of six quality criteria. Estimates of 12-month prevalence of any CAM use (excluding prayer) from surveys using consistent measurement methods showed remarkable stability in Australia (49%, 52%, 52%; 1993, 2000, 2004) and USA (36%, 38%; 2002, 2007). CONCLUSIONS: There was evidence of substantial CAM use in the 15 countries surveyed. Where national trends were discernable because of consistent measurement, there was no evidence to suggest a change in 12-month prevalence of CAM use since the previous systematic reviews were published in 2000. Periodic surveys are important to monitor population-level CAM use. Use of government-sponsored health surveys may enhance robustness of population-based prevalence estimates. Comparisons across countries could be improved by standardising approaches to data collection.

A pilot 'cohort multiple randomised controlled trial' of treatment by a homeopath for women with menopausal hot flushes.

INTRODUCTION: In order to address the limitations of the standard pragmatic RCT design, the innovative 'cohort multiple RCT' design was developed. The design was first piloted by addressing a clinical question " What is the clinical and cost effectiveness of treatment by a homeopath for women with menopausal hot flushes?". METHODS: A cohort with the condition of interest (hot flushes) was recruited through an observational study of women's midlife health and consented to provide observational data and have their data used comparatively. The 'Hot Flush' Cohort were then screened in order to identify patients eligible for a trial of the offer of treatment by a homeopath (Eligible Trial Group). A proportion of the Eligible Trial Group was then randomly selected to the Offer Group and offered treatment. A "patient centred" approach to information and consent was adopted. Patients were not (i) told about treatments that they would not be offered, and trial intervention information was only given to the Offer Group after random selection. Patients were not (ii) given prior information that their treatment would be decided by chance. RESULTS: The 'cohort multiple RCT' design was acceptable to the NHS Research Ethics Committee. The majority of patients completed multiple questionnaires. Acceptance of the offer was high (17/24). DISCUSSION: This pilot identified the feasibility of an innovative design in practice. Further research is required to test the concept of undertaking multiple trials within a cohort of patients and to assess the acceptability of the "patient centred" approach to information and consent.

Epigenetics and child health: basic principles.

Epigenetic mechanisms are believed to play an important role in disease, development and ageing with early life representing a window of particular epigenomic plasticity. The knowledge upon which these claims are based is beginning to expand. This review summarises evidence pointing to the determinants of epigenetic patterns, their juxtaposition at the interface of the environment, their influence on gene function and the relevance of this information to child health.