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Additional file 2. Table S1: Top 10 sites with differential methylation in response to folic acid also show neurodevelopmental associations. Table S2: Top 10 ranking gene body regions showing differential methylation.

A summery of presentations made during the DSM Science and Technology Award Symposium at the 13th European Nutrition Conference

Additional file 1: Methods. Supplementary details in relation to magnetoencephalographic brain imaging. Table S1. Maternal characteristics during pregnancy in all FASSTT trial participants and in the sample whose children completed the FASSTT Offspring trial at 11 years. Table S2. Full Scale IQ, composite and subtest scores for the WISC-IV cognitive assessment in FASSTT Offspring trial participants. Table S3. Maternal characteristics during pregnancy in all FASSTT trial participants and in the sub-sample whose children completed the MEG assessment in the FASSTT Offspring trial.

Figure S3. Median methylation levels at imprint control regions. Methylation levels at imprint control regions (ICR) were assessed by matching EPIC array probes to the imprint germline DMR intervals defined by [48] (A) or [49] (B) then taking the average (median) across each. The identities of each ICR and number of probes are indicated below. Boxes show the median and interquartile range for the individual averages from each group (Placebo n = 45, Treated n = 41), whiskers represent the range of values, dots indicate outliers. (PDF 1518 kb)

Additional file 1: Table S1a. Characteristics of responders and non-responders to participation in the FASSTT Offspring trial at 7 years. Table S1b. Characteristics of non-responders to participation in the FASSTT Offspring trial at 7 years by treatment group. Table S2. Anthropometric measurements of FASSTT Offspring trial participants at age 3 and 7 years. Table S3. WPPSI -III test scores of FASSTT Offspring trial participants at 7 years. Table S4a. Maternal serum folate status at 36th GW and WPPSI-III test scores of FASSTT Offspring trial participants at 7 years. Table S4b. Maternal RBC folate status at 36th GW and WPPSI-III test scores of FASSTT Offspring trial participants at 7 years.

Periconceptional folic acid (FA) has an established role in the prevention of neural tube defects (NTDs), leading to global recommendations for FA supplementation before and in early pregnancy. However, it is unclear whether there are any benefits for offspring brain health arising from continued maternal FA supplementation beyond the first trimester. The aim of this study was to investigate the role of maternal folate nutrition during pregnancy in relation to cognitive performance and brain function in the offspring at 11 years. The children of mothers who had participated in a randomised trial of Folic Acid Supplementation in the Second and Third Trimesters (FASSTT) were investigated, providing a unique opportunity to examine offspring brain health in relation to maternal folate (the FASSTT Offspring trial; n=68). Cognitive performance was assessed using the Wechsler Intelligence Scale for Children, Fourth UK Edition (WISC-IV). The WISC-IV measures Full Scale IQ and specific domains of cognitive performance: Verbal Comprehension, Perceptual Reasoning, Working Memory and Processing Speed. Brain function was measured using magnetoencephalography (MEG) in a subset of the child participants (n=33). The results showed no significant difference in Full Scale IQ between the children of mothers who had received folic acid versus placebo during pregnancy (P=0.993). Processing Speed subtest scores were however significantly higher in the folic acid group compared with placebo (Symbol Search: P=0.046 and Cancellation: P=0.011). The application of MEG analysis showed that at rest, there were differences in brain functioning with significantly lower overall power at Broad band [1u201348Hz] (P=0.041) and a trend (not significant) towards lower power in all other frequency bands (Theta, Mu, Beta, Low Gamma and High Gamma) in children from the FA group compared with placebo. Results for the responses to the language task (congruent and incongruent sentences) in children from the FA group showed significantly lower power within the Theta band [4u20138Hz] and significantly higher power within high frequency bands i.e. Beta [13u201330 Hz] and High Gamma [49u201370 Hz]. This suggested more efficient language processing abilities in these children compared to children of mothers in the placebo group. The findings provide scientific evidence that continuing FA supplementation beyond the periconceptional period that is protective against NTDs, may be beneficial for brain health in the offspring. Furthermore, this study demonstrates that MEG is a useful tool for objective assessment of functional brain activity in healthy children in response to nutrition intervention.Conflict of interest:There is no conflict of interest

Background: Current evidence indicates that exercise therapy (ET) has a short and medium-term benefit for hip osteoarthritis (OA), but evidence is inconclusive regarding the effect of manual therapy (MT). The primary aim of this randomised controlled trial was to determine the effectiveness of ET with and without MT on clinical outcomes for individuals with hip OA. A secondary aim was to ascertain the effect of an 8-week waiting period on outcomes. Methods: 131 men and women with hip OA recruited in four hospitals were initially randomised to one of three groups: ET (n = 45), a combination of ET and MT (n = 43) and wait-list control (n = 43). The two intervention groups underwent individualised ET or ET/MT for 8 weeks. Patients in the control group waited 8 weeks and were randomised to receive either ET or ET/MT after 9 week follow-up, and pooled with original treatment group data: ET (n = 66) and ET/ MT (n = 65). All participants were followed up at 9 and 18 weeks and the control group was reassessed at 27 weeks (18 weeks post-treatment) by the same blinded assessor. The primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Other outcomes included sit-to-stand, 50-foot walk test, pain severity, hip range of motion (ROM), anxiety, depression, quality of life (QOL), analgesic usage, physical activity, patient-perceived change and patient satisfaction. Intention-to-treat analysis was performed to determine within-group change and between-group differences for the three groups at baseline and 9 weeks, and the two treatment groups at baseline, 9 and 18 weeks. Results: Eight patients (6.1%) were lost to follow-up at 9 weeks and 19 (14.5%) were lost to follow-up by 18 weeks. Both ET (n = 66) and ET/MT groups (n = 65) showed significant within-group improvements in WOMAC, pain severity, sit-to-stand and HROM measures at 9 weeks, which were still evident at 18 weeks. There was no significant within-group change in anxiety, depression, QOL, analgesic usage, 50-foot walk test or physical activity. There was no significant difference between the two intervention groups for any of the outcomes. Regarding the results of the original ET, ET/MT and control group allocation, there was a significant improvement in one or both ET and ET/MT groups compared with the control group in the same outcomes, as well as patient perceived improvement at 9 weeks. There was no significant difference between the three groups in analgesic usage, WOMAC stiffness subscale, sit-to-stand and 50 foot walk tests, QOL and physical activity. There was an overall deterioration in anxiety and depression scores. Conclusions: The addition of MT to an 8 week programme of ET for hip OA resulted in similar improvements in pain, function and ROM at 9 and 18 weeks. The significant improvement which occurred in the same outcomes in the two treatment groups compared with a wait-list control of 8 weeks has implications for waiting list management Disclosure statement: The authors have declared no conflicts of interest

Figure S2. QQ plot shows no evidence of population substructure effects. The observed Chi-squared (χ2) values (open circles), plotted as –log10 of the p value for both sample groups, fit tightly to the expected χ2 values (red line), indicating little evidence of association due to population substructure effects and that the top hits which deviate from the line (right-hand side) are likely to represent true differences due to loci with large effects. (PDF 332 kb)

Figure S2. QQ plot shows no evidence of population substructure effects. The observed Chi-squared (χ2) values (open circles), plotted as –log10 of the p value for both sample groups, fit tightly to the expected χ2 values (red line), indicating little evidence of association due to population substructure effects and that the top hits which deviate from the line (right-hand side) are likely to represent true differences due to loci with large effects. (PDF 332 kb)

Table S1. Pyrosequencing and transcriptional primer sets used in this study. Pyroassay primers are given as bisulfite converted sequence. The same primers were used for both RT-PCR and RT-qPCR. (DOCX 15 kb)

Figure S1. Correlation between folate levels in cord blood and mother. Scatterplot shows log-converted red blood cell folate (RCF) levels in nanomoles per liter (nmol/l) at gestational week 36 (GW36) for mothers (post-intervention) and matched cord blood. The line of best fit shows significant correlation between mothers and offspring (r = 0.619; p =

Figure S1. Correlation between folate levels in cord blood and mother. Scatterplot shows log-converted red blood cell folate (RCF) levels in nanomoles per liter (nmol/l) at gestational week 36 (GW36) for mothers (post-intervention) and matched cord blood. The line of best fit shows significant correlation between mothers and offspring (r = 0.619; p =