Antidepressant Exposure and DNA Methylation: Insights from a Methylome-Wide Association Study.

Importance: Understanding antidepressant mechanisms could help design more effective and tolerated treatments. Objective: Identify DNA methylation (DNAm) changes associated with antidepressant exposure. Design: Case-control methylome-wide association studies (MWAS) of antidepressant exposure were performed from blood samples collected between 2006-2011 in Generation Scotland (GS). The summary statistics were tested for enrichment in specific tissues, gene ontologies and an independent MWAS in the Netherlands Study of Depression and Anxiety (NESDA). A methylation profile score (MPS) was derived and tested for its association with antidepressant exposure in eight independent cohorts, alongside prospective data from GS. Setting: Cohorts; GS, NESDA, FTC, SHIP-Trend, FOR2107, LBC1936, MARS-UniDep, ALSPAC, E-Risk, and NTR. Participants: Participants with DNAm data and self-report/prescription derived antidepressant exposure. Main Outcomes and Measures: Whole-blood DNAm levels were assayed by the EPIC/450K Illumina array (9 studies, N exposed = 661, N unexposed = 9,575) alongside MBD-Seq in NESDA (N exposed = 398, N unexposed = 414). Antidepressant exposure was measured by self- report and/or antidepressant prescriptions. Results: The self-report MWAS (N = 16,536, N exposed = 1,508, mean age = 48, 59% female) and the prescription-derived MWAS (N = 7,951, N exposed = 861, mean age = 47, 59% female), found hypermethylation at seven and four DNAm sites (p < 9.42x10 -8 ), respectively. The top locus was cg26277237 ( KANK1, p self-report = 9.3x10 -13 , p prescription = 6.1x10 -3 ). The self-report MWAS found a differentially methylated region, mapping to DGUOK-AS1 ( p adj = 5.0x10 -3 ) alongside significant enrichment for genes expressed in the amygdala, the "synaptic vesicle membrane" gene ontology and the top 1% of CpGs from the NESDA MWAS (OR = 1.39, p < 0.042). The MPS was associated with antidepressant exposure in meta-analysed data from external cohorts (N studies = 9, N = 10,236, N exposed = 661, f3 = 0.196, p < 1x10 -4 ). Conclusions and Relevance: Antidepressant exposure is associated with changes in DNAm across different cohorts. Further investigation into these changes could inform on new targets for antidepressant treatments. 3 Key Points: Question: Is antidepressant exposure associated with differential whole blood DNA methylation?Findings: In this methylome-wide association study of 16,536 adults across Scotland, antidepressant exposure was significantly associated with hypermethylation at CpGs mapping to KANK1 and DGUOK-AS1. A methylation profile score trained on this sample was significantly associated with antidepressant exposure (pooled f3 [95%CI]=0.196 [0.105, 0.288], p < 1x10 -4 ) in a meta-analysis of external datasets. Meaning: Antidepressant exposure is associated with hypermethylation at KANK1 and DGUOK-AS1 , which have roles in mitochondrial metabolism and neurite outgrowth. If replicated in future studies, targeting these genes could inform the design of more effective and better tolerated treatments for depression.

Processability of Atypical WC-Co Composite Feedstock by Laser Powder-Bed Fusion.

Processing of tool materials for cutting applications presents challenges in additive manufacturing (AM). Processes must be carefully managed in order to promote the formation of favourable high-integrity 'builds'. In this study, for the first time, a satelliting process is used to prepare a WCM-Co (12 wt.% Co) composite. Melting trials were undertaken to evaluate the consolidation behaviour of single tracks within a single layer. Tracks with continuous and relatively uniform surface morphology were obtained. These features are essential for high-quality AM builds in order to encourage good bonding between subsequent tracks within a layer which may reduce porosity within a 3D deposition. This study elucidates the formation of track irregularities, melting modes, crack sensitivity, and balling as a function of laser scanning speed and provides guidelines for future production of WCM-Co by laser powder-bed fusion.

A web-based dietary intervention in early pregnancy and neonatal outcomes: a randomized controlled trial.

BACKGROUND: Maternal nutrition is a determinant of pregnancy outcomes. Few studies have evaluated the potential of online nutrition resources to modify behaviour. This randomized controlled trial aimed to determine whether access to a customized evidence-based nutrition website in pregnancy improved neonatal outcomes. METHODS: Women <18 weeks gestation were recruited at their convenience. The control group received standard care. In addition to standard care, the intervention group received access to an evidence-based nutrition website, customized to the preferences of pregnant women. RESULTS: Of the 250 women, there were no differences in characteristics between the two groups. Of the women, 91.0% reported they make a conscious effort currently to eat a healthy diet. However, only 19.6% met dietary requirements for calcium, 13.2% for iron, 2.7% for folate and 2.3% for iodine. The most popular website section was pregnancy nutrition advice but engagement was not sustained. Access to the website was not associated with any improvement in clinical outcomes (P > 0.05). CONCLUSIONS: We found that provision of a customized website providing nutrition information, did not improve neonatal outcomes. Future studies should explore whether redesign with website interactivity or embedding information on popular digital platforms sustains women's engagement and modifies dietary behaviour.

Drug use among men who have sex with men in Ireland: Prevalence and associated factors from a national online survey.

BACKGROUND: Little is known about the prevalence and determinants of drug use among men who have sex with men (MSM) in Ireland. The aims of this study were to measure the prevalence of recreational drug use among MSM in a national sample, and to identify sub-groups of MSM who may benefit from targeted preventive interventions. METHODS: The MSM Internet Survey Ireland (MISI) 2015 was a community-recruited, nationally-promoted, self-completed online survey for MSM. MISI 2015 included standardised questions on recreational drugs, poppers, and drugs associated with chemsex (i.e. crystal methamphetamine, GBL/GHB, mephedrone, ketamine). Multivariable-adjusted logistic regression was used to identify factors associated with use of these substances. RESULTS: In the previous year, 36% of MSM used recreational drugs, 33% used poppers, and 7% used drugs associated with chemsex. Five percent were diagnosed HIV-positive. Recreational drug users were significantly younger than non-users (median = 27 vs. 32 years; p < 0.001); popper users were significantly older than non-users (median = 34 vs. 28 years; p < 0.001). The odds of recreational drug use were higher among MSM diagnosed HIV-positive (vs. never tested; AOR 2.27, 95%CI 1.39-3.70). Use of poppers, and use of drugs associated with chemsex, were also higher among MSM diagnosed HIV-positive (vs. never tested; AOR 3.77, 95%CI 2.41-5.90, and AOR 5.87, 95%CI 3.08-11.18 respectively). CONCLUSIONS: The prevalence of recreational drug use is higher among MSM than in the general population in Ireland, and it is particularly high among MSM diagnosed HIV-positive. Targeted harm reduction messages and preventive interventions are warranted to complement population-based approaches to reducing drug use in this population.

Inequalities in HIV testing uptake and needs among men who have sex with men living in Ireland: findings from an internet survey.

OBJECTIVES: HIV disproportionately affects men who have sex with men (MSM) in Ireland. The aim of this study was to improve understanding of HIV testing among MSM living in Ireland to inform prevention and testing initiatives. METHODS: We used data from the MSM Internet Survey Ireland 2015 (MISI 2015), a cross-sectional survey of MSM living in Ireland. We identified factors associated with never having tested for HIV using univariable and multivariable logistic regression. We identified preferred sites for future tests and examined the relationships between unmet HIV testing needs and socio-demographic groups. RESULTS: More than one-third (n = 1006; 36%) of MSM had never tested for HIV. Multivariable logistic regression showed that untested men were more likely to be aged 18-24 years, live outside Dublin, have a lower level of education, be born in Ireland, identify as bisexual, be out to fewer people, and not have had sex with a man in the previous 12 months. The same groups of men also had the least knowledge about HIV and were least confident in accessing an HIV test. Men who had never tested for HIV were more likely to prefer testing by their general practitioner (GP) or using home sampling HIV kits and less likely to prefer testing in a sexual health clinic. CONCLUSIONS: HIV prevention and testing programmes for MSM should be targeted towards younger men, those living outside Dublin and those with lower levels of education. We recommend increased promotion and availability of free HIV testing services in a range of clinical and nonclinical settings (including self-sampling and home testing).

The relationship between early pregnancy dietary intakes and subsequent birthweight and neonatal adiposity.

Background: Maternal nutrition intakes may influence neonatal birthweight and adiposity; however, inconsistencies within the literature exist. The relationships between maternal dietary intakes in early pregnancy and both birthweight and neonatal adiposity requires elucidation. This study examined the relationship between early pregnancy dietary intakes and subsequent birthweight and neonatal adiposity. Methods: Women were recruited at their convenience after sonographic confirmation of a singleton pregnancy. Women completed a Willet food frequency questionnaire evaluating habitual food and nutrient intakes at their first antenatal visit. Neonatal body composition was measured using air-displacement plethysmography. Results: Of the 385 mother-neonate dyads, mean maternal age was 30.8 ± 5.3 years, mean Body Mass Index (BMI) was 24.5 ± 4.8 kg/m2 and 41.8% (n = 161) were nulliparous. There were no relationships between maternal food intakes and birthweight (P > 0.05) (n = 385). On multivariable analysis there was a positive relationship between polyunsaturated fat and neonatal fat mass index (FMI) (beta = 0.015, 95% CI = 0.002-0.028, P = 0.04) (n = 80). Conclusion: Dietary intakes of polyunsaturated fat in early pregnancy are positively associated with neonatal FMI at birth on multivariable analysis. Further longitudinal studies need to explore this association and the long-term implications for the neonate.

Time-Resolved Tomographic Quantification of the Microstructural Evolution of Ice Cream.

Ice cream is a complex multi-phase colloidal soft-solid and its three-dimensional microstructure plays a critical role in determining the oral sensory experience or mouthfeel. Using in-line phase contrast synchrotron X-ray tomography, we capture the rapid evolution of the ice cream microstructure during heat shock conditions in situ and operando, on a time scale of minutes. The further evolution of the ice cream microstructure during storage and abuse was captured using ex situ tomography on a time scale of days. The morphology of the ice crystals and unfrozen matrix during these thermal cycles was quantified as an indicator for the texture and oral sensory perception. Our results reveal that the coarsening is due to both Ostwald ripening and physical agglomeration, enhancing our understanding of the microstructural evolution of ice cream during both manufacturing and storage. The microstructural evolution of this complex material was quantified, providing new insights into the behavior of soft-solids and semi-solids, including many foodstuffs, and invaluable data to both inform and validate models of their processing.

Pilot evaluation of an online weight management programme.

This intervention examined the efficacy of a six-week online weight loss programme. Students and staff of a third level institution (n=183) were recruited to the programme which provided individualised dietary advice for weight loss. Eighty-five participants (mean age 29.7 years, mean BMI 28.9kg/m2, 33% male) met the minimum inclusion criterion of logging on to the study website at least twice. All participants who completed the full six-week programme lost weight (n=31), with significant reductions in mean weight (2.8kg), BMI (0.9kg/m2) and waist circumference (4.1cm) observed between the start and end of the programme (all P<0.001). Among "completers", males lost more weight than females (4.2kg vs. 1.9kg, P=0.004). One in four completers lost >5% of their bodyweight, with reductions in biscuit and alcohol consumption being most predictive of weight loss. These findings suggest that individualised online dietary advice is effective in achieving short-term weight loss, especially in males.

Preferences of women for web-based nutritional information in pregnancy.

OBJECTIVES: During pregnancy, women are increasingly turning to web-based resources for information. This study examined the use of web-based nutritional information by women during pregnancy and explored their preferences. STUDY DESIGN: Cross-sectional observational study. METHODS: Women were enrolled at their convenience from a large maternity hospital. Clinical and sociodemographic details were collected and women's use of web-based resources was assessed using a detailed questionnaire. RESULTS: Of the 101 women, 41.6% were nulliparous and the mean age was 33.1 years (19-47 years). All women had internet access and only 3% did not own a smartphone. Women derived pregnancy-related nutritional information from a range of online resources, most commonly: What to Expect When You're Expecting (15.1%), Babycenter (12.9%), and Eumom (9.7%). However, 24.7% reported using Google searches. There was minimal use of publically funded or academically supported resources. The features women wanted in a web-based application were recipes (88%), exercise advice (71%), personalized dietary feedback (37%), social features (35%), videos (24%) and cooking demonstrations (23%). CONCLUSIONS: This survey highlights the risk that pregnant women may get nutritional information from online resources which are not evidence-based. It also identifies features that women want from a web-based nutritional resource.

Knowledge about folic acid supplementation in women presenting for antenatal care.

BACKGROUND/OBJECTIVES: The incidence of neural tube defects (NTDs) in Ireland has increased in recent years. This study examines knowledge about folic acid (FA) supplementation for the prevention of NTDs among women presenting for antenatal care. SUBJECTS/METHODS: Women were recruited at their convenience in the first trimester after sonographic confirmation of an ongoing singleton pregnancy. A detailed questionnaire was completed under the supervision of a research dietitian. Clinical and socio-demographic details were collected. RESULTS: Of the 587 women studied, 96% took FA during early pregnancy. Of these, 56.4% cited brain/spinal development or the prevention of brain/spinal defects, spina bifida or NTDs as the reason for taking FA. Multivariate analysis showed that women who were experiencing material deprivation or who were living in Ireland <5 years were least likely to be knowledgeable about the benefits of FA supplementation (P<0.05 for both). Over half (57.1%) of the women did not take FA preconceptionally. The main reason reported for not supplementing preconceptionally was that the woman did not expect to get pregnant (76.4%). Over one-third of women (35%), however, reported that they did not know they needed to take FA before becoming pregnant. CONCLUSIONS: These results highlight the need for a renewed public health campaign in Ireland about the importance of FA. As well as focusing on women who have recently come to live in Ireland, this campaign needs focus on women living in deprivation, as these are the women most at risk of having inadequate knowledge about the importance of FA in improving pregnancy outcomes.

Use of a web-based dietary assessment tool in early pregnancy.

BACKGROUND: Maternal diet is critical to fetal development and lifelong health outcomes. In this context, dietary quality indices in pregnancy should be explicitly underpinned by data correlating food intake patterns with nutrient intakes known to be important for gestation. AIMS: Our aim was to assess the correlation between dietary quality scores derived from a novel online dietary assessment tool (DAT) and nutrient intake data derived from the previously validated Willett Food Frequency Questionnaire (WFFQ). METHODS: 524 women completed the validated semi-quantitive WFFQ and online DAT questionnaire in their first trimester. Spearman correlation and Kruskal-Wallis tests were used to test associations between energy-adjusted and energy-unadjusted nutrient intakes derived from the WFFQ, and diet and nutrition scores obtained from the DAT. RESULTS: Positive correlations were observed between respondents' diet and nutrition scores derived from the online DAT, and their folate, vitamin B12, iron, calcium, zinc and iodine intakes/MJ of energy consumed derived from the WFFQ (all P < 0.001). Negative correlations were observed between participants' diet and nutrition scores and their total energy intake (P = 0.02), and their percentage energy from fat, saturated fat, and non-milk extrinsic sugars (NMES) (all P ≤ 0.001). Median dietary fibre, beta carotene, folate, vitamin C and vitamin D intakes derived from the WFFQ, generally increased across quartiles of diet and nutrition score (all P < 0.001). CONCLUSIONS: Scores generated by this web-based DAT correlate with important nutrient intakes in pregnancy, supporting its use in estimating overall dietary quality among obstetric populations.

A review of European guidelines on periconceptional folic acid supplementation.

Strong evidence that folic acid (FA) prevents the majority of cases of neural tube defects (NTDs) has led to national organisations developing guidelines for women concerning periconceptional supplementation. In Europe, there is evidence of national variations in the incidence of NTDs, with a recent Irish study reporting an increase in the rate. This review compares the periconceptional FA supplementation guidelines between the different countries in Europe. An online search of country-specific guidelines produced before 2015 concerning periconceptional FA supplementation was conducted. If an English version was not available directly, the EUROCAT register was searched for the English version of the recommendations. We identified national guidelines from 20 European countries. Over half recommended that FA supplements be taken by women planning a pregnancy, but three recommended that they should be taken by all women of child-bearing age. Four guidelines recommended starting FA at least 4 weeks preconceptionally, but no country recommended starting FA at least 12 weeks preconceptionally as suggested by recently published studies. There is a need for further consideration of the duration of preconceptional FA supplementation specifically. The latest scientific evidence in this area should inform the development of European guidelines on FA, as there is wide variation in current recommendations. Overall, the wide variation in national guidelines concerning periconceptional FA supplementation may in part explain the differences in national rates of NTDs reported by EUROCAT. National guidelines on FA supplementation should be standardised across European countries.

Dietary contributors to hypertension in adults reviewed.

Recent national surveys which measured respondents' blood pressure (BP) levels have shown a high prevalence of hypertension amongst the Irish population, with approximately two-thirds of men and over half of women aged 45 years and over affected. Higher prevalence rates are observed with advancing age. Established diet- and lifestyle-related risk factors for hypertension such as high salt intake, high alcohol consumption and physical inactivity are pervasive in Ireland and are believed to contribute significantly to the high national prevalence of this condition. Additional dietary deficits have been implicated in the development of hypertension, however, including low fruit and vegetable intake, low dairy food consumption and low intake of oily fish. Deficiencies of single micro-nutrients such as folate, riboflavin, vitamin C and vitamin D have also been recently recognised as risk factors for hypertension. For each of these factors, there is evidence that the food and nutrient intakes of many Irish adults fall short of the ideal. These dietary and nutritional deficits, when superimposed on Ireland's existing health-subversive behaviours and escalating rates of obesity, constitute a potent constellation of risk factors for hypertension. However, they also represent viable and potentially effective targets for health promotion initiatives. This review aims to describe the main nutritional, dietary and lifestyle contributors to hypertension in Ireland with a view to informing future interventions aimed at alleviating Ireland's burden of hypertensive disease.

Evidence of residual feed intake reranking in crossbred replacement heifers.

The objective of the study was to examine whether residual feed intake (RFI) reranking exists between 2 consecutive periods in replacement heifers fed the same diet. The study collected feed intake and BW data from 190 crossbred heifers over a 3-yr period (61 in 2007, 68 in 2008, and 61 in 2009) during the winter-spring season. The heifers were fed a roughage-based diet (90% barley silage and 10% rolled barley grain) throughout the feeding trial, which was broken down into 2 feeding periods with ADG of 0.94 and 0.90 kg•d(-1) in the first and second periods, respectively. The RFI was calculated for the entire period using different models, which included ADG, mid-metabolic BW, body composition, and feeding activity. Gain:feed ratio and Kleiber ratio were also calculated. Rank correlations among the RFI calculated from different models were obtained, as well as rank correlations between the 2 feeding periods for the feed efficiency measures. Including body composition and feeding activity only improved the R(2) by 1 to 5%. The rank correlations among the different models were high (90 to 95%) for RFI calculated for the entire feeding period. However, the RFI calculated within the second feeding period had greater rank correlation than the RFI calculated from the entire feeding period. Compared with G:F and Kleiber ratio, RFI gave lesser reranking between periods 1 and 2. About 49% of the heifers maintained their RFI class, whereas 51% of the heifers had a different RFI class in period 2. Furthermore, 41% of the heifers changed their RFI in period 2 by <0.5 SD, whereas the rest of the heifers changed by ≥0.5 SD. These results indicate that reranking exists in heifers despite receiving the same diet in the 2 feeding periods and that the reranking may be more serious in heifers (28%) with extreme RFI performances in each period.

The cognitive and behavioural phenotype of Roifman syndrome.

BACKGROUND: Roifman syndrome (OMIM 300258) is a multi-system disorder with a physical phenotype that includes Beta-cell immunodeficiency, intra-uterine and postnatal growth retardation, spondyloepiphyseal dysplasia, retinal dystrophy and characteristic facial dysmorphism. So far, six cases, all boys, have been reported in the literature. Roifman postulated that the syndrome may be due to a mutation in an X-linked gene or an autosomal gene giving rise to a sex-limited trait, but the definitive pathogenetic mechanism has still not been elucidated. Very little is known about the cognitive and behavioural phenotype of Roifman syndrome and no standardized measures of cognitive abilities have been reported. METHODS: We report the seventh case of a boy with Roifman syndrome and present the first systematic documentation of the cognitive and behavioural phenotype of an individual with the syndrome. RESULTS: In spite of having been reported as appearing intellectually 'able', formal evaluation showed very significant intellectual disability and neuropsychological impairment across cognitive domains. CONCLUSIONS: The findings suggest that Roifman syndrome may be an example of an X-linked mental retardation syndrome (XLMRS).

Effects of alcohol ethoxylate and pluronic detergents on the development of pasture bloat in cattle and sheep.

A series of studies was conducted to determine the efficacy and possible modes of action of a water-soluble mixture of alcohol ethoxylate and pluronic detergents (AEPD; Blocare 4511, ANCARE, Auckland, NZ) in preventing pasture bloat in ruminants grazing or fed freshly harvested alfalfa. Ten cannulated Suffolk wethers were offered freshly harvested alfalfa; five were given a daily intraruminal dose of 40 ml of 50% AEPD (vol/vol) 1 h before feeding, and five (controls) were dosed with water. Viscosity of ruminal fluid was reduced (P < 0.001) in AEPD-treated wethers, relative to the controls, for the first 2 h after feeding but not at 4 h after feeding and beyond. Treatment with AEPD did not affect dry matter (DM) intake, digestibility of DM, acid detergent fiber, or neutral detergent fiber, or N digestion and retention, implying that AEPD likely would not affect milk production. In a crossover grazing study, five of the wethers were given AEPD in drinking water (0.1%, vol/vol); treatment with AEPD was 100% effective for preventing bloat in sheep grazing early-bloom alfalfa for 4 h daily. Replicate grazing studies were conducted with cattle in Lethbridge, AB; Lacombe, AB; and Kamloops, BC. Treated animals received AEPD in the water (0.06%, vol/vol) and grazed vegetative alfalfa for 6 h daily. As it did with sheep, AEPD treatment effectively precluded the bloat observed in control animals. Consequently, AEPD may be a valuable tool for alfalfa pasture-based dairy production although further study is required to develop an integrated model for optimal administration under a variety of climatic conditions.

Estrus synchronization and pregnancy rates in beef cattle given CIDR-B, prostaglandin and estradiol, or GnRH.

Two experiments were conducted to determine estrous response and pregnancy rate in beef cattle given a controlled internal drug release (CIDR-B) device plus prostaglandin F2 alpha (PGF) at CIDR-B removal, and estradiol or gonadotropin releasing hormone (GnRH). In Experiment I, crossbred beef heifers received a CIDR-B device and 1 mg estradiol benzoate (EB), plus 100 mg progesterone (E + P group; n = 41), 100 micrograms gonadotropin releasing hormone (GnRH group; n = 42), or no further treatment (Control group; n = 42), on Day 0. On Day 7, CIDR-B devices were removed and heifers were treated with PGF. Heifers in the E + P group were given 1 mg EB, 24 h after PGF, and then inseminated 30 h later. Heifers in the GnRH group were given 100 micrograms GnRH, 54 h after PGF, and concurrently inseminated. Control heifers were inseminated 12 h after onset of estrus. The estrous rate was lower (P < 0.01) in the GnRH group (55%) than in either the E + P (100%) or Control (83%) groups. The mean interval from CIDR-B removal to estrus was shorter (P < 0.01) and less variable (P < 0.01) in the E + P group than in the GnRH or Control groups. Pregnancy rate in the E + P group (76%) was higher (P < 0.01) than in the GnRH (48%) or Control (38%) groups. In Experiment II, 84 cows were treated similarly to the E + P group in Experiment I. Cows received 100 mg progesterone and either 1 mg EB or 5 mg estradiol-17 beta (E-17 beta) on Day 0 and either 1 mg of EB or 1 mg of E-17 beta on Day 8 (24 h after CIDR-B removal), in a 2 x 2 factorial design, and were inseminated 30 h later. There were no differences among groups for estrous rates or conception rates. The mean interval from CIDR-B removal to estrus was 44.2 h, s = 11.2. Conception rates were 67%, 62%, 52%, and 71% in Groups E-17 beta/E-17 beta, E-17 beta/EB, EB/E-17 beta, and EB/EB, respectively. In cattle given a CIDR-B device and estradiol plus progesterone, treatment with either EB or E-17 beta effectively synchronized estrus and resulted in acceptable conception rates to fixed-time artificial insemination.