Does continuity of care impact decision making in the next birth after a caesarean section (VBAC)? A randomised controlled trial

BACKGROUND: Caesarean section (CS) has short and long-term health effects for both the woman and her baby. One of the greatest contributors to the CS rate is elective repeat CS. Vaginal birth after caesarean (VBAC) is an option for many women; despite this the proportion of women attempting VBAC remains low. Potentially the relationship that women have with their healthcare professional may have a major influence on the uptake of VBAC. Models of service delivery, which enable an individual approach to care, may make a difference to the uptake of VBAC. Midwifery continuity of care could be an effective model to encourage and support women to choose VBAC. METHODS/DESIGN: A randomised, controlled trial will be undertaken. Eligible pregnant women, whose most recent previous birth was by lower-segment CS, will be randomly allocated 1:1 to an intervention group or control group. The intervention provides midwifery continuity of care to women through pregnancy, labour, birth and early postnatal care. The control group will receive standard hospital care from different midwives through pregnancy, labour, birth and early postnatal care. Both groups will receive an obstetric consultation during pregnancy and at any other time if required. Clinical care will follow the same guidelines in both groups. DISCUSSION: This study will determine whether midwifery continuity of care influences the decision to attempt a VBAC and impacts on mode of birth, maternal experiences with care and the health of the neonate. Outcomes from this study might influence the way maternity care is provided to this group of women and thus impact on the CS rate. This information will provide high level evidence to policy makers, health service managers and practitioners who are working towards addressing the increased rate of CS. TRIAL REGISTRATION: This trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN1261100121492

Investigating the relationship between DNA methylation age acceleration and risk factors for Alzheimer’s disease

This work was supported by a Alzheimer's Research UK Major Project grant (ARUK-PG2017B-10). Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). We are grateful to all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team that includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, health-care assistants and nurses. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland, and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” [STRADL];104036/Z/14/Z). DNA methylation data collection was funded by the Wellcome Trust Strategic Award (10436/Z/14/Z). The research was conducted in the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE), part of the cross-council Lifelong Health and Wellbeing Initiative (MR/K026992/1); funding from the Biotechnology and Biological Sciences Research Council (BBSRC) and Medical Research Council (MRC) is gratefully acknowledged. CCACE supports I.J.D. with some additional support from the Dementias Platform UK (MR/L015382/1). A.M.M. and H.C.W. have received support from the Sackler Institute.Peer reviewedPublisher PD

Exile Vol. XX No. 1

ARTWORK by Sue Sartarelli cover, 24 by Chris Schulze 5, 24, 29 by Heather Richey 6 by Katheryn Riedl 7 by Jane Joldersma 10 by Jan Mosher 12 Pat Victory 15 Rona Rosen 20, 31 Arthur Ernst 21 Kim McMullen 24 FICTION First Time by Bud Foufos 3-4 Father\u27s Last Party by Vic Coccimiglio 11 untitled by Catherine Bader 16-17 God and Sergeant Mays by J. Frank Burkhard 22 Pages of a Story by Peter Porteous 27-31 POETRY The Rest by Ezra Pound (preface) In the Midst of an Echo by Phil Mercurio 4 Sierra Madre Prose by John Purcell 5 untitled by Sue Payne 6 untitled by Cathy Graff 6 untitled by Sharon Singleton 7 Big Al by Phil Mercurio 9-10 untitled by Sharon Singleton 12 Folksinger by Alison Orleans 13 Sweat Rebellion by S. Hunt 13 Blackgrey by Laurie Wharton 14 What is she to you? by Peter Porteous 18 Pojects by Mary Mueller 21 untitled by Dawn Patnode 25 The Barn by Mary Schloss 25 PHOTOGRAPHY by Bruce Andre 1, 18 by Jane Joldersma 4, 23, 26 by Breese Olander 8 by Pam Purcell 8 by Loree Ruman 13, 14 Foster Schmidt 19 Chip Andreae 19, 23 Nancy Pickenson 26 Nancy Chorpenning 32 Many thanks to the advertising agencie -2 Pgs. 25 and 26 are out of order in the published edition and can be found between pages 8 and 9

Epigenome-wide association study of global cortical volumes in Generation Scotland:Scottish Family Health Study

Funding This work was supported by the Wellcome Trust [104036/Z/14/Z]. Acknowledgements Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006] and is currently supported by the Wellcome Trust [216767/Z/19/Z]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) Reference 104036/Z/14/Z). MCB is supported by a Guarantors of Brain Non-clinical Post-Doctoral Fellowship. AMM is supported by the Wellcome Trust (104036/Z/14/Z, 216767/Z/19/Z, 220857/Z/20/Z) and UKRI MRC (MC_PC_17209, MR/S035818/1). KLE is supported by the NARSAD Independent Investigator Award (Grant ID: 21956). JMW is supported by UK Dementia Research Institute which is funded by the MRC, Alzheimer’s Research UK and Alzheimer’s Society, by the Fondation Leducq (16 CVD 05), and the Row Fogo Centre for Research Into Ageing and the Brain (BRO- D.FID3668413). This work is part of a project that has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 847776.Peer reviewedPublisher PD

GWAS on family history of Alzheimer’s disease

Alzheimer’s disease (AD) is a public health priority for the 21st century. Risk reduction currently revolves around lifestyle changes with much research trying to elucidate the biological underpinnings. We show that self-report of parental history of Alzheimer’s dementia for case ascertainment in a genome-wide association study of 314,278 participants from UK Biobank (27,696 maternal cases, 14,338 paternal cases) is a valid proxy for an AD genetic study. After meta-analysing with published consortium data (n = 74,046 with 25,580 cases across the discovery and replication analyses), three new AD-associated loci (P < 5 × 10−8) are identified. These contain genes relevant for AD and neurodegeneration: ADAM10, BCKDK/KAT8 and ACE. Novel gene-based loci include drug targets such as VKORC1 (warfarin dose). We report evidence that the association of SNPs in the TOMM40 gene with AD is potentially mediated by both gene expression and DNA methylation in the prefrontal cortex. However, it is likely that multiple variants are affecting the trait and gene methylation/expression. Our discovered loci may help to elucidate the biological mechanisms underlying AD and, as they contain genes that are drug targets for other diseases and disorders, warrant further exploration for potential precision medicine applications

Associations of negative affective biases and depressive symptoms in a community-based sample

Acknowledgements. We thank professor Jonathan Roiser (University College London, UK) and professor emeritus Ian Deary (University of Edinburgh, UK) for their input on task selection and statistical analysis. We also acknowledge all researchers who have contributed to the collection of data for the current study. Most importantly, we would like to thank all participants of Generation Scotland, and particularly those of the STRADL subcohort, for their participation in the research. Financial support. Stratifying Resilience and Depression Longitudinally is supported by the Wellcome Trust through a Strategic Award (Grant No. 104036/Z/14/Z) and through an Investigator Award (Grant No. 220857/Z/ 20/Z). The Chief Scientist Office of the Scottish Government Health Department (Grant No. CZD/16/6), Scottish Funding Council (Grant No. HR03006) and Wellcome Trust (Grant No. 216767/Z/19/Z) provided core support for Generation Scotland.Peer reviewedPublisher PD

Associations of negative affective biases and depressive symptoms in a community-based sample

Background: Major depressive disorder (MDD) was previously associated with negative affective biases. Evidence from larger population-based studies, however, is lacking, including whether biases normalise with remission. We investigated associations between affective bias measures and depressive symptom severity across a large community-based sample, followed by examining differences between remitted individuals and controls. Methods: Participants from Generation Scotland (N = 1109) completed the: (i) Bristol Emotion Recognition Task (BERT), (ii) Face Affective Go/No-go (FAGN), and (iii) Cambridge Gambling Task (CGT). Individuals were classified as MDD-current (n = 43), MDD-remitted (n = 282), or controls (n = 784). Analyses included using affective bias summary measures (primary analyses), followed by detailed emotion/condition analyses of BERT and FAGN (secondary analyses). Results: For summary measures, the only significant finding was an association between greater symptoms and lower risk adjustment for CGT across the sample (individuals with greater symptoms were less likely to bet more, despite increasingly favourable conditions). This was no longer significant when controlling for non-affective cognition. No differences were found for remitted-MDD v. controls. Detailed analysis of BERT and FAGN indicated subtle negative biases across multiple measures of affective cognition with increasing symptom severity, that were independent of non-effective cognition [e.g. greater tendency to rate faces as angry (BERT), and lower accuracy for happy/neutral conditions (FAGN)]. Results for remitted-MDD were inconsistent. Conclusions: This suggests the presence of subtle negative affective biases at the level of emotion/condition in association with depressive symptoms across the sample, over and above those accounted for by non-affective cognition, with no evidence for affective biases in remitted individuals

Blunted Medial Prefrontal Cortico-Limbic Reward-Related Effective Connectivity and Depression

Stratifying Resilience and Depression Longitudinally (STRADL) was supported by the Wellcome Trust through a Strategic Award (Grant No. 104036/Z/14/Z). Parts of the work were supported by a China Scholarship Council (Grant No. 201506040037 to SX), National Institutes of Health (Grant No. DA027764 to MRD), Lister Institute Prize Fellowship 2016–2021 (to DJS), Dr Mortimer and Theresa Sackler Foundation (AMM, HCW, and SML), Centre for Cognitive Ageing and Cognitive Epidemiology (IJD and AMM), Medical Research Council and Biotechnology and Biological Sciences Research Council (Grant No. MR/K026992/1), Royal College of Physicians of Edinburgh John, Margaret, Alfred and Stewart Sim fellowship (to HCW), and University of Edinburgh, Edinburgh Scientific Academic TmPCk College Fellowship (to HCW). The Chief Scientist Office of the Scottish Government Health Department (Grant No. CZD/16/6) and Scottish Funding Council (Grant No. HR03006) provided core support for Generation Scotland. Data acquisition was additionally supported by the Scottish Mental Health Research Network and Scottish Government’s Support for Science initiative. LR, HCW, and AMM, received financial support from Pfizer (formerly Wyeth) in relation to imaging studies of people with schizophrenia and bipolar disorder. AMM has previously received grant support from Lilly and Janssen. SML has received honoraria for lectures, chairing meetings, and consultancy work from Janssen in connection with brain imaging and therapeutic initiatives for psychosis. JDS has received funding via an honorarium associated with a lecture or Wyeth and funding from Indivior for a study on opioid dependency. No other disclosures were reported. The authors declare no conflict of interest.Peer reviewedPublisher PD

Haplotype-based association analysis of general cognitive ability in Generation Scotland, the English Longitudinal Study of Ageing, and UK Biobank

Background: Cognitive ability is a heritable trait with a polygenic architecture, for which several associated variants have been identified using genotype-based and candidate gene approaches. Haplotype-based analyses are a complementary technique that take phased genotype data into account, and potentially provide greater statistical power to detect lower frequency variants. Methods: In the present analysis, three cohort studies (ntotal = 48,002) were utilised: Generation Scotland: Scottish Family Health Study (GS:SFHS), the English Longitudinal Study of Ageing (ELSA), and the UK Biobank. A genome-wide haplotype-based meta-analysis of cognitive ability was performed, as well as a targeted meta-analysis of several gene coding regions. Results: None of the assessed haplotypes provided evidence of a statistically significant association with cognitive ability in either the individual cohorts or the meta-analysis. Within the meta-analysis, the haplotype with the lowest observed P-value overlapped with the D-amino acid oxidase activator (DAOA) gene coding region. This coding region has previously been associated with bipolar disorder, schizophrenia and Alzheimer’s disease, which have all been shown to impact upon cognitive ability. Another potentially interesting region highlighted within the current genome-wide association analysis (GS:SFHS: P = 4.09 x 10-7), was the butyrylcholinesterase (BCHE) gene coding region. The protein encoded by BCHE has been shown to influence the progression of Alzheimer’s disease and its role in cognitive ability merits further investigation. Conclusions: Although no evidence was found for any haplotypes with a statistically significant association with cognitive ability, our results did provide further evidence that the genetic variants contributing to the variance of cognitive ability are likely to be of small effect