Xanthine oxidase inhibition and white matter hyperintensity progression following ischaemic stroke and transient ischaemic attack (XILO-FIST): a multicentre, double-blinded, randomised, placebo-controlled trial

Acknowledgments This work was supported by the Stroke Association and British Heart Foundation [grant number TSA BHF 2013/01]. The work of Dr David Dickie and Dr Terry Quinn is funded by the Stroke Association. We would like to thank Christine McAlpine, Ruth Graham, Glasgow Royal Infirmary, UK; Lauren Pearce, Royal United Hospital, UK; Caroline Fornolles, Louise Tate, Frances Justin, Luton and Dunstable University Hospital, UK; Dean Waugh, Leeds Teaching Hospitals NHS Trust, UK; Donal Concannon, Altnagelvin Hospital, UK; Sharon Tysoe, Nina Francia, Nisha Menon, Raji Prabakaran, Southend University Hospital, UK; Amy Ashton, Caroline Watchurst, Marilena Marinescu, Sabaa Obarey, Scheherazade Feerick, University College London NHS Foundation Trust, UK; and Janice Irvine, Sandra Williams, and German Guzman Gutierrez, Aberdeen Royal Infirmary, UK; Caroline Fox and Joanne Topliffe, Broomfield Hospital, Essex, UK.Peer reviewedPublisher PD

Building a Successful Service: Developing Open Access Funding and Advocacy at University College London

The UK Research Councils (RCUK) introduced an open access pol- icy, and accompanying funding for Article Processing Charges (APCs), in April 2013. This article describes University College London (UCL)’s experience of managing its institutional, RCUK, and Wellcome Trust open access funds, and highlights its success in exceeding the RCUK target in the first year of the policy. A large institution, processing around 1,770 APCs in 2013–2014, UCL has established a dedicated Open Access Funding Team. As well as advising authors on funders’ and publishers’ requirements, man- aging payments, and liaising with publishers, the Team delivers a comprehensive open access advocacy programme throughout the institution. Researchers who have used the Team’s services show astonishing levels of enthusiasm for open access, and for UCL’s approach to supporting them

An Exploratory Study of Long-Term Outcome Measures in Critical Illness Survivors: Construct Validity of Physical Activity, Frailty, and Health-Related Quality of Life Measures

Dr. McNelly was supported by the Batchworth Trust (supports research into rehabilitation; grant for part-time salary), the Moulton Charitable Foundation (supports research into disability; grant for part-time salary), and the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre (on-going project award). Dr. Puthucheary was funded by an NIHR doctorate fellowship. Dr. Harridge received support for article research from the Research Councils UK (RCUK). Dr. Hart received funding from the NIHR Clinical Research Facility at Guy’s and St Thomas’ NHS Foundation Trust, and the NIHR Biomedical Research Centre, Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. Dr. Montgomery was funded by University College London, the National Institute of Health Research and University College London Hospitals. The NIHR doctorate fellowship (£479,000; 2010–2014) underpinned the core patient population study on which this follow-up was built; Batchworth Trust (£15,000; January 2013 to July 2014); Moulton Foundation (£45, 000; August 2014 to June 2017); and European Society of intensive Care Medicine (£18,000; Single donation 2010). Additional funding was received from the Whittington Hospital NHS Trust. Dr Hart’s institution received other support from the NIHR Biomedical Research Centre Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. Dr Montgomery’s institution received funding from the National Institute of Health Research (UK), European Society of Intensive Care Medicine, and Whittington Hospital NHS Trust

Autoantibodies targeting TLR and SMAD pathways define new subgroups in systemic lupus erythematosus

T.J.V. was awarded funding to from the George Koukis Foundation and an Arthritis Research UK Special Strategic Award. The study received support from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and the Biomedical Research Centre based at Guy’s & St. Thomas’ National Health Service (NHS) Foundation Trust, in partnership with King’s College London. The TwinsUK study was funded by the Wellcome Trust; European Community’s Seventh Framework Programme (FP7/2007-2013)

The Brighton declaration: the value of non-communicable disease modelling in population health sciences.

The Brighton declaration arose out of a one day workshop held in Brighton in September 2013 as part of the Society for Social Medicine annual conference. The workshop convened UK based non-communicable disease modellers to discuss the challenges and opportunities for non-communicable disease modelling in the UK. The declaration describes the value and importance of non-communicable disease modelling, both for research and for informing health policy. The declaration also describes challenges and issues for non-communicable disease modelling. The declaration has been endorsed by many non-communicable disease modellers in the UK.The following academics collaborated with the authors to finalise this article are and acknowledged as co-signatories on its content. The authors are extremely grateful for their input. University of Cambridge: Ali Abbas, Marko Tanio; University of Edinburgh: Dr Susannah McLean; UK Health Forum: Martin Brown, Tim Marsh, Marco Mesa-Frias, Lise Retat; Imperial College London: Anthony Laverty; The London School of Hygiene and Tropical Medicine: Zaid Chalabi; University College London: Luz Sanchez Romero; University of Oxford: Anja Mizdrak, Mike Rayner, Marco Springmann; University of Sheffield: Alan Brennan, James Chilcott, John Holmes, Petra Meier, John Mooney; University of Southampton: Grant Aitken. ADMB and OTM are funded by the Wellcome Trust. PS is funded by the British Heart Foundation. JW is funded by an MRC Population Health Scientist Fellowship.This is the final published version. The article was originally published in the European Journal of Epidemiology (2014) 29, 867–870, DOI 10.1007/s10654-014-9978-0

Hypermethylation in the ZBTB20 gene is associated with major depressive disorder.

This is the final version of the article. Available from BioMed Central via the DOI in this record.BACKGROUND: Although genetic variation is believed to contribute to an individual's susceptibility to major depressive disorder, genome-wide association studies have not yet identified associations that could explain the full etiology of the disease. Epigenetics is increasingly believed to play a major role in the development of common clinical phenotypes, including major depressive disorder. RESULTS: Genome-wide MeDIP-Sequencing was carried out on a total of 50 monozygotic twin pairs from the UK and Australia that are discordant for depression. We show that major depressive disorder is associated with significant hypermethylation within the coding region of ZBTB20, and is replicated in an independent cohort of 356 unrelated case-control individuals. The twins with major depressive disorder also show increased global variation in methylation in comparison with their unaffected co-twins. ZBTB20 plays an essential role in the specification of the Cornu Ammonis-1 field identity in the developing hippocampus, a region previously implicated in the development of major depressive disorder. CONCLUSIONS: Our results suggest that aberrant methylation profiles affecting the hippocampus are associated with major depressive disorder and show the potential of the epigenetic twin model in neuro-psychiatric disease.The study was funded by the Wellcome Trust; European Community’s Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research (NIHR) Clinical Research Facility at Guy’s & St Thomas’ Davies et al. Genome Biology 2014, 15:R56 Page 9 of 12 http://genomebiology.com/2014/15/4/R56 NHS Foundation Trust and NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. Matthew Davies is supported by the EU FP7 grant EuroBATS (No. 259749). Tim Spector is an NIHR senior Investigator and is holder of an ERC Advanced Principal Investigator award. Further funding support for this project was obtained from the European Research Council (project number 250157). The members of the UK Brain Expression Consortium (UKBEC) are: (1) Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK: John A Hardy, Mina Ryten, and Daniah Trabzuni; (2) Department of Medical and Molecular Genetics, King's College London, UK: Michael E Weale, Adaikalavan Ramasamy and Paola Forabosco; (3) Department of Pathology, The University of Edinburgh, Wilkie Building, Teviot Place, Edinburgh, UK: Colin Smith and Robert Walker. Australia: funding for phenotype and blood collection was from NHMRC grants to Nick Martin and NIH grants to Andrew Heath and Pamela Madden. We thank David Smyth for database management, Lisa Bowdler for sample preparation, and the twins for their cooperation

Safe staffing levels - a national imperative. The UK nursing Labour Market Review 2013

LondonThis report is the 2013 annual review of the UK nursing labour market commissioned by the Royal College of Nursing. Events over the last twelve months point to the urgent need to address both the national security of the supply of nurses, and the local ability to determine evidence-based nurse staffing levels.div_PaSThe Mid Staffordshire NHS Foundation Trust Public Inquiry (2013) Report of the Mid Staffordshire NHS Foundation Trust Public Inquiry: executive summary. London: Stationery Office (Chair: R Francis). www.midstaffspublicinquiry.com/sites/default/files/report/Executive%20summary.pdf 2 Royal College of Nursing (2013) Mid Staffordshire NHS Foundation Trust Public Inquiry Report: Response of the Royal College of Nursing. RCN, London http://www.rcn.org.uk/__data/assets/pdf_file/0010/530956/004476.pdf 3 See e.g. Healthcare Improvement Scotland (2013) Announced Inspection Report - care for older people in acute hospitals, Aberdeen Royal Infirmary, NHS Grampian. Healthcare Improvement Scotland, Edinburgh www.healthcareimprovementscotland.org/our_work/inspecting_and_regulating_care/opah_grampian/aberde en_royal_infirmary_jun13.aspx 4 Scottish Government (2012) News Releases. Nurse staffing levels. 26th November. Scottish Government, Edinburgh. http://www.scotland.gov.uk/News/Releases/2012/11/staff261112 5 Buckland L (2013) 67 million boost to NHS staff to avert age crisis. Scotland on Sunday, August 11, p6. 6 Royal College of Nursing, Wales (2013) RCN in Wales responds to Health Minister's 10 million nurse recruitment announcement. www.rcn.org.uk/newsevents/news/article/wales/rcn_in_wales_responds_to_health_ministers_10_million_nu rse_recruitment_funding 7 DHSSPS (2013) Health Minister and RCN agree on nursing priorities for Workforce Plans. www.northernireland.gov.uk/news-dhssps-080713-health-minister-and 8 Department of Health (2013) The Cavendish Review. Review of healthcare assistants and support workers in NHS and social care. Department of Health, London. www.gov.uk/government/uploads/system/uploads/attachment_data/file/212732/Cavendish_Review_ACCESS IBLE_-_FINAL_VERSION_16-7-13.pdf 9 NHS England (2013) Review into the quality of care and treatment provided by 14 hospital trusts in England: overview report. NHS England, London. www.nhs.uk/NHSEngland/bruce-keogh-review/Documents/outcomes/keogh-review-final-report.pdf 10 National Advisory Group on the Safety of Patients in England (2013) A promise to learn- a commitment to act: Improving the Safety of Patients in England. NHS England, London www.gov.uk/government/uploads/system/uploads/attachment_data/file/226703/Berwick_Report.pdf 11 Imison C, Bohmer R (2013) NHS and social care workforce: Meeting our needs now and in the future? King's Fund, London www.kingsfund.org.uk/sites/files/kf/field/field_publication_file/perspectives-nhs-social-care-workforcejul13. pdf 12 Centre for Workforce Intelligence (2013) Future nursing workforce projections - starting the discussion, London: CfWI. www.cfwi.org.uk/publications/future-nursing-workforce-projectionsstarting% 20the%20discussion 13 Buchan J Seccombe I (2011) A decisive decade. The 2011 UK nursing labour market review. Royal College of Nursing, London. www.rcn.org.uk/__data/assets/pdf_file/0006/405483/LMR2011_FINAL.pdf 14 RCN Scotland (2013) Student numbers maintained, but looming shortage of nurses, warns RCN. RCN Edinburgh, 25 February. www.rcn.org.uk/newsevents/news/article/scotland/student_numbers_maintained,_but_looming_shortage_of _nurses,_warns_rcn 15 Department of Health (2013) Delivering high quality, effective, compassionate care: Developing the right people with the right skills and the right values. A mandate from the Government to Health Education England: April 2013 to March 2015. Department of Health, London http://hee.nhs.uk/wp-content/blogs.dir/321/files/2013/05/29257_2900971_Delivering_Accessible.pdf 16 National Audit Office (2013). Managing the transition to the reformed health system. NAO, London. www.nao.org.uk/report/managing-the-transition-to-the-reformed-health-system/ 17 Timmins N (2013) The four UK health systems: Learning from each other. King's Fund, London www.kingsfund.org.uk/sites/files/kf/field/field_publication_summary/four-uk-health-systems-jun13.pdf 18 Audit Scotland (2012) NHS financial performance 2011/12. Audit Scotland, Edinburgh www.audit-scotland.gov.uk/docs/health/2012/nr_121025_nhs_finances.pdf 19 National Audit Office (2012) Progress in making NHS efficiency savings. NAO London. 34 www.nao.org.uk/report/progress-in-making-nhs-efficiency-savings/ 20 Jones N, Charlesworth A (2013) The anatomy of health spending 2011/12. Nuffield Trust, London. www.nuffieldtrust.org.uk/publications/anatomy-health-spending-201112-review-nhs-expenditure-and-labourproductivity 21 Roberts A, Marshall L, Charlesworth A (2012) A decade of austerity? Nuffield Trust, London www.nuffieldtrust.org.uk/sites/files/nuffield/121203_a_decade_of_austerity_full_report_1.pdf 22 Duffin C (2013) Stop start recruitment of nurses is damaging morale and patient care. Nursing Standard 27(48) p5 23 Department of Health (2013) National health visitor plan: progress and future implementation. DH London. www.gov.uk/government/publications/health-visitor-vision 24 NHS Employers (2013) NHS Staff Council. NHS Working Longer Review: Audit of existing research. NHS Staff Council/ University of Bath 25 Nursing Times News (2013) Retirement age health visitors offered sweeteners to stay in work. Nursing Times 27 (44), July 3 26 Sprinks J (2013) Minister tells trusts to cut spending on agency staff and equipment. Nursing Standard 27 (50), p10. 27 UCAS annual datasets (subject dataset v2.0, JACS3 subject line B7 Nursing) 28 NHS Education for Scotland, 2011, Untangling a complex issue: Nursing & Midwifery Student Recruitment and Retention Delivery Group Annual report 2010-11 www.nes.scot.nhs.uk/media/536359/delivery_group_-_annual_report_2010-11_final.pdf 29 Nursing Times, 27 September 2011, Huge fall in numbers dropping out of nursing courses 30 http://hee.nhs.uk/2013/05/09/top-nurses-to-oversee-pilots-on-pre-degree-care-experience/ 31 Centre for Workforce Intelligence (2013) Horizon scanning - A strategic review of the future healthcare workforce: Informing the nursing workforce www.cfwi.org.uk/publications/horizon-scanning-a-strategic-review-of-the-future-healthcare-workforceinforming- the-nursing-workforce 32 Queens Nursing Institute (2013) District Nurse Education 2012/13. QNI London www.qni.org.uk/campaigns/report_on_district_nurse_education 33 RCN Policy Unit (2012) The Community Nursing Workforce in England. RCN, London 34 Department of Health (2013) Care in local communities - district nurse vision and model. DH London. www.gov.uk/government/uploads/system/uploads/attachment_data/file/213363/vision-district-nursing- 04012013.pdf 35 Nursing Times (2013) Retirement age health visitors offered sweeteners to stay in work. Nursing Times, 27 (44) July 3rd. 36 http://frontlinefirst.rcn.org.uk/sites/frontlinefirst/index.php/blog/entry/scotlands-families-deserve-healthvisitors 37 Sprinks J (2013) Drafting in of Danish health visitors is just a short term fix, says Unison. Nursing Standard 27 (51), p9 38 House of Commons, Health Committee (2007) Workforce Planning: Fourth Report of Session 2006-07 Volume I Report, together with formal minutes. Health Committee, London: The Stationery Office Limited www.publications.parliament.uk/pa/cm200607/cmselect/cmhealth/171/171i.pdf R C N L A B O U R M A R K E T R E V I E W The RCN represents nurses and nursing, promotes excellence in practice and shapes health policies September 2013 RCN Online www.rcn.org.uk RCN Direct www.rcn.org.uk/direct 0345 772 6100 Published bypub3274pu

‘Changing our Heads’ : evaluation of the partnership between Shpresa Programme and Solace Women’s Aid to develop a specialist service for Albanian Speaking Women experiencing violence in London

In 2012, Shpresa programme, an Albanian community organisation, developed a partnership with Solace Women’s Aid (Solace), a specialist VAWG support service, to engage Albanian Speaking Women (ASW) in London around experiences of violence and abuse. There are three elements of support and intervention in the project: • workshops on domestic violence, delivered by an Albanian speaking worker, which are incorporated into Shpresa’s women’s support group sessions (the ARISE project); • individual casework, also delivered by an Albanian speaking worker based at Solace (the Empower project); and • workshops with children and young people about domestic violence. While some organisations provide specialist support for women from Eastern European communities who are experiencing violence (see Thiara, 2015), this project is the first to combine the expertise of an Albanian community organisation and a VAWG service provider. This meant a knowledge exchange between the two organisations, extending the skills and capacity of Shpresa staff and volunteers about domestic violence, and of Solace about the needs of Albanian speaking women (ASW), was core to the partnership. The project was funded by Trust for London and the Henry Smith Charity. In September 2013, the Child and Woman Abuse Studies Unit (CWASU) at London Metropolitan University were commissioned by Trust for London to evaluate the project. The evaluation brief required a focus on what lessons can be learned from this model of provision – a small community organisation acting as service commissioner - to inform the development of sustainable services for women from newly arrived communities in London. This final report is based on two years of delivery of the project, from 1st October 2013 to 30th September 2015. As a small scale process evaluation, the children’s workshops were not included.1 The report: • sets out the background to the partnership between Shpresa and Solace; • provides an overview of the project context by summarising what is known about Albanian communities in the UK and on Albanian-speaking women and violence; • outlines the evaluation methodology; • presents evidence of how the project met its objectives; and • offers reflections on this model of partnership for future commissioning. The title of the report - ‘Changing our Heads’ - refers to the way that workers spoke about the process of challenging attitudes and values, and also speaks to changes in practices that were necessary by each organisation in this new partnership

Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans.

Venous malformations (VMs) are painful and deforming vascular lesions composed of dilated vascular channels, which are present from birth. Mutations in the TEK gene, encoding the tyrosine kinase receptor TIE2, are found in about half of sporadic (nonfamilial) VMs, and the causes of the remaining cases are unknown. Sclerotherapy, widely accepted as first-line treatment, is not fully efficient, and targeted therapy for this disease remains underexplored. We have generated a mouse model that faithfully mirrors human VM through mosaic expression of Pik3ca(H1047R), a constitutively active mutant of the p110α isoform of phosphatidylinositol 3-kinase (PI3K), in the embryonic mesoderm. Endothelial expression of Pik3ca(H1047R)resulted in endothelial cell (EC) hyperproliferation, reduction in pericyte coverage of blood vessels, and decreased expression of arteriovenous specification markers. PI3K pathway inhibition with rapamycin normalized EC hyperproliferation and pericyte coverage in postnatal retinas and stimulated VM regression in vivo. In line with the mouse data, we also report the presence of activating PIK3CA mutations in human VMs, mutually exclusive with TEK mutations. Our data demonstrate a causal relationship between activating Pik3ca mutations and the genesis of VMs, provide a genetic model that faithfully mirrors the normal etiology and development of this human disease, and establish the basis for the use of PI3K-targeted therapies in VMs.Postdoctoral fellowships were from EMBO (A LTF 165-2013) to S.D.C, EU Marie Curie (MEIF-CT-2005-010264) to E.T. and EU Marie Curie (PIIF-GA-2009-252846) to I.M.B. M.Z.-T. is supported by the EPSRC Early Career Fellowship of T.L.K. (EP/L006472/1). D.J.S. is a BHF Intermediate Basic Science Research Fellow (FS/15/33/31608). A.L.D is supported by the UK NIHR Joint UCL/University College London Hospitals Biomedical Research Centre. V.E.R.P. was supported by the Wellcome Trust (097721/Z/11/Z). R.K.S. is supported by the Wellcome Trust (WT098498), the Medical Research Council (M RC_MC_UU_12012/5). R.G.K. is supported by the NIHR Rare Diseases Translational Research Collaboration. V.W. is supported by the European FPVI Integrated Project ‘Eurostemcell’. M.F.L. and A.B. are supported by the King’s College London and UCL Comprehensive Cancer Imaging Centre CR-UK and EPSRC, in association with the MRC and DoH (England). W.A.P. is supported by funding from the National Health and Medical Research Council (NHMRC) of Australia. Work in the laboratory of M.G. is supported by research grants SAF2013-46542-P and SAF2014-59950-P from MICINN (Spain), 2014-SGR-725 from the Catalan Government, the People Programme (Marie Curie Actions) from the European Union's Seventh Framework Programme FP7/2007-2013/ (REA grant agreement 317250), the Institute of Health Carlos III (ISC III) and the European Regional Development Fund (ERDF) under the integrated Project of Excellence no. PIE13/00022 (ONCOPROFILE). Work in the laboratory of B.V. is supported by Cancer Research UK (C23338/A15965) and the UK NIHR University College London Hospitals Biomedical Research Centre.This is the author accepted manuscript. The final version is available from the American Association for the Advancement of Science via http://dx.doi.org/10.1126/scitranslmed.aad998

What works in work with violent offenders: An overview.

SOMEC is a two-year project running from January 2013 to January 2015 investigating current processes for information exchange and procedures to manage the harm posed by serious violent or sexual offenders travelling across the European Union. SOMEC is co-funded by the European Commission Directorate-General for Home Affairs - HOME/2011/AG/4000002521 30-CE-0519712/00-87. SOMEC Partners, Beneficiary Partners: National Offender Management Service (UK), The Home Office (UK) Association of Chief Police Officers (UK), ACPO Criminal Records Office (UK), National Crime Agency (UK), London Probation Trust (UK), De Montfort University (UK), CEP- Confederation of European Probation (EU), Department of Justice (Prison and Probation) Catalonia (ES), Dutch Ministry of Security and Justice (NL), Latvian State Probation Service (LV), Latvian State Police (LV). Associate Partners: The Ministry of Interior, Macedonia (MA), Probation Chiefs Association (UK), The Scottish Government (UK), The Police Service Northern Ireland (UK), Probation Board for Northern Ireland (UK), Europol (EU), Eurojust (EU).This short overview captures key themes and findings about the effective assessment and management of violent offenders. It is not exhaustive but has attempted to be wide ranging. The overview concentrates on recent papers after 2007, but utilises earlier work if it is seen as relevant. The review has not used a systematic literature review methodology due to constraints of time and resources. This is also a very broad field of study and the review touches on key areas but recognises that further work is needed. A key word search1 of the following data bases/search engines was used: De Montfort and Birmingham University Websites. Further literature was pursued on a thematic basis following this initial search. The review is dominated by studies from Anglophone countries although sources from Europe have also been included when published in English