Mechanisms and pathways to impact in public health research: a preliminary analysis of research funded by the National Institute for Health Research (NIHR).

BACKGROUND: The mechanisms and pathways to impacts from public health research in the UK have not been widely studied. Through the lens of one funder (NIHR), our aims are to map the diversity of public health research, in terms of funding mechanisms, disciplinary contributions, and public health impacts, identify examples of impacts, and pathways to impact that existing reporting mechanisms may not otherwise have captured, and provide illustrations of how public health researchers perceive the generation of non-academic impact from their work. METHODS: A total of 1386 projects were identified as 'public health research' by the NIHR and listed in the NIHR Public Health Overview database (2000-2016). From these, a subset of 857 projects were matched as potentially having begun reporting impacts via an external data-gathering platform (Researchfish). Data on the 857 projects were analyzed quantitatively, and nine projects were selected to investigate further through semi-structured interviews with principal investigators. Two workshops took place to validate emerging and final findings and facilitate analysis. RESULTS: In addition to the NIHR School for Public Health Research and the NIHR Public Health Research Programme, 89% of projects contained in the NIHR Public Health Overview portfolio as 'public health research' are funded via other NIHR research programmes, suggesting significant diversity in disciplines contributing to public health research and outcomes. The pathways to impact observed in our in-depth case studies include contributing to debates on what constitutes appropriate evidence for national policy change, acknowledging local 'unintended' impacts, building trusted relationships with stakeholders across health and non-health sectors and actors, collaborating with local authorities, and using non-academic dissemination channels. CONCLUSIONS: Public health as a discipline contributes substantially to impact beyond academia. To support the diversity of these impacts, we need to recognise localized smaller-scale impacts, and the difference in types of evidence required for community and local authority-based impacts. This will also require building capacity and resources to enable impact to take place from public health research. Finally, support is required for engagement with local authorities and working with non-health sectors that contribute to health outcomes.

TOP2B: The First Thirty Years.

Type II DNA topoisomerases (EC 5.99.1.3) are enzymes that catalyse topological changes in DNA in an ATP dependent manner. Strand passage reactions involve passing one double stranded DNA duplex (transported helix) through a transient enzyme-bridged break in another (gated helix). This activity is required for a range of cellular processes including transcription. Vertebrates have two isoforms: topoisomerase IIα and ß. Topoisomerase IIß was first reported in 1987. Here we review the research on DNA topoisomerase IIß over the 30 years since its discovery.

Hepatitis C: Understanding Factors That Influence the Physicians' Treatment Decisions.

This study aimed to inform Hepatitis C (HCV) treatment by (1) better understanding the nexus of factors physicians consider when making HCV treatment decisions; (2) investigating the comparative influence and importance of specific factors and the trade-offs implicated in the decisionmaking process; and (3) examining how much thrombocytopenia impacts treatment decisions and how it impacts treatment. To meet this goal, we conducted five analyses, focusing on four European countries characterised by different approaches to healthcare organisation and financing, which alongside cultural differences may have potential implications for treatment pathways for patients with HCV infection. These were: France, Italy, Spain, and the United Kingdom. These analysis included: Review the academic literature and of relevant national and European guidelines;Conduct key informant interviews (KIIs) with national experts to contextualise the data from the literature review and further explore some emerging themes;Map the patient journey in the four countries to identify stages HCV patients pass through once they have entered the healthcare system and map, for each stage, potential points of departure from the typical journey;Design and conduct of Discrete Choice Experiments (DCEs) to quantitatively assess the importance of factors that influence treatment decisions;Conduct expert workshop to help build scenarios identifying challenges to HCV treatment.The five analyses build on one another, with the first three providing evidence that fed into the design of the DCEs and with the DCE results in turn serving as the key inputs into building the scenarios for the expert workshop.

The National Institute for Health Research at 10 Years: An Impact Synthesis: 100 Impact Case Studies.

The National Institute for Health Research (NIHR) funds and supports world-leading clinical and applied health and social care research, as well as research infrastructure in the NHS. Providing £1 billion of funding each year, NIHR aims to: drive the faster translation of new treatments, technologies and diagnostics to improve outcomes for health and care services; promote the wealth of the nation, including via inward investment from the health research community; pull basic science discoveries through into tangible benefits for patients and the public; and provide research evidence to support more effective and cost-effective NHS delivery. To mark its tenth anniversary, the Department of Health commissioned the Policy Research in Science and Medicine unit to consider the question: "What are the ways in which NIHR has benefited the health research landscape in the past ten years?" This study identifies and celebrates 100 examples of positive change resulting from NIHR's support of research. A synthesis of 100 case studies is provided, which highlights the benefits and wider impacts of research, capacity building, and other activities undertaken with NIHR's support since its creation in 2006. The study concludes with a reflection of how the NIHR has transformed R&D in and for the NHS and wider health service, and the people they serve. The study draws together---for the first time---examples of the breadth of NIHR's impacts in a single resource. It will be of interest to healthcare professionals involved in research, academics working in health and social care, and members of the public wishing to understand the value of research in the NHS and the wider health and care system.

Leadership as a Health Research Policy Intervention: An Evaluation of the NIHR Leadership Programme (Phase 2).

In early 2012, the National Institute for Health Research (NIHR) leadership programme was re-commissioned for a further three years following an evaluation by RAND Europe. During this new phase of the programme, we conducted a real-time evaluation, the aim of which was to allow for reflection on and adjustment of the programme on an on-going basis as events unfold. This approach also allowed for participants on the programme to contribute to and positively engage in the evaluation. The study aimed to understand the outputs and impacts from the programme, and to test the underlying assumptions behind the NIHR Leadership Programme as a science policy intervention. Evidence on outputs and impacts of the programme were collected around the motivations and expectations of participants, programme design and individual-, institutional- and system-level impacts.

Genome-wide ChIP-seq analysis of human TOP2B occupancy in MCF7 breast cancer epithelial cells.

We report the whole genome ChIP seq for human TOP2B from MCF7 cells. Using three different peak calling methods, regions of binding were identified in the presence or absence of the nuclear hormone estradiol, as TOP2B has been reported to play a role in ligand-induced transcription. TOP2B peaks were found across the whole genome, 50% of the peaks fell either within a gene or within 5 kb of a transcription start site. TOP2B peaks coincident with gene promoters were less frequently associated with epigenetic features marking active promoters in estradiol treated than in untreated cells. Significantly enriched transcription factor motifs within the DNA sequences underlying the peaks were identified. These included SP1, KLF4, TFAP2A, MYF, REST, CTCF, ESR1 and ESR2. Gene ontology analysis of genes associated with TOP2B peaks found neuronal development terms including axonogenesis and axon guidance were significantly enriched. In the absence of functional TOP2B there are errors in axon guidance in the zebrafish eye. Specific heparin sulphate structures are involved in retinal axon targeting. The glycosaminoglycan biosynthesis-heparin sulphate/heparin pathway is significantly enriched in the TOP2B gene ontology analysis, suggesting changes in this pathway in the absence of TOP2B may cause the axon guidance faults.

The impact of the National Institute for Health Research Health Technology Assessment programme, 2003-13: a multimethod evaluation.

BACKGROUND: The National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme supports research tailored to the needs of NHS decision-makers, patients and clinicians. This study reviewed the impact of the programme, from 2003 to 2013, on health, clinical practice, health policy, the economy and academia. It also considered how HTA could maintain and increase its impact. METHODS: Interviews (n = 20): senior stakeholders from academia, policy-making organisations and the HTA programme. Bibliometric analysis: citation analysis of publications arising from HTA programme-funded research. Researchfish survey: electronic survey of all HTA grant holders. Payback case studies (n = 12): in-depth case studies of HTA programme-funded research. RESULTS: We make the following observations about the impact, and routes to impact, of the HTA programme: it has had an impact on patients, primarily through changes in guidelines, but also directly (e.g. changing clinical practice); it has had an impact on UK health policy, through providing high-quality scientific evidence - its close relationships with the National Institute for Health and Care Excellence (NICE) and the National Screening Committee (NSC) contributed to the observed impact on health policy, although in some instances other organisations may better facilitate impact; HTA research is used outside the UK by other HTA organisations and systematic reviewers - the programme has an impact on HTA practice internationally as a leader in HTA research methods and the funding of HTA research; the work of the programme is of high academic quality - the Health Technology Assessment journal ensures that the vast majority of HTA programme-funded research is published in full, while the HTA programme still encourages publication in other peer-reviewed journals; academics agree that the programme has played an important role in building and retaining HTA research capacity in the UK; the HTA programme has played a role in increasing the focus on effectiveness and cost-effectiveness in medicine - it has also contributed to increasingly positive attitudes towards HTA research both within the research community and the NHS; and the HTA focuses resources on research that is of value to patients and the UK NHS, which would not otherwise be funded (e.g. where there is no commercial incentive to undertake research). The programme should consider the following to maintain and increase its impact: providing targeted support for dissemination, focusing resources when important results are unlikely to be implemented by other stakeholders, particularly when findings challenge vested interests; maintaining close relationships with NICE and the NSC, but also considering other potential users of HTA research; maintaining flexibility and good relationships with researchers, giving particular consideration to the Technology Assessment Report (TAR) programme and the potential for learning between TAR centres; maintaining the academic quality of the work and the focus on NHS need; considering funding research on the short-term costs of the implementation of new health technologies; improving the monitoring and evaluation of whether or not patient and public involvement influences research; improve the transparency of the priority-setting process; and continuing to monitor the impact and value of the programme to inform its future scientific and administrative development.

The future of anticoagulation management in atrial fibrillation in Europe: An assessment of today's challenges with recommendations for the future.

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia, affecting approximately 1-2 per cent of the population worldwide. Those who suffer from AF have a five times higher risk of stroke. AF prevalence increases with age and it affects roughly 18 per cent of the population over 85. Consequently, as populations age, AF is becoming an increasingly significant public health issue. Over recent years there have been developments in treatment and management options, both for treating the arrhythmia directly, and assessing and reducing the risk of AF-related stroke, but there is a need to ensure that available knowledge is applied optimally to benefit patients so that opportunities to prevent AF-related stroke are not missed. The aims of this project were to assess the current landscape and explore the direction of future developments in AF management in Europe, with a focus on the use of anticoagulants in the prevention of AF-related stroke. Through rapid evidence assessment, key informant interviews, PESTLE analysis and the development and exploration of future scenarios, we have developed sets of shorter- and longer-term recommendations for improving AF-related patient outcomes. The short-term recommendations are: i) improve AF awareness among the public and policymakers; ii) support education about AF management for healthcare professionals and patients; and iii) maintain engagement in AF-related research across the health services.

Health and Healthcare: Assessing the Real World Data Policy Landscape in Europe.

Real-world data (RWD) is an umbrella term for different types of data that are not collected in conventional randomised controlled trials. RWD in the healthcare sector comes from various sources and includes patient data, data from clinicians, hospital data, data from payers and social data. There are already examples of ways in which research has contributed to the provision, construction and capture of RWD to improve health outcomes. However, to maximise the potential of these new pools of data in the healthcare sector, stakeholders need to identify pathways and processes which will allow them to efficiently access and use RWD in order to achieve better research outcomes and improved healthcare delivery. Current efforts to improve access to RWD and facilitate its use take place in a context of resource scarcity. Based on a literature review, case studies, a small set of interviews of experts from public and private organisations and a scenario based workshop, the study outlined possible strategies to illustrate how RWD standards development could facilitate RWD-based research. By investigating the current forms and uses of RWD in Europe, this study has highlighted their significant potential for assessing the (short- or long-term) impact of different drugs or medical treatments and for informing and improving healthcare service delivery. Although the potential of RWD use seems quite clear, this research reveals barriers that restrict further development towards its full exploitation: the absence of common standards for defining the content and quality of RWD, methodological barriers that may limit the potential benefits of RWD analysis, governance issues underlying the absence of standards for collaboration between stakeholders, and privacy concerns and binding data protection legislation which can be seen to restrict access and use of data.

Regulatory Cultures and Research Governance.

This research is intended to help improve understanding of health research governance in the UK by exploring the regulatory practices and cultures in other countries and sectors. It is a comparative study of the practice of those who are subject to regulatory requirements in the health research, medical drugs, environmental and financial sectors. The research is informed by a review of a small subset of literature which is particularly relevant to this question, and focuses on different elements of regulation and regulatory governance for each of the different sectors.

Model for MLL translocations in therapy-related leukemia involving topoisomerase IIß-mediated DNA strand breaks and gene proximity.

Topoisomerase poisons such as the epipodophyllotoxin etoposide are widely used effective cytotoxic anticancer agents. However, they are associated with the development of therapy-related acute myeloid leukemias (t-AMLs), which display characteristic balanced chromosome translocations, most often involving the mixed lineage leukemia (MLL) locus at 11q23. MLL translocation breakpoints in t-AMLs cluster in a DNase I hypersensitive region, which possesses cryptic promoter activity, implicating transcription as well as topoisomerase II activity in the translocation mechanism. We find that 2-3% of MLL alleles undergoing transcription do so in close proximity to one of its recurrent translocation partner genes, AF9 or AF4, consistent with their sharing transcription factories. We show that most etoposide-induced chromosome breaks in the MLL locus and the overall genotoxicity of etoposide are dependent on topoisomerase IIß, but that topoisomerase IIα and -ß occupancy and etoposide-induced DNA cleavage data suggest factors other than local topoisomerase II concentration determine specific clustering of MLL translocation breakpoints in t-AML. We propose a model where DNA double-strand breaks (DSBs) introduced by topoisomerase IIß into pairs of genes undergoing transcription within a common transcription factory become stabilized by antitopoisomerase II drugs such as etoposide, providing the opportunity for illegitimate end joining and translocation.