http://bura.brunel.ac.uk/handle/2438/145 2013-05-22T12:22:02Z 2013-05-22T12:22:02Z Takian, A Petrakaki, D Cornford, T Sheikh, A Barber, N http://bura.brunel.ac.uk/handle/2438/7365 2013-04-22T13:30:50Z 2012-01-01T00:00:00Z

Title: Methodological reflections on the evaluation of the implementation and adoption of national electronic health record systems Authors: Takian, A; Petrakaki, D; Cornford, T; Sheikh, A; Barber, N Abstract: Introduction/purpose of presentation: Far-reaching policy commitments to information technology-centered transformations of healthcare systems have now been made in many countries. There is as yet little empirical evidence to justify such decisions, hence the need for rigorous independent evaluation of current implementation efforts. Such evaluations however pose a number of important challenges. This presentation has been designed as a part of a Panel based on our experience of evaluating the National Health Service’s (NHS) implementation of electronic health records (EHR) systems in hospitals throughout England. We discuss the methodological challenges encountered in planning and undertaking an evaluation of a program of this scale and reflect on why and how we adapted our evaluation approach—both conceptually and methodologically—in response to these challenges. Study design/population studied: Critical reflections on a multi-disciplinary and multi-facet independent evaluation of a national program to implement electronic health record systems into 12 ‘early wave’ NHS hospitals in England. Findings: Our initial plan was to employ a mixed methods longitudinal ‘before-during-after’ study design. We however found this unsustainable in the light of fluxes in policy, contractual issues and over-optimistic schedules for EHR deployments. More importantly, this research design failed adequately to address the core of multi-faceted evolving EHRs as understood by key stakeholders and as worked out in their distinct work settings. Thus conventional outcomes-centric evaluations may not easily scale-up when evaluating transformational programs and may indeed prove misleading. New assumptions concerning the implementation process of EHR need to be developed that recognize the constantly changing milieu of policy, product, projects and professions that are inherent to such national implementations. The approaches we subsequently developed substitute the positivist view that EHR initiatives are self-evident and self-contained interventions, which are amenable to traditional quantitative evaluations, to one that focuses on how they are understood by various stakeholders and made to work in specific contexts. These assumptions recast the role of evaluation towards an approach that explores and interprets processes of socio-technical change that surround EHR implementation and adoption as seen by multiple stakeholders. Conclusions and policy implications: There is likely to be an increase in politically-driven national programs of reform of healthcare based on information and communication technologies. Programs on such a scale are inherently complex with extended temporalities and extensive and dynamic sets of stakeholders. They are, in short, different and pose new evaluation challenges that previously formulated evaluation methods for health information systems cannot easily address. This calls for methodological innovation amongst research teams and their supporting bodies. We argue that evaluation of such system-wide transformation programs are likely to demand both breadth and depth of experience within a multidisciplinary research team, constant questioning of what is and what can be evaluated and how, and a particular way of working that emphasizes continuous dialogue and reflexivity. Making this transition is essential to enable evaluations that can usefully inform policy-making. Health policy experts urgently need to reassess the evaluation strategies they employ as they come to address national policies for system-wide transformation based on new electronic health infrastructures. Description: Copyright @ 2012, International Journal of Integrated Care (IJIC). This work is licensed under a (http://creativecommons.org/licenses/by/3.0) Creative Commons Attribution 3.0 Unported License.

2012-01-01T00:00:00Z Sandi, C Al-Mahdawi, S Pook, MA http://bura.brunel.ac.uk/handle/2438/7332 2013-04-03T12:39:50Z 2013-01-01T00:00:00Z

Title: Epigenetics in Friedreich's ataxia: Challenges and opportunities for therapy Authors: Sandi, C; Al-Mahdawi, S; Pook, MA Abstract: Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by homozygous expansion of a GAA·TTC trinucleotide repeat within the first intron of the FXN gene, leading to reduced FXN transcription and decreased levels of frataxin protein. Recent advances in FRDA research have revealed the presence of several epigenetic modifications that are either directly or indirectly involved in this FXN gene silencing. Although epigenetic marks may be inherited from one generation to the next, modifications of DNA and histones can be reversed, indicating that they are suitable targets for epigenetic-based therapy. Unlike other trinucleotide repeat disorders, such as Huntington disease, the large expansions of GAA·TTC repeats in FRDA do not produce a change in the frataxin amino acid sequence, but they produce reduced levels of normal frataxin. Therefore, transcriptional reactivation of the FXN gene provides a good therapeutic option. The present paper will initially focus on the epigenetic changes seen in FRDA patients and their role in the silencing of FXN gene and will be concluded by considering the potential epigenetic therapies. Description: Copyright © 2013 Chiranjeevi Sandi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

2013-01-01T00:00:00Z Ulus-Senguloglu, G Arlett, CF Plowman, PN Parnell, J Patel, N Bourton, EC Parris, CN http://bura.brunel.ac.uk/handle/2438/7233 2013-02-27T11:07:06Z 2012-01-01T00:00:00Z

Title: Elevated expression of artemis in human fibroblast cells is associated with cellular radiosensitivity and increased apoptosis Authors: Ulus-Senguloglu, G; Arlett, CF; Plowman, PN; Parnell, J; Patel, N; Bourton, EC; Parris, CN Abstract: Background: The objective of this study was to determine the molecular mechanism(s) responsible for cellular radiosensitivity in two human fibroblast cell lines 84BR and 175BR derived from two cancer patients. Methods: Clonogenic assays were performed following exposure to increasing doses of gamma radiation to confirm radiosensitivity. γ-H2AX foci assays were used to determine the efficiency of DNA double strand break (DSB) repair in cells. Quantitative-PCR (Q-PCR) established the expression levels of key DNA DSB repair proteins. Imaging flow cytometry using Annexin V-FITC was used to compare artemis expression and apoptosis in cells. Results: Clonogenic cellular hypersensitivity in the 84BR and 175BR cell lines was associated with a defect in DNA DSB repair measured by the γ-H2AX foci assay. Q-PCR analysis and imaging flow cytometry revealed a two-fold overexpression of the artemis DNA repair gene which was associated with an increased level of apoptosis in the cells before and after radiation exposure. Over-expression of normal artemis protein in a normal immortalised fibroblast cell line NB1-Tert resulted in increased radiosensitivity and apoptosis. Conclusion: We conclude elevated expression of artemis is associated with higher levels of DNA DSB, radiosensitivity and elevated apoptosis in two radio-hypersensitive cell lines. These data reveal a potentially novel mechanism responsible for radiosensitivity and show that increased artemis expression in cells can result in either radiation resistance or enhanced sensitivity. Description: Copyright @ 2012 Nature Publishing Group

2012-01-01T00:00:00Z Bourton, EC Plowman, PN Zahir, SA Senguloglu, GU Serrai, H Bottley, G Parris, CN http://bura.brunel.ac.uk/handle/2438/7229 2013-02-27T11:07:23Z 2012-01-01T00:00:00Z

Title: Multispectral imaging flow cytometry reveals distinct frequencies of γ-H2AX foci induction in DNA double strand break repair defective human cell lines Authors: Bourton, EC; Plowman, PN; Zahir, SA; Senguloglu, GU; Serrai, H; Bottley, G; Parris, CN Abstract: The measurement of γ-H2AX foci induction in cells provides a sensitive and reliable method for the quantitation of DNA damage responses in a variety of cell types. Accurate and rapid methods to conduct such observations are desirable. In this study we have employed the novel technique of multispectral imaging flow cytometry to compare the induction and repair of γ-H2AX foci in three human cell types with different capacities for the repair of DNA double strand breaks (DSB). A repair normal fibroblast cell line MRC5-SV1, a DSB repair defective ataxia telangiectasia (AT5BIVA) cell line, and a DNA-PKcs deficient cell line XP14BRneo17 were exposed to 2 Gy gamma radiation from a 60Cobalt source. Thirty minutes following exposure we observed a dramatic induction of foci in the nuclei of these cells. After 24 hrs there was a predictable reduction on the number of foci in the MRC5-SV1 cells, consistent with the repair of DNA DSB. In the AT5BIVA cells, persistence of the foci over a 24 hour period was due to the failure in the repair of DNA DSB. However, in the DNA-PKcs defective cells (XP14BRneo17) we observed an intermediate retention of foci in the nuclei indicative of partial repair of DNA DSB. In summary, the application of imaging flow cytometry has permitted an evaluation of foci in a large number of cells (20,000) for each cell line at each time point. This provides a novel method to determine differences in repair kinetics between different cell types. We propose that imaging flow cytometry provides an alternative platform for accurate automated high through-put analysis of foci induction in a variety of cell types. Description: Copyright @ 2012 International Society for Advancement of Cytometry. The article can be accessed from the links below.

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