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  1. AU="Michael Holland"
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  4. AU=Congreve Miles
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  11. AU="Dufour, A"
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  13. AU="Rieber, Julia"
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  15. AU="Romeu Fontanillas, Teresa"
  16. AU="Fleming, Renée"
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  18. AU="Sally J L Moore"
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  1. Artikel ; Online: The lived experience of a novel disruptive therapy in a group of men and boys with haemophilia A with inhibitors

    Simon Fletcher / Kathryn Jenner / Michael Holland / Kate Khair

    Health Expectations, Vol 25, Iss 1, Pp 443-

    Emi & Me

    2022  Band 454

    Abstract: Abstract Background People with haemophilia A and inhibitors (PwHi) suffer more orthopaedic complications, bleeding and pain than those without inhibitors. The advent of emicizumab as a prophylactic treatment has led to a reduction in bleed frequency and ...

    Abstract Abstract Background People with haemophilia A and inhibitors (PwHi) suffer more orthopaedic complications, bleeding and pain than those without inhibitors. The advent of emicizumab as a prophylactic treatment has led to a reduction in bleed frequency and a significant improvement in overall quality of life. No research to date has examined the nature of this improvement on treated individuals and their families. Aims The Emi & Me study aims to capture the real‐life experience of using emicizumab for PwHi and their families. Methods Participants were recruited through treatment centres, social media and by word of mouth. Each participant and a family member, if available, took part in a semistructured qualitative interview. All interviews were recorded, transcribed verbatim and analysed thematically. All elements of the study were reviewed by local statutory authorities and informed consent was sought from all participants. Results Fifteen PwHi, mean age 27.2 years (range 8–63 years), most with a family member, participated in a single qualitative interview online (n = 13), by telephone (n = 1) or in person (n = 1). Mean time on emicizumab was 2.26 years (range 1–5 years). Six major themes emerged: bleeds; pain; treatment burden; control; freedom (for both PwHi and family members) and missed potential. Emicizumab prophylaxis has delivered significant improvements in the lives of the participants. Despite these improvements, some participants felt that their pre‐existing physical disabilities and the lack of physiotherapy provision had prevented them achieving similar improvements in their functional ability. Conclusion This study shows that in reducing bleeds, pain and treatment burden, emicizumab had given PwHi greater control over their condition, allowing a sense of freedom they had not experienced with factor VIII or bypassing agent prophylaxis. However, for emicizumab to be truly effective, there is a need to ensure the continued availability and accessibility of robust multidisciplinary support services. Without this, it is unlikely that PwHi will realize the life‐changing potential offered either by emicizumab or any other novel treatment approach. Patient or Public Contribution A patient participant (who did not wish to be included as an author of the paper) was involved in the design of the study protocol and interview guide.
    Schlagwörter burden of treatment ; decision‐making ; disruptive therapies ; emicizumab ; haemophilia ; inhibitors ; Medicine (General) ; R5-920 ; Public aspects of medicine ; RA1-1270
    Thema/Rubrik (Code) 360
    Sprache Englisch
    Erscheinungsdatum 2022-02-01T00:00:00Z
    Verlag Wiley
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  2. Artikel ; Online: The experiences of people with haemophilia and their families of gene therapy in a clinical trial setting

    Simon Fletcher / Kathryn Jenner / Luke Pembroke / Michael Holland / Kate Khair

    Orphanet Journal of Rare Diseases, Vol 17, Iss 1, Pp 1-

    regaining control, the Exigency study

    2022  Band 9

    Abstract: Abstract Background Gene therapy has the potential to change the life experience of people with haemophilia and family members. Few studies have sought to explore the impact of gene therapy on both individuals and families. The aim of this study was to ... ...

    Abstract Abstract Background Gene therapy has the potential to change the life experience of people with haemophilia and family members. Few studies have sought to explore the impact of gene therapy on both individuals and families. The aim of this study was to capture real-life experiences of gene therapy in People with haemophilia and their families. Results Sixteen participants with severe haemophilia (11 haemophilia A, five haemophilia B), mean age 41.4 years (range 23–75 years), took part in a single qualitative interview; ten were accompanied by a family member. Mean time since transfection was 3.56 years (range 1–10 years). Participants saw their involvement in gene therapy as a positive experience, freeing them from the personal burden of haemophilia and furthering treatment options for the wider haemophilia community. However, participants reported being unprepared for the side effects of immunosuppression. Some also reported feeling unsupported and having little control over what was happening as their factor levels became the focus of the process. Conclusion The results suggest that strategies need to be put into place to enable PwH fully to understand the process of gene therapy, and thereby make an informed choice as to whether it is a treatment they might wish for themselves. These include early and ongoing education, increased provision of psychosocial support and ongoing qualitative research.
    Schlagwörter Haemophilia A ; Haemophilia B ; Genetic therapy ; Decision making ; Informed consent ; Clinical trial ; Medicine ; R
    Thema/Rubrik (Code) 150
    Sprache Englisch
    Erscheinungsdatum 2022-04-01T00:00:00Z
    Verlag BMC
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  3. Artikel ; Online: Characterizing Epitope Binding Regions of Entire Antibody Panels by Combining Experimental and Computational Analysis of Antibody

    Benjamin D. Brooks / Adam Closmore / Juechen Yang / Michael Holland / Tina Cairns / Gary H. Cohen / Chris Bailey-Kellogg

    Molecules, Vol 25, Iss 3659, p

    Antigen Binding Competition

    2020  Band 3659

    Abstract: Vaccines and immunotherapies depend on the ability of antibodies to sensitively and specifically recognize particular antigens and specific epitopes on those antigens. As such, detailed characterization of antibody–antigen binding provides important ... ...

    Abstract Vaccines and immunotherapies depend on the ability of antibodies to sensitively and specifically recognize particular antigens and specific epitopes on those antigens. As such, detailed characterization of antibody–antigen binding provides important information to guide development. Due to the time and expense required, high-resolution structural characterization techniques are typically used sparingly and late in a development process. Here, we show that antibody–antigen binding can be characterized early in a process for whole panels of antibodies by combining experimental and computational analyses of competition between monoclonal antibodies for binding to an antigen. Experimental “epitope binning” of monoclonal antibodies uses high-throughput surface plasmon resonance to reveal which antibodies compete, while a new complementary computational analysis that we call “dock binning” evaluates antibody–antigen docking models to identify why and where they might compete, in terms of possible binding sites on the antigen. Experimental and computational characterization of the identified antigenic hotspots then enables the refinement of the competitors and their associated epitope binding regions on the antigen. While not performed at atomic resolution, this approach allows for the group-level identification of functionally related monoclonal antibodies (i.e., communities) and identification of their general binding regions on the antigen. By leveraging extensive epitope characterization data that can be readily generated both experimentally and computationally, researchers can gain broad insights into the basis for antibody–antigen recognition in wide-ranging vaccine and immunotherapy discovery and development programs.
    Schlagwörter epitope binning ; epitope mapping ; epitope prediction ; antibody:antigen interactions ; protein docking ; glycoprotein D (gD) ; Organic chemistry ; QD241-441
    Thema/Rubrik (Code) 570
    Sprache Englisch
    Erscheinungsdatum 2020-08-01T00:00:00Z
    Verlag MDPI AG
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  4. Artikel ; Online: Explaining variable effects of an adaptable implementation package to promote evidence-based practice in primary care

    Liz Glidewell / Cheryl Hunter / Vicky Ward / Rosemary R. C. McEachan / Rebecca Lawton / Thomas A. Willis / Suzanne Hartley / Michelle Collinson / Michael Holland / Amanda J. Farrin / Robbie Foy / on behalf of the ASPIRE programme team

    Implementation Science, Vol 17, Iss 1, Pp 1-

    a longitudinal process evaluation

    2022  Band 24

    Abstract: Abstract Background Implementing evidence-based recommendations is challenging in UK primary care, especially given system pressures and multiple guideline recommendations competing for attention. Implementation packages that can be adapted and hence ... ...

    Abstract Abstract Background Implementing evidence-based recommendations is challenging in UK primary care, especially given system pressures and multiple guideline recommendations competing for attention. Implementation packages that can be adapted and hence applied to target multiple guideline recommendations could offer efficiencies for recommendations with common barriers to achievement. We developed and evaluated a package of evidence-based interventions (audit and feedback, educational outreach and reminders) incorporating behaviour change techniques to target common barriers, in two pragmatic trials for four “high impact” indicators: risky prescribing; diabetes control; blood pressure control; and anticoagulation in atrial fibrillation. We observed a significant, cost-effective reduction in risky prescribing but there was insufficient evidence of effect on the other outcomes. We explored the impact of the implementation package on both social processes (Normalisation Process Theory; NPT) and hypothesised determinants of behaviour (Theoretical Domains Framework; TDF). Methods We conducted a prospective multi-method process evaluation. Observational, administrative and interview data collection and analyses in eight primary care practices were guided by NPT and TDF. Survey data from trial and process evaluation practices explored fidelity. Results We observed three main patterns of variation in how practices responded to the implementation package. First, in integration and achievement, the package “worked” when it was considered distinctive and feasible. Timely feedback directed at specific behaviours enabled continuous goal setting, action and review, which reinforced motivation and collective action. Second, impacts on team-based determinants were limited, particularly when the complexity of clinical actions impeded progress. Third, there were delivery delays and unintended consequences. Delays in scheduling outreach further reduced ownership and time for improvement. Repeated stagnant or declining feedback that ...
    Schlagwörter Tailored intervention ; Adaptable implementation package ; Theoretical Domains Framework ; Normalization Process Theory ; Process evaluation ; Audit and feedback ; Medicine (General) ; R5-920
    Thema/Rubrik (Code) 360
    Sprache Englisch
    Erscheinungsdatum 2022-01-01T00:00:00Z
    Verlag BMC
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  5. Artikel ; Online: Streamlined extract preparation for Escherichia coli-based cell-free protein synthesis by sonication or bead vortex mixing

    Prashanta Shrestha / Troy Michael Holland / Bradley Charles Bundy

    BioTechniques, Vol 53, Iss 3, Pp 163-

    2012  Band 174

    Abstract: Escherichia coli-based cell extract is a vital component of inexpensive and high-yielding cell-free protein synthesis reactions. However, effective preparation of E. coli cell extract is limited to high-pressure (French press-style or impinge-style) or ... ...

    Abstract Escherichia coli-based cell extract is a vital component of inexpensive and high-yielding cell-free protein synthesis reactions. However, effective preparation of E. coli cell extract is limited to high-pressure (French press-style or impinge-style) or bead mill homogenizers, which all require a significant capital investment. Here we report the viability of E. coli cell extract prepared using equipment that is both common to biotechnology laboratories and able to process small volume samples. Specifically, we assessed the low-capital-cost lysis techniques of: (i) sonication, (ii) bead vortex mixing, (iii) freeze-thaw cycling, and (iv) lysozyme incubation to prepare E. coli cell extract for cell-free protein synthesis (CFPS). We also used simple shake flask fermentations with a commercially available E. coli strain. In addition, RNA polymerase was overexpressed in the E. coli cells prior to lysis, thus eliminating the need to add independently purified RNA polymerase to the CFPS reaction. As a result, high-yielding E. coli-based extract was prepared using equipment requiring a reduced capital investment and common to biotechnology laboratories. To our knowledge, this is the first successful prokaryote-based CFPS reaction to be carried out with extract prepared by sonication or bead vortex mixing.
    Schlagwörter sonication ; vortex mixing ; bead mill ; Escherichia coli ; extracts preparation ; cell-free ; Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 540
    Sprache Englisch
    Erscheinungsdatum 2012-09-01T00:00:00Z
    Verlag Future Science Ltd
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  6. Artikel ; Online: An adaptable implementation package targeting evidence-based indicators in primary care

    Thomas A Willis / Michelle Collinson / Liz Glidewell / Amanda J Farrin / Michael Holland / David Meads / Claire Hulme / Duncan Petty / Sarah Alderson / Suzanne Hartley / Armando Vargas-Palacios / Paul Carder / Stella Johnson / Robbie Foy / ASPIRE programme team

    PLoS Medicine, Vol 17, Iss 2, p e

    A pragmatic cluster-randomised evaluation.

    2020  Band 1003045

    Abstract: BACKGROUND:In primary care, multiple priorities and system pressures make closing the gap between evidence and practice challenging. Most implementation studies focus on single conditions, limiting generalisability. We compared an adaptable ... ...

    Abstract BACKGROUND:In primary care, multiple priorities and system pressures make closing the gap between evidence and practice challenging. Most implementation studies focus on single conditions, limiting generalisability. We compared an adaptable implementation package against an implementation control and assessed effects on adherence to four different evidence-based quality indicators. METHODS AND FINDINGS:We undertook two parallel, pragmatic cluster-randomised trials using balanced incomplete block designs in general practices in West Yorkshire, England. We used 'opt-out' recruitment, and we randomly assigned practices that did not opt out to an implementation package targeting either diabetes control or risky prescribing (Trial 1); or blood pressure (BP) control or anticoagulation in atrial fibrillation (AF) (Trial 2). Within trials, each arm acted as the implementation control comparison for the other targeted indicator. For example, practices assigned to the diabetes control package acted as the comparison for practices assigned to the risky prescribing package. The implementation package embedded behaviour change techniques within audit and feedback, educational outreach, and computerised support, with content tailored to each indicator. Respective patient-level primary endpoints at 11 months comprised the following: achievement of all recommended levels of haemoglobin A1c (HbA1c), BP, and cholesterol; risky prescribing levels; achievement of recommended BP; and anticoagulation prescribing. Between February and March 2015, we recruited 144 general practices collectively serving over 1 million patients. We stratified computer-generated randomisation by area, list size, and pre-intervention outcome achievement. In April 2015, we randomised 80 practices to Trial 1 (40 per arm) and 64 to Trial 2 (32 per arm). Practices and trial personnel were not blind to allocation. Two practices were lost to follow-up but provided some outcome data. We analysed the intention-to-treat (ITT) population, adjusted for potential confounders at patient level (sex, age) and practice level (list size, locality, pre-intervention achievement against primary outcomes, total quality scores, and levels of patient co-morbidity), and analysed cost-effectiveness. The implementation package reduced risky prescribing (odds ratio [OR] 0.82; 97.5% confidence interval [CI] 0.67-0.99, p = 0.017) with an incremental cost-effectiveness ratio of £1,359 per quality-adjusted life year (QALY), but there was insufficient evidence of effect on other primary endpoints (diabetes control OR 1.03, 97.5% CI 0.89-1.18, p = 0.693; BP control OR 1.05, 97.5% CI 0.96-1.16, p = 0.215; anticoagulation prescribing OR 0.90, 97.5% CI 0.75-1.09, p = 0.214). No statistically significant effects were observed in any secondary outcome except for reduced co-prescription of aspirin and clopidogrel without gastro-protection in patients aged 65 and over (adjusted OR 0.62; 97.5% CI 0.39-0.99; p = 0.021). Main study limitations concern our inability to make any inferences about the relative effects of individual intervention components, given the multifaceted nature of the implementation package, and that the composite endpoint for diabetes control may have been too challenging to achieve. CONCLUSIONS:In this study, we observed that a multifaceted implementation package was clinically and cost-effective for targeting prescribing behaviours within the control of clinicians but not for more complex behaviours that also required patient engagement. TRIAL REGISTRATION:The study is registered with the ISRCTN registry (ISRCTN91989345).
    Schlagwörter Medicine ; R
    Thema/Rubrik (Code) 360
    Sprache Englisch
    Erscheinungsdatum 2020-02-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  7. Artikel ; Online: Developing and evaluating packages to support implementation of quality indicators in general practice

    Robbie Foy / Thomas Willis / Liz Glidewell / Rosie McEachan / Rebecca Lawton / David Meads / Michelle Collinson / Cheryl Hunter / Claire Hulme / Robert West / Vicky Ward / Suzanne Hartley / Paul Carder / Sarah Alderson / Michael Holland / Peter Heudtlass / Daniele Bregantini / Laetitia Schmitt / Susan Clamp /
    Tim Stokes / Emma Ingleson / Martin Rathfelder / Stella Johnson / Judith Richardson / Bruno Rushforth / Duncan Petty / Armando Vargas-Palacios / Gemma Louch / Jane Heyhoe / Ian Watt / Amanda Farrin

    Programme Grants for Applied Research, Vol 8, Iss

    the ASPIRE research programme, including two cluster RCTs

    2020  Band 4

    Abstract: Background: Dissemination of clinical guidelines is necessary but seldom sufficient by itself to ensure the reliable uptake of evidence-based practice. There are further challenges in implementing multiple clinical guidelines and clinical practice ... ...

    Abstract Background: Dissemination of clinical guidelines is necessary but seldom sufficient by itself to ensure the reliable uptake of evidence-based practice. There are further challenges in implementing multiple clinical guidelines and clinical practice recommendations in the pressurised environment of general practice. Objectives: We aimed to develop and evaluate an implementation package that could be adapted to support the uptake of a range of clinical guideline recommendations and be sustainably integrated within general practice systems and resources. Over five linked work packages, we developed ‘high-impact’ quality indicators to show where a measurable change in clinical practice can improve patient outcomes (work package 1), analysed adherence to selected indicators (work package 2), developed an adaptable implementation package (work package 3), evaluated the effects and cost-effectiveness of adapted implementation packages targeting four indicators (work package 4) and examined intervention fidelity and mechanisms of action (work package 5). Setting and participants: Health-care professionals and patients from general practices in West Yorkshire, UK. Design: We reviewed recommendations from existing National Institute for Health and Care Excellence clinical guidance and used a multistage consensus process, including 11 professionals and patients, to derive a set of ‘high-impact’ evidence-based indicators that could be measured using routinely collected data (work package 1). In 89 general practices that shared data, we found marked variations and scope for improvement in adherence to several indicators (work package 2). Interviews with 60 general practitioners, practice nurses and practice managers explored perceived determinants of adherence to selected indicators and suggested the feasibility of adapting an implementation package to target different indicators (work package 3). We worked with professional and patient panels to develop four adapted implementation packages. These targeted risky prescribing ...
    Schlagwörter primary care ; implementation ; diabetes ; hypertension ; prescribing ; atrial fibrillation ; audit and feedback ; educational outreach ; computerised prompts ; theoretical domains framework ; behaviour change techniques ; cluster-randomised trial ; clinical guidelines ; Public aspects of medicine ; RA1-1270
    Thema/Rubrik (Code) 360
    Sprache Englisch
    Erscheinungsdatum 2020-03-01T00:00:00Z
    Verlag NIHR Journals Library
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  8. Artikel ; Online: Vibrio vulnificus MO6-24/O Lipopolysaccharide Stimulates Superoxide Anion, Thromboxane B2, Matrix Metalloproteinase-9, Cytokine and Chemokine Release by Rat Brain Microglia in Vitro

    Alejandro M. S. Mayer / Mary L. Hall / Michael Holland / Cristina De Castro / Antonio Molinaro / Monica Aldulescu / Jeffrey Frenkel / Lauren Ottenhoff / David Rowley / Jan Powell

    Marine Drugs, Vol 12, Iss 4, Pp 1732-

    2014  Band 1756

    Abstract: Although human exposure to Gram-negative Vibrio vulnificus (V. vulnificus) lipopolysaccharide (LPS) has been reported to result in septic shock, its impact on the central nervous system’s innate immunity remains undetermined. The purpose of this study ... ...

    Abstract Although human exposure to Gram-negative Vibrio vulnificus (V. vulnificus) lipopolysaccharide (LPS) has been reported to result in septic shock, its impact on the central nervous system’s innate immunity remains undetermined. The purpose of this study was to determine whether V. vulnificus MO6-24/O LPS might activate rat microglia in vitro and stimulate the release of superoxide anion (O2−), a reactive oxygen species known to cause oxidative stress and neuronal injury in vivo. Brain microglia were isolated from neonatal rats, and then treated with either V. vulnificus MO6-24/O LPS or Escherichia coli O26:B6 LPS for 17 hours in vitro. O2− was determined by cytochrome C reduction, and matrix metalloproteinase-2 (MMP-2) and MMP-9 by gelatinase zymography. Generation of cytokines tumor necrosis factor alpha (TNF-α), interleukin-1 alpha (IL-1α), IL-6, and transforming growth factor-beta 1 (TGF-β1), chemokines macrophage inflammatory protein (MIP-1α)/chemokine (C-C motif) ligand 3 (CCL3), MIP-2/chemokine (C-X-C motif) ligand 2 (CXCL2), monocyte chemotactic protein-1 (MCP-1)/CCL2, and cytokine-induced neutrophil chemoattractant-2alpha/beta (CINC-2α/β)/CXCL3, and brain-derived neurotrophic factor (BDNF), were determined by specific immunoassays. Priming of rat microglia by V. vulnificus MO6-24/O LPS in vitro yielded a bell-shaped dose-response curve for PMA (phorbol 12-myristate 13-acetate)-stimulated O2− generation: (1) 0.1–1 ng/mL V. vulnificus LPS enhanced O2− generation significantly but with limited inflammatory mediator generation; (2) 10–100 ng/mL V. vulnificus LPS maximized O2− generation with concomitant release of thromboxane B2 (TXB2), matrix metalloproteinase-9 (MMP-9), and several cytokines and chemokines; (3) 1000–100,000 ng/mL V. vulnificus LPS, with the exception of TXB2, yielded both attenuated O2− production, and a progressive decrease in MMP-9, cytokines and chemokines investigated. Thus concentration-dependent treatment of neonatal brain microglia with V. vulnificus MO6-24/O LPS resulted in a ...
    Schlagwörter LPS ; Escherichia coli ; Vibrio vulnificus ; rat microglia ; cytokine ; chemokine ; superoxide ; thromboxane ; metalloproteinase ; neuroinflammation ; MMP-9 ; Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 630
    Sprache Englisch
    Erscheinungsdatum 2014-03-01T00:00:00Z
    Verlag MDPI AG
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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