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Plymouth, United Kingdom

Chambers N.,University of Manchester | Sheaff R.,University of Plymouth | Mahon A.,University of Manchester | Byng R.,Research Way | And 4 more authors.
BMC Health Services Research | Year: 2013

Background: The direction of health service policy in England is for more diversification in the design, commissioning and provision of health care services. The case study which is the subject of this paper was selected specifically because of the partnering with a private sector organisation to manage whole system redesign of primary care and to support the commissioning of services for people with long term conditions at risk of unplanned hospital admissions and associated service provision activities. The case study forms part of a larger Department of Health funded project on the practice of commissioning which aims to find the best means of achieving a balance between monitoring and control on the one hand, and flexibility and innovation on the other, and to find out what modes of commissioning are most effective in different circumstances and for different services. Methods. A single case study method was adopted to explore multiple perspectives of the complexities and uniqueness of a public-private partnership referred to as the "Livewell project". 10 single depth interviews were carried out with key informants across the GP practices, the PCT and the private provider involved in the initiative. Results: The main themes arising from single depth interviews with the case study participants include a particular understanding about the concept of commissioning in the context of primary care, ambitions for primary care redesign, the importance of key roles and strong relationships, issues around the adoption and spread of innovation, and the impact of the current changes to commissioning arrangements. The findings identified a close and high trust relationship between GPs (the commissioners) and the private commissioning support and provider firm. The antecedents to the contract for the project being signed indicated the importance of leveraging external contacts and influence (resource dependency theory). Conclusions: The study has surfaced issues around innovation adoption in the healthcare context. The case identifies 'negotiated order', managerial performance of providers and disciplinary control as three media of power used in combination by commissioners. The case lends support for stewardship and resource dependency governance theories as explanations of the underpinning conditions for effective commissioning in certain circumstances within a quasi marketised healthcare system. © 2013 Chambers et al; licensee BioMed Central Ltd.

Ammoun S.,University of Plymouth | Cunliffe C.H.,New York University | Allen J.C.,New York University | Chiriboga L.,New York University | And 5 more authors.
Neuro-Oncology | Year: 2010

Vestibular schwannomas (VS) arising sporadically or in patients with neurofibromatosis type 2 (NF2) consistently lack expression of Merlin, a tumor suppressor. Conventional treatment options include surgery and radiotherapy but there is no validated medical option. Recent evidence suggests that Merlin deficiency may result in abnormal activation of receptor tyrosine kinases (RTKs) and downstream signaling, promoting tumor growth. Although small-molecule RTK inhibitors are widely available for clinical use, no such therapy has been validated in patients with VS. To screen for RTK activation, surgical VS specimens from patients with and without NF2 were analyzed by phospho-RTK profiling arrays. Downstream signaling pathway activation was analyzed by phospho-MAPK arrays. Activated RTKs and downstream kinases were validated immunohistochemically in corresponding formalin-fixed, paraffin-embedded tissues. Phospho-RTK arrays and immunohistochemistry showed consistent overexpression and activation of EGFR family receptors and evidence of ERK1/2 downstream signaling was observed in all samples analyzed (n = 11). Based on the findings, the small-molecule EGFR/ErbB2 kinase inhibitor lapatinib was selected for evaluation of target inhibition and treatment efficacy in our in vitro human schwannoma model. EGFR/ErbB2 targeted therapy with lapatinib inhibited ErbB2 phosphorylation and survivin upregulation, as well as downstream ERK1/2 and AKT activation, resulting in decreased proliferation. We conclude that EGFR family receptor activation is a consistent feature of both sporadic and NF2-related VS. Molecular targeted therapy with lapatinib downregulates survivin and has antiproliferative activity in a preclinical VS model. Based on these findings, a clinical trial with lapatinib for the treatment of VS is currently underway. © The Author(s) 2010.

Sneyd J.R.,University of Plymouth | Sneyd J.R.,Research Way | Holmes K.A.,Plymouth Hospitals NHS Trust
Current Opinion in Anaesthesiology | Year: 2011

Purpose of Review: The comparison of inhalational and intravenous anaesthesia has been the subject of many controlled trials and meta-analyses. These reported diverse endpoints typically including measures of the speed and quality of induction of anaesthesia, haemodynamic changes, operating conditions, various measures of awakening, postoperative nausea and vomiting and discharge from the recovery area and from hospital as well as recovery of psychomotor function. In a more patient-focused Health Service, measures with greater credibility are overall patient satisfaction, time to return to work and long-term morbidity and mortality. In practice, studies using easier to measure proxy endpoints dominate - even though the limitations of such research are well known. Recent Findings: Recent study endpoints are more ambitious and include impact on survival from cancer and the possibility of differential neurotoxic impact on the developing brain and implications for neuro-behavioural performance. Summary: Economic analysis of anaesthesia is complex and most published studies are naive, focusing on drug acquisition costs and facility timings, real health economics are much more difficult. Preferred outcome measures would be whole institution costs or the ability to reliably add an extra case to an operating list, close an operating room and reduce the number of operating sessions offered or permanently decrease staffing. Alongside this, however, potential long-term patient outcomes should be considered. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Reilly J.M.,University College London | Reilly J.M.,Astrazeneca | Dharmalingam B.,University College London | Dharmalingam B.,University of Liverpool | And 6 more authors.
Experimental Neurology | Year: 2016

Complex regional pain syndrome (CRPS) is thought to have an auto-immune component. One such target recently proposed from the effects of auto-immune IgGs on Ca2+ transients in cardiac myocytes and cell lines is the α1-adrenoceptor. We have tested whether such IgGs exerted comparable effects on nociceptive sensory neurons isolated from rat dorsal root ganglia. Depolarisation-induced [Ca2+]i transients were generated by applying 30 mM KCl for 2min and monitored by Fura-2 fluorescence imaging. No IgGs tested (including 3 from CRPS patients) had any significant effect on these [Ca2+]i transients. However, IgG from one CRPS patient consistently and significantly reduced the K+-induced response of cells that had been pre-incubated for 24 h with a mixture of inflammatory mediators (1 μM histamine, 5-hydroxytryptamine, bradykinin and PGE2). Since this pre-incubation also appeared to induce a comparable inhibitory response to the α1-agonist phenylephrine, this is compatible with the α1-adrenoceptor as a target for CRPS auto-immunity. A mechanism whereby this might enhance pain is suggested. © 2015.

Dogra Y.,University of Exeter | Ferguson D.C.J.,University of Exeter | Dodd N.J.F.,University of Plymouth | Smerdon G.R.,Research Way | And 2 more authors.
Redox Biology | Year: 2016

Methyl-aminolevulinate-based photodynamic therapy (MAL-PDT) is utilised clinically for the treatment of non-melanoma skin cancers and pre-cancers and the hydroxypyridinone iron chelator, CP94, has successfully been demonstrated to increase MAL-PDT efficacy in an initial clinical pilot study. However, the biochemical and photochemical processes leading to CP94-enhanced photodynamic cell death, beyond the well-documented increases in accumulation of the photosensitiser protoporphyrin IX (PpIX), have not yet been fully elucidated. This investigation demonstrated that MAL-based photodynamic cell killing of cultured human squamous carcinoma cells (A431) occurred in a predominantly necrotic manner following the generation of singlet oxygen and ROS. Augmenting MAL-based photodynamic cell killing with CP94 co-treatment resulted in increased PpIX accumulation, MitoSOX-detectable ROS generation (probably of mitochondrial origin) and necrotic cell death, but did not affect singlet oxygen generation. We also report (to our knowledge, for the first time) the detection of intracellular PpIX-generated singlet oxygen in whole cells via electron paramagnetic resonance spectroscopy in conjunction with a spin trap. © 2016 The Authors.

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