The complexity of leadership in coproduction practices: a guiding framework based on a systematic literature review.

BACKGROUND: As coproduction in public services increases, understanding the role of leadership in this context is essential to the tasks of establishing relational partnerships and addressing power differentials among groups. The aims of this review are to explore models of coproduction leadership and the processes involved in leading coproduction as well as, based on that exploration, to develop a guiding framework for coproduction practices. METHODS: A systematic review that synthesizes the evidence reported by 73 papers related to coproduction of health and welfare. RESULTS: Despite the fact that models of coleadership and collective leadership exhibit a better fit with the relational character of coproduction, the majority of the articles included in this review employed a leader-centric underlying theory. The practice of coproduction leadership is a complex activity pertaining to interactions among people, encompassing nine essential practices: initiating, power-sharing, training, supporting, establishing trust, communicating, networking, orchestration, and implementation. CONCLUSIONS: This paper proposes a novel framework for coproduction leadership practices based on a systematic review of the literature and a set of reflective questions. This framework aims to help coproduction leaders and participants understand the complexity, diversity, and flexibility of coproduction leadership and to challenge and enhance their capacity to collaborate effectively.

In-PREP: a new learning design framework and methodology applied to a relational care training intervention for healthcare assistants.

BACKGROUND: 'Older People's Shoes' is a training intervention designed for healthcare assistants (HCAs) to improve the relational care of older people in hospital. The intervention formed part of a broader evaluation, in this paper we describe its development from a learning design and methodological perspective. METHODS: Learning theory and an instructional design model were key components of the In-PREP (Input, Process, Review and Evaluation, Product) development methodology used in the design of the 'Older People's Shoes' training intervention to improve the delivery of relational care by front-line hospital staff. An expert panel, current evidence, and pedagogical theory were used to co-design a training programme tailored to a challenging work environment and taking account of trainees' diverse educational experience. Peer review and process evaluation were built into the development model. RESULTS: In-PREP provided a methodological scaffold for producing evidence-based, peer-reviewed, co-designed training. The product, 'Older People's Shoes', involved a one-day Train the Trainers event, followed by delivery of a two-day, face-to-face training programme by the trainers, with accompanying handbooks underpinned by a range of digital resources. Evaluation found the approach met learner needs, was applicable in practice and won approval from trainers. DISCUSSION: In-PREP enables high quality learning content, alignment with learner needs and a product that is relevant, practical and straightforward to implement.

Lost in the shadows: reflections on the dark side of co-production.

This article is a response to Oliver et al.'s Commentary 'The dark side of coproduction: do the costs outweigh the benefits for health research?' recently published in Health Research Policy and Systems (2019, 17:33). The original commentary raises some important questions about how and when to co-produce health research, including highlighting various professional costs to those involved. However, we identify four related limitations in their inquiry, as follows: (1) the adoption of a problematically expansive definition of co-production that fails to acknowledge key features that distinguish co-production from broader collaboration; (2) a strong focus on technocratic rationales for co-producing research and a relative neglect of democratic rationales; (3) the transposition of legitimate concerns relating to collaboration between researchers and practitioners onto work with patients, service users and marginalised citizens; and (4) the presentation of bad practice as an inherent flaw, or indeed 'dark side', of co-production without attending to the corrupting influence of contextual factors within academic research that facilitate and even promote such malpractice. The Commentary's limitations can be seen to reflect the contemporary use of the term 'co-production' more broadly. We describe this phenomenon as 'cobiquity' - an apparent appetite for participatory research practice and increased emphasis on partnership working, in combination with the related emergence of a plethora of 'co' words, promoting a conflation of meanings and practices from different collaborative traditions. This phenomenon commonly leads to a misappropriation of the term 'co-production'. Our main motivation is to address this imprecision and the detrimental impact it has on efforts to enable co-production with marginalised and disadvantaged groups. We conclude that Oliver et al. stray too close to 'the problem' of 'co-production' seeing only the dark side rather than what is casting the shadows. We warn against such a restricted view and argue for greater scrutiny of the structural factors that largely explain academia's failure to accommodate and promote the egalitarian and utilitarian potential of co-produced research.

Spontaneously hypertensive rats display reduced microglial activation in response to ischemic stroke and lipopolysaccharide.

BACKGROUND: For successful translation to clinical stroke studies, the Stroke Therapy Academic Industry Round Table criteria have been proposed. Two important criteria are testing of therapeutic interventions in conscious animals and the presence of a co-morbidity factor. We chose to work with hypertensive rats since hypertension is an important modifiable risk factor for stroke and influences the clinical outcome. We aimed to compare the susceptibility to ischemia in hypertensive rats with those in normotensive controls in a rat model for induction of ischemic stroke in conscious animals. METHODS: The vasoconstrictor endothelin-1 was stereotactically applied in the vicinity of the middle cerebral artery of control Wistar Kyoto rats (WKYRs) and spontaneously hypertensive rats (SHRs) to induce a transient decrease in striatal blood flow, which was measured by the laser Doppler technique. Infarct size was assessed histologically by cresyl violet staining. Sensory-motor functions were measured at several time points using the neurological deficit score. Activation of microglia and astrocytes in the striatum and cortex was investigated by immunohistochemistry using antibodies against CD68/Iba-1 and glial fibrillary acidic protein. RESULTS AND CONCLUSIONS: The SHRs showed significantly larger infarct volumes and more pronounced sensory-motor deficits, compared to the WKYRs at 24 h after the insult. However, both differences disappeared between 24 and 72 h. In SHRs, microglia were less susceptible to activation by lipopolysaccharide and there was a reduced microglial activation after induction of ischemic stroke. These quantitative and qualitative differences may be relevant for studying the efficacy of new treatments for stroke in accordance to the Stroke Therapy Academic Industry Round Table criteria.

The neuroprotective effect of post ischemic brief mild hypothermic treatment correlates with apoptosis, but not with gliosis in endothelin-1 treated rats.

BACKGROUND: Stroke remains one of the most common diseases with a serious impact on quality of life but few effective treatments exist. Mild hypothermia (33°C) is a promising neuroprotective therapy in stroke management. This study investigated whether a delayed short mild hypothermic treatment is still beneficial as neuroprotective strategy in the endothelin-1 (Et-1) rat model for a transient focal cerebral ischemia. Two hours of mild hypothermia (33°C) was induced 20, 60 or 120 minutes after Et-1 infusion. During the experiment the cerebral blood flow (CBF) was measured via Laser Doppler Flowmetry in the striatum, which represents the core of the infarct. Functional outcome and infarct volume were assessed 24 hours after the insult. In this sub-acute phase following stroke induction, the effects of the hypothermic treatment on apoptosis, phagocytosis and astrogliosis were assessed as well. Apoptosis was determined using caspase-3 immunohistochemistry, phagocytic cells were visualized by CD-68 expression and astrogliosis was studied by glial fibrillary acidic protein (GFAP) staining. RESULTS: Cooling could be postponed up to 1 hour after the onset of the insult without losing its positive effects on neurological deficit and infarct volume. These results correlated with the caspase-3 staining. In contrast, the increased CD-68 expression post-stroke was reduced in the core of the insult with all treatment protocols. Hypothermia also reduced the increased levels of GFAP staining, even when it was delayed up to 2 hours after the insult. The study confirmed that the induction of the hypothermia treatment in the Et-1 model does not affect the CBF. CONCLUSIONS: These data indicate that in the Et-1 rat model, a short mild hypothermic treatment delayed for 1 hour is still neuroprotective and correlates with apoptosis. At the same time, hypothermia also establishes a lasting inhibitory effect on the activation of astrogliosis.

The neuroprotective action of candesartan is related to interference with the early stages of 6-hydroxydopamine-induced dopaminergic cell death.

Several studies have revealed that manipulation of the renin angiotensin system results in reduced progression of nigrostriatal damage in different animal models of Parkinson's disease. In the present work, the effect of daily treatment of rats with the angiotensin II (Ang II) type 1 (AT(1) ) receptor antagonist candesartan (3 mg/kg per day, s.c.) initiated 7 days before the intrastriatal injection of 6-hydroxydopamine (6-OHDA) was investigated by means of tyrosine hydroxylase-positive cell counts in the substantia nigra, and dopamine and 3,4-dihydroxyphenylacetic acid measurements in the striatum. In this experimental set-up, candesartan protected dopaminergic neurons of the nigrostriatal tract against the neurotoxin-induced cell death. However, the beneficial effects of AT(1) receptor blockade were not confirmed when treatment was started 24 h after the lesion, suggesting that candesartan interferes with the early events of the 6-OHDA-induced cell death. Stimulation of the AT(1) receptor with Ang II increased the formation of hydroxyl radicals in the striatum of intact rats as measured by the in vivo microdialysis salicylate trapping technique. This Ang II-induced production of reactive oxygen species was suppressed by candesartan perfusion. Furthermore, the Ang II-induced production of reactive oxygen species was nicotinamide adenine dinucleotide phosphate - oxidase and protein kinase C dependent as it could be blocked in the presence of apocynin, an nicotinamide adenine dinucleotide phosphate - oxidase inhibitor, and chelerythrine, an inhibitor of protein kinase C. Together, these data further support the hypothesis that Ang II might contribute in an early stage to the neurotoxicity of 6-OHDA by reinforcing the cascade of oxidative stress.

Mild hypothermia causes differential, time-dependent changes in cytokine expression and gliosis following endothelin-1-induced transient focal cerebral ischemia.

BACKGROUND: Stroke is an important cause of morbidity and mortality and few therapies exist thus far. Mild hypothermia (33°C) is a promising neuroprotective strategy to improve outcome after ischemic stroke. However, its complete mechanism of action has not yet been fully elaborated. This study is the first to investigate whether this neuroprotection occurs through modulation of the neuroinflammatory response after stroke in a time-dependent manner. METHODS: The Endothelin-1 (Et-1) model was used to elicit a transient focal cerebral ischemia in male Wistar rats. In this model, the core and penumbra of the insult are represented by the striatum and the cortex respectively. We assessed the effects of 2 hours of hypothermia, started 20 minutes after Et-1 injection on neurological outcome and infarct volume. Furthermore, pro- and anti-inflammatory cytokine expression was determined using ELISA. Microgliosis and astrogliosis were investigated using CD-68 and GFAP staining respectively. All parameters were determined 8, 24, 72 hours and 1 week after the administration of Et-1. RESULTS: Et-1 infusion caused neurological deficit and a reproducible infarct size which increased up to 3 days after the insult. Both parameters were significantly reduced by hypothermia. The strongest reduction in infarct volume with hypothermia, at 3 days, corresponded with increased microglial activation. Reducing the brain temperature affected the stroke induced increase in interleukin-1ß and tumor necrosis factor α in the striatum, 8 hours after its induction, but not at later time points. Transforming growth factor ß increased as a function of time after the Et-1-induced insult and was not influenced by cooling. Hypothermia reduced astrogliosis at 1 and 3 days after stroke onset. CONCLUSIONS: The beneficial effects of hypothermia after stroke on infarct volume and functional outcome coincide with a time-dependent modulation of the cytokine expression and gliosis.

A co-design study to develop supportive interventions to improve psychological and social adaptation among adults with new-onset type 1 diabetes in Denmark and the UK.

OBJECTIVE: To develop supportive interventions for adults with new-onset type 1 diabetes (T1D) to facilitate positive adaptive strategies during their transition into a life with diabetes. DESIGN: The study used a co-design approach informed by Design Thinking to stimulate participants' reflections on their experiences of current care and generate ideas for new supportive interventions. Visual illustrations were used to depict support needs and challenges. Initial discussions of these needs and challenges were facilitated by researchers and people with diabetes in workshops. Data comprising transcribed audio recordings of the workshop discussions and materials generated during the workshops were analysed thematically. SETTINGS: Specialised diabetes centres in Denmark and the United Kingdom. PARTICIPANTS: Adults with new-onset T1D (n=24) and healthcare professionals (HCPs) (n=56) participated in six parallel workshops followed by four joint workshops with adults (n=29) and HCPs (n=24) together. RESULTS: The common solution prioritised by both adults with new-onset T1D and HCP participants was the development of an integrated model of care addressing the psychological and social elements of the diagnosis, alongside information on diabetes self-management. Participants also indicated a need to develop the organisation, provision and content of care, along with the skills HCPs need to optimally deliver that care. The co-designed interventions included three visual conversation tools that could be used flexibly in the care of adults with new-onset T1D to support physical, psychological and social adaptation to T1D. CONCLUSION: This co-design study has identified the care priorities for adults who develop T1D, along with some practical conversational tools that may help guide HCPs in attending to the disruptive experience of the diagnosis and support adults in adjusting into a life with diabetes.

The dual role of the neuroinflammatory response after ischemic stroke: modulatory effects of hypothermia.

Neuroinflammation is a key element in the ischemic cascade after cerebral ischemia that results in cell damage and death in the subacute phase. However, anti-inflammatory drugs do not improve outcome in clinical settings suggesting that the neuroinflammatory response after an ischemic stroke is not entirely detrimental. This review describes the different key players in neuroinflammation and their possible detrimental and protective effects in stroke. Because of its inhibitory influence on several pathways of the ischemic cascade, hypothermia has been introduced as a promising neuroprotective strategy. This review also discusses the influence of hypothermia on the neuroinflammatory response. We conclude that hypothermia exerts both stimulating and inhibiting effects on different aspects of neuroinflammation and hypothesize that these effects are key to neuroprotection.

Exploring the sustainability of quality improvement interventions in healthcare organisations: a multiple methods study of the 10-year impact of the 'Productive Ward: Releasing Time to Care' programme in English acute hospitals.

BACKGROUND: The 'Productive Ward: Releasing Time to Care' programme is a quality improvement (QI) intervention introduced in English acute hospitals a decade ago to: (1) Increase time nurses spend in direct patient care. (2) Improve safety and reliability of care. (3) Improve experience for staff and patients. (4) Make changes to physical environments to improve efficiency. OBJECTIVE: To explore how timing of adoption, local implementation strategies and processes of assimilation into day-to-day practice relate to one another and shape any sustained impact and wider legacies of a large-scale QI intervention. DESIGN: Multiple methods within six hospitals including 88 interviews (with Productive Ward leads, ward staff, Patient and Public Involvement representatives and senior managers), 10 ward manager questionnaires and structured observations on 12 randomly selected wards. RESULTS: Resource constraints and a managerial desire for standardisation meant that, over time, there was a shift away from the original vision of empowering ward staff to take ownership of Productive Ward towards a range of implementation 'short cuts'. Nonetheless, material legacies (eg, displaying metrics data; storage systems) have remained in place for up to a decade after initial implementation as have some specific practices (eg, protected mealtimes). Variations in timing of adoption, local implementation strategies and contextual changes influenced assimilation into routine practice and subsequent legacies. Productive Ward has informed wider organisational QI strategies that remain in place today and developed lasting QI capabilities among those meaningfully involved in its implementation. CONCLUSIONS: As an ongoing QI approach Productive Ward has not been sustained but has informed contemporary organisational QI practices and strategies. Judgements about the long-term sustainability of QI interventions should consider the evolutionary and adaptive nature of change processes.

Insulin-like growth factor I: a potential neuroprotective compound for the treatment of acute ischemic stroke?

BACKGROUND AND PURPOSE: Insulin-like growth factor I (IGF-I) exerts neuroprotective effects in both white and gray matter under different detrimental conditions. The purpose of this review is to collect the evidence whether IGF-I is a candidate neuroprotective drug in patients with acute ischemic stroke. RESULTS: IGF-I was found to be neuroprotective in animal models of focal brain ischemia when given >or=2 hours after the insult. Different routes of administration (eg, cerebroventricular, intravenous, and intranasal) were found to be effective. In addition to inhibition of apoptosis and reduction of the infarct volume, IGF-I also improved neurological outcome. Furthermore, there are strong indications that IGF-I can also stimulate the regeneration of neural tissue. CONCLUSIONS: Additional studies are required to reveal the neuroprotective mechanisms of IGF-I in detail and to elucidate the role of IGF-binding proteins. Preclinical studies in relevant animal models for studying stroke (ie, hypertensive, diabetic, or aged animals) should be done testing different doses and routes of IGF-I administration and different combinations of IGF-I and IGF-binding proteins.

Reversible neurochemical changes mediated by delayed intrastriatal glial cell line-derived neurotrophic factor gene delivery in a partial Parkinson's disease rat model.

BACKGROUND: Efficient protection of dopaminergic neurons against a subsequent 6-hydroxydopamine lesion by glial cell line-derived neurotrophic factor (GDNF) gene delivery has been demonstrated. By contrast, the neurorestorative effects of GDNF administered several weeks after the toxin have been less characterized. In particular, whether these were permanent or dependent on the continuous presence of GDNF remains elusive. METHODS: A tetracycline-inducible adeno-associated virus (AAV)-1 vector expressing human GDNF cDNA was administered unilaterally in the rat striatum 5 weeks after 6-hydroxydopamine. Rats were treated with doxycycline (dox) or untreated from the day of vector injection until sacrifice (4 or 14 weeks). A sub-group was dox-treated for 7 weeks then untreated until 14 weeks. The motor behavior was assessed by amphetamine-induced rotations and spontaneous forelimb asymmetry. The amounts of tyrosine hydroxylase (TH), serine-40-phosphorylated TH (S40-TH) and aromatic amino acid decarboxylase (AADC) proteins were compared by western blotting and the dopamine levels quantified by high-performance liquid chromatography. RESULTS: Dox-dependent behavioral improvements were demonstrated 4 weeks post-vector injection. At later time points, spontaneous partial recovery was observed in all rats, but no further improvement was found in dox-treated animals. TH levels were significantly increased in dox-treated rats at all time points. By contrast, striatal dopamine and S40-TH were increased at 4 weeks, but not 14 weeks, and AADC remained unchanged. Dox withdrawal after 7 weeks, resulted in TH levels comparable to the controls at 14 weeks. CONCLUSIONS: Delayed GDNF gene delivery only transiently improved dopaminergic function. Over the long term, TH was more abundant, but not functional, and the increase was lost when GDNF gene expression was switched off.

In vivo neurochemical effects of the NR2B selective NMDA receptor antagonist CR 3394 in 6-hydroxydopamine lesioned rats.

Microdialysis in intact and denervated striatum of unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats was used to investigate whether CR 3394, N-[2-(3,5-dimethyl-1-adamantyl)ethyl]acetamidine, an adamantane derivative with preferential selectivity for the NR2B subunit of the NMDA receptor, has dopamine releasing properties in vivo. We also investigated whether this NMDA antagonist can potentiate the effects of L-Dopa on extracellular dopamine in these animals. After systemic injection, there was no significant effect of CR 3394 on extracellular dopamine, at all doses studied (1, 5 and 20 mg/kg i.p.), in either intact or in denervated striatum. On the other hand, striatal perfusion with 100 microM of the compound elicited release of dopamine in intact, but not in denervated striatum. In denervated striatum of the 6-OHDA-lesioned rats, CR 3394 (5 mg/kg) significantly enhanced the dopamine release induced by L-Dopa administration (25 mg/kg i.p.) in combination with benserazide (10 mg/kg i.p.). In particular, the onset of action of L-Dopa was potentiated. However, when combined with a subthreshold dose of L-Dopa (5 mg/kg), the effects of CR 3394 were lost. We conclude that CR 3394, like other NR2B receptor antagonists, has dopamine releasing properties in vivo. It enhances the effects of suprathreshold doses of L-Dopa in the denervated striatum, but not of low doses of L-Dopa. Therefore, future studies are necessary to establish the potential of selective NR2B receptor antagonists as L-Dopa-sparing agents.

Critical Evaluation of Acetylcholine Determination in Rat Brain Microdialysates using Ion-Pair Liquid Chromatography with Amperometric Detection.

Liquid chromatography with amperometric detection remains the most widely used method for acetylcholine quantification in microdialysis samples. Separation of acetylcholine from choline and other matrix components on a microbore chromatographic column (1 mm internal diameter), conversion of acetylcholine in an immobilized enzyme reactor and detection of the produced hydrogen peroxide on a horseradish peroxidase redox polymer coated glassy carbon electrode, achieves sufficient sensitivity for acetylcholine quantification in rat brain microdialysates. However, a thourough validation within the concentration range required for this application has not been carried out before. Furthermore, a rapid degradation of the chromatographic columns and enzyme systems have been reported. In the present study an ion-pair liquid chromatography assay with amperometric detection was validated and its long-term stability evaluated. Working at pH 6.5 dramatically increased chromatographic stability without a loss in sensitivity compared to higher pH values. The lower limit of quantification of the method was 0.3 nM. At this concentration the repeatability was 15.7%, the inter-day precision 8.7% and the accuracy 103.6%. The chromatographic column was stable over 4 months, the immobilized enzyme reactor up to 2-3 months and the enzyme coating of the amperometric detector up to 1-2 months. The concentration of acetylcholine in 30 µl microdialysates obtained under basal conditions from the hippocampus of freely moving rats was 0.40 ± 0.12 nM (mean ± SD, n = 30). The present method is therefore suitable for acetylcholine determination in rat brain microdialysates.

The challenges of training, support and assessment of healthcare support workers: A qualitative study of experiences in three English acute hospitals.

BACKGROUND: Ever-growing demands on care systems have increased reliance on healthcare support workers. In the UK, their training has been variable, but organisation-wide failures in care have prompted questions about how this crucial section of the workforce should be developed. Their training, support and assessment has become a policy priority. OBJECTIVES: This paper examines: healthcare support workers' access to training, support and assessment; perceived gaps in training provision; and barriers and facilitators to implementation of relevant policies in acute care. DESIGN AND SETTINGS: We undertook a qualitative study of staff caring for older inpatients at ward, divisional or organisational-level in three acute National Health Service hospitals in England in 2014. PARTICIPANTS: 58 staff working with older people (30 healthcare support workers and 24 staff managing or working alongside them) and 4 healthcare support worker training leads. METHODS: One-to-one semi-structured interviews included: views and experiences of training and support; translation of training into practice; training, support and assessment policies and difficulties of implementing them. Transcripts were analysed to identify themes. RESULTS: Induction training was valued, but did not fully prepare healthcare support workers for the realities of the ward. Implementation of hospital policies concerning supervision and formal assessment of competencies varied between and within hospitals, and was subject to availability of appropriate staff and competing demands on staff time. Gaps identified in training provision included: caring for people with cognitive impairment; managing the emotions of patients, families and themselves; and having difficult conversations. Access to ongoing training was affected by: lack of time; infrequent provision; attitudes of ward managers to additional support workforce training, and their need to balance this against patients' and other staff members' needs; and the use of e-learning as a default mode of training delivery. CONCLUSIONS: With the current and unprecedented policy focus on training, support and assessment of healthcare support workers, our study suggests improved training would be welcomed by them and their managers. Provision of training, support and assessment could be improved by organisational policy that promotes and protects healthcare support worker training; formalising the provision and availability of on-ward support; and training and IT support provided on a drop-in basis. Challenges in implementation are likely to be faced in all international settings where there is increased reliance on a support workforce. While recent policies in the UK offers scope to overcome some of these challenges there is a risk that some will be exacerbated.

Involvement of insulin-regulated aminopeptidase and/or aminopeptidase N in the angiotensin IV-induced effect on dopamine release in the striatum of the rat.

Locally administered angiotensin IV causes a dose-dependent increase of the dopamine levels in the striatum of the rat. The aminopeptidases insulin-regulated aminopeptidase (IRAP) and/or aminopeptidase N (AP-N) are proposed to be involved in this effect since both enzymes are inhibited by angiotensin IV. In agreement with this hypothesis we demonstrate that by using the AP-N selective inhibitor 7B, about 60% of the aminopeptidase activity in striatal membranes could be attributed to AP-N (pK(i)=9.20). Higher concentrations of 7B are capable of inhibiting IRAP as well (pK(i)=7.26). Interestingly, in vivo, inhibition of IRAP or AP-N activity does not appear to be involved in the angiotensin IV-mediated effect in the striatum since 7B itself is not capable to induce dopamine release such as observed with angiotensin IV. However, 7B at a concentration selective for inhibition of AP-N (100 nM) potentiates the angiotensin IV-mediated increase of dopamine, suggesting that inhibition of AP-N lengthens the half-life of angiotensin IV. On the other hand, inhibition of both AP-N and IRAP by perfusion of 500 nM 7B completely abolishes the effect of angiotensin IV. We therefore hypothesize that the effect of angiotensin IV on dopamine release in the striatum is mediated via activation of IRAP and/or AP-N, possibly acting as receptors for angiotensin IV.

Developing a novel peer support intervention to promote resilience after stroke.

Stroke can lead to physical, mental and social long-term consequences, with the incidence of stroke increasing with age. However, there is a lack of evidence of how to improve long-term outcomes for people with stroke. Resilience, the ability to 'bounce back', flourish or thrive in the face of adversity improves mental health and quality of life in older adults. However, the role of resilience in adjustment after stroke has been little investigated. The purpose of this study is to report on the development and preliminary evaluation of a novel intervention to promote resilience after stroke. We applied the first two phases of the revised UK Medical Research Council (UKMRC) framework for the development and evaluation of complex interventions: intervention development (phase 1) and feasibility testing (phase 2). Methods involved reviewing existing evidence and theory, interviews with 22 older stroke survivors and 5 carers, and focus groups and interviews with 38 professionals to investigate their understandings of resilience and its role in adjustment after stroke. We used stakeholder consultation to co-design the intervention and returned to the literature to develop its theoretical foundations. We developed a 6-week group-based peer support intervention to promote resilience after stroke. Theoretical mechanisms of peer support targeted were social learning, meaning-making, helping others and social comparison. Preliminary evaluation with 11 older stroke survivors in a local community setting found that it was feasible to deliver the intervention, and acceptable to stroke survivors, peer facilitators, and professionals in stroke care and research. This study demonstrates the application of the revised UKMRC framework to systematically develop an empirically and theoretically robust intervention to promote resilience after stroke. A future randomised feasibility study is needed to determine whether a full trial is feasible with a larger sample and wider age range of people with stroke.

Peripheral inflammation modifies the effect of intrathecal IL-1beta on spinal PGE2 production mainly through cyclooxygenase-2 activity. A spinal microdialysis study in freely moving rats.

Acute inflammation induces upregulation of IL-1beta both at the site of the peripheral inflammation and in the cerebrospinal fluid (CSF). The central increase of IL-1beta mainly contributes to the development of hypersensitivity. However, the spinal mechanisms for the effects of IL-1beta in nociceptive transmission are incompletely understood. It is also unknown whether previous sensitization changes IL-1beta activity. We therefore investigated the dose-effect relationship of intrathecal (i.t.) IL-1beta on spinal PGE(2) production in the absence and presence of peripheral formalin inflammation with spinal microdialysis in freely moving rats. The possible involvement of cyclooxygenase (COX) isoforms in the IL-1beta-mediated spinal PGE(2) production on the background of peripheral formalin inflammation was further evaluated with the selective COX-1 and COX-2 inhibitors. We found that the i.t. administration of IL-1beta, with doses of 1, 2, 8, or 16 ng, increased PGE(2) levels in CSF in a dose-related fashion. This IL-1beta-evoked PGE(2) release occurred within 30min after IL-1beta administration, peaked at 30-60 min interval, and returned gradually to the baseline level within 4h. Peripheral formalin inflammation in the paw induced a more prolonged effect of spinal IL-1beta with larger PGE(2) releases in the CSF compared with the non-inflammatory state, suggesting that peripheral inflammation enhances central sensitization. The COX-2 inhibitor SC58236 (15 mg/kg) reduced the IL-1beta-mediated PGE(2) increase in CSF by 86% while the COX-1 inhibitor SC58560 (15 mg/kg) had less effect (28%). Our study suggests that mainly the COX-2 enzyme mediates the IL-1beta-induced increase in spinal PGE(2) in the presence of peripheral formalin inflammation.

Capillary and nano-liquid chromatography-tandem mass spectrometry for the quantification of small molecules in microdialysis samples: comparison with microbore dimensions.

Enhanced sensitivity is a well known benefit of miniaturised LC-electrospray (ESI)-MS/MS methods. The suitability of miniaturised LC-MS/MS for quantification of small molecules in dialysates was investigated using the anti-epileptic drug oxcarbazepine, its active metabolite, 10,11-dihydro-10-hydroxycarbamazepine, and the internal standard for microdialysis probe calibration, 2-methyl-5H-dibenz(b,f)azepine-5-carboxamide, as test compounds. ESI-MS detection is sensitive to matrix effects. Therefore, dialysate matrix effects were investigated by comparing the responses of standards made in water, Ringer's solution (salt solution used as perfusion fluid) and blank dialysate matrix. Due to the occurrence of ion suppression or enhancement, direct injection of dialysis samples onto the analytical column could not be applied for quantification of small molecules in dialysis samples. Column switching was necessary for desalting and preconcentration of the dialysates. However, this approach was not able to completely eliminate salt effects when the injection volume exceeded 1 microL. No differences in response between Ringer's solution and dialysate matrix were detected at capillary and nano-dimensions. Calibration standards should be prepared with Ringer's solution instead of water for quantitative analysis of microdialysates. A microbore, capillary and nano-LC-ESI-MS/MS method were compared in terms of method feasibility, linearity, sensitivity, accuracy and precision. Downscaling to capillary and nano-dimensions resulted in a gain in detection sensitivity of 5 and 50, respectively. Miniaturised LC-MS/MS was found to be fit for quantification of small molecules in dialysates with acceptable accuracy and method precision.