Social prescribing for people living with dementia (PLWD) and their carers: what works, for whom, under what circumstances and why - protocol for a complex intervention systematic review.

INTRODUCTION: Dementia is a complex medical condition that poses significant challenges to healthcare systems and support services. People living with dementia (PLWD) and their carers experience complex needs often exacerbated by social isolation and challenges in accessing support. Social prescribing (SP) seeks to enable PLWD and their carers to access community and voluntary sector resources to support them address such needs. Existing research, however, does not describe what SP interventions are currently in place in dementia care. Little is known about the needs these interventions are designed to address, the reasons that lead PLWD and their carers to participate in them, their effectiveness and the extent to which they could increase positive health outcomes if adopted and how. METHODS AND ANALYSIS: A complex intervention systematic review of SP for PLWD and/or their carers will be conducted using an iterative logic model approach. Six electronic (MEDLINE, EMBASE, PsycINFO, CINAHL, Scopus and Cochrane/CENTRAL) and two grey literature databases (EThOS and CORE) were searched for publications between 1 January 2003 and June 2023, supplemented by handsearching of reference lists of included studies. Study selection, data extraction and risk of bias assessment, using Gough's Weight of Evidence Framework, will be independently performed by two reviewers. A narrative approach will be employed to synthesise and report quantitative and qualitative data. Reporting will be informed by the Preferred Reporting Items for Systematic Review and Meta-Analysis Complex Interventions extension statement and checklist. ETHICS AND DISSEMINATION: No ethical approval is required due to this systematic review operating only with secondary sources. Findings will be disseminated through peer-reviewed publications, conference presentations and meetings with key stakeholders including healthcare professionals, patient and carer groups, community organisations (eg, the Social Prescribing Network and the Evidence Collaborative at the National Academy for Social Prescribing), policymakers and funding bodies. PROSPERO REGISTRATION NUMBER: CRD42023428625.

Global mortality and readmission rates following COPD exacerbation-related hospitalisation: a meta-analysis of 65 945 individual patients.

Background: Exacerbations of COPD (ECOPD) have a major impact on patients and healthcare systems across the world. Precise estimates of the global burden of ECOPD on mortality and hospital readmission are needed to inform policy makers and aid preventive strategies to mitigate this burden. The aims of the present study were to explore global in-hospital mortality, post-discharge mortality and hospital readmission rates after ECOPD-related hospitalisation using an individual patient data meta-analysis (IPDMA) design. Methods: A systematic review was performed identifying studies that reported in-hospital mortality, post-discharge mortality and hospital readmission rates following ECOPD-related hospitalisation. Data analyses were conducted using a one-stage random-effects meta-analysis model. This study was conducted and reported in accordance with the PRISMA-IPD statement. Results: Data of 65 945 individual patients with COPD were analysed. The pooled in-hospital mortality rate was 6.2%, pooled 30-, 90- and 365-day post-discharge mortality rates were 1.8%, 5.5% and 10.9%, respectively, and pooled 30-, 90- and 365-day hospital readmission rates were 7.1%, 12.6% and 32.1%, respectively, with noticeable variability between studies and countries. Strongest predictors of mortality and hospital readmission included noninvasive mechanical ventilation and a history of two or more ECOPD-related hospitalisations <12 months prior to the index event. Conclusions: This IPDMA stresses the poor outcomes and high heterogeneity of ECOPD-related hospitalisation across the world. Whilst global standardisation of the management and follow-up of ECOPD-related hospitalisation should be at the heart of future implementation research, policy makers should focus on reimbursing evidence-based therapies that decrease (recurrent) ECOPD.

Implementing an intervention to enhance care delivery and consistency for people with hip fracture and cognitive impairment in acute hospital wards: a mixed methods process evaluation of a randomised controlled feasibility trial (PERFECTED).

OBJECTIVES: To determine how, and under what circumstances, the PERFECT-ER intervention was implemented in five acute hospital wards and impacted on staff practices and perceptions. DESIGN: Mixed methods process evaluation (undertaken between 2016 and 2018). SETTING: Five acute hospital wards across three different UK regions. PARTICIPANTS: Patients (n=3) admitted to acute wards with hip fracture and cognitive impairment, their relatives (n=29) and hospital staff (n=63). INTERVENTIONS: PERFECT-ER, a multicomponent intervention designed to enhance the recovery of patients with hip fracture and cognitive impairment was implemented for 18 months. PERFECT-ER was implemented at ward level ensuring that multiple new and existing practices were undertaken consistently, on the assumption that collectively, small individual advances would improve care delivery for patients. PRIMARY AND SECONDARY OUTCOME MEASURES: Implementation of the PERFECT-ER intervention examined through regular intervention scores, service improvement staff reports and action plans, and semi-structured interviews and focus groups. RESULTS: The process evaluation identified points of implementation vulnerability and strength. All wards implemented some elements of PERFECT-ER. Implementation was fragile when ward pressures were high and when ward staff perceived the relative priority of intervention practices to be low. Adaptations to the implementation process may have reduced whole-ward staff engagement with implementation. However, strategical enlistment of senior ward influencers (such as ward managers, orthogeriatricians) combined with service improvement lead in-ward peer pressure tactics facilitated implementation processes. CONCLUSIONS: Our study suggests that implementation was expediated when senior staff were on board as opinion leaders and formally appointed internal implementation leaders exerted their power. Within hierarchical settings such as acute wards, key individuals appeared to influence implementation through endorsement and sometimes enforcement. This indicates that whole-ward interventions may not always require cognitive engagement from all ward staff to implement changes. Future ward-level implementation studies could consider how best to engage staff and most importantly, which staff to best target. TRIAL REGISTRATION NUMBER: ISRCTN99336264.

Implementing PERFECT-ER with Plan-Do-Study-Act on acute orthopaedic hospital wards: Building knowledge from an implementation study using Normalization Process Theory.

BACKGROUND: Delivering care to growing numbers of patients with increasingly 'complex' needs is currently compromised by a system designed to treat patients within organizational clinical specialties, making this difficult to reconfigure to fit care to needs. Problematic experiences of people with cognitive impairment(s) admitted to hospitals with a hip fracture, exemplify the complex challenges that result if their care is not tailored. This study explored whether a flexible, multicomponent intervention, adapting services to the needs of this patient group, could be implemented in acute hospital settings. METHODS: We used action research with case study design to introduce the intervention using a Plan-Do-Study-Act (PDSA) model to three different hospital sites (cases) across England. The qualitative data for this paper was researcher-generated (notes from observations and teleconference meetings) and change agent-generated (action plans and weekly reflective reports of change agents' activities). Normalization Process Theory (NPT) was used to analyze and explain the work of interacting actors in implementing and then normalizing (embedding) the intervention across contexts and times. Data analysis was abductive, generating inductive codes then identified with NPT constructs. Across the three cases, change agents had to work through numerous implementation challenges: needing to make sense of the intervention package, the PDSA model as implementation method, and their own role as change agents and to orientate these within their action context (coherence). They had to work to encourage colleagues to invest in these changes (cognitive participation) and find ways to implement the intervention by mobilising changes (collective action). Finally, they created strategies for clinical routines to continue to self-review, reconfiguring actions and future plans to enable the intervention to be sustained (reflexive monitoring). CONCLUSIONS: Successful implementation of the (PERFECT-ER) intervention requires change agents to recognize and engage with local values, and then to enable its fit with practice and wider contextual goals. A context of constant change fragments normalization. Thus, sustaining practice change over time is fragile and requires change agents to continue a recursive two-way sense-making process. This enables implementation and normalization to re-energize and overcome barriers to change.

PERFECTED enhanced recovery pathway (PERFECT-ER) versus standard acute hospital care for people after hip fracture surgery who have cognitive impairment: a feasibility cluster randomised controlled trial.

OBJECTIVES: Assess feasibility of a cluster randomised controlled trial (RCT) to measure clinical and cost-effectiveness of an enhanced recovery pathway for people with hip fracture and cognitive impairment (CI). DESIGN: Feasibility trial undertaken between 2016 and 2018. SETTING: Eleven acute hospitals from three UK regions. PARTICIPANTS: 284 participants (208 female:69 male). INCLUSION CRITERIA: aged >60 years, confirmed proximal hip fracture requiring surgical fixation and CI; preoperative AMTS ≤8 in England or a 4AT score ≥1 in Scotland; minimum of 5 days on study ward; a 'suitable informant' able to provide proxy measures, recruited within 7 days of hip fracture surgery. EXCLUSION CRITERIA: no hip surgery; not expected to survive beyond 4 weeks; already enrolled in a clinical trial. INTERVENTION: PERFECT-ER, an enhanced recovery pathway with 15 quality targets supported by a checklist and manual, a service improvement lead a process lead and implemented using a plan-do-study-act model. PRIMARY AND SECONDARY OUTCOME MEASURES: Feasibility outcomes: recruitment and attrition, intervention acceptability, completion of participant reported outcome measures, preliminary estimates of potential effectiveness using mortality, EQ-5D-5L, economic and clinical outcome scores. RESULTS: 282 participants were consented and recruited (132, intervention) from a target of 400. Mean recruitment rates were the same in intervention and control sites, (range: 1.2 and 2.7 participants/month). Retention was 230 (86%) at 1 month and 54%(144) at 6 months. At 3 months a relatively small effect (one quarter of an SD) was observed on health-related quality of life of the patient measured with EQ-5D-5L proxy in the intervention group. CONCLUSION: This trial design was feasible with modifications to recruitment. Mechanisms for delivering consistency in the PERFECT-ER intervention and participant retention need to be addressed. However, an RCT may be a suboptimal research design to evaluate this intervention due to the complexity of caring for people with CI after hip fracture. TRIAL REGISTRATION NUMBER: ISRCTN99336264.

Effects of fluid and drinking on pneumonia mortality in older adults: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Advice to drink plenty of fluid is common in respiratory infections. We assessed whether low fluid intake (dehydration) altered outcomes in adults with pneumonia. METHODS: We systematically reviewed trials increasing fluid intake and well-adjusted, well-powered observational studies assessing associations between markers of low-intake dehydration (fluid intake, serum osmolality, urea or blood urea nitrogen, urinary output, signs of dehydration) and mortality in adult pneumonia patients (with any type of pneumonia, including community acquired, health-care acquired, aspiration, COVID-19 and mixed types). Medline, Embase, CENTRAL, references of reviews and included studies were searched to 30/10/2020. Studies were assessed for inclusion, risk of bias and data extracted independently in duplicate. We employed random-effects meta-analysis, sensitivity analyses, subgrouping and GRADE assessment. Prospero registration: CRD42020182599. RESULTS: We identified one trial, 20 well-adjusted cohort studies and one case-control study. None suggested that more fluid (hydration) was associated with harm. Ten of 13 well-powered observational studies found statistically significant positive associations in adjusted analyses between dehydration and medium-term mortality. The other three studies found no significant effect. Meta-analysis suggested doubled odds of medium-term mortality in dehydrated (compared to hydrated) pneumonia patients (GRADE moderate-quality evidence, OR 2.3, 95% CI 1.8 to 2.8, 8619 deaths in 128,319 participants). Heterogeneity was explained by a dose effect (greater dehydration increased risk of mortality further), and the effect was consistent across types of pneumonia (including community-acquired, hospital-acquired, aspiration, nursing and health-care associated, and mixed pneumonia), age and setting (community or hospital). The single trial found that educating pneumonia patients to drink ≥1.5 L fluid/d alongside lifestyle advice increased fluid intake and reduced subsequent healthcare use. No studies in COVID-19 pneumonia met the inclusion criteria, but 70% of those hospitalised with COVID-19 have pneumonia. Smaller COVID-19 studies suggested that hydration is as important in COVID-19 pneumonia mortality as in other pneumonias. CONCLUSIONS: We found consistent moderate-quality evidence mainly from observational studies that improving hydration reduces the risk of medium-term mortality in all types of pneumonia. It is remarkable that while many studies included dehydration as a potential confounder, and major pneumonia risk scores include measures of hydration, optimal fluid volume and the effect of supporting hydration have not been assessed in randomised controlled trials of people with pneumonia. Such trials, are needed as potential benefits may be large, rapid and implemented at low cost. Supporting hydration and reversing dehydration has the potential to have rapid positive impacts on pneumonia outcomes, and perhaps also COVID-19 pneumonia outcomes, in older adults.

Rehabilitation to enable recovery from COVID-19: a rapid systematic review.

OBJECTIVES: To establish the evidence for rehabilitation interventions tested in populations of patients admitted to ICU and critical care with severe respiratory illness, and consider whether the evidence is generalizable to patients with COVID-19. METHODS: The authors undertook a rapid systematic review. Medline (via OvidSP), CINAHL Complete (via EBSCOhost), Cochrane Library, Cochrane Database of Systematic Reviews and CENTRAL (via Wiley), Epistemonikos (via Epistemonikos.org), PEDro (via pedro.org.au) and OTseeker (via otseeker.com) searched to 7 May 2020. The authors included systematic reviews, RCTs and qualitative studies involving adults with respiratory illness requiring intensive care who received rehabilitation to enhance or restore resulting physical impairments or function. Data were extracted by one author and checked by a second. TIDier was used to guide intervention descriptions. Study quality was assessed using Critical Skills Appraisal Programme (CASP) tools. RESULTS: Six thousand nine hundred and three titles and abstracts were screened; 24 systematic reviews, 11 RCTs and eight qualitative studies were included. Progressive exercise programmes, early mobilisation and multicomponent interventions delivered in ICU can improve functional independence. Nutritional supplementation in addition to rehabilitation in post-ICU hospital settings may improve performance of activities of daily living. The evidence for rehabilitation after discharge from hospital following an ICU admission is inconclusive. Those receiving rehabilitation valued it, engendering hope and confidence. CONCLUSIONS: Exercise, early mobilisation and multicomponent programmes may improve recovery following ICU admission for severe respiratory illness that could be generalizable to those with COVID-19. Rehabilitation interventions can bring hope and confidence to individuals but there is a need for an individualised approach and the use of behaviour change strategies. Further research is needed in post-ICU settings and with those who have COVID-19. Registration: Open Science Framework https://osf.io/prc2y.

Making body work sequences visible: an ethnographic study of acute orthopaedic hospital wards.

Within health and social care, academic attention is increasingly paid to understanding the nature and centrality of body work. Relatively little is known about how and where body work specifically fits into the wider work relations that produce it in healthcare settings. We draw on ethnographic observations of staff practice in three National Health Service acute hospital wards in the United Kingdom to make visible the micro-processes of patient care sequences including both body work and the work contextualising and supporting it. Our data, produced in 2015, show body work interactions in acute care to be critically embedded within a context of initiating, preparing, moving and restoring and proceeding. Shades of privacy and objectification of the body are present throughout these sequences. While accomplishing tasks away from the physical body, staff members must also maintain physical and cognitive work focussed on producing body work. Thus, patient care is necessarily complex, requiring much staff time and energy to deliver it. We argue that by making visible the micro-processes that hospital patient care depends on, including both body work and the work sequences supporting it, the complex physical and cognitive workload required to deliver care can be better recognised. (A virtual version of this abstract is available at: https://www.youtube.com/channel/UC_979cmCmR9rLrKuD7z0ycA).

Effect of Polyarginine Peptide R18D Following a Traumatic Brain Injury in Sprague-Dawley Rats.

BACKGROUND: Despite extensive studies, there are still no clinically available neuroprotective treatments for traumatic brain injury. OBJECTIVES: In previous studies we demonstrated beneficial treatment effects of polyarginine peptides R18 (18-mer of arginine; 300 nmol/kg) and R18D (18-mer of D-arginine; 1000 nmol/kg) in a rat model of impact-acceleration closed-head injury. METHODS: We examined the efficacy of R18D when intravenously administered at a low (100 nmol/kg) and high (1000 nmol/kg) dose, 30 minutes after a closed-head injury in male Sprague-Dawley rats. RESULTS: At postinjury day 3, treatment with R18D at the high dose significantly reduced axonal injury (P = 0.044), whereas the low-dose treatment of R18D showed a trend for reduced axonal injury. Following assessment in the Barnes maze, both doses of R18D treatment appeared to improve learning and memory recovery compared with vehicle treatment at postinjury days 1 and 3, albeit not to a statistically significant level. Rotarod assessment of vestibulomotor recovery did not differ between R18D and the vehicle treatment groups. CONCLUSIONS: R18D modestly decreased axonal injury only at the highest dose used but had no significant effect on functional recovery. These findings warrant further studies with additional doses to better understand peptide pharmacodynamics and provide information to guide optimal dosing.

Enhanced rehabilitation and care models for adults with dementia following hip fracture surgery.

BACKGROUND: Hip fracture is a major injury that causes significant problems for affected individuals and their family and carers. Over 40% of people with hip fracture have dementia or cognitive impairment. The outcomes of these individuals after surgery are poorer than for those without dementia. It is unclear which care and rehabilitation interventions achieve the best outcomes for these people. This is an update of a Cochrane Review first published in 2013. OBJECTIVES: (a) To assess the effectiveness of models of care including enhanced rehabilitation strategies designed specifically for people with dementia following hip fracture surgery compared to usual care. (b) To assess for people with dementia the effectiveness of models of care including enhanced rehabilitation strategies that are designed for all older people, regardless of cognitive status, following hip fracture surgery, compared to usual care. SEARCH METHODS: We searched ALOIS (www.medicine.ox.ac.uk/alois), the Cochrane Dementia and Cognitive Improvement Group Specialised Register, MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), CINAHL (EBSCOhost), Web of Science Core Collection (ISI Web of Science), LILACS (BIREME), ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform on 16 October 2019. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials evaluating the effectiveness of any model of enhanced care and rehabilitation for people with dementia after hip fracture surgery compared to usual care. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted data. We assessed risk of bias of the included trials. We synthesised data only if we considered the trials to be sufficiently homogeneous in terms of participants, interventions, and outcomes. We used the GRADE approach to rate the overall certainty of evidence for each outcome. MAIN RESULTS: We included seven trials with a total of 555 participants. Three trials compared models of enhanced care in the inpatient setting with conventional care. Two trials compared an enhanced care model provided in inpatient settings and at home after discharge with conventional care. Two trials compared geriatrician-led care in-hospital to conventional care led by the orthopaedic team. None of the interventions were designed specifically for people with dementia, therefore the data included in the review were from subgroups of people with dementia or cognitive impairment participating in randomised controlled trials investigating models of care for all older people following hip fracture. The end of follow-up in the trials ranged from the point of acute hospital discharge to 24 months after discharge. We considered all trials to be at high risk of bias in more than one domain. As subgroups of larger trials, the analyses lacked power to detect differences between the intervention groups. Furthermore, there were some important differences in baseline characteristics of participants between the experimental and control groups. Using the GRADE approach, we downgraded the certainty of the evidence for all outcomes to low or very low. The effect estimates for almost all comparisons were very imprecise, and the overall certainty for most results was very low. There were no data from any study for our primary outcome of health-related quality of life. There was only very low certainty for our other primary outcome, activities of daily living and functional performance, therefore we were unable to draw any conclusions with confidence. There was low-certainty that enhanced care and rehabilitation in-hospital may reduce rates of postoperative delirium (odds ratio 0.04, 95% confidence interval (CI) 0.01 to 0.22, 2 trials, n = 141) and very low-certainty associating it with lower rates of some other complications. There was also low-certainty that, compared to orthopaedic-led management, geriatrician-led management may lead to shorter hospital stays (mean difference 4.00 days, 95% CI 3.61 to 4.39, 1 trial, n = 162). AUTHORS' CONCLUSIONS: We found limited evidence that some of the models of enhanced rehabilitation and care used in the included trials may show benefits over usual care for preventing delirium and reducing length of stay for people with dementia who have been treated for hip fracture. However, the certainty of these results is low. Data were available from only a small number of trials, and the certainty for all other results is very low. Determining the optimal strategies to improve outcomes for this growing population of patients should be a research priority.

The electronic frailty index as an indicator of community healthcare service utilisation in the older population.

BACKGROUND: older people with frailty are particularly high users of healthcare services, however a lack of standardised recording of frailty in different healthcare electronic datasets has limited investigations into healthcare service usage and demand of the older frail population. OBJECTIVES: to investigate the community service demand of frail patients using the electronic frailty index (eFI) as a measure of frailty. STUDY DESIGN AND SETTING: a retrospective cohort study using anonymised linked healthcare patient data from primary care, community services and acute hospitals in Norfolk. PARTICIPANTS: patients aged 65 and over who had an eFI assessment score established in their primary care electronic patient record in Norwich based General Practices. RESULTS: we include data from 22,859 patients with an eFI score. Frailty severity increased with age and was associated with increased acute hospital admission within a 6-month window. Patients with a frail eFI score were also more likely to have a community service referral within a 6-month window of frailty assessment, with a RR of 1.84 (1.76-1.93) for mild frailty, 1.96 (1.83-2.09) for moderate frailty and 2.95 (2.76-3.14) for severe frailty scores. We also found that frail patients had more community referrals per patient then those classified as fit and required more care plans per community referral. CONCLUSIONS: eFI score was an indicator of community service use, with increasing severity of frailty being associated with higher community healthcare requirements. The eFI may help planning of community services for the frail population.

Comparison of neuroprotective efficacy of poly-arginine R18 and R18D (D-enantiomer) peptides following permanent middle cerebral artery occlusion in the Wistar rat and in vitro toxicity studies.

We have previously demonstrated that arginine-rich and poly-arginine peptides possess potent neuroprotective properties, with poly-arginine peptide R18 identified as being highly effective at reducing infarct volume following middle cerebral artery occlusion (MCAO) in the Sprague Dawley rat. Since peptides synthesised using D-isoform amino acids have greater stability than L-isoform peptides due to increased resistance to proteolytic degradation, they represent potentially more effective peptide therapeutics. Therefore we compared the neuroprotective efficacy of R18 and its D-enantiomer R18D following permanent MCAO in the Wistar rat. Furthermore, as increased peptide stability may also increase peptide toxicity, we examined the effects of R18 and R18D on cultured cortical neurons, astrocytes, brain endothelial cells (bEND.3), and embryonic kidney cells (HEK293) following a 10-minute or 24-hour peptide exposure duration. The in vivo studies demonstrated that R18D resulted in a greater reduction in mean infarct volume compared to R18 (33%, p = 0.004 vs 12%, p = 0.27) after intravenous administration at 300 nmol/kg 30 minutes after MCAO. Both R18D and R18 reduced cerebral hemisphere swelling to a comparable degree (27%, p = 0.03 and 30%, p = 0.02), and improved neurological assessment scores (1.5, p = 0.02 and 2, p = 0.058 vs 3 for vehicle). No abnormal histological findings specific to peptide treatments were observed in hematoxylin and eosin stained sections of kidney, liver, spleen, lung and heart. In vitro studies demonstrated that R18 and R18D were most toxic to neurons, followed by astrocytes, HEK293 and bEND.3 cells, but only at high concentrations and/or following 24-hour exposure. These findings further highlight the neuroprotective properties of poly-arginine peptides, and indicate that R18D at the dose examined is more potent than R18 in Wistar rats, and justify continued investigation of the R18 peptide as a novel neuroprotective agent for stroke.

Poly-arginine R18 and R18D (D-enantiomer) peptides reduce infarct volume and improves behavioural outcomes following perinatal hypoxic-ischaemic encephalopathy in the P7 rat.

We examined the neuroprotective efficacy of the poly-arginine peptide R18 and its D-enantiomer R18D in a perinatal hypoxic-ischaemic (HI) model in P7 Sprague-Dawley rats. R18 and R18D peptides were administered intraperitoneally at doses of 30, 100, 300 or 1000 nmol/kg immediately after HI (8% O2/92%N2 for 2.5 h). The previously characterised neuroprotective JNKI-1-TATD peptide at a dose of 1000 nmol/kg was used as a control. Infarct volume and behavioural outcomes were measured 48 h after HI. For the R18 and R18D doses examined, total infarct volume was reduced by 25.93% to 43.80% (P = 0.038 to < 0.001). By comparison, the JNKI-1-TATD reduced lesion volume by 25.27% (P = 0.073). Moreover, R18 and R18D treatment resulted in significant improvements in behavioural outcomes, while with JNKI-1-TATD there was a trend towards improvement. As an insight into the likely mechanism underlying the effects of R18, R18D and JNKI-1-TATD, the peptides were added to cortical neuronal cultures exposed to glutamic acid excitotoxicity, resulting in up to 89, 100 and 71% neuroprotection, respectively, and a dose dependent inhibition of neuronal calcium influx. The study further confirms the neuroprotective properties of poly-arginine peptides, and suggests a potential therapeutic role for R18 and R18D in the treatment of HIE.

PERFECTED enhanced recovery (PERFECT-ER) care versus standard acute care for patients admitted to acute settings with hip fracture identified as experiencing confusion: study protocol for a feasibility cluster randomized controlled trial.

BACKGROUND: Health and social care provision for an ageing population is a global priority. Provision for those with dementia and hip fracture has specific and growing importance. Older people who break their hip are recognised as exceptionally vulnerable to experiencing confusion (including but not exclusively, dementia and/or delirium and/or cognitive impairment(s)) before, during or after acute admissions. Older people experiencing hip fracture and confusion risk serious complications, linked to delayed recovery and higher mortality post-operatively. Specific care pathways acknowledging the differences in patient presentation and care needs are proposed to improve clinical and process outcomes. METHODS: This protocol describes a multi-centre, feasibility, cluster-randomised, controlled trial (CRCT) to be undertaken across ten National Health Service hospital trusts in the UK. The trial will explore the feasibility of undertaking a CRCT comparing the multicomponent PERFECTED enhanced recovery intervention (PERFECT-ER), which acknowledges the differences in care needs of confused older patients experiencing hip fracture, with standard care. The trial will also have an integrated process evaluation to explore how PERFECT-ER is implemented and interacts with the local context. The study will recruit 400 hip fracture patients identified as experiencing confusion and will also recruit "suitable informants" (individuals in regular contact with participants who will complete proxy measures). We will also recruit NHS professionals for the process evaluation. This mixed methods design will produce data to inform a definitive evaluation of the intervention via a large-scale pragmatic randomised controlled trial (RCT). DISCUSSION: The trial will provide a preliminary estimate of potential efficacy of PERFECT-ER versus standard care; assess service delivery variation, inform primary and secondary outcome selection, generate estimates of recruitment and retention rates, data collection difficulties, and completeness of outcome data and provide an indication of potential economic benefits. The process evaluation will enhance knowledge of implementation delivery and receipt. TRIAL REGISTRATION: ISRCTN, 99336264 . Registered on 5 September 2016.

Assessment of R18, COG1410, and APP96-110 in Excitotoxicity and Traumatic Brain Injury.

Cationic arginine-rich and poly-arginine peptides (referred to as CARPs) have potent neuroprotective properties in in vitro excitotoxicity and in vivo models of stroke. Traumatic brain injury (TBI) shares many pathophysiological processes as stroke, including excitotoxicity. Therefore, we evaluated our lead peptide, poly-arginine R18, with the COG1410 and APP96-110 peptides, which have neuroprotective actions following TBI. In an in vitro cortical neuronal glutamic acid excitotoxicity injury model, R18 was highly neuroprotective and reduced neuronal calcium influx, while COG1410 and APP96-110 displayed modest neuroprotection and were less effective at reducing calcium influx. In an impact-acceleration closed-head injury model (Marmarou model), R18, COG1410, and APP96-110 were administered intravenously (300 nmol/kg) at 30 minutes after injury in male Sprague-Dawley rats. When compared to vehicle, no peptide significantly improved functional outcomes, however the R18 and COG1410 treatment groups displayed positive trends in the adhesive tape test and rotarod assessments. Similarly, no peptide had a significant effect on hippocampal neuronal loss, however a significant reduction in axonal injury was observed for R18 and COG1410. In conclusion, this study has demonstrated that R18 is significantly more effective than COG1410 and APP96-110 at reducing neuronal injury and calcium influx following excitotoxicity, and that both R18 and COG1410 reduce axonal injury following TBI. Additional dose response and treatment time course studies are required to further assess the efficacy of R18 in TBI.

Delayed 2-h post-stroke administration of R18 and NA-1 (TAT-NR2B9c) peptides after permanent and/or transient middle cerebral artery occlusion in the rat.

Following positive results with the poly-arginine peptide R18 when administered intravenously 30 or 60min after permanent and/or transient middle cerebral artery occlusion (MCAO; 90min) in the rat, we examined the effectiveness of the peptide when administered 2h after MCAO. R18 was administered intravenously (1000nmol/kg via jugular vein) after permanent MCAO or a transient 3-h MCAO or when administered intra-arterially (100nmol/kg via internal carotid artery) immediately after reperfusion following a transient 2-h MCAO. In the transient MCAO studies, the neuroprotective NA-1 peptide was used as a positive control. Infarct volume, cerebral edema and functional outcomes were measured 24h after MCAO. Following permanent or transient MCAO, neither R18 nor NA-1 significantly reduced infarct volume. However, following permanent MCAO, R18 appeared to reduce cerebral edema (p=0.006), whereas following a transient 3-h MCAO, R18 improved the time to remove adhesive tape (p=0.04) without significantly affecting cerebral edema. There was also a trend (p=0.07) towards improved rota-rod performance with R18 in both permanent and transient 3-h MCAO. Following a transient 2-h MCAO, R18 had no significant effects on cerebral edema or neurological score but did lessen the extent of weight loss. Overall, while R18 had no effect on infarct volume, the peptide reduced cerebral edema after permanent MCAO, and improved some functional outcomes after transient MCAO.

Modification to the Rice-Vannucci perinatal hypoxic-ischaemic encephalopathy model in the P7 rat improves the reliability of cerebral infarct development after 48hours.

BACKGROUND: The Rice-Vannucci model of hypoxic-ischaemic encephalopathy (HIE) has been associated with a high degree of variability with respect to the development of cerebral infarction and infarct lesion volume. For this reason, we examined the occurrence of communicational blood flow within the common carotid (CCA), internal (ICA), and external (ECA) carotid arteries following CCA occlusion as a source of variability in the model. NEW METHOD: We propose a novel modification to the Rice-Vannucci model, whereby both the CCA and ECA are permanently ligated; mitigating communicational blood flow. RESULTS: Using magnetic resonance angiography, phase-contrast velocity encoding, and pulsed arterial spin labelling, the modified Rice-Vannucci model (CCA/ECA occlusion) was demonstrated to mitigate communicational blood flow, whilst significantly reducing ipsilateral hemispherical cerebral blood flow (CBF). Comparatively, the original Rice-Vannucci model (CCA occlusion) demonstrated anterograde and retrograde blood flow within the ICA and CCA, respectively, with a non-significant reduction in ipsilateral CBF. Furthermore, CCA/ECA occlusion plus hypoxia (8% O2/92% N2; 2.5h) resulted in 100% of animals presenting with an infarct (vs 87%), significantly larger infarct volume at 48h (18.5% versus 10.0%; p<0.01), reduced standard deviation (±10% versus ±15%), and significantly worsened functional outcomes when compared to CCA occlusion plus hypoxia. COMPARISON WITH EXISTING METHOD: We compared a modified Rice-Vannucci model (CCA/ECA occlusion±hypoxia) to the commonly used Rice-Vannucci model (CCA occlusion±hypoxia). CONCLUSION: This study demonstrates that CCA/ECA occlusion in the Rice-Vannucci model of HIE reduces infarct volume variability by limiting communicational blood flow.

Assessment of the Neuroprotective Effects of Arginine-Rich Protamine Peptides, Poly-Arginine Peptides (R12-Cyclic, R22) and Arginine-Tryptophan-Containing Peptides Following In Vitro Excitotoxicity and/or Permanent Middle Cerebral Artery Occlusion in Rats.

We have demonstrated that arginine-rich and poly-arginine peptides possess potent neuroprotective properties with arginine content and peptide positive charge being particularly critical for neuroprotective efficacy. In addition, the presence of other amino acids within arginine-rich peptides, as well as chemical modifications, peptide length and cell-penetrating properties also influence the level of neuroprotection. Against this background, we have examined the neuroprotective efficacy of arginine-rich protamine peptides, a cyclic (R12-c) poly-arginine peptide and a R22 poly-arginine peptide, as well as arginine peptides containing tryptophan or other amino acids (phenylalanine, tyrosine, glycine or leucine) in in vitro glutamic acid excitotoxicity and in vivo rat permanent middle cerebral artery occlusion models of stroke. In vitro studies demonstrated that protamine and poly-arginine peptides (R12-c, R22) were neuroprotective. Arginine-tryptophan-containing peptides were highly neuroprotective, with R12W8a being the most potent arginine-rich peptide identified in our laboratory. Peptides containing phenylalanine or tyrosine substituted in place of tryptophan in R12W8a were also highly neuroprotective, whereas leucine, and in particular glycine substitutions, decreased peptide efficacy. In vivo studies with protamine administered intravenously at 1000 nmol/kg 30 min after MCAO significantly reduced infarct volume and cerebral oedema by 22.5 and 38.6%, respectively. The R12W8a peptide was highly toxic when administered intravenously at 300 or 100 nmol/kg and ineffective at reducing infarct volume when administered at 30 nmol/kg 30 min after MCAO, unlike R18 (30 nmol/kg), which significantly reduced infarct volume by 20.4%. However, both R12W8a and R18 significantly reduced cerebral oedema by 19.8 and 42.2%, respectively. Protamine, R12W8a and R18 also reduced neuronal glutamic acid-induced calcium influx. These findings further highlight the neuroprotective properties of arginine-rich peptides and support the view that they represent a new class of neuroprotective agent.

Neuroprotective efficacy of poly-arginine R18 and NA-1 (TAT-NR2B9c) peptides following transient middle cerebral artery occlusion in the rat.

We examined the efficacy of R18 in a transient MCAO model and compared its effectiveness to the well-characterized neuroprotective NA-1 peptide. R18 and NA-1 peptides were administered intravenously (30, 100, 300, 1000nmol/kg), 60min after the onset of 90min of MCAO. Infarct volume, cerebral swelling and functional outcomes (neurological score, adhesive tape and rota-rod) were measured 24h after MCAO. R18 reduced total infarct volume by 35.1% (p=0.008), 24.8% (p=0.059), 12.2% and 9.6% for the respective 1000 to 30nmol/kg doses, while the corresponding doses of NA-1 reduced lesion volume by 26.1% (p=0.047), 16.6%, 16.5% and 7%, respectively. R18 also reduced hemisphere swelling by between 46.1% (1000 and 300nmol/kg; p=0.009) and 24.4% (100nmol/kg; p=0.066), while NA-1 reduced swelling by 25.7% (1000nmol/kg; p=0.054). In addition, several R18 and NA-1 treatment groups displayed a significant improvement in at least one parameter of the adhesive tape test. These results confirm the neuroprotective properties of R18, and suggest that the peptide is a more effective neuroprotective agent than NA-1. This provides strong justification for the continuing development of R18 as a neuroprotective treatment for stroke.

Freedom of Information Act: scalpel or just a sharp knife?

The concluding statement of the Burns Commission, established to evaluate whether changes are needed to the Freedom of Information Act (FOIA), ruled no major legislative changes were required. As such Freedom of Information (FOI) legislation still enables anyone to obtain information from public authorities. In this brief report article we explore arguments regarding FOI as an instrument for healthcare research using an international research programme as a case study.