ORCID Profile
0000-0002-3282-8502
Current Organisation
The University of Edinburgh
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Publisher: Cold Spring Harbor Laboratory
Date: 15-07-2019
DOI: 10.1101/703181
Abstract: Reproducible science requires transparent reporting. The ARRIVE guidelines were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here we introduce ARRIVE 2019. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise the items and split the guidelines into two sets, the ARRIVE Essential 10, which constitute the minimum requirement, and the Recommended Set, which describes the research context. This ision facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers to verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration document that serves 1) to explain the rationale behind each item in the guidelines, 2) to clarify key concepts and 3) to provide illustrative ex les. We aim through these changes to help ensure that researchers, reviewers and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.
Publisher: Elsevier BV
Date: 2014
DOI: 10.1016/J.JNEUMETH.2013.09.010
Abstract: Meta-analyses of data from human studies are invaluable resources in the life sciences and the methods to conduct these are well documented. Similarly there are a number of benefits in conducting meta-analyses on data from animal studies they can be used to inform clinical trial design, or to try and explain discrepancies between preclinical and clinical trial results. However there are inherit differences between animal and human studies and so applying the same techniques for the meta-analysis of preclinical data is not straightforward. For ex le preclinical studies are frequently small and there is often substantial heterogeneity between studies. This may have an impact on both the method of calculating an effect size and the method of pooling data. Here we describe a practical guide for the meta-analysis of data from animal studies including methods used to explore sources of heterogeneity.
Publisher: SAGE Publications
Date: 12-09-2010
Abstract: Objective. An enriched environment (EE) refers to conditions that facilitate or enhance sensory, cognitive, motor, and social stimulation relative to standard (laboratory) conditions. Despite numerous published studies investigating this concept in animal stroke models, there is still debate around its efficacy. The authors performed a systematic review and meta-analysis to determine the efficacy of an EE on neurobehavioral scores, learning, infarct size, and mortality in animal models of ischemic stroke. Methods. Systematic review of controlled studies of the use of an EE in experimental stroke was conducted. Data extracted were analyzed using weighted mean difference meta-analysis. For pooled tests of neurobehavioral scores, a random effects standardized method was used. Results. Animals recovering in an EE poststroke had mean neurobehavioral scores 0.9 standard deviations (95% confidence interval [CI] = 0.5-1.3 P .001) above the mean scores of animals recovering in standard conditions and showed a trend toward improvement in learning (25.1% improvement 95% CI = 3.7-46.6 P = .02). There was no significant increase in death. Animals exposed to an EE had 8.0% larger infarcts than control animals (95% CI = 1.8-14.1 P = .015). Conclusions. The results indicate significant improvements in sensorimotor function with EE poststroke but suggest a small increase in infarct volume. Clarification of the underlying mechanisms requires further study but should not overshadow the observed functional improvements and their application to clinical trials during stroke rehabilitation.
Publisher: eLife Sciences Publications, Ltd
Date: 08-09-2017
DOI: 10.7554/ELIFE.24260
Abstract: Meta-analyses are increasingly used for synthesis of evidence from biomedical research, and often include an assessment of publication bias based on visual or analytical detection of asymmetry in funnel plots. We studied the influence of different normalisation approaches, s le size and intervention effects on funnel plot asymmetry, using empirical datasets and illustrative simulations. We found that funnel plots of the Standardized Mean Difference (SMD) plotted against the standard error (SE) are susceptible to distortion, leading to overestimation of the existence and extent of publication bias. Distortion was more severe when the primary studies had a small s le size and when an intervention effect was present. We show that using the Normalised Mean Difference measure as effect size (when possible), or plotting the SMD against a s le size-based precision estimate, are more reliable alternatives. We conclude that funnel plots using the SMD in combination with the SE are unsuitable for publication bias assessments and can lead to false-positive results.
Publisher: Public Library of Science (PLoS)
Date: 13-10-2015
Publisher: SAGE Publications
Date: 19-06-2012
DOI: 10.1111/J.1747-4949.2012.00805.X
Abstract: The mortality and morbidity associated with stroke makes the development of new drugs a research priority. Recent unsuccessful clinical trials have reduced enthusiasm for the development of neuroprotective drugs. Here, we use empirical evidence derived from systematic reviews of stroke drug development to identify stages of drug development which might be improved. We then propose exemplar strategies which may be helpful, along with some basic economic modelling of what the impact of such strategies might be. This suggests that relatively straightforward measures might reduce the costs of drug development by $5.8 bn or 31%.
Publisher: Wiley
Date: 14-07-2020
DOI: 10.1113/JP280389
Abstract: Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and ide the items of the guidelines into 2 sets, the ‘ARRIVE Essential 10,’ which constitutes the minimum requirement, and the ‘Recommended Set,’ which describes the research context. This ision facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative ex les. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.
Publisher: European Association for Health Information and Libraries EAHIL
Date: 24-06-2021
DOI: 10.32384/JEAHIL17465
Abstract: Throughout the global coronavirus pandemic, we have seen an unprecedented volume of COVID-19 researchpublications. This vast body of evidence continues to grow, making it difficult for research users to keep up with the pace of evolving research findings. To enable the synthesis of this evidence for timely use by researchers, policymakers, and other stakeholders, we developed an automated workflow to collect, categorise, and visualise the evidence from primary COVID-19 research studies. We trained a crowd of volunteer reviewers to annotate studies by relevance to COVID-19, study objectives, and methodological approaches. Using these human decisions, we are training machine learning classifiers and applying text-mining tools to continually categorise the findings and evaluate the quality of COVID-19 evidence.
Publisher: Public Library of Science (PLoS)
Date: 09-08-2013
Publisher: Cold Spring Harbor Laboratory
Date: 28-06-2022
DOI: 10.1101/2022.06.27.22276964
Abstract: Mandates and recommendations related to embedding open science practices within the research lifecycle are increasingly common. Few stakeholders, however, are monitoring compliance to their mandates or recommendations. It is necessary to monitor the current state of open science to track changes over time and to identify areas to create interventions to drive improvements. Monitoring open science practices requires that they are defined and operationalized. Involving the biomedical community, we sought to reach consensus on a core set of open science practices to monitor at biomedical research institutions. To establish consensus in a structured and systematic fashion, we conducted a modified 3-round Delphi study. Participants in Round 1 were 80 in iduals from 20 biomedical research institutions that exhibit interest in or actively support open science. Participants were research administrators, researchers, specialists in dedicated open science roles, and librarians. In Rounds 1 and 2, participants completed an online survey evaluating a set of potential open science practices that could be important and meaningful to monitor in an automated institutional open science dashboard. Participants voted on the inclusion of each item and provided a rationale for their choice. We defined consensus as 80% agreement. Between rounds, participants received aggregated voting scores for each item and anonymized comments from all participants, and were asked to re-vote on items that did not reach consensus. For Round 3, we hosted two half- day virtual meetings with 21 and 17 participants respectively to discuss and vote on all items that had not reached consensus after Round 2. Ultimately, participants reached consensus to include a 19 open science practices. A group of international stakeholders used a modified Delphi process to agree upon open science practices to monitor in a proposed open science dashboard for biomedical institutions. The core set of 19 open science practices identified by participants will form the foundation for institutional dashboards that display compliance with open science practices. They will now be assessed and tested for automatic inclusion in terms of technical feasibility. Using user-centered design, participating institutions will be involved in creating a dashboard prototype, which can then be implemented to monitor rates of open science practices at biomedical institutions. Our methods and approach may also transfer to other research settings–other disciplines could consider using our consensus list as a starting point for agreement upon a discipline-specific set of open science practices to monitor. The findings may also be of broader value to the development of policy, education, and interventions.
Publisher: SAGE Publications
Date: 17-09-2008
Abstract: As a research community, we have failed to show that drugs, which show substantial efficacy in animal models of cerebral ischemia, can also improve outcome in human stroke. Accumulating evidence suggests this may be due, at least in part, to problems in the design, conduct, and reporting of animal experiments which create a systematic bias resulting in the overstatement of neuroprotective efficacy. Here, we set out a series of measures to reduce bias in the design, conduct and reporting of animal experiments modeling human stroke.
Publisher: Wiley
Date: 14-07-2020
DOI: 10.1113/EP088870
Publisher: Springer Science and Business Media LLC
Date: 21-07-2012
Publisher: Public Library of Science (PLoS)
Date: 17-12-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2009
DOI: 10.1161/STROKEAHA.108.525386
Abstract: Background and Purpose— As a research community, we have failed to demonstrate that drugs which show substantial efficacy in animal models of cerebral ischemia can also improve outcome in human stroke. Summary of Review— Accumulating evidence suggests this may be due, at least in part, to problems in the design, conduct and reporting of animal experiments which create a systematic bias resulting in the overstatement of neuroprotective efficacy. Conclusions— Here, we set out a series of measures to reduce bias in the design, conduct and reporting of animal experiments modeling human stroke.
Publisher: Oxford University Press (OUP)
Date: 03-05-2007
DOI: 10.1093/BRAIN/AWM083
Abstract: Induced hypothermia is proposed as a treatment for acute ischaemic stroke, but there have been too few clinical trials involving too few patients to draw any conclusions about the therapeutic benefit of cooling. Animal studies of induced hypothermia in focal cerebral ischaemia have tested cooling throughout a wide range of target temperatures, durations and intervals between stroke onset and the initiation of hypothermia. These studies, therefore, provide an opportunity to evaluate the effectiveness of different treatment strategies in animal models to inform the design of future clinical trials. We performed a systematic review and meta-analysis of the evidence for efficacy of hypothermia in animal models of ischaemic stroke, and identified 101 publications reporting the effect of hypothermia on infarct size or functional outcome, including data from a total of 3353 animals. Overall, hypothermia reduced infarct size by 44% [95% confidence interval (CI), 40-47%]. Efficacy was highest with cooling to lower temperatures (< or =31 degrees C), where treatment was started before or at the onset of ischaemia and in temporary rather than permanent ischaemia models. However, a substantial reduction in infarct volume was also observed with cooling to 35 degrees C (30% 95% CI, 21-39%), with initiation of treatment between 90 and 180 min (37% 95% CI, 28-46%) and in permanent ischaemia models (37% 95% CI, 30-43%). The effects of hypothermia on functional outcome were broadly similar. We conclude that in animal models of focal cerebral ischaemia, hypothermia improves outcome by about one-third under conditions that may be achievable for large numbers of patients with ischaemic stroke. Large randomized clinical trials testing the effect of hypothermia in patients with acute ischaemic stroke are warranted.
Publisher: Springer Science and Business Media LLC
Date: 19-11-2013
DOI: 10.1038/NRNEUROL.2013.232
Abstract: Translational neuroscience is in the doldrums. The stroke research community was among the first to recognize that the motivations inherent in our system of research can cause investigators to take shortcuts, and can introduce bias and reduce generalizability, all of which leads ultimately to the recurrent failure of apparently useful drug candidates in clinical trials. Here, we review the evidence for these problems in stroke research, where they have been most studied, and in other translational research domains, which seem to be bedevilled by the same issues. We argue that better scientific training and simple changes to the way that we fund, assess and publish research findings could reduce wasted investment, speed drug development, and create a healthier research environment. For 'phase III' preclinical studies--that is, those studies that build the final justification for conducting a clinical trial--we argue for a need to apply the same attention to detail, experimental rigour and statistical power in our animal experiments as in the clinical trials themselves.
Publisher: Public Library of Science (PLoS)
Date: 20-05-2019
Publisher: Elsevier BV
Date: 09-2007
DOI: 10.1016/J.TINS.2007.06.009
Abstract: The development of stroke drugs has been characterized by success in animal studies and subsequent failure in clinical trials. Animal studies might have overstated efficacy, or clinical trials might have understated efficacy in either case we need to better understand the reasons for failure. Techniques borrowed from clinical trials have recently allowed the impact of publication and study-quality biases on published estimates of efficacy in animal experiments to be described. On the basis of these data, we propose minimum standards for the range and quality of pre-clinical animal data. We believe the adoption of these standards will lead to improved effectiveness and efficiency in the selection of drugs for clinical trials in stroke and in the design of those trials.
Publisher: Public Library of Science (PLoS)
Date: 31-05-2016
Publisher: Public Library of Science (PLoS)
Date: 30-03-2010
Publisher: Public Library of Science (PLoS)
Date: 10-11-2015
Publisher: SAGE Publications
Date: 02-2009
DOI: 10.1111/J.1747-4949.2009.00241.X
Abstract: As a research community, we have failed to demonstrate that drugs that show substantial efficacy in animal models of cerebral ischemia can also improve outcome in human stroke. Accumulating evidence suggests that this may be due, at least in part, to problems in the design, conduct and reporting of animal experiments, which create a systematic bias resulting in the overstatement of neuroprotective efficacy. Here, we set out a series of measures to reduce bias in the design, conduct and reporting of animal experiments modeling human stroke.
Publisher: Center for Open Science
Date: 25-08-2022
Abstract: Existing strategies to identify relevant studies for systematic review may not perform equally well across research domains. We compare four approaches based on either human or automated screening of either title and abstract or full text and report the training of a machine learning algorithm to identify in vitro studies from bibliographic records.We used a systematic review of oxygen-glucose deprivation (OGD) in PC-12 cells to compare approaches. For human screening, two reviewers independently screened studies based on title and abstract or full text, with disagreements reconciled by a third. For automated screening, we applied text mining to either title and abstract or full text. We trained a machine learning algorithm with decisions from 2,000 randomly selected PubMed Central records enriched with a dataset of known in vitro studies.Full text approaches performed best, with human (sensitivity 0.990, specificity 1.000, precision 0.994) outperforming text mining (sensitivity 0.972, specificity 0.980, precision 0.764). For title and abstract, text mining (sensitivity 0.890, specificity 0.995, precision 0.922) outperformed human screening (sensitivity 0.862, specificity 0.998, precision 0.975). At our target sensitivity of 95% the algorithm performed with specificity of 0.850 and precision of 0.700.In this in vitro systematic review, human screening based on title and abstract erroneously excluded 14% of relevant studies, perhaps because title and abstract provide an incomplete description of methods used. Our algorithm might be used as a first selection phase in in vitro systematic reviews to limit the extent of full text screening required.
Publisher: American Medical Association (AMA)
Date: 2014
DOI: 10.1001/JAMANEUROL.2013.4684
Abstract: Blockade of small GTPase-RhoA signaling pathway is considered a candidate translational strategy to improve functional outcome after spinal cord injury (SCI) in humans. Pooling preclinical evidence by orthodox meta-analysis is confounded by missing data (publication bias). To conduct a systematic review and meta-analysis of RhoA/Rho-associated coiled-coil containing protein kinase (ROCK) blocking approaches to (1) analyze the impact of bias that may lead to inflated effect sizes and (2) determine the normalized effect size of functional locomotor recovery after experimental thoracic SCI. We conducted a systematic search of PubMed, EMBASE, and Web of Science and hand searched related references. Studies were selected if they reported the effect of RhoA/ROCK inhibitors (C3-exoenzmye, fasudil, Y-27632, ibuprofen, siRhoA, and p21) in experimental spinal cord hemisection, contusion, or transection on locomotor recovery measured by the Basso, Beattie, and Bresnahan score or the Basso Mouse Scale for Locomotion. Two investigators independently assessed the identified studies. Details of in idual study characteristics from each publication were extracted and effect sizes pooled using a random effects model. We assessed risk for bias using a 9-point-item quality checklist and calculated publication bias with Egger regression and the trim and fill method. A stratified meta-analysis was used to assess the impact of study characteristics on locomotor recovery. Thirty studies (725 animals) were identified. RhoA/ROCK inhibition was found to improve locomotor outcome by 21% (95% CI, 16.0-26.6). Assessment of publication bias by the trim and fill method suggested that 30% of experiments remain unpublished. Inclusion of these theoretical missing studies suggested a 27% overestimation of efficacy, reducing the overall efficacy to a 15% improvement in locomotor recovery. Low study quality was associated with larger estimates of neurobehavioral outcome. Taking into account publication bias, RhoA/ROCK inhibition improves functional outcome in experimental SCI by 15%. This is a plausible strategy for the pharmacological augmentation of neurorehabilitation after human SCI. These findings support the necessity of a systematic analysis to identify preclinical bias before embarking on a clinical trial.
Publisher: SAGE Publications
Date: 30-12-2009
Abstract: Erythropoietin (EPO) has shown promise as a neuroprotectant in animal models of ischemic stroke. EPO is thought not only to protect neurons from cell death, but also to promote regeneration after stroke. Here, we report a systematic review and meta-analysis of the efficacy of EPO in animal models of focal cerebral ischemia. Primary outcomes were infarct size and neurobehavioral outcome. Nineteen studies involving 346 animals for infarct size and 425 animals for neurobehavioral outcome met our inclusion criteria. Erythropoietin improved infarct size by 30.0% (95% CI: 21.3 to 38.8) and neurobehavioral outcome by 39.8% (33.7 to 45.9). Studies that randomized to treatment group or that blinded assessment of outcome showed lower efficacy. Erythropoietin was tested in animals with hypertension in no studies reporting infarct size and in 7.5% of the animals reporting neurobehavioral outcome. These findings show efficacy for EPO in experimental stroke, but when the impact of common sources of bias are considered, this efficacy falls, suggesting we may be overestimating its potential benefit. As common human co-morbidities may reduce therapeutic efficacy, broader testing to delineate the range of circumstances in which EPO works best would be beneficial.
Publisher: SAGE Publications
Date: 21-07-2010
Abstract: Thrombolysis with recombinant tissue plasminogen activator (rtPA) improves outcome in animal models of stroke and in clinical trial, but is associated with increased intracranial hemorrhage. Here, we explore the impact of biologic and experimental design factors on efficacy and bleeding. We conducted a systematic review of studies describing the effect of tPA in thrombotic occlusion models of ischemic stroke followed by random effects meta-analysis, meta-regression, and trim and fill. We identified 202, 66, 128, and 54 comparisons reporting infarct volume, neurobehavioral score, hemorrhage, and mortality, respectively. The rtPA reduced infarct volume by 25.2% (95% confidence interval=21.8 to 28.6, 3388 animals), improved neurobehavioral score by 18.0% (12.6% to 23.3%, n=1243), increased the risk of hemorrhage (odds ratio=1.71, 1.42 to 2.07, n=2833) and had no significant effect on mortality (odds ratio=0.82, 0.62 to 1.08, n=1274). There was an absolute reduction in efficacy of 1.1% (0.7% to 1.4%) for every 10 minutes delay to treatment. Cumulative meta-analysis showed that the estimate of efficacy fell as more data became available. Publication bias inflated efficacy by 5.1% (infarct volume) and 8.1% (neurobehavioral score). This data set was large enough to be adequately powered to estimate with precision the impact of biologic and experimental factors on the efficacy and safety of rtPA.
Publisher: Public Library of Science (PLoS)
Date: 30-03-2010
Publisher: SAGE Publications
Date: 03-07-2012
DOI: 10.1111/J.1747-4949.2012.00834.X
Abstract: Hypothermia is a promising experimental treatment for acute ischemic stroke. Human trials are still at an early stage, with the focus now on using hypothermia in awake patients. Pethidine (meperidine) is the principle agent used to control shivering in humans however, whether it has any modulating effects on the neuroprotective efficacy of hypothermia is unknown. The aim of this study was to determine if pethidine influences the neuroprotective effect of hypothermia in experimental stroke. Seventy-two male spontaneously hypertensive rats were anesthetized with isoflurane and randomly assigned to either normothermia (37·4°C rectal temperature) hypothermia (33°C maintained for 130 mins) normothermia plus pethidine (2·5 mg/kg) or hypothermia plus pethidine. Temporary (90 mins) endovascular occlusion of the middle cerebral artery was induced blinded to treatment allocation and was confirmed with laser Doppler flowmetry. Pethidine and cooling were started immediately after vessel occlusion. Animals in the normothermia group had active temperature management using a heat l and fan. Assessments of outcome were carried out 24 after the induction of injury. Thirteen animals met our prespecified criteria for exclusion, and data for 59 rats were presented here. Hypothermia was associated with a 63% reduction in infarct size, and pethidine had no significant impact on the efficacy of hypothermia. No effects were observed in neurobehavioral outcome or edema volume across experimental groups. The effects of hypothermia in a model of focal ischemia are not affected by administration of pethidine.
Publisher: Portico
Date: 05-2019
Publisher: SAGE Publications
Date: 19-02-2014
Abstract: The use of systematic review and meta-analysis of preclinical studies has become more common, including those of studies describing the modeling of cerebrovascular diseases. Empirical evidence suggests that too many preclinical experiments lack methodological rigor, and this leads to inflated treatment effects. The aim of this review is to describe the concepts of systematic review and meta-analysis and consider how these tools may be used to provide empirical evidence to spur the field to improve the rigor of the conduct and reporting of preclinical research akin to their use in improving the conduct and reporting of randomized controlled trials in clinical research. As with other research domains, systematic reviews are subject to bias. Therefore, we have also suggested guidance for their conduct, reporting, and critical appraisal.
Publisher: SAGE Publications
Date: 19-05-2010
Abstract: No single animal model is able to encompass all of the variables known to affect human ischemic stroke. This review highlights the major strengths and weaknesses of the most commonly used animal models of acute ischemic stroke in the context of matching model and experimental aim. Particular emphasis is placed on the relationships between outcome and underlying vascular variability, physiologic control, and use of models of comorbidity. The aim is to provide, for novice and expert alike, an overview of the key controllable determinants of experimental stroke outcome to help ensure the most effective application of animal models to translational research.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2014
DOI: 10.1161/STROKEAHA.114.006304
Abstract: Poststroke depression is a prevalent complication of stroke with unclear pathogenesis. The benefits of antidepressants in this context and their effects on stroke recovery other than effects on mood are not clearly defined, with some studies suggesting efficacy in improving functional outcome in both depressed and nondepressed stroke patients. We have analyzed the preclinical animal data on antidepressant treatment in focal cerebral ischemia, modeled±depression, to help inform clinical trial design. We performed a systematic review and meta-analysis of data from experiments testing the efficacy of antidepressants versus no treatment to reduce infarct volume or improve neurobehavioral or neurogenesis outcomes in animal models of stroke. We used random-effects metaregression to test the impact of study quality and design characteristics and used trim and fill to assess publication bias. We identified 44 publications describing the effects of 22 antidepressant drugs. The median quality checklist score was 5 of a possible 10 (interquartile range, 4–7). Overall, antidepressants reduced infarct volume by 27.3% (95% confidence interval, 20.7%–33.8%) and improved neurobehavioral outcomes by 53.7% (46.4%–61.1%). There was little evidence for an effect of selective serotonin reuptake inhibitors on infarct volume. For neurobehavioral outcomes there was evidence of publication bias. Selective serotonin reuptake inhibitors were the most frequently studied antidepressant subtype and improved neurobehavioral outcome by 51.8% (38.6%–64.9%) and increased neurogenesis by 2.2 SD (1.3–3.0). In line with current clinical data and despite some limitations, antidepressant treatments seem to improve infarct volume and neurobehavioral outcome in animal models of ischemic stroke.
Publisher: SAGE Publications
Date: 18-02-2014
Abstract: Background. Regular exercise reduces the risk of a first-ever stroke and is associated with smaller infarcts. Although evidence has suggested that therapeutic exercise following stroke is beneficial, we do not yet know whether exercise reduces stroke severity and improves functional recovery. The mechanisms underlying any benefit remain unclear. Objective. To conduct a systematic review and meta-analysis of studies testing exercise in animal models of ischemic stroke where outcomes were measured as infarct volume, neurobehavioral score, neurogenesis, or a combination of these. We also sought evidence of publication bias. Methods. We searched 3 online databases for publications reporting the use of exercise in focal cerebral ischemia. We used DerSimonian and Laird normalized random-effects meta-analysis and meta-regression to determine the impact of study quality and design on the efficacy of exercise. Results. Overall, exercise reduced infarct volume by 25.2% (95% confidence interval [CI] = 19.0%-31.3% 65 experiments and 986 animals) and improved neurobehavioral score by 38.2% (95% CI = 29.1%-47.3% 42 experiments n = 771). For both outcomes, larger effects were seen when exercise preceded ischemia rather than came after it. For neurobehavioral scores, we found evidence of publication bias. Reported study quality was moderate (median score 5/10). Both model-specific (eg, type of ischemia) and exercise-specific characteristics influenced reported outcome. Conclusion. Exercise, either before or after ischemia, reduced infarct volume and improved neurobehavioral score. However, overall estimates of efficacy were higher in studies at risk of bias, and for neurobehavioral outcomes, there was evidence of a substantial publication bias.
Publisher: Wiley
Date: 02-2011
DOI: 10.1002/ANA.22243
Abstract: Interventions that improve functional outcome after acute intracerebral hemorrhage (ICH) in animals might benefit humans. Therefore, we systematically reviewed the literature to find studies of nonsurgical treatments tested in animal models of ICH. In July 2009 we searched Ovid Medline (from 1950), Embase (from 1980), and ISI Web of Knowledge (from 1969) for controlled animal studies of nonsurgical interventions given after the induction of ICH that reported neurobehavioral outcome. We assessed study quality and performed meta-analysis using a weighted mean difference random effects model. Of 13,343 publications, 88 controlled studies described the effects of 64 different medical interventions (given a median of 2 hours after ICH induction) on 38 different neurobehavioral scales in 2,616 treated or control animals (median 14 rodents per study). Twenty-seven (31%) studies randomized treatment allocation, and 7 (8%) reported allocation concealment these studies had significantly smaller effect sizes than those without these attributes (p 1 study. Meta-regression revealed that together, structural outcome and the intervention used accounted for 65% of the observed heterogeneity in neurobehavioral score (p < 0.001, adjusted r(2) = 0.65). Further animal studies of the interventions that we found to improve both functional and structural outcomes in animals, using better experimental designs, could target efforts to translate effective treatments for ICH in animals into randomized controlled trials in humans.
Publisher: SAGE Publications
Date: 19-06-2012
Abstract: Background. Constraint-induced movement therapy (CIMT) is used to counteract learned nonuse observed following stroke in humans and has been shown to improve function. Variations of CIMT used in animal models of stroke have the potential to inform and improve our understanding of this intervention. Objective. To conduct a systematic review of studies investigating constraint in experimental stroke. The authors aimed to assess the quality and establish the efficacy of constraint on neurobehavior, cognitive function, infarct size, and stress and mortality and to determine the optimal dose or time to administration. Methods. Systematic review with meta-analysis was used. Data were analyzed using DerSimonian and Laird weighted-mean-difference random effects meta-analysis. Results. The quality scores of the 8 articles (15 studies) included were moderate (median 5/10 interquartile range, 4.8-6.0). There was a trend for animals with constraint to have worse neurobehavioral scores (−10% worse 95% confidence interval [CI] = −20 to 0 P = .06). Infarct volumes were not significantly different between groups (−3% larger with constraint 95% CI = −15 to 9 P = .63). Cognitive function was significantly better after constraint, although this estimate was based on only 28 animals from 2 studies. Insufficient data prevented analysis of the effect of constraint on stress and mortality. Conclusions. This meta-analysis showed no benefit of constraint on neurobehavioral scores, which is at odds with some human studies. Animal models may help us efficiently explore the biological basis of rehabilitation interventions however, review of the data in this study raise uncertainty about its effectiveness in humans.
Publisher: Cold Spring Harbor Laboratory
Date: 19-07-2018
DOI: 10.1101/370874
Abstract: The ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines are widely endorsed but compliance is limited. We sought to determine whether journal-requested completion of an ARRIVE checklist improves full compliance with the guidelines. In a randomised controlled trial, manuscripts reporting in vivo animal research submitted to PLOS ONE (March-June 2015) were allocated to either requested completion of an ARRIVE checklist or current standard practice. We measured the change in proportion of manuscripts meeting all ARRIVE guideline checklist items between groups. We randomised 1,689 manuscripts, 1,269 were sent for peer review and 762 accepted for publication. The request to complete an ARRIVE checklist had no effect on full compliance with the ARRIVE guidelines. Details of animal husbandry (ARRIVE sub-item 9a) was the only item to show improved reporting, from 52.1% to 74.1% (X 2 =34.0, df=1, p=2.1×10 −7 ). These results suggest that other approaches are required to secure greater implementation of the ARRIVE guidelines.
Publisher: Public Library of Science (PLoS)
Date: 23-08-2013
Publisher: Cold Spring Harbor Laboratory
Date: 15-07-2019
DOI: 10.1101/703355
Abstract: Improving the reproducibility of biomedical research is a major challenge. Transparent and accurate reporting are vital to this process it allows readers to assess the reliability of the findings, and repeat or build upon the work of other researchers. The NC3Rs developed the ARRIVE guidelines in 2010 to help authors and journals identify the minimum information necessary to report in publications describing in vivo experiments. Despite widespread endorsement by the scientific community, the impact of the ARRIVE guidelines on the transparency of reporting in animal research publications has been limited. We have revised the ARRIVE guidelines to update them and facilitate their use in practice. The revised guidelines are published alongside this paper. This Explanation and Elaboration document was developed as part of the revision. It provides further information about each of the 21 items in ARRIVE 2019, including the rationale and supporting evidence for their inclusion in the guidelines, elaboration of details to report, and ex les of good reporting from the published literature.
Publisher: Public Library of Science (PLoS)
Date: 14-07-2020
Publisher: F1000 Research Ltd
Date: 03-01-2019
DOI: 10.12688/F1000RESEARCH.15869.1
Abstract: Introduction: Globally, stroke is the second leading cause of death. Despite the burden of illness and death, few acute interventions are available to patients with ischemic stroke. Over 1,000 potential neuroprotective therapeutics have been evaluated in preclinical models. It is important to use robust evidence synthesis methods to appropriately assess which therapies should be translated to the clinical setting for evaluation in human studies. This protocol details planned methods to conduct a systematic review to identify and appraise eligible studies and to use a network meta-analysis to synthesize available evidence to answer the following questions: in preclinical in vivo models of focal ischemic stroke, what are the relative benefits of competing therapies tested in combination with the gold standard treatment alteplase in (i) reducing cerebral infarction size, and (ii) improving neurobehavioural outcomes? Methods: We will search Ovid Medline and Embase for articles on the effects of combination therapies with alteplase. Controlled comparison studies of preclinical in vivo models of experimentally induced focal ischemia testing the efficacy of therapies with alteplase versus alteplase alone will be identified. Outcomes to be extracted include infarct size (primary outcome) and neurobehavioural measures. Risk of bias and construct validity will be assessed using tools appropriate for preclinical studies. Here we describe steps undertaken to perform preclinical network meta-analysis to synthesise all evidence for each outcome and obtain a comprehensive ranking of all treatments. This will be a novel use of this evidence synthesis approach in stroke medicine to assess pre-clinical therapeutics. Combining all evidence to simultaneously compare mutliple therapuetics tested preclinically may provide a rationale for the clinical translation of therapeutics for patients with ischemic stroke. Dissemination : Review findings will be submitted to a peer-reviewed journal and presented at relevant scientific meetings to promote knowledge transfer. Registration: PROSPERO number to be submitted following peer review.
Publisher: SAGE Publications
Date: 12-06-2012
DOI: 10.1111/J.1747-4949.2012.00797.X
Abstract: Stem cell therapy holds great promise in medicine, but clinical development should be based on a sound understanding of potential weaknesses in supporting experimental data. The aim of this article was to provide a systematic overview of evidence relating to the efficacy of stem cell-based therapies in animal models of stroke to foster the clinical application of stem cell-based therapies and to inform the design of large-scale clinical trials. We conducted a systematic search for reports of experiments using stem cells in animal models of cerebral ischaemia, and performed DerSimmonian and Laird random effects meta-analysis. We assessed the impact of study characteristics, of publication bias and of measures to reduce bias. We identified 6059 publications, 117 met our prespecified inclusion criteria. One hundred eighty-seven experiments using 2332 animals described changes in structural outcome and 192 experiments using 2704 animals described changes in functional outcome. Median study quality score was 4 (interquartile range 3 to 6) and less than half of studies reported randomization or blinded outcome assessment only three studies reported a s le size calculation. Nonrandomized studies gave significantly higher estimates of improvement in structural outcome, and there was evidence of a significant publication bias. For structural outcome autologous (i.e. self-derived) stem cells were more effective than allogeneic (donor-derived) cells, but for functional outcome, the reverse was true. A significant dose–response relationship was observed only for structural outcome. For structural outcome, there was an absolute reduction in efficacy of 1.5% (−2.4 to −0.6) for each days delay to treatment functional outcome was independent of the time of administration. While stem cells appear to be of some benefit in animal models of stroke the internal and external validity of this literature is potentially confounded by poor study quality and by publication bias. The clinical development of stem cell-based therapies, in stroke and elsewhere, should acknowledge these potential weaknesses in the supporting animal data.
Publisher: Public Library of Science (PLoS)
Date: 14-07-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2008
DOI: 10.1161/STROKEAHA.108.515957
Abstract: Background and Purpose— The neutral results of the SAINT II trial have again highlighted difficulties translating neuroprotective efficacy from bench to bedside. Animal studies are susceptible to study quality biases, which may lead to overstatement of efficacy. We report the impact of study quality on published estimates of the efficacy of NXY-059 in animal models of stroke. Methods— We conducted a systematic review and stratified meta-analysis of published studies describing the efficacy of NXY-059 in experimental focal cerebral ischemia. Results— Overall, NXY-059 improved infarct volume by 43.3% (95% CI, 34.7 to 52.8). Only 2 of 9 publications reported randomization, concealment of treatment allocation, and blinded outcome assessment. Studies not reporting these quality items gave substantially higher estimates of efficacy than did higher-quality studies. Conclusions— The reported efficacy of NXY-059 in animal models of stroke is confounded by low study quality. The failure of SAINT II highlights the need for substantial improvements in the design, conduct, and reporting of animal studies journals can play an important role in this by adopting standards for animal studies similar to those agreed over 10 years ago for clinical trials.
Publisher: Public Library of Science (PLoS)
Date: 16-07-2013
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2002
End Date: 2005
Funder: Canadian Institutes of Health Research
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