ORCID Profile
0000-0001-9187-9839
Current Organisations
NHS Forth Valley
,
The University of Edinburgh
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Publisher: Springer Science and Business Media LLC
Date: 30-11-2011
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: Elsevier BV
Date: 05-2017
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: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2004
DOI: 10.1161/01.STR.0000125719.25853.20
Abstract: Background and Purpose— The extensive neuroprotective literature describing the efficacy of candidate drugs in focal ischemia has yet to lead to the development of effective stroke treatments. Ideally, the choice of drugs taken forward to clinical trial should be based on an unbiased assessment of all available data. Such an assessment might include not only the efficacy of a drug but also the in vivo characteristics and limits—in terms of time window, dose, species, and model of ischemia used—to that efficacy. To our knowledge, such assessments have not been made. Nicotinamide is a candidate neuroprotective drug with efficacy in experimental stroke, but the limits to and characteristics of that efficacy have not been fully described. Methods— Systematic review and modified meta-analysis of studies of experimental stroke describing the efficacy of nicotinamide. The search strategy ensured ascertainment of studies published in full and those published in abstract only. DerSimonian and Laird random effects meta-analysis was used to account for heterogeneity between studies. Results— Nicotinamide improved outcome by 0.287 (95% confidence interval 0.227 to 0.347) it was more effective in temporary ischemia models, after intravenous administration, in animals without comorbidities, and in studies published in full rather than in abstract. Studies scoring highly on a quality measure gave more precise estimates of the global effect. Conclusions— Meta-analysis provides an effective technique for the aggregation of data from experimental stroke studies. We propose new standards for reporting such studies and a systematic approach to aggregating data from the neuroprotective literature.
Publisher: Elsevier BV
Date: 03-2008
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: SAGE Publications
Date: 05-2006
DOI: 10.1111/J.1747-4949.2006.00026.X
Abstract: Severe atheroma of the aortic arch has now been established as an important risk factor and mechanism for stroke and peripheral embolism. The odds ratio for stroke or peripheral embolism in patients with severe arch atheroma is greater than four, and for mobile atheroma it is greater than 12. The prevalence of severe arch atheroma among patients presenting with acute ischaemic stroke, at over 20%, is in the same order as that of atrial fibrillation and carotid atherosclerosis. In patients with ischaemic stroke for which no cause has been identified, it is reasonable to determine as to whether they have severe arch atheroma by performing a transoesophageal echocardiogram. Recurrent stroke is common in patients with aortic arch atheroma that are thicker than 4 mm or with mobile components, particularly in the elderly, cigarette smokers, and those with hypertension or diabetes. Patients found to have severe atheroma are at high risk of recurrent events (14·2% per year) and may, therefore, need an aggressive secondary prevention strategy. Currently, there is uncertainty as to what this should be, but either combination antiplatelet therapy (aspirin plus clopidogrel) or anticoagulation with warfarin (target INR 2·0–3·0) are commonly used. Which of these is most effective will be evident after the completion of the aortic arch related cerebral hazard trial.
Publisher: Springer Science and Business Media LLC
Date: 15-01-2019
Publisher: SAGE Publications
Date: 19-06-2012
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: SAGE Publications
Date: 06-2009
Abstract: Correction to: Journal of Cerebral Blood Flow & Metabolism (2009) 29, 221–223 doi:10.1038/jcbfm.2008.101 Following the publication of this article, the authors noted that Dr Buchan's first name was misspelled. The correct and complete author name is above.
Publisher: Portico
Date: 02-2021
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: 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: SAGE Publications
Date: 13-01-2017
Abstract: To assess the true effect of novel therapies for ischaemic stroke, a positive control that can validate the experimental model and design is vital. Hypothermia may be a good candidate for such a positive control, given the convincing body of evidence from animal models of ischaemic stroke. Taking conditions under which substantial efficacy had been seen in a meta-analysis of hypothermia for focal ischaemia in animal models, we undertook three randomised and blinded studies examining the effect of hypothermia induced immediately following the onset of middle cerebral artery occlusion on infarct volume in rats (n = 15, 23, 264). Hypothermia to a depth of 33℃ and maintained for 130 min significantly reduced infarct volume compared to normothermia treatment (by 27–63%) and depended on ischaemic duration (F(3,244) = 21.242, p 0.05). However, the protective effect varied across experiments with differences in both the size of the infarct observed in normothermic controls and the time to reach target temperature. Our results highlight the need for s le size and power calculations to take into account variations between in idual experiments requiring induction of focal ischaemia.
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: BMJ
Date: 08-2015
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: Wiley
Date: 17-02-2006
DOI: 10.1002/ANA.20741
Abstract: Preclinical evaluation of neuroprotectants fostered high expectations of clinical efficacy. When not matched, the question arises whether experiments are poor indicators of clinical outcome or whether the best drugs were not taken forward to clinical trial. Therefore, we endeavored to contrast experimental efficacy and scope of testing of drugs used clinically and those tested only experimentally. We identified neuroprotectants and reports of experimental efficacy via a systematic search. Controlled in vivo and in vitro experiments using functional or histological end points were selected for analysis. Relationships between outcome, drug mechanism, scope of testing, and clinical trial status were assessed statistically. There was no evidence that drugs used clinically (114 drugs) were more effective experimentally than those tested only in animal models (912 drugs), for ex le, improvement in focal models averaged 31.3 +/- 16.7% versus 24.4 +/- 32.9%, p > 0.05, respectively. Scope of testing using Stroke Therapy Academic Industry Roundtable (STAIR) criteria was highly variable, and no relationship was found between mechanism and efficacy. The results question whether the most efficacious drugs are being selected for stroke clinical trials. This may partially explain the slow progress in developing treatments. Greater rigor in the conduct, reporting, and analysis of animal data will improve the transition of scientific advances from bench to bedside.
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: Elsevier BV
Date: 12-2008
Publisher: Public Library of Science (PLoS)
Date: 24-08-2015
Publisher: Portland Press Ltd.
Date: 30-04-2018
DOI: 10.1042/CS20171620
Abstract: Cerebral small vessel disease (SVD) is a major contributor to stroke, cognitive impairment and dementia with limited therapeutic interventions. There is a critical need to provide mechanistic insight and improve translation between pre-clinical research and the clinic. A 2-day workshop was held which brought together experts from several disciplines in cerebrovascular disease, dementia and cardiovascular biology, to highlight current advances in these fields, explore synergies and scope for development. These proceedings provide a summary of key talks at the workshop with a particular focus on animal models of cerebral vascular disease and dementia, mechanisms and approaches to improve translation. The outcomes of discussion groups on related themes to identify the gaps in knowledge and requirements to advance knowledge are summarized.
Publisher: Springer Science and Business Media LLC
Date: 15-08-2016
Publisher: American Association for the Advancement of Science (AAAS)
Date: 14-05-2010
Abstract: Lombardi et al . (Reports, 23 October 2009, p. 585) reported an association between the human gammaretrovirus XMRV and chronic fatigue syndrome. However, their results may be misleading because of various potential sources of bias and confounding. If real, the association may lack generalizability because of the specific characteristics of the cases studied and could be due to reverse causality.
Publisher: Public Library of Science (PLoS)
Date: 19-05-2021
DOI: 10.1371/JOURNAL.PBIO.3001009
Abstract: The replicability of research results has been a cause of increasing concern to the scientific community. The long-held belief that experimental standardization begets replicability has also been recently challenged, with the observation that the reduction of variability within studies can lead to idiosyncratic, lab-specific results that cannot be replicated. An alternative approach is to, instead, deliberately introduce heterogeneity, known as “heterogenization” of experimental design. Here, we explore a novel perspective in the heterogenization program in a meta-analysis of variability in observed phenotypic outcomes in both control and experimental animal models of ischemic stroke. First, by quantifying interin idual variability across control groups, we illustrate that the amount of heterogeneity in disease state (infarct volume) differs according to methodological approach, for ex le, in disease induction methods and disease models. We argue that such methods may improve replicability by creating erse and representative distribution of baseline disease state in the reference group, against which treatment efficacy is assessed. Second, we illustrate how meta-analysis can be used to simultaneously assess efficacy and stability (i.e., mean effect and among-in idual variability). We identify treatments that have efficacy and are generalizable to the population level (i.e., low interin idual variability), as well as those where there is high interin idual variability in response for these, latter treatments translation to a clinical setting may require nuance. We argue that by embracing rather than seeking to minimize variability in phenotypic outcomes, we can motivate the shift toward heterogenization and improve both the replicability and generalizability of preclinical research.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-12-2015
Publisher: Public Library of Science (PLoS)
Date: 21-12-2017
Publisher: Public Library of Science (PLoS)
Date: 30-08-2017
Publisher: Springer Science and Business Media LLC
Date: 11-05-2016
Publisher: Wiley
Date: 06-09-2004
Publisher: Elsevier BV
Date: 09-2008
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: BMJ
Date: 22-11-2018
DOI: 10.1136/BMJ.K4577
Abstract: To determine prevalence and types of potentially serious incidental findings on magnetic resonance imaging (MRI) in apparently asymptomatic adults, describe factors associated with potentially serious incidental findings, and summarise information on follow-up and final diagnoses. Systematic review and meta-analyses. Citation searches of relevant articles and authors’ files in Medline and Embase (from inception to 25 April 2017). Eligible studies included prevalence and types of incidental findings detected among apparently asymptomatic adults undergoing MRI of the brain, thorax, abdomen, or brain and body. Data on study population and methods, prevalence and types of incidental findings, and final diagnoses were extracted. Pooled prevalence was estimated by random effects meta-analysis, and heterogeneity by τ 2 statistics. Prevalence of potentially serious incidental findings on MRI of the brain, thorax, abdomen, and brain and body. Of 5905 retrieved studies, 32 (0.5%) met the inclusion criteria (n=27 643 participants). Pooled prevalence of potentially serious incidental findings was 3.9% (95% confidence interval 0.4% to 27.1%) on brain and body MRI, 1.4% (1.0% to 2.1%) on brain MRI, 1.3% (0.2% to 8.1%) on thoracic MRI, and 1.9% (0.3% to 12.0%) on abdominal MRI. Pooled prevalence rose after including incidental findings of uncertain potential seriousness (12.8% (3.9% to 34.3%), 1.7% (1.1% to 2.6%), 3.0% (0.8% to 11.3%), and 4.5% (1.5% to 12.9%), respectively). There was generally substantial heterogeneity among included studies. About half the potentially serious incidental findings were suspected malignancies (brain, 0.6% (95% confidence interval 0.4% to 0.9%) thorax, 0.6% (0.1% to 3.1%) abdomen, 1.3% (0.2% to 9.3%) brain and body, 2.3% (0.3% to 15.4%)). There were few informative data on potential sources of between-study variation or factors associated with potentially serious incidental findings. Limited data suggested that relatively few potentially serious incidental findings had serious final diagnoses (48/234, 20.5%). A substantial proportion of apparently asymptomatic adults will have potentially serious incidental findings on MRI, but little is known of their health consequences. Systematic, long term follow-up studies are needed to better inform on these consequences and the implications for policies on feedback of potentially serious incidental findings. Prospero CRD42016029472.
Publisher: Elsevier BV
Date: 03-2014
Publisher: Wiley
Date: 14-07-2020
DOI: 10.1113/EP088870
Publisher: SAGE Publications
Date: 05-06-2013
Abstract: Hypertension is an established target for long-term stroke prevention but procedures for management of hypertension in acute stroke are less certain. Here, we analyze basic science data to examine the impact of hypertension on candidate stroke therapies and of anti-hypertensive treatments on stroke outcome. Methods: Data were pooled from 3,288 acute ischemic stroke experiments (47,899 animals) testing the effect of therapies on infarct size (published 1978-2010). Data were combined using meta-analysis and meta-regression, partitioned on the basis of hypertension, stroke model, and therapy. Results: Hypertensive animals were used in 10% of experiments testing 502 therapies. Hypertension was associated with lower treatment efficacy, especially in larger infarcts. Overall, anti-hypertensives did not provide greater benefit than other drugs, although benefits were evident in hypertensive animals even when given after stroke onset. Fifty-eight therapies were tested in both normotensive and hypertensive animals: some demonstrated superior efficacy in hypertensive animals (hypothermia) while others worked better in normotensive animals (tissue plasminogen activator, anesthetic agents). Discussion: Hypertension has a significant effect on the efficacy of candidate stroke drugs: standard basic science testing may overestimate the efficacy which could be reasonably expected from certain therapies and for hypertensive patients with large or temporary occlusions.
Publisher: Public Library of Science (PLoS)
Date: 30-03-2010
Publisher: Portland Press Ltd.
Date: 2023
DOI: 10.1042/CS20220594
Abstract: Objective: 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. Methods: 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 2000 randomly selected PubMed Central records enriched with a dataset of known in vitro studies. Results: Full-text approaches performed best, with human (sensitivity: 0.990, specificity: 1.000 and precision: 0.994) outperforming text mining (sensitivity: 0.972, specificity: 0.980 and precision: 0.764). For title and abstract, text mining (sensitivity: 0.890, specificity: 0.995 and precision: 0.922) outperformed human screening (sensitivity: 0.862, specificity: 0.998 and precision: 0.975). At our target sensitivity of 95% the algorithm performed with specificity of 0.850 and precision of 0.700. Conclusion: 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: Cold Spring Harbor Laboratory
Date: 12-09-2017
DOI: 10.1101/187245
Abstract: To determine whether a change in editorial policy, including the implementation of a checklist, has been associated with improved reporting of measures which might reduce the risk of bias. The study protocol has been published at DOI: 10.1007/s11192-016-1964-8. Observational cohort study. Articles describing research in the life sciences published in Nature journals, submitted after May 1st 2013. Mandatory completion of a checklist at the point of manuscript revision. (1) Articles describing research in the life sciences published in Nature journals, submitted before May 2013 (2) Similar articles in other journals matched for date and topic. Change in proportion of Nature publications describing in vivo research published before and after May 2013 reporting the Landis 4 items (randomisation, blinding, s le size calculation, exclusions). We included 448 NPG papers (223 published before May 2013, 225 after) identified by an in idual hired by NPG for this specific task, working to a standard procedure and an independent investigator used Pubmed Related Citations to identify 448 non-NPG papers with a similar topic and date of publication in other journals and then redacted all publications for time sensitive information and journal name. Redacted manuscripts were assessed by 2 trained reviewers against a 74 item checklist, with discrepancies resolved by a third. 394 NPG and 353 matching non-NPG publications described in vivo research. The number of NPG publications meeting all relevant Landis 4 criteria increased from 0/203 prior to May 2013 to 31/181 (16.4%) after (2-s le test for equality of proportions without continuity correction, X 2 = 36.2, df = 1, p = 1.8 x 10-9). There was no change in the proportion of non‐ NPG publications meeting all relevant Landis 4 criteria (1/164 before, 1/189 after). There were more substantial improvements in the in idual prevalences of reporting of randomisation, blinding, exclusions and s le size calculations for in vivo experiments, and less substantial improvements for in vitro experiments. There was a substantial improvement in the reporting of risks of bias in in vivo research in NPG journals following a change in editorial policy, to a level that to our knowledge has not been previously observed. However, there remain opportunities for further improvement.
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: 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: Elsevier BV
Date: 02-2016
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: Public Library of Science (PLoS)
Date: 09-02-2017
Publisher: Portico
Date: 03-2021
Publisher: SAGE Publications
Date: 02-2012
Abstract: Combination therapy has been identified as a promising strategy to improve stroke management. We conducted a systematic review and meta-analysis of evidence from animal models of ischemic stroke to determine whether combining treatments improved efficacy. Multiple databases were searched and data were extracted from focal ischemia experiments comparing control groups, single treatments, and combination treatments. Of 11,430 papers identified, 142 met the inclusion criteria these tested 126 treatments in 373 experiments using 8,037 animals ( I 2 = 85 to 96%). Taken together, single treatments reduced infarct size by 20% and improved neurological score by 12% compared with control a second therapy improved efficacy by an additional 18% and 25%, respectively. Publication bias may affect combination efficacy for infarct size but not neurological score. Combining thrombolysis with other therapies may extend the time window from 4.4 to 8 hours in animal models, although testing beyond 6 hours is required to confirm this. Benefits of additional therapy decreased as the efficacy of the primary treatment increased, with combination efficacy reaching a ceiling at 60% to 80% protection. Combining treatments may bring benefits and extend the time window for treatment. More evidence is needed due to potential publication bias and heterogeneity.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-03-2021
DOI: 10.1097/J.PAIN.0000000000002269
Abstract: We report a systematic review and meta-analysis of studies that assessed the antinociceptive efficacy of cannabinoids, cannabis-based medicines, and endocannabinoid system modulators on pain-associated behavioural outcomes in animal models of pathological or injury-related persistent pain. In April 2019, we systematically searched 3 online databases and used crowd science and machine learning to identify studies for inclusion. We calculated a standardised mean difference effect size for each comparison and performed a random-effects meta-analysis. We assessed the impact of study design characteristics and reporting of mitigations to reduce the risk of bias. We meta-analysed 374 studies in which 171 interventions were assessed for antinociceptive efficacy in rodent models of pathological or injury-related pain. Most experiments were conducted in male animals (86%). Antinociceptive efficacy was most frequently measured by attenuation of hypersensitivity to evoked limb withdrawal. Selective cannabinoid type 1, cannabinoid type 2, nonselective cannabinoid receptor agonists (including delta-9-tetrahydrocannabinol) and peroxisome proliferator-activated receptor-alpha agonists (predominantly palmitoylethanolamide) significantly attenuated pain-associated behaviours in a broad range of inflammatory and neuropathic pain models. Fatty acid amide hydrolase inhibitors, monoacylglycerol lipase inhibitors, and cannabidiol significantly attenuated pain-associated behaviours in neuropathic pain models but yielded mixed results in inflammatory pain models. The reporting of criteria to reduce the risk of bias was low therefore, the studies have an unclear risk of bias. The value of future studies could be enhanced by improving the reporting of methodological criteria, the clinical relevance of the models, and behavioural assessments. Notwithstanding, the evidence supports the hypothesis of cannabinoid-induced analgesia.
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.JSTROKECEREBROVASDIS.2018.03.015
Abstract: Developing new medicines is a complex process where understanding the reasons for both failure and success takes us forward. One gap in our understanding of most candidate stroke drugs before clinical trial is whether they have a protective effect on human tissues. NXY-059 is a spin-trap reagent hypothesized to have activity against the damaging oxidative biology which accompanies ischemic stroke. Re-examination of the preclinical in vivo dataset for this agent in the wake of the failed SAINT-II RCT highlighted the presence of a range of biases leading to overestimation of the magnitude of NXY-059's effects in laboratory animals. Therefore, NXY-059 seemed an ideal candidate to evaluate in human neural tissues to determine whether human tissue testing might improve screening efficiency. The aim of this randomized and blinded study was to assess the effects of NXY-059 on human stem cell-derived neurons in the presence of ischemia-like injury induced by oxygen glucose deprivation or oxidative stress induced by hydrogen peroxide or sodium nitroprusside. In MTT assays of cell survival, lactate dehydrogenase assays of total cell death and terminal deoxynucleotidyl transferase dUTP nick end labeling staining of apoptotic-like cell death, NXY-059 at concentrations ranging from 1 µm to 1 mm was completely without activity. Conversely an antioxidant cocktail comprising 100 µm each of ascorbate, reduced glutathione, and dithiothreitol used as a positive control provided marked neuronal protection in these assays. These findings support our hypothesis that stroke drug screening in human neural tissues will be of value and provides an explanation for the failure of NXY-059 as a human stroke drug.
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.JCLINEPI.2017.08.008
Abstract: A living systematic review (LSR) should keep the review current as new research evidence emerges. Any meta-analyses included in the review will also need updating as new material is identified. If the aim of the review is solely to present the best current evidence standard meta-analysis may be sufficient, provided reviewers are aware that results may change at later updates. If the review is used in a decision-making context, more caution may be needed. When using standard meta-analysis methods, the chance of incorrectly concluding that any updated meta-analysis is statistically significant when there is no effect (the type I error) increases rapidly as more updates are performed. Inaccurate estimation of any heterogeneity across studies may also lead to inappropriate conclusions. This paper considers four methods to avoid some of these statistical problems when updating meta-analyses: two methods, that is, law of the iterated logarithm and the Shuster method control primarily for inflation of type I error and two other methods, that is, trial sequential analysis and sequential meta-analysis control for type I and II errors (failing to detect a genuine effect) and take account of heterogeneity. This paper compares the methods and considers how they could be applied to LSRs.
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.JCLINEPI.2017.08.009
Abstract: While it is important for the evidence supporting practice guidelines to be current, that is often not the case. The advent of living systematic reviews has made the concept of "living guidelines" realistic, with the promise to provide timely, up-to-date and high-quality guidance to target users. We define living guidelines as an optimization of the guideline development process to allow updating in idual recommendations as soon as new relevant evidence becomes available. A major implication of that definition is that the unit of update is the in idual recommendation and not the whole guideline. We then discuss when living guidelines are appropriate, the workflows required to support them, the collaboration between living systematic reviews and living guideline teams, the thresholds for changing recommendations, and potential approaches to publication and dissemination. The success and sustainability of the concept of living guideline will depend on those of its major pillar, the living systematic review. We conclude that guideline developers should both experiment with and research the process of living guidelines.
Publisher: BMJ
Date: 04-2008
Abstract: Models are used to adjust for case mix and to stratify treatment allocation in clinical trials and can, if accurate enough, be used to aid decision-making in in idual patients. We aimed to validate, in patients assessed within 6 hours of onset, a previously described six simple variable (SSV) model that was developed in stroke patients who were assessed sub-acutely. The explanatory variables in the model are age, living alone, independent pre-stroke, Glasgow Coma Scale verbal score, ability to lift arms and ability to walk. The six variables were collected at randomisation in the Third International Stroke Trial (IST3) trial of recombinant tissue plasminogen activator in ischaemic stroke. We assessed survival to 30 days and functional status at 6 months using the Oxford Handicap Scale. We constructed receiver operator characteristic (ROC) curves to establish the model's discriminatory performance and tested its calibration by charting predicted versus actual outcomes. 537 patients (mean age, 74 years) were included, of whom 422 (79%) survived 30 days and 179 (33%) were alive and independent at 6 months. The SSV model had an area under the ROC curve of 0.73 for 30-day survival and 0.82 for independent survival at 6 months. Calibration was satisfactory. This study confirms the external validity of the SSV model in an ischaemic stroke population assessed within 6 hours of symptom onset. The SSV model comprising easily collected variables can therefore be used to stratify patients in hyper-acute stroke trials, but probably is not accurate enough for decision-making in in idual patients.
Publisher: Springer Science and Business Media LLC
Date: 10-2012
DOI: 10.1038/NATURE11556
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2009
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1111/J.1538-7836.2011.04486.X
Abstract: Deep vein thrombosis (DVT) is an important complication of stroke, but the evidence to support commonly used prophylactic strategies is conflicting. To describe the incidence, extent, associated clinical features and evolution of DVT after stroke. The CLOTS trials 1 and 2 together randomized 5632 immobile stroke patients in 135 hospitals in nine countries. We screened patients for asymptomatic DVT with compression duplex ultrasound (CDU) at about 7-10 days and again at about 25-30 days after enrollment. Six hundred and forty-one (11.4%) of 5632 patients had DVT detected on the first CDU scan at a median of 8 days (interquartile range [IQR] 7-10 days) after enrollment, and an additional 176 (3.1%) had a DVT on the second CDU scan at a median of 28 days (IQR 26-30 days). Of the 817 with DVTs, 289 (35%) were symptomatic and 39 (5%) had pulmonary embolism (PE) confirmed by imaging. Six hundred and seventy-six (83%) were unilateral, 141 (17%) were bilateral, 322 (39%) were limited to calf veins, 172 (21%) were popliteal, and 323 (40%) were femoral. Among the 542 patients with DVT and a weak leg, the DVT affected the weaker leg in 396 (73%), the stronger leg in 59 (11%), and was bilateral in 87 (16%). Among the 318 patients with a DVT detected on the first CDU scan who had a second scan, the DVT regressed in 148 (47%), stayed the same in 140 (44%), and progressed in only 30 (9%). Although most DVTs develop within the first week, some develop later, and some early DVTs progress. Any prophylaxis needs to be started early but ideally continued for at least 4 weeks.
Publisher: Portico
Date: 05-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2013
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 07-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2004
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: Elsevier
Date: 2013
Publisher: Elsevier BV
Date: 11-2020
Publisher: Springer Science and Business Media LLC
Date: 05-03-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2014
DOI: 10.1161/STROKEAHA.113.004251
Abstract: Severe atherosclerosis in the aortic arch is associated with a high risk of recurrent vascular events, but the optimal antithrombotic strategy is unclear. This prospective randomized controlled, open-labeled trial, with blinded end point evaluation (PROBE design) tested superiority of aspirin 75 to 150 mg/d plus clopidogrel 75 mg/d (A+C) over warfarin therapy (international normalized ratio 2–3) in patients with ischemic stroke, transient ischemic attack, or peripheral embolism with plaque in the thoracic aorta mm and no other identified embolic source. The primary end point included cerebral infarction, myocardial infarction, peripheral embolism, vascular death, or intracranial hemorrhage. Follow-up visits occurred at 1 month and then every 4 months post randomization. The trial was stopped after 349 patients were randomized during a period of 8 years and 3 months. After a median follow-up of 3.4 years, the primary end point occurred in 7.6% (13/172) and 11.3% (20/177) of patients on A+C and on warfarin, respectively (log-rank, P =0.2). The adjusted hazard ratio was 0.76 (95% confidence interval, 0.36–1.61 P =0.5). Major hemorrhages including intracranial hemorrhages occurred in 4 and 6 patients in the A+C and warfarin groups, respectively. Vascular deaths occurred in 0 patients in A+C arm compared with 6 (3.4%) patients in the warfarin arm (log-rank, P =0.013). Time in therapeutic range (67% of the time for international normalized ratio 2–3) analysis by tertiles showed no significant differences across groups. Because of lack of power, this trial was inconclusive and results should be taken as hypothesis generating. URL: www.clinicaltrials.gov . Unique identifier: NCT00235248.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2006
DOI: 10.1161/01.STR.0000202588.95876.A7
Abstract: Background and Purpose— Greater stroke mortality has been reported among lower socioeconomic groups. We aimed to determine whether fatal, nonfatal, and overall stroke incidence varied by socioeconomic status. Methods— All suspected strokes occurring in 22 postcodes (population of 306 631) of Melbourne, Australia, during a 24-month period between 1997 and 1999 were found and assessed. Multiple overlapping sources were used to ascertain cases with standard clinical definitions for stroke. Socioeconomic disadvantage was assigned in 4 bands from least to greatest using an area-based measure developed by the Australian Bureau of Statistics. Results— Overall stroke incidence (number per 100 000 population per year), adjusted to the European population 45 to 84 years of age, increased with increasing socioeconomic disadvantage: 200 (95% CI, 173 to 228) 251 (95% CI, 220 to 282) 309 (95% CI, 274 to 343) and 366 (95% CI, 329 to 403 χ 2 for ranks P .0001). Similar incidence patterns were observed for both fatal and nonfatal stroke. Nonfatal stroke contributed most to this incidence pattern: 146 (95% CI, 122 to 169) 181 (95% CI, 155 to 207) 223 (95% CI, 194 to 252) and 280 (95% CI, 247 to 313 χ 2 for ranks P .0001). Conclusions— In this population-based study, both fatal and nonfatal stroke incidence increased with increasing socioeconomic disadvantage. The greater contributor to this incidence pattern was nonfatal stroke incidence. This may have implications for service provision to those least able to afford it. Area-based identification of those most disadvantaged may provide a simple and effective way of targeting regions for stroke prevention strategies.
Publisher: Wiley
Date: 11-2017
DOI: 10.1111/EPI.13908
Abstract: Current antiseizure therapy is ineffective in approximately one third of people with epilepsy and is often associated with substantial side effects. In addition, most current therapeutic paradigms offer treatment, but not cure, and no therapies are able to modify the underlying disease, that is, can prevent or halt the process of epileptogenesis or alleviate the cognitive and psychiatric comorbidities. Preclinical research in the field of epilepsy has been extensive, but unfortunately, not all the animal models being used have been validated for their predictive value. The overall goal of TASK2 of the AES/ILAE Translational Task Force is to organize and coordinate systematic reviews on selected topics regarding animal research in epilepsy. Herein we describe our strategy. In the first part of the paper we provide an overview of the usefulness of systematic reviews and meta-analysis for preclinical research and explain the essentials for their conduct. Then we describe in detail the protocol for a first systematic review, which will focus on the identification and characterization of outcome measures reported in animal models of epilepsy. The specific goals of this study are to define systematically the phenotypic characteristics of the most commonly used animal models, and to effectively compare these with the manifestations of human epilepsy. This will provide epilepsy researchers with detailed information on the strengths and weaknesses of epilepsy models, facilitating their refinement and future research. Ultimately, this could lead to a refined use of relevant models for understanding the mechanism(s) of the epilepsies and developing novel therapies.
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: Elsevier BV
Date: 07-2019
Publisher: Springer Science and Business Media LLC
Date: 14-07-2020
DOI: 10.1186/S12917-020-02451-Y
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: Public Library of Science (PLoS)
Date: 10-11-2015
Publisher: Portland Press Ltd.
Date: 05-2023
DOI: 10.1042/CS20220494
Abstract: Systematic reviews and meta-analysis are the cornerstones of evidence-based decision making and priority setting. However, traditional systematic reviews are time and labour intensive, limiting their feasibility to comprehensively evaluate the latest evidence in research-intensive areas. Recent developments in automation, machine learning and systematic review technologies have enabled efficiency gains. Building upon these advances, we developed Systematic Online Living Evidence Summaries (SOLES) to accelerate evidence synthesis. In this approach, we integrate automated processes to continuously gather, synthesise and summarise all existing evidence from a research domain, and report the resulting current curated content as interrogatable databases via interactive web applications. SOLES can benefit various stakeholders by (i) providing a systematic overview of current evidence to identify knowledge gaps, (ii) providing an accelerated starting point for a more detailed systematic review, and (iii) facilitating collaboration and coordination in evidence synthesis.
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: 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: 03-01-2014
DOI: 10.1111/IJS.12224
Abstract: Hypothermia provides neuroprotection after cardiac arrest, hypoxic-ischemic encephalopathy, and in animal models of ischemic stroke. However, as drug development for stroke has been beset by translational failure, we sought additional evidence that hypothermia protects human neurons against ischemic injury. Human embryonic stem cells were cultured and differentiated to provide a source of neurons expressing β III tubulin, microtubule-associated protein 2, and the Neuronal Nuclei antigen. Oxygen deprivation, oxygen-glucose deprivation, and H 2 O 2 -induced oxidative stress were used to induce relevant injury. Hypothermia to 33°C protected these human neurons against H 2 O 2 -induced oxidative stress reducing lactate dehydrogenase release and Terminal deoxynucleotidyl transferase dUTP nick end labeling-staining by 53% ( P ≤ 0·0001 95% confidence interval 34·8–71·04) and 42% ( P ≤ 0·0001 95% confidence interval 27·5–56·6), respectively, after 24 h in culture. Hypothermia provided similar protection against oxygen-glucose deprivation (42%, P ≤ 0·001, 95% confidence interval 18·3–71·3 and 26%, P ≤ 0·001 95% confidence interval 12·4–52·2, respectively) but provided no protection against oxygen deprivation alone. Protection (21%) persisted against H 2 O 2 -induced oxidative stress even when hypothermia was initiated six-hours after onset of injury ( P ≤ 0·05 95% confidence interval 0·57–43·1). We conclude that hypothermia protects stem cell-derived human neurons against insults relevant to stroke over a clinically relevant time frame. Protection against H 2 O 2 -induced injury and combined oxygen and glucose deprivation but not against oxygen deprivation alone suggests an interaction in which protection benefits from reduction in available glucose under some but not all circumstances.
Publisher: Elsevier BV
Date: 2019
Publisher: Cold Spring Harbor Laboratory
Date: 31-01-2018
DOI: 10.1101/255760
Abstract: Here we outline a method of applying existing machine learning (ML) approaches to aid citation screening in an on-going broad and shallow systematic review of preclinical animal studies, with the aim of achieving a high performing algorithm comparable to human screening. We applied ML approaches to a broad systematic review of animal models of depression at the citation screening stage. We tested two independently developed ML approaches which used different classification models and feature sets. We recorded the performance of the ML approaches on an unseen validation set of papers using sensitivity, specificity and accuracy. We aimed to achieve 95% sensitivity and to maximise specificity. The classification model providing the most accurate predictions was applied to the remaining unseen records in the dataset and will be used in the next stage of the preclinical biomedical sciences systematic review. We used a cross validation technique to assign ML inclusion likelihood scores to the human screened records, to identify potential errors made during the human screening process (error analysis). ML approaches reached 98.7% sensitivity based on learning from a training set of 5749 records, with an inclusion prevalence of 13.2%. The highest level of specificity reached was 86%. Performance was assessed on an independent validation dataset. Human errors in the training and validation sets were successfully identified using assigned the inclusion likelihood from the ML model to highlight discrepancies. Training the ML algorithm on the corrected dataset improved the specificity of the algorithm without compromising sensitivity. Error analysis correction leads to a 3% improvement in sensitivity and specificity, which increases precision and accuracy of the ML algorithm. This work has confirmed the performance and application of ML algorithms for screening in systematic reviews of preclinical animal studies. It has highlighted the novel use of ML algorithms to identify human error. This needs to be confirmed in other reviews, , but represents a promising approach to integrating human decisions and automation in systematic review methodology.
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: 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: 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: Elsevier BV
Date: 09-2010
Publisher: Elsevier BV
Date: 07-2015
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.JCLINEPI.2017.08.011
Abstract: New approaches to evidence synthesis, which use human effort and machine automation in mutually reinforcing ways, can enhance the feasibility and sustainability of living systematic reviews. Human effort is a scarce and valuable resource, required when automation is impossible or undesirable, and includes contributions from online communities ("crowds") as well as more conventional contributions from review authors and information specialists. Automation can assist with some systematic review tasks, including searching, eligibility assessment, identification and retrieval of full-text reports, extraction of data, and risk of bias assessment. Workflows can be developed in which human effort and machine automation can each enable the other to operate in more effective and efficient ways, offering substantial enhancement to the productivity of systematic reviews. This paper describes and discusses the potential-and limitations-of new ways of undertaking specific tasks in living systematic reviews, identifying areas where these human/machine "technologies" are already in use, and where further research and development is needed. While the context is living systematic reviews, many of these enabling technologies apply equally to standard approaches to systematic reviewing.
Publisher: Center for Open Science
Date: 18-08-2022
Abstract: Systematic reviews and meta-analysis are the cornerstones of evidence-based decision making and priority setting. However, traditional systematic reviews are time and labour intensive, limiting their feasibility to comprehensively evaluate the latest evidence in research-intensive areas. Recent developments in automation, machine learning and systematic review technologies have enabled efficiency gains. Building upon these advances, we developed Systematic Online Living Evidence Summaries (SOLES) to accelerate evidence synthesis. In this approach, we integrate automated processes to continuously gather, synthesise and summarise all existing evidence from a research domain, and report the resulting current curated content as interrogatable databases via interactive web applications. SOLES can benefit various stakeholders by (i) providing a systematic overview of current evidence to identify knowledge gaps, (ii) providing an accelerated starting point for a more detailed systematic review, and (iii) facilitating collaboration and coordination in evidence synthesis.
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: 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
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.JCLINEPI.2017.08.010
Abstract: Systematic reviews are difficult to keep up to date, but failure to do so leads to a decay in review currency, accuracy, and utility. We are developing a novel approach to systematic review updating termed "Living systematic review" (LSR): systematic reviews that are continually updated, incorporating relevant new evidence as it becomes available. LSRs may be particularly important in fields where research evidence is emerging rapidly, current evidence is uncertain, and new research may change policy or practice decisions. We hypothesize that a continual approach to updating will achieve greater currency and validity, and increase the benefits to end users, with feasible resource requirements over time.
Publisher: Elsevier BV
Date: 04-2015
Publisher: SAGE Publications
Date: 27-10-2010
Abstract: There is some evidence that in animal models of acute ischaemic stroke, combinations of neuroprotective agents might be more efficacious than the same agents administered alone. Hence, we developed pragmatic, empirical criteria based on therapeutic target, cost, availability, efficacy, administration, and safety to select drugs for testing in combination in animal models of acute stroke. Magnesium sulphate, melatonin, and minocycline were chosen from a library of neuroprotective agents, and were tested in a more ‘realistic’ model favoured by the STAIR (Stroke Therapy Academic Industry Roundtable). Outcome was assessed with infarct volume, neurologic score, and two newly developed scales measuring general health and physiologic homeostasis. Owing to the failure to achieve neuroprotection in aged, hypertensive animals with drug delivery at 3 hours, the bar was lowered in successive experiments to determine whether neuroprotection could be achieved under conditions more conducive to recovery. Testing in younger animals showed more favourable homeostasis and general health scores than did testing in older animals, but infarct volume and neurologic scores did not differ with age, and treatment efficacy was again not shown. Testing with shorter occlusions resulted in smaller infarct volumes nevertheless, treatment efficacy was still not observed. It was concluded that this combination, in these stroke models, was not effective.
Publisher: Elsevier BV
Date: 10-2020
Publisher: S. Karger AG
Date: 2005
DOI: 10.1159/000086121
Abstract: i Background: /i Patients with ischaemic stroke due to occlusion of the basilar or vertebral arteries may develop a rapid deterioration in neurological status leading to coma and often to death. While intra-arterial thrombolysis may be used in this context, no randomised controlled data exist to support its safety or efficacy. i Methods: /i Randomised controlled trial of intra-arterial urokinase within 24 h of symptom onset in patients with stroke and angiographic evidence of posterior circulation vascular occlusion. i Results: /i Sixteen patients were randomised, and there was some imbalance between groups, with more severe strokes occurring in the treatment arm. A good outcome was observed in 4 of 8 patients who received intra-arterial urokinase compared with 1 of 8 patients in the control group. i Conclusions: /i These results support the need for a large-scale study to establish the efficacy of intra-arterial thrombolysis for acute basilar artery occlusion.
Publisher: eLife Sciences Publications, Ltd
Date: 20-05-2021
Publisher: Portico
Date: 02-2019
Publisher: Public Library of Science (PLoS)
Date: 13-10-2015
Publisher: Center for Open Science
Date: 05-12-2022
Abstract: Introduction: The gut may play an important role in Major Depressive Disorder and interventions targeting gut microbiota- may serve as potential treatments. Prebiotics have been reported to reduce anxiety and depressive-like phenotypes in mice, rats, and humans. Bimuno®, a commercially available beta-galactooligasaccharide, has been shown to increase gut microbiota ersity. Aim: To investigate the effect of Bimuno® on rat anxiety- and depressive-like behaviour in the Flinders Sensitive (FSL) and Resistant Line (FRL) rats. Methods: Guided by our published protocol, 64 8-14 week old male rats, (32 FSL and 32 FRL), were randomised to receive Bimuno® or control (4g/kg) daily for 4 weeks. We assessed despair (using the Forced Swim Test) and anxiety-like (Elevated Plus Maze) behaviours, and locomotion using the open field test. All behavioural tests were conducted and assessed blinded to rat line and treatment allocation. We recorded animals’ weight and food and water intake weekly. We used two-way ANOVA to investigate the effect of treatment (control or prebiotic) and strain (FSL or FRL) on despair and anxiety-like behaviours. Results: Treatment with Bimuno® had no effect on performance in the Forced Swim Test or the Elevated Plus Maze. We observed the expected behavioural differences between the FSL and FRL rats. Discussion: We only used male animals and our s le size calculation was informed by published data. While confirmatory studies are needed, the present study questions the role of the microbiome reported in the literature.
Publisher: SAGE Publications
Date: 09-02-2005
Abstract: FK506 is a candidate drug for acute stroke. For such drugs, any decision to proceed to clinical trial should be based on a full and unbiased assessment of the animal data, and consideration should be given to the limitations of those data. Such an assessment should include not only the efficacy of a drug but also the in vivo characteristics and limits to that efficacy. Here we use systematic review and meta-analysis to assess the evidence for a protective effect of FK506 in animal models of stroke. In all, 29 studies were identified describing procedures involving 1759 animals. The point estimate for the effect of FK506 was a 31.3% (95% confidence interval 27.2% to 35.4%) improvement in outcome. Efficacy was higher with ketamine anaesthesia and temporary ischaemia and was lower in rats, in animals with comorbidities, and where outcome was measured as infarct size alone. Reported study quality was modest by clinical trial standards, and efficacy was lower in high-quality studies. These findings show a substantial efficacy for FK506 in experimental stroke, but raise concerns that our estimate of effect size might be too high because of factors such as study quality and possible publication bias.
Publisher: Portico
Date: 03-2022
Publisher: Cold Spring Harbor Laboratory
Date: 30-01-2018
DOI: 10.1101/256776
Abstract: Meta-analysis is increasingly used to summarise the findings identified in systematic reviews of animal studies modelling human disease. Such reviews typically identify a large number of in idually small studies, testing efficacy under a variety of conditions. This leads to substantial heterogeneity, and identifying potential sources of this heterogeneity is an important function of such analyses. However, the statistical performance of different approaches (normalised compared with standardised mean difference estimates of effect size stratified meta-analysis compared with meta-regression) is not known. Using data from 3116 experiments in focal cerebral ischaemia to construct a linear model predicting observed improvement in outcome contingent on 25 independent variables. We used stochastic simulation to attribute these variables to simulated studies according to their prevalence. To ascertain the ability to detect an effect of a given variable we introduced in addition this “variable of interest” of given prevalence and effect. To establish any impact of a latent variable on the apparent influence of the variable of interest we also introduced a “latent confounding variable” with given prevalence and effect, and allowed the prevalence of the variable of interest to be different in the presence and absence of the latent variable. Generally, the normalised mean difference (NMD) approach had higher statistical power than the standardised mean difference (SMD) approach. Even when the effect size and the number of studies contributing to the meta-analysis was small, there was good statistical power to detect the overall effect, with a low false positive rate. For detecting an effect of the variable of interest, stratified meta-analysis was associated with a substantial false positive rate with NMD estimates of effect size, while using an SMD estimate of effect size had very low statistical power. Univariate and multivariable meta-regression performed substantially better, with low false positive rate for both NMD and SMD approaches power was higher for NMD than for SMD. The presence or absence of a latent confounding variables only introduced an apparent effect of the variable of interest when there was substantial asymmetry in the prevalence of the variable of interest in the presence or absence of the confounding variable. In meta-analysis of data from animal studies, NMD estimates of effect size should be used in preference to SMD estimates, and meta-regression should, where possible, be chosen over stratified meta-analysis. The power to detect the influence of the variable of interest depends on the effect of the variable of interest and its prevalence, but unless effects are very large adequate power is only achieved once at least 100 experiments are included in the meta-analysis.
Publisher: BMJ
Date: 11-2020
DOI: 10.1136/BMJOPEN-2020-040492
Abstract: Informing research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results. In the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019. UK stroke services. 3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms the remaining participants had died (380), withdrawn consent or did not respond. Of those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email. It is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future. ISRCTN83290762 Post-results.
Publisher: BMJ
Date: 11-12-2015
DOI: 10.1136/BMJ.H6432
Abstract: To report the number of participants needed to recruit per baby born to trial staff during AVERT, a large international trial on acute stroke, and to describe trial management consequences. Retrospective observational analysis. 56 acute stroke hospitals in eight countries. 1074 trial physiotherapists, nurses, and other clinicians. Number of babies born during trial recruitment per trial participant recruited. With 198 site recruitment years and 2104 patients recruited during AVERT, 120 babies were born to trial staff. Births led to an estimated 10% loss in time to achieve recruitment. Parental leave was linked to six trial site closures. The number of participants needed to recruit per baby born was 17.5 (95% confidence interval 14.7 to 21.0) additional trial costs associated with each birth were estimated at 5736 Australian dollars on average. The staff absences registered in AVERT owing to parental leave led to delayed trial recruitment and increased costs, and should be considered by trial investigators when planning research and estimating budgets. However, the celebration of new life became a highlight of the annual AVERT collaborators' meetings and helped maintain a cohesive collaborative group. Australian New Zealand Clinical Trials Registry no 12606000185561. Participation in a rehabilitation trial does not guarantee successful reproductive activity.
Publisher: Public Library of Science (PLoS)
Date: 09-08-2013
Publisher: Portico
Date: 07-2021
Publisher: Public Library of Science (PLoS)
Date: 17-12-2013
Publisher: Elsevier BV
Date: 06-2019
Publisher: Springer Science and Business Media LLC
Date: 11-2015
DOI: 10.1038/527031A
Publisher: Impact Journals, LLC
Date: 29-01-2018
Publisher: Wiley
Date: 23-09-2022
DOI: 10.1002/ANA.26495
Abstract: The purpose of this study was to test e‐ASPECTS software in patients with stroke. Marketed as a decision‐support tool, e‐ASPECTS may detect features of ischemia or hemorrhage on computed tomography (CT) imaging and quantify ischemic extent using Alberta Stroke Program Early CT Score (ASPECTS). Using CT from 9 stroke studies, we compared software with masked experts. As per indications for software use, we assessed e‐ASPECTS results for patients with/without middle cerebral artery (MCA) ischemia but no other cause of stroke. In an analysis outside the intended use of the software, we enriched our dataset with non‐MCA ischemia, hemorrhage, and mimics to simulate a representative “front door” hospital population. With final diagnosis as the reference standard, we tested the diagnostic accuracy of e‐ASPECTS for identifying stroke features (ischemia, hyperattenuated arteries, and hemorrhage) in the representative population. We included 4,100 patients (51% women, median age = 78 years, National Institutes of Health Stroke Scale [NIHSS] = 10, onset to scan = 2.5 hours). Final diagnosis was ischemia (78%), hemorrhage (14%), or mimic (8%). From 3,035 CTs with expert‐rated ASPECTS, most (2084/3035, 69%) e‐ASPECTS results were within one point of experts. In the representative population, the diagnostic accuracy of e‐ASPECTS was 71% (95% confidence interval [CI] = 70–72%) for detecting ischemic features, 85% (83–86%) for hemorrhage. Software identified more false positive ischemia (12% vs 2%) and hemorrhage (14% vs %) than experts. On independent testing, e‐ASPECTS provided moderate agreement with experts and overcalled stroke features. Therefore, future prospective trials testing impacts of artificial intelligence (AI) software on patient care and outcome are required before widespread implementation of stroke decision‐support software. ANN NEUROL 2022 :943–957
Publisher: Public Library of Science (PLoS)
Date: 20-05-2019
Publisher: SAGE Publications
Date: 14-07-2020
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: American Medical Association (AMA)
Date: 23-04-2014
Abstract: Whether conservative management is superior to interventional treatment for unruptured brain arteriovenous malformations (bAVMs) is uncertain because of the shortage of long-term comparative data. To compare the long-term outcomes of conservative management vs intervention for unruptured bAVM. Population-based inception cohort study of 204 residents of Scotland aged 16 years or older who were first diagnosed as having an unruptured bAVM during 1999-2003 or 2006-2010 and followed up prospectively for 12 years. Conservative management (no intervention) vs intervention (any endovascular embolization, neurosurgical excision, or stereotactic radiosurgery alone or in combination). Cox regression analyses, with multivariable adjustment for prognostic factors and baseline imbalances if hazards were proportional, to compare rates of the primary outcome (death or sustained morbidity of any cause by Oxford Handicap Scale [OHS] score ≥2 for ≥2 successive years [0 = no symptoms and 6 = death]) and the secondary outcome (nonfatal symptomatic stroke or death due to bAVM, associated arterial aneurysm, or intervention). Of 204 patients, 103 underwent intervention. Those who underwent intervention were younger, more likely to have presented with seizure, and less likely to have large bAVMs than patients managed conservatively. During a median follow-up of 6.9 years (94% completeness), the rate of progression to the primary outcome was lower with conservative management during the first 4 years of follow-up (36 vs 39 events 9.5 vs 9.8 per 100 person-years adjusted hazard ratio, 0.59 95% CI, 0.35-0.99), but rates were similar thereafter. The rate of the secondary outcome was lower with conservative management during 12 years of follow-up (14 vs 38 events 1.6 vs 3.3 per 100 person-years adjusted hazard ratio, 0.37 95% CI, 0.19-0.72). Among patients aged 16 years or older diagnosed as having unruptured bAVM, use of conservative management compared with intervention was associated with better clinical outcomes for up to 12 years. Longer follow-up is required to understand whether this association persists.
Publisher: Public Library of Science (PLoS)
Date: 05-05-2021
DOI: 10.1371/JOURNAL.PBIO.3001177
Abstract: In an effort to better utilize published evidence obtained from animal experiments, systematic reviews of preclinical studies are increasingly more common—along with the methods and tools to appraise them (e.g., SYstematic Review Center for Laboratory animal Experimentation [SYRCLE’s] risk of bias tool). We performed a cross-sectional study of a s le of recent preclinical systematic reviews (2015–2018) and examined a range of epidemiological characteristics and used a 46-item checklist to assess reporting details. We identified 442 reviews published across 43 countries in 23 different disease domains that used 26 animal species. Reporting of key details to ensure transparency and reproducibility was inconsistent across reviews and within article sections. Items were most completely reported in the title, introduction, and results sections of the reviews, while least reported in the methods and discussion sections. Less than half of reviews reported that a risk of bias assessment for internal and external validity was undertaken, and none reported methods for evaluating construct validity. Our results demonstrate that a considerable number of preclinical systematic reviews investigating erse topics have been conducted however, their quality of reporting is inconsistent. Our study provides the justification and evidence to inform the development of guidelines for conducting and reporting preclinical systematic reviews.
Publisher: Elsevier BV
Date: 03-2012
Publisher: Portland Press Ltd.
Date: 13-10-2017
DOI: 10.1042/CS20160722
Abstract: Background: Findings from in vivo research may be less reliable where studies do not report measures to reduce risks of bias. The experimental stroke community has been at the forefront of implementing changes to improve reporting, but it is not known whether these efforts are associated with continuous improvements. Our aims here were firstly to validate an automated tool to assess risks of bias in published works, and secondly to assess the reporting of measures taken to reduce the risk of bias within recent literature for two experimental models of stroke. Methods: We developed and used text analytic approaches to automatically ascertain reporting of measures to reduce risk of bias from full-text articles describing animal experiments inducing middle cerebral artery occlusion (MCAO) or modelling lacunar stroke. Results: Compared with previous assessments, there were improvements in the reporting of measures taken to reduce risks of bias in the MCAO literature but not in the lacunar stroke literature. Accuracy of automated annotation of risk of bias in the MCAO literature was 86% (randomization), 94% (blinding) and 100% (s le size calculation) and in the lacunar stroke literature accuracy was 67% (randomization), 91% (blinding) and 96% (s le size calculation). Discussion: There remains substantial opportunity for improvement in the reporting of animal research modelling stroke, particularly in the lacunar stroke literature. Further, automated tools perform sufficiently well to identify whether studies report blinded assessment of outcome, but improvements are required in the tools to ascertain whether randomization and a s le size calculation were reported.
Publisher: Cold Spring Harbor Laboratory
Date: 27-10-2020
DOI: 10.1101/2020.10.26.354274
Abstract: The reproducibility of research results has been a cause of increasing concern to the scientific community. The long-held belief that experimental standardization begets reproducibility has also been recently challenged, with the observation that the reduction of variability within studies can lead to idiosyncratic, lab-specific results that are irreproducible. An alternative approach is to, instead, deliberately introduce heterogeneity known as “heterogenization” of experimental design. Here, we explore a novel perspective in the heterogenization program in a meta-analysis of variability in observed phenotypic outcomes in both control and experimental animal models of ischaemic stroke. First, by quantifying inter-in idual variability across control groups we illustrate that the samount of heterogeneity in disease-state (infarct volume) differs according to methodological approach, for ex le, in disease-induction methods and disease models. We argue that such methods may improve reproducibility by creating erse and representative distribution of baseline disease-state in the reference group, against which treatment efficacy is assessed. Second, we illustrate how meta-analysis can be used to simultaneously assess efficacy and stability (i.e., mean effect and among-in idual variability). We identify treatments that have efficacy and are generalizable to the population level (i.e. low inter-in idual variability), as well as those where there is high inter-in idual variability in response for these latter treatments translation to a clinical setting may require nuance. We argue that by embracing rather than seeking to minimise variability in phenotypic outcomes, we can motivate the shift towards heterogenization and improve both the reproducibility and generalizability of preclinical research.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2013
Publisher: eLife Sciences Publications, Ltd
Date: 24-05-2021
DOI: 10.7554/ELIFE.63294
Abstract: While high risk of failure is an inherent part of developing innovative therapies, it can be reduced by adherence to evidence-based rigorous research practices. Supported through the European Union’s Innovative Medicines Initiative, the EQIPD consortium has developed a novel preclinical research quality system that can be applied in both public and private sectors and is free for anyone to use. The EQIPD Quality System was designed to be suited to boost innovation by ensuring the generation of robust and reliable preclinical data while being lean, effective and not becoming a burden that could negatively impact the freedom to explore scientific questions. EQIPD defines research quality as the extent to which research data are fit for their intended use. Fitness, in this context, is defined by the stakeholders, who are the scientists directly involved in the research, but also their funders, sponsors, publishers, research tool manufacturers, and collaboration partners such as peers in a multi-site research project. The essence of the EQIPD Quality System is the set of 18 core requirements that can be addressed flexibly, according to user-specific needs and following a user-defined trajectory. The EQIPD Quality System proposes guidance on expectations for quality-related measures, defines criteria for adequate processes (i.e. performance standards) and provides ex les of how such measures can be developed and implemented. However, it does not prescribe any pre-determined solutions. EQIPD has also developed tools (for optional use) to support users in implementing the system and assessment services for those research units that successfully implement the quality system and seek formal accreditation. Building upon the feedback from users and continuous improvement, a sustainable EQIPD Quality System will ultimately serve the entire community of scientists conducting non-regulated preclinical research, by helping them generate reliable data that are fit for their intended use.
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: Elsevier BV
Date: 07-2019
Publisher: Springer Science and Business Media LLC
Date: 23-05-2022
DOI: 10.1038/S41393-022-00811-Z
Abstract: Systematic review and meta-analysis of preclinical literature. To assess the effects of biomaterial-based combination (BMC) strategies for the treatment of Spinal Cord Injury (SCI), the effects of in idual biomaterials in the context of BMC strategies, and the factors influencing their efficacy. To assess the effects of different preclinical testing paradigms in BMC strategies. We performed a systematic literature search of Embase, Web of Science and PubMed. All controlled preclinical studies describing an in vivo or in vitro model of SCI that tested a biomaterial in combination with at least one other regenerative strategy (cells, drugs, or both) were included. Two review authors conducted the study selection independently, extracted study characteristics independently and assessed study quality using a modified CAMARADES checklist. Effect size measures were combined using random-effects models and heterogeneity was explored using meta-regression with tau 2 , I 2 and R 2 statistics. We tested for small-study effects using funnel plot–based methods. 134 publications were included, testing over 100 different BMC strategies. Overall, treatment with BMC therapies improved locomotor recovery by 25.3% (95% CI, 20.3–30.3 n = 102) and in vivo axonal regeneration by 1.6 SD (95% CI 1.2–2 SD n = 117) in comparison with injury only controls. BMC strategies improve locomotor outcomes after experimental SCI. Our comprehensive study highlights gaps in current knowledge and provides a foundation for the design of future experiments.
Publisher: Elsevier BV
Date: 06-2012
Publisher: Elsevier BV
Date: 06-2012
Publisher: Wiley
Date: 14-07-2020
DOI: 10.1111/BPH.15193
Publisher: Wiley
Date: 12-2016
DOI: 10.1002/EBM2.24
Publisher: Springer Science and Business Media LLC
Date: 05-03-2020
DOI: 10.1186/S12915-020-0755-0
Abstract: Research synthesis is the process of bringing together findings and attributes from different publications, for ex le, to give a more complete description of phenomena than is usually possible in a single work. We bring the Research Synthesis Series to BMC Biology to promote meta-analyses, other research syntheses including meta-research studies, and research synthesis methodologies in biology, facilitating their dissemination to broader communities.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2015
DOI: 10.1161/STROKEAHA.114.007953
Abstract: The characteristics of intracerebral hemorrhage (ICH) may vary by ICH location because of differences in the distribution of underlying cerebral small vessel diseases. Therefore, we investigated the incidence, characteristics, and outcome of lobar and nonlobar ICH. In a population-based, prospective inception cohort study of ICH, we used multiple overlapping sources of case ascertainment and follow-up to identify and validate ICH diagnoses in 2010 to 2011 in an adult population of 695 335. There were 128 participants with first-ever primary ICH. The overall incidence of lobar ICH was similar to nonlobar ICH (9.8 [95% confidence interval, 7.7–12.4] versus 8.6 [95% confidence interval, 6.7–11.1] per 100 000 adults/y). At baseline, adults with lobar ICH were more likely to have preceding dementia (21% versus 5% P =0.01), lower Glasgow Coma Scale scores (median, 13 versus 14 P =0.03), larger ICHs (median, 38 versus 11 mL P .001), subarachnoid extension (57% versus 5% P .001), and subdural extension (15% versus 3% P =0.02) than those with nonlobar ICH. One-year case fatality was lower after lobar ICH than after nonlobar ICH (adjusted odds ratio for death at 1 year: lobar versus nonlobar ICH 0.21 95% confidence interval, 0.07–0.63 P =0.006, after adjustment for known predictors of outcome). There were 4 recurrent ICHs, which occurred exclusively in survivors of lobar ICH (annual risk of recurrent ICH after lobar ICH, 11.8% 95% confidence interval, 4.6%–28.5% versus 0% after nonlobar ICH log-rank P =0.04). The baseline characteristics and outcome of lobar ICH differ from other locations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2009
DOI: 10.1161/STROKEAHA.108.541128
Abstract: The initial Stroke Therapy Academic Industry Roundtable (STAIR) recommendations published in 1999 were intended to improve the quality of preclinical studies of purported acute stroke therapies. Although recognized as reasonable, they have not been closely followed nor rigorously validated. Substantial advances have occurred regarding the appropriate quality and breadth of preclinical testing for candidate acute stroke therapies for better clinical translation. The updated STAIR preclinical recommendations reinforce the previous suggestions that reproducibly defining dose response and time windows with both histological and functional outcomes in multiple animal species with appropriate physiological monitoring is appropriate. The updated STAIR recommendations include: the fundamentals of good scientific inquiry should be followed by eliminating randomization and assessment bias, a priori defining inclusion/exclusion criteria, performing appropriate power and s le size calculations, and disclosing potential conflicts of interest. After initial evaluations in young, healthy male animals, further studies should be performed in females, aged animals, and animals with comorbid conditions such as hypertension, diabetes, and hypercholesterolemia. Another consideration is the use of clinically relevant biomarkers in animal studies. Although the recommendations cannot be validated until effective therapies based on them emerge from clinical trials, it is hoped that adherence to them might enhance the chances for success.
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: Elsevier BV
Date: 07-2004
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Malcolm Robert Macleod.