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Final (accepted) author’s version (‘Author manuscript’) of article published Stroke. 2016 Jun 28. pii: STROKEAHA.116.013244. [Epub ahead of print] PMID: 27354221Thomas Willis Lecture: Is translational stroke research broken, and if so, how can we fix it?Prof.Dr. Ulrich Dirnagl, MD1,2,3,4,51 Department of Experimental Neurology, Charité Universit?tsmedizin Berlin, Germany2 NeuroCure Clinical Research Center, Charité - Universit?tsmedizin Berlin, Germany3 Center for Stroke Research, Charité Universit?tsmedizin Berlin, Germany4 German Center for Neurodegenerative Diseases (DZNE), Berlin Site, Berlin, Germany 5 Berlin Institute of Health, Berlin, Germany5 German Center for Cardiovascular Research (DZHK), Berlin site, Berlin, GermanyAddress for correspondence:Prof.Dr.Ulrich DirnaglDept. Neurology and Experimental Neurology and Center for Stroke Research Berlin, Charité Universit?tsmedizin BerlinCharitépl.1 10117 Berlin, GermanyPhone: +49-30-450560-134Email: ulrich.dirnagl@charite.deAbstract:Based on research, mainly in rodents, tremendous progress has been made in our basic understanding of the pathophysiology of stroke. After many failures however, few scientists today deny that bench to bedside translation in stroke has a disappointing track record. I here summarize a number of measures to improve the predictiveness of preclinical stroke research, some of which are currently in various stages of implementation: We must reduce preventable (‘detrimental’) attrition. Key measures for this this revolve around improving preclinical study design. Internal validity must be improved by reducing bias, external validity will improve by including aged, comorbid rodents of both sexes in our modeling. False positives and inflated effect sizes can be reduced by increasing statistical power, which necessitates increasing group sizes. Compliance to reporting guidelines and checklists needs to be enforced by journals and funders. Customizing study designs to exploratory and confirmatory studies will leverage the complementary strengths of both modes of investigation. All studies should publish their full data sets. On the other hand, we should embrace inevitable ‘NULL results’. This entails planning experiments in such a way that they produce high quality evidence when NULL results are obtained and making these available to the community. A collaborative effort is needed to implement some of these recommendations. Just as in clinical medicine, multicenter approaches help to obtain sufficient group sizes and robust results. Translational stroke research is not broken, but its engine needs an overhauling to render more predictive results. Over the last few decades preclinical research on stroke has led to tremendous progress in our basic understanding of the pathophysiological events that follow focal cerebral ischemiaADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0166-2236", "PMID" : "10441299", "abstract" : "Brain injury following transient or permanent focal cerebral ischaemia (stroke) develops from a complex series of pathophysiological events that evolve in time and space. In this article, the relevance of excitotoxicity, peri-infarct depolarizations, inflammation and apoptosis to delayed mechanisms of damage within the peri-infarct zone or ischaemic penumbra are discussed. While focusing on potentially new avenues of treatment, the issue of why many clinical stroke trials have so far proved disappointing is addressed. This article provides a framework that can be used to generate testable hypotheses and treatment strategies that are linked to the appearance of specific pathophysiological events within the ischaemic brain.", "author" : [ { "dropping-particle" : "", "family" : "Dirnagl", "given" : "U", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Iadecola", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moskowitz", "given" : "M A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Trends in neurosciences", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "1999", "9" ] ] }, "page" : "391-7", "title" : "Pathobiology of ischaemic stroke: an integrated view.", "type" : "article-journal", "volume" : "22" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹", "plainTextFormattedCitation" : "1", "previouslyFormattedCitation" : "¹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }1,ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.neuron.2010.07.002", "ISSN" : "1097-4199", "PMID" : "20670828", "abstract" : "This review focuses on mechanisms and emerging concepts that drive the science of stroke in a therapeutic direction. Once considered exclusively a disorder of blood vessels, growing evidence has led to the realization that the biological processes underlying stroke are driven by the interaction of neurons, glia, vascular cells, and matrix components, which actively participate in mechanisms of tissue injury and repair. As new targets are identified, new opportunities emerge that build on an appreciation of acute cellular events acting in a broader context of ongoing destructive, protective, and reparative processes. The burden of disease is great, and its magnitude widens as a role for blood vessels and stroke in vascular and nonvascular dementias becomes more clearly established. This review then poses a number of fundamental questions, the answers to which may generate new directions for research and possibly new treatments that could reduce the impact of this enormous economic and societal burden.", "author" : [ { "dropping-particle" : "", "family" : "Moskowitz", "given" : "Michael A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lo", "given" : "Eng H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Iadecola", "given" : "Costantino", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neuron", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2010", "7", "29" ] ] }, "page" : "181-98", "title" : "The science of stroke: mechanisms in search of treatments.", "type" : "article-journal", "volume" : "67" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²", "plainTextFormattedCitation" : "2", "previouslyFormattedCitation" : "²" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }2. Numerous cellular and molecular targets have been identified for brain protective and restorative therapies, and many of these are highly effective in rodents. The incidence as well as morbidity and mortality of strokeADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1159/000441106", "ISSN" : "1423-0208", "PMID" : "26505985", "abstract" : "BACKGROUND World mapping is an important tool to visualize stroke burden and its trends in various regions and countries. OBJECTIVES To show geographic patterns of incidence, prevalence, mortality, disability-adjusted life years (DALYs) and years lived with disability (YLDs) and their trends for ischemic stroke and hemorrhagic stroke in the world for 1990-2013. METHODOLOGY Stroke incidence, prevalence, mortality, DALYs and YLDs were estimated following the general approach of the Global Burden of Disease (GBD) 2010 with several important improvements in methods. Data were updated for mortality (through April 2014) and stroke incidence, prevalence, case fatality and severity through 2013. Death was estimated using an ensemble modeling approach. A new software package, DisMod-MR 2.0, was used as part of a custom modeling process to estimate YLDs. All rates were age-standardized to new GBD estimates of global population. All estimates have been computed with 95% uncertainty intervals. RESULTS Age-standardized incidence, mortality, prevalence and DALYs/YLDs declined over the period from 1990 to 2013. However, the absolute number of people affected by stroke has substantially increased across all countries in the world over the same time period, suggesting that the global stroke burden continues to increase. There were significant geographical (country and regional) differences in stroke burden in the world, with the majority of the burden borne by low- and middle-income countries. CONCLUSIONS Global burden of stroke has continued to increase in spite of dramatic declines in age-standardized incidence, prevalence, mortality rates and disability. Population growth and aging have played an important role in the observed increase in stroke burden.", "author" : [ { "dropping-particle" : "", "family" : "Feigin", "given" : "Valery L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mensah", "given" : "George A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Norrving", "given" : "Bo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Murray", "given" : "Christopher J L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Roth", "given" : "Gregory A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "GBD 2013 Stroke Panel Experts Group", "given" : "", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neuroepidemiology", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "230-6", "title" : "Atlas of the Global Burden of Stroke (1990-2013): The GBD 2013 Study.", "type" : "article-journal", "volume" : "45" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³", "plainTextFormattedCitation" : "3", "previouslyFormattedCitation" : "³" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }3 have decreased. Stroke unitsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/14651858.CD000197.pub3", "ISSN" : "1469-493X", "PMID" : "24026639", "abstract" : "BACKGROUND Organised stroke unit care is provided by multidisciplinary teams that exclusively manage stroke patients in a ward dedicated to stroke patients, with a mobile stroke team or within a generic disability service (mixed rehabilitation ward). OBJECTIVES To assess the effect of stroke unit care compared with alternative forms of care for people following a stroke. SEARCH METHODS We searched the trials registers of the Cochrane Stroke Group (January 2013) and the Cochrane Effective Practice and Organisation of Care (EPOC) Group (January 2013), MEDLINE (2008 to September 2012), EMBASE (2008 to September 2012) and CINAHL (1982 to September 2012). In an effort to identify further published, unpublished and ongoing trials, we searched 17 trial registers (January 2013), performed citation tracking of included studies, checked reference lists of relevant articles and contacted trialists. SELECTION CRITERIA Randomised controlled clinical trials comparing organised inpatient stroke unit care with an alternative service. After formal risk of bias assessment, we have now excluded previously included quasi-randomised trials. DATA COLLECTION AND ANALYSIS Two review authors initially assessed eligibility and trial quality. We checked descriptive details and trial data with the co-ordinators of the original trials. MAIN RESULTS We included 28 trials, involving 5855 participants, comparing stroke unit care with an alternative service. More-organised care was consistently associated with improved outcomes. Twenty-one trials (3994 participants) compared stroke unit care with care provided in general wards. Stroke unit care showed reductions in the odds of death recorded at final (median one year) follow-up (odds ratio (OR) 0.87, 95% confidence interval (CI) 0.69 to 0.94; P = 0.005), the odds of death or institutionalised care (OR 0.78, 95% CI 0.68 to 0.89; P = 0.0003) and the odds of death or dependency (OR 0.79, 95% CI 0.68 to 0.90; P = 0.0007). Sensitivity analyses indicated that the observed benefits remained when the analysis was restricted to securely randomised trials that used unequivocally blinded outcome assessment with a fixed period of follow-up. Outcomes were independent of patient age, sex, initial stroke severity or stroke type, and appeared to be better in stroke units based in a discrete ward. There was no indication that organised stroke unit care resulted in a longer hospital stay. AUTHORS' CONCLUSIONS Stroke patients who receive organised inpati\u2026", "author" : [ { "dropping-particle" : "", "family" : "Stroke Unit Trialists' Collaboration", "given" : "", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Cochrane database of systematic reviews", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "CD000197", "title" : "Organised inpatient (stroke unit) care for stroke.", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁴", "plainTextFormattedCitation" : "4", "previouslyFormattedCitation" : "⁴" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }4 and recanalization via intravenous t-PAADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/14651858.CD000213.pub3", "ISSN" : "1469-493X", "PMID" : "25072528", "abstract" : "BACKGROUND Most strokes are due to blockage of an artery in the brain by a blood clot. Prompt treatment with thrombolytic drugs can restore blood flow before major brain damage has occurred and improve recovery after stroke in some people. Thrombolytic drugs, however, can also cause serious bleeding in the brain, which can be fatal. One drug, recombinant tissue plasminogen activator (rt-PA), is licensed for use in selected patients within 4.5 hours of stroke in Europe and within three hours in the USA. There is an upper age limit of 80 years in some countries, and a limitation to mainly non-severe stroke in others. Forty per cent more data are available since this review was last updated in 2009. OBJECTIVES To determine whether, and in what circumstances, thrombolytic therapy might be an effective and safe treatment for acute ischaemic stroke. SEARCH METHODS We searched the Cochrane Stroke Group Trials Register (last searched November 2013), MEDLINE (1966 to November 2013) and EMBASE (1980 to November 2013). We also handsearched conference proceedings and journals, searched reference lists and contacted pharmaceutical companies and trialists. SELECTION CRITERIA Randomised trials of any thrombolytic agent compared with control in people with definite ischaemic stroke. DATA COLLECTION AND ANALYSIS Two review authors applied the inclusion criteria, extracted data and assessed trial quality. We verified the extracted data with investigators of all major trials, obtaining additional unpublished data if available. MAIN RESULTS We included 27 trials, involving 10,187 participants, testing urokinase, streptokinase, rt-PA, recombinant pro-urokinase or desmoteplase. Four trials used intra-arterial administration, while the rest used the intravenous route. Most data come from trials that started treatment up to six hours after stroke. About 44% of the trials (about 70% of the participants) were testing intravenous rt-PA. In earlier studies very few of the participants (0.5%) were aged over 80 years; in this update, 16% of participants are over 80 years of age due to the inclusion of IST-3 (53% of participants in this trial were aged over 80 years). Trials published more recently utilised computerised randomisation, so there are less likely to be baseline imbalances than in previous versions of the review. More than 50% of trials fulfilled criteria for high-grade concealment; there were few losses to follow-up for the main outcomes.Thrombolytic therapy, mostly admi\u2026", "author" : [ { "dropping-particle" : "", "family" : "Wardlaw", "given" : "Joanna M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Murray", "given" : "Veronica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Berge", "given" : "Eivind", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zoppo", "given" : "Gregory J", "non-dropping-particle" : "del", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Cochrane database of systematic reviews", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "CD000213", "title" : "Thrombolysis for acute ischaemic stroke.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁵", "plainTextFormattedCitation" : "5", "previouslyFormattedCitation" : "⁵" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }5 or thrombectomyADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1161/STROKEAHA.115.009847", "ISSN" : "1524-4628", "PMID" : "26396032", "abstract" : "BACKGROUND AND PURPOSE Stroke affects \u2248700,000 patients annually. Recent randomized controlled trials comparing endovascular thrombectomy (ET) with medical therapy, including intravenous thrombolysis (IVT) with tissue-type plasminogen activator, have shown effectiveness of ET for some stroke patients. The study objective is to evaluate the effect of ET on good outcome in stroke patients. METHODS We searched PubMed, Embase, Web of Science, SCOPUS, , and Cochrane databases to identify original research publications between 1996 and 2015 that (1) reported clinical outcomes in patients for stroke at 90 days with the modified Rankin Scale; (2) included at least 10 patients per group; (3) compared outcome with a control arm, and (4) included anterior circulation strokes in each arm. Two authors reviewed articles for inclusion independently. RESULTS Nine of 23 809 studies met inclusion criteria. In primary analysis, ET was associated with increased odds for good outcome (odds ratio [OR], 1.75; 95% confidence interval [CI], 1.20-2.54). In secondary analysis, younger patients (OR, 1.85; 95% CI, 1.50-2.28), older patients (OR, 1.93; 95% CI, 1.10-3.37), patients receiving intravenous thrombolysis (OR, 1.83; 95% CI, 1.46-2.31), patients with worse strokes (OR, 2.23; 95% CI, 1.56-3.18), and patients with more moderate strokes (OR, 1.72; 95% CI, 1.36-2.18) had increased odds for good outcome. Symptomatic intracranial hemorrhage and mortality were similar between ET and control patients. No evidence of publication bias was seen. CONCLUSIONS ET improves good outcomes after anterior circulation stroke. ET should be strongly considered for all patients presenting within 6 hours of onset with a stroke affecting a proximal, anterior circulation vessel without a contraindication to ET.", "author" : [ { "dropping-particle" : "", "family" : "Yarbrough", "given" : "Chester K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ong", "given" : "Charlene J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beyer", "given" : "Alexander B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lipsey", "given" : "Kim", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Derdeyn", "given" : "Colin P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Stroke; a journal of cerebral circulation", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2015", "11" ] ] }, "page" : "3177-83", "title" : "Endovascular Thrombectomy for Anterior Circulation Stroke: Systematic Review and Meta-Analysis.", "type" : "article-journal", "volume" : "46" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁶", "plainTextFormattedCitation" : "6", "previouslyFormattedCitation" : "⁶" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }6 are impressive clinical success stories benefitting many patients. Intriguingly, however, practically none of these clinical breakthroughs are the result of ‘bench to bedside’ translation. On the contrary, almost all therapies that were preclinically successful have failed in actual stroke patientsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/ana.20741", "ISBN" : "0364-5134 (Print)\\n0364-5134 (Linking)", "ISSN" : "03645134", "PMID" : "16453316", "abstract" : "OBJECTIVE: 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. METHODS: 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. RESULTS: There was no evidence that drugs used clinically (114 drugs) were more effective experimentally than those tested only in animal models (912 drugs), for example, 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. INTERPRETATION: 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.", "author" : [ { "dropping-particle" : "", "family" : "O'Collins", "given" : "Victoria E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macleod", "given" : "Malcolm R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Donnan", "given" : "Geoffrey A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Horky", "given" : "Laura L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Worp", "given" : "Bart H.", "non-dropping-particle" : "Van Der", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Howells", "given" : "David W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of Neurology", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2006" ] ] }, "page" : "467-477", "title" : "1,026 Experimental treatments in acute stroke", "type" : "article-journal", "volume" : "59" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁷", "plainTextFormattedCitation" : "7", "previouslyFormattedCitation" : "⁷" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }7. This exceedingly high rate of attrition in translational stroke research has already been the subject of a number of articles. There are no simple explanations, and stroke research is certainly not the only biomedical field struggling with a translational roadblock. In the following I would like to emphasize factors for which quantitative meta-analytical evidence exists that suggests that they contribute to attrition. My selection is biased towards items in the preclinical realm that pose straightforward opportunities for improvement. In addition, inspired by work from bioethicsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pbio.1001863", "ISSN" : "1545-7885", "PMID" : "24844265", "abstract" : "Preclinical researchers confront two overarching agendas related to drug development: selecting interventions amid a vast field of candidates, and producing rigorous evidence of clinical promise for a small number of interventions. We suggest that each challenge is best met by two different, complementary modes of investigation. In the first (exploratory investigation), researchers should aim at generating robust pathophysiological theories of disease. In the second (confirmatory investigation), researchers should aim at demonstrating strong and reproducible treatment effects in relevant animal models. Each mode entails different study designs, confronts different validity threats, and supports different kinds of inferences. Research policies should seek to disentangle the two modes and leverage their complementarity. In particular, policies should discourage the common use of exploratory studies to support confirmatory inferences, promote a greater volume of confirmatory investigation, and customize design and reporting guidelines for each mode.", "author" : [ { "dropping-particle" : "", "family" : "Kimmelman", "given" : "Jonathan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mogil", "given" : "Jeffrey S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dirnagl", "given" : "Ulrich", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS biology", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2014", "5" ] ] }, "page" : "e1001863", "title" : "Distinguishing between exploratory and confirmatory preclinical research will improve translation.", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁸", "plainTextFormattedCitation" : "8", "previouslyFormattedCitation" : "⁸" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }8,ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/hast.433", "ISSN" : "0093-0334", "PMID" : "25628068", "abstract" : "The so-called drug pipeline is not really about drugs and not much like a pipeline. It is really about the production and dissemination of information, and it is much more like a web. The misunderstanding leads to a poor understanding of what's wrong with clinical translation and how it can be improved.", "author" : [ { "dropping-particle" : "", "family" : "Kimmelman", "given" : "Jonathan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "London", "given" : "Alex John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Hastings Center report", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "0" ] ] }, "page" : "27-39", "title" : "The structure of clinical translation: efficiency, information, and ethics.", "type" : "article-journal", "volume" : "45" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁹", "plainTextFormattedCitation" : "9", "previouslyFormattedCitation" : "⁹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }9, and meta-researchADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pbio.1002264", "ISSN" : "1545-7885", "PMID" : "26431313", "abstract" : "As the scientific enterprise has grown in size and diversity, we need empirical evidence on the research process to test and apply interventions that make it more efficient and its results more reliable. Meta-research is an evolving scientific discipline that aims to evaluate and improve research practices. It includes thematic areas of methods, reporting, reproducibility, evaluation, and incentives (how to do, report, verify, correct, and reward science). Much work is already done in this growing field, but efforts to-date are fragmented. We provide a map of ongoing efforts and discuss plans for connecting the multiple meta-research efforts across science worldwide.", "author" : [ { "dropping-particle" : "", "family" : "Ioannidis", "given" : "John P A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fanelli", "given" : "Daniele", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dunne", "given" : "Debbie Drake", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Goodman", "given" : "Steven N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS biology", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "2015", "10" ] ] }, "page" : "e1002264", "title" : "Meta-research: Evaluation and Improvement of Research Methods and Practices.", "type" : "article-journal", "volume" : "13" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁰", "plainTextFormattedCitation" : "10", "previouslyFormattedCitation" : "¹⁰" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }10. I would like to propose, somewhat counter-intuitively, that there are instances where we need to embrace attrition. Collectively, I argue for an update of our intellectual framework for translational research.To a large extent, bench to bedside translation is a ‘black box’. Innumerable factors impact on whether and to what extent preclinical evidence is transferable to clinical evidence. Attrition lurks on all levels: Preclinically, when moving to first in man, when trying to obtain safety or initial signs of efficacy, and in large clinical trials aiming at regulatory approval.Can mice mimic human stroke pathophysiology?The most basic and dramatic threat to the validity of bench to bedside translation concerns the question of whether preclinical models can predict human pathophysiology and therapeutic outcomes. This relates to the concept and construct validity of how we model the different types of strokes, and in a more general sense to whether non-human (in particular rodent) physiology and pathobiology are sufficiently similar to that of humans. There are indeed very few best practice cases which unequivocally demonstrate translational success for a treatment. Unfortunately, tPA, which was effective in a rabbit model of embolic strokeADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0036-8075", "PMID" : "3934754", "abstract" : "Intravenous administration of tissue plasminogen activator immediately after the injection of numerous small blood clots into the carotid circulation in rabbit embolic stroke model animals caused a significant reduction in neurological damage. In vitro studies indicate that tissue plasminogen activator produced substantial lysis of clots at concentrations comparable to those expected in vivo, suggesting that this may be the mechanism of action of this drug. Drug-induced hemorrhages were not demonstrable. Tissue plasminogen activator may be of value for the immediate treatment of embolic stroke.", "author" : [ { "dropping-particle" : "", "family" : "Zivin", "given" : "J A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fisher", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "DeGirolami", "given" : "U", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hemenway", "given" : "C C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stashak", "given" : "J A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Science (New York, N.Y.)", "id" : "ITEM-1", "issue" : "4731", "issued" : { "date-parts" : [ [ "1985", "12", "13" ] ] }, "page" : "1289-92", "title" : "Tissue plasminogen activator reduces neurological damage after cerebral embolism.", "type" : "article-journal", "volume" : "230" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹¹", "plainTextFormattedCitation" : "11", "previouslyFormattedCitation" : "¹¹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }11 before its clinical efficacy had been established in the seminal NINDS trialADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJM199512143332401", "ISSN" : "0028-4793", "PMID" : "7477192", "abstract" : "BACKGROUND Thrombolytic therapy for acute ischemic stroke has been approached cautiously because there were high rates of intracerebral hemorrhage in early clinical trials. We performed a randomized, double-blind trial of intravenous recombinant tissue plasminogen activator (t-PA) for ischemic stroke after recent pilot studies suggested that t-PA was beneficial when treatment was begun within three hours of the onset of stroke. METHODS The trial had two parts. Part 1 (in which 291 patients were enrolled) tested whether t-PA had clinical activity, as indicated by an improvement of 4 points over base-line values in the score of the National Institutes of Health stroke scale (NIHSS) or the resolution of the neurologic deficit within 24 hours of the onset of stroke. Part 2 (in which 333 patients were enrolled) used a global test statistic to assess clinical outcome at three months, according to scores on the Barthel index, modified Rankin scale, Glasgow outcome scale, and NIHSS: RESULTS In part 1, there was no significant difference between the group given t-PA and that given placebo in the percentages of patients with neurologic improvement at 24 hours, although a benefit was observed for the t-PA group at three months for all four outcome measures. In part 2, the long-term clinical benefit of t-PA predicted by the results of part 1 was confirmed (global odds ratio for a favorable outcome, 1.7; 95 percent confidence interval, 1.2 to 2.6). As compared with patients given placebo, patients treated with t-PA were at least 30 percent more likely to have minimal or no disability at three months on the assessment scales. Symptomatic intracerebral hemorrhage within 36 hours after the onset of stroke occurred in 6.4 percent of patients given t-PA but only 0.6 percent of patients given placebo (P < 0.001). Mortality at three months was 17 percent in the t-PA group and 21 percent in the placebo group (P = 0.30). CONCLUSIONS Despite an increased incidence of symptomatic intracerebral hemorrhage, treatment with intravenous t-PA within three hours of the onset of ischemic stroke improved clinical outcome at three months.", "container-title" : "The New England journal of medicine", "id" : "ITEM-1", "issue" : "24", "issued" : { "date-parts" : [ [ "1995", "12", "14" ] ] }, "page" : "1581-7", "title" : "Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group.", "type" : "article-journal", "volume" : "333" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹²", "plainTextFormattedCitation" : "12", "previouslyFormattedCitation" : "¹²" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }12, has proved to be the exception rather than the rule. We therefore have to rely on indirect evidence, such as similar phenotypes of pathophysiologic phenomena in experimental and human stroke. Examples include immunodepression after strokeADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1471-003X (Print) 1471-003X (Linking)", "abstract" : "Infections are a leading cause of morbidity and mortality in patients with acute CNS injury. It has recently become clear that CNS injury significantly increases susceptibility to infection by brain-specific mechanisms: CNS injury induces a disturbance of the normally well balanced interplay between the immune system and the CNS. As a result, CNS injury leads to secondary immunodeficiency - CNS injury-induced immunodepression (CIDS) - and infection. CIDS might serve as a model for the study of the mechanisms and mediators of brain control over immunity. More importantly, understanding CIDS will allow us to work on developing effective therapeutic strategies, with which the outcome after CNS damage by a host of diseases could be improved by eliminating a major determinant of poor recovery.", "author" : [ { "dropping-particle" : "", "family" : "Meisel", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schwab", "given" : "J M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Prass", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Meisel", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dirnagl", "given" : "U", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nat Rev Neurosci", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "2005" ] ] }, "note" : "Oct\n\n \nCentral nervous system injury-induced immune deficiency syndrome\n\n \nMeisel, Christian\nSchwab, Jan M\nPrass, Konstantin\nMeisel, Andreas\nDirnagl, Ulrich\nResearch Support, Non-U.S. Gov&#039;t\nReview\nEngland\nNature reviews. Neuroscience\nNat Rev Neurosci. 2005 Oct;6(10):775-86.\n\n \neng", "page" : "775-786", "publisher-place" : "Department of Medical Immunology, Charite, Humboldt University, 10098 Berlin, Germany.", "title" : "Central nervous system injury-induced immune deficiency syndrome", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹³", "plainTextFormattedCitation" : "13", "previouslyFormattedCitation" : "¹³" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }13 or spreading depolarizationADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.neuron.2015.04.004", "ISSN" : "1097-4199", "PMID" : "25996134", "abstract" : "The term spreading depolarization (SD) refers to waves of abrupt, sustained mass depolarization in gray matter of the CNS. SD, which spreads from neuron to neuron in affected tissue, is characterized by a rapid near-breakdown of the neuronal transmembrane ion gradients. SD can be induced by hypoxic conditions--such as from ischemia--and facilitates neuronal death in energy-compromised tissue. SD has also been implicated in migraine aura, where SD is assumed to ascend in well-nourished tissue and is typically benign. In addition to these two ends of the \"SD continuum,\" an SD wave can propagate from an energy-depleted tissue into surrounding, well-nourished tissue, as is often the case in stroke and brain trauma. This review presents the neurobiology of SD--its triggers and propagation mechanisms--as well as clinical manifestations of SD, including overlaps and differences between migraine aura and stroke, and recent developments in neuromonitoring aimed at better diagnosis and more targeted treatments.", "author" : [ { "dropping-particle" : "", "family" : "Dreier", "given" : "Jens P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reiffurth", "given" : "Clemens", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neuron", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2015", "5", "20" ] ] }, "page" : "902-22", "title" : "The stroke-migraine depolarization continuum.", "type" : "article-journal", "volume" : "86" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁴", "plainTextFormattedCitation" : "14", "previouslyFormattedCitation" : "¹⁴" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }14. More examples, and a more elaborated argument for why modeling of stroke in rodents can indeed be predictive for human pathobiology and treatments can be found in Dirnagl and EndresADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1161/STROKEAHA.113.004075", "ISSN" : "1524-4628", "PMID" : "24652307", "author" : [ { "dropping-particle" : "", "family" : "Dirnagl", "given" : "Ulrich", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Endres", "given" : "Matthias", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Stroke; a journal of cerebral circulation", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2014", "5" ] ] }, "page" : "1510-8", "title" : "Found in translation: preclinical stroke research predicts human pathophysiology, clinical phenotypes, and therapeutic outcomes.", "type" : "article-journal", "volume" : "45" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁵", "plainTextFormattedCitation" : "15", "previouslyFormattedCitation" : "¹⁵" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }15.Internal validity: Keeping cognitive biases in check To provide a solid basis for clinical development, evidence at the bench must be robust and reliable. Lack of these attributes can lead to attrition and wasted resources, unethical use of animals in research, and can potentially put patients at risk. Robustness and reliability of research are threatened by a number of biases and consequently low internal validity. Selection bias is controlled by randomization, which safeguards that experimental groups are similar except for the experimental manipulation. Concealing the allocation to experimental groups, a form of blinding, prevents performance bias. Finally, detection bias is kept in check by blinded assessment of outcomes. The conceptual framework of these measures, which are intended to ‘keep all other things equal’ (save the intervention), was well developed decades ago for clinical trials. In this highly regulated area of biomedical research, internal validity is a central consideration when planning and reporting a study and a key criterion of review boards and regulators. Surprisingly, in experimental biomedicine, internal validity appears to be much less of a concern. Indeed, in the wake of what has been termed a ‘reproducibility crisis’, the internal validity of preclinical research has recently been put into questionADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1161/CIRCRESAHA.114.303819", "ISSN" : "1524-4571", "PMID" : "25552691", "abstract" : "Medical and scientific advances are predicated on new knowledge that is robust and reliable and that serves as a solid foundation on which further advances can be built. In biomedical research, we are in the midst of a revolution with the generation of new data and scientific publications at a previously unprecedented rate. However, unfortunately, there is compelling evidence that the majority of these discoveries will not stand the test of time. To a large extent, this reproducibility crisis in basic and preclinical research may be as a result of failure to adhere to good scientific practice and the desperation to publish or perish. This is a multifaceted, multistakeholder problem. No single party is solely responsible, and no single solution will suffice. Here we review the reproducibility problems in basic and preclinical biomedical research, highlight some of the complexities, and discuss potential solutions that may help improve research quality and reproducibility.", "author" : [ { "dropping-particle" : "", "family" : "Begley", "given" : "C Glenn", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ioannidis", "given" : "John P A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Circulation research", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2015", "1", "2" ] ] }, "page" : "116-26", "title" : "Reproducibility in science: improving the standard for basic and preclinical research.", "type" : "article-journal", "volume" : "116" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁶", "plainTextFormattedCitation" : "16", "previouslyFormattedCitation" : "¹⁶" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }16. Meta-researchADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pbio.1002264", "ISSN" : "1545-7885", "PMID" : "26431313", "abstract" : "As the scientific enterprise has grown in size and diversity, we need empirical evidence on the research process to test and apply interventions that make it more efficient and its results more reliable. Meta-research is an evolving scientific discipline that aims to evaluate and improve research practices. It includes thematic areas of methods, reporting, reproducibility, evaluation, and incentives (how to do, report, verify, correct, and reward science). Much work is already done in this growing field, but efforts to-date are fragmented. We provide a map of ongoing efforts and discuss plans for connecting the multiple meta-research efforts across science worldwide.", "author" : [ { "dropping-particle" : "", "family" : "Ioannidis", "given" : "John P A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fanelli", "given" : "Daniele", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dunne", "given" : "Debbie Drake", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Goodman", "given" : "Steven N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS biology", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "2015", "10" ] ] }, "page" : "e1002264", "title" : "Meta-research: Evaluation and Improvement of Research Methods and Practices.", "type" : "article-journal", "volume" : "13" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁰", "plainTextFormattedCitation" : "10", "previouslyFormattedCitation" : "¹⁰" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }10 has provided ample evidence that despite an international discussion and the introduction of guidelinesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pbio.1000412", "ISSN" : "1545-7885", "PMID" : "20613859", "author" : [ { "dropping-particle" : "", "family" : "Kilkenny", "given" : "Carol", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Browne", "given" : "William J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cuthill", "given" : "Innes C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Emerson", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Altman", "given" : "Douglas G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS biology", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2010" ] ] }, "page" : "e1000412", "title" : "Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research.", "type" : "article-journal", "volume" : "8" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁷", "plainTextFormattedCitation" : "17", "previouslyFormattedCitation" : "¹⁷" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }17,ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nature11556", "ISBN" : "doi:10.1038/nature11556", "ISSN" : "1476-4687", "PMID" : "23060188", "abstract" : "The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. 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"10.1371/journal.pbio.1002273", "ISSN" : "1545-7885", "PMID" : "26460723", "abstract" : "The reliability of experimental findings depends on the rigour of experimental design. Here we show limited reporting of measures to reduce the risk of bias in a random sample of life sciences publications, significantly lower reporting of randomisation in work published in journals of high impact, and very limited reporting of measures to reduce the risk of bias in publications from leading United Kingdom institutions. Ascertainment of differences between institutions might serve both as a measure of research quality and as a tool for institutional efforts to improve research quality.", "author" : [ { "dropping-particle" : "", "family" : "Macleod", "given" : "Malcolm R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lawson McLean", "given" : "Aaron", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kyriakopoulou", "given" : "Aikaterini", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Serghiou", "given" : "Stylianos", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wilde", "given" : "Arno", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sherratt", "given" : "Nicki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hirst", "given" : "Theo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hemblade", "given" : "Rachel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bahor", "given" : "Zsanett", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nunes-Fonseca", "given" : "Cristina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Potluru", "given" : "Aparna", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thomson", "given" : "Andrew", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Baginskaite", "given" : "Julija", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Baginskitae", "given" : "Julija", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Egan", "given" : "Kieren", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vesterinen", "given" : "Hanna", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Currie", "given" : "Gillian L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Churilov", "given" : "Leonid", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Howells", "given" : "David W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sena", "given" : "Emily S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS biology", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "2015", "10" ] ] }, "page" : "e1002273", "title" : "Risk of Bias in Reports of In Vivo Research: A Focus for Improvement.", "type" : "article-journal", "volume" : "13" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁹", "plainTextFormattedCitation" : "19", "previouslyFormattedCitation" : "¹⁹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }19. We have recently studied the effect of attrition bias, which so far has received relatively little attention although it seems highly prevalent and may substantially skew experimental evidence. We reviewed 100 randomly selected reports published between 2000 and 2013 describing 522 experiments that used rodents to test cancer or stroke treatments, and compared the numbers of animals reported in the papers’ methods and results sections. In close to two-thirds of the experiments it was impossible to trace the flow of animals through the study, and thus to decide whether any animals had been dropped from their final analysis. Of those that did report numbers, around 30% reported that they had dropped rodents from their study analysis, but fewer than 25 % of those explained why. Using simulated data we demonstrated that this can lead to a major distortion of the resultsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pbio.1002331", "ISSN" : "1545-7885", "PMID" : "26726833", "abstract" : "Given small sample sizes, loss of animals in preclinical experiments can dramatically alter results. However, effects of attrition on distortion of results are unknown. We used a simulation study to analyze the effects of random and biased attrition. As expected, random loss of samples decreased statistical power, but biased removal, including that of outliers, dramatically increased probability of false positive results. Next, we performed a meta-analysis of animal reporting and attrition in stroke and cancer. Most papers did not adequately report attrition, and extrapolating from the results of the simulation data, we suggest that their effect sizes were likely overestimated.", "author" : [ { "dropping-particle" : "", "family" : "Holman", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Piper", "given" : "SK", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grittner", "given" : "U", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Diamantaras", "given" : "AA", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kimmelman", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Siegerink", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dirnagl", "given" : "U", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLOS Biology", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016" ] ] }, "page" : "1-12", "title" : "Where Have All the Rodents Gone? The Effects of Attrition in Experimental Research on Cancer and Stroke", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁰", "plainTextFormattedCitation" : "20", "previouslyFormattedCitation" : "²⁰" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }20, especially when group sizes are small. Power failure: False positives and inflated effect sizesGroup sizes in preclinical medicine are exceedingly small. An analysis of more than 2000 experimental stroke studies performed over the last few decades reveals a mean group size of 8ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2015", "5", "23" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "Camarades", "given" : "", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "0" ] ] }, "title" : "Collaborative Approach to Meta Analysis and Review of Animal Data from Experimental Studies", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²¹", "plainTextFormattedCitation" : "21", "previouslyFormattedCitation" : "²¹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }21. The CAMARADES databaseADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2015", "5", "23" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "Camarades", "given" : "", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "0" ] ] }, "title" : "Collaborative Approach to Meta Analysis and Review of Animal Data from Experimental Studies", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²¹", "plainTextFormattedCitation" : "21", "previouslyFormattedCitation" : "²¹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }21 also contains the normalized effect sizes of all these studies, which can be used to calculate the mean statistical power. With a mere 45 % the statistical power of the preclinical stroke literature is slightly lower than that in effect when we toss a coin (50 %). Yet, perplexingly, this is still superior to the 23 % median power calculated for over 700 primary neuroscience studiesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nrn3475", "ISBN" : "1471-0048 (Electronic)\\n1471-003X (Linking)", "ISSN" : "1471-0048", "PMID" : "23571845", "abstract" : "A study with low statistical power has a reduced chance of detecting a true effect, but it is less well appreciated that low power also reduces the likelihood that a statistically significant result reflects a true effect. Here, we show that the average statistical power of studies in the neurosciences is very low. The consequences of this include overestimates of effect size and low reproducibility of results. There are also ethical dimensions to this problem, as unreliable research is inefficient and wasteful. Improving reproducibility in neuroscience is a key priority and requires attention to well-established but often ignored methodological principles.", "author" : [ { "dropping-particle" : "", "family" : "Button", "given" : "Katherine S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ioannidis", "given" : "John P A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mokrysz", "given" : "Claire", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nosek", "given" : "Brian A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Flint", "given" : "Jonathan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Robinson", "given" : "Emma S J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Munaf\u00f2", "given" : "Marcus R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature reviews. Neuroscience", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2013", "5" ] ] }, "page" : "365-76", "title" : "Power failure: why small sample size undermines the reliability of neuroscience.", "type" : "article-journal", "volume" : "14" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²²", "plainTextFormattedCitation" : "22", "previouslyFormattedCitation" : "²²" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }22. A power of 45 % means not only that an effect, if indeed present, can only be detected in 45 % of those cases (high false negative rate). It also means that in these cases effect sizes will be overestimated by more than 40 % (‘Winner’s curseADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nrn3475", "ISBN" : "1471-0048 (Electronic)\\n1471-003X (Linking)", "ISSN" : "1471-0048", "PMID" : "23571845", "abstract" : "A study with low statistical power has a reduced chance of detecting a true effect, but it is less well appreciated that low power also reduces the likelihood that a statistically significant result reflects a true effect. Here, we show that the average statistical power of studies in the neurosciences is very low. The consequences of this include overestimates of effect size and low reproducibility of results. There are also ethical dimensions to this problem, as unreliable research is inefficient and wasteful. Improving reproducibility in neuroscience is a key priority and requires attention to well-established but often ignored methodological principles.", "author" : [ { "dropping-particle" : "", "family" : "Button", "given" : "Katherine S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ioannidis", "given" : "John P A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mokrysz", "given" : "Claire", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nosek", "given" : "Brian A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Flint", "given" : "Jonathan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Robinson", "given" : "Emma S J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Munaf\u00f2", "given" : "Marcus R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature reviews. Neuroscience", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2013", "5" ] ] }, "page" : "365-76", "title" : "Power failure: why small sample size undermines the reliability of neuroscience.", "type" : "article-journal", "volume" : "14" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1098/rsos.140216", "ISBN" : "2054-5703", "ISSN" : "2054-5703", "PMID" : "26064558", "abstract" : "If you use P = 0.05 to suggest that you have made a discovery, you\u2019ll be wrong at least 30% of the time. If, as is often the case, experiments are under-powered, you\u2019ll de wrong most of the time. This conclusion is demonstrated from several points of view. First, tree diagrams which show the close analogy with the screening test problem. Similar conclusions are drawn by repeated simulations of t tests. These mimic what\u2019s done in real life, which makes the results more persuasive The simulation method is used is used also to evaluate the extent effect sizes are over-estimated, especially in under-powered experiments. A script is supplied to allow the reader to do simulations themselves, with numbers appropriate for their own work. The interpretation of an observed result of, say, P = 0.047 is investigated from several points of view. It is concluded that if you wish to keep your false discovery rate below 5%, you need to use a 3-sigma rule, or to insist on P \u2264 0.001. And never use the word \u201csignificant\u201d.", "author" : [ { "dropping-particle" : "", "family" : "Colquhoun", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Royal Society Open Science", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "1-15", "title" : "An investigation of the false discovery rate and the misinterpretation of P values", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^22,23", "plainTextFormattedCitation" : "22,23", "previouslyFormattedCitation" : "^22,23" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }22,23). In addition, and most worryingly, given reasonable prior probabilities for the effectiveness of the tested compounds (or hypotheses) a power of only 45 % will lead to false positive rates of around 50 %. John Ioannidis concluded in his 2005 landmark paperADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pmed.0020124", "ISBN" : "3540239081", "ISSN" : "15491277", "PMID" : "16060722", "abstract" : "Summary\\n There is increasing concern that most current published research findings are false. The probability that a research claim is true may depend on study power and bias, the number of other studies on the same question, and, importantly, the ratio of true to no relationships among the relationships probed in each scientific field. In this framework, a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance. Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true. Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias. In this essay, I discuss the implications of these problems for the conduct and interpretation of research.", "author" : [ { "dropping-particle" : "", "family" : "Ioannidis", "given" : "John P A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS Medicine", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "2005", "8" ] ] }, "page" : "0696-0701", "title" : "Why most published research findings are false", "type" : "article-journal", "volume" : "2" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁴", "plainTextFormattedCitation" : "24", "previouslyFormattedCitation" : "²⁴" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }24 that due to the synergistic effects of insufficiently controlled bias (e.g. by non-blinding, see above) and low statistical power, ‘most published research findings are false’. Publication bias: Show me the evidenceIn clinical medicine, where lawmakers, regulators, and journal editors mandate preregistration of trials, it is estimated that the results of only 50% of all studies are eventually publishedADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/S0140-6736(13)62296-5", "ISSN" : "01406736", "author" : [ { "dropping-particle" : "", "family" : "Chan", "given" : "An-Wen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Song", "given" : "Fujian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vickers", "given" : "Andrew", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jefferson", "given" : "Tom", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dickersin", "given" : "Kay", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "G\u00f8tzsche", "given" : "Peter C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Krumholz", "given" : "Harlan M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ghersi", "given" : "Davina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Worp", "given" : "H Bart", "non-dropping-particle" : "van der", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Lancet", "id" : "ITEM-1", "issue" : "9913", "issued" : { "date-parts" : [ [ "2014", "1" ] ] }, "page" : "257-266", "publisher" : "Elsevier", "title" : "Increasing value and reducing waste: addressing inaccessible research", "type" : "article-journal", "volume" : "383" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁵", "plainTextFormattedCitation" : "25", "previouslyFormattedCitation" : "²⁵" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }25. In preclinical medicine, where preregistration is virtually non-existent and studies often have no clearly defined beginning or end, we cannot know what and how much high quality evidence is produced but never reported. However, judging from the almost complete dearth of any studies in the preclinical literature that reject the NULL hypothesis, we can only speculate that there is an exceedingly strong publication bias towards ‘effective drugs’ or ‘confirmed hypotheses’. Sena at al. systematically reviewed 525 original publications in the preclinical stroke literatureADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pbio.1000344", "ISBN" : "1545-7885 (Electronic)\\r1544-9173 (Linking)", "ISSN" : "15449173", "PMID" : "20361022", "abstract" : "The consolidation of scientific knowledge proceeds through the interpretation and then distillation of data presented in research reports, first in review articles and then in textbooks and undergraduate courses, until truths become accepted as such both amongst \"experts\" and in the public understanding. Where data are collected but remain unpublished, they cannot contribute to this distillation of knowledge. If these unpublished data differ substantially from published work, conclusions may not reflect adequately the underlying biological effects being described. The existence and any impact of such \"publication bias\" in the laboratory sciences have not been described. Using the CAMARADES (Collaborative Approach to Meta-analysis and Review of Animal Data in Experimental Studies) database we identified 16 systematic reviews of interventions tested in animal studies of acute ischaemic stroke involving 525 unique publications. Only ten publications (2%) reported no significant effects on infarct volume and only six (1.2%) did not report at least one significant finding. Egger regression and trim-and-fill analysis suggested that publication bias was highly prevalent (present in the literature for 16 and ten interventions, respectively) in animal studies modelling stroke. Trim-and-fill analysis suggested that publication bias might account for around one-third of the efficacy reported in systematic reviews, with reported efficacy falling from 31.3% to 23.8% after adjustment for publication bias. We estimate that a further 214 experiments (in addition to the 1,359 identified through rigorous systematic review; non publication rate 14%) have been conducted but not reported. It is probable that publication bias has an important impact in other animal disease models, and more broadly in the life sciences.", "author" : [ { "dropping-particle" : "", "family" : "Sena", "given" : "Emily S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bart van der Worp", "given" : "H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bath", "given" : "Philip M W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Howells", "given" : "David W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macleod", "given" : "Malcolm R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Worp", "given" : "H Bart", "non-dropping-particle" : "van der", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bath", "given" : "Philip M W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Howells", "given" : "David W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macleod", "given" : "Malcolm R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS Biology", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2010", "3" ] ] }, "page" : "e1000344", "title" : "Publication bias in reports of animal stroke studies leads to major overstatement of efficacy", "type" : "article-journal", "volume" : "8" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁶", "plainTextFormattedCitation" : "26", "previouslyFormattedCitation" : "²⁶" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }26. Only ten publications (2%) reported no significant effects on infarct volume and only six (1.2%) did not report even one significant finding. If this correctly reflects the success rate of hypothesizing and drug treatments in the experimental stroke field, I argue that it is wasteful and potentially unethical to conduct experiments at all: Experiments must necessarily demonstrate that what has been hypothesized must be true (or that drugs work)! Oddly, at the risk of producing a false negative! Meta-analytical evidence has unequivocally demonstrated the prevalence of publication bias and the detrimental effects it can have. In the experimental stroke literature, publication bias accounts for at least 30% of the published effect sizesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pbio.1000344", "ISBN" : "1545-7885 (Electronic)\\r1544-9173 (Linking)", "ISSN" : "15449173", "PMID" : "20361022", "abstract" : "The consolidation of scientific knowledge proceeds through the interpretation and then distillation of data presented in research reports, first in review articles and then in textbooks and undergraduate courses, until truths become accepted as such both amongst \"experts\" and in the public understanding. Where data are collected but remain unpublished, they cannot contribute to this distillation of knowledge. If these unpublished data differ substantially from published work, conclusions may not reflect adequately the underlying biological effects being described. The existence and any impact of such \"publication bias\" in the laboratory sciences have not been described. Using the CAMARADES (Collaborative Approach to Meta-analysis and Review of Animal Data in Experimental Studies) database we identified 16 systematic reviews of interventions tested in animal studies of acute ischaemic stroke involving 525 unique publications. Only ten publications (2%) reported no significant effects on infarct volume and only six (1.2%) did not report at least one significant finding. Egger regression and trim-and-fill analysis suggested that publication bias was highly prevalent (present in the literature for 16 and ten interventions, respectively) in animal studies modelling stroke. Trim-and-fill analysis suggested that publication bias might account for around one-third of the efficacy reported in systematic reviews, with reported efficacy falling from 31.3% to 23.8% after adjustment for publication bias. We estimate that a further 214 experiments (in addition to the 1,359 identified through rigorous systematic review; non publication rate 14%) have been conducted but not reported. It is probable that publication bias has an important impact in other animal disease models, and more broadly in the life sciences.", "author" : [ { "dropping-particle" : "", "family" : "Sena", "given" : "Emily S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bart van der Worp", "given" : "H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bath", "given" : "Philip M W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Howells", "given" : "David W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macleod", "given" : "Malcolm R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Worp", "given" : "H Bart", "non-dropping-particle" : "van der", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bath", "given" : "Philip M W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Howells", "given" : "David W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macleod", "given" : "Malcolm R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS Biology", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2010", "3" ] ] }, "page" : "e1000344", "title" : "Publication bias in reports of animal stroke studies leads to major overstatement of efficacy", "type" : "article-journal", "volume" : "8" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁶", "plainTextFormattedCitation" : "26", "previouslyFormattedCitation" : "²⁶" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }26. Low external validity: Stroke treatments for healthy young male rodentsWith few exceptions, stroke research is conducted in healthy, very young, male inbred rodent strains raised under specific pathogen-free (SPF) conditions and fed a diet optimized for high fertility and overall health. The equivalent human cohort would be healthy pubertal twins raised in 6 m2 isolator tents on an enriched granola diet (fig.1), but stroke patients are elderly, of both sexes, comorbid, on multiple medications, and have had exposure to numerous pathogens and antigens throughout their life. Studies on outbreds, different strains, comorbidities, aging, gender and diet as well as housing conditions have demonstrated the strong impact of these factors on stroke outcome in experimental animals and on treatment efficacy. As a general rule, the closer stroke models have mimicked stroke patients, for example after aged animals and comorbidities had been studied, the more substantial has been the loss in efficacy of the treatment effects (e.g. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3727/096368916X690557", "ISSN" : "1555-3892", "PMID" : "26811151", "abstract" : "Aging and vascular comorbidities such as hypertension comprise critical cofactors that influence how the brain responds to stroke. Ischemic stress induces neurogenesis and oligodendrogenesis in younger brains. However, it remains unclear whether these compensatory mechanisms can be maintained even under pathologically hypertensive and aged states. To clarify the age-related remodeling capacity after stroke under hypertensive conditions, we assessed infarct volume, behavioral outcomes, and surrogate markers of neurogenesis and oligodendrogenesis in acute and subacute phases after transient focal cerebral ischemia in 3- and 12-month-old spontaneously hypertensive rats (SHRs). Hematoxylin and eosin staining showed that 3- and 12-month-old SHRs exhibited similar infarction volumes at both 3 and 14 days after focal cerebral ischemia. However, recovery of behavioral deficits (neurological score assessment and adhesive removal test) was significantly less in 12-month-old SHRs compared to 3-month-old SHRs. Concomitantly, numbers of nestin(+) neural stem/progenitor cells (NSPCs) near the infarct border area or subventricular zone in 12-month-old SHRs were lower than 3-month-old SHRs at day 3. Similarly, numbers of PDGFR-\u03b1(+) oligodendrocyte precursor cells (OPCs) in the corpus callosum were lower in 12-month-old SHRs at day 3. Lower levels of NSPC and OPC numbers were accompanied by lower expression levels of phosphorylated CREB. By day 14 postischemia, NSPC and OPC numbers in 12-month-old SHRs recovered to similar levels as in 3-month-old SHRs, but the numbers of proliferating NSPCs (Ki-67(+)nestin(+) cells) and proliferating OPCs (Ki-67(+)PDGFR-\u03b1(+) cells) remained lower in the older brains even at day 14. Taken together, these findings suggest that aging may also decrease poststroke compensatory responses for neurogenesis and oligodendrogenesis even under hypertensive conditions.", "author" : [ { "dropping-particle" : "", "family" : "Liang", "given" : "Anna C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mandeville", "given" : "Emiri T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maki", "given" : "Takakuni", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shindo", "given" : "Akihiro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Som", "given" : "Angel T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Egawa", "given" : "Naohiro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Itoh", "given" : "Kanako", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chuang", "given" : "Tsu Tshen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McNeish", "given" : "John D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holder", "given" : "Julie C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lok", "given" : "Josephine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lo", "given" : "Eng H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Arai", "given" : "Ken", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell transplantation", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2016" ] ] }, "page" : "705-14", "title" : "Effects of Aging on Neural Stem/Progenitor Cells and Oligodendrocyte Precursor Cells After Focal Cerebral Ischemia in Spontaneously Hypertensive Rats.", "type" : "article-journal", "volume" : "25" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁷", "plainTextFormattedCitation" : "27", "previouslyFormattedCitation" : "²⁷" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }27,ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1186/2040-7378-5-12", "ISSN" : "2040-7378", "PMID" : "24499655", "abstract" : "BACKGROUND Exogenous administration of the anti-inflammatory cytokine, interleukin 10 (IL-10), is known to promote neuroprotection and mitigate neuroinflammation after ischemia. However, endogenous expression and localization of IL-10 and its receptor (IL-10R) in the post-ischemic brain are still to be elucidated. In this investigation we aimed at determining the temporospatial expression of IL-10 in the rat brain relative to its systemic levels after ischemic stroke. METHODS Wistar rats were subjected to either permanent (pMCAO) or 3-h temporary (tMCAO) middle cerebral artery occlusion and euthanized at either 24 or 72\u00a0h. IL-10/IL-10R levels were quantified in ischemic and contralesional hemispheres and compared to shams using multiplex bead array and Western blotting, respectively. Localization of IL-10/IL-10R with markers for neurons, microglia, astrocytes & endothelial cells were examined using double labeling immunofluorescence. IL-10 was also quantified in the brain tissue of spontaneously hypertensive rats (SHRs) at 24\u00a0h after tMCAO. RESULTS After both pMCAO and tMCAO in Wistars, IL-10 was significantly upregulated in both hemispheres by\u2009\u2248\u200950% at 24\u00a0h while IL-10R expression was significantly decreased only at 72\u00a0h in the ischemic hemisphere. IL-10 and IL-10R expression highly co-localized with viable neurons in the ischemic penumbra and contralesional hemisphere. In hypertensive rats, IL-10 showed no significant contralesional upregulation and declined significantly in the ischemic side at 24\u00a0h post-ischemia. CONCLUSION Our data highlights the involvement of the ischemic and contralesional neurons in the endogenous anti-inflammatory response after ischemic stroke through increased production of IL-10. This increase in IL-10 is blunted in hypertensive animals and may contribute to worse outcomes.", "author" : [ { "dropping-particle" : "", "family" : "Fouda", "given" : "Abdelrahman Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kozak", "given" : "Anna", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alhusban", "given" : "Ahmed", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Switzer", "given" : "Jeffrey A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fagan", "given" : "Susan C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Experimental & translational stroke medicine", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "12", "title" : "Anti-inflammatory IL-10 is upregulated in both hemispheres after experimental ischemic stroke: Hypertension blunts the response.", "type" : "article-journal", "volume" : "5" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁸", "plainTextFormattedCitation" : "28", "previouslyFormattedCitation" : "²⁸" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }28,ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.neurobiolaging.2015.11.006", "ISSN" : "1558-1497", "PMID" : "26827651", "abstract" : "Stroke is a major cause of disability for which no neuroprotective measures are available. Age is the principal nonmodifiable risk factor for this disease. Previously, we reported that exposure to hydrogen sulfide for 48\u00a0hours after stroke lowers whole body temperature and confers neuroprotection in aged animals. Because the duration of hypothermia in most clinical trials is between 24 and 48\u00a0hours, we questioned whether 24\u00a0hours exposure to gaseous hypothermia confers the same neuroprotective efficacy as 48\u00a0hours exposure. We found that a shorter exposure to hypothermia transiently reduced both inflammation and infarct size. However, after 1 week, the infarct size became even larger than in controls and after 2\u00a0weeks there was no beneficial effect on regenerative processes such as neurogenesis. Behaviorally, hypothermia also had a limited beneficial effect. Finally, after hydrogen sulfide-induced hypothermia, the poststroke aged rats experienced a persistent sleep impairment during their active nocturnal period. Our data suggest that cellular events that are delayed by hypothermia in aged rats may, in the long term, rebound, and diminish the beneficial effects.", "author" : [ { "dropping-particle" : "", "family" : "Sandu", "given" : "Raluca Elena", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buga", "given" : "Ana-Maria", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Balseanu", "given" : "Adrian Tudor", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moldovan", "given" : "Mihai", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Popa-Wagner", "given" : "Aurel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurobiology of aging", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016", "2" ] ] }, "page" : "127-40", "title" : "Twenty-four hours hypothermia has temporary efficacy in reducing brain infarction and inflammation in aged rats.", "type" : "article-journal", "volume" : "38" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁹", "plainTextFormattedCitation" : "29", "previouslyFormattedCitation" : "²⁹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }29). Counterintuitively, in view of the lack of efficacy of the same drugs in clinical trials this may serve as a further indicator for the good prediction of rodent models of stroke!Figure 1: Questionable external validity. Top: Human cohort equivalent to rodents studied in stroke models. Bottom: Typical cohort of humans at risk for strokeTiming of treatment: Same tissue clock in mice and men? Clearly, the exceedingly high attrition rate of clinical stroke trials cannot be blamed on low internal or external validity of preclinical stroke research alone. A multitude of reasons may have led to false negative clinical results, for example insufficient sample sizes paired with overoptimistic expectations concerning effect size. Another problem frequently quoted may have been study designs in which time to treatment exceeded the biological time window within which brain tissue is not yet fully committed to cell death. In a recent reviewADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/S1474-4422(16)00114-9", "ISSN" : "14744422", "author" : [ { "dropping-particle" : "", "family" : "Chamorro", "given" : "\u00c1ngel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dirnagl", "given" : "Ulrich", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Urra", "given" : "Xabier", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Planas", "given" : "Anna M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Lancet Neurology", "id" : "ITEM-1", "issue" : "0", "issued" : { "date-parts" : [ [ "2016", "5" ] ] }, "page" : "245-254", "publisher" : "Elsevier", "title" : "Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation", "type" : "article-journal", "volume" : "0" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³⁰", "plainTextFormattedCitation" : "30", "previouslyFormattedCitation" : "³⁰" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }30 we looked at the time window of major recent neuroprotection trials and found a median targeted inclusion time window of 16 hours. In animal models of stroke robust protection is usually observed only with the first 1-2 hours after occlusion of the artery. The fact that the time window for efficacy of thrombolysis is almost identical in rodentsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/jcbfm.2010.116", "ISSN" : "1559-7016", "PMID" : "20648038", "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\u2009minutes 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.", "author" : [ { "dropping-particle" : "", "family" : "Sena", "given" : "Emily S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Briscoe", "given" : "Catherine L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Howells", "given" : "David W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Donnan", "given" : "Geoffrey A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sandercock", "given" : "Peter A G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macleod", "given" : "Malcolm R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism", "id" : "ITEM-1", "issue" : "12", "issued" : { "date-parts" : [ [ "2010", "12" ] ] }, "page" : "1905-13", "title" : "Factors affecting the apparent efficacy and safety of tissue plasminogen activator in thrombotic occlusion models of stroke: systematic review and meta-analysis.", "type" : "article-journal", "volume" : "30" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³¹", "plainTextFormattedCitation" : "31", "previouslyFormattedCitation" : "³¹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }31 and man is indirect evidence that the tissue clock of brain tissue after focal cerebral ischemia is indeed similar in rodent and man. Except for the FASTMAG trialADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJMoa1408827", "ISSN" : "1533-4406", "PMID" : "25651247", "abstract" : "BACKGROUND Magnesium sulfate is neuroprotective in preclinical models of stroke and has shown signals of potential efficacy with an acceptable safety profile when delivered early after stroke onset in humans. Delayed initiation of neuroprotective agents has hindered earlier phase 3 trials of neuroprotective agents. METHODS We randomly assigned patients with suspected stroke to receive either intravenous magnesium sulfate or placebo, beginning within 2 hours after symptom onset. A loading dose was initiated by paramedics before the patient arrived at the hospital, and a 24-hour maintenance infusion was started on the patient's arrival at the hospital. The primary outcome was the degree of disability at 90 days, as measured by scores on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability). RESULTS Among the 1700 enrolled patients (857 in the magnesium group and 843 in the placebo group), the mean (\u00b1SD) age was 69\u00b113 years, 42.6% were women, and the mean pretreatment score on the Los Angeles Motor Scale of stroke severity (range, 0 to 10, with higher scores indicating greater motor deficits) was 3.7\u00b11.3. The final diagnosis of the qualifying event was cerebral ischemia in 73.3% of patients, intracranial hemorrhage in 22.8%, and a stroke-mimicking condition in 3.9%. The median interval between the time the patient was last known to be free of stroke symptoms and the start of the study-drug infusion was 45 minutes (interquartile range, 35 to 62), and 74.3% of patients received the study-drug infusion within the first hour after symptom onset. There was no significant shift in the distribution of 90-day disability outcomes on the global modified Rankin scale between patients in the magnesium group and those in the placebo group (P=0.28 by the Cochran-Mantel-Haenszel test); mean scores at 90 days did not differ between the magnesium group and the placebo group (2.7 in each group, P=1.00). No significant between-group differences were noted with respect to mortality (15.4% in the magnesium group and 15.5% in the placebo group, P=0.95) or all serious adverse events. CONCLUSIONS Prehospital initiation of magnesium sulfate therapy was safe and allowed the start of therapy within 2 hours after the onset of stroke symptoms, but it did not improve disability outcomes at 90 days. (Funded by the National Institute of Neurological Disorders and Stroke; FAST-MAG number, NCT00059332.).", "author" : [ { "dropping-particle" : "", "family" : "Saver", "given" : "Jeffrey L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Starkman", "given" : "Sidney", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eckstein", "given" : "Marc", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stratton", "given" : "Samuel J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pratt", "given" : "Franklin D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hamilton", "given" : "Scott", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Conwit", "given" : "Robin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liebeskind", "given" : "David S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sung", "given" : "Gene", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kramer", "given" : "Ian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moreau", "given" : "Gary", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Goldweber", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanossian", "given" : "Nerses", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "FAST-MAG Investigators and Coordinators", "given" : "", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2015", "2", "5" ] ] }, "page" : "528-36", "title" : "Prehospital use of magnesium sulfate as neuroprotection in acute stroke.", "type" : "article-journal", "volume" : "372" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³²", "plainTextFormattedCitation" : "32", "previouslyFormattedCitation" : "³²" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }32 none of the plethora of stroke trials were aimed at treatment within the ‘golden hour’. Although this may be understandable from a practical standpoint, it may be speculated that a number of potent neuroprotectants have been ‘wasted’ because treatment was too late. Due to the neutral study results the drugs will probably never be tested again. Fortunately, innovations and improvements in hyper acute stroke care and trial methodology now allow us to put neuroprotection to the ultimate test in the golden hour. Several ongoing trials use randomization in the field and ultra-acute treatment either by paramedics (Frontier trial, Identifier: NCT02315443, and ref. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1161/STROKEAHA.113.001301", "ISSN" : "1524-4628", "PMID" : "24003041", "abstract" : "BACKGROUND AND PURPOSE The practicalities of doing ambulance-based trials where paramedics perform all aspects of a clinical trial involving patients with ultra-acute stroke have not been assessed. METHODS We performed a randomized controlled trial with screening, consent, randomization, and treatment performed by paramedics prior to hospitalization. Patients with probable ultra-acute stroke (<4 hours) and systolic blood pressure (SBP) >140 mm Hg were randomized to transdermal glyceryl trinitrate (GTN; 5 mg/24 hours) or none (blinding under gauze dressing) for 7 days with the first dose given by paramedics. The primary outcome was SBP at 2 hours. RESULTS Of a planned 80 patients, 41 (25 GTN, 16 no GTN) were enrolled >22 months with median age [interquartile range] 79 [16] years; men 22 (54%); SBP 168 [46]; final diagnosis: stroke 33 (80%) and transient ischemic attack 3 (7%). Time to randomization was 55 [75] minutes. After treatment with GTN versus no GTN, SBP at 2 hours was 153 [31] versus 174 [27] mm Hg, respectively, with difference -18 [30] mm Hg (P=0.030). GTN improved functional outcome with a shift in the modified Rankin Scale by 1 [3] point (P=0.040). The rates of death, 4 (16%) versus 6 (38%; P=0.15), and serious adverse events, 14 (56%) versus 10 (63%; P=0.75), did not differ between GTN and no GTN. CONCLUSIONS Paramedics can successfully enroll patients with ultra-acute stroke into an ambulance-based trial. GTN reduces SBP at 2 hours and seems to be safe in ultra-acute stroke. A larger trial is needed to assess whether GTN improves functional outcome. CLINICAL TRIAL REGISTRATION URL . Unique identifier: 66434824.", "author" : [ { "dropping-particle" : "", "family" : "Ankolekar", "given" : "Sandeep", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fuller", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cross", "given" : "Ian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Renton", "given" : "Cheryl", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cox", "given" : "Patrick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sprigg", "given" : "Nikola", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Siriwardena", "given" : "A Niroshan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bath", "given" : "Philip M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Stroke; a journal of cerebral circulation", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2013", "11" ] ] }, "page" : "3120-8", "title" : "Feasibility of an ambulance-based stroke trial, and safety of glyceryl trinitrate in ultra-acute stroke: the rapid intervention with glyceryl trinitrate in Hypertensive Stroke Trial (RIGHT, ISRCTN66434824).", "type" : "article-journal", "volume" : "44" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³³", "plainTextFormattedCitation" : "33", "previouslyFormattedCitation" : "³³" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }33) or dedicated mobile stroke units with specialist teams deployed to the home of the patientADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1001/jamaneurol.2014.3188", "ISSN" : "2168-6157", "PMID" : "25402214", "abstract" : "IMPORTANCE The effectiveness of intravenous thrombolysis in acute ischemic stroke is time dependent. The effects are likely to be highest if the time from symptom onset to treatment is within 60 minutes, termed the golden hour. OBJECTIVE To determine the achievable rate of golden hour thrombolysis in prehospital care and its effect on outcome. DESIGN, SETTING, AND PARTICIPANTS The prospective controlled Prehospital Acute Neurological Treatment and Optimization of Medical Care in Stroke study was conducted in Berlin, Germany, within an established infrastructure for stroke care. Weeks were randomized according to the availability of a specialized ambulance (stroke emergency mobile unit (STEMO) from May 1, 2011, through January 31, 2013. We included 6182 consecutive adult patients for whom a stroke dispatch (44.1% male; mean [SD] age, 73.9 [15.0] years) or regular care (45.0% male; mean [SD] age, 74.2 [14.9] years) were included. INTERVENTIONS The STEMO was deployed when the dispatchers suspected an acute stroke during emergency calls. If STEMO was not available (during control weeks, when the unit was already in operation, or during maintenance), patients received conventional care. The STEMO is equipped with a computed tomographic scanner plus a point-of-care laboratory and telemedicine connection. The unit is staffed with a neurologist trained in emergency medicine, a paramedic, and a technician. Thrombolysis was started in STEMO if a stroke was confirmed and no contraindication was found. MAIN OUTCOMES AND MEASURES Rates of golden hour thrombolysis, 7- and 90-day mortality, secondary intracerebral hemorrhage, and discharge home. RESULTS Thrombolysis rates in ischemic stroke were 200 of 614 patients (32.6%) when STEMO was deployed and 330 of 1497 patients (22.0%) when conventional care was administered (P <\u2009.001). Among all patients who received thrombolysis, the proportion of golden hour thrombolysis was 6-fold higher after STEMO deployment (62 of 200 patients [31.0%] vs 16 of 330 [4.9%]; P <\u2009.01). Compared with patients with a longer time from symptom onset to treatment, patients who received golden hour thrombolysis had no higher risks for 7- or 90-day mortality (adjusted odds ratios, 0.38 [95% CI, 0.09-1.70]; P =\u2009.21 and 0.69 [95% CI, 0.32-1.53]; P =\u2009.36) and were more likely to be discharged home (adjusted odds ratio, 1.93 [95% CI, 1.09-3.41]; P =\u2009.02). CONCLUSIONS AND RELEVANCE The use of STEMO increases the percentage of patients receiving throm\u2026", "author" : [ { "dropping-particle" : "", "family" : "Ebinger", "given" : "Martin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kunz", "given" : "Alexander", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wendt", "given" : "Matthias", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rozanski", "given" : "Michal", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Winter", "given" : "Benjamin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Waldschmidt", "given" : "Carolin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weber", "given" : "Joachim", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Villringer", "given" : "Kersten", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fiebach", "given" : "Jochen B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Audebert", "given" : "Heinrich J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "JAMA neurology", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2015", "1" ] ] }, "page" : "25-30", "title" : "Effects of golden hour thrombolysis: a Prehospital Acute Neurological Treatment and Optimization of Medical Care in Stroke (PHANTOM-S) substudy.", "type" : "article-journal", "volume" : "72" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³⁴", "plainTextFormattedCitation" : "34", "previouslyFormattedCitation" : "³⁴" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }34. These approaches enable a one hour time window for treatment and thus offer the ultimate test for neuroprotection. Two study modes: discovery and confirmationMost preclinical stroke researchers aim at finding new pathophysiological mechanisms or drugs (‘exploration’, ‘discovery’). To emphasize the clinical relevance of their findings they often at the same time use the results of these exploratory studies to support inferences confirming the utility of their discovery for treatment in humans. This may increase the chances of publishing this work in prestigious journals. But these claims are often not backed up by the sort of robustness and external validity required to advocate translation to humans. Measured against their promise, all attempts to translate preclinically effective treatments into guideline-based stroke therapy have failed. I propose that confounding exploration with confirmation can be a major contributor to the translational roadblock. In a recent articleADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pbio.1001863", "ISSN" : "1545-7885", "PMID" : "24844265", "abstract" : "Preclinical researchers confront two overarching agendas related to drug development: selecting interventions amid a vast field of candidates, and producing rigorous evidence of clinical promise for a small number of interventions. We suggest that each challenge is best met by two different, complementary modes of investigation. In the first (exploratory investigation), researchers should aim at generating robust pathophysiological theories of disease. In the second (confirmatory investigation), researchers should aim at demonstrating strong and reproducible treatment effects in relevant animal models. Each mode entails different study designs, confronts different validity threats, and supports different kinds of inferences. Research policies should seek to disentangle the two modes and leverage their complementarity. In particular, policies should discourage the common use of exploratory studies to support confirmatory inferences, promote a greater volume of confirmatory investigation, and customize design and reporting guidelines for each mode.", "author" : [ { "dropping-particle" : "", "family" : "Kimmelman", "given" : "Jonathan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mogil", "given" : "Jeffrey S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dirnagl", "given" : "Ulrich", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS biology", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2014", "5" ] ] }, "page" : "e1001863", "title" : "Distinguishing between exploratory and confirmatory preclinical research will improve translation.", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁸", "plainTextFormattedCitation" : "8", "previouslyFormattedCitation" : "⁸" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }8 we have posited that distinguishing between exploratory and confirmatory preclinical research will improve translation. In exploratory investigation, researchers should aim at generating robust pathophysiological theories of disease. In confirmatory investigation, researchers should collect strong and reproducible treatment effects in relevant animal models. We should disentangle these two modes and customize design and reporting guidelines for each mode. Table 1 gives a tentative overview on how discriminating between exploratory and confirmatory studies might entail different study designs. Such a policy can leverage the complementary strengths of both modes and will help to improve the refinement of pathophysiological theories, as well as the generation of reliable evidence in disease models for the efficacy of treatments in humans. Adopting this approach would also reveal that most preclinical stroke research date is heavily biased towards exploration, and that confirmation is often missing.Table 1: Suggested differences between exploratory and confirmatory preclinical study designs. Exploratory('Discovery')ConfirmatoryHypothesis++++Establish pathophysiology++++Sequence and details of experiments established at onset++++Defined primary endpoint-++Sample size calculation++++Blinding++++++Randomization++++++External validity (aging, comorbidities, etc.)-++Predefined in/exclusion criteria+++++Test statistics++++Preregistration-++High sensitivity (high type I error rate, low type II error rate): Find what might work++++High specificity (low type I error rate, high type II error rate): Weed out false positives++++Can failure foster progress?The standard model of bench to bedside translation is linear. It leads from novel mechanism or compound to a new and effective therapy in a straight line, and as quickly as possible. Disruptions of this process at any stage we call attrition. The metrics for translational success are time spent from discovery to licensing, and the ratio of licensed drugs to failed attempts (‘attrition rate’). In this model attrition equals failure. Provocatively, London and KimmelmanADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/hast.433", "ISSN" : "1552146X", "PMID" : "25628068", "abstract" : "The last two decades have witnessed a crescendo of allegations that clinical translation is rife with waste and inefficiency. Patient advocates argue that excessively demanding regulations delay access to life-saving drugs, research funders claim that too much basic science languishes in academic laboratories, journal editors allege that biased reporting squanders public investment in biomedical research, and drug companies (and their critics) argue that far too much is expended in pharmaceutical development. But how should stakeholders evaluate the efficiency of translation and proposed reforms to drug development? Effective reforms require an accurate model of the systems they aspire to improve\u2014their components, their proper functions, and their pathologies. However, there is currently no explicit and well-developed model of translation for evaluating such criticisms. In what follows, we offer an explicit model of clinical translation. Many discussions of clinical translation and its pathologies presume that its main output is tangible: new drugs, vaccines, devices, and diagnostics. We disagree. We argue that the principal output of clinical translation is information\u2014in particular, information about the coordinated set of materials, practices, and constraints needed to safely unlock the therapeutic or preventive activities of drugs, biologics, and diagnostics. To develop this information calls for a process far different from a simple linear progression of clinical trials; it requires exploratory sampling of many different elements in this set. Our model points to some limitations and liabilities of influential proposals for reforming research. It also reveals some underrecognized opportunities for improving the efficiency of clinical translation.", "author" : [ { "dropping-particle" : "", "family" : "Kimmelman", "given" : "Jonathan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "London", "given" : "Alex John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Hastings Center Report", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "27-39", "title" : "The Structure of Clinical Translation: Efficiency, Information, and Ethics", "type" : "article-journal", "volume" : "45" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³⁵", "plainTextFormattedCitation" : "35", "previouslyFormattedCitation" : "³⁵" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }35,ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.7554/eLife.12844", "ISSN" : "2050-084X", "PMID" : "26599839", "abstract" : "The high rates of attrition that occur in drug development are widely regarded as problematic, but the failure of well-designed studies benefits both researchers and healthcare systems by, for example, generating evidence about disease theories and demonstrating the limits of proven drugs. A wider recognition of these benefits will help the biomedical research enterprise to take full advantage of all the information generated during the drug development process.", "author" : [ { "dropping-particle" : "", "family" : "London", "given" : "Alex John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kimmelman", "given" : "Jonathan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "eLife", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "e12844", "title" : "Why clinical translation cannot succeed without failure.", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³⁶", "plainTextFormattedCitation" : "36", "previouslyFormattedCitation" : "³⁶" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }36, as well as IoannidisADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/hast.429", "ISSN" : "0093-0334", "PMID" : "25739779", "author" : [ { "dropping-particle" : "", "family" : "Ioannidis", "given" : "John P A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Hastings Center report", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "0" ] ] }, "page" : "39-40", "title" : "Translational research may be most successful when it fails.", "type" : "article-journal", "volume" : "45" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³⁷", "plainTextFormattedCitation" : "37", "previouslyFormattedCitation" : "³⁷" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }37 argue that failures in the translational process may not only be necessary, but may often be more important than success. Although the quest for novel effective treatments remains the prime mover, they argue that the ultimate goal should be to increase useful information, which includes high quality negative results. Any negative result in well designed studies that provide good quality evidence results in information which can, among other benefits, correct mechanistic concepts, define dosing and timing of treatments, and free up resources for other avenues of investigation. Failures can rule out dead ends, identify research lines that should be modified and inappropriate methods. In particular in the clinical stages of translation, unsuccessful translation trajectories can be critical for maximizing efficient healthcare. Drugs are only clinically useful if we know dosages, treatment schedules, and timing at the bedside. We collect this knowledge by probing the windows beyond which a drug is no longer clinically useful. Kimmelman and LondonADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.7554/eLife.12844", "ISSN" : "2050-084X", "PMID" : "26599839", "abstract" : "The high rates of attrition that occur in drug development are widely regarded as problematic, but the failure of well-designed studies benefits both researchers and healthcare systems by, for example, generating evidence about disease theories and demonstrating the limits of proven drugs. A wider recognition of these benefits will help the biomedical research enterprise to take full advantage of all the information generated during the drug development process.", "author" : [ { "dropping-particle" : "", "family" : "London", "given" : "Alex John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kimmelman", "given" : "Jonathan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "eLife", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "e12844", "title" : "Why clinical translation cannot succeed without failure.", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³⁶", "plainTextFormattedCitation" : "36", "previouslyFormattedCitation" : "³⁶" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }36 remind us that in basic and preclinical biomedical research‘[…] identifying promising interventions is akin to exploring a vast, multidimensional landscape of agents, doses, disease indications and treatment schedules. The methods used to explore this landscape […] often rely on small sample sizes and/or surrogate endpoints. This allows large areas of the landscape to be explored quickly and at relatively low cost. However, economy and speed come at a cost, since small and less rigorous studies tend to produce more false positives (i.e., studies that show spurious clinical promise due to bias or random variation). […] In particular, base rates for discovering truly effective interventions are likely to be low in areas where our knowledge of disease process, mechanism and pharmacology is underdeveloped. As is well known in diagnosis, when base rates are low, false positive tests due to random variation are frequent, even if tests are sensitive.’As discussed above, biomedical research is heavily biased against NULL results. As a consequence, and if Kimmelman and London are correct, this must be highly wasteful since available information remains un- or underutilized. Embracing attrition has a number of important implications for experimental design and reporting: We should plan experiments so that they lead to useful information even when the NULL is rejected; we should not stop our experiments as soon as first signs of a potential NULL results appear, and of course we should publish NULL results.Overcoming the roadblockFew scientists today deny that bench to bedside translation in stroke has a disappointing track record. Analyzing the strengths, weaknesses, opportunities, and threats of this complex process can help to improve its efficiency. Based on the evidence provided by recent meta-research and several best-practice examples I propose the following measures, many of which are currently in various stages of implementation:We should try to reduce preventable (‘detrimental’) attrition. Key measures to achieve this revolve around improving preclinical study design. Internal validity should be improved by reduction of bias, e.g. by randomization, blinded treatment allocation and outcome assessment, and predefined in/exclusion criteria, among others. External validity can be improved by including aged, comorbid rodents of both sexes in our modeling. False positives and inflated effect sizes can be reduced by increasing statistical power, which essentially means increasing group sizes. Adherence to reporting guidelines and checklists (such as ARRIVE) is currently low, and needs to be enforced by journals and funders. When planning, conducting and reporting preclinical studies we should discriminate between exploration and confirmation. Customizing study designs can leverage the complementary strengths of both modes of investigation. In particular for confirmatory studies we should consider publication of study protocols. All studies should publish their full data sets ('Open science').We should embrace inevitable ‘NULL results’. Failures are a necessary element of the translational research enterprise, and may actually promote our understanding of pathophysiology and successful translation in the long run. This implies planning experiments in such a way that they produce high quality evidence if the NULL results were obtained, and of course, then making these available to the community. Some of these recommendations are hard or even impossible to implement for individual laboratories. A collaborative effort is needed to overcome these bottlenecks. Just as in clinical medicine, multicenter approaches help to obtain large enough group sizes and robustness of results. MULTIPARTADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2016", "5", "23" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "MULTIPART", "given" : "", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "0" ] ] }, "title" : "Multicentre Preclinical Animal Research Team", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³⁸", "plainTextFormattedCitation" : "38", "previouslyFormattedCitation" : "³⁸" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }38, a European Union funded project with participation of NIH/NINDS will provide a scalable framework for such efforts. First multicenter preclinical stroke studies have recently been publishedADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1126/scitranslmed.aaa9853", "ISSN" : "1946-6242", "PMID" : "26246166", "abstract" : "Numerous treatments have been reported to provide a beneficial outcome in experimental animal stroke models; however, these treatments (with the exception of tissue plasminogen activator) have failed in clinical trials. To improve the translation of treatment efficacy from bench to bedside, we have performed a preclinical randomized controlled multicenter trial (pRCT) to test a potential stroke therapy under circumstances closer to the design and rigor of a clinical randomized control trial. Anti-CD49d antibodies, which inhibit the migration of leukocytes into the brain, were previously investigated in experimental stroke models by individual laboratories. Despite the conflicting results from four positive and one inconclusive preclinical studies, a clinical trial was initiated. To confirm the preclinical results and to test the feasibility of conducting a pRCT, six independent European research centers investigated the efficacy of anti-CD49d antibodies in two distinct mouse models of stroke in a centrally coordinated, randomized, and blinded approach. The results pooled from all research centers revealed that treatment with CD49d-specific antibodies significantly reduced both leukocyte invasion and infarct volume after the permanent distal occlusion of the middle cerebral artery, which causes a small cortical infarction. In contrast, anti-CD49d treatment did not reduce lesion size or affect leukocyte invasion after transient proximal occlusion of the middle cerebral artery, which induces large lesions. These results suggest that the benefits of immune-targeted approaches may depend on infarct severity and localization. This study supports the feasibility of performing pRCTs.", "author" : [ { "dropping-particle" : "", "family" : "Llovera", "given" : "Gemma", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hofmann", "given" : "Kerstin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Roth", "given" : "Stefan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Salas-P\u00e9rdomo", "given" : "Angelica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ferrer-Ferrer", "given" : "Maura", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Perego", "given" : "Carlo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zanier", "given" : "Elisa R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mamrak", "given" : "Uta", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rex", "given" : "Andre", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Party", "given" : "H\u00e9l\u00e8ne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Agin", "given" : "V\u00e9ronique", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fauchon", "given" : "Claudine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Orset", "given" : "Cyrille", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Haelewyn", "given" : "Beno\u00eet", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Simoni", "given" : "Maria-Grazia", "non-dropping-particle" : "De", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dirnagl", "given" : "Ulrich", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grittner", "given" : "Ulrike", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Planas", "given" : "Anna M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Plesnila", "given" : "Nikolaus", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vivien", "given" : "Denis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liesz", "given" : "Arthur", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Science translational medicine", "id" : "ITEM-1", "issue" : "299", "issued" : { "date-parts" : [ [ "2015", "8", "5" ] ] }, "page" : "299ra121", "title" : "Results of a preclinical randomized controlled multicenter trial (pRCT): Anti-CD49d treatment for acute brain ischemia.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³⁹", "plainTextFormattedCitation" : "39", "previouslyFormattedCitation" : "³⁹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }39,ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/srep13428", "ISSN" : "2045-2322", "PMID" : "26310318", "abstract" : "Biomedical research suffers from a dramatically poor translational success. For example, in ischemic stroke, a condition with a high medical need, over a thousand experimental drug targets were unsuccessful. Here, we adopt methods from clinical research for a late-stage pre-clinical meta-analysis (MA) and randomized confirmatory trial (pRCT) approach. A profound body of literature suggests NOX2 to be a major therapeutic target in stroke. Systematic review and MA of all available NOX2(-/y) studies revealed a positive publication bias and lack of statistical power to detect a relevant reduction in infarct size. A fully powered multi-center pRCT rejects NOX2 as a target to improve neurofunctional outcomes or achieve a translationally relevant infarct size reduction. Thus stringent statistical thresholds, reporting negative data and a MA-pRCT approach can ensure biomedical data validity and overcome risks of bias.", "author" : [ { "dropping-particle" : "", "family" : "Kleikers", "given" : "Pamela W M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hooijmans", "given" : "Carlijn", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "G\u00f6b", "given" : "Eva", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Langhauser", "given" : "Friederike", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rewell", "given" : "Sarah S J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Radermacher", "given" : "Kim", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ritskes-Hoitinga", "given" : "Merel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Howells", "given" : "David W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kleinschnitz", "given" : "Christoph", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schmidt", "given" : "Harald H H W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Scientific reports", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "13428", "title" : "A combined pre-clinical meta-analysis and randomized confirmatory trial approach to improve data validity for therapeutic target validation.", "type" : "article-journal", "volume" : "5" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁴⁰", "plainTextFormattedCitation" : "40", "previouslyFormattedCitation" : "⁴⁰" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }40 ,ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1177/0271678X15606714", "ISSN" : "1559-7016", "PMID" : "26661169", "abstract" : "Stroke represents a global challenge and is a leading cause of permanent disability worldwide. Despite much effort, translation of research findings to clinical benefit has not yet been successful. Failure of neuroprotection trials is considered, in part, due to the low quality of preclinical studies, low level of reproducibility across different laboratories and that stroke co-morbidities have not been fully considered in experimental models. More rigorous testing of new drug candidates in different experimental models of stroke and initiation of preclinical cross-laboratory studies have been suggested as ways to improve translation. However, to our knowledge, no drugs currently in clinical stroke trials have been investigated in preclinical cross-laboratory studies. The cytokine interleukin 1 is a key mediator of neuronal injury, and the naturally occurring interleukin 1 receptor antagonist has been reported as beneficial in experimental studies of stroke. In the present paper, we report on a preclinical cross-laboratory stroke trial designed to investigate the efficacy of interleukin 1 receptor antagonist in different research laboratories across Europe. Our results strongly support the therapeutic potential of interleukin 1 receptor antagonist in experimental stroke and provide further evidence that interleukin 1 receptor antagonist should be evaluated in more extensive clinical stroke trials.", "author" : [ { "dropping-particle" : "", "family" : "Maysami", "given" : "Samaneh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wong", "given" : "Raymond", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pradillo", "given" : "Jesus M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Denes", "given" : "Adam", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dhungana", "given" : "Hiramani", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Malm", "given" : "Tarja", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koistinaho", "given" : "Jari", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Orset", "given" : "Cyrille", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rahman", "given" : "Mahbubur", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rubio", "given" : "Marina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schwaninger", "given" : "Markus", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vivien", "given" : "Denis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bath", "given" : "Philip M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rothwell", "given" : "Nancy J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Allan", "given" : "Stuart M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2016", "3" ] ] }, "page" : "596-605", "title" : "A cross-laboratory preclinical study on the effectiveness of interleukin-1 receptor antagonist in stroke.", "type" : "article-journal", "volume" : "36" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁴¹", "plainTextFormattedCitation" : "41", "previouslyFormattedCitation" : "⁴¹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }41.Translational stroke research is not broken, but in need of an overhaul. Its engine must be made more efficient, its results more predictive. I have focused on a few potential remedies informed by recent meta research, and limited my analysis to preclinical research. Researchers, funders, journals, and professional societies must work together to develop desperately needed novel and effective therapies for a disease which puts a tremendous burden on patients, their families, as well as health systems and economies.Acknowledgements:I would like to thank John Ioannidis, Malcolm Macleod, and Jonathan Kimmelman for inspiration and guidance. Disclosure: The author declares no conflict of interest.ReferencesADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY 1. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 1999;22:391–7. 2. Moskowitz MA, Lo EH, Iadecola C. The science of stroke: mechanisms in search of treatments. Neuron. 2010;67:181–98. 3. 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