A user's guide to the NINDS rt-PA stroke trial database.
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ABSTRACT:
SUBMITTER: Dachs RJ
PROVIDER: S-EPMC2386834 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and purposeIschemic stroke lesion volumes have proven difficult to analyze due to the extremely skewed shape of their underlying distribution. We introduce an extension of generalized linear models, beta regression, as a possible method of modeling extremely skewed distributions as evidenced in ischemic stroke lesion volumes.MethodsThe NINDS rt-PA clinical trials measured ischemic stroke lesion volume as a secondary trial outcome. Three-month lesion volumes from these trials were analyzed using beta regression. A multi-variable regression model associating explanatory variables with ischemic stroke lesion volumes was constructed using accepted model building strategies and compared with the previously published volumetric analysis.ResultsBeta regression produced a similar model when compared to the previous analysis published by the study group. All previously identified variables of importance were detected in the model building process. The age by treatment interaction described in previous studies was also found in this analysis, confirming the strong effect age has on stroke outcomes. Further, a treatment effect was elicited in terms of odds ratios, yielding a previously unknown quantification of the effect of rt-PA on lesion volumes.ConclusionsBeta regression proved adept in modeling ischemic stroke lesions and offered the interpretation of covariates in terms of odds ratios. Beta regression is seen as a legitimate alternative to analyze ischemic stroke volumes.
| S-EPMC3186717 | biostudies-literature
Project description:Since Food and Drug Administration approval of intravenous tissue-type plasminogen activator (tPA) for treatment of acute ischemic stroke in 1996, it has become clear that several criteria used for exclusion from therapy were not based on actual data or operationally defined for use in clinical practice. All eligibility criteria from the National Institute of Neurological Disorders and Stroke (NINDS) recombinant tPA Stroke Study were adopted within the alteplase package insert as contraindications/warnings. Many clinicians have expressed the need for clarification and better definition of these treatment criteria.A group of investigators who also practice as stroke physicians convened a collaborative endeavor to work toward developing more clinically meaningful and consensus-driven exclusion criteria for intravenous tPA. The first of these exclusion criteria chosen was rapidly improving stroke symptoms (RISS). We reviewed and clarified the historical context and intention with the original investigators, held e-mail discussions, convened an in-person RISS Summit, and obtained the understanding of experienced stroke physicians broadly.Historically, the intent of this exclusion criterion within the NINDS recombinant tPA Stroke Trial was to avoid treatment of transient ischemic attacks-who would have recovered completely without treatment. There was unanimous consensus that, in the absence of other contraindications, patients who experience improvement of any degree, but have a persisting neurological deficit that is potentially disabling, should be treated with intravenous tPA. This statement is supported from the methods established for the original NINDS trial, on the basis of detailed discussions and interviews with the former NINDS trialists. It was agreed that improvement should only be monitored for the extent of time needed to prepare and administer the intravenous tPA bolus/infusion. An explicit operational definition of RISS was developed by consensus to guide future decision making in acute stroke. There was unanimous agreement that all neurological deficits present at the time of the treatment decision should be considered in the context of individual risk and benefit, as well as the patient's baseline functional status.A structured framework and quantitative approach toward defining RISS emerged through expert opinion and consensus. The term, RISS, should be reserved for those who improve to a mild deficit, specifically one which is perceived to be nondisabling. This is recommended to guide decision making on intravenous tPA eligibility going forward, including the design of future studies. An additional study of patients with rapid improvement to nonmild deficits is not justified because these patients should be treated.
| S-EPMC3789593 | biostudies-literature
Project description:In acute ischemic stroke, the only FDA-approved drug; recombinant tissue plasminogen activator (rt-PA) is limited by restricted time-window due to an enhanced risk of hemorrhagic transformation which is thought to be caused by metalloproteinase (MMP). In experimental stroke inhibitors of the mitogen-activated protein kinase kinase extracellular signal-regulated kinase kinase (MEK) 1/2 pathways reduce the MMPs. This study evaluated whether a MEK1/2 inhibitor in combination with rt-PA can prevent the detrimental effects of delayed rt-PA therapy in stroke. Thromboembolic stroke was induced in C57 black/6J mice and the MEK1/2 inhibitor U0126 was administrated 3.5 h and rt-PA 4 h post stroke-onset. Treatment with rt-PA demonstrated enhanced MMP-9 protein levels and hemorrhagic transformation which was prevented when U0126 was given in conjunction with rt-PA. By blocking the MMP-9 with U0126 the safety of rt-PA administration was improved and demonstrates a promising adjuvant strategy to reduce the harmful effects of delayed rt-PA treatment in acute ischemic stroke.
| S-EPMC8184783 | biostudies-literature
Project description:Objective:To investigate the feasibility and safety of remote ischemic postconditioning (RIPC) in acute ischemic stroke patients after intravenous recombinant tissue plasminogen activator (rt-PA) thrombolysis (IVT). Methods:We performed a pilot randomized trial involving acute ischemic stroke patients with IVT. The patients were randomized 1:1 to receive RIPC or standard medical therapy. In the RIPC group, the participants underwent instant RIPC within 2 h of IVT, followed by repeated RIPC therapy for 7 days. The feasibility end point was the completion of RIPC and time from the first RIPC to finishing IVT in the RIPC group. The safety end point included tissue and neurovascular injury resulting from RIPC, changes in vital signs, level of plasma myoglobin, any hemorrhagic transformation, and other adverse events. Results:Thirty patients (15 RIPC and 15 Control) were recruited after IVT. The mean age was 65.7 ± 10.2 years, with a National Institutes of Health Stroke Scale (NIHSS) score of 6.5 (4.0-10.0). The completion rate for RIPC was 97.0%. The mean time from first RIPC to completing IVT was 66.0 (25.0-75.0) min in the RIPC group. One case of hemorrhagic transformation was observed in the RIPC group. No significant difference was found in the level of myoglobin between the two groups (P > 0.05). Interpretation:RIPC is effective and safe for AIS patients after intravenous rt-PA thrombolysis.
| S-EPMC6389851 | biostudies-literature
Project description:Transcriptional programs instruct the generation and maintenance of diverse subtypes of neural cells, establishment of distinct brain regions, formation and function of neural circuits, and ultimately behavior. Spatiotemporal and cell type-specific analyses of the transcriptome, the sum total of all RNA transcripts in a cell or an organ, can provide insights into the role of genes in brain development and function, and their potential contribution to disorders of the brain. In the previous decade, advances in sequencing technology and funding from the National Institutes of Health and private foundations for large-scale genomics projects have led to a growing collection of brain transcriptome databases. These valuable resources provide rich and high-quality datasets with spatiotemporal, cell type-specific, and single-cell precision. Most importantly, many of these databases are publicly available via user-friendly web interface, making the information accessible to individual scientists without the need for advanced computational expertise. Here, we highlight key publicly available brain transcriptome databases, summarize the tissue sources and methods used to generate the data, and discuss their utility for neuroscience research.
| S-EPMC5858588 | biostudies-literature
Project description:In order to understand how changes in individual performance (growth, survival or reproduction) influence population dynamics and evolution, ecologists are increasingly using parameterized mathematical models. For continuously structured populations, where some continuous measure of individual state influences growth, survival or reproduction, integral projection models (IPMs) are commonly used. We provide a detailed description of the steps involved in constructing an IPM, explaining how to: (i) translate your study system into an IPM; (ii) implement your IPM; and (iii) diagnose potential problems with your IPM. We emphasize how the study organism's life cycle, and the timing of censuses, together determine the structure of the IPM kernel and important aspects of the statistical analysis used to parameterize an IPM using data on marked individuals. An IPM based on population studies of Soay sheep is used to illustrate the complete process of constructing, implementing and evaluating an IPM fitted to sample data. We then look at very general approaches to parameterizing an IPM, using a wide range of statistical techniques (e.g. maximum likelihood methods, generalized additive models, nonparametric kernel density estimators). Methods for selecting models for parameterizing IPMs are briefly discussed. We conclude with key recommendations and a brief overview of applications that extend the basic model. The online Supporting Information provides commented R code for all our analyses.
| S-EPMC4258094 | biostudies-literature
Project description:BackgroundWomen have been reported to show more frequent recanalization and better recovery after intravenous (IV) recombinant tissue plasminogen activator (rt-PA) treatment for acute stroke compared with men. To investigate this we studied a series of stroke patients receiving IV rt-PA and undergoing acute transcranial doppler (TCD) examination.MethodsAcute stroke patients received IV rt-PA and had acute TCD examination within 4 hours of symptom onset at 4 major stroke centers. TCD findings were interpreted using the Thrombolysis in Brain Ischemia (TIBI) flow grading system. The recanalization rates, and poor 3-month outcomes (modified Rankin scale >2) of men and women were compared using the chi-square test. Multiple regression analysis was used to assess sex as a predictor of recanalization and poor 3-month outcome after controlling for age, baseline NIH Stroke Scale (NIHSS), time to treatment, hypertension, and blood glucose.Results369 patients had TCD examinations before or during IV rt-PA treatment. The 199 (53.9%) men and 170 (46.1%) women had mean ages of 67 ± 13 and 70 ± 14 years, respectively. The sexes did not differ significantly in baseline stroke severity, time to TCD examination, or time to thrombolysis. Of the men, 68 (34.2%) had complete recanalization, 58 (29.1%) had partial recanalization, and 73 (36.6%) had no recanalization. Of the women, 53 (31.2%) had complete recanalization, 46 (27%) had partial recanalization, and 71 (41.8%) had no recanalization (p = 0.6). Multiple regression analyses showed no difference between the sexes in recanalization rate, time to recanalization, or clinical outcome at 3 months.ConclusionsIn our study; sex is not a significant predictor of recanalization rate, time to recanalization or 3-month outcome in stroke patients following IV rt-PA.Trial registrationData from CLOTBUST trial Clinicaltrials.gov Identifier: NCT01240356.
| S-EPMC3994292 | biostudies-literature
Project description:Cell-free protein synthesis (CFPS) is a platform technology that provides new opportunities for protein expression, metabolic engineering, therapeutic development, education, and more. The advantages of CFPS over in vivo protein expression include its open system, the elimination of reliance on living cells, and the ability to focus all system energy on production of the protein of interest. Over the last 60 years, the CFPS platform has grown and diversified greatly, and it continues to evolve today. Both new applications and new types of extracts based on a variety of organisms are current areas of development. However, new users interested in CFPS may find it challenging to implement a cell-free platform in their laboratory due to the technical and functional considerations involved in choosing and executing a platform that best suits their needs. Here we hope to reduce this barrier to implementing CFPS by clarifying the similarities and differences amongst cell-free platforms, highlighting the various applications that have been accomplished in each of them, and detailing the main methodological and instrumental requirement for their preparation. Additionally, this review will help to contextualize the landscape of work that has been done using CFPS and showcase the diversity of applications that it enables.
| S-EPMC6481089 | biostudies-literature
Project description:BackgroundThrombolysis with intravenous rt-PA is currently the only approved acute therapy for ischemic stroke. Re-occlusion after initial recanalization occurs in up to 34% in patients treated with rt-PA, probably caused by platelet activation. In acute myocardial infarction, the combination of thrombolysis and antiplatelet therapy leads to a greater reduction of mortality compared to thrombolysis alone. In patients with acute ischemic stroke, several studies showed that patients already on antiplatelet treatment prior to thrombolysis had an equal or even better outcome compared to patients without prior antiplatelet treatment, despite an increased risk of intracerebral bleeding. Based on the fear of intracerebral haemorrhage, current international guidelines recommend postponing antiplatelet therapy until 24 hours after thrombolysis. Remarkably, prior use of antiplatelet therapy is not a contra-indication for thrombolysis. We hypothesize that antiplatelet therapy in combination with rt-PA thrombolysis will improve outcome by enhancing fibrinolysis and preventing re-occlusion.Methods/designARTIS is a randomised multi-center controlled trial with blind endpoint assessment. Our objective is to investigate whether immediate addition of aspirin to rt-PA thrombolysis improves functional outcome in ischemic stroke. Patients with acute ischemic stroke eligible for rt-PA thrombolysis are randomised to receive 300 mg aspirin within 1.5 hours after start of thrombolysis or standard care, consisting of antiplatelet therapy after 24 hours. Primary outcome is poor functional health at 3 months follow-up (modified Rankin Scale 3 - 6).DiscussionThis is the first clinical trial investigating the combination of rt-PA and acute aspirin by means of a simple and cheap adjustment of current antiplatelet regimen. We expect the net benefit of improved functional outcome will overcome the possible slightly increased risk of intracerebral haemorrhage.Trial registrationThe Netherlands National Trial Register NTR822. The condensed rationale of the ARTIS-Trial has already been published in Cerebrovascular Diseases.
| S-EPMC2886039 | biostudies-literature
Project description:Background and purposeSex and race disparities in recombinant tissue plasminogen activator (rt-PA) use have been reported. We sought to explore sex and race differences in the utilization of rt-PA at primary stroke centers (PSCs) compared to non-PSCs across the US.MethodsData from the National (Nationwide) Inpatient Sample (NIS) 2004-2010 was utilized to assess sex differences in treatment for ischemic stroke in PSCs compared to non-PSCs.ResultsThere were 304,152 hospitalizations with a primary diagnosis of ischemic stroke between 2004 and 2010 in the analysis: 75,160 (24.7%) patients were evaluated at a PSC. A little over half of the patients evaluated at PSCs were female (53.8%). A lower proportion of women than men received rt-PA at both PSCs (6.8 vs. 7.5%, p?<?0.001) and non-PSCs (2.3 vs. 2.8%, p?<?0.001). After adjustment for potential confounders the odds of being treated with rt-PA remained lower for women regardless of presentation to a PSC (OR 0.87, 95% CI 0.81-0.94) or non-PSC (OR 0.88, 95% CI 0.82-0.94). After stratifying by sex and race, the lowest absolute treatment rates were observed in black women (4.4% at PSC, 1.9% at non-PSC). The odds of treatment, relative to white men, was however lowest for white women (PSC OR?=?0.85, 95% CI 0.78-0.93; non-PSC OR?=?0.80, 95% CI 0.75-0.85). In the multivariable model, sex did not modify the effect of PSC certification on rt-PA utilization (p-value for interaction?=?0.58).ConclusionWomen are less likely to receive rt-PA than men at both PSCs and non-PSCs. Absolute treatment rates are lowest in black women, although the relative difference in men and women was greatest for white women.
| S-EPMC5623663 | biostudies-literature