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Supplemental material, Supplemental_Methods_and_Results for Effects of Exercise Intensity on Acute Circulating Molecular Responses Poststroke by Pierce Boyne, Colleen Meyrose, Jennifer Westover, Dustyn Whitesel, Kristal Hatter, Darcy S. Reisman, Daniel Carl, Jane C. Khoury, Myron Gerson, Brett Kissela and Kari Dunning in Neurorehabilitation and Neural Repair

Objective: Association between acute ambient fine particulate matter (PM2.5, aerodynamic diameter less than 2.5 and cardiovascular events are well documented. However, it remains unclear whether acute exposure to PM2.5 acts as a trigger for hemorrhagic (intracerebral or subarachnoid hemorrhage) or non-hemorrhagic (infarct or transient ischemic attack) stroke onset. We, therefore, examined the association between ambient PM2.5 and stroke onset, and whether this relationship differs by stroke subtype, age, sex, and race. Methods: We used a time-stratified case-crossover design to examine the association between exposure to PM2.5 and stroke onset for the calendar year 2010. Data were collected from the Greater Cincinnati Northern Kentucky Stroke Study. We included patients 20 years and older, initially ascertained through hospital ICD-9 discharge codes. Daily ambient concentrations of PM2.5 were estimated from the patient's residential addresses using a spatiotemporal model. Conclusion: Our findings suggest that short-term PM2.5 exposure, particularly at three days before the event, is associated with stroke onset but varies according to stroke subtype, age, sex, and race., One coauthor didnt want to submit the paper on the arxiv

Supplemental data from "Reference Curves and Association between PAPP-A2 and IGF-I Bioavailability throughout Childhood: A Cross-Sectional Study"

Supplemental information about PAPP-A2, Free IGF-I, and IGFBP-3 throughout childhood

Supplemental information about PAPP-A2, Free IGF-I, and IGFBP-3 throughout childhood

High quality historical control data, if incorporated, may reduce sample size, trial cost, and duration. A too optimistic use of the data, however, may result in bias under prior-data conflict. Motivated by well-publicized two-arm comparative trials in stroke, we propose a Bayesian design that both adaptively incorporates historical control data and selectively adapt the treatment allocation ratios within an ongoing trial responsively to the relative treatment effects. The proposed design differs from existing designs that borrow from historical controls. As opposed to reducing the number of subjects assigned to the control arm blindly, this design does so adaptively to the relative treatment effects only if evaluation of cumulated current trial data combined with the historical control suggests the superiority of the intervention arm. We used the effective historical sample size approach to quantify borrowed information on the control arm and modified the treatment allocation rules of the doubly adaptive biased coin design to incorporate the quantity. The modified allocation rules were then implemented under the Bayesian framework with commensurate priors addressing prior-data conflict. Trials were also more frequently concluded earlier in line with the underlying truth, reducing trial cost, and duration and yielded parameter estimates with smaller standard errors.

BACKGROUND: Intracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography.METHODS: In a systematic review of OVID MEDLINE-with additional hand-searching of relevant studies' bibliographies- from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5-24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known.FINDINGS: Of 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56-76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36-0·70; pINTERPRETATION: In this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination. These models could inform the location and frequency of observations on patients in clinical practice, explain treatment effects in prior randomised trials, and guide the design of future trials.FUNDING: UK Medical Research Council and British Heart Foundation.

Background:\ud Intracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography.\ud \ud Methods:\ud In a systematic review of OVID MEDLINE—with additional hand-searching of relevant studies' bibliographies— from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5–24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known.\ud \ud Findings:\ud Of 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56–76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36–0·70; p

Altres ajuts: UK Medical Research Council and British Heart Foundation. Intracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography. In a systematic review of OVID MEDLINE-with additional hand-searching of relevant studies' bibliographies- from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5-24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known. Of 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56-76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36-0·70; p

Supplemental material, DS_10.1177_0363546518788343 for Age-Dependent Patellofemoral Pain: Hip and Knee Risk Landing Profiles in Prepubescent and Postpubescent Female Athletes by Ryan T. Galloway, Yingying Xu, Timothy E. Hewett, Kim Barber Foss, Adam W. Kiefer, Christopher A. DiCesare, Robert A. Magnussen, Jane Khoury, Kevin R. Ford, Jed A. Diekfuss, Dustin Grooms, Gregory D. Myer and Alicia M. Montalvo in The American Journal of Sports Medicine

Severe obesity is associated with mobility limitations and higher incidence of multijoint musculoskeletal pain. It is unknown whether substantial weight loss improves these important outcomes in adolescents with severe obesity.To examine the association of bariatric surgery with functional mobility and musculoskeletal pain in adolescents with severe obesity up to 2 years after surgery.The Teen-Longitudinal Assessment of Bariatric Surgery Study is a prospective, multicenter, observational study, which enrolled 242 adolescents (≤19 years of age) who were undergoing bariatric surgery from March 2007 through February 2012 at 5 US adolescent bariatric surgery centers. This analysis was conducted in November 2015.Roux-en-Y gastric bypass (n = 161), sleeve gastrectomy (n = 67), or laparoscopic adjustable gastric band (n = 14).Participants completed a 400-m walk test prior to bariatric surgery (n = 206) and at 6 months (n = 195), 12 months (n = 176), and 24 months (n = 149) after surgery. Time to completion, resting heart rate (HR), immediate posttest HR, and HR difference (resting HR minus posttest HR) were measured and musculoskeletal pain concerns, during and after the test, were documented. Data were adjusted for age, sex, race/ethnicity, baseline body mass index (calculated as weight in kilograms divided by height in meters squared), and surgical center (posttest HR and HR difference were further adjusted for changes in time to completion).Of the 206 adolescents with severe obesity included in the study, 156 were female (75.7%), the mean (SD) age was 17.1 (1.6) years, and the mean (SD) body mass index was 51.7 (8.5). Compared with baseline, significant improvements were observed at 6 months for the walk test time to completion (mean, 376 seconds; 95% CI, 365-388 to 347 seconds; 95% CI, 340-358; P .01), resting HR (mean, 84 beats per minute [bpm]; 95% CI, 82-86 to 74 bpm; 95% CI, 72-76), posttest HR (mean, 128 bpm; 95% CI, 125-131 to 113 bpm; 95% CI, 110-116), and HR difference (mean, 40 bpm; 95% CI, 36-42 to 34 bpm; 95% CI, 31-37). These changes in time to completion, resting HR, and HR difference persisted at 12 months and 24 months. Posttest HR further improved from 6 months to 12 months (mean, 113 bpm; 95% CI, 110-116 to 108 bpm; 95% CI, 105-111). There were statistically significant reductions in musculoskeletal pain concerns at all points.These data provide evidence that bariatric surgery in adolescents with severe obesity is associated with significant improvement in functional mobility and in the reduction of walking-related musculoskeletal pain up to 2 years after surgery.

Missed diagnoses of acute ischemic stroke (AIS) in the ED may result in lost opportunities to treat AIS. Our objectives were to describe the rate and clinical characteristics of missed AIS in the ED, to determine clinical predictors of missed AIS, and to report tissue plasminogen (tPA) eligibility among those with missed strokes.

The Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue-Type Plasminogen Activator (r-tPA; CLEAR) in Acute Ischemic Stroke (AIS) and CLEAR-Enhanced Regimen (CLEAR-ER) trials demonstrated safety of reduced dose r-tPA plus the glycoprotein 2b/3a inhibitor, eptifibatide, in AIS compared with r-tPA alone. The objective of the CLEAR-Full Dose Regimen (CLEAR-FDR) trial was to estimate the rate of symptomatic intracerebral hemorrhage (sICH) in AIS patients treated with the combination of full-dose r-tPA plus eptifibatide.CLEAR-FDR was a single-arm, prospective, open-label, multisite study. Patients aged 18 to 85 years treated with 0.9 mg/kg IV r-tPA within 3 hours of symptom onset were enrolled. After obtaining consent, eptifibatide (135 μg/kg bolus and 2-hour infusion at 0.75 μg/kg per minute) was administered. The primary end point was the proportion of patients who experienced sICH within 36 hours. An independent clinical monitor adjudicated if an sICH had occurred and an independent neuroradiologist reviewed all images. The stopping rule was 3 sICHs within the first 19 patients or 4 sICHs within 29 patients.From October 2013 to December 2014, 27 patients with AIS were enrolled. Median age was 73 years (range, 34-85; interquartile range, 65-80) and median National Institute of Health stroke scale score was 12 (range, 6-26; interquartile range, 9-16). One sICH (3.7%; 95% confidence interval, 0.7%-18%) was observed.These results demonstrate comparable safety of full-dose r-tPA plus eptifibatide with historical rates of sICH with r-tPA alone and support proceeding with a phase 3 trial evaluating full-dose r-tPA combined with eptifibatide to improve outcomes after AIS.

Latent profile analysis (LPA) has been used previously to classify neurobehavioral responses of infants prenatally exposed to cocaine and other drugs of abuse. The objective of this study was to define NICU Network Neurobehavioral Scale (NNNS) profile response patterns in a cohort of infants with no known cocaine exposure or other risks for neurobehavior deficits, and determine whether these profiles predict neurobehavioral outcomes in these low-risk infants.NNNS exams were performed on 355 low-risk infants at approximately 5 weeks after birth. LPA was used to define discrete profiles based on the standard NNNS summary scales. Associations between the infant profiles and neurobehavioral outcomes at one to three years of age were examined.Twelve of the 13 summary scales were used and three discrete NNNS profiles identified: social/easy going infants (44%), hypotonic infants (24%), and high arousal/difficult infants (32%). Statistically significant associations between NNNS profiles and later neurobehavioral outcomes were found for psychomotor development and externalizing behaviors. Hypotonic infants had both lower psychomotor development and lower externalizing scores compared to the other two profiles.Three distinct profiles of the NNNS summary scores were identifiable using LPA among infants with no known cocaine exposure. These profile patterns were associated with early childhood neurobehavioral outcome, similar to findings reported in a study of infants with substantial cocaine exposure, demonstrating the utility of this profiling technique in both exposed and unexposed populations.

The publication of the European Cooperative Acute Stroke Study (ECASS III) expanded the treatment time to thrombolysis for acute ischemic stroke from 3 to 4.5 hours from symptom onset. The impact of the expanded time window on treatment rates has not been comprehensively evaluated in a population-based study.All patients with an ischemic stroke presenting to an emergency department during calendar year 2005 in the 17 hospitals that compromise the large 1.3 million Greater Cincinnati/Northern Kentucky population were included in the analysis. Criteria for exclusion from thrombolytic therapy are analyzed retrospectively for both the standard and expanded timeframes with varying door-to-needle times.During the study period, 1838 ischemic strokes presenting to an emergency department were identified. A small proportion of them arrived in the expanded time window (3.4%) compared with the standard time window (22%). Only 0.5% of those who arrived in this timeframe met eligibility criteria for thrombolysis compared with 5.9% using standard eligibility criteria in the standard timeframe. These results did not vary significantly by repeated analysis varying the door-to-needle time or the expanded time window's exclusion criteria.In reality, the expanded time window for thrombolysis in acute ischemic stroke benefits few patients. If we are to improve recombinant tissue-type plasminogen activator administration rates, our focus should be on improving stroke awareness, transport to facilities with ability to administer thrombolysis, and familiarity of physicians with acute stroke treatment guidelines.

Sex is suggested to be an important determinant of ischemic stroke risk factors, etiology, and outcome. However, the basis for this remains unclear. The Y chromosome is unique in males. Genes expressed in males on the Y chromosome that are associated with stroke may be important genetic contributors to the unique features of males with ischemic stroke, which would be helpful for explaining sex differences observed between men and women.We compared Y chromosome gene expression in males with ischemic stroke and male controls.Blood samples were obtained from 40 male patients ≤3, 5, and 24 hours after ischemic stroke and from 41 male controls (July 2003-April 2007). RNA was isolated from blood and was processed using Affymetrix Human U133 Plus 2.0 expression arrays (Affymetrix Inc., Santa Clara, California). Y chromosome genes differentially expressed between male patients with stroke and male control subjects were identified using an ANCOVA adjusted for age and batch. A P0.05 and a fold change1.2 were considered significant.Seven genes on the Y chromosome were differentially expressed in males with ischemic stroke compared with controls. Five of these genes (VAMP7, CSF2RA, SPRY3, DHRSX, and PLCXD1) are located on pseudoautosomal regions of the human Y chromosome. The other 2 genes (EIF1AY and DDX3Y) are located on the nonrecombining region of the human Y chromosome. The identified genes were associated with immunology, RNA metabolism, vesicle fusion, and angiogenesis.Specific genes on the Y chromosome are differentially expressed in blood after ischemic stroke. These genes provide insight into potential molecular contributors to sex differences in ischemic stroke.

Texto completo: acesso restrito. p. 288–290 Submitted by Edileide Reis (leyde-landy@hotmail.com) on 2014-08-26T12:35:44Z No. of bitstreams: 1 Tereza C. M. Ribeiro.pdf: 141152 bytes, checksum: d5b0268224afef15d175185ab448dbfe (MD5) Rejected by Delba Rosa (delba@ufba.br), reason: Por gentileza, certifique-se do endereço eletrônico: http://dx.doi.org/ 10.1097/MPG.0b013e31823a8a4c on 2014-09-15T16:12:40Z (GMT) Submitted by Edileide Reis (leyde-landy@hotmail.com) on 2014-09-17T12:02:27Z No. of bitstreams: 1 Tereza C. M. Ribeiro.pdf: 141152 bytes, checksum: d5b0268224afef15d175185ab448dbfe (MD5) Approved for entry into archive by Delba Rosa (delba@ufba.br) on 2014-09-26T14:58:04Z (GMT) No. of bitstreams: 1 Tereza C. M. Ribeiro.pdf: 141152 bytes, checksum: d5b0268224afef15d175185ab448dbfe (MD5) Made available in DSpace on 2014-09-26T14:58:04Z (GMT). No. of bitstreams: 1 Tereza C. M. Ribeiro.pdf: 141152 bytes, checksum: d5b0268224afef15d175185ab448dbfe (MD5) Previous issue date: 2012-02 Healthy 9- to 48-month-old children (n = 133) were randomized to receive a cow's-milk–based follow-on formula (control) or the same formula with polydextrose and galactooligosaccharides (PDX/GOS) for 108 days. Pediatricians assessed diarrheal disease, stool pattern, acute respiratory infection, systemic antibiotic use, and growth. The 2 groups had similar weight-for-length/height z score and similar odds of having diarrheal disease, acute respiratory infection, and systemic antibiotic use; however, PDX/GOS had greater odds of increased defecation than control (P

When defining allergic outcomes in epidemiology studies results of the skin prick test (SPT) panel is often dichotomized as positive/negative or categorized based on the number of positive responses. Item Response Theory (IRT) models, however, may prove to be a better alternative with the ability to generate scores that account for both type and number of positive SPTs. IRT was applied to SPT responses administered to 537 children at age two in order to determine predictability of allergic disease at age four. The children received SPTs to 15 aeroallergens and two foods. Atopy predisposition scores were obtained from the IRT model using the posterior distribution of the latent trait, atopy. These scores were used to predict persistent wheeze, rhino-conjunctivitis, and eczema at age four. Results were compared to the dichotomized and categorical (positive to ≥ 2, positive to one, versus negative to all allergens) SPT variables. At age two, 39% of children had at least one positive SPT. All three allergic disease outcomes were significantly associated with IRT atopy scores: persistent wheeze odds ratio (OR)=1.7 (95% confidence interval (CI): 1.2, 2.3); rhino-conjunctivitis OR=1.7 (95% CI:1.2, 2.3); eczema OR=1.6 (95% CI: 1.2, 2.3). In contrast, rhino-conjunctivitis was the only outcome significantly associated with the dichotomized SPT variable with an OR=1.9 (95% CI:1.2, 3.0). For the categorical SPT variable, all three allergic symptoms were significantly associated with positive to ≥ 2 allergens compared to negative to all, but no difference was observed between those with positive to one compared to negative to all. The IRT model proved to be an informative methodology to assess the predictability of early SPT responses and identify the allergens most associated with atopy predisposition.

Maternal smoking during pregnancy is associated with increased risk of childhood overweight body mass index (BMI). Less is known about the association between prenatal secondhand tobacco smoke (SHS) exposure and childhood BMI. We followed 292 mother-child dyads from early pregnancy to 3 years of age. Prenatal tobacco smoke exposure during pregnancy was quantified using self-report and serum cotinine biomarkers. We used linear mixed models to estimate the association between tobacco smoke exposure and BMI at birth, 4 weeks, and 1, 2, and 3 years. During pregnancy, 15% of women reported SHS exposure and 12% reported active smoking, but 51% of women had cotinine levels consistent with SHS exposure and 10% had cotinine concentrations indicative of active smoking. After adjustment for confounders, children born to active smokers had higher BMI at 2 and 3 years of age (self-report or serum cotinine), compared to unexposed children. Children born to women with prenatal serum cotinine concentrations indicative of SHS exposure had higher BMI at 2 (Mean Difference [MD]:0.3; 95% confidence interval [CI]:−0.1, 0.7) and 3 (MD:0.4; [0, 0.8]) years compared to unexposed children. Using self-reported prenatal exposure resulted in non-differential exposure misclassification of SHS exposures that attenuated the association between SHS exposure and BMI compared to serum cotinine concentrations. These findings suggest active and secondhand prenatal tobacco smoke exposure may be related to an important public health problem in childhood and later life. In addition, accurate quantification of prenatal secondhand tobacco smoke exposures is essential to obtaining valid estimates.

Multiple approaches are being studied to enhance the rate of thrombolysis for acute ischemic stroke. Treatment of myocardial infarction with a combination of a reduced-dose fibrinolytic agent and a glycoprotein (GP) IIb/IIIa receptor antagonist has been shown to improve the rate of recanalization versus fibrinolysis alone. The combined approach to lysis utilizing eptifibatide and recombinant tissue-type plasminogen activator (rt-PA) (CLEAR) stroke trial assessed the safety of treating acute ischemic stroke patients within 3 hours of symptom onset with this combination.The CLEAR trial was a National Institutes of Health/National Institute of Neurological Disorders and Stroke-funded multicenter, double-blind, randomized, dose-escalation and safety study. Patients were randomized 3:1 to either low-dose rt-PA (tier 1=0.3 mg/kg, tier 2=0.45 mg/kg) plus eptifibatide (75 microg/kg bolus followed by 0.75 microg/kg per min infusion for 2 hours) or standard-dose rt-PA (0.9 mg/kg). The primary safety end point was the incidence of symptomatic intracerebral hemorrhage within 36 hours. Secondary analyses were performed regarding clinical efficacy.Ninety-four patients (40 in tier 1 and 54 in tier 2) were enrolled. The combination group of the 2 dose tiers (n=69) had a median age of 71 years and a median baseline National Institutes of Health Stroke Scale (NIHSS) score of 14, and the standard-dose rt-PA group (n=25) had a median age of 61 years and a median baseline NIHSS score of 10 (P=0.01 for NIHSS score). Fifty-two (75%) of the combination treatment group and 24 (96%) of the standard treatment group had a baseline modified Rankin scale score of 0 (P=0.04). There was 1 (1.4%; 95% CI, 0% to 4.3%) symptomatic intracranial hemorrhage in the combination group and 2 (8.0%; 95% CI, 0% to 19.2%) in the rt-PA-only arm (P=0.17). During randomization in tier 2, a review by the independent data safety monitoring board demonstrated that the safety profile of combination therapy at the tier 2 doses was such that further enrollment was statistically unlikely to indicate inadequate safety for the combination treatment group, the ultimate outcome of the study. Thus, the study was halted. There was a trend toward increased clinical efficacy of standard-dose rt-PA compared with the combination treatment group.The safety of the combination of reduced-dose rt-PA plus eptifibatide justifies further dose-ranging trials in acute ischemic stroke.

We sought to evaluate arterial recanalization as measured by changes in the presence of hyperdense artery sign (HAS) on initial and 24-hour computed tomography scans in patients treated with recombinant tissue plasminogen activator (rt-PA) or placebo, and to assess the effect of rt-PA on patient outcomes in this population.Patients in the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Trial composed the study group. We determined the percentage of patients with HAS in rt-PA- and placebo-treated groups who had persistence (HAS +/+) or resolution (HAS +/-) of HAS on 24-hour computed tomography, and compared outcomes in those with resolution or persistence of the sign in these treatment groups.Baseline HAS occurred in 79 of 604 eligible patients (13%). The two treatment groups were similar, although patients treated with rt-PA were significantly older. Of the 79 patients with HAS on baseline computed tomography scan, 14 of 37 (38%) treated with rt-PA had resolution of HAS at 24 hours compared with 7 of 42 (17%) treated with placebo (P = .03). Infarct volumes at 24 hours were significantly smaller in patients treated with rt-PA with resolution of the sign, compared with those who had persistence of the sign (P = .004). In our analysis, functional outcomes were not significantly improved based on resolution of HAS in either treatment group. There were 4 symptomatic ICHs in the rt-PA-treated group with HAS as compared with two in the placebo-treated group.Among patients with HAS at baseline in the NINDS rt-PA Stroke Trial, intravenous rt-PA increased recanalization as measured by resolution of HAS and reduced infarct volumes at 24 hours.

SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocoland related documents. (DOC 122 kb)