Reply

No Abstract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50352/1/410320425_ftp.pd

Mismatch-based delayed thrombolysis: a meta-analysis

<p><b>Background and Purpose</b>: Clinical benefit from thrombolysis is reduced as stroke onset to treatment time increases. The use of "mismatch" imaging to identify patients for delayed treatment has face validity and has been used in case series and clinical trials. We undertook a meta-analysis of relevant trials to examine whether present evidence supports delayed thrombolysis among patients selected according to mismatch criteria.</p> <p><b>Methods</b>: We collated outcome data for patients who were enrolled after 3 hours of stroke onset in thrombolysis trials and had mismatch on pretreatment imaging. We selected the trials on the basis of a systematic search of the Web of Knowledge. We compared favorable outcome, reperfusion and/or recanalization, mortality, and symptomatic intracerebral hemorrhage between the thrombolyzed and nonthrombolyzed groups of patients and the probability of a favorable outcome among patients with successful reperfusion and clinical findings for 3 to 6 versus 6 to 9 hours from poststroke onset. Results are expressed as adjusted odds ratios (a-ORs) with 95% CIs. Heterogeneity was explored by test statistics for clinical heterogeneity, I2 (inconsistency), and L’Abbé plot.</p> <p><b>Results</b>: We identified articles describing the DIAS, DIAS II, DEDAS, DEFUSE, and EPITHET trials, giving a total of 502 mismatch patients thrombolyzed beyond 3 hours. The combined a-ORs for favorable outcomes were greater for patients who had successful reperfusion (a-OR=5.2; 95% CI, 3 to 9; I2=0%). Favorable clinical outcome was not significantly improved by thrombolysis (a-OR=1.3; 95% CI, 0.8 to 2.0; I2=20.9%). Odds for reperfusion/recanalization were increased among patients who received thrombolytic therapy (a-OR=3.0; 95% CI, 1.6 to 5.8; I2=25.7%). The combined data showed a significant increase in mortality after thrombolysis (a-OR=2.4; 95% CI, 1.2 to 4.9; I2=0%), but this was not confirmed when we excluded data from desmoteplase doses that were abandoned in clinical development (a-OR=1.6; 95% CI, 0.7 to 3.7; I2=0%). Symptomatic intracerebral hemorrhage was significantly increased after thrombolysis (a-OR=6.5; 95% CI, 1.2 to 35.4; I2=0%) but not significant after exclusion of abandoned doses of desmoteplase (a-OR=5.4; 95% CI, 0.9 to 31.8; I2=0%).</p> <p><b>Conclusions</b>: Delayed thrombolysis amongst patients selected according to mismatch imaging is associated with increased reperfusion/recanalization. Recanalization/reperfusion is associated with improved outcomes. However, delayed thrombolysis in mismatch patients was not confirmed to improve clinical outcome, although a useful clinical benefit remains possible. Thrombolysis carries a significant risk of symptomatic intracerebral hemorrhage and possibly increased mortality. Criteria to diagnose mismatch are still evolving. Validation of the mismatch selection paradigm is required with a phase III trial. Pending these results, delayed treatment, even according to mismatch selection, cannot be recommended as part of routine care.</p&gt

Speckle Imaging of Gamma2 Velorum: The Inner Wind Possibly Resolved

Accurately quantifying the rates dM/dt at which massive stars lose mass is essential to any understanding of their evolution. All dM/dt estimates to date assume wind clumping factors; not allowing for clumping leads to overestimates of dM/dt and underestimates of lifetimes and masses when these stars explode as supernovae. Mid-IR spectroscopy suggested that the wind of the nearest Wolf-Rayet star, Gamma2 Vel, is resolved with a Full Width at 10 per cent intensity of 0.5 arcsec, or 171 AU at the 342 pc distance of the star. As the Zorro speckle imager on Gemini-South is capable of 0.02 arcsec resolution, we have used it to image Gamma2 Vel at two orbital phases (0.30 and 0.44) with two narrowband and two intermediate-band filters in an attempt to resolve its wind. Our observations demonstrate that the wind of Gamma2 Vel may be resolved as a 0.07 arcsec westward elongation through an 832 nm filter at orbital phase 0.3 . If confirmed, this is the smallest scale (24 AU) at which a WR star wind asymmetry has been directly imaged. Similar imaging at multiple phases is needed to determine if the asymmetry is due to stochastic wind clumping, co-rotating interaction regions or colliding-wind, cone-shaped shocks.Comment: 7 pages, 4 Figures, in press in MNRA

Enhancing the development and approval of acute stroke therapies: Stroke Therapy Academic Industry roundtable

BACKGROUND: Previous Stroke Therapy Academic Industry Roundtable (STAIR) meetings focused on preclinical evidence of drug efficacy and enhancing acute stroke trial design and performance. A fourth (STAIR-IV) was held to discuss relevant issues related to acute stroke drug development and regulatory approval. SUMMARY OF REVIEW: The STAIR-IV meeting had 3 main focus areas. The first topic was novel approaches to statistical design of acute stroke trials and appropriate outcome measures. The second focus was the need for better cooperation among participants in stroke therapy development that may be addressed through a national consortium of stroke trial centers in the United States and elsewhere. Lastly, regulatory issues related to the approval of novel mono and multiple acute stroke therapies were discussed. CONCLUSIONS: The development of additional acute stroke therapies represents a large unmet need with many remaining challenges and also opportunities to incorporate novel approaches to clinical trial design that will lead to regulatory approval. The STAIR-IV meeting explored new concepts of trial methodology and data analysis, initiatives for implementing a US clinical trialist consortium, and pertinent regulatory issues to expedite approval of novel therapies

Anticoagulant vs. antiplatelet therapy in patients with cryptogenic stroke and patent foramen ovale: an individual participant data meta-analysis

Aims The preferred antithrombotic strategy for secondary prevention in patients with cryptogenic stroke (CS) and patent foramen ovale (PFO) is unknown. We pooled multiple observational studies and used propensity score-based methods to estimate the comparative effectiveness of oral anticoagulation (OAC) compared with antiplatelet therapy (APT). Methods and results Individual participant data from 12 databases of medically treated patients with CS and PFO were analysed with Cox regression models, to estimate database-specific hazard ratios (HRs) comparing OAC with APT, for both the primary composite outcome [recurrent stroke, transient ischaemic attack (TIA), or death] and stroke alone. Propensity scores were applied via inverse probability of treatment weighting to control for confounding. We synthesized database-specific HRs using random-effects meta-analysis models. This analysis included 2385 (OAC = 804and APT = 1581) patients with 227 composite endpoints (stroke/TIA/death). The difference between OAC and APT was not statistically significant for the primary composite outcome [adjusted HR = 0.76, 95% confidence interval (CI) 0.52-1.12] or for the secondary outcome of stroke alone (adjusted HR = 0.75, 95% CI 0.44-1.27). Results were consistent in analyses applying alternative weighting schemes, with the exception that OAC had a statistically significant beneficial effect on the composite outcome in analyses standardized to the patient population who actually received APT (adjusted HR = 0.64, 95% CI 0.42-0.99). Subgroup analyses did not detect statistically significant heterogeneity of treatment effects across clinically important patient groups. Conclusion We did not find a statistically significant difference comparing OAC with APT; our results justify randomized trials comparing different antithrombotic approaches in these patient

Best practice guidelines for environmental DNA biomonitoring in Australia and New Zealand

Environmental DNA (eDNA)- based methods are increasingly used by government agencies to detect pests and threatened species, and for broader biodiversity monitor-ing. Given rapid technological advances and a growing number of commercial service providers, there is a need to standardize methods for quality assurance and to main-tain confidence in eDNA- based results. Here, we introduce two documents to pro-vide best- practice guidelines for Australian and New Zealand eDNA researchers and end- users (available from https://sedna socie ty.com/publications ): the Environmental DNA protocol development guide for biomonitoring provides minimum standard consid-erations for eDNA and environmental RNA projects across the complete workflow, from ethical considerations and experimental design to interpreting and communicat-ing results. The Environmental DNA test validation guidelines outline key steps to be used in assay development and validation for species-specific testing and metabar-coding. Both guidelines were developed as an initiative of the Australian Government Department of Agriculture, Fisheries and Forestry and led by the Southern eDNA Society in a collaborative process including multiple consultation rounds with eDNA experts, end-users, and stakeholders to adapt the guidelines to Australian and New Zealand needs. The aim of these guidelines is not to be prescriptive, but to set mini-mum standards to support a consistent and best- practice approach to eDNA testing. We anticipate that the guidelines will be reviewed and regularly updated as required. Our aspiration is that these best- practice guidelines will ensure environmental man-agers are provided with robust scientific evidence to support decision- making

Anticoagulant vs. antiplatelet therapy in patients with cryptogenic stroke and patent foramen ovale: an individual participant data meta-analysis.

AIMS The preferred antithrombotic strategy for secondary prevention in patients with cryptogenic stroke (CS) and patent foramen ovale (PFO) is unknown. We pooled multiple observational studies and used propensity score-based methods to estimate the comparative effectiveness of oral anticoagulation (OAC) compared with antiplatelet therapy (APT). METHODS AND RESULTS Individual participant data from 12 databases of medically treated patients with CS and PFO were analysed with Cox regression models, to estimate database-specific hazard ratios (HRs) comparing OAC with APT, for both the primary composite outcome [recurrent stroke, transient ischaemic attack (TIA), or death] and stroke alone. Propensity scores were applied via inverse probability of treatment weighting to control for confounding. We synthesized database-specific HRs using random-effects meta-analysis models. This analysis included 2385 (OAC = 804 and APT = 1581) patients with 227 composite endpoints (stroke/TIA/death). The difference between OAC and APT was not statistically significant for the primary composite outcome [adjusted HR = 0.76, 95% confidence interval (CI) 0.52-1.12] or for the secondary outcome of stroke alone (adjusted HR = 0.75, 95% CI 0.44-1.27). Results were consistent in analyses applying alternative weighting schemes, with the exception that OAC had a statistically significant beneficial effect on the composite outcome in analyses standardized to the patient population who actually received APT (adjusted HR = 0.64, 95% CI 0.42-0.99). Subgroup analyses did not detect statistically significant heterogeneity of treatment effects across clinically important patient groups. CONCLUSION We did not find a statistically significant difference comparing OAC with APT; our results justify randomized trials comparing different antithrombotic approaches in these patients

A clinical practice guideline for the management of patients with acute spinal cord injury: recommendations on the use of methylprednisolone sodium succinate

Introduction: The objective of this guideline is to outline the appropriate use of methylprednisolone sodium succinate (MPSS) in patients with acute spinal cord injury (SCI). Methods: A systematic review of the literature was conducted to address key questions related to the use of MPSS in acute SCI. A multidisciplinary Guideline Development Group used this information, in combination with their clinical expertise, to develop recommendations for the use of MPSS. Based on GRADE (Grading of Recommendation, Assessment, Development and Evaluation), a strong recommendation is worded as "we recommend," whereas a weaker recommendation is indicated by "we suggest." Results: The main conclusions from the systematic review included the following: (1) there were no differences in motor score change at any time point in patients treated with MPSS compared to those not receiving steroids; (2) when MPSS was administered within 8 hours of injury, pooled results at 6- and 12-months indicated modest improvements in mean motor scores in the MPSS group compared with the control group; and (3) there was no statistical difference between treatment groups in the risk of complications. Our recommendations were: (1) "We suggest not offering a 24-hour infusion of high-dose MPSS to adult patients who present after 8 hours with acute SCI"; (2) "We suggest a 24-hour infusion of high-dose MPSS be offered to adult patients within 8 hours of acute SCI as a treatment option"; and (3) "We suggest not offering a 48-hour infusion of high-dose MPSS to adult patients with acute SCI." Conclusions: These guidelines should be implemented into clinical practice to improve outcomes and reduce morbidity in SCI patients