Contemporary outcome measures in acute stroke research: choice of primary outcome measure

BACKGROUND AND PURPOSE: The diversity of available outcome measures for acute stroke trials is challenging and implies that the scales may be imperfect. To assist researchers planning trials and to aid interpretation, this article reviews and makes recommendations on the available choices of scales. The aim is to identify an approach that will be universally accepted and that should be included in most acute trials, without seeking to restrict options for special circumstances. METHODS: The article considers outcome measures that have been widely used or are currently advised. It examines desirable properties for outcome measures such as validity, relevance, responsiveness, statistical properties, availability of training, cultural and language issues, resistance to comorbidity, as well as potential weaknesses. Tracking and agreement among outcomes are covered. RESULTS: Typical ranges of scores for the common scales are described, along with their statistical properties, which in turn influence optimal analytic techniques. The timing of recovery on scores and usual practice in trial design are considered. CONCLUSIONS: The preferred outcome measure for acute trials is the modified Rankin Scale, assessed at 3 months after stroke onset or later. The interview should be conducted by a certified rater and should involve both the patient and any relevant caregiver. Incremental benefits at any level of the modified Rankin Scale may be acceptable. The modified Rankin Scale is imperfect but should be retained in its present form for comparability with existing treatment comparisons. No second measure should be required, but correlations with supporting scales may be used to confirm consistency in direction of effects on other measures

Structure and superconductivity of two different phases of Re3W

Two superconducting phases of Re(3)W have been found with different physical properties. One phase crystallizes in a noncentrosymmetric cubic (alpha-Mn) structure and has a superconducting transition temperature T(c) of 7.8 K. The other phase has a hexagonal centrosymmetric structure and is superconducting with a T(c) of 9.4 K. Switching between the two phases is possible by annealing the sample or remelting it. The properties of both phases of Re(3)W have been characterized by powder neutron diffraction, magnetization, and resistivity measurements. The temperature dependences of the lower and upper critical fields have been measured for both phases. These are used to determine the penetration depths and the coherence lengths for these systems

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

Thermal Analysis of a Metallic Wing Glove for a Mach-8 Boundary-Layer Experiment

A metallic 'glove' structure has been built and attached to the wing of the Pegasus(trademark) space booster. An experiment on the upper surface of the glove has been designed to help validate boundary-layer stability codes in a free-flight environment. Three-dimensional thermal analyses have been performed to ensure that the glove structure design would be within allowable temperature limits in the experiment test section of the upper skin of the glove. Temperature results obtained from the design-case analysis show a peak temperature at the leading edge of 490 F. For the upper surface of the glove, approximately 3 in. back from the leading edge, temperature calculations indicate transition occurs at approximately 45 sec into the flight profile. A worst-case heating analysis has also been performed to ensure that the glove structure would not have any detrimental effects on the primary objective of the Pegasus a launch. A peak temperature of 805 F has been calculated on the leading edge of the glove structure. The temperatures predicted from the design case are well within the temperature limits of the glove structure, and the worst-case heating analysis temperature results are acceptable for the mission objectives

Randomised trial of once- or twice-daily MMX mesalazine for maintenance of remission in ulcerative colitis

AIM: Maintenance treatment in ulcerative colitis should be as convenient as possible, to increase the chance of compliance. MMX mesalazine is a once-daily, high-strength (1.2 g/tablet) formulation of 5-aminosalicylic acid. This study evaluated the safety and efficacy of MMX mesalazine dosed once or twice daily as maintenance therapy in patients with ulcerative colitis. METHODS: This multicentre, randomised, open-label trial enrolled patients with strictly defined clinical and endoscopic remission, immediately following an episode of mild to moderate ulcerative colitis. Patients were randomised to MMX mesalazine 2.4 g/day as a single (2x1.2 g tablet) or divided dose (1x1.2 g tablet twice daily) for 12 months. RESULTS: 174 patients (37.9%; safety population n = 459) experienced 384 adverse events, the majority of which were mild or moderate in intensity. Eighteen patients (3.9%), nine in each group, experienced a total of 22 serious adverse events (10 in the once-daily and 12 in the twice-daily group). Most serious adverse events were gastrointestinal, experienced by 5 patients in the once-daily and 4 in the twice-daily group. At month 12, 64.4% (efficacy population, n = 451) of patients in the once-daily and 68.5% of patients in the twice-daily group were in clinical and endoscopic remission (p = 0.351). At month 12, 88.9% and 93.2% in each group, respectively, had maintained clinical remission (were relapse free). CONCLUSIONS: MMX mesalazine 2.4 g/day administered as a single or divided dose demonstrated a good safety profile, was well tolerated and was effective as maintenance treatment. High clinical and endoscopic remission rates can be achieved with once-daily dosing. TRIAL REGISTRATION NUMBER: NCT00151944

Homogeneous nucleation of colloidal melts under the influence of shearing fields

We study the effect of shear flow on homogeneous crystal nucleation, using Brownian Dynamics simulations in combination with an umbrella sampling like technique. The symmetry breaking due to shear results in anisotropic radial distribution functions. The homogeneous shear rate suppresses crystal nucleation and leads to an increase of the size of the critical nucleus. These observations can be described by a simple, phenomenological extension of classical nucleation theory. In addition, we find that nuclei have a preferential orientation with respect to the direction of shear. On average the longest dimension of a nucleus is along the vorticity direction, while the shortest dimension is preferably perpendicular to that and slightly tilted with respect to the gradient direction.Comment: 10 pages, 8 figures, Submitted to J. Phys.: Condens. Matte

Effects of alteplase for acute stroke on the distribution of functional outcomes: a pooled analysis of 9 trials

Background—Thrombolytic therapy with intravenous alteplase within 4.5 hours of ischemic stroke onset increases the overall likelihood of an excellent outcome (no, or nondisabling, symptoms). Any improvement in functional outcome distribution has value, and herein we provide an assessment of the effect of alteplase on the distribution of the functional level by treatment delay, age, and stroke severity. Methods—Prespecified pooled analysis of 6756 patients from 9 randomized trials comparing alteplase versus placebo/open control. Ordinal logistic regression models assessed treatment differences after adjustment for treatment delay, age, stroke severity, and relevant interaction term(s). Results—Treatment with alteplase was beneficial for a delay in treatment extending to 4.5 hours after stroke onset, with a greater benefit with earlier treatment. Neither age nor stroke severity significantly influenced the slope of the relationship between benefit and time to treatment initiation. For the observed case mix of patients treated within 4.5 hours of stroke onset (mean 3 hours and 20 minutes), the net absolute benefit from alteplase (ie, the difference between those who would do better if given alteplase and those who would do worse) was 55 patients per 1000 treated (95% confidence interval, 13–91; P=0.004). Conclusions—Treatment with intravenous alteplase initiated within 4.5 hours of stroke onset increases the chance of achieving an improved level of function for all patients across the age spectrum, including the over 80s and across all severities of stroke studied (top versus bottom fifth means: 22 versus 4); the earlier that treatment is initiated, the greater the benefit

A Coupled Map Lattice Model for Rheological Chaos in Sheared Nematic Liquid Crystals

A variety of complex fluids under shear exhibit complex spatio-temporal behaviour, including what is now termed rheological chaos, at moderate values of the shear rate. Such chaos associated with rheological response occurs in regimes where the Reynolds number is very small. It must thus arise as a consequence of the coupling of the flow to internal structural variables describing the local state of the fluid. We propose a coupled map lattice (CML) model for such complex spatio-temporal behaviour in a passively sheared nematic liquid crystal, using local maps constructed so as to accurately describe the spatially homogeneous case. Such local maps are coupled diffusively to nearest and next nearest neighbours to mimic the effects of spatial gradients in the underlying equations of motion. We investigate the dynamical steady states obtained as parameters in the map and the strength of the spatial coupling are varied, studying local temporal properties at a single site as well as spatio-temporal features of the extended system. Our methods reproduce the full range of spatio-temporal behaviour seen in earlier one-dimensional studies based on partial differential equations. We report results for both the one and two-dimensional cases, showing that spatial coupling favours uniform or periodically time-varying states, as intuitively expected. We demonstrate and characterize regimes of spatio-temporal intermittency out of which chaos develops. Our work suggests that such simplified lattice representations of the spatio-temporal dynamics of complex fluids under shear may provide useful insights as well as fast and numerically tractable alternatives to continuum representations.Comment: 32 pages, single column, 20 figure

Transport Far From Equilibrium --- Uniform Shear Flow

The BGK model kinetic equation is applied to spatially inhomogeneous states near steady uniform shear flow. The shear rate of the reference steady state can be large so the states considered include those very far from equilibrium. The single particle distribution function is calculated exactly to first order in the deviations of the hydrodynamic field gradients from their values in the reference state. The corresponding non-linear hydrodynamic equaitons are obtained and the set of transport coefficients are identified as explicit functions of the shear rate. The spectrum of the linear hydrodynamic equation is studied in detail and qualitative differences from the spectrum for equilibrium fluctuations are discussed. Conditions for instabilities at long wavelengths are identified and disccused.Comment: 32 pages, 1 figure, RevTeX, submitted to Phys. Rev.

Stability of Uniform Shear Flow

The stability of idealized shear flow at long wavelengths is studied in detail. A hydrodynamic analysis at the level of the Navier-Stokes equation for small shear rates is given to identify the origin and universality of an instability at any finite shear rate for sufficiently long wavelength perturbations. The analysis is extended to larger shear rates using a low density model kinetic equation. Direct Monte Carlo Simulation of this equation is computed with a hydrodynamic description including non Newtonian rheological effects. The hydrodynamic description of the instability is in good agreement with the direct Monte Carlo simulation for $t < 50t_0$, where $t_0$ is the mean free time. Longer time simulations up to $2000t_0$ are used to identify the asymptotic state as a spatially non-uniform quasi-stationary state. Finally, preliminary results from molecular dynamics simulation showing the instability are presented and discussed.Comment: 25 pages, 9 figures (Fig.8 is available on request) RevTeX, submitted to Phys. Rev.