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Background/Aims: Standard approaches to trial design and analyses can be inefficient and non-pragmatic. Failure to consider a range of outcomes impedes evidence-based interpretation and reduces power. Traditional approaches synthesizing information obtained from separate analysis of each outcome fail to incorporate associations between outcomes and recognize the cumulative nature of outcomes in individual patients, suffer from competing risk complexities during interpretation, and since efficacy and safety analyses are often conducted on different populations, generalizability is unclear. Pragmatic and efficient approaches to trial design and analyses are needed. Methods: Approaches providing a pragmatic assessment of benefits and harms of interventions, summarizing outcomes experienced by patients, and providing sample size efficiencies are described. Ordinal outcomes recognize finer gradations of patient responses. Desirability of outcome ranking is an ordinal outcome combining benefits and harms within patients. Analysis of desirability of outcome ranking can be based on rank-based methodologies including the desirability of outcome ranking probability, the win ratio, and the proportion in favor of treatment. Partial credit analyses, involving grading the levels of the desirability of outcome ranking outcome similar to an academic test, provides an alternative approach. The methodologies are demonstrated using the acute stroke or transient ischemic attack treated with aspirin or ticagrelor and patient outcomes study (SOCRATES; NCT01994720), a randomized clinical trial. Results: Two 5-level ordinal outcomes were developed for SOCRATES. The first was based on a modified Rankin scale. The odds ratio is 0.86 (95% confidence interval = 0.75, 0.99; p = 0.04) indicating that the odds of worse stroke categorization for a trial participant assigned to ticagrelor is 0.86 times that of a trial participant assigned to aspirin. The 5-level desirability of outcome ranking outcome incorporated and prioritized survival; the number of strokes, myocardial infarction, and major bleeding events; and whether a stroke event was disabling. The desirability of outcome ranking probability and win ratio are 0.504 (95% confidence interval = 0.499, 0.508; p = 0.10) and 1.11 (95% confidence interval = 0.98, 1.26; p = 0.10), respectively, implying that the probability of a more desirable result with ticagrelor is 50.4% and that a more desirable result occurs 1.11 times more frequently on ticagrelor versus aspirin. Conclusion: Ordinal outcomes can improve efficiency through required pre-specification, careful construction, and analyses. Greater pragmatism can be obtained by composing outcomes within patients. Desirability of outcome ranking provides a global assessment of the benefits and harms that more closely reflect the experience of patients. The desirability of outcome ranking probability, the proportion in favor of treatment, the win ratio, and partial credit can more optimally inform patient treatment, enhance the understanding of the totality of intervention effects on patients, and potentially provide efficiencies over standard analyses. The methods provide the infrastructure for incorporating patient values and estimating personalized effects.

Background and Purpose— Ticagrelor is an effective antiplatelet therapy among patients with atherosclerotic disease and, therefore, could be more effective than aspirin in preventing recurrent stroke and cardiovascular events among patients with embolic stroke of unknown source (ESUS), which includes patients with ipsilateral stenosis Methods— We randomized 13 199 patients with a noncardioembolic, nonsevere ischemic stroke or high-risk transient ischemic attack to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2–90) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2–90) within 24 hours of symptom onset. In all patients, investigators informed on the presence of ipsilateral stenosis ≥50%, small deep infarct Results— ESUS was identified in 4329 (32.8%) patients. There was no treatment-by-ESUS category interaction ( P =0.83). Hazard ratio in ESUS patients was 0.87 (95% confidence interval, 0.68–1.10; P =0.24). However, hazard ratio was 0.51 (95% confidence interval, 0.29–0.90; P =0.02) in ESUS patients with ipsilateral stenosis P =0.89) in the remaining ESUS patients (n=3368; P for heterogeneity =0.04). Conclusions— In this post hoc, exploratory analysis, we found no treatment-by-ESUS category interaction. ESUS subgroups have heterogeneous response to treatment (Funded by AstraZeneca). Clinical Trial Registration— URL: http://www.c linicalt rials.gov . Unique identifier: NCT01994720.

Summary Background Ticagrelor is an effective antiplatelet therapy for patients with coronary atherosclerotic disease and might be more effective than aspirin in preventing recurrent stroke and cardiovascular events in patients with acute cerebral ischaemia of atherosclerotic origin. Our aim was to test for a treatment-by-ipsilateral atherosclerotic stenosis interaction in a subgroup analysis of patients in the Acute Stroke or Transient Ischaemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial. Methods SOCRATES was a randomised, double-blind, controlled trial of ticagrelor versus aspirin in patients aged 40 years or older with a non-cardioembolic, non-severe acute ischaemic stroke, or high-risk transient ischaemic attack from 674 hospitals in 33 countries. We randomly allocated patients (1:1) to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2–90, given orally) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2–90, given orally) within 24 h of symptom onset. Investigators classified all patients into atherosclerotic and non-atherosclerotic groups for the prespecified, exploratory analysis reported in this study. The primary endpoint was the time to occurrence of stroke, myocardial infarction, or death within 90 days. Efficacy analysis was by intention to treat. The SOCRATES trial is registered with ClinicalTrials.gov, number NCT01994720. Findings Between Jan 7, 2014, and Oct 29, 2015, we randomly allocated 13 199 patients (6589 [50%] to ticagrelor and 6610 [50%] to aspirin). Potentially symptomatic ipsilateral atherosclerotic stenosis was reported in 3081 (23%) of 13 199 patients. We found a treatment-by-atherosclerotic stenosis interaction (p=0·017). 103 (6·7%) of 1542 patients with ipsilateral stenosis in the ticagrelor group and 147 (9·6%) of 1539 patients with ipsilateral stenosis in the aspirin group had an occurrence of stroke, myocardial infarction, or death within 90 days (hazard ratio 0·68 [95% CI 0·53–0·88]; p=0·003). In 10 118 patients with no ipsilateral stenosis, 339 (6·7%) of 5047 patients in the ticagrelor group had an occurrence of stroke, myocardial infarction, or death within 90 days compared with 350 (6·9%) of 5071 in the aspirin group (0·97 [0·84–1·13]; p=0·72). There were no significant differences in the proportion of life-threatening bleeding or major or minor bleeding events in patients with ipsilateral stenosis in the ticagrelor group compared with the aspirin group. Interpretation In this prespecified exploratory analysis, ticagrelor was superior to aspirin at preventing stroke, myocardial infarction, or death at 90 days in patients with acute ischaemic stroke or transient ischaemic attack when associated with ipsilateral atherosclerotic stenosis. An understanding of stroke mechanisms and causes is important to deliver safe and efficacious treatments for early stroke prevention. Funding AstraZeneca.

Background and Purpose— In the SOCRATES trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes), ticagrelor was not superior to aspirin. Because of differences in patient demographics and stroke disease pattern in Asia, outcomes of ticagrelor versus aspirin were assessed among Asian patients in a prespecified exploratory analysis. Methods— Baseline demographics, treatment effects, and safety of ticagrelor and aspirin were assessed among Asian patients. Differences in outcomes between groups were assessed using Cox proportional hazard model. Results— A total of 3858 (29.2%) SOCRATES participants were recruited in Asia. Among the Asian patients, the primary end point event occurred in 186 (9.6%) of the 1933 patients treated with ticagrelor, versus 224 (11.6%) of the 1925 patients treated with aspirin (hazard ratio, 0.81; 95% confidence interval, 0.67–0.99). The exploratory P value for treatment-by-region interaction was 0.27. The primary end point event rate in the Asian subgroup was numerically higher than that in the non-Asian group (10.6% versus 5.7%; nominal P Conclusions— The event rates were numerically higher in the Asian patients. Among the Asian patients with acute stroke or transient ischemic attacks, there was a trend toward a lower hazard ratio in reducing risk of the primary end point of stroke, myocardial infarction, or death in the ticagrelor group. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01994720.

Rationale The risk of recurrent ischemia is high in the acute period after ischemic stroke and transient ischemic attack. Aspirin is recommended by guidelines for this indication, but more intensive antiplatelet therapy may be justified. Aims We aim to evaluate whether ticagrelor, a potent antiplatelet agent that blocks the P2Y12 receptor without requiring metabolic activation, reduces the risk of major vascular events compared with aspirin when randomization occurs within 24 h after symptom onset of a nonsevere ischemic stroke or high-risk transient ischemic attack. Design Acute Stroke or Transient Ischemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) is a randomized, double-blind, event-driven trial and will include an estimated 13 600 participants randomized in 33 countries worldwide to collect 844 primary events. Study outcomes The primary endpoint is the composite of stroke (ischemic or hemorrhagic), myocardial infarction, and death. Time to the first primary endpoint will be compared in the treatment groups during 90-day follow-up, with major hemorrhage serving as the primary safety endpoint. Participants will be followed for an additional 30 days after the randomized treatment period. Discussion The SOCRATES trial fulfills an important clinical need by evaluating a potent antiplatelet agent as a superior alternative to current standard of care in patients presenting acutely with ischemic stroke or transient ischemic attack.

Background: Patients with minor acute ischemic stroke or transient ischemic attack are at high risk for subsequent stroke, and more potent antiplatelet therapy in the acute setting is needed. However, the potential benefit of more intense antiplatelet therapy must be assessed in relation to the risk for major bleeding. The SOCRATES trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes) was the first trial with ticagrelor in patients with acute ischemic stroke or transient ischemic attack in which the efficacy and safety of ticagrelor were compared with those of aspirin. The main safety objective was assessment of PLATO (Platelet Inhibition and Patient Outcomes)–defined major bleeds on treatment, with special focus on intracranial hemorrhage (ICrH). Methods: An independent adjudication committee blinded to study treatment classified bleeds according to the PLATO, TIMI (Thrombolysis in Myocardial Infarction), and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definitions. The definitions of ICrH and major bleeding excluded cerebral microbleeds and asymptomatic hemorrhagic transformations of cerebral infarctions so that the definitions better discriminated important events in the acute stroke population. Results: A total of 13 130 of 13 199 randomized patients received at least 1 dose of study drug and were included in the safety analysis set. PLATO major bleeds occurred in 31 patients (0.5%) on ticagrelor and 38 patients (0.6%) on aspirin (hazard ratio, 0.83; 95% confidence interval, 0.52–1.34). The most common locations of major bleeds were intracranial and gastrointestinal. ICrH was reported in 12 patients (0.2%) on ticagrelor and 18 patients (0.3%) on aspirin. Thirteen of all 30 ICrHs (4 on ticagrelor and 9 on aspirin) were hemorrhagic strokes, and 4 (2 in each group) were symptomatic hemorrhagic transformations of brain infarctions. The ICrHs were spontaneous in 6 and 13, traumatic in 3 and 3, and procedural in 3 and 2 patients on ticagrelor and aspirin, respectively. In total, 9 fatal bleeds occurred on ticagrelor and 4 on aspirin. The composite of ICrH or fatal bleeding included 15 patients on ticagrelor and 18 on aspirin. Independently of bleeding classification, PLATO, TIMI, or GUSTO, the relative difference between treatments for major/severe bleeds was similar. Nonmajor bleeds were more common on ticagrelor. Conclusions: Antiplatelet therapy with ticagrelor in patients with acute ischemic stroke or transient ischemic attack showed a bleeding profile similar to that of aspirin for major bleeds. There were few ICrHs. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01994720.

Background: The risk of recurrent ischemia is high in the acute period after transient ischemic attack (TIA) and minor stroke. Therefore, event rates and treatment effects may vary in relation to time to loading dose (TLD) of antiplatelet treatment. We aimed to explore safety and efficacy of ticagrelor in relation to TLD from the onset of the index event. Methods: In the SOCRATES trial (NCT01994720), we randomized 13,199 patients with a non-cardioembolic, non-severe ischemic stroke or high-risk TIA to ticagrelor (180 mg loading dose on day 1, followed by 90 mg twice daily for days 2-90) or aspirin (300 mg on day 1, followed by 100 mg daily for days 2-90) within 24 hours of symptom onset. Ticagrelor was not found to be superior to aspirin in reducing the rate of the primary composite endpoint of stroke, myocardial infarction, or death at 90 days. Patients were categorized according to TLD as Results: TLD was Conclusion: In this pre-specified exploratory analysis, ticagrelor showed a greater treatment effect over aspirin in patients with TLD

Background: In the SOCRATES study (NCT01994720), addition of ticagrelor to patients on aspirin treatment before randomization may confer the effect of dual antiplatelet therapy as the antiplatelet effect of aspirin persists for more than a week. We aimed to explore safety and efficacy of ticagrelor in this pre-specified group of patients who had received aspirin prior to randomization. Methods: We randomized 13,199 patients with a non-cardioembolic, non-severe ischemic stroke or high-risk transient ischemic attack (TIA) to ticagrelor (180mg loading dose on day 1 followed by 90mg twice daily for days 2-90) or aspirin (300mg on day 1 followed by 100mg daily for days 2-90) within 24 hours of symptom onset. The prior aspirin group consisted of patients who had received aspirin within 7 days before randomization. The primary endpoint was the time to the occurrence of stroke, myocardial infarction, or death within 90 days. Results: The 4,232 patients with prior aspirin usage were older, had more vascular risk factors and vascular disease than the 8,967 patients with no prior aspirin usage. In the prior aspirin group, a primary endpoint occurred in 138/2,130 (6.5%) patients randomized to ticagrelor and in 177/2,102 (8.3%) patients randomized to aspirin (HR 0.76; 95% CI, 0.61-0.95, P=0.016) while for the non-aspirin group in 304/4,459 (6.9%) patients randomized to ticagrelor and in 320/4,508 (7.1%) patients randomized to aspirin (HR 0.96; 95%CI, 0.82-1.12, P=0.59). There was no significant treatment-by-prior-aspirin interaction (P=0.098). Major bleeding occurred in 0.7% of patients randomized to ticagrelor and in 0.4% randomized to aspirin (HR 1.58; 95% CI 0.68-3.65, P=0.28) in the prior aspirin group. Conclusion: In this pre-specified exploratory analysis, ticagrelor showed a numerically greater treatment effect over aspirin in patients taking prior aspirin, although the interaction for treatment by prior aspirin was not statistically significant. Further study is needed to evaluate the combination of ticagrelor and aspirin in patients with minor stroke/TIA.

A new framework for the estimation of diffusion coefficients from data on fluorescence recovery after photobleaching (FRAP) with confocal laser scanning microscopy (CLSM) is presented. It is a pixel-based statistical methodology that efficiently utilizes all information about the diffusion process in the available set of images. The likelihood function for a series of images is maximized which gives both an estimate of the diffusion coefficient and a corresponding error. This framework opens up possibilities (1) to obtain localized diffusion coefficient estimates in both homogeneous and heterogeneous materials, (2) to account for time differences between the registrations at the pixels within each image, and (3) to plan experiments optimized with respect to the number of replications, the number of bleached regions for each replicate, pixel size, the number of pixels, the number of images in each series etc. To demonstrate the use of the new framework, we have applied it to a simple system with polyethylene glycol (PEG) and water where we find good agreement with diffusion coefficient estimates from NMR diffusometry. In this experiment, it is also shown that the effect of the point spread function is negligible, and we find fluorochrome-concentration levels that give a linear response function for the fluorescence intensity.

Fluorescence recovery after photobleaching (FRAP) is a versatile tool for determining diffusion and interaction/binding properties in biological and material sciences. An understanding of the mechanisms controlling the diffusion requires a deep understanding of structure–interaction–diffusion relationships. In cell biology, for instance, this applies to the movement of proteins and lipids in the plasma membrane, cytoplasm and nucleus. In industrial applications related to pharmaceutics, foods, textiles, hygiene products and cosmetics, the diffusion of solutes and solvent molecules contributes strongly to the properties and functionality of the final product. All these systems are heterogeneous, and accurate quantification of the mass transport processes at the local level is therefore essential to the understanding of the properties of soft (bio)materials. FRAP is a commonly used fluorescence microscopy-based technique to determine local molecular transport at the micrometer scale. A brief high-intensity laser pulse is locally applied to the sample, causing substantial photobleaching of the fluorescent molecules within the illuminated area. This causes a local concentration gradient of fluorescent molecules, leading to diffusional influx of intact fluorophores from the local surroundings into the bleached area. Quantitative information on the molecular transport can be extracted from the time evolution of the fluorescence recovery in the bleached area using a suitable model. A multitude of FRAP models has been developed over the years, each based on specific assumptions. This makes it challenging for the non-specialist to decide which model is best suited for a particular application. Furthermore, there are many subtleties in performing accurate FRAP experiments. For these reasons, this review aims to provide an extensive tutorial covering the essential theoretical and practical aspects so as to enable accurate quantitative FRAP experiments for molecular transport measurements in soft (bio)materials.

Large naturalistic driving studies give extremely detailed insight into how traffic accidents happen and what causes them. However, even in very large studies there are only relatively few crashes. Hence one additionally selects and studies crash surrogates, so called “near-crashes”, i.e. situations when a crash almost happened. The selection procedures invariably entail severe risks of causing bias. In this paper we use extreme value statistics to develop two methods to study the extent and form of this bias. The methods are applied to a large naturalistic driving study, the 100-car study. Both methods identified a severe discrepancy between the rear-striking near-crashes and the rear-striking crashes. Perhaps surprisingly, one conclusion is that, for rear-striking and in this study, the crashes have little relevance for increasing traffic safety. We believe substantial efforts should be made to develop statistical methods for using near-crashes and crashes in future large naturalistic driving studies (such as the SHRP2 study).

Self-diffusion in polymer solutions studied with pulsed-field gradient nuclear magnetic resonance (PFG NMR) is typically based either on a single self-diffusion coefficient, or a log-normal distribution of selfdiffusion coefficients, or in some cases mixtures of these. Experimental data on polyethylene glycol (PEG) solutions and simulations were used to compare a model based on a gamma distribution of selfdiffusion coefficients to more established models such as the single exponential, the stretched exponential, and the log-normal distribution model with regard to performance and consistency. Even though the gamma distribution is very similar to the log-normal distribution, its NMR signal attenuation can be written in a closed form and therefore opens up for increased computational speed. Estimates of the mean self-diffusion coefficient, the spread, and the polydispersity index that were obtained using the gamma model were in excellent agreement with estimates obtained using the log-normal model. Furthermore, we demonstrate that the gamma distribution is by far superior to the log-normal, and comparable to the two other models, in terms of computational speed. This effect is particularly striking for multi-component signal attenuation. Additionally, the gamma distribution as well as the log-normal distribution incorporates explicitly a physically plausible model for polydispersity and spread, in contrast to the single exponential and the stretched exponential. Therefore, the gamma distribution model should be preferred in many experimental situations. Refereed/Peer-reviewed

In Jonasson et al. (2008), we presented a new pixel-based maximum likelihood framework for the estimation of diffusion coefficients from data on fluorescence recovery after photobleaching (FRAP) with confocal laser scanning microscopy (CLSM). The main method there, called the Gaussian profile method below, is based on the assumption that the initial intensity profile after photobleaching is approximately Gaussian. In the present paper, we introduce a method, called the Monotone profile method, where the maximum likelihood framework is extended to a general initial bleaching profile only assuming that the profile is a non-decreasing function of the distance to the bleaching centre. The statistical distribution of the image noise is further assumed to be Poisson instead of normal, which should be a more realistic description of the noise in the detector. The new Monotone profile method and the Gaussian profile method are applied to FRAP data on swelling of super absorbent polymers (SAP) in water with a Fluorescein probe. The initial bleaching profile is close to a step function at low degrees of swelling and close to a Gaussian profile at high degrees of swelling. The results obtained from the analysis of the FRAP data are corroborated with NMR diffusometry analysis of SAP with a polyethylene glycol probe having size similar to the Fluorescein. The comparison of the Gaussian and Monotone profile methods is also performed by use of simulated data. It is found that the new Monotone profile method is accurate for all types of initial profiles studied, but it suffers from being computationally slow. The fast Gaussian profile method is sufficiently accurate for most of the profiles studied, but underestimates the diffusion coefficient for profiles close to a step function. We also provide a diagnostic plot, which indicates whether the Gaussian profile method is acceptable or not. Refereed/Peer-reviewed

Confocal or multi-photon laser scanning microscopes are convenient tools to perform FRAP diffusion measurements. Despite its popularity, accurate FRAP remains often challenging since current methods are either limited to relatively large bleach regions or can be complicated for non-specialists. In order to bring reliable quantitative FRAP measurements to the broad community of laser scanning microscopy users, here we have revised FRAP theory and present a new pixel based FRAP method relying on the photo bleaching of rectangular regions of any size and aspect ratio. The method allows for fast and straightforward quantitative diffusion measurements due to a closed-form expression for the recovery process utilizing all available spatial and temporal data. After a detailed validation, its versatility is demonstrated by diffusion studies in heterogeneous biopolymer mixtures.

ObjectivesThis study was undertaken to determine if ticagrelor augments adenosine-induced coronary blood flow and the sensation of dyspnea in human subjects.BackgroundTicagrelor is a P2Y12 receptor antagonist that showed superior clinical benefit versus clopidogrel in a phase III trial (PLATO [Platelet Inhibition and Patient Outcomes]). Ticagrelor has been shown to inhibit cell uptake of adenosine and enhance adenosine-mediated hyperemia responses in a dog model.MethodsIn this double-blind, placebo-controlled study, 40 healthy male subjects were randomized to receive a single dose of ticagrelor (180 mg) or placebo in a crossover fashion. Coronary blood flow velocity (CBFV) was measured by using transthoracic Doppler echocardiography at rest after multiple stepwise adenosine infusions given before and after study drug, and again after the infusion of theophylline.ResultsTicagrelor significantly increased the area under the curve of CBFV versus the adenosine dose compared with placebo (p = 0.008). There was a significant correlation between ticagrelor plasma concentrations and increases in the area under the curve (p < 0.001). In both treatment groups, the adenosine-induced increase in CBFV was significantly attenuated by theophylline, with no significant differences between subjects receiving ticagrelor or placebo (p = 0.39). Furthermore, ticagrelor significantly enhanced the sensation of dyspnea during adenosine infusion, and the effects were diminished by theophylline.ConclusionsTicagrelor enhanced adenosine-induced CBFV and the sensation of dyspnea in these healthy male subjects via an adenosine-mediated mechanism. (Study to Assess the Effect of Ticagrelor on Coronary Blood Flow in Healthy Male Subjects; NCT01226602)

Ticagrelor (T) is a reversibly binding, direct-acting, oral P2Y12 antagonist used for prevention of atherothrombotic events in patients with acute coronary syndrome. One of its known potential side-effects is dyspnea. In addition to its antiplatelet effects, T also blocks cellular adenosine reuptake