Time-dependent Treatment Research Articles

Using multiple timescale models for the evaluation of a time-dependent treatment.

In survival analysis, the absolute measure of cumulative risk provided by the Kaplan-Meier estimator is still the most used quantity for its easy calculation and direct interpretability. However, for describing the survival after an intervention that may occur at different times from baseline observation, the Kaplan-Meier estimator generally yields to biased results if intervention is considered as fixed at baseline. The main focus of the present paper is to extend the use of a multiple timescale model in the presence of a time dependent intervention. The aim is to obtain 1) an estimate of treatment effect in terms of hazard ratios by flexible modeling, 2) a valid prediction tool, i.e. estimate of prognosis for a patient who changes treatment later in time, and 3) an appropriate graphical representation of survival in the presence of a time dependent treatment change, accounting for different timescales. We will show the advantages of this approach on the comparison of chemotherapy versus transplant in children with high-risk acute lymphoblastic leukemia in first remission. We considered a model with two timescales that accounts for the change in treatment at different times in the disease course. An alternative approach to survival estimates is also proposed which has some advantages over the traditional landmark approach: it uses all the data available to plot survival from the date of remission, it avoids the arbitrary choice of a landmark time and explicitly models the change in hazard due to transplant.

Impact of paliperidone palmitate versus oral atypical antipsychotics on healthcare outcomes in schizophrenia patients.

To assess impact of initial treatment and time-dependent treatment with paliperidone palmitate (PP) versus oral atypical antipsychotics (OAAs) on healthcare resource utilization and costs. A retrospective longitudinal study was conducted among Medicaid beneficiaries with schizophrenia. Inverse probability treatment weighting method and marginal structural models were used to estimate the impact of treatment on healthcare resource utilization and costs, respectively. Compared to OAAs, PP was associated with lower medical costs (mean monthly cost difference [MMCD] = -US$256; p = 0.008), which offset the higher pharmacy expense (MMCD = US$122; p < 0.001) resulting in nonsignificant cost savings associated with PP (MMCD = -US$91; p = 0.689). PP was associated with comparable overall costs to OAAs, but with significantly lower medical costs, particularly attributable to reduced inpatient visits and long-term care admissions.

On the feasibility of re-stimulation of shale wells

As a result of advances in horizontal completions and multi-stage hydraulic fracturing, the U.S. has been able to economically develop several decades of worth of natural gas. However, a considerable concern has risen on the economic viability of shale gas development for reasons associated with the fast production declines as well as recent down-turns of natural gas prices besides rises in the costs of new technologies. Therefore, an economic analysis is required to investigate the profitability of the re-fracturing treatment of unconventional gas resources. Net present value of cash flows and internal rate of return are calculated for a range of gas prices considering 20 years of natural gas production from a typical unconventional shale gas reservoir. A systematic comparison is then accomplished for three scenarios: (1) re-fracturing versus no re-fracturing, (2) combination of re-fracturing and drilling new wells, and (3) time-dependent re-fracturing treatment. Further, this paper incorporates the cost of re-fracturing treatment, the cost of drilling a new horizontal well, the water treatment cost, as well as the current and future price of natural gas in the model. The findings of this work would help the future re-stimulation development plans of the emerging unconventional shale gas plays.

Agreement with evidence for tissue Plasminogen Activator use among emergency physicians: a cross-sectional survey.

BackgroundEmergency department staff play a crucial role in the triage of stroke patients and therefore the capacity to deliver time-dependent treatments such as tissue Plasminogen Activator. This study aimed to identify among emergency physicians, (1) rates of agreement with evidence supporting tissue Plasminogen Activator use in acute stroke care; and (2) individual and hospital factors associated with high agreement with evidence supporting tissue Plasminogen Activator use.MethodsAustralian fellows and trainees of the Australasian College for Emergency Medicine were invited to complete an online cross-sectional survey assessing perceptions of tissue Plasminogen Activator use in acute stroke. Demographic and hospital characteristics were also collected.Results429 Australasian College for Emergency Medicine members responded (13% response rate). Almost half (47.2%) did not agree with any statements regarding the benefits of tissue Plasminogen Activator use for acute stroke. Perceived routine administration of tissue Plasminogen Activator by the head of respondents’ emergency department was significantly associated with high agreement with the evidence supporting tissue Plasminogen Activator use in acute stroke.ConclusionsAgreement with evidence supporting tissue Plasminogen Activator use in acute stroke is not high among responding Australian emergency physicians. In order for tissue Plasminogen Activator treatment to become widely accepted and adopted in emergency settings, beliefs and attitudes towards treatment need to be in accordance with clinical practice guidelines.Electronic supplementary materialThe online version of this article (doi:10.1186/s13104-015-1242-5) contains supplementary material, which is available to authorized users.

Visualizing Acute Stroke Data to Improve Clinical Outcomes.

Acute stroke care has highly time-dependent treatments that require teams of personnel to achieve good outcomes. It is estimated that for every minute the middle cerebral artery remains blocked in an ischemic stroke, 1.9 million neurons are lost.1 Reducing the variance and improving door-to-needle (DTN) time for thrombolysis and time from computed tomography (CT)-to-groin puncture for endovascular therapy will improve outcomes for patients with stroke.1–5 Therefore, reducing variance and improving treatment times are critical components for quality assurance efforts in stroke care. Feedback of DTN performance data has been used in quality improvement initiatives for acute stroke treatment.6,7 In a similar manner, we have observed that the first step of simply providing healthcare personnel with their measured metrics is an inducement to improve and work faster. However, the acute stroke performance data need to be presented in manner that is easy to understand, and it should be available through commonly used modalities to facilitate widespread use. ### Background on Information Visualization Information visualization is a discipline in its own right that combines graphical display in static or dynamic form to reveal a new understanding of data. In clinical medicine, novel methods of information visualization can lead to improved clinical outcomes at both the population and individual levels.8 Famously, in the mid-1800s, John Snow was able to isolate a contaminated water-well and show that cholera was water born by mapping the location and frequency of cholera infections in London’s Soho district.9 Florence Nightingale used her rose petal graphic to show the rise in mortality because of hospital-acquired infections during the Crimean war.10 Simplifying clinical concepts into graphics that are easy to understand can provide insight into the causes of poor health outcomes and lead to positive changes. ### Visualizations in Health Care There has been a rise in the use of …

The longitudinal relationship between quality of life and survival in advanced stage cancer

Quality of Life (QoL) at baseline is frequently found to be a prognostic factor in cancer studies. However, little is known about the relationship of the trajectory of QoL and survival in patients with advanced cancer. This study evaluates the effects of both level and change of QoL on survival to explore the potential of utilizing longitudinal information of QoL for prognosis. A series of joint models were used in a sample (N = 512) of patients diagnosed with advanced cancer (sample consisted of nine different cancer sites) with assessments of QoL across six time points and with survival information recorded up to 28 months after diagnosis. We used FACT-G as the QoL measure, and we evaluated the effects of change in QoL controlling for the time-dependent effects of chemotherapy and radiation. The median survival for patients was 14.2 months, and 10% of the sample had survived beyond 28 months after the diagnosis of advanced cancer. The effect of change of QoL on survival was significant (hazard ratio = 0.98; p < 0.001) controlling for time-dependent treatment effects. Also, the slope of the trajectory in QoL was found to be a significant predictor of survival (hazard ratio = 0.18; p < 0.001). These preliminary findings suggest that the patient's longitudinal experience in QoL may be a significant prognostic factor of survival, a novel finding with potentially important implications in medical decision making. Longitudinal information on QoL can be used for updating the patient's prognosis of survival.

In vitro cytotoxicity evaluation of HDAC inhibitor Apicidin in pancreatic carcinoma cells subsequent time and dose dependent treatment

Apicidin is a potent histone deacetylase inhibitor (HDACI) that selectively binds to histone deacetylases (HDACs) class I and interferes with the deacetylation process, which results in modification of acetylation level of cellular proteins. The aim of the study was to investigate the potential time and dose dependent cytotoxicity of the test compound, Apicidin, in pancreatic cancer cells Capan-1 and Panc-1 as well as estimate maximal tolerable dose (MTD) of the test agent and determine EC50 using four complementary colorimetric cytotoxicity or viability assays. The cells were treated with increasing concentrations of Apicidin (0–5000nM) for 2, 4 and 6h (short term exposure) or 24, 48 and 72h (long term exposure) before conducting cytotoxic analyses with lactate dehydrogenase assay or viability analyses with sulforhodamine B (SRB), methyl tetrazolium (MTT) and crystal violet (CV) assays. In order to investigate whether Apicidin irreversibly affects the cells already during the short term exposure, the medium containing Apicidin was removed and replaced with fresh culturing medium after 6h of treatment. The cells were then incubated for additional 24, 48 or 72h before carrying out the analysis. The results obtained from cytotoxicity and viability assays indicated, that Apicidin was well tolerated by both cell lines at concentrations below 100nM at any given time point and at all applied concentrations during the short term (6h or less) treatment. Continuous prolonged term exposures (48h or greater) of the cells to Apicidin with concentration exceeding 100nM resulted in significantly increasing cytotoxicity and sustained significant loss of cell viability. Moreover, long term exposure of pancreatic cancer cells Capan-1 and Panc-1 to Apicidin concentrations exceeding 100nM showed an initial anti-proliferative effect before cytotoxicity onset. In summary, MTD was exposure time dependent and estimated to 100nM for long term treatment and to at least 5000nM for treatment not greater than 6h. EC50 concentration of Apicidin was established after long term treatment, however with some variation when comparing the different assays and cell lines. Results from this study may encourage reinvestigating the capacity of potent HDACI Apicidin as an attractive agent for interfering with the deacetylation process catalyzed by HDACs for potential pancreatic cancer intervention.

Assessing potentially time-dependent treatment effect from clinical trials and observational studies for survival data, with applications to the Women's Health Initiative combined hormone therapy trial.

For risk and benefit assessment in clinical trials and observational studies with time-to-event data, the Cox model has usually been the model of choice. When the hazards are possibly non-proportional, a piece-wise Cox model over a partition of the time axis may be considered. Here, we propose to analyze clinical trials or observational studies with time-to-event data using a certain semiparametric model. The model allows for a time-dependent treatment effect. It includes the important proportional hazards model as a sub-model and can accommodate various patterns of time-dependence of the hazard ratio. After estimation of the model parameters using a pseudo-likelihood approach, simultaneous confidence intervals for the hazard ratio function are established using a Monte Carlo method to assess the time-varying pattern of the treatment effect. To assess the overall treatment effect, estimated average hazard ratio and its confidence intervals are also obtained. The proposed methods are applied to data from the Women's Health Initiative. To compare the Women's Health Initiative clinical trial and observational study, we use the propensity score in building the regression model. Compared with the piece-wise Cox model, the proposed model yields a better model fit and does not require partitioning of the time axis.

On generalized cross validation for stable parameter selection in disease models

Abstract In this paper we study advantages and limitations of the Generalized Cross Validation (GCV) approach for selecting a regularization parameter in the case of a partially stochastic linear irregular operator equation. The research has been motivated by an inverse problem in epidemiology, where the goal was to reconstruct a time dependent treatment recovery rate for plasmodium falciparum, the most dangerous form of malaria. Initial numerical simulations gave rise to a theoretical analysis of the expected value of the GCV function and the efficiency of the GCV method for different noise levels. It was shown that, as opposed to L-curve, the GCV does not necessarily generate a systematic error in the value of the regularization parameter for Tikhonov's stabilizing algorithm.

Intracellular delivery of BSA by phosphonate@silica nanoparticles.

Intracellular protein (BSA) delivery by a phosphonate@mesoporous silica nanoparticle vehicle, PMSN, with high load capacity for the relatively large test protein BSA, is described. Wide pore (11.6 nm) PMSN nanoparticles were synthesised and loaded with a BSA cargo to give BSA#@PMSN*, where # and * signify Fluorescein and Rhodamine fluorescent labels respectively. Internalisation of BSA#@PMSN*s by HeLa cells was analysed from confocal microscopy and TEM images after dose and time dependent treatments. No evidence of cytotoxicity was observed after 24 h and in contrast to PMSN* no significant loss of BSA#@PMSN* was observed after 3 h incubation of the loaded cells in DMEM. Receptor blocking experiments showed caveolar uptake of PMSN* and folate receptor mediated uptake of BSA#@PMSN*s.

LymPHOS 2.0: an update of a phosphosite database of primary human T cells.

LymPHOS is a web-oriented database containing peptide and protein sequences and spectrometric information on the phosphoproteome of primary human T-Lymphocytes. Current release 2.0 contains 15 566 phosphorylation sites from 8273 unique phosphopeptides and 4937 proteins, which correspond to a 45-fold increase over the original database description. It now includes quantitative data on phosphorylation changes after time-dependent treatment with activators of the TCR-mediated signal transduction pathway. Sequence data quality has also been improved with the use of multiple search engines for database searching. LymPHOS can be publicly accessed at http://www.lymphos.org.Database URL: http://www.lymphos.org.

Adjusting for treatment switching in randomised controlled trials - A simulation study and a simplified two-stage method.

Estimates of the overall survival benefit of new cancer treatments are often confounded by treatment switching in randomised controlled trials (RCTs) - whereby patients randomised to the control group are permitted to switch onto the experimental treatment upon disease progression. In health technology assessment, estimates of the unconfounded overall survival benefit associated with the new treatment are needed. Several switching adjustment methods have been advocated in the literature, some of which have been used in health technology assessment. However, it is unclear which methods are likely to produce least bias in realistic RCT-based scenarios. We simulated RCTs in which switching, associated with patient prognosis, was permitted. Treatment effect size and time dependency, switching proportions and disease severity were varied across scenarios. We assessed the performance of alternative adjustment methods based upon bias, coverage and mean squared error, related to the estimation of true restricted mean survival in the absence of switching in the control group. We found that when the treatment effect was not time-dependent, rank preserving structural failure time models (RPSFTM) and iterative parameter estimation methods produced low levels of bias. However, in the presence of a time-dependent treatment effect, these methods produced higher levels of bias, similar to those produced by an inverse probability of censoring weights method. The inverse probability of censoring weights and structural nested models produced high levels of bias when switching proportions exceeded 85%. A simplified two-stage Weibull method produced low bias across all scenarios and provided the treatment switching mechanism is suitable, represents an appropriate adjustment method.

Theoretical power spectra of mixed modes in low-mass red giant stars

CoRoT and Kepler observations of red giant stars revealed very rich spectra of non-radial solar-like oscillations. Of particular interest was the detection of mixed modes that exhibit significant amplitude, both in the core and at the surface of the stars. It opens the possibility of probing the internal structure from their inner-most layers up to their surface along their evolution on the red giant branch as well as on the red-clump. Our objective is primarily to provide physical insight into the physical mechanism responsible for mixed-modes amplitudes and lifetimes. Subsequently, we aim at understanding the evolution and structure of red giants spectra along with their evolution. The study of energetic aspects of these oscillations is also of great importance to predict the mode parameters in the power spectrum. Non-adiabatic computations, including a time-dependent treatment of convection, are performed and provide the lifetimes of radial and non-radial mixed modes. We then combine these mode lifetimes and inertias with a stochastic excitation model that gives us their heights in the power spectra. For stars representative of CoRoT and Kepler observations, we show under which circumstances mixed modes have heights comparable to radial ones. We stress the importance of the radiative damping in the determination of the height of mixed modes. Finally, we derive an estimate for the height ratio between a g-type and a p-type mode. This can thus be used as a first estimate of the detectability of mixed-modes.

Neurocognitive change in the era of HIV combination antiretroviral therapy: the longitudinal CHARTER study.

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) can show variable clinical trajectories. Previous longitudinal studies of HAND typically have been brief, did not use adequate normative standards, or were conducted in the context of a clinical trial, thereby limiting our understanding of incident neurocognitive (NC) decline and recovery. We investigated the incidence and predictors of NC change over 16-72 (mean, 35) months in 436 HIV-infected participants in the CNS HIV Anti-Retroviral Therapy Effects Research cohort. Comprehensive laboratory, neuromedical, and NC assessments were obtained every 6 months. Published, regression-based norms for NC change were used to generate overall change status (decline vs stable vs improved) at each study visit. Survival analysis was used to examine the predictors of time to NC change. Ninety-nine participants (22.7%) declined, 265 (60.8%) remained stable, and 72 (16.5%) improved. In multivariable analyses, predictors of NC improvements or declines included time-dependent treatment status and indicators of disease severity (current hematocrit, albumin, total protein, aspartate aminotransferase), and baseline demographics and estimated premorbid intelligence quotient, non-HIV-related comorbidities, current depressive symptoms, and lifetime psychiatric diagnoses (overall model P < .0001). NC change is common in HIV infection and appears to be driven by a complex set of risk factors involving HIV disease, its treatment, and comorbid conditions.

Pulsations as a driver for LBV variability

Among the most spectacular variable stars are the Luminous Blue Variables (LBVs), which can show three types of variability. The LBV phase of evolution is poorly understood, and the driving mechanisms for the variability are not known. The most common type of variability, the S Dor instability, occurs on timescales of tens of years. During an S Dor outburst, the visual magnitude of the star increases, while the bolometric magnitude stays approximately constant. In this work, we investigate pulsation as a possible trigger for the S Dor type outbursts. We calculate the pulsations of envelope models using a nonlinear hydrodynamics code including a time-dependent convection treatment. We initialize the pulsation in the hydrodynamic model based on linear non-adiabatic calculations. Pulsation properties for a full grid of models from 20 to 85 M$_{\odot}$ were calculated, and in this paper we focus on the few models that show either long-period pulsations or outburst-like behaviour, with photospheric radial velocities reaching 70-80 km/s. At the present time, our models cannot follow mass loss, so once the outburst event begins, our simulations are terminated. Our results show that pulsations alone are not able to drive enough surface expansion to eject the outer layers. However, the outbursts and long-period pulsations discussed here produce large variations in effective temperature and luminosity, which are expected to produce large variations in the radiatively driven mass-loss rates.

Modeling nonlinear time-dependent treatment effects: an application of the generalized time-varying effect model (TVEM).

The goal of this article is to introduce to social and behavioral scientists the generalized time-varying effect model (TVEM), a semiparametric approach for investigating time-varying effects of a treatment. The method is best suited for data collected intensively over time (e.g., experience sampling or ecological momentary assessments) and addresses questions pertaining to effects of treatment changing dynamically with time. Thus, of interest is the description of timing, magnitude, and (nonlinear) patterns of the effect. Our presentation focuses on practical aspects of the model. A step-by-step demonstration is presented in the context of an empirical study designed to evaluate effects of surgical treatment on quality of life among early stage lung cancer patients during posthospitalization recovery (N = 59; 61% female, M age = 66.1 years). Frequency and level of distress associated with physical symptoms were assessed twice daily over a 2-week period, providing a total of 1,544 momentary assessments. Traditional analyses (analysis of covariance [ANCOVA], repeated-measures ANCOVA, and multilevel modeling) yielded findings of no group differences. In contrast, generalized TVEM identified a pattern of the effect that varied in time and magnitude. Group differences manifested after Day 4. Generalized TVEM is a flexible statistical approach that offers insight into the complexity of treatment effects and allows modeling of nonnormal outcomes. The practical demonstration, shared syntax, and availability of a free set of macros aim to encourage researchers to apply TVEM to complex data and stimulate important scientific discoveries.

One- and two-photon absorption in solution: the effects of a passive auxiliary beam.

The efficiencies of one- and two-photon absorption by chromophores in solution may be significantly modified by a sufficiently intense beam of off-resonant light. A molecular analysis based on quantum electrodynamics (QED) fully accounts for this phenomenon of laser-modified absorption. A time-dependent perturbation-theory treatment describes the process in terms of stimulated forward Rayleigh-scattering of the auxiliary beam occurring simultaneously with the absorption interaction(s). Our formulation accommodates media modifications to the basic character of light-matter interactions, taking into account the refractive and dispersive properties of a solution-phase environment. This introduces the bulk refractive index of the solvent directly into the QED framework. The measurable electronic response of molecules freely rotating in solution is defined by an average of all orientations. We explicitly derive fixed-orientation and rotationally averaged calculations for the Fermi-rule rate of laser-modified one- and two-photon absorption. For a given beam polarization geometry, the solution-phase molecular response is expressible as a set of natural invariant scalars. These results reveal details of the dependence on the beam polarisations and on the rotationally averaged molecular response: we illustrate the breadth of variation available via geometric manipulation of beam polarization, and raise new possibilities for quantum weak measurements of laser states.

Rapid Attainment of Tacrolimus Trough Levels Early Post-Transplant Reduces Risk of Treatment Failure in De Novo Kidney Transplant Patients: A Covariate Analysis of a Phase 3 Double-Blind Study.

Envarsus, a novel once-daily, MeltDose formulation of tacrolimus (Tac), has greater bioavailability, a more consistent concentration profile, noninferior efficacy and similar safety and with lower total daily dose (TDD) vs. traditional twice-daily Tac (Prograf). From a Phase 3, double-blind, double-dummy, multicenter trial of de novo kidney transplant recipients (KTR) randomized to once-daily Envarsus (n=268) or twice-daily Prograf (n=275), we explored the relationship between Tac trough level as a time-dependent covariate and treatment failure (graft loss, death, biopsy-proven acute rejection, or lost to follow-up). Treatment failure rates were similar between Envarsus (18.3%) and Prograf (19.6%); however, events occurred later for Envarsus-treated KTR (at a mean of 101.7 days posttransplant) vs. Prograf (mean: 83.3 days). Kaplan-Meier analysis showed comparable efficacy throughout the study (figure). Within the first 3 months posttransplant, when KTR have the greatest rejection risk, treatment failure rates were LCP-Tacro: 10.4% and Prograf: 14.2%, P=0.124. In days 2-4, TDD was higher for Envarsus (˜12mg) vs. Prograf (˜8mg), reflecting the higher Envarsus starting dose (0.17mg/kg vs. 0.10mg/kg for Prograf). Tac trough levels were notably greater in the Envarsus group vs. the Prograf group in the first 2 weeks after dosing; thereafter, trough levels were similar. Higher Tac trough level was significantly (P<0.001) associated with a decreased risk for treatment failure (Hazard ratio: 0.85; 95% CI 0.82-0.95). These findings support improved bioavailability of Envarsus results in a dose-sparing effect and permits rapid attainment of therapeutic levels. These results confirm the hypothesis that low levels of Tac pose an increased risk of treatment failure in de novo KTR.Figure: No Caption available.DISCLOSURES:Rostaing, L.: Other, Chiesi, advisory board. Budde, K.: Grant/Research Support, AiCuris, Astellas, BmT GmbH, Bristol-Myers Squibb, speaker's fees, honoraria, travel expenses, Chiesi, Hexal, Novartis, Roche, Pfizer, Siemens, speaker's fees, honoraria, travel expenses, Veloxis, speaker's fees, honoraria, travel expenses, Other, Bristol-Myers Squibb, Chiesi, Effimune, Hexal,, consultant, Novartis, Pfizer, Veloxis, consultant. Bunnapradist, S.: Grant/Research Support, Veloxis, Genentech, Novartis, Speaker's Bureau, Novartis, Other, Veloxis, Advisory Board.

On the Role of Optimal Counseling and Antiviral Therapy on Controlling HCV among Intravenous Drug Misusers

Hepatitis C virus (HCV) remains a major health challenge despite the availability of highly effective antiviral drugs. Prior studies suggest that many physicians are reluctant to treat intravenous drug misusers due to low levels of treatment adherence associated with intravenous drug misusers. HCV treatment guidelines and recommendations stipulate that HCV patients in treatment should abstain from intravenous drug misuse activities in order to reduce the likelihood of treatment failure, drug resistance, reinfection, superinfection, or mixed infection. In this paper, a mathematical model for exploring the transmission dynamics of HCV among intravenous drug misusers is proposed. The model incorporates essential characteristics of intravenous drug misusers such as relapse and nonadherence to treatment guidelines. With the aid of optimal control theory we assess the effects of time dependent HCV screening and treatment. Results from this study provide a framework for designing the appropriate strategies on controlling the long-term dynamics of HCV among intravenous drug users.

Putting It All Together for Best Stroke Practice, All the Time

See related article, p 1387. Each year nearly 800 000 people in the United States have a clinically evident stroke. Despite the availability of an effective and time-dependent treatment, intravenous recombinant tissue-type plasminogen activator (r-tPA), in 2011, only 33.8%1 of eligible ischemic stroke patients received treatment within 60 minutes from time of hospital arrival, as recommended by current acute stroke guidelines.2 This suboptimal expediency of treatment, nearly constant for a decade, represents lost opportunity for optimal neurological outcome and reduced mortality. The pooled analyses of the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS), European Cooperative Acute Stroke Study (ECASS), and National Institute of Neurological Disorders and Stroke r-tPA Stroke Study (NINDS) r-tPA trials by Hacke et al3 in 2004 showed a strong association between early treatment and improved outcomes in patients with ischemic stroke treated with r-tPA. A recent analysis of the Get With the Guidelines Stroke registry by Saver et al4 confirmed that earlier treatment yields better patient outcomes. The American Heart Association/American Stroke Association Target Stroke initiative was created to provide a framework through which hospitals could reduce their door-to-needle (DTN) times. In the development of the Target Stroke program, best practice strategies were identified by a multidisciplinary work group after reviewing published literature and expert consensus. Strategies proven successful in reducing time to treatment of ST-segment–elevation myocardial infarction were identified as best practice strategies that could be easily and effectively adopted by acute care hospitals in the treatment of stroke. Eleven such strategies were promoted, including prehospital notification; the use of single-call stroke team activation; rapid triage, imaging, and laboratory testing; and …