Paired associative stimulation as a tool to assess plasticity enhancers in chronic stroke

Background and Purpose: The potential for adaptive plasticity in the post-stroke brain is difficult to estimate, as is the demonstration of central nervous system (CNS) target engagement of drugs that show promise in facilitating stroke recovery. We set out to determine if paired associative stimulation (PAS) can be used (a) as an assay of CNS plasticity in patients with chronic stroke, and (b) to demonstrate CNS engagement by memantine, a drug which has potential plasticity-modulating effects for use in motor recovery following stroke. Methods: We examined the effect of PAS in fourteen participants with chronic hemiparetic stroke at five time-points in a within-subjects repeated measures design study: baseline off-drug, and following a week of orally administered memantine at doses of 5, 10, 15, and 20 mg, comprising a total of seventy sessions. Each week, MEP amplitude pre and post-PAS was assessed in the contralesional hemisphere as a marker of enhanced or diminished plasticity. Strength and dexterity were recorded each week to monitor motor-specific clinical status across the study period. Results: We found that MEP amplitude was significantly larger after PAS in baseline sessions off-drug, and responsiveness to PAS in these sessions was associated with increased clinical severity. There was no observed increase in MEP amplitude after PAS with memantine at any dose. Motor threshold (MT), strength, and dexterity remained unchanged during the study. Conclusion: Paired associative stimulation successfully induced corticospinal excitability enhancement in chronic stroke subjects at the group level. However, this response did not occur in all participants, and was associated with increased clinical severity. This could be an important way to stratify patients for future PAS-drug studies. PAS was suppressed by memantine at all doses, regardless of responsiveness to PAS off-drug, indicating CNS engagement

Robotic arm rehabilitation in chronic stroke patients with aphasia may promote speech and language recovery (but effect is not enhanced by supplementary tDCS)

Objective: This study aimed to determine the extent to which robotic arm rehabilitation for chronic stroke may promote recovery of speech and language function in individuals with aphasia. Methods: We prospectively enrolled 17 individuals from a hemiparesis rehabilitation study pairing intensive robot assisted therapy with sham or active tDCS and evaluated their speech (N = 17) and language (N = 9) performance before and after a 12-week (36 session) treatment regimen. Performance changes were evaluated with paired t-tests comparing pre- and post-test measures. There was no speech therapy included in the treatment protocol. Results: Overall, the individuals significantly improved on measures of motor speech production from pre-test to post-test. Of the subset who performed language testing (N = 9), overall aphasia severity on a standardized aphasia battery improved from pre-test baseline to post-test. Active tDCS was not associated with greater gains than sham tDCS. Conclusions: This work indicates the importance of considering approaches to stroke rehabilitation across different domains of impairment, and warrants additional exploration of the possibility that robotic arm motor treatment may enhance rehabilitation for speech and language outcomes. Further investigation into the role of tDCS in the relationship of limb and speech/language rehabilitation is required, as active tDCS did not increase improvements over sham tDCS

Robotic Arm Rehabilitation in Chronic Stroke Patients With Aphasia May Promote Speech and Language Recovery (but Effect Is Not Enhanced by Supplementary tDCS)

Objective: This study aimed to determine the extent to which robotic arm rehabilitation for chronic stroke may promote recovery of speech and language function in individuals with aphasia.Methods: We prospectively enrolled 17 individuals from a hemiparesis rehabilitation study pairing intensive robot assisted therapy with sham or active tDCS and evaluated their speech (N = 17) and language (N = 9) performance before and after a 12-week (36 session) treatment regimen. Performance changes were evaluated with paired t-tests comparing pre- and post-test measures. There was no speech therapy included in the treatment protocol.Results: Overall, the individuals significantly improved on measures of motor speech production from pre-test to post-test. Of the subset who performed language testing (N = 9), overall aphasia severity on a standardized aphasia battery improved from pre-test baseline to post-test. Active tDCS was not associated with greater gains than sham tDCS.Conclusions: This work indicates the importance of considering approaches to stroke rehabilitation across different domains of impairment, and warrants additional exploration of the possibility that robotic arm motor treatment may enhance rehabilitation for speech and language outcomes. Further investigation into the role of tDCS in the relationship of limb and speech/language rehabilitation is required, as active tDCS did not increase improvements over sham tDCS

Estimators of Effect Modification of Cumulative Incidence: Aalen-Johansen and Targeted Minimum Loss-based Estimator

Thesis (Master's)--University of Washington, 2015-12In time to event settings there are many occasions in which multiple events can occur. This competing risks phenomenon is often encountered in vaccine trials when interest is given to efficacy against a specific subtype of the disease, particularly those included (or not) in the formulation of the vaccine. In these settings, the parameter of interest is cumulative incidence - the probability of being infected by a particular subtype by a certain time. In this thesis we present and compare two estimators of cumulative incidence in various simulated scenarios and compare additive and multiplicative treatment effects as well as effect modification across groups. We apply these estimators to two phase-III double-blind placebo controlled trials of Sanofi Pasteur's dengue vaccine, which has recently been approved in Mexico and is likely to gain approval from the FDA and many other countries in 2016

Automated expiratory ventilation assistance through a small endotracheal tube can improve venous return and cardiac output

Abstract Background Positive pressure ventilation can decrease venous return and cardiac output. It is not known if expiratory ventilation assistance (EVA) through a small endotracheal tube can improve venous return and cardiac output. Results In a porcine model, switching from conventional positive pressure ventilation to (EVA) with − 8 cmH20 expiratory pressure increased the venous return and cardiac output. The stroke volume increased by 27% when the subjects were switched from conventional ventilation to EVA [53.8 ± 7.7 (SD) vs. 68.1 ± 7.7 ml, p = 0.003]. After hemorrhage, subjects treated with EVA had higher median cardiac output, higher mean systemic arterial pressure, and lower central venous pressure at 40 and 60 min when compared with subjects treated with conventional ventilation with PEEP 0 cmH20. The median cardiac output was 41% higher in the EVA group than the control group at 60 min [2.70 vs. 1.59 L/min, p = 0.029]. Conclusion EVA through a small endotracheal tube increased venous return, cardiac output, and mean arterial pressure compared with conventional positive pressure ventilation. The effects were most significant during hypovolemia from hemorrhage. EVA provided less effective ventilation than conventional positive pressure ventilation

Rapidly Improving ARDS in Therapeutic Randomized Controlled Trials

BACKGROUND: Observational studies suggest that some patients meeting criteria for ARDS no longer fulfill the oxygenation criterion early in the course of their illness. This subphenotype of rapidly improving ARDS has not been well characterized. We attempted to assess the prevalence, characteristics, and outcomes of rapidly improving ARDS and to identify which variables are useful to predict it. METHOD: A secondary analysis was performed of patient level data from six ARDS Network randomized controlled trials. We defined rapidly improving ARDS, contrasted with ARDS > 1 day, as extubation or a PaO2 to FiO(2) ratio (PaO2:FiO(2)) > 300 on the first study day following enrollment. RESULTS: The prevalence of rapidly improving ARDS was 10.5% (458 of 4,361 patients) and increased over time. Of the 1,909 patients enrolled in the three most recently published trials, 197 (10.3%) were extubated on the first study day, and 265 (13.9%) in total had rapidly improving ARDS. Patients with rapidly improving ARDS had lower baseline severity of illness and lower 60-day mortality (10.2% vs 26.3%; P < .0001) than ARDS > 1 day. PaO2:FiO(2) at screening, change in PaO2:FiO(2) from screening to enrollment, use of vasopressor agents, FiO(2) at enrollment, and serum bilirubin levels were useful predictive variables. CONCLUSIONS: Rapidly improving ARDS, mostly defined by early extubation, is an increasingly prevalent and distinct subphenotype, associated with better outcomes than ARDS > 1 day. Enrollment of patients with rapidly improving ARDS may negatively affect the prognostic enrichment and contribute to the failure of therapeutic trials

Persistent severe acute respiratory distress syndrome for the prognostic enrichment of trials.

BackgroundAcute respiratory distress syndrome (ARDS) is heterogeneous. As an indication of the heterogeneity of ARDS, there are patients whose syndrome improves rapidly (i.e., within 24 hours), others whose hypoxemia improves gradually and still others whose severe hypoxemia persists for several days. The latter group of patients with persistent severe ARDS poses challenges to clinicians. We attempted to assess the baseline characteristics and outcomes of persistent severe ARDS and to identify which variables are useful to predict it.MethodsA secondary analysis of patient-level data from the ALTA, EDEN and SAILS ARDSNet clinical trials was conducted. We defined persistent severe ARDS as a partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2:FiO2) of equal to or less than 100 mmHg on the second study day following enrollment. Regularized logistic regression with an L1 penalty [Least Absolute Shrinkage and Selection Operator (LASSO)] techniques were used to identify predictive variables of persistent severe ARDS.ResultsOf the 1531 individuals with ARDS alive on the second study day after enrollment, 232 (15%) had persistent severe ARDS. Of the latter, 100 (43%) individuals had mild or moderate hypoxemia at baseline. Usage of vasopressors was greater [144/232 (62%) versus 623/1299 (48%); pConclusionsPatients with persistent severe ARDS have distinct baseline characteristics and poor prognosis. Identifying such patients at enrollment may be useful for the prognostic enrichment of trials

Persistent severe acute respiratory distress syndrome for the prognostic enrichment of trials

Background Acute respiratory distress syndrome (ARDS) is heterogeneous. As an indication of the heterogeneity of ARDS, there are patients whose syndrome improves rapidly (i.e., within 24 hours), others whose hypoxemia improves gradually and still others whose severe hypoxemia persists for several days. The latter group of patients with persistent severe ARDS poses challenges to clinicians. We attempted to assess the baseline characteristics and outcomes of persistent severe ARDS and to identify which variables are useful to predict it. Methods A secondary analysis of patient-level data from the ALTA, EDEN and SAILS ARDSNet clinical trials was conducted. We defined persistent severe ARDS as a partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2:FiO(2)) of equal to or less than 100 mmHg on the second study day following enrollment. Regularized logistic regression with an L1 penalty [Least Absolute Shrinkage and Selection Operator (LASSO)] techniques were used to identify predictive variables of persistent severe ARDS. Results Of the 1531 individuals with ARDS alive on the second study day after enrollment, 232 (15%) had persistent severe ARDS. Of the latter, 100 (43%) individuals had mild or moderate hypoxemia at baseline. Usage of vasopressors was greater [144/232 (62%) versus 623/1299 (48%); p< 0.001] and baseline severity of illness was higher in patients with versus without persistent severe ARDS. Mortality at 60 days [95/232 (41%) versus 233/1299 (18%); p< 0.001] was higher, and ventilator-free (p< 0.001), intensive care unit-free [0 (0-14) versus 19 (7-23); p< 0.001] and non-pulmonary organ failure-free [3 (0-21) versus 20 (1-26); p<0.001] days were fewer in patients with versus without persistent severe ARDS. PaO2:FiO(2), FiO(2), hepatic failure and positive end-expiratory pressure at enrollment were useful predictive variables. Conclusions Patients with persistent severe ARDS have distinct baseline characteristics and poor prognosis. Identifying such patients at enrollment may be useful for the prognostic enrichment of trials

Brachytherapy improves outcomes in young men (≤60 years) with prostate cancer: A SEER analysis

PURPOSE—The aim of the study was to compare prostate cancer–specific mortality (PCSM) in young men with clinically localized prostate cancer treated by either external beam radiation (EBRT) alone or brachytherapy with or without external beam radiation. METHODS AND MATERIALS—Utilizing the Surveillance, Epidemiology and End Results database, 15,505 patients ≤60 years of age diagnosed with prostate cancer between 2004 and 2009 and treated with radiation therapy alone were identified. Incidence of PCSM was determined for both groups and compared using competing risk models. RESULTS—The overall 8-year PCSM for the study population was 1.9% (95% confidence interval [CI]: 1.6–2.2). For patients treated with EBRT or brachytherapy with or without external beam, the 8-year PCSM was found to be 2.8% (CI: 2.2–3.4) and 1.2% (CI: 0.9–1.6), respectively (p \u3c 0.001). Univariable analysis demonstrated that brachytherapy was associated with lower PCSM risk (hazard ratio = 0.40; CI: 0.30–0.54; p \u3c 0.001). High Gleason risk category, black race, higher Tumor (T) stage, and higher grade were all associated with greater mortality risk (p \u3c 0.01). On multivariable analysis, brachytherapy continued to be associated with a significantly lower mortality risk (hazard ratio = 0.65; CI: 0.47–0.89;p = 0.008). Subgroup analyses found that among those with Gleason score ≥8, younger patients had increased risk of PCSM (p = 0.001). CONCLUSIONS—In men ≤60 years of age with prostate cancer, radiation therapy continues to offer excellent outcomes. After adjusting for relevant variables, the use of brachytherapy was associated with reduced PCSM compared to treatment with EBRT alone