Steady-state statistical properties and implementation of randomization designs with maximum tolerated imbalance restriction for two-arm equal allocation clinical trials.

In recent decades, several randomization designs have been proposed in the literature as better alternatives to the traditional permuted block design (PBD), providing higher allocation randomness under the same restriction of the maximum tolerated imbalance (MTI). However, PBD remains the most frequently used method for randomizing subjects in clinical trials. This status quo may reflect an inadequate awareness and appreciation of the statistical properties of these randomization designs, and a lack of simple methods for their implementation. This manuscript presents the analytic results of statistical properties for five randomization designs with MTI restriction based on their steady-state probabilities of the treatment imbalance Markov chain and compares them to those of the PBD. A unified framework for randomization sequence generation and real-time on-demand treatment assignment is proposed for the straightforward implementation of randomization algorithms with explicit formulas of conditional allocation probabilities. Topics associated with the evaluation, selection, and implementation of randomization designs are discussed. It is concluded that for two-arm equal allocation trials, several randomization designs offer stronger protection against selection bias than the PBD does, and their implementation is not necessarily more difficult than the implementation of the PBD.

Apixaban to Prevent Recurrence After Cryptogenic Stroke in Patients With Atrial Cardiopathy: The ARCADIA Randomized Clinical Trial.

Importance: Atrial cardiopathy is associated with stroke in the absence of clinically apparent atrial fibrillation. It is unknown whether anticoagulation, which has proven benefit in atrial fibrillation, prevents stroke in patients with atrial cardiopathy and no atrial fibrillation. Objective: To compare anticoagulation vs antiplatelet therapy for secondary stroke prevention in patients with cryptogenic stroke and evidence of atrial cardiopathy. Design, Setting, and Participants: Multicenter, double-blind, phase 3 randomized clinical trial of 1015 participants with cryptogenic stroke and evidence of atrial cardiopathy, defined as P-wave terminal force greater than 5000 µV × ms in electrocardiogram lead V1, serum N-terminal pro-B-type natriuretic peptide level greater than 250 pg/mL, or left atrial diameter index of 3 cm/m2 or greater on echocardiogram. Participants had no evidence of atrial fibrillation at the time of randomization. Enrollment and follow-up occurred from February 1, 2018, through February 28, 2023, at 185 sites in the National Institutes of Health StrokeNet and the Canadian Stroke Consortium. Interventions: Apixaban, 5 mg or 2.5 mg, twice daily (n = 507) vs aspirin, 81 mg, once daily (n = 508). Main Outcomes and Measures: The primary efficacy outcome in a time-to-event analysis was recurrent stroke. All participants, including those diagnosed with atrial fibrillation after randomization, were analyzed according to the groups to which they were randomized. The primary safety outcomes were symptomatic intracranial hemorrhage and other major hemorrhage. Results: With 1015 of the target 1100 participants enrolled and mean follow-up of 1.8 years, the trial was stopped for futility after a planned interim analysis. The mean (SD) age of participants was 68.0 (11.0) years, 54.3% were female, and 87.5% completed the full duration of follow-up. Recurrent stroke occurred in 40 patients in the apixaban group (annualized rate, 4.4%) and 40 patients in the aspirin group (annualized rate, 4.4%) (hazard ratio, 1.00 [95% CI, 0.64-1.55]). Symptomatic intracranial hemorrhage occurred in 0 patients taking apixaban and 7 patients taking aspirin (annualized rate, 1.1%). Other major hemorrhages occurred in 5 patients taking apixaban (annualized rate, 0.7%) and 5 patients taking aspirin (annualized rate, 0.8%) (hazard ratio, 1.02 [95% CI, 0.29-3.52]). Conclusions and Relevance: In patients with cryptogenic stroke and evidence of atrial cardiopathy without atrial fibrillation, apixaban did not significantly reduce recurrent stroke risk compared with aspirin. Trial Registration: ClinicalTrials.gov Identifier: NCT03192215.

Transcranial Direct-Current Stimulation in Subacute Aphasia: A Randomized Controlled Trial.

BACKGROUND: Transcranial direct-current stimulation (tDCS) is a promising adjunct to therapy for chronic aphasia. METHODS: This single-center, randomized, double-blind, sham-controlled efficacy trial tested the hypothesis that anodal tDCS augments language therapy in subacute aphasia. Secondarily, we compared the effect of tDCS on discourse measures and quality of life and compared the effects on naming to previous findings in chronic stroke. Right-handed English speakers with aphasia <3 months after left hemisphere ischemic stroke were included, unless they had prior neurological or psychiatric disease or injury or were taking certain medications (34 excluded; final sample, 58). Participants were randomized 1:1, controlling for age, aphasia type, and severity, to receive 20 minutes of tDCS (1 mA) or sham-tDCS in addition to fifteen 45-minute sessions of naming treatment (plus standard care). The primary outcome variable was change in naming accuracy of untrained pictures pretreatment to 1-week posttreatment. RESULTS: Baseline characteristics were similar between the tDCS (N=30) and sham (N=28) groups: patients were 65 years old, 53% male, and 2 months from stroke onset on average. In intent-to-treat analysis, the adjusted mean change from baseline to 1-week posttreatment in picture naming was 22.3 (95% CI, 13.5-31.2) for tDCS and 18.5 (9.6-27.4) for sham and was not significantly different. Content and efficiency of picture description improved more with tDCS than sham. Groups did not differ in quality of life improvement. No patients were withdrawn due to adverse events. CONCLUSIONS: tDCS did not improve recovery of picture naming but did improve recovery of discourse. Discourse skills are critical to participation. Future research should examine tDCS in a larger sample with richer functional outcomes. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02674490.

Optimal Randomization Designs for Large Multicenter Clinical Trials: From the National Institutes of Health Stroke Trials Network Funded by National Institutes of Health/National Institute of Neurological Disorders and Stroke Experience.

From 2016 to 2021, the National Institutes of Health Stroke Trials Network funded by National Institutes of Health/National Institute of Neurological Disorders and Stroke initiated ten multicenter randomized controlled clinical trials. Optimal subject randomization designs are demanded with 4 critical properties: (1) protection of treatment assignment randomness, (2) achievement of the desired treatment allocation ratio, (3) balancing of baseline covariates, and (4) ease of implementation. For acute stroke trials, it is necessary to minimize the time between eligibility assessment and treatment initiation. This article reviews the randomization designs for 3 trials currently enrolling in Stroke Trials Network funded by National Institutes of Health/National Institute of Neurological Disorders and Stroke, the SATURN (Statins in Intracerebral Hemorrhage Trial), the MOST (Multiarm Optimization of Stroke Thrombolysis Trial), and the FASTEST (Recombinant Factor VIIa for Hemorrhagic Stroke Trial). Randomization methods utilized in these trials include minimal sufficient balance, block urn design, big stick design, and step-forward randomization. Their advantages and limitations are reviewed and compared with traditional stratified permuted block design and minimization.

Effect of Cilostazol in Animal Models of Cerebral Ischemia and Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis.

BACKGROUND: Cilostazol, a phosphodiesterase III inhibitor, appears to be a promising agent for preventing cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage. Here, the authors perform a systematic review and meta-analysis to quantitatively assess the effects of cilostazol on brain structural and functional outcomes in animal models of cerebral ischemia and subarachnoid hemorrhage-induced cerebral vasospasm. METHODS: By using the PRISMA guidelines, a search of the PubMed, Scopus, and Web of Science was conducted to identify relevant studies. Study quality of each included study for both systematic reviews were scored by using an adapted 15-item checklist from the Collaborative Approach to Meta-Analysis of Animal Data from Experimental Studies. We calculated a standardized mean difference as effect size for each comparison. For each outcome, comparisons were combined by using random-effects modeling to account for heterogeneity, with a restricted maximum likelihood estimate of between-study variance. RESULTS: A total of 22 (median [Q1, Q3] quality score of 7 [5, 8]) and 6 (median [Q1, Q3] quality score of 6 [6, 6]) studies were identified for cerebral ischemia and subarachnoid hemorrhage-induced cerebral vasospasm, respectively. Cilostazol significantly reduced the infarct volume in cerebral ischemia models with a pooled standardized mean difference estimate of - 0.88 (95% confidence interval [CI] [- 1.07 to - 0.70], p < 0.0001). Cilostazol significantly reduced neurofunctional deficits in cerebral ischemia models with a pooled standardized mean difference estimate of - 0.66 (95% CI [- 1.06 to - 0.28], p < 0.0001). Cilostazol significantly improved the basilar artery diameter in subarachnoid hemorrhage-induced cerebral vasospasm with a pooled standardized mean difference estimate of 2.30 (95% CI [0.94 to 3.67], p = 0.001). Cilostazol also significantly improved the basilar artery cross-section area with a pooled standardized mean estimate of 1.88 (95% CI [0.33 to 3.43], p < 0.05). Overall, there was between-study heterogeneity and asymmetry in the funnel plot observed in all comparisons. CONCLUSIONS: Published animal data support the overall efficacy of cilostazol in reducing infarct volume and neurofunctional deficits in cerebral ischemia models and cerebral vasospasm in subarachnoid hemorrhage models.

Lessons Learned from Phase II and Phase III Trials Investigating Therapeutic Agents for Cerebral Ischemia Associated with Aneurysmal Subarachnoid Hemorrhage.

One of the challenges in bringing new therapeutic agents (since nimodipine) in for the treatment of cerebral ischemia associated with aneurysmal subarachnoid hemorrhage (aSAH) is the incongruence in therapeutic benefit observed between phase II and subsequent phase III clinical trials. Therefore, identifying areas for improvement in the methodology and interpretation of results is necessary to increase the value of phase II trials. We performed a systematic review of phase II trials that continued into phase III trials, evaluating a therapeutic agent for the treatment of cerebral ischemia associated with aSAH. We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines for systematic reviews, and review was based on a peer-reviewed protocol (International Prospective Register of Systematic Reviews no. 222965). A total of nine phase III trials involving 7,088 patients were performed based on eight phase II trials involving 1558 patients. The following therapeutic agents were evaluated in the selected phase II and phase III trials: intravenous tirilazad, intravenous nicardipine, intravenous clazosentan, intravenous magnesium, oral statins, and intraventricular nimodipine. Shortcomings in several design elements of the phase II aSAH trials were identified that may explain the incongruence between phase II and phase III trial results. We suggest the consideration of the following strategies to improve phase II design: increased focus on the selection of surrogate markers of efficacy, selection of the optimal dose and timing of intervention, adjustment for exaggerated estimate of treatment effect in sample size calculations, use of prespecified go/no-go criteria using futility design, use of multicenter design, enrichment of the study population, use of concurrent control or placebo group, and use of innovative trial designs such as seamless phase II to III design. Modifying the design of phase II trials on the basis of lessons learned from previous phase II and phase III trial combinations is necessary to plan more effective phase III trials.

Intensive Blood Pressure Lowering and DWI Lesions in Intracerebral Hemorrhage: Exploratory Analysis of the ATACH-2 Randomized Trial.

BACKGROUND: With the increasing use of magnetic resonance imaging in the assessment of acute intracerebral hemorrhage, diffusion-weighted imaging hyperintense lesions have been recognized to occur at sites remote to the hematoma in up to 40% of patients. We investigated whether blood pressure reduction was associated with diffusion-weighted imaging hyperintense lesions in acute intracerebral hemorrhage and whether such lesions are associated with worse clinical outcomes by analyzing imaging data from a randomized trial. METHODS: We performed exploratory subgroup analyses in an open-label randomized trial that investigated acute blood pressure lowering in 1000 patients with intracerebral hemorrhage between May 2011 and September 2015. Eligible participants were assigned to an intensive systolic blood pressure target of 110-139 mm Hg versus 140-179 mm Hg with the use of intravenous nicardipine. Of these, 171 patients had requisite magnetic resonance imaging sequences for inclusion in these subgroup analyses. The primary outcome was the presence of diffusion-weighted imaging hyperintense lesions. Secondary outcomes included death or disability and serious adverse event at 90 days. RESULTS: Diffusion-weighted imaging hyperintense lesions were present in 25% of patients (mean age 62 years). Hematoma volume > 30 cm3 was an adjusted predictor (adjusted relative risk 2.41, 95% confidence interval 1.00-5.80) of lesion presence. Lesions occurred in 25% of intensively treated patients and 24% of standard treatment patients (relative risk 1.01, 95% confidence interval 0.71-1.43, p = 0.97). Patients with diffusion-weighted imaging hyperintense lesions had similar frequencies of death or disability at 90 days, compared with patients without lesions. CONCLUSIONS: Randomized assignment to intensive acute blood pressure lowering did not result in a greater frequency of diffusion-weighted imaging hyperintense lesion. Alternative mechanisms of diffusion-weighted imaging hyperintense lesion formation other than hemodynamic fluctuations need to be explored. Clinical trial registration ClinicalTrials.gov (Ref. NCT01176565; https://clinicaltrials.gov/ct2/show/NCT01176565 ).

The Revised Hearing Handicap Inventory and Screening Tool Based on Psychometric Reevaluation of the Hearing Handicap Inventories for the Elderly and Adults.

OBJECTIVES: The present study evaluates the items of the Hearing Handicap Inventory for the Elderly and Hearing Handicap Inventory for Adults (HHIE/A) using Mokken scale analysis (MSA), a type of nonparametric item response theory, and develops updated tools with optimal psychometric properties. DESIGN: In a longitudinal study of age-related hearing loss, 1447 adults completed the HHIE/A and audiometric testing at baseline. Discriminant validity of the emotional consequences and social/situational effects subscales of the HHIE/A was assessed, and nonparametric item response theory was used to explore dimensionality of the items of the HHIE/A and to refine the scales. RESULTS: The HHIE/A items form strong unidimensional scales measuring self-perceived hearing handicap, but with a lack of discriminant validity of the two distinct subscales. Two revised scales, the 18-item Revised Hearing Handicap Inventory and the 10-item Revised Hearing Handicap Inventory-Screening, were developed from the common items of the original HHIE/A that met the assumptions of MSA. The items on both of the revised scales can be ordered in terms of increasing difficulty. CONCLUSIONS: The results of the present study suggest that the newly developed Revised Hearing Handicap Inventory and Revised Hearing Handicap Inventory-Screening are strong unidimensional, clinically informative measures of self-perceived hearing handicap that can be used for adults of all ages. The real-data example also demonstrates that MSA is a valuable alternative to classical psychometric analysis.

White Matter Hyperintensities and Blood Pressure Lowering in Acute Intracerebral Hemorrhage: A Secondary Analysis of the ATACH-2 Trial.

BACKGROUND: It is not clear whether subsets of patients with intracerebral hemorrhage (ICH) benefit from intensive blood pressure (BP) lowering. We evaluated whether white matter hyperintensities (WMH) burden influences response to this therapy. METHODS: Retrospective secondary analysis of the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 trial. Patients were randomized to intensive (systolic BP target: 110-139 mmHg) versus standard (systolic BP target: 140-179 mmHg) BP treatment with intravenous nicardipine within 4.5 h from onset between May 2011 and September 2015. WMH were rated on magnetic resonance images (fluid-attenuated inversion recovery sequences), defining moderate-severe WMH as total Fazekas scale score ≥ 3 (range 0-6). The main outcome was death or major disability at 90 days (modified Rankin scale ≥ 3). The secondary outcome was ICH expansion, defined as hematoma growth > 33% from baseline to follow-up CT scan. Predictors of the outcomes of interest were explored with multivariable logistic regression. RESULTS: A total of 195/1000 patients had MRI images available for analysis, of whom 161 (82.6%) had moderate-severe WMH. When compared to patients with none-mild WMH, those with moderate-severe WMH did not have an increased risk of death or major disability (adjusted relative risk: 1.83, 95% CI 0.71-4.69) or ICH expansion (adjusted relative risk: 1.14, 95% CI 0.38-3.37). WMH burden did not modify the effect of intensive BP treatment on outcome (all p for interaction ≥ 0.2). CONCLUSION: The majority of acute ICH patients have moderate-severe WMH, but advanced small vessel disease burden marked by WMH does not influence ICH-related outcomes or response to intensive BP reduction.

Time From Hearing Aid Candidacy to Hearing Aid Adoption: A Longitudinal Cohort Study.

OBJECTIVES: Although many individuals with hearing loss could benefit from intervention with hearing aids, many do not seek or delay seeking timely treatment after the onset of hearing loss. There is limited data-based evidence estimating the delay in adoption of hearing aids with anecdotal estimates ranging from 5 to 20 years. The present longitudinal study is the first to assess time from hearing aid candidacy to adoption in a 28-year ongoing prospective cohort of older adults, with the additional goal of determining factors influencing delays in hearing aid adoption, and self-reported successful use of hearing aids. DESIGN: As part of a longitudinal study of age-related hearing loss, a wide range of demographic, biologic, and auditory measures are obtained yearly or every 2 to 3 years from a large sample of adults, along with family, medical, hearing, noise exposure, and hearing aid use histories. From all eligible participants (age ≥18; N = 1530), 857 were identified as hearing aid candidates either at baseline or during their participation, using audiometric criteria. Longitudinal data were used to track transition to hearing aid candidacy and hearing aid adoption. Demographic and hearing-related characteristics were compared between hearing aid adopters and nonadopters. Unadjusted estimated overall time (in years) to hearing aid adoption and estimated delay times were stratified by demographic and hearing-related factors and were determined using a time-to-event analysis (survival analysis). Factors influencing rate of adoption in any given time period were examined along with factors influencing successful hearing aid adoption. RESULTS: Age, number of chronic health conditions, sex, retirement status, and education level did not differ significantly between hearing aid adopters and nonadopters. In contrast, adopters were more likely than nonadopters to be married, of white race, have higher socioeconomic status, have significantly poorer higher frequency (2.0, 3.0, 4.0, 6.0, and 8.0 kHz) pure-tone averages, poorer word recognition in quiet and competing multi-talker babble, and reported more hearing handicap on the Hearing Handicap Inventory for the Elderly/Adults emotional and social subscales. Unadjusted estimation of time from hearing aid candidacy to adoption in the full participant cohort was 8.9 years (SE ± 0.37; interquartile range = 3.2-14.9 years) with statistically significant stratification for race, hearing as measured by low- and high-frequency pure-tone averages, keyword recognition in low-context sentences in babble, and the Hearing Handicap Inventory for the Elderly/Adults social score. In a subgroup analysis of the 213 individuals who adopted hearing aids and were assigned a success classification, 78.4% were successful. No significant predictors of success were found. CONCLUSIONS: The average delay in adopting hearing aids after hearing aid candidacy was 8.9 years. Nonwhite race and better speech recognition (in a more difficult task) significantly increased the delay to treatment. Poorer hearing and more self-assessed hearing handicap in social situations significantly decreased the delay to treatment. These results confirm the assumption that adults with hearing loss significantly delay seeking treatment with hearing aids.

Treatment effect on ordinal functional outcome using piecewise multistate Markov model with unobservable baseline: an application to the modified Rankin scale.

In clinical trials, longitudinally assessed ordinal outcomes are commonly dichotomized and only the final measure is used for primary analysis, partly for ease of clinical interpretation. Dichotomization of the ordinal scale and failure to utilize the repeated measures can reduce statistical power. Additionally, in certain emergent settings, the same measure cannot be assessed at baseline prior to treatment. For such a data set, a piecewise-constant multistate Markov model that incorporates a latent model for the unobserved baseline measure is proposed. These models can be useful in analyzing disease history data and are advantageous in clinical applications where a disease process naturally moves through increasing stages of severity. Two examples are provided using acute stroke clinical trials data. Conclusions drawn in this article are consistent with those from the primary analysis for treatment effect in both of the motivating examples. Use of these models allows for a more refined examination of treatment effect and describes the movement between health states from baseline to follow-up visits which may provide more clinical insight into the treatment effect.

Phantom-based standardization of CT angiography images for spot sign detection.

PURPOSE: The CT angiography (CTA) spot sign is a strong predictor of hematoma expansion in intracerebral hemorrhage (ICH). However, CTA parameters vary widely across centers and may negatively impact spot sign accuracy in predicting ICH expansion. We developed a CT iodine calibration phantom that was scanned at different institutions in a large multicenter ICH clinical trial to determine the effect of image standardization on spot sign detection and performance. METHODS: A custom phantom containing known concentrations of iodine was designed and scanned using the stroke CT protocol at each institution. Custom software was developed to read the CT volume datasets and calculate the Hounsfield unit as a function of iodine concentration for each phantom scan. CTA images obtained within 8 h from symptom onset were analyzed by two trained readers comparing the calibrated vs. uncalibrated density cutoffs for spot sign identification. ICH expansion was defined as hematoma volume growth >33%. RESULTS: A total of 90 subjects qualified for the study, of whom 17/83 (20.5%) experienced ICH expansion. The number of spot sign positive scans was higher in the calibrated analysis (67.8 vs 38.9% p < 0.001). All spot signs identified in the non-calibrated analysis remained positive after calibration. Calibrated CTA images had higher sensitivity for ICH expansion (76 vs 52%) but inferior specificity (35 vs 63%) compared with uncalibrated images. CONCLUSION: Normalization of CTA images using phantom data is a feasible strategy to obtain consistent image quantification for spot sign analysis across different sites and may improve sensitivity for identification of ICH expansion.

Postprandial Clearance of Oxidized Low-Density Lipoprotein in Patients with Stroke Due to Atherosclerosis.

BACKGROUND: Oxidized low-density lipoprotein (OxLDL) is a contributor to atherosclerosis development. OxLDL formation increases in the postprandial state due to oxidative stress in subjects with coronary artery disease (CAD) and diabetes, but has not been studied in patients with atherosclerotic stroke. We aimed to determine differences in postprandial OxLDL in patients with atherosclerotic stroke compared to stroke from other causes. METHODS: Patients with ischemic stroke but no history of CAD (n = 42) were enrolled and categorized by stroke subtype as extracranial atherosclerosis (EC), n = 12; intracranial atherosclerosis (IC), n = 16; or other cause, n = 14. After fasting overnight, subjects consumed a standardized fat meal. OxLDL levels were measured at t = 0 and t = 4 hours postprandial using enzyme-linked immunosorbent assay. Comparisons between the mean changes in OxLDL between the groups were performed using the analysis of variance procedure. RESULTS: The IC group had the highest mean baseline level of OxLDL and the greatest decline during the postprandial period. There was a trend toward a difference in the mean change in OxLDL between the 3 groups (P = .0553). Subjects with atherosclerotic stroke (EC and IC groups) had higher fasting OxLDL and had a significant decline in OxLDL compared to those with stroke from other causes (P = .0164). CONCLUSIONS: Subjects with stroke due to atherosclerosis, particularly intracranially, demonstrated high fasting OxLDL and a decline in OxLDL during the postprandial period. This decline in OxLDL may indicate an accelerated clearance of OxLDL resulting from meal-induced oxidative stress.

Individual Differences in Response to Transcranial Direct Current Stimulation With Language Therapy in Subacute Stroke.

BACKGROUND: Transcranial direct current stimulation (tDCS) can be used to improve post-stroke aphasia. However, given the mixed evidence for its efficacy, individual differences may moderate the relative benefit of this strategy. In planned exploratory subgroup analyses, we examined whether age, education, sex, brain-derived neurotrophic factor status, and baseline performance individually impacted improvement in picture naming between baseline and 1 week after the end of the therapy, then whether the combination of factors that predicted recovery of naming and discourse differed for those who received concurrent tDCS. OBJECTIVE: Examine whether individual differences influenced the effect of tDCS on language recovery. METHODS: In this randomized, double-blind, sham-controlled, efficacy study of tDCS combined with language therapy for subacute post-stroke aphasia, patients completed an evaluation including the Philadelphia Naming Test and Cookie Theft picture description, which was analyzed for Content Units (CU) and Syllables/CU. Individual factors were examined using linear models including the interaction between treatment group and subgroup. RESULTS: Significant interactions were observed between tDCS group and both age and education. The predictors of a positive response to tDCS differed from the predictors of a positive response to language treatment alone. While baseline performance was an important predictor of future performance regardless of treatment group, responses to treatment without tDCS were influenced by age whereas responses to treatment with tDCS were not. CONCLUSIONS: Age and education influence the efficacy of different treatment strategies. Refinement of treatment selection is important to the overall individualization and optimization of post-stroke patient care. TRIAL REGISTRATION: ClinicalTrials.gov NCT02674490.

Predicting Outcomes of Language Rehabilitation: Prognostic Factors for Immediate and Long-Term Outcomes After Aphasia Therapy.

BACKGROUND: Aphasia therapy is an effective approach to improve language function in chronic aphasia. However, it remains unclear what prognostic factors facilitate therapy response at the individual level. Here, we utilized data from the POLAR (Predicting Outcomes of Language Rehabilitation in Aphasia) trial to (a) determine therapy-induced change in confrontation naming and long-term maintenance of naming gains and (b) examine the extent to which aphasia severity, age, education, time postonset, and cognitive reserve predict naming gains at 1 week, 1 month, and 6 months posttherapy. METHOD: A total of 107 participants with chronic (≥ 12 months poststroke) aphasia underwent extensive case history, cognitive-linguistic testing, and a neuroimaging workup prior to receiving 6 weeks of impairment-based language therapy. Therapy-induced change in naming performance (measured as raw change on the 175-item Philadelphia Naming Test [PNT]) was assessed 1 week after therapy and at follow-up time points 1 month and 6 months after therapy completion. Change in naming performance over time was evaluated using paired t tests, and linear mixed-effects models were constructed to examine the association between prognostic factors and therapy outcomes. RESULTS: Naming performance was improved by 5.9 PNT items (Cohen's d = 0.56, p < .001) 1 week after therapy and by 6.4 (d = 0.66, p < .001) and 7.5 (d = 0.65, p < .001) PNT items at 1 month and 6 months after therapy completion, respectively. Aphasia severity emerged as the strongest predictor of naming improvement recovery across time points; mild (ß = 5.85-9.02) and moderate (ß = 9.65-11.54) impairment predicted better recovery than severe (ß = 1.31-3.37) and very severe (ß = 0.20-0.32) aphasia. Age was an emergent prognostic factor for recovery 1 month (ß = -0.14) and 6 months (ß = -0.20) after therapy, and time postonset (ß = -0.05) was associated with retention of naming gains at 6 months posttherapy. CONCLUSIONS: These results suggest that therapy-induced naming improvement is predictable based on several easily measurable prognostic factors. Broadly speaking, these results suggest that prognostication procedures in aphasia therapy can be improved and indicate that personalization of therapy is a realistic goal in the near future. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.22141829.

Family history of alcohol dependence and antidepressant response to an N-methyl-D-aspartate antagonist in bipolar depression.

OBJECTIVES: Both ketamine and ethanol are N-methyl-d-aspartate (NMDA) receptor antagonists. Ketamine has rapid antidepressant properties in major depressive disorder (MDD) as well as bipolar depression. In individuals with MDD, a positive family history of alcohol dependence (FHP) was associated with greater improvement in depressive symptoms after ketamine administration compared to individuals whose family history of alcohol dependence was negative (FHN). This study investigated whether FHP influences ketamine's antidepressant and perceptual effects in individuals with bipolar depression. METHODS: A post hoc analysis was conducted on 33 subjects with DSM-IV bipolar disorder (BD) type I or II depression pooled from two previously published studies. All subjects had undergone a double-blind, randomized, crossover trial of a single intravenous infusion of ketamine (0.5 mg/kg) combined with lithium or valproate therapy. Subjects were rated at baseline; at 40, 80, 120, and 230 min; and at days 1, 2, 3, 7, 10, and 14 post-infusion. The primary outcome measure was Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Patients were categorized as FHP when they reported at least one first-degree relative with alcohol dependence. Measures of psychosis, dissociation, and dysphoria were also collected. RESULTS: After ketamine infusion, subjects with FHP showed significantly greater improvement on MADRS scores than FHN subjects. In addition, patients with FHP had attenuated psychotomimetic and dissociative scores compared to FHN patients. CONCLUSIONS: FHP appears to predict a more sustained antidepressant response to ketamine in individuals with BD. Family history of alcoholism may be an important consideration in the development of glutamatergic-based therapies for depression.

Interpreting a Bayesian phase II futility clinical trial.

BACKGROUND: A resurgence of research into phase II trial design in the mid-2000s led to the use of futility designs in a wide variety of disease areas. Phase II futility studies differ from efficacy studies in that their null hypothesis is that treatment, relative to control, does not meet or exceed the level of benefit required to justify additional study. A rejection of the null hypothesis indicates that the treatment should not proceed to a larger confirmatory trial. METHODS: Bayesian approaches to the design of phase II futility clinical trials are presented and allow for the quantification of key probabilities, such as the predictive probability of current trial success or even the predictive probability of a future trial's success. RESULTS: We provide an illustration of the design and interpretation of a phase II futility study constructed in a Bayesian framework. We focus on the operating characteristics of our motivating trial based on a simulation study, as well as the general interpretation of trial outcomes, type I, and type II errors in this framework. CONCLUSIONS: Phase II futility clinical trials, when designed under in a Bayesian framework, offer an alternative approach to the design of mid-phase studies which provide unique benefits relative to trials designed in a frequentist framework and designs which focus on treatment efficacy.

Speech Entrainment for Aphasia Recovery (SpARc) phase II trial design.

BACKGROUND: and purpose: Speech entrainment therapy (SET) is a computerized therapeutic approach that involves mimicking an audiovisual speech model to improve speech production. In a pilot study using SET for treatment of post-stroke non-fluent aphasia, significant gains were achieved in verbs per minute (VPM) during discourse using untrained items 1 and 6 weeks after treatment, suggesting that SET may yield meaningful improvements in fluent spontaneous speech for individuals with non-fluent aphasia. METHODS: The Speech Entrainment for Aphasia Recovery (SpARc) trial is a prospective, randomized, assessor-blinded, multicenter phase II clinical trial studying persons with chronic post-stroke non-fluent aphasia. Participants will be randomized to 3 weeks, 4.5 weeks, or 6 weeks of SET delivered via telehealth or a no SET control condition for 6 weeks. 80 adults (ages 21-81) with history of left hemisphere ischemic or hemorrhagic stroke with residual chronic (>6 months post stroke) non-fluent aphasia diagnosed by the Western Aphasia Battery-Revised (WAB-R) will be randomized (1:1:1:1) over 4 years. The trial will be conducted at the clinical research facilities at three sites: the Medical University of South Carolina, the University of South Carolina, and the University of Utah. CONCLUSIONS: This paper details the trial design of the SpARc trial, which aims to determine the dose of SET that will generate the highest effect size on speech fluency, VPM, sustained at 3 months post-treatment compared to a no SET control arm, for individuals with chronic post-stroke non-fluent aphasia to permit a future definitive trial to test the clinical utility of SET.

Individualized response to semantic versus phonological aphasia therapies in stroke.

Attempts to personalize aphasia treatment to the extent where it is possible to reliably predict individual response to a particular treatment have yielded inconclusive results. The current study aimed to (i) compare the effects of phonologically versus semantically focussed naming treatment and (ii) examine biographical and neuropsychological baseline factors predictive of response to each treatment. One hundred and four individuals with chronic post-stroke aphasia underwent 3 weeks of phonologically focussed treatment and 3 weeks of semantically focussed treatment in an unblinded cross-over design. A linear mixed-effects model was used to compare the effects of treatment type on proportional change in correct naming across groups. Correlational analysis and stepwise regression models were used to examine biographical and neuropsychological predictors of response to phonological and semantic treatment across all participants. Last, chi-square tests were used to explore the association between treatment response and phonological and semantic deficit profiles. Semantically focussed treatment was found to be more effective at the group-level, independently of treatment order (P = 0.041). Overall, milder speech and language impairment predicted good response to semantic treatment (r range: 0.256-0.373) across neuropsychological tasks. The Western Aphasia Battery-Revised Spontaneous Speech score emerged as the strongest predictor of semantic treatment response (R 2 = 0.188). Severity of stroke symptoms emerged as the strongest predictor of phonological treatment response (R 2 = 0.103). Participants who showed a good response to semantic treatment were more likely to present with fluent speech compared to poor responders (P = 0.005), whereas participants who showed a good response to phonological treatment were more likely to present with apraxia of speech (P = 0.020). These results suggest that semantic treatment may be more beneficial to the improvement of naming performance in aphasia than phonological treatment, at the group-level. In terms of personalized predictors, participants with relatively mild impairments and fluent speech responded better to semantic treatment, while phonological treatment benefitted participants with more severe impairments and apraxia of speech.

Reliability of an Automated Computerized Hematoma Volumetric Analysis Protocol in Patients with Chronic Subdural Hemorrhage.

BACKGROUND: Hematoma volume in chronic subdural hematoma (CSDH) may predict neurologic deterioration and need for surgical evacuation. Several computer software-assisted methods exist for accurate volume measurements of intracerebral hemorrhage, but no reliable method has been identified for measurement of CSDH volume. METHODS: A total of 30 consecutive patients with CSDH from 2018-2019 admitted to our institution were selected. The noncontrast computed tomography head studies were reviewed by 2 residents. The region of interest method on a Horos Open Source Medical Image Viewer (version 3.3.6) was utilized for volume measurement by each resident (resident-1 and resident-2) independently. Resident-1 repeated the protocol on the same studies 1 month later. We calculated the intra- and interobserver reliability of hematoma volume measurements using the Bland-Altman method. RESULTS: Mean age of the patients was 79 years (range, 50-92 years). For interobserver analysis, resident-1 mean hematoma volume was 85.46 cm3 (range, 6.40-178.63 cm3) and was 87.15 cm3 (range, 8.79-165.97 cm3) for resident-2. The Bland-Altman coefficient of variation was 13.15% (range, 0.07%-46.29%, 97% within the limits of acceptance). For intraobserver analysis, the initial average volume measured by resident-1 was 85.46 cm3 (range, 6.40-178.63 cm3) and subsequent was 95.26 cm3 (range, 10.48-182.99 cm3). The Bland-Altman coefficient of variation was 13.76% (range, 0.81%-48.34%, 97% within the limits of acceptance). CONCLUSIONS: We are reporting inter- and intraobserver reliability for a novel volumetric analysis of CSDH volume using Horos Medical Image Viewer region of interest generated volume calculation. This method is accurate and efficient and could have important clinical and research implications for risk stratification.