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Background The enrollment into clinical trials of persons at risk for autosomal dominant Alzheimer’s disease (ADAD) in whom the onset of disease can be accurately predicted facilitates the interpretation of outcomes (e.g., biomarkers, treatment efficacy). Attitudes toward involvement in such studies are biased by intrinsic cultural and social characteristics. Our objective was to study how demographic factors such as country of residence, age, sex, schooling, parenthood, and urbanization affect attitudes towards participation in hypothetical clinical trials in Mexican families at risk for ADAD living either in Mexico or in the United States. Methods Participants were 74 members of different families known to harbor an ADAD mutation living in Mexico ( n = 50) or in the United States ( n = 24). Participants were asked, in a written questionnaire, their interest in participating in four hypothetical clinical trial scenarios of increasing perceived invasiveness. The questionnaire then asked about their willingness should there be a 50% chance of being assigned to a placebo group. The influences of demographic variables on decisions were performed using Wilcoxon rank-sum for continuous variables and Fisher’s exact test for categorical variables. Results Participants who live in Mexico, who have or plan to have children, who do not attend or do not plan to attend school, and who live in rural areas gave more positive responses regarding their willingness to participate compared to those living in the U.S. The 50% chance of being in a placebo group increased the willingness to participate for family members living in Mexico. The main reason for participation was to help future generations, while the main reasons for refusal were not wanting to undergo genetic testing and consideration of adverse effects. Conclusions We found a higher level of willingness to participate in clinical trials among persons living in rural Mexico and our data suggest that altruism towards future generations is a major motivation, though this was balanced against concerns regarding side effects. Our results emphasize the importance of sharing information and assessing its understanding in potential participants with diverse backgrounds in the nature of ADAD and regarding the design of clinical trials prior to their enrollment in such studies.

Background Recruiting to multi-site trials is challenging, particularly when striving to ensure the randomized sample is demographically representative of the larger disease-suffering population. While previous studies have reported disparities by race and ethnicity in enrollment and randomization, they have not typically investigated whether disparities exist in the recruitment process prior to consent. To identify participants most likely to be eligible for a trial, study sites frequently include a prescreening process, generally conducted by telephone, to conserve resources. Collection and analysis of such prescreening data across sites could provide valuable information to improve understanding of recruitment intervention effectiveness, including whether traditionally underrepresented participants are lost prior to screening. Methods We developed an infrastructure within the National Institute on Aging (NIA) Alzheimer’s Clinical Trials Consortium (ACTC) to centrally collect a subset of prescreening variables. Prior to study-wide implementation in the AHEAD 3–45 study (NCT NCT04468659), an ongoing ACTC trial recruiting older cognitively unimpaired participants, we completed a vanguard phase with seven study sites. Variables collected included age, self-reported sex, self-reported race, self-reported ethnicity, self-reported education, self-reported occupation, zip code, recruitment source, prescreening eligibility status, reason for prescreen ineligibility, and the AHEAD 3–45 participant ID for those who continued to an in-person screening visit after study enrollment. Results Each of the sites was able to submit prescreening data. Vanguard sites provided prescreening data on a total of 1029 participants. The total number of prescreened participants varied widely among sites (range 3–611), with the differences driven mainly by the time to receive site approval for the main study. Key learnings instructed design/informatic/procedural changes prior to study-wide launch. Conclusion Centralized capture of prescreening data in multi-site clinical trials is feasible. Identifying and quantifying the impact of central and site recruitment activities, prior to participants signing consent, has the potential to identify and address selection bias, instruct resource use, contribute to effective trial design, and accelerate trial enrollment timelines.

Background and Purpose: Previous studies have found mortality among ischemic stroke patients to be higher on weekends. We sought to evaluate whether weekend admission was associated with worse outcomes in a large comprehensive stroke center (CSC) cohort. Methods: Consecutive ischemic stroke patients presenting within 6 h of symptom onset were identified using the 8 CSC SPOTRIAS (Specialized Programs of Translational Research in Acute Stroke) database. Patients who received intra-arterial therapy or who were enrolled in a nonobservational clinical trial were excluded. All patients meeting the inclusion criteria were then divided into two groups: weekday admissions or weekend admissions. Weekend admission was defined as Friday 17:01 to Monday 08:59. The remainder were classified as weekday admissions. Multivariate logistic regression was used, adjusting for age, stroke severity on admission [according to the National Institutes of Health Stroke Scale (NIHSS)] and admission glucose, in order to compare the outcomes of the weekend versus the weekday groups. Results: Eight thousand five hundred and eighty-one subjects from the combined SPOTRIAS database were screened from 2002 to 2009; 2,090 (24.4%) of these met the inclusion criteria. There was no significant difference in tissue plasminogen activator treatment rates between the weekday and weekend groups (58.5 vs. 60.4%, p = 0.397). Weekend admission was not a significant independent predictor of inhospital mortality (8.4 vs. 9.9%, p = 0.056), length of stay (4 vs. 5 days, p = 0.442), favorable discharge disposition (38.0 vs. 42.2%, p = 0.122), favorable functional outcome at discharge (41.6 vs. 43.4%, p = 0.805), favorable 90-day functional outcome (54.2 vs. 46.9%, p = 0.301), or 90-day mortality (18.2 vs. 19.8%, p = 0.680) when adjusting for age, NIHSS and admission glucose. Conclusions: In this large cohort of ischemic stroke patients treated at CSCs, we did not observe the ‘weekend effect.’ This may be due to access to stroke specialists 24 h a day on 365 days a year, nurses with stroke experience and the organized system for delivering care that is available at CSCs. These results suggest that EMS protocol should be reexamined regarding the preferential delivery of weekend stroke victims to hospitals that provide all levels of reperfusion therapy. This further highlights the importance of organized stroke care.

INTRODUCTION The long‐term implications of disclosing Alzheimer's disease (AD) biomarker information to cognitively unimpaired individuals are unknown. METHODS We compared participants who disclosed their elevated amyloid imaging result in a preclinical AD trial to those who disclosed a not elevated result and enrolled in an observational cohort that underwent parallel assessments. Our primary outcome was a score > 0 on the Columbia Suicidality Severity Rating Scale (CSSRS) at any visit; we also considered suicidal behaviors (CSSRS > 5). RESULTS Among 1707 total participants (68% elevated amyloid, mean [standard deviation] age 71.5 [4.7], 60% female, 90% non‐Hispanic White), followed for a mean 218 (74.1) weeks, there were no suicides and few indications of suicidal thoughts (n = 124 [7%]) or behaviors (n = 13 [<1%]). In a generalized estimating equation model controlling for covariates, we observed no effect of amyloid status on the primary outcome of CSSRS > 0 (odds ratio = 1.6, 95% confidence interval = 0.76, 3.37). DISCUSSION With a structured approach, brain amyloid results can be returned safely. Highlights The Anti‐Amyloid Treatment in Asymptomatic Alzheimer's study was among the first and largest studies to include biomarker disclosure in a population without cognitive impairment. Routine psychological assessment provided a novel assessment of the impact of disclosure in this sample. Learning an elevated brain amyloid result through a protocolized approach was not associated with suicidal thoughts or behaviors compared to a matched cohort who learned they did not have elevated brain amyloid. Future research will be needed to ensure similar safety in more real‐world settings.

ObjectivesTo confirm that levetiracetam (LEV) demonstrates predictable pharmacokinetics(PK) at higher doses and to study the pharmacodynamics(PD) of LEV.DesignPharmacokinetic data from the NEOLEV1 and NEOLEV2 trials were analysed using a non-linear mixed effects modelling approach. A post hoc analysis of the effect of LEV on seizure burden was conducted.SettingNeonatal intensive care unit.PatientsTerm neonates with electrographically confirmed seizures.InterventionsIn NEOLEV1, neonates with seizures persisting following phenobarbital (PHB) received LEV 20 or 40 mg/kg bolus followed by 5 or 10 mg/kg maintenance dose(MD) daily. In NEOLEV2, patients received a 40 mg/kg intravenous LEV load, followed by 10 mg/kg doses 8 hourly. If seizures persisted, a further 20 mg/kg intravenous load was given. If seizures persisted, PHB was given. PK data were collected from 16 NEOLEV1 patients and 33 NEOLEV2 patients. cEEG data from 48 NEOLEV2 patients were analysed to investigate onset of action and seizure burden reduction.Main outcome measuresClearance (CL) and volume of distribution (Vd) were determined. Covariates that significantly affected LEV disposition were identified.ResultsPrimary outcome: The median initial LEV level was 57 µg/mL (range 19–107) after the first loading dose and at least 12 µg/mL at 48 hours in all infants. CL and Vd were estimated to be 0.0538 L/hour and 0.832 L, respectively. A direct relationship between postnatal age and CL was observed. The final population pharmacokinetic(PopPK) model described the observed data well without significant biases. CL and Vd were described as CL (L/hour)=0.0538×(weight in kg/3.34)0.75×(postnatal age in days/5.5) 0.402 and Vd (L)=0.832×(weight in kg/3.34).Seizure burden reduced within 30 min of LEV administration. 28% of patients were completely seizure free after LEV. In an additional 25% of patients, seizure burden reduced by 50%.ConclusionsLEV pharmacokinetics remained predictable at higher doses. Very high-dose LEV can now be studied in neonates.Trial registration number NCT01720667.

Mild traumatic brain injury (mTBI) is a common injury for service members in recent military conflicts. There is insufficient evidence of how best to treat the consequences of mTBI. In a randomized, clinical trial, we evaluated the efficacy of telephone-delivered problem-solving treatment (PST) on psychological and physical symptoms in 356 post-deployment active duty service members from Joint Base Lewis McChord, Washington, and Fort Bragg, North Carolina. Members with medically confirmed mTBI sustained during deployment to Iraq and Afghanistan within the previous 24 months received PST or education-only (EO) interventions. The PST group received up to 12 biweekly telephone calls from a counselor for subject-selected problems. Both groups received 12 educational brochures describing common mTBI and post-deployment problems, with follow-up for all at 6 months (end of PST), and at 12 months. At 6 months, the PST group significantly improved on a measure of psychological distress (Brief Symptom Inventory; BSI-18) compared to the EO group (p = 0.005), but not on post-concussion symptoms (Rivermead Post-Concussion Symptoms Questionnaire [RPQ]; p = 0.19), the two primary endpoints. However, these effects did not persist at 12-month follow-up (BSI, p = 0.54; RPQ, p = 0.45). The PST group also had significant short-term improvement on secondary endpoints, including sleep (p = 0.01), depression (p = 0.03), post-traumatic stress disorder (p = 0.04), and physical functioning (p = 0.03). Participants preferred PST over EO (p < 0.001). Telephone-delivered PST appears to be a well-accepted treatment that offers promise for reducing psychological distress after combat-related mTBI and could be a useful adjunct treatment post-mTBI. Further studies are required to determine how to sustain its effects. (Trial registration: ClinicalTrials.gov Identifier: NCT01387490 https://clinicaltrials.gov)

A number of human head finite element (FE) models have been developed from different research groups over the years to study the mechanisms of traumatic brain injury. These models can vary substantially in model features and parameters, making it important to evaluate whether simulation results from one model are readily comparable with another, and whether response-based injury thresholds established from a specific model can be generalized when a different model is employed. The purpose of this study is to parametrically compare regional brain mechanical responses from three validated head FE models to test the hypothesis that regional brain responses are dependent on the specific head model employed as well as the region of interest (ROI). The Dartmouth Scaled and Normalized Model (DSNM), the Simulated Injury Monitor (SIMon), and the Wayne State University Head Injury Model (WSUHIM) were selected for comparisons. For model input, 144 unique kinematic conditions were created to represent the range of head impacts sustained by male collegiate hockey players during play. These impacts encompass the 50th, 95th, and 99th percentile peak linear and rotational accelerations at 16 impact locations around the head. Five mechanical variables (strain, strain rate, strain × strain rate, stress, and pressure) in seven ROIs reported from the FE models were compared using Generalized Estimating Equation statistical models. Highly significant differences existed among FE models for nearly all output variables and ROIs. The WSUHIM produced substantially higher peak values for almost all output variables regardless of the ROI compared to the DSNM and SIMon models ( p  < 0.05). DSNM also produced significantly different stress and pressure compared with SIMon for all ROIs ( p  < 0.05), but such differences were not consistent across ROIs for other variables. Regardless of FE model, most output variables were highly correlated with linear and rotational peak accelerations. The significant disparities in regional brain responses across head models regardless of the output variables strongly suggest that model-predicted brain responses from one study should not be extended to other studies in which a different model is utilized. Consequently, response-based injury tolerance thresholds from a specific model should not be generalized to other studies either in which a different model is used. However, the similar relationships between regional responses and the linear/rotational peak accelerations suggest that each FE model can be used independently to assess regional brain responses to impact simulations in order to perform statistical correlations with medical images and/or well-selected experiments with documented injury findings.

Background: Prior epidemiological work has shown higher mortality in ischemic stroke patients admitted on weekends, which has been termed the ‘weekend effect’. Our aim was to assess stroke patient outcomes in order to determine the significance of the ‘weekend effect’ at 2 comprehensive stroke centers. Methods: Consecutive stroke patients were identified using prospective databases. Patients were categorized into 4 groups: intracerebral hemorrhage (ICH group), ischemic strokes not treated with IV t-PA (intravenous tissue plasminogen activator; IS group), acute ischemic strokes treated with IV t-PA (AIS-TPA group), and transient ischemic attack (TIA group). Weekend admission was defined as the period from Friday, 17:01, to Monday, 08:59. Patients treated beyond the 3-hour window, receiving intra-arterial therapy, or enrolled in nonobservational clinical trials were excluded. Patient demographics, NIHSS scores, and admission glucose levels were examined. Adverse events, poor functional outcome (modified Rankin scale, mRS, 3–6), and mortality were compared. Results: A total of 2,211 patients were included (1,407 site 1, 804 site 2). Thirty-six percent (800/2,211) arrived on a weekend. No significant differences were found in the ICH, IS, AIS-TPA, or TIA groups with respect to the rate of symptomatic ICH, mRS on discharge, discharge disposition, 90-day mRS, or 90-day mortality when comparing weekend and weekday groups. Using multivariate logistic regression to adjust for site, age, admission NIHSS, and blood glucose, weekend admission was not a significant independent predictive factor for in-hospital mortality in all strokes (OR = 1.10, 95% CI 0.74–1.63, p = 0.631). Conclusions: Our results suggest that comprehensive stroke centers (CSC) may ameliorate the ‘weekend effect’ in stroke patients. These results may be due to 24/7 availability of stroke specialists, advanced neuroimaging, or ongoing training and surveillance of specialized nursing care available at CSC. While encouraging, these results require confirmation in prospective studies.

Introduction The negative efficacy study examining the γ-secretase inhibitor semagacestat in mild to moderate Alzheimer’s disease (AD) included a number of biomarkers of the disease as well as safety outcomes. We analyzed these data to explore relationships between drug exposure and pharmacodynamic effects and to examine the correlations among outcome measures. Methods The study was a multicenter, randomized, placebo-controlled trial of two dose regimens of semagacestat and a placebo administered for 18 months to individuals with mild to moderate AD. Changes in measures of central and peripheral drug activity were compared between the three treatment groups using one-way analysis of variance. The relationship between changes in each of the outcome measures and measures of drug exposure and peripheral pharmacodynamic effect were assessed using Spearman’s correlation coefficient. Results Assignment to the active treatment arms was associated with reduction in plasma amyloid-β (Aβ) peptides, increase in ventricular volume, decrease in cerebrospinal fluid phosphorylated tau (p-tau) and several other laboratory measures and adverse event categories. Within the active arms, exposure to drug, as indicated by area under the concentration curve (AUC) of blood concentration, was associated with reduction in plasma Aβ peptides and a subset of laboratory changes and adverse event rates. Ventricular volume increase, right hippocampal volume loss and gastrointestinal symptoms were related to change in plasma Aβ peptide but not AUC, supporting a link to inhibition of γ-secretase cleavage of the amyloid precursor protein. Cognitive decline correlated with ventricular expansion and reduction in p-tau. Conclusion These findings may inform future studies of drugs targeting secretases involved in Aβ generation. Trial registration ClinicalTrials.gov Identifier: NCT00594568 . Registered 11 January 2008.

Background Therapeutic hypothermia is a promising neuroprotective therapy with multiple mechanisms of action. We demonstrated the feasibility of thrombolysis combined with endovascular hypothermia, but not all patients achieved effective cooling. We sought to identify the factors that determined effective cooling. Methods In 26 patients who underwent endovascular hypothermia, we computed four measures of effective cooling: time to reach target; Area-Under-the-Curve (AUC) 34 ratio; AUC-34; and AUC-35. By multivariate regression, we examined the effects of age, weight, starting temperature, body mass index, body surface area (BSA), gender, shivering, and total meperidine dose on the four outcome measures. Results In univariate analyses, all four outcome measures were significantly influenced by BSA ( p  < 0.01 in all univariate analyses). Time to reach target temperature was quicker in older patients ( p  < 0.01). Shivering and meperidine dose were highly intercorrelated ( r  = 0.6, p  < 0.01) and both marginally influenced all four outcome measures. In multivariate analysis, AUC ratio and time to reach target temperature were significantly influenced by BSA ( p  < 0.01) and meperidine ( p  < 0.05); AUC-34 was influenced only by BSA ( p  < 0.01). The AUC-35 was influenced by BSA ( p  < 0.01), shivering, and total meperidine dose ( p  < 0.05). Conclusions The most important determinant of effective cooling during endovascular hypothermia is BSA; larger patients are more difficult to cool and maintain in therapeutic range. Older patients cool more quickly. Shivering was well controlled by the combination of meperidine, buspirone, and surface counter-warming and only minimally influenced cooling effectiveness. Future trials of therapeutic hypothermia may include added measures to cool larger patients more effectively.