Wirksamkeit und Nebenwirkungen eines vierwöchigen aeroben Gangtrainings im Vergleich zu einer Entspannungstherapie bei Patienten nach subakutem Schlaganfall

Introduction: Despite ongoing research no pharmaceutical means has proven efficacious to improve functional recovery in stroke patients. One promising therapeutic intervention is aerobic gait training as it is hypothesized to improve systemic oxygenation and cerebral recovery processes while being functional. For the early subacute phase after stroke, first exploratory studies could show an increase in mobility and improved functionality through aerobic training but feasibility in this high-risk population remains unclear. In this study we aimed to address the effect of an aerobic gait training compared to an active control intervention in the subacute phase after stroke and assess its feasibility, including safety, training adherence and treatment fidelity. Methods: The multicenter, randomized controlled, endpoint-blinded trial ‘Physical Fitness Training in Patients with Subacute Stroke – Phys-Stroke’ recruited 200 patients in the subacute phase (5 – 45 days) after moderate to severe stroke. Participants were randomized (1:1) to receive either a four week aerobic, bodyweight supported gait training (n = 105) with five sessions per week á 25 minutes or a progressive muscle relaxation therapy (n = 95) of equal amount. Co-primary efficacy endpoints were changes in maximal walking speed and in Barthel index score at three months post stroke. Secondary endpoints included six minute walking distance, gait energy cost and change in lesion volume. Safety measures were assessed until six months post stroke and included the serious adverse events (SAE) recurrent cerebro- or cardiovascular event, referral to an acute hospital or death. Adjusted analysis of co-variance were used to analyze both primary endpoints independently in the full analysis set. Poisson regression analysis were performed to assess incidence rate ratios (IRR) of SAE between both intervention groups. Results: Compared to relaxation therapy, aerobic training did not improve maximal walking speed (adjusted treatment effect 0.1 m/s (95% confidence interval 0.0 to 0.2 m/s), p=0.23) or Barthel index score (0, 95% CI −5 to 5, p=0.99) significantly at three months post stroke. Exploratory findings revealed an interaction effect of female sex with training (0.3 m/s, 95% CI 0.1 to 0.5) and a treatment effect of change in lesion volume (-21.8 ml, 95% CI -40.4 to -3.2). Incidence rates (per 100 patient months) were higher in the training group compared to relaxation for all SAE combined (6.31 vs 3.22; IRR 1.70, 95% CI 0.96 to 3.12). Discussion: Aerobic training delivered in the subacute phase after moderate to severe stroke was not found to be superior on maximal walking speed or activities of daily living compared to relaxation therapy. Additionally, a higher rate of SAE in the training group questions feasibility of aerobic exercise in this stroke population. Results are in contrast to previous smaller studies and should be considered in future guidelines.Einleitung: Bisher hat sich kein pharmazeutisches Mittel zur Verbesserung der funktionellen Erholung bei Schlaganfallpatient:innen als wirksam erwiesen. Eine vielversprechende therapeutische Intervention ist das aerobe Gangtraining. Für die frühe subakute Phase nach Schlaganfall konnten erste explorative Studien eine Steigerung der Mobilität und eine verbesserte Funktionalität durch aerobes Training zeigen, aber die sichere Durchführung in dieser Hochrisikopopulation bleibt unklar. Ziel dieser Studie war es, den Effekt eines aeroben Gangtrainings im Vergleich zu einer aktiven Kontrollintervention in der subakuten Phase nach Schlaganfall zu untersuchen und dessen Durchführbarkeit, einschließlich der Sicherheit, Trainings- und Therapietreue zu bewerten. Methoden: Die multizentrische, randomisierte, kontrollierte, Studie 'Physical Fitness Training in Patients with Subacute Stroke - Phys-Stroke' rekrutierte 200 Patient:innen in der subakuten Phase (5 - 45 Tage) nach moderatem bis schwerem Schlaganfall. Die Teilnehmer:innen wurden randomisiert (1:1), um entweder ein vierwöchiges aerobes, körpergewichtsunterstütztes Gangtraining (n = 105) mit fünf Sitzungen pro Woche á 25 Minuten oder eine gleichwertige progressive Muskelentspannungstherapie (n = 95) zu erhalten. Ko-primäre Endpunkte waren Veränderungen in der maximalen Ganggeschwindigkeit und im Barthel-Index drei Monate nach dem Schlaganfall. Zu den sekundären Endpunkten gehörten die sechs Minuten Gehstrecke, der Energieaufwand beim Gehen und die Veränderung des Läsionsvolumens. Sicherheitsendpunkte wurden bis sechs Monate nach dem Schlaganfall erhoben und umfassten die schwerwiegenden unerwünschten Ereignisse (SUE) rezidivierendes zerebro- oder kardiovaskuläres Ereignis, Einweisung in ein Akutkrankenhaus oder Tod. Ergebnisse: Im Vergleich zur Entspannung verbesserte das aerobe Training bis drei Monate nach dem Schlaganfall weder die maximale Ganggeschwindigkeit (adjustierter Behandlungseffekt 0,1 m/s (95% Konfidenzintervall 0,0 bis 0,2 m/s), p=0,23) noch den Barthel-Index (0 (-5 bis 5), p=0,99) signifikant. Explorative Ergebnisse zeigten einen Interaktionseffekt des weiblichen Geschlechts mit dem Training (0,3 m/s, 95% CI 0,1 bis 0,5) und einen Behandlungseffekt auf die Veränderung des Läsionsvolumens (-21,8 ml, 95% CI -40,4 bis -3,2). Die Inzidenzraten (pro 100 Patientenmonate) waren in der Trainingsgruppe im Vergleich zur Entspannungsgruppe für alle SUE zusammen höher (6,31 vs. 3,22; IRR 1,70, 95% CI 0,96 bis 3,12). Diskussion: Aerobes Training in der subakuten Phase nach mittelschwerem bis schwerem Schlaganfall erwies sich im Vergleich zur Entspannungstherapie nicht als überlegen in Bezug auf die maximale Ganggeschwindigkeit oder Aktivitäten des täglichen Lebens. Zusätzlich stellt eine höhere Rate an SUE in der Trainingsgruppe die Durchführbarkeit von aerobem Training in dieser Population in Frage

Applying time series analyses on continuous accelerometry data—A clinical example in older adults with and without cognitive impairment

Introduction: Many clinical studies reporting accelerometry data use sum score measures such as percentage of time spent in moderate to vigorous activity which do not provide insight into differences in activity patterns over 24 hours, and thus do not adequately depict circadian activity patterns. Here, we present an improved functional data analysis approach to model activity patterns and circadian rhythms from accelerometer data. As a use case, we demonstrated its application in patients with mild cognitive impairment (MCI) and age-matched healthy older volunteers (HOV). Methods: Data of two studies were pooled for this analysis. Following baseline cognitive assessment participants were provided with accelerometers for seven consecutive days. A function on scalar regression (FoSR) approach was used to analyze 24 hours accelerometer data. Results: Information on 48 HOV (mean age 65 SD 6 years) and 18 patients with MCI (mean age 70, SD 8 years) were available for this analysis. MCI patients displayed slightly lower activity in the morning hours (minimum relative activity at 6:05 am: -41.3%, 95% CI -64.7 to -2.5%, p = 0.031) and in the evening (minimum relative activity at 21:40 am: -48.4%, 95% CI -68.5 to 15.4%, p = 0.001) as compared to HOV after adjusting for age and sex. Discussion: Using a novel approach of FoSR, we found timeframes with lower activity levels in MCI patients compared to HOV which were not evident if sum scores of amount of activity were used, possibly indicating that changes in circadian rhythmicity in neurodegenerative disease are detectable using easy-to-administer accelerometry. Clinical trials: Effects of Brain Stimulation During Nocturnal Sleep on Memory Consolidation in Patients With Mild Cognitive Impairments, ClinicalTrial.gov identifier: NCT01782391. Effects of Brain Stimulation During a Daytime Nap on Memory Consolidation in Patients With Mild Cognitive Impairment, ClinicalTrial.gov identifier: NCT01782365

Physical Fitness Training in Patients with Subacute Stroke (PHYS-STROKE): multicentre, randomised controlled, endpoint blinded trial

OBJECTIVE: To determine the safety and efficacy of aerobic exercise on activities of daily living in the subacute phase after stroke. DESIGN: Multicentre, randomised controlled, endpoint blinded trial. SETTING: Seven inpatient rehabilitation sites in Germany (2013-17). PARTICIPANTS: 200 adults with subacute stroke (days 5-45 after stroke) with a median National Institutes of Health stroke scale (NIHSS, range 0-42 points, higher values indicating more severe strokes) score of 8 (interquartile range 5-12) were randomly assigned (1:1) to aerobic physical fitness training (n=105) or relaxation sessions (n=95, control group) in addition to standard care. INTERVENTION: Participants received either aerobic, bodyweight supported, treadmill based physical fitness training or relaxation sessions, each for 25 minutes, five times weekly for four weeks, in addition to standard rehabilitation therapy. Investigators and endpoint assessors were masked to treatment assignment. MAIN OUTCOME MEASURES: The primary outcomes were change in maximal walking speed (m/s) in the 10 m walking test and change in Barthel index scores (range 0-100 points, higher scores indicating less disability) three months after stroke compared with baseline. Safety outcomes were recurrent cardiovascular events, including stroke, hospital readmissions, and death within three months after stroke. Efficacy was tested with analysis of covariance for each primary outcome in the full analysis set. Multiple imputation was used to account for missing values. RESULTS: Compared with relaxation, aerobic physical fitness training did not result in a significantly higher mean change in maximal walking speed (adjusted treatment effect 0.1 m/s (95% confidence interval 0.0 to 0.2 m/s), P=0.23) or mean change in Barthel index score (0 (-5 to 5), P=0.99) at three months after stroke. A higher rate of serious adverse events was observed in the aerobic group compared with relaxation group (incidence rate ratio 1.81, 95% confidence interval 0.97 to 3.36). CONCLUSIONS: Among moderately to severely affected adults with subacute stroke, aerobic bodyweight supported, treadmill based physical fitness training was not superior to relaxation sessions for maximal walking speed and Barthel index score but did suggest higher rates of adverse events. These results do not appear to support the use of aerobic bodyweight supported fitness training in people with subacute stroke to improve activities of daily living or maximal walking speed and should be considered in future guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT01953549

Evolution of Blood-Brain Barrier Permeability in Subacute Ischemic Stroke and Associations With Serum Biomarkers and Functional Outcome

Background and Purpose: In the setting of acute ischemic stroke, increased blood-brain barrier permeability (BBBP) as a sign of injury is believed to be associated with increased risk of poor outcome. Pre-clinical studies show that selected serum biomarkers including C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF alpha), matrix metallopeptidases (MMP), and vascular endothelial growth factors (VEGFs) may play a role in BBBP post-stroke. In the subacute phase of stroke, increased BBBP may also be caused by regenerative mechanisms such as vascular remodeling and therefore may improve functional recovery. Our aim was to investigate the evolution of BBBP in ischemic stroke using contrast-enhanced (CE) magnetic resonance imaging (MRI) and to analyze potential associations with blood-derived biomarkers as well as functional recovery in subacute ischemic stroke patients. Methods: This is an exploratory analysis of subacute ischemic stroke patients enrolled in the BAPTISe study nested within the randomized controlled PHYS-STROKE trial (interventions: 4 weeks of aerobic fitness training vs. relaxation). Patients with at least one CE-MRI before (v1) or after (v2) the intervention were eligible for this analysis. The prevalence of increased BBBP was visually assessed on T1-weighted MR-images based on extent of contrast-agent enhancement within the ischemic lesion. The intensity of increased BBBP was assessed semi-quantitatively by normalizing the mean voxel intensity within the region of interest (ROI) to the contralateral hemisphere ("normalized CE-ROI"). Selected serum biomarkers (high-sensitive CRP, IL-6, TNF-alpha, MMP-9, and VEGF) at v1 (before intervention) were analyzed as continuous and dichotomized variables defined by laboratory cut-off levels. Functional outcome was assessed at 6 months after stroke using the modified Rankin Scale (mRS). Results: Ninety-three patients with a median baseline NIHSS of 9 [IQR 6-12] were included into the analysis. The median time to v1 MRI was 30 days [IQR 18-37], and the median lesion volume on v1 MRI was 4 ml [IQR 1.2-23.4]. Seventy patients (80%) had increased BBBP visible on v1 MRI. After the trial intervention, increased BBBP was still detectable in 52 patients (74%) on v2 MRI. The median time to v2 MRI was 56 days [IQR 46-67]. The presence of increased BBBP on v1 MRI was associated with larger lesion volumes and more severe strokes. Aerobic fitness training did not influence the increase of BBBP evaluated at v2. In linear mixed models, the time from stroke onset to MRI was inversely associated with normalized CE-ROI (coefficient -0.002, Standard Error 0.007, p < 0.01). Selected serum biomarkers were not associated with the presence or evolution of increased BBBP. Multivariable regression analysis did not identify the occurrence or evolution of increased BBBP as an independent predictor of favorable functional outcome post-stroke. Conclusion: In patients with moderate-to-severe subacute stroke, three out of four patients demonstrated increased BBB permeability, which decreased over time. The presence of increased BBBP was associated with larger lesion volumes and more severe strokes. We could not detect an association between selected serum biomarkers of inflammation and an increased BBBP in this cohort. No clear association with favorable functional outcome was observed

Building a Systematic Online Living Evidence Summary of COVID-19 Research

Throughout the global coronavirus pandemic, we have seen an unprecedented volume of COVID-19 researchpublications. This vast body of evidence continues to grow, making it difficult for research users to keep up with the pace of evolving research findings. To enable the synthesis of this evidence for timely use by researchers, policymakers, and other stakeholders, we developed an automated workflow to collect, categorise, and visualise the evidence from primary COVID-19 research studies. We trained a crowd of volunteer reviewers to annotate studies by relevance to COVID-19, study objectives, and methodological approaches. Using these human decisions, we are training machine learning classifiers and applying text-mining tools to continually categorise the findings and evaluate the quality of COVID-19 evidence

Course of subject participation

Definition of subject's participation within the Phys-Stroke Trial. Subjects are categorized in Screening failures, per Protocol subjects, withdrawal from Treatment and Lost-to-follow-up