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Abstract Background Health-related quality of life (HRQL) has become an important outcome parameter in cardiology. The MOS 36-ltem Short-Form Health Survey (SF-36) and the PROMIS-29 are two widely used generic measures providing composite HRQL scores. The domains of the SF-36, a well-established instrument utilized for several decades, can be aggregated to physical (PCS) and mental (MCS) component summary scores. Alternative scoring algorithms for correlated component scores (PCSc and MCSc) have also been suggested. The PROMIS-29 is a newer but increasingly used HRQL measure. Analogous to the SF-36, physical and mental health summary scores can be derived from PROMIS-29 domain scores, based on a correlated factor solution. So far, scores from the PROMIS-29 are not directly comparable to SF-36 results, complicating the aggregation of research findings. Thus, our aim was to provide algorithms to convert PROMIS-29 data to well-established SF-36 component summary scores. Methods Data from n = 662 participants of the Berlin Long-term Observation of Vascular Events (BeLOVE) study were used to estimate linear regression models with either PROMIS-29 domain scores or aggregated PROMIS-29 physical/mental health summary scores as predictors and SF-36 physical/mental component summary scores as outcomes. Data from a subsequent assessment point (n = 259) were used to evaluate the agreement between empirical and predicted SF-36 scores. Results PROMIS-29 domain scores as well as PROMIS-29 health summary scores showed high predictive value for PCS, PCSc, and MCSc (R2 ≥ 70%), and moderate predictive value for MCS (R2 = 57% and R2 = 40%, respectively). After applying the regression coefficients to new data, empirical and predicted SF-36 component summary scores were highly correlated (r > 0.8) for most models. Mean differences between empirical and predicted scores were negligible (|SMD|

Abstract Thalamic aphasia results from focal thalamic lesions that cause dysfunction of remote but functionally connected cortical areas due to language network perturbation. However, specific local and network-level neural substrates of thalamic aphasia remain incompletely understood. Using lesion symptom mapping, we demonstrate that lesions in the left ventrolateral and ventral anterior thalamic nucleus are most strongly associated with aphasia in general and with impaired semantic and phonemic fluency and complex comprehension in particular. Lesion network mapping (using a normative connectome based on fMRI data from 1000 healthy individuals) reveals a Thalamic aphasia network encompassing widespread left-hemispheric cerebral connections, with Broca’s area showing the strongest associations, followed by the superior and middle frontal gyri, precentral and paracingulate gyri, and globus pallidus. Our results imply the critical involvement of the left ventrolateral and left ventral anterior thalamic nuclei in engaging left frontal cortical areas, especially Broca’s area, during language processing.

Background Oral anticoagulation (OAC) is key in stroke prevention in patients with atrial fibrillation (AF) but there is uncertainty regarding the optimal timing of OAC (re)initiation after stroke, as recent large randomised controlled trials have methodological weaknesses and excluded stroke patients on therapeutic anticoagulation at stroke onset as well as patients started on a vitamin K antagonist after stroke. The ‘1–3–6–12 days rule’, based on expert consensus and referring to stroke severity, was used in clinical practice to initiate OAC after acute ischaemic stroke or transient ischaemic attack (TIA) since publication in 2013.Methods We retrospectively assessed whether compliance to the ‘1–3–6–12 days rule’ was associated with the composite endpoint (recurrent stroke, systemic embolism, myocardial infarction, major bleeding or all-cause death).Results Among 708 registry patients with known AF before stroke and hospitalisation within 72 hours after stroke, 432 were anticoagulated at stroke onset. OAC was started according to the ‘1–3–6–12 days rule’ in 255 (39.2%) patients. Non-adherence to the ‘1–3–6–12 days rule’ was not associated with the composite endpoint within 3 months in 661 patients who (re-)started on OAC (log-rank test: p=0.74).Results were similar for 521 patients (re)started on a non-vitamin K-dependent OAC.Conclusion (Re)starting OAC after stroke followed the ‘1–3–6–12 days rule’ in about 40% of all patients with AF, and more often in those anticoagulated at stroke onset. Adherence to the ‘1–3–6–12 days rule’ did not reduce the composite clinical endpoint, if OAC was restarted within 3 months of stroke/TIA.Trial registration number NCT02306824.

Abstract Background With an increasing collection of patient-reported outcomes (PROs) to measure health-related quality of life (HRQoL) in oncological patients, there is still a lack of standardised strategies on how to interpret and use these data in patient care. Prior research has shown support for the use of digital PRO monitoring together with alarm systems to notify clinicians when the PRO values are deteriorating. This system has demonstrated advantages in improving HRQoL and increasing survival rates among oncology patients. Hence, we designed the PRO B study, a superiority multi-centre randomised controlled trial, to investigate the effects of alarm-based monitoring in metastatic breast cancer patients in Germany. The study protocol for the PRO B study was published in September 2021, and this manuscript describes a formal statistical analysis plan (SAP) for the PRO B study to improve the transparency and quality of this trial. Methods and design The trial aimed to recruit 1000 patients with metastatic breast cancer. However, as of the completion of recruitment on June 15, 2023, we have successfully enrolled 924 patients from 52 breast cancer centres. Patients were 1:1 stratified randomised to the intervention and control groups. App-based PRO questionnaires are sent weekly to the intervention group and every 3 months to the control group. Only patients in the intervention group trigger an alarm if their PRO scores deteriorate, and they are subsequently contacted by the local care team within 48 h. The primary outcome is the fatigue score at 6 months, and secondary outcomes are other HRQoL and overall survival. Evaluation of the superiority of the intervention will be done using a linear mixed model with random intercepts for study centres. Conclusion This detailed SAP defines the main components of the statistical analysis for the PRO B study to assist the statistician and prevent bias in selecting analysis and reporting findings. Version 1 of the SAP was finalised on January 18, 2024. Trial registration DRKS (German Clinical Trials Register) DRKS00024015 . Registered on February 15, 2021.

Abstract Background Repeated sessions of training and non-invasive brain stimulation have the potential to enhance cognition in patients with cognitive impairment. We hypothesized that combining cognitive training with anodal transcranial direct current stimulation (tDCS) will lead to performance improvement in the trained task and yield transfer to non-trained tasks. Methods In our randomized, sham-controlled, double-blind study, 46 patients with cognitive impairment (60–80 years) were randomly assigned to one of two interventional groups. We administered a 9-session cognitive training (consisting of a letter updating and a Markov decision-making task) over 3 weeks with concurrent 1-mA anodal tDCS over the left dorsolateral prefrontal cortex (20 min in tDCS, 30 s in sham group). Primary outcome was trained task performance (letter updating task) immediately after training. Secondary outcomes included performance in tasks testing working memory (N-back task), decision-making (Wiener Matrices test) and verbal memory (verbal learning and memory test), and resting-state functional connectivity (FC). Tasks were administered at baseline, at post-assessment, and at 1- and 7-month follow-ups (FU). MRI was conducted at baseline and 7-month FU. Thirty-nine participants (85%) successfully completed the intervention. Data analyses are reported on the intention-to-treat (ITT) and the per-protocol (PP) sample. Results For the primary outcome, no difference was observed in the ITT (β = 0.1, 95%-CI [− 1.2, 1.3, p = 0.93] or PP sample (β = − 0.2, 95%-CI [− 1.6, 1.2], p = 0.77). However, secondary analyses in the N-back working memory task showed that, only in the PP sample, the tDCS outperformed the sham group (PP: % correct, β = 5.0, 95%-CI [− 0.1, 10.2], p = 0.06, d-prime β = 0.2, 95%-CI [0.0, 0.4], p = 0.02; ITT: % correct, β = 3.0, 95%-CI [− 3.9, 9.9], p = 0.39, d-prime β = 0.1, 95%-CI [− 0.1, 0.3], p = 0.5). Frontoparietal network FC was increased from baseline to 7-month FU in the tDCS compared to the sham group (p FDR

Abstract Introduction Various developments result in increasing workloads in general practices. New models of care and a restructuring of the division of tasks could provide relief. One approach is to extend the delegation of medical tasks from general practitioners (GPs) to medical practice assistants (MPAs). So far, there has been a lack of information about specific situations in which patients are willing to be treated exclusively by MPAs. Methods In three German federal states, patients who visited a general practice were surveyed exploratively and cross-sectionally with a self-designed, paper-based questionnaire. The data were analysed descriptively and multivariate. A mixed binary logistic regression model was calculated to account for cluster effects at practice level (random intercept model). The dependent variable was patients' acceptance of task delegation. Results A total of 1861 questionnaires from 61 general practices were included in the analysis. Regarding the current problem/request, a total of 30% of respondents could imagine being treated only by MPAs. Regarding theoretical reasons for consultation, more than half of the patients agreed to be treated by MPAs. According to the regression model, MPAs were preferred when patients were younger (10-year OR = 0.84, 95%-CI [0.75, 0.93]) or had a less complicated issue (OR = 0.44, 95%-CI [0.26, 0.8]). For four current problems/requests (“acute complaints” OR = 0.27, 95%-CI [0.17, 0.45], “routine health check” OR = 0.48, 95%-CI [0.3, 0.79], “new problem” OR = 0.13, 95%-CI [0.06, 0.28], “known problem” OR = 0.16, 95%-CI [0.1, 0.27]) patients prefer to be treated by GPs instead of MPAs. Discussion For the first time, statements could be made on patients’ acceptance of task delegation in relation to current and theoretical reasons for treatment in general practices in Germany. The discrepancy in response behaviour on a theoretical and individual level could be explained by different contexts of questions and differences at practice level. Overall, patients seem to be open to increased delegation of medical tasks, depending on the reason for treatment. Selection and response biases should be considered in the interpretation. Conclusion The results are not completely opposed to an extension of task delegation. Further interventional studies could provide information on the possible effects of expansion of delegable tasks.

ObjectiveSurgical resection of motor eloquent tumors poses the risk of causing postoperative motor deficits which leads to reduced quality of life in these patients. Currently, rehabilitative procedures are limited with physical therapy being the main treatment option. This study investigated the efficacy of repetitive navigated transcranial magnetic stimulation (rTMS) for treatment of motor deficits after supratentorial tumor resection.MethodsThis randomized, double-blind, sham-controlled trial (DRKS00010043) recruited patients with a postoperatively worsened upper extremity motor function immediately postoperatively. They were randomly assigned to receive rTMS (1Hz, 110% RMT, 15 minutes, 7 days) or sham stimulation to the motor cortex contralateral to the injury followed by physical therapy. Motor and neurological function as well as quality of life were assessed directly after the intervention, one month and three months postoperatively.ResultsThirty patients were recruited for this study. There was no significant difference between both groups in the primary outcome, the Fugl Meyer score three months postoperatively [Group difference (95%-CI): 5.05 (-16.0; 26.1); p=0.631]. Patients in the rTMS group presented with better hand motor function one month postoperatively. Additionally, a subgroup of patients with motor eloquent ischemia showed lower NIHSS scores at all timepoints.ConclusionsLow-frequency rTMS facilitated the recovery process in stimulated hand muscles, but with limited generalization to other functional deficits. Long-term motor deficits were not impacted by rTMS. Given the reduced life expectancy in these patients a shortened recovery duration of deficits can still be of high significance.Clinical Trial Registrationhttps://drks.de/DRKS00010043.

Aim: The 2021 European Resuscitation Council (ERC) guidelines recommend two automated external defibrillators (AEDs)/km2 and at least 10 first responders/km2. We examined 1) access to AEDs and volunteer first responders in line with these guidelines and 2) its associations with socioeconomic factors and income inequality, focusing on small spatial scales. Method: We considered data on 776 AEDs in February 2022 and 1,173 out-of-hospital cardiac arrests (OHCAs) including 713 OHCA with app-alerted volunteer first responders from February to September 2022 in Berlin. We fit multilevel models to analyse AED area coverage and Poisson models to examine first responder availability across 12 districts and 536 neighbourhoods. Results: Median AED area coverage according to the 2021 ERC guidelines was 43.1% (interquartile range (IQR) 2.3–87.2) at the neighbourhood level and median number of available first responders per OHCA case was one (IQR 0.0–1.0). AED area coverage showed a positive association with average income tax per capita, with better coverage in the highest compared to the lowest quartile neighbourhoods (coefficient: 0.13, 95% confidence interval (CI): 0.01–0.25). First responder availability was not associated with income tax. AED area coverage and first responder availability were positively associated with income inequality, with better coverage (coefficient: 0.13, 95% CI: 0.04–0.23) and availability (rate ratio: 1.31, 95% CI: 1.03–1.67) in quartiles of highest as compared to lowest inequality. Conclusion: Access to resuscitation resources is neither equitable nor in accordance with the 2021 ERC guidelines. Ensuring better access necessitates understanding of socioeconomic factors and income inequality at small spatial scales.

IntroductionAcute ischemic stroke (AIS) is a time-critical medical emergency. For patients with large-vessel occlusions (LVO), mechanical thrombectomy (MT) is the gold-standard treatment. Mobile Stroke Units (MSUs) provide on-site diagnostic capabilities via computed tomography (CT) and have been shown to improve functional outcomes in stroke patients, but are cost-efficient only in urban areas. Blood biomarkers have recently emerged as possible alternative to cerebral imaging for LVO diagnosis. Prehospital LVO diagnosis offers the potential to transport patients directly to centers that have MT treatment available. In this study, we assess the accuracy of combining two biomarkers, HFABP and NT-proBNP, with clinical indicators to detect LVO using ultra-early prehospital blood samples. The study was registered in the German Clinical Trials Register (DRKS-ID: DRKS00030399).Methods and analysisWe plan a multicenter prospective observational study with 800 patients with suspected stroke enrolled within 24 h of symptom onset. Study participants will be recruited at three sites (MSUs) in Berlin, Germany. Blood-samples will be taken pre-hospitally at the scene and tested for HFABP and NT-proBNP levels. Additional clinical data and information on final diagnosis will be collected and documented in an electronic case report form (eCRF). Sensitivity and specificity of the combination will be calculated through iterative permutation-response calculations.DiscussionThis study aims to evaluate the diagnostic capabilities of a combination of the biomarkers HFABP and NT-proBNP in LVO prediction. In contrast to most other biomarker studies to date, by employing MSUs as study centers, ultra-early levels of biomarkers can be analyzed. Point-of-care LVO detection in suspected stroke could lead to faster treatment in both urban and rural settings and thus improve functional outcomes on a broader scale.Clinical trial registrationDeutsches Register klinischer Studien https://drks.de/search/de/trial/DRKS00030399, DRKS00030399

Abstract Background The extent of resection of glioma is one of the most important predictors of the survival duration of patients after surgery. The presence of eloquent areas within or near a tumor often limits resection, as resection of these areas would result in functional loss and reduced quality of life. The aim of this randomized, triple-blind, sham-controlled study is to investigate the capability of repetitive navigated transcranial magnetic stimulation (rnTMS) over the primary motor cortex to facilitate the functional reorganization of the motor network. Methods One hundred forty-eight patients with tumors in movement-relevant areas will be included in this randomized, sham-controlled, bicentric, triple-blind clinical trial. Patients considered at high risk for postoperative motor deficits according to an initial nTMS assessment will receive inhibitory rnTMS at 1 Hz for 30 min followed by a short motor training of 10 min. Stimulation will be applied to the fiber endings of the corticospinal tract closest to the tumor based on individualized tractography. Stimulation will be performed twice daily for each 30 min for 5–28 days depending on the individually available time between study inclusion and surgery. The intervention is controlled by a sham stimulation group (1:1 randomization), where a plastic adapter will be placed on the coil. We expect a comparable or better motor status 3 months postoperatively as measured by the British Medical Research Council (BMRC) score for the affected upper extremity (non-inferiority) and a higher rate of gross total resections (superiority) in the rnTMS compared to the sham group. Discussion The generated reorganization of the brain’s areas for motor function should allow a more extensive and safer removal of the tumor while preserving neurological and motor function. This would improve both survival and quality of life of our patients. Trial registration DRKS.de DRKS00017232 . Registered on 28 January 2020.

Abstract The combination of repeated behavioral training with transcranial direct current stimulation (tDCS) holds promise to exert beneficial effects on brain function beyond the trained task. However, little is known about the underlying mechanisms. We performed a monocenter, single-blind randomized, placebo-controlled trial comparing cognitive training to concurrent anodal tDCS (target intervention) with cognitive training to concurrent sham tDCS (control intervention), registered at ClinicalTrial.gov (Identifier NCT03838211). The primary outcome (performance in trained task) and secondary behavioral outcomes (performance on transfer tasks) were reported elsewhere. Here, underlying mechanisms were addressed by pre-specified analyses of multimodal magnetic resonance imaging before and after a three-week executive function training with prefrontal anodal tDCS in 48 older adults. Results demonstrate that training combined with active tDCS modulated prefrontal white matter microstructure which predicted individual transfer task performance gain. Training-plus-tDCS also resulted in microstructural grey matter alterations at the stimulation site, and increased prefrontal functional connectivity. We provide insight into the mechanisms underlying neuromodulatory interventions, suggesting tDCS-induced changes in fiber organization and myelin formation, glia-related and synaptic processes in the target region, and synchronization within targeted functional networks. These findings advance the mechanistic understanding of neural tDCS effects, thereby contributing to more targeted neural network modulation in future experimental and translation tDCS applications.

Abstract Background About 25% of all ischaemic strokes are related to cardio-embolism, most often due to atrial fibrillation (AF). Little is known about the extent and standardization of routine cardiac diagnostic work-up at certified stroke-units in Germany. Methods The MonDAFIS study included non-AF patients with acute ischaemic stroke or transient ischaemic attack (TIA) at 38 certified stroke-units in Germany. Here, we analysed routine diagnostic work-up and disregarded study-related Holter-ECG monitoring. We compared duration of stroke-unit stay, number of 24-h Holter-ECGs, and echocardiography performed between university-based comprehensive stroke centres (UCSC, 12 hospitals, 1606 patients), non university-based comprehensive stroke centres (nUCSC, 14 hospitals, 892 patients), and primary stroke centres at non-university hospitals (PCS, 12 hospitals, 933 patients) using multivariable mixed regression analyses. Detection of a first AF episode in-hospital was also compared between hospitals of different stroke-unit levels. Results In 3431 study patients (mean age 66.2 years, 39.5% female, median NIHSS = 2 on admission), median duration of the stroke-unit stay was 72 h (IQR 42–86). Stroke-unit stay was longer (categorised ≤ 24/ > 24- ≤ 72/ > 72 h) for patients with severe stroke (NIHSS score ≥ 5/

Introduction Wheezing is common in preschool children and its clinical assessment often challenging for caretakers. This study aims to evaluate the impact of a novel digital wheeze detector (WheezeScan™) on disease control in a home care setting. Methods A multicentre randomised open-label controlled trial was conducted in Berlin, Istanbul and London. Participants aged 4–84 months with a doctor's diagnosis of recurrent wheezing in the past 12 months were included. While the control group followed usual care, the intervention group received the WheezeScan™ for at-home use for 120 days. Parents completed questionnaires regarding their child's respiratory symptoms, disease-related and parental quality of life, and caretaker self-efficacy at baseline (T0), 90 days (T1) and 4 months (T2). Results A total of 167 children, with a mean±sd age of 3.2±1.6 years, were enrolled in the study (intervention group n=87; control group n=80). There was no statistically significant difference in wheeze control assessed by TRACK (mean difference 3.8, 95% CI −2.3–9.9; p=0.2) at T1 between treatment groups (primary outcome). Children's and parental quality of life and parental self-efficacy were comparable between both groups at T1. The evaluation of device usability and perception showed that parents found it useful. Conclusion In the current study population, the wheeze detector did not show significant impact on the home management of preschool wheezing. Hence, further research is needed to better understand how the perception and usage behaviour may influence the clinical impact of a digital support.

BackgroundMyasthenia gravis (MG) is a rare autoimmune disease and chronic condition that necessitates specialized care. Patients experience a significant burden of disease affecting various aspects of their lives. The aim of this study was to investigate the impact of MG on family planning, challenges associated with pregnancy, childcare responsibilities and the extent to which MG patients perceive and utilize social support.MethodsThis analysis used data from our main data of a large cross-sectional study built on a questionnaire-based survey encompassing 1,660 MG patients and members of the German Myasthenia Association (Deutsche Myasthenie Gesellschaft), and focused on sociodemographic, clinical and family planning relevant data points.ResultsDecisions regarding family planning were significantly impacted for individuals with MG when MG symptoms started either before or during their family planning (men: n = 19 and 29.7%; women: n = 156 and 58.4%). In this subgroup a substantial proportion opted against parenthood due to MG (men: n = 8 and 50.0%; women: n = 54 and 38.0% and/or another n = 12 and 8.4% of female participants encountered partner-related refusals). In the subgroup of female SP with MG starting before or during family planning who have reported ever been pregnant the self-reported miscarriage rate was 29.0% (n = 51). MG patients with medium incomes or moderate disease severity reported lower levels of perceived social support. 42.7% (n = 606) of participants needed assistance in negotiations with health insurers and 28.0% (n = 459) needed support for transportation to medical appointments.ConclusionThis study shows a significant impact of MG on family planning decisions, affecting both women and men, and often resulting in life-altering decisions such as voluntary childlessness due to MG. The significance of social support becomes evident as a vital factor, especially when navigating through the healthcare system. Tailored healthcare approaches, organized guidance and comprehensive support is needed to enable informed decision-making and offer assistance for MG patients.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT03979521, Registered 7 June 2019 (retrospectively registered).

Abstract Background Fragmented and complex healthcare systems make it difficult to provide continuity of care for patients with advanced cancer near the end of life. Nurse‐based cross‐sectoral navigation support has the potential to increase patients' quality of life. The objective of this paper was to evaluate associations between navigation support and health care utilization, and the associated costs of care. Methods The evaluation is based on claims data from 37 statutory health insurance funds. Non‐randomized recruitment of the intervention group (IG) took place between 2018 and 2019 in four German hospitals. The comparison group (CG) was defined ex post. It comprises nonparticipating clients of the involved health insurance funds matched on age, gender, and diagnosis in a 1:4 ratio to the IG. Healthcare resource utilization was compared using incident rate ratios (IRRs) based on negative binomial regression models. Linear mixed models were performed to compare differences in lengths of hospital stays and costs between groups. Results A total of 717 patients were included (IG: 149, CG: 568). IG patients showed shorter average lengths of hospital stays (IG: 11 days [95% CI: 10, 13] vs. CG: 15 days [95% CI: 14, 16], p

Remembering objects and their associated location (object–location memory; OLM), is a fundamental cognitive function, mediated by cortical and subcortical brain regions. Previously, the combination of OLM training and transcranial direct current stimulation (tDCS) suggested beneficial effects, but the evidence remains heterogeneous. Here, we applied focal tDCS over the right temporoparietal cortex in 52 participants during a two-day OLM training, with anodal tDCS (2 mA, 20 min) or sham (40 s) on the first day. The focal stimulation did not enhance OLM performance on either training day (stimulation effect: −0.09, 95%CI: [−0.19; 0.02], p = 0.08). Higher electric field magnitudes in the target region were not associated with individual performance benefits. Participants with content-related learning strategies showed slightly superior performance compared to participants with position-related strategies. Additionally, training gains were associated with individual verbal learning skills. Consequently, the lack of behavioral benefits through focal tDCS might be due to the involvement of different cognitive processes and brain regions, reflected by participant’s learning strategies. Future studies should evaluate whether other brain regions or memory-relevant networks may be involved in the modulation of object–location associations, investigating other target regions, and further exploring individualized stimulation parameters.

Introduction The Berlin Long-term Observation of Vascular Events is a prospective cohort study that aims to improve prediction and disease-overarching mechanistic understanding of cardiovascular (CV) disease progression by comprehensively investigating a high-risk patient population with different organ manifestations.Methods and analysis A total of 8000 adult patients will be recruited who have either suffered an acute CV event (CVE) requiring hospitalisation or who have not experienced a recent acute CVE but are at high CV risk. An initial study examination is performed during the acute treatment phase of the index CVE or after inclusion into the chronic high risk arm. Deep phenotyping is then performed after ~90 days and includes assessments of the patient’s medical history, health status and behaviour, cardiovascular, nutritional, metabolic, and anthropometric parameters, and patient-related outcome measures. Biospecimens are collected for analyses including ‘OMICs’ technologies (e.g., genomics, metabolomics, proteomics). Subcohorts undergo MRI of the brain, heart, lung and kidney, as well as more comprehensive metabolic, neurological and CV examinations. All participants are followed up for up to 10 years to assess clinical outcomes, primarily major adverse CVEs and patient-reported (value-based) outcomes. State-of-the-art clinical research methods, as well as emerging techniques from systems medicine and artificial intelligence, will be used to identify associations between patient characteristics, longitudinal changes and outcomes.Ethics and dissemination The study was approved by the Charité—Universitätsmedizin Berlin ethics committee (EA1/066/17). The results of the study will be disseminated through international peer-reviewed publications and congress presentations.Study registration First study phase: Approved WHO primary register: German Clinical Trials Register: https://drks.de/search/de/trial/DRKS00016852; WHO International Clinical Registry Platform: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00016852. Recruitment started on July 18, 2017.Second study phase: Approved WHO primary register: German Clinical Trials Register DRKS00023323, date of registration: November 4, 2020, URL: http://www.drks.de/ DRKS00023323. Recruitment started on January 1, 2021.

Abstract Purpose Given the psychosocial burdens patients in advanced stages of cancer face, innovative care concepts are needed. At the same time, such vulnerable patient groups are difficult to reach for participation in intervention studies and randomized patient inclusion may not be feasible. This article aims to identify systematic biases respectively selection effects occurring during the recruitment phase and to discuss their potential causes based on a non-randomized, multicenter intervention study with patients in advanced stages of cancer. Methods Patients diagnosed with at least one of 16 predefined cancers were recruited at four hospitals in three German cities. The effect of social care nurses’ continuous involvement in acute oncology wards was measured by health-related quality of life (EORTC QLQ-C30), information and participation preferences, decisional conflicts, doctor-patient communication, health literacy and symptom perception. Absolute standardized mean difference was calculated as a standardized effect size to test baseline characteristics balance between the intervention and control groups. Results The study enrolled 362 patients, 150 in the intervention and 212 in the control group. Except for gender, both groups differed in relevant socio-demographic characteristics, e.g. regarding age and educational background. With respect to the distribution of diagnoses, the intervention group showed a higher symptom burden than the control group. Moreover, the control group reported better quality of life at baseline compared to the intervention group (52.6 points (SD 21.7); 47.8 points (SD 22.0), ASMD = 0.218, p = 0.044). Conclusion Overall, the intervention group showed more social and health vulnerability than the control group. Among other factors, the wide range of diagnoses included and structural variation between the recruiting clinics increased the risk for bias. We recommend a close, continuous monitoring of relevant social and health-related characteristics during the recruitment phase as well as the use of appropriate statistical analysis strategies for adjustment, such as propensity score methods. Trial registration: German Clinical Trials Register (DRKS-ID: DRKS00013640 ); registered on 29th December 2017.

Gaucher disease (GD) is a rare autosomal recessive disorder arising from bi-allelic variants in the GBA1 gene, encoding glucocerebrosidase. Deficiency of this enzyme leads to progressive accumulation of the sphingolipid glucosylsphingosine (lyso-Gb1). The international, multicenter, observational “Lyso-Gb1 as a Long-term Prognostic Biomarker in Gaucher Disease”—LYSO-PROOF study succeeded in enrolling a cohort of 160 treatment-naïve GD patients from diverse geographic regions and evaluated the potential of lyso-Gb1 as a specific biomarker for GD. Using genotypes based on established classifications for clinical presentation, patients were stratified into type 1 GD (n = 114) and further subdivided into mild (n = 66) and severe type 1 GD (n = 48). Due to having previously unreported genotypes, 46 patients could not be classified. Though lyso-Gb1 values at enrollment were widely distributed, they displayed a moderate and statistically highly significant correlation with disease severity measured by the GD-DS3 scoring system in all GD patients (r = 0.602, p < 0.0001). These findings support the utility of lyso-Gb1 as a sensitive biomarker for GD and indicate that it could help to predict the clinical course of patients with undescribed genotypes to improve personalized care in the future.

BackgroundPatient navigation programmes were introduced in the United States and recently gained interest in Germany, where the health care system is fragmented. Navigation programmes aim to decrease barriers to care for patients with age-associated diseases and complex care paths. Here we describe a feasibility study to evaluate a patient-oriented navigation model that was developed in a first project phase by integrating data about barriers to care, vulnerable patient populations and existing support services.MethodsWe designed a mixed-methods feasibility study that consists of two two-arm randomized controlled trials aligned with observational cohorts. The intervention group of the RCTs gets support by personal navigators for 12 months. The control group receives a brochure with regional support offers for patients and caregivers. The feasibility of the patient-oriented navigation model for two prototypic age-associated diseases, lung cancer and stroke, is evaluated with regard to its acceptance, demand, practicality and efficacy. This investigation includes process evaluation measures with detailed documentation of the screening and recruitment process, questionnaires about satisfaction with navigation, observant participation and qualitative interviews. Estimates of efficacy for patient-reported outcomes are obtained at three follow-up time points including satisfaction with care and health-related quality of life. Furthermore, we analyze health insurance data from patients of the RCT insured at a large German health insurance (AOK Nordost) to investigate heath care utilization, costs and cost effectiveness.Trial registrationThe study is registered at the German Clinical Trial Register (DRKS-ID: DRKS00025476).

Introduction: The hippocampus is the most prominent single region of interest (ROI) for the diagnosis and prediction of Alzheimer’s disease (AD). However, its suitability in the earliest stages of cognitive decline, i.e., subjective cognitive decline (SCD), remains uncertain which warrants the pursuit of alternative or complementary regions. The amygdala might be a promising candidate, given its implication in memory as well as other psychiatric disorders, e.g. depression and anxiety, which are prevalent in SCD. In this 7 tesla (T) magnetic resonance imaging (MRI) study, we aimed to compare the contribution of volumetric measurements of the hippocampus, the amygdala, and their respective subfields, for early diagnosis and prediction in an AD-related study population. Methods: Participants from a longitudinal study were grouped into SCD (n = 29), mild cognitive impairment (MCI, n = 23), AD (n = 22) and healthy control (HC, n = 31). All participants underwent 7T MRI at baseline and extensive neuropsychological testing at up to three visits (baseline n = 105, 1-year n = 78, 3-year n = 39). Analysis of covariance (ANCOVA) was used to assess group differences of baseline volumes of the amygdala and the hippocampus and their subfields. Linear mixed models were used to estimate the effects of baseline volumes on yearly changes of a z-scaled memory score. All models were adjusted to age, sex and education. Results: Compared to the HC group, individuals with SCD showed smaller amygdala ROI volumes (range across subfields −11% to −1%), but not hippocampus ROI volumes (-2% to 1%) except for the hippocampus-amygdala-transition-area (-7%). However, cross-sectional associations between baseline memory and volumes were smaller for amygdala ROIs (std. ß [95% CI] ranging between 0.16 [0.08; 0.25] and 0.46 [0.31; 0.60]) than hippocampus ROIs (between 0.32 [0.19; 0.44] and 0.53 [0.40; 0.67]). Further, the association of baseline volumes with yearly memory change in the HC and SCD groups was similarly weak for amygdala ROIs and hippocampus ROIs. In the MCI group, volumes of amygdala ROIs were associated with a relevant yearly memory decline [95% CI] ranging between −0.12 [−0.24; 0.00] and −0.26 [−0.42; −0.09] for individuals with 20% smaller volumes than the HC group. However, effects were stronger for hippocampus ROIs with a corresponding yearly memory decline ranging between −0.21 [−0.35; −0.07] and −0.31 [−0.50; −0.13]. Conclusion: Volumes of amygdala ROIs, as determined by 7T MRI, might contribute to objectively and non-invasively identify patients with SCD, and thus aid early diagnosis and treatment of individuals at risk to develop dementia due to AD, however associations with other psychiatric disorders should be evaluated in further studies. The amygdala’s value in the prediction of longitudinal memory changes in the SCD group remains questionable. Primarily in patients with MCI, memory decline over 3 years appears to be more strongly associated with volumes of hippocampus ROIs than amygdala ROIs.

Background: Two statistical models have been established to evaluate characteristics associated with postoperative motor outcome in patients with glioma associated to the motor cortex (M1) or the corticospinal tract (CST). One model is based on a clinicoradiological prognostic sum score (PrS) while the other one relies on navigated transcranial magnetic stimulation (nTMS) and diffusion-tensor-imaging (DTI) tractography. The objective was to compare the models regarding their prognostic value for postoperative motor outcome and extent of resection (EOR) with the aim of developing a combined, improved model. Methods: We retrospectively analyzed a consecutive prospective cohort of patients who underwent resection for motor associated glioma between 2008 and 2020, and received a preoperative nTMS motor mapping with nTMS-based diffusion tensor imaging tractography. The primary outcomes were the EOR and the motor outcome (on the day of discharge and 3 months postoperatively according to the British Medical Research Council (BMRC) grading). For the nTMS model, the infiltration of M1, tumor-tract distance (TTD), resting motor threshold (RMT) and fractional anisotropy (FA) were assesed. For the PrS score (ranging from 1 to 8, lower scores indicating a higher risk), we assessed tumor margins, volume, presence of cysts, contrast agent enhancement, MRI index (grading white matter infiltration), preoperative seizures or sensorimotor deficits. Results: Two hundred and three patients with a median age of 50 years (range: 20–81 years) were analyzed of whom 145 patients (71.4%) received a GTR. The rate of transient new motor deficits was 24.1% and of permanent new motor deficits 18.8%. The nTMS model demonstrated a good discrimination ability for the short-term motor outcome at day 7 of discharge (AUC = 0.79, 95 %CI: 0.72–0.86) and the long-term motor outcome after 3 months (AUC = 0.79, 95 %CI: 0.71–0.87). The PrS score was not capable to predict the postoperative motor outcome in this cohort but was moderately associated with the EOR (AUC = 0.64; CI 0.55–0.72). An improved, combined model was calculated to predict the EOR more accurately (AUC = 0.74, 95 %CI: 0.65–0.83). Conclusion: The nTMS model was superior to the clinicoradiological PrS model for potentially predicting the motor outcome. A combined, improved model was calculated to estimate the EOR. Thus, patient counseling and surgical planning in patients with motor-associated tumors should be performed using functional nTMS data combined with tractography.

Background: Head and brain anatomy have been related to e-field strength induced by transcranial electrical stimulation (tES). Individualization based on anatomic factors require high-quality structural magnetic resonance images, which are not always available. Head circumference (HC) can serve as an alternative means, but its linkage to electric field strength has not yet been established. Methods: We simulated electric fields induced by tES based on individual T1w- and T2w-images of 47 healthy adults, for four conventional (“standard”) and four corresponding focal (”4x1”) electrode montages. Associations of electric field strength with individual HC were calculated using linear mixed models. Results: Larger HC was associated with lower electric field strength across montages. We provide mathematical equations to estimate individual electric field strength based on the HC. Conclusion: HC can be used as an alternative to estimate interindividual differences of the tES-induced electric field strength and to prospectively individualize stimulation dose, e.g., in the clinical context.

Abstract Background Despite the progress of research and treatment for breast cancer, still up to 30% of the patients afflicted will develop distant disease. Elongation of survival and maintaining the quality of life (QoL) become pivotal issues guiding the treatment decisions. One possible approach to optimise survival and QoL is the use of patient-reported outcomes (PROs) to timely identify acute disease-related burden. We present the protocol of a trial that investigates the effect of real-time PRO data captured with electronic mobile devices on QoL in female breast cancer patients with metastatic disease. Methods This study is a randomised, controlled trial with 1:1 randomisation between two arms. A total of 1000 patients will be recruited in 40 selected breast cancer centres. Patients in the intervention arm receive a weekly request via an app to complete the PRO survey. Symptoms will be assessed by study-specific optimised short forms based on the EORTC QLQ-C30 domains using items from the EORTC CAT item banks. In case of deteriorating PRO scores, an alarm is sent to the treating study centre as well as to the PRO B study office. Following the alarm, the treating breast cancer centre is required to contact the patient to inquire about the reported symptoms and to intervene, if necessary. The intervention is not specified and depends on the clinical need determined by the treating physician. Patients in the control arm are prompted by the app every 3 months to participate in the PRO survey, but their response will not trigger an alarm. The primary outcome is the fatigue level 6 months after enrolment. Secondary endpoints include among others hospitalisations, use of rescue services and overall QoL. Discussion Within the PRO B intervention group, we expect lower fatigue levels 6 months after intervention start, higher levels of QoL, less unplanned hospitalisations and less emergency room visits compared to controls. In case of positive results, our approach would allow a fast and easy transfer into clinical practice due to the use of the already nationwide existing IT infrastructure of the German Cancer Society and the independent certification institute OnkoZert. Trial registration DRKS (German Clinical Trials Register) DRKS00024015 . Registered on 15 February 2021

Abstract Background Neuromyelitis optica spectrum disorder (NMOSD) is a frequently disabling neuroinflammatory syndrome with a relapsing course. Blood-based disease severity and prognostic biomarkers for NMOSD are a yet unmet clinical need. Here, we evaluated serum glial fibrillary acidic protein (sGFAP) and neurofilament light (sNfL) as disease severity and prognostic biomarkers in patients with aquaporin-4 immunoglobulin (Ig)G positive (AQP4-IgG+) NMOSD. Methods sGFAP and sNfL were determined by single-molecule array technology in a prospective cohort of 33 AQP4-IgG+ patients with NMOSD, 32 of which were in clinical remission at study baseline. Sixteen myelin oligodendrocyte glycoprotein IgG-positive (MOG-IgG+) patients and 38 healthy persons were included as controls. Attacks were recorded in all AQP4-IgG+ patients over a median observation period of 4.25 years. Results In patients with AQP4-IgG+ NMOSD, median sGFAP (109.2 pg/ml) was non-significantly higher than in MOG-IgG+ patients (81.1 pg/ml; p = 0.83) and healthy controls (67.7 pg/ml; p = 0.07); sNfL did not substantially differ between groups. Yet, in AQP4-IgG+, but not MOG-IgG+ patients, higher sGFAP was associated with worse clinical disability scores, including the Expanded Disability Status Scale (EDSS, standardized effect size = 1.30, p = 0.007) and Multiple Sclerosis Functional Composite (MSFC, standardized effect size = − 1.28, p = 0.01). While in AQP4-IgG+, but not MOG-IgG+ patients, baseline sGFAP and sNfL were positively associated (standardized effect size = 2.24, p = 0.001), higher sNfL was only non-significantly associated with worse EDSS (standardized effect size = 1.09, p = 0.15) and MSFC (standardized effect size = − 1.75, p = 0.06) in patients with AQP4-IgG+ NMOSD. Patients with AQP4-IgG+ NMOSD with sGFAP > 90 pg/ml at baseline had a shorter time to a future attack than those with sGFAP ≤ 90 pg/ml (adjusted hazard ratio [95% confidence interval] = 11.6 [1.3–105.6], p = 0.03). In contrast, baseline sNfL levels above the 75th age adjusted percentile were not associated with a shorter time to a future attack in patients with AQP4-IgG+ NMOSD. Conclusion These findings suggest a potential role for sGFAP as biomarker for disease severity and future disease activity in patients with AQP4-IgG+ NMOSD in phases of clinical remission.

ObjectRecent studies demonstrated that gross total resection of brain metastases cannot always be achieved. Subtotal resection (STR) can result in an early recurrence and might affect patient survival. We initiated a prospective observational study to establish a MRI-based risk assessment for incomplete resection of brain metastases.MethodsAll patients in whom ≥1 brain metastasis was resected were prospectively included in this study (DRKS ID: DRKS00021224; Nov 2020 – Nov 2021). An interdisciplinary board of neurosurgeons and neuroradiologists evaluated the pre- and postoperative MRI (≤48h after surgery) for residual tumor. Extensive neuroradiological analyses were performed to identify risk factors for an unintended STR which were integrated into a regression tree analysis to determine the patients’ individual risk for a STR.ResultsWe included 150 patients (74 female; mean age: 61 years), in whom 165 brain metastases were resected. A STR was detected in 32 cases (19.4%) (median residual tumor volume: 1.36ml, median EORrel: 93.6%), of which 6 (3.6%) were intended STR (median residual tumor volume: 3.27ml, median EORrel: 67.3%) - mainly due to motor-eloquent location - and 26 (15.8%) were unintended STR (uSTR) (median residual tumor volume: 0.64ml, median EORrel: 94.7%). The following risk factors for an uSTR could be identified: subcortical metastasis ≥5mm distant from cortex, diffuse contrast agent enhancement, proximity to the ventricles, contact to falx/tentorium and non-transcortical approaches. Regression tree analysis revealed that the individual risk for an uSTR was mainly associated to the distance from the cortex (distance ≥5mm vs.

Abstract Background Patient-reported outcome measures (PROMs) are commonly-used surrogates for clinical outcomes in cancer research. When researching severe diseases such as cancer, it is difficult to avoid the problem of incomplete questionnaires from drop-outs or missing data from patients who pass away during the observation period. The aim of this exploratory study was to explore patient characteristics and the patient-reported outcomes associated with the time-to-dropout. Methods In an Oncological Social Care Project (OSCAR) study, the condition of the participants was assessed four times within 12 months (t0: baseline, t1: 3 months, t2: 6 months, and t3: 12 months) by validated PROMs. We performed competing-risk regressions based on Fine and Gray’s proportional sub-distribution hazards model for exploring factors associated with time-to-dropout. Death was considered a competing risk. Results Three hundred sixty-two participants were analyzed in the study. 193 (53.3%) completed a follow-up after 12 months, 67 (18.5%) patients dropped out, and 102 patients (28.2%) died during the study period. Poor subjective social support was related to a higher risk of drop-out (SHR = 2.10; 95%CI: 1.01–4.35). Lower values in health-related quality of life were related to drop-out and death. The sub-scales global health status/QoL, role functioning, physical functioning, and fatigue symptom in the EORTC QLQ-C30 were key characteristics of early drop-out. Conclusion Severely affected cancer patients with poor social support and poor quality of life seem more likely to drop out of studies than patients with higher levels of social support and a better quality of life. This should be considered when planning studies to assess advanced cancer patients. Methods of close continued monitoring should be actively used when patient experiences a substantial deterioration in their health-related quality of life and symptoms during the study. Results for such studies have to be interpreted with caution in light of specific drop-out mechanisms. Trial registration OSCAR study was registered to the German Clinical Trials Register (DRKS-ID: DRKS00013640 ). Registered 29 December 2017.

Abstract Objective Neglect after stroke is a disabling disorder and its rehabilitation is a major challenge. Transcranial direct current stimulation (tDCS) seems to be a promising adjuvant technique to improve standard care neglect therapy. Since electric fields are influenced by age-related factors, higher current densities are probably needed for effective treatment in aged stroke patients. Validation of treatment efficacy requires sham-controlled experiments, but increased current densities might comprise blinding. Therefore, a pilot study was conducted to test sham adequacy when using current density of 0.8 A/m2. Whether especially neglect patients who mainly suffer from perceptual and attentional deficits are able to differentiate beyond chance active from sham tDCS was investigated in a randomized cross-over design (active/sham stimulation) in 12 early subacute patients with left-sided hemineglect. Stimulation (0.8 A/m2) was performed simultaneous to standard care neglect therapy. Results Odds ratio of correct guessing an atDCS condition compared to wrongly judge an atDCS condition as sham was 10.00 (95%CI 0.65–154.40, p = 0.099). However, given the small sample size and high OR, although likely somewhat overestimated, results require careful interpretation and blinding success in neglect studies with current densities of 0.8 A/m2 should be further confirmed.

AbstractBackground Hereditary Transthyretin-Related Amyloidosis, a clinically heterogeneous autosomal dominant disease caused by pathogenic variants in the TTR gene, is characterized by the deposition of insoluble misfolded protein fibrils. The diagnosis, especially in non-endemic areas, is typically delayed by 4–5 years; a misdiagnosis due to clinical heterogeneity is common. The study objective was to define the prevalence of Hereditary Transthyretin-Related Amyloidosis in patients with polyneuropathy and/or cardiomyopathy of no obvious aetiology.Method A multicenter observational “Epidemiological analysis for the hereditary Transthyretin-Related AMyloidosis”—TRAM study was performed in Germany, Austria, and Switzerland.Results A total of 5141 participants were recruited by 50 neurologic and 27 cardiologic specialized centres. Genetic analysis demonstrated a 1.1% Hereditary Transthyretin-Related Amyloidosis positivity rate among patients with polyneuropathy and/or cardiomyopathy of not obvious aetiology. Twenty-one various TTR variants (TTR-positive) were identified. Body Mass Index was lower in the TTR-positive patients as an indicator for the involvement of the autonomic nervous system; the age of onset of clinical manifestations was higher in TTR-positive patients. There were no other genotype-phenotype correlations or the prevalence of specific clinical manifestations in TTR-positive patients.Conclusions Our data support the fact that Hereditary Transthyretin-Related Amyloidosis is underdiagnosed in polyneuropathy and cardiomyopathy patients. Routine implementation of genetic testing is recommended in patients with unexplained polyneuropathy and/or cardiomyopathy to accelerate the earlier diagnosis and the time-sensitive treatment initiation.KEY MESSAGESMore than 5.000 participants with CM and/or PNP of no obvious aetiology were recruited in the observational “Epidemiological analysis for the hereditary Transthyretin-Related AMyloidosis” TRAM study and screened for pathogenic TTR variants.The study demonstrated >1% of patients with CM and/or PNP of unclear aetiology are positive for a pathogenic TTR variant.Routine genetic testing is recommended in patients with unexplained CM and/or PNP to accelerate the initial diagnosis and timely treatment initiation.

Abstract Background Outpatient follow-up care for stroke survivors is often inadequate and mostly self-organized by the patients themselves. In the German health care system, there are no standard care programs for patients after they are discharged from the hospital to support them with their multifaceted and heterogeneous health care needs. The objective of this complex intervention study was to evaluate the effectiveness of a post-stroke care coordination program in comparison to standard care in the first year after a stroke. Methods Patients aged 55 and older who had survived a stroke or a transient ischemic attack (TIA) within the last 6 months before enrollment were included. Participants received care coordination either by telephone or face-to-face for up to 1 year. Patients’ health insurance claims data were used to measure outcomes. The control group consisted of stroke survivors receiving standard care and was constructed by exact matching based on six criteria. Outcome measures were health services utilization, rate of recurrent events, readmissions and accompanying costs, and mortality. Outcomes were tested using different multiple models. Results In total, N = 361 patients were included in the analyses. Intervention participants had seen an outpatient neurologist more often (OR = 4.75; 95% CI: 2.71–8.31) and were readmitted to a hospital less frequently (IRR = 0.42; 95% CI: 0.29–0.61), resulting in lower hospital costs (IQR = €0–1910 in the intervention group, IQR = €0–4375 in the control group). There were no substantial group differences in the rate of recurrent events and mortality. Conclusion This study showed the beneficial potential of care coordination for a vulnerable patient population: the utilization rate of important health services was increased, and the rate of hospital readmissions decreased as a result. Future research should focus on the risk of recurrent strokes and the long-term effects of improved care. Trial registration DRKS00017526 on DRKS – German Clinical Trials Register (retrospectively registered: 21 June 2019).

Abstract Background Given the growing older population worldwide, and the associated increase in age-related diseases, such as Alzheimer’s disease (AD), investigating non-invasive methods to ameliorate or even prevent cognitive decline in prodromal AD is highly relevant. Previous studies suggest transcranial direct current stimulation (tDCS) to be an effective method to boost cognitive performance, especially when applied in combination with cognitive training in healthy older adults. So far, no studies combining tDCS concurrent with an intense multi-session cognitive training in prodromal AD populations have been conducted. Methods The AD-Stim trial is a monocentric, randomized, double-blind, placebo-controlled study, including a 3-week tDCS-assisted cognitive training with anodal tDCS over left DLPFC (target intervention), compared to cognitive training plus sham (control intervention). The cognitive training encompasses a letter updating task and a three-stage Markov decision-making task. Forty-six participants with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) will be randomized block-wise to either target or control intervention group and participate in nine interventional visits with additional pre- and post-intervention assessments. Performance in the letter updating task after training and anodal tDCS compared to sham stimulation will be analyzed as primary outcome. Further, performance on the second training task and transfer tasks will be investigated. Two follow-up visits (at 1 and 7 months post-training) will be performed to assess possible maintenance effects. Structural and functional magnetic resonance imaging (MRI) will be applied before the intervention and at the 7-month follow-up to identify possible neural predictors for successful intervention. Significance With this trial, we aim to provide evidence for tDCS-induced improvements of multi-session cognitive training in participants with SCD and MCI. An improved understanding of tDCS effects on cognitive training performance and neural predictors may help to develop novel approaches to counteract cognitive decline in participants with prodromal AD. Trial registration ClinicalTrials.gov , NCT04265378 . Registered on 07 February 2020. Retrospectively registered. Protocol version: Based on BB 004/18 version 1.2 (May 17, 2019). Sponsor: University Medicine Greifswald.

Introduction A substantial number of patients diagnosed with COVID-19 experience long-term persistent symptoms. First evidence suggests that long-term symptoms develop largely independently of disease severity and include, among others, cognitive impairment. For these symptoms, there are currently no validated therapeutic approaches available. Cognitive training interventions are a promising approach to counteract cognitive impairment. Combining training with concurrent transcranial direct current stimulation (tDCS) may further increase and sustain behavioural training effects. Here, we aim to examine the effects of cognitive training alone or in combination with tDCS on cognitive performance, quality of life and mental health in patients with post-COVID-19 subjective or objective cognitive impairments.Methods and analysis This study protocol describes a prospective randomised open endpoint-blinded trial. Patients with post-COVID-19 cognitive impairment will either participate in a 3-week cognitive training or in a defined muscle relaxation training (open-label interventions). Irrespective of their primary intervention, half of the cognitive training group will additionally receive anodal tDCS, all other patients will receive sham tDCS (double-blinded, secondary intervention). The primary outcome will be improvement of working memory performance, operationalised by an n-back task, at the postintervention assessment. Secondary outcomes will include performance on trained and untrained tasks and measures of health-related quality of life at postassessment and follow-up assessments (1 month after the end of the trainings).Ethics and dissemination Ethical approval was granted by the Ethics Committee of the University Medicine Greifswald (number: BB 066/21). Results will be available through publications in peer-reviewed journals and presentations at national and international conferences.Trial registration number NCT04944147.

Abstract Aims Heart failure (HF) is frequent in patients with acute ischaemic stroke (AIS) and associated with higher morbidity and mortality. Assessment of cardiac function in AIS patients using cardiovascular MRI (CMR) may help to detect HF. We report the rate of systolic and diastolic dysfunction in a cohort of patients with AIS using CMR and compare cine real‐time (CRT) sequences with the reference of segmented cine steady‐state free precession sequences. Methods and results Patients with AIS without known atrial fibrillation were prospectively enrolled in the HEart and BRain Interfaces in Acute Ischemic Stroke (HEBRAS) study (NCT 02142413) and underwent CMR at 3 Tesla within 7 days after AIS. Validity of CRT sequences was determined in 50 patients. A total of 229 patients were included in the analysis (mean age 66 years; 35% women; HF 2%). Evaluation of cardiac function was successful in 172 (75%) patients. Median time from stroke onset to CMR was 82 h (interquartile range 56–111) and 54 h (interquartile range 31–78) from cerebral MRI to CMR. Systolic dysfunction was observed in 43 (25%) and diastolic dysfunction in 102 (59%) patients. Diagnostic yield was similar using CRT or segmented cine imaging (no significant difference in left ventricular ejection fraction, myocardial mass, time to peak filling rate, and peak filling rate ratio E/A). Intraobserver and interobserver agreement was high (κ = 0.78–1.0 for all modalities). Conclusions Cardiovascular MRI at 3 Tesla is an appropriate method for the evaluation of cardiac function in a selected cohort of patients with AIS. Systolic and diastolic dysfunction is frequent in these patients. CRT imaging allows reliable assessment of systolic and diastolic function.

Abstract Background Sudden unexpected infant death (SUID) - including sudden infant death syndrome (SIDS) - continues to be a major contributor to infant mortality worldwide. Our objective was to analyse time trends and to identify country-clusters. Methods The National Statistical Offices of 52 countries provided the number of deaths and live births (1969–2012). We calculated infant mortality rates per 1000 live births for SUID, SIDS, and all-cause mortality. Overall, 29 countries provided sufficient data for time course analyses of SUID. To sensitively model change over time, we smoothed the curves of mortality rates (1980–2010). We performed a hierarchical cluster analysis to identify clusters of time trends for SUID and SIDS, including all-cause infant mortality. Results All-cause infant mortality declined from 28.5 to 4.8 per 1000 live births (mean 12.4; 95% confidence interval 12.0–12.9) between 1969 and 2012. The cluster analysis revealed four country-clusters. Clusters 1 and 2 mostly contained countries showing the typical peak of SUID mortality during the 1980s. Cluster 1 had higher SUID mortality compared to cluster 2. All-cause infant mortality was low in both clusters but higher in cluster 1 compared to cluster 2. Clusters 3 and 4 had low rates of SUID without a peak during the 1980s. Cluster 3 had the highest all-cause infant mortality of all clusters. Cluster 4 had an intermediate all-cause infant mortality. The time trends of SUID and SIDS mortality were similar. Conclusions The country-specific time trends in SUID varied considerably. The identification of country-clusters may promote research into how changes in sleep position, smoking, immunisation, or other factors are related to our findings.

Abstract Background Cognitive and motor-performance decline with age and the process is accelerated by decline in general health. In this study, we aimed to estimate the effects of COPD and HB levels on cognitive and motor performance in the general older population and assess potential interaction. Methods The English Longitudinal Study of Aging is a population-based cohort study including measurements of lung-function and HB levels together with cognitive and motor performance testing. Data were collected from 5709 participants including three measurement time over eight years. COPD was defined using lung-function-parameters and clinical symptoms. HB was assessed continuously and low HB was defined using clinical anemia cutoffs. Linear mixed-effects regression models were used to quantify the associations of COPD and HB with outcome measures, both individually and in combination. Results Participants with both low HB and COPD demonstrated worse motor performance compared to individuals with only one exposure, resulting in up to 1 s (95%CI, 0.04–1.8) longer time needed to complete the five times sit to stand task than what would be expected based on purely additive effects. Additionally in individuals with COPD, the time to complete the motor-performance task per unit decrease in continuous HB levels was longer than in participants without COPD after full adjustment for confounding (up to 1.38 s/unit HB level, 95% CI: 0.65–2.11). Conclusion In persons with COPD low HB levels may contribute to low motor-performance in a supra additive fashion. Further studies should re-evaluate whether earlier treatment of lower HB in these individuals might be beneficial.

Abstract Introduction Given rapid global population aging, developing interventions against age‐associated cognitive decline is an important medical and societal goal. We evaluated a cognitive training protocol combined with transcranial direct current stimulation (tDCS) on trained and non‐trained functions in non‐demented older adults. Methods Fifty‐six older adults (65–80 years) were randomly assigned to one of two interventional groups, using age and baseline performance as strata. Both groups performed a nine‐session cognitive training over 3 weeks with either concurrent anodal tDCS (atDCS, 1 mA, 20 minutes) over the left dorsolateral prefrontal cortex (target intervention) or sham stimulation (control intervention). Primary outcome was performance on the trained letter updating task immediately after training. Secondary outcomes included performance on other executive and memory (near and far transfer) tasks. All tasks were administered at baseline, post‐intervention, and at 1‐ and 7‐month follow‐up assessments. Prespecified analyses to investigate treatment effects were conducted using mixed‐model analyses. Results No between‐group differences emerged in the trained letter updating and Markov decision‐making tasks at post‐intervention and at follow‐up timepoints. Secondary analyses revealed group differences in one near‐transfer task: Superior n‐back task performance was observed in the tDCS group at post‐intervention and at follow‐up. No such effects were observed for the other transfer tasks. Improvements in working memory were associated with individually induced electric field strengths. Discussion Cognitive training with atDCS did not lead to superior improvement in trained task performance compared to cognitive training with sham stimulation. Thus, our results do not support the immediate benefit of tDCS‐assisted multi‐session cognitive training on the trained function. As the intervention enhanced performance in a near‐transfer working memory task, we provide exploratory evidence for effects on non‐trained working memory functions in non‐demented older adults that persist over a period of 1 month.

Background: This randomized controlled trial investigated if uni- and bihemispheric transcranial direct current stimulation (tDCS) of the motor cortex can enhance the effects of visuo-motor grip force tracking task training and transfer to clinical assessments of upper extremity motor function.Methods: In a randomized, double-blind, sham-controlled trial, 40 chronic stroke patients underwent 5 days of visuo-motor grip force tracking task training of the paretic hand with either unilateral or bilateral (N = 15/group) or placebo tDCS (N = 10). Immediate and long-term (3 months) effects on training outcome and motor recovery (Upper Extremity Fugl-Meyer, UE-FM, Wolf Motor Function Test, and WMFT) were investigated.Results: Trained task performance significantly improved independently of tDCS in a curvilinear fashion. In the anodal stimulation group UE-FM scores were higher than in the sham group at day 5 (adjusted mean difference: 2.6, 95%CI: 0.6–4.5, p = 0.010) and at 3 months follow up (adjusted mean difference: 2.8, 95%CI: 0.8–4.7, p = 0.006). Neither training alone, nor the combination of training and tDCS improved WMFT performance.Conclusions: Visuo-motor grip force tracking task training can facilitate recovery of upper extremity function. Only minimal add-on effects of anodal but not dual tDCS were observed.Clinical Trial Registration:https://clinicaltrials.gov/ct2/results?recrs=&cond=&term=NCT01969097&cntry=&state=&city=&dist=, identifier: NCT01969097, retrospectively registered on 25/10/2013.

Abstract Background Cancer patients experience psychological and social distress due to their medical treatment and social issues. However, continuous and specialized social support is still lacking. In Germany, a group of company health insurance funds has developed an approach to support cancer patients with monthly structured interviews conducted by specially trained Social Care Nurses. The nurses will identify patient needs in order to provide help with medical, personal, and social matters. One aim of the scientific evaluation is to analyze the effect of the consultations on various patient-reported outcomes, especially quality of life. The evaluation concept will be described in this study protocol. Methods/design The evaluation is a non-randomized, controlled, multi-center intervention study with a mixed-method design. It consists of three research modules which include primary data from questionnaires, and claims data from the health insurance funds. In Module 1, cancer patients will be recruited to form an intervention group (OSCAR, n = 150) and a control group (n = 200) in four study centers for a period of 1 year. One baseline and three follow-up questionnaires will be conducted to survey the patient-reported outcomes. Relevant secondary outcomes are health literacy, participation, and physician-patient communication. In Module 2, claims data will be used to analyze cost effects and thereby assess effectivity and hospitalization. Module 3 will involve a qualitative analysis of project diaries kept by the Social Care Nurses. The diaries will record the nurses’ practical experiences and the benefits of deploying OSCAR across the German healthcare system. Discussion OSCAR is an innovative way of providing cancer patients with continuous support to improve their quality of life. The evaluation concept aims to assess the effects of the monthly consultations by the Social Care Nurses on the patients, and will use a mixed-method design. The results are important for assessing the transferability of OSCAR to the healthcare system as a whole. Trial registration German Clinical Trials Register (DRKS-ID: DRKS00013640). Registered 29 December 2017.

Abstract Background Stroke patients are often affected by long-term disabilities with needs concerning social issues. There is relatively little consideration of social recovery of patients and the support required to return to work, receive social benefits, participate in daily life activities, maintain contact with family and friends and to organize financial affairs. In our study we aimed to investigate if existing tools record social needs adequately. We analyzed the current provision of social support provided in long-term care after stroke and whether unmet social needs were associated with quality of life, caregiver burden, overall function and degree of disability. Methods Our analysis is part of the Managing Aftercare of Stroke study (MAS-I), a cross-sectional exploratory study of patient needs 2–3 years after initial stroke. Assessment tools included the Nikolaus-score (social situation), the EuroQoL (quality of life), the German Burden Scale for Family Caregivers (caregiver burden), the modified Rankin Scale (disability / dependence), Stroke Impact Scale (function and degree of disability) and the Stroke Survivor Needs Questionnaire (unmet needs). Results Overall 57 patients were included in MAS-I, with ten patients classified in urgent need of socio-economic support according to the Nikolaus-score. Patients with lower than normal Nikolaus-score had a higher degree of disability. Thirty percent of all patients had never received professional social support. Social worker contact happened mostly during the stay in acute hospital or rehabilitation institution. Only four patients (11%) reported long-term support after discharge. Apart from social worker contact during acute care, 43% of patients had unmet needs in the long-term aftercare. Forty percent of all patients included in MAS-I were recommended for social work intervention after an in-depth analysis of their situation. Finally, we saw that unmet social needs were associated with lower quality of life and higher caregiver burden. Conclusions Our data suggest significant unmet needs in social care in long-term stroke patients. Screening tools for unmet social needs such as the Nikolaus-score do not holistically report patients’ needs. Trial registration Clinicaltrials.Gov NCT02320994. Registered 19 December 2014 (retrospectively registered).

Abstract Background Studies investigating the Mobile Stroke Unit (MSU) concept have shown increased thrombolysis rates, reduced alarm-to-treatment times and improved prehospital triage. Yet, so far, there is no definite scientific proof of better functional outcome after MSU deployment compared to regular ambulances. Methods We provide a revised protocol for the second part of the B_PROUD trial as organization of the MSU dispatch did not meet the anticipated standards in the first part. B_PROUD is a pragmatic, prospective study comparing functional outcomes of treatment candidates with or without MSU care. Treatment candidates are defined as patients with a final diagnosis of ischemic stroke or transient ischemic attack, onset-to-dispatch-times ≤4 h, disabling symptoms not resolved at time of ambulance arrival, and the ability to ambulate prior to the qualifying event. These patients are included if their emergency call prompted a stroke alarm at the dispatch center during MSU operation hours (7 am–11 pm, Monday-Sunday) and if the emergency is located within the MSU operation area in Berlin, Germany. The intervention group consists of patients who are cared for by the MSU. When the MSU is already in operation for another emergency, MSU dispatches are handled by regular ambulances (about 45%). These dispatches create the control group. Blinded stroke physicians assess the modified Rankin Scale (mRS) score in recorded structured interviews 3 months after stroke. The primary outcome is the degree of disability and death over the full range of the mRS. As a change to the previously published protocol and only pertinent in case of more than 9% lost-to-follow-up, a co-primary outcome was introduced consisting of the proportions of death, new institutional care or severe disability in patients with additional use of information from registration offices. Perspective The results will inform parties involved in acute stroke care organization on the effectiveness of the MSU concept. Trial registration The protocol is registered in (NCT03931616) and has been approved by the ethical review committee of the Charité – University Medicine Berlin (EA4/109/15) on September 2, 2015. The study protocol of B_PROUD part 1 had been published in the International Journal of Stroke as “Berlin Prehospital Or Usual Delivery of acute stroke care (B_PROUD) – study protocol” (doi: https://doi.org/10.1177/1747493017700152) on March 22, 2017 [1] previous to first patient’s registration.

Abstract Background Given the global increase in the aging population and age-related diseases, the promotion of healthy aging is one of the most crucial public health issues. This trial aims to contribute to the establishment of effective approaches to promote cognitive and brain health in older individuals with subjective cognitive decline (SCD). Presence of SCD is known to increase the risk of objective cognitive decline and progression to dementia due to Alzheimer’s disease. Therefore, it is our primary goal to determine whether spermidine supplementation has a positive impact on memory performance in this at-risk group, as compared with placebo. The secondary goal is to examine the effects of spermidine intake on other neuropsychological, behavioral, and physiological parameters. Methods The SmartAge trial is a monocentric, randomized, double-blind, placebo-controlled phase IIb trial. The study will investigate 12 months of intervention with spermidine-based nutritional supplementation (target intervention) compared with 12 months of placebo intake (control intervention). We plan to recruit 100 cognitively normal older individuals with SCD from memory clinics, neurologists and general practitioners in private practice, and the general population. Participants will be allocated to one of the two study arms using blockwise randomization stratified by age and sex with a 1:1 allocation ratio. The primary outcome is the change in memory performance between baseline and post-intervention visits (12 months after baseline). Secondary outcomes include the change in memory performance from baseline to follow-up assessment (18 months after baseline), as well as changes in neurocognitive, behavioral, and physiological parameters (including blood and neuroimaging biomarkers), assessed at baseline and post-intervention. Discussion The SmartAge trial aims to provide evidence of the impact of spermidine supplementation on memory performance in older individuals with SCD. In addition, we will identify possible neurophysiological mechanisms of action underlying the anticipated cognitive benefits. Overall, this trial will contribute to the establishment of nutrition intervention in the prevention of Alzheimer’s disease. Trial registration ClinicalTrials.gov, NCT03094546. Registered 29 March 2017—retrospectively registered. Protocol version Based on EA1/250/16 version 1.5

Variations in head and brain anatomy determine the strength and distribution of electrical fields in humans and may account for inconsistent behavioral and neurophysiological results in transcranial electrical stimulation (tES) studies. However, it is insufficiently understood which anatomical features contribute to the variability of the modelled electric fields, and if their impact varies across age groups. In the present study, we tested the associations of global head anatomy, indexed by extra- and intra-cranial volumes, with electric field measures, comparing young and older adults. We modelled six “conventional” electrode montages typically used in tES studies using SimNIBS software in 40 individuals (20 young, 20 older adults; 20-35, 64-79 years). We extracted individual electric field strengths and focality values for each montage to identify tissue volumes that account for variability of the induced electric fields in both groups. Linear mixed models explained most of the inter-individual variability of the overall induced field strength in the brain, but not of field focality. Higher absolute head volume and relative volume of skin, skull and cerebrospinal fluid (CSF) were associated with lower overall electric field strengths. Additionally, we found interactions of age group with head volume and CSF, indicating that this relationship was mitigated in the older group. Our results demonstrate the importance to adjust brain stimulation not only according to brain atrophy, but also to additional parameters of head anatomy. Future studies need to elucidate the mechanisms underlying individual variability of tES effects in young and older adults, and verify the usefulness of the proposed models in terms of neurophysiology and behavior in empirical studies.

Objectives: Injury to major white matter pathways during language-area associated glioma surgery often leads to permanent loss of neurological function. The aim was to establish standardized tractography of language pathways as a predictor of language outcome in clinical neurosurgery. Methods: We prospectively analyzed 50 surgical cases of patients with left perisylvian, diffuse gliomas. Standardized preoperative Diffusion-Tensor-Imaging (DTI)-based tractography of the 5 main language tracts (Arcuate Fasciculus [AF], Frontal Aslant Tract [FAT], Inferior Fronto-Occipital Fasciculus [IFOF], Inferior Longitudinal Fasciculus [ILF], Uncinate Fasciculus [UF]) and spatial analysis of tumor and tracts was performed. Postoperative imaging and the resulting resection map were analyzed for potential surgical injury of tracts. The language status was assessed preoperatively, postoperatively and after 3 months using the Aachen Aphasia Test and Berlin Aphasia Score. Correlation analyses, two-step cluster analysis and binary logistic regression were used to analyze associations of tractography results with language outcome after surgery. Results: In 14 out of 50 patients (28%), new aphasic symptoms were detected 3 months after surgery. The preoperative infiltration of the AF was associated with functional worsening (cc = 0.314; p = 0.019). Cluster analysis of tract injury profiles revealed two areas particularly related to aphasia: the temporo-parieto-occipital junction (TPO; temporo-parietal AF, middle IFOF, middle ILF) and the temporal stem/peri-insular white matter (middle IFOF, anterior ILF, temporal UF, temporal AF). Injury to these areas (TPO: OR: 23.04; CI: 4.11 – 129.06; temporal stem: OR: 21.96; CI: 2.93 – 164.41) was associated with a higher-risk of persisting aphasia. Conclusions: Tractography of language pathways can help to determine the individual aphasia risk profile pre-surgically. The TPO and temporal stem/peri-insular white matter were confirmed as functional nodes particularly sensitive to surgical injuries.

IntroductionMany 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).MethodsData 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.ResultsInformation 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.DiscussionUsing 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 trialsEffects 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.

Background: The natural polyamine spermidine, known to be important for cellular function, decreases during aging. Previous research has demonstrated beneficial impact of spermidine intake on memory functions in both animal models and humans, suggesting that spermidine may be a preventive approach to delay age-related cognitive decline and possibly even Alzheimer’s disease (AD). However, the association of spermidine intake with brain health in humans is still unknown. In this study, we aimed to determine the association between dietary spermidine intake and structural brain measures in older individuals with subjective cognitive decline (SCD) and healthy controls (HC). Methods: Dietary spermidine intake and adherence to Mediterranean Diet (MeDi) were assessed by a self-reported food frequency questionnaire in 90 older adults with SCD and 47 HC. Processing of structural MRI data yielded global brain volumes, hippocampal volume, mean and regional cortical thickness, and cortical thickness in a template encompassing AD-vulnerable regions. In exploratory analyses, the association between spermidine intake and structural brain measures was assessed using adjusted and unadjusted linear regression models. Additionally, we tested for differential associations as a function of group. Mediation analyses were performed to examine whether dietary spermidine intake mediates the associations between adherence to MeDi and structural brain measures. Results: Higher spermidine intake was associated with larger hippocampal volume (standardized β ​= ​0.262, p ​= ​0.002), greater mean cortical thickness (standardized β ​= ​0.187, p ​= ​0.031), and greater cortical thickness in AD-vulnerable brain regions (standardized β ​= ​0.176, p ​= ​0.042), the parietal (standardized β ​= ​0.202, p ​= ​0.020), and temporal lobes (standardized β ​= ​0.217, p ​= ​0.012). No significant differential effect emerged between older adults with SCD and HC. Moreover, a substantial mediating effect of dietary spermidine intake on the associations between adherence to MeDi and structural brain measures was observed. Conclusion: Higher dietary spermidine intake was positively associated with several structural brain measures, irrespective of the presence of SCD, and substantially mediated the relationship of adherence to MeDi and structural brain measures. Our data suggest that higher spermidine intake might be a promising dietary approach to preserve brain health in older adults, a hypothesis currently tested in an interventional trial.

Objectives: To evaluate the impact of resting-state functional MRI scan length on the diagnostic accuracy, image quality and lesion volume estimation of BOLD delay maps used for brain perfusion assessment in acute ischemic stroke.Methods: Sixty-three acute ischemic stroke patients received a 340 s resting-state functional MRI within 24 h of stroke symptom onset. BOLD delay maps were calculated from the full scan and four shortened versions (68 s, 136 s, 204 s, 272 s). The BOLD delay lesions on these maps were compared in terms of spatial overlap and volumetric agreement with the lesions derived from the full scans and with time-to-maximum (Tmax) lesions derived from DSC-MRI in a subset of patients (n = 10). In addition, the interpretability and quality of these maps were compared across different scan lengths using mixed models.Results: Shortened BOLD delay scans showed a small volumetric bias (ranging from 0.05 to 5.3 mL; between a 0.13% volumetric underestimation and a 7.7% overestimation relative to the mean of the volumes, depending on scan length) compared to the full scan. Decreased scan length was associated with decreased spatial overlap with both the BOLD delay lesions derived from the full scans and with Tmax lesions. Only the two shortest scan lengths (68 and 136 s) were associated with substantially decreased interpretability, decreased structure clarity, and increased noisiness of BOLD delay maps.Conclusions: BOLD delay maps derived from resting-state fMRI scans lasting 272 and 204 s provide sufficient diagnostic quality and adequate assessment of perfusion lesion volumes. Such shortened scans may be helpful in situations where quick clinical decisions need to be made.

BACKGROUND:In stroke studies, ordinal logistic regression (OLR) is often used to analyze outcome on the modified Rankin Scale (mRS), whereas the non-parametric Mann-Whitney measure of superiority (MWS) has also been suggested. It is unclear how these perform comparatively when confounding adjustment is warranted. AIMS:Our aim is to quantify the performance of OLR and MWS in different confounding variable settings. METHODS:We set up a simulation study with three different scenarios; (1) dichotomous confounding variables, (2) continuous confounding variables, and (3) confounding variable settings mimicking a study on functional outcome after stroke. We compared adjusted ordinal logistic regression (aOLR) and stratified Mann-Whitney measure of superiority (sMWS), and also used propensity scores to stratify the MWS (psMWS). For comparability, OLR estimates were transformed to a MWS. We report bias, the percentage of runs that produced a point estimate deviating by more than 0.05 points (point estimate variation), and the coverage probability. RESULTS:In scenario 1, there was no bias in both sMWS and aOLR, with similar point estimate variation and coverage probabilities. In scenario 2, sMWS resulted in more bias (0.04 versus 0.00), and higher point estimate variation (41.6% versus 3.3%), whereas coverage probabilities were similar. In scenario 3, there was no bias in both methods, point estimate variation was higher in the sMWS (6.7%) versus aOLR (1.1%), and coverage probabilities were 0.98 (sMWS) versus 0.95 (aOLR). With psMWS, bias remained 0.00, with less point estimate variation (1.5%) and a coverage probability of 0.95. CONCLUSIONS:The bias of both adjustment methods was similar in our stroke simulation scenario, and the higher point estimate variation in the MWS improved with propensity score based stratification. The stratified MWS is a valid alternative for adjusted OLR only when the ratio of number of strata versus number of observations is relatively low, but propensity score based stratification extends the application range of the MWS.