Background and objectivesThis study investigates whether ultra-early follow-up imaging can reliably identify patients at risk for hematoma expansion (HE) in acute intracerebral hemorrhage (ICH).MethodsIn this multicenter study, we analyzed data from patients with primary ICH who underwent at least two non-contrast cranial computed tomography (NCCT) scans within 7 days of symptom onset or last known well. To define the optimal time window, hematoma growth dynamics were retrospectively assessed in a large cohort (n = 1,663). Based on these findings, a prospective sub-study included patients with repeated imaging within 200 min (n = 46). HE was defined as >6 mL or >33% volume increase between the admission and the second follow-up scan. The diagnostic performance of early volume increase was evaluated using receiver operating characteristic (ROC) analysis.ResultsThe highest proportion of patients with active hemorrhage was detected within the first 200 min in the initial phase of this study. In the prospective sub-study, percentage volume increase between admission and early follow-up imaging demonstrated excellent diagnostic performance for HE (AUC = 0.819). At an optimized cutoff, the model yielded a sensitivity of 0.885 and a positive predictive value (PPV) of 74%. Among patients with early expansion already visible at follow-up, 50% showed further volume increase on the final scan. A separate analysis limited to follow-up imaging within the first 120 min after symptom onset (n = 27) revealed a higher diagnostic accuracy, with an AUC of 0.846 (sensitivity 0.857; PPV 71%).ConclusionICH evolves rapidly in the first hours after onset. Follow-up imaging within the first 200 min can diagnose hematoma growth with high sensitivity and good accuracy. However, the inability to distinguish between ongoing and completed expansion underscores the need for additional imaging or clinical markers to support clinical decisions.

Introduction Following a cerebrovascular event, the associated risks for further major adverse cerebro- and cardiovascular events and death (MACE) and important aspects of cognitive, mental and patient-reported outcomes are currently not understood, particularly long-term. Here, we present the study design of the ongoing Berlin Long-term Observation of Vascular Events (BeLOVE) stroke stratum and report data of the first study phase.Methods and analysis BeLOVE is a prospective, longitudinal, observational, hospital-based cohort study. Its stroke stratum enrols adult patients with acute ischaemic stroke, transient ischaemic attack (TIA) or non-traumatic intracerebral haemorrhage. Patients undergo deep phenotyping including cerebral and cardiac MRI, ECG, echocardiography and bio-sampling including multi-omics analyses. Regular, standardised follow-ups take place annually over a period of up to 10 years and record the frequency of MACE as the primary outcome.Secondary outcomes include the frequency, progression and interactions of functional impairments, namely post-stroke cognition, pain, depression, seizures and their relationship to quality of life.The first study phase included 758 patients (median 69 years, 37% female). At 2-year follow-up, the cumulative incidence (95% CI) of the composite primary endpoint MACE was 0.107 (0.085 to 0.132) and that of first ischaemic stroke, first myocardial infarction and death were 0.066 (0.049 to 0.086), 0.015 (0.008 to 0.026) and 0.040 (0.027 to 0.056), respectively.Ethics and dissemination Each participant will provide informed written consent during the acute in-hospital phase. Data will be available for research purposes via a written request to the data use and access committee.Trial registration number German Clinical Trials Register: http://www.drks.de/DRKS00023323 on 4 November 2020.

BACKGROUND:White matter hyperintensity (WMH) segmentation using BIANCA (Brain Intensity AbNormality Classification Algorithm) in stroke populations is complicated by vascular lesions that share T2-hyperintense signal characteristics with WMH. Whether preprocessing decisions in the treatment of lesions affect segmentation accuracy has not yet been systematically evaluated in cerebrovascular cohorts involving multiple scanners. METHODS:We compared fixed probability thresholds and locally adaptive thresholding with LOCATE (LOCally Adaptive Threshold Estimation), and three lesion-handling approaches: lesions present (non removed), replaced with zero intensities (removed), and replaced with normal-appearing white matter intensities (NAWM; inpainted), using the BeLOVE cohort (Berlin Longterm Observation of Vascular Events) and the WMH Segmentation Challenge dataset. Phase I (n = 89) optimized thresholding via stratified 5-fold cross-validation. Phase II assessed preprocessing effects on segmentation accuracy (Phase II-A, n = 89) and volume agreement (Phase II-B, n = 211). RESULTS:BIANCA with LOCATE adaptive thresholding achieved moderate segmentation overlap (mean Dice 0.567), with lesion-level detection exceeding an F1 of 0.85. Preprocessing effects were statistically detectable but negligible in magnitude, with near-perfect agreement between all conditions. Stroke lesion volume was the highest-ranked predictor of volume differences between conditions; these scaled with lesion size but remained negligible in magnitude across all subgroups. CONCLUSIONS:BIANCA with LOCATE achieved moderate WMH segmentation performance with the best sensitivity-precision trade-off in this multi-scanner cerebrovascular cohort. Preprocessing effects were negligible at the group level. However, large lesions distort the FLAIR intensity distribution on which BIANCA relies for classification, which justifies lesion removal as a recommended preprocessing step.

Abstract Background and Objectives Normal appearing white matter (NAWM) may already harbor subtle microstructural alterations not yet visible on conventional MRI. Quantitative Multi-Parametric Mapping (qMPM) such as Magnetization Transfer saturation (MTsat), longitudinal relaxation rate (R1), and Proton Density (PD) offer new possibilities for analyzing NAWM which are sensitive to demyelination, axonal loss, and edema. We aimed to characterize these alterations within white matter hyperintensities (WMH) and the perilesional NAWM (pNAWM), to gain insights into the underlying process of lesion progression. We also investigated their association with cerebrovascular risk factors (CVRF) and long-term cognitive performance. Methods This investigation included the cerebral MRI data of 245 participants from the prospective Berlin Longterm Observation of Vascular Events (BeLOVE) study. Furthermore, 121 participants’ cognitive performance was evaluated at baseline and longitudinally at 2 years follow-up using Montreal Cognitive Assessment (MoCA). Regions of interest (ROIs) of WMH, pNAWM at 1, 2, 3 mm were assessed in comparison to the mirrored contralesional white matter (cWM). Linear mixed effects models were employed to demonstrate the pairwise comparisons between each region using estimated marginal means and the association of MPM metrics with CVRFs. Linear regression was used to assess the association with cognitive performance. Results In 245 participants, (mean age 62 years, SD: 12 years; 29.8% females), MPM metrics demonstrated a clear spatial gradient of microstructural injury. MTsat and R1 values were lower in WMH compared to cWM (ß = -0.48 (-0.52 - -0.44) and ß = -0.07 (-0.08 - -0.06), p<0.001, respectively) and showed gradual recovery with increasing distance indicating a microstructural gradient in pNAWM. Conversely, PD values were higher in WMH and decreased peripherally (ß = 2.32 (2.05 – 2.61, p<0.001). No substantial associations were found between MPM parameters and CVRFs in our cohort. At baseline and 2-year follow-up, cognitive performance was associated with higher pNAWM R1 values, whereas MTsat were only moderately associated. Discussion Quantitative MPM reliably detects microstructural alterations not only within WMH, but also in pNAWM, confirming the high sensitivity of qMPM to subtle tissue pathology and support its utility as a promising biomarker for longitudinal studies and monitoring therapeutic effects.

BackgroundMobile Stroke Units (MSU) shorten time to intravenous thrombolysis (IVT) and improve functional outcome, but they rely on computed tomography (CT) making them highly specialized and costly. Alternative technologies can potentially identify imaging-based IVT contraindications like intracranial hemorrhage (ICH) or malignancies (IM), e.g., by transcranial color-coded sonography (TCCS) and near-infrared spectroscopy (NIRS).MethodsUsing a simulation approach, we analyzed magnetic resonance imaging (MRI) scans of stroke-suspected patients within 4.5 h of symptom onset to assess TCCS and NIRS for identifying imaging-based IVT contraindications. Our study included both primary and sensitivity analyses, each employing conservative and optimistic scenarios. The primary analysis integrated clinical information from the emergency department, while the sensitivity analysis evaluated overall performance across all patients, regardless of clinical information. The conservative scenario defined TCCS detecting acute deep-brain hemorrhages or tumors >20 mm from scalp surface or > 10 mL in volume or causing >4 mm midline-shift, while NIRS was defined detecting them <20 mm from scalp surface with a volume > 3.5 mL. The optimistic scenario defined TCCS detecting intracranial or subarachnoid acute/subacute hematoma or tumors >20 mm from scalp surface or > 5 mL in volume or causing >2 mm midline-shift, while NIRS was defined detecting them <35 mm from the scalp surface with volume > 3.5 mL.ResultsWe assessed 1,089 consecutive patients undergoing acute MRI, identifying 69 with imaging-based IVT contraindications, of which 40 had additional non-imaging contraindications. In the primary analysis, among those 29 patients without non-imaging-based contraindications, TCCS/NIRS would have detected 15 of 25 ICH and 3 of 4 malignant tumors in the conservative scenario. In the optimistic scenario, 18 of 25 ICH and all malignant tumors would have been detected. In the sensitivity analyses, the conservative scenario would have detected 30 of 52 ICH and 8 of 17 malignant tumors, while the optimistic scenario would have identified 37 of 52 ICH and 12 of 17 malignant tumors.ConclusionWhile TCCS and NIRS technologies exhibit potential for identifying IVT contraindications in pre-hospital settings, comprehensive evaluation in real-world scenarios is imperative to ascertain their operational constraints.

BACKGROUND AND OBJECTIVES:Prehospital stroke management on mobile stroke units (MSUs) shortens time to IV thrombolysis (IVT) and improves functional outcomes. Because IVT effects are time-dependent, optimizing workflows and dispatch-related processes may enhance MSU benefits. The B_PROUD-2.0 study aimed to determine the effect of additional MSU dispatch on functional outcomes in acute stroke patients under optimized MSU organization and service delivery. METHODS:In the nonrandomized, controlled B_PROUD-2.0 study (May 2019-April 2021) conducted in Berlin, Germany, MSUs were simultaneously dispatched with conventional care ambulances for suspected stroke emergency calls, whenever available. We compared outcomes and process parameters between dispatch groups (additional MSU dispatch vs conventional care only) among patients with cerebral ischemia with disabling neurologic symptoms and no contraindications to reperfusion treatments. We used data from the Berlin dispatch center and records from the B_SPATIAL registry, consisting of 15 Berlin hospitals with stroke units. We performed pooled analyses with the B_PROUD-1.0 primary population (February 2017-April 2021) and with an extended cohort that also included patients with reperfusion treatment contraindications. The primary and co-primary outcomes were 3-month modified Rankin Scale scores (0: no deficits to 6: death) and 3-tiered disability scale scores. Effect estimates for these outcomes were obtained from ordinal logistic regressions, adjusting for a priori selected covariates after multiple imputation for missing values. RESULTS:Coronavirus disease 2019 pandemic and limited funding hindered full implementation of procedural improvements. A total of 1,050 patients (mean age: 74 years, 46.7% female) were included in B_PROUD-2.0 (vs 1,500 planned). We found no statistically significant effect of MSU dispatch on primary (common odds ratio [cOR] 0.90, 95% CI 0.72-1.14) or co-primary (cOR 0.86, 95% CI 0.63-1.17) outcomes in B_PROUD-2.0, and higher odds of IVT ≤1 hour of dispatch in the MSU group (OR 10.15, 95% CI 7.10-14.51). In pooled B_PROUD-1.0+2.0 primary population analyses (N = 2,666, mean age: 73 years, 46.8% female), we found a beneficial effect on primary (cOR 0.80, 95% CI 0.67-0.96) and co-primary (cOR 0.79, 95% CI 0.64-0.97) outcomes. The average effect on all stroke/TIA patients in the extended cohort (N = 4,336, mean age 75 years, 47.6% female) was also favorable (primary cOR 0.85, 95% CI 0.75-0.95; co-primary cOR 0.86, 95% CI 0.75-0.99). DISCUSSION:While we did not observe statistically significant differences in functional outcomes in the underpowered B_PROUD-2.0 study, we found beneficial effects considering both B_PROUD study periods, also when including all stroke/TIA patients. TRIAL REGISTRATION INFORMATION:ClinicalTrials.gov: NCT03931616. Registered: April 26, 2019. First patient enrolled: May 9, 2019. CLASSIFICATION OF EVIDENCE:The B_PROUD-2.0 study provides Class III evidence that the addition of MSUs to conventional care ambulances did not improve functional outcomes at 3 months compared with conventional care ambulances alone in patients with acute ischemic stroke.

IntroductionAcute ischemic stroke (AIS) is a leading cause of permanent disability in adults and one of the most time-sensitive emergencies in modern medicine. Rapid diagnosis and initiation of thrombolytic therapy, as well as immediate access to mechanical thrombectomy for patients with large-vessel occlusion (LVO), are critical determinants of favorable outcomes. While Mobile Stroke Units (MSUs) – ambulances equipped with computed tomography (CT) imaging – have demonstrated efficacy in improving outcomes, their deployment is often constrained to urban environments due to cost-efficiency considerations. Blood biomarkers offer a potentially cost-effective alternative for stroke diagnosis and subtyping. Especially for patients with LVO, a prehospital biomarker-based identification could enable a streamlined transport strategy directly to thrombectomy-capable stroke centers. In this study, we evaluate the diagnostic accuracy and feasibility of a novel point-of-care test (POCT) in predicting LVO stroke, along with the levels of vascular biomarkers—NT-proBNP, D-Dimer, and H-FABP—from ultra-early whole-blood samples of patients with suspected stroke in a prehospital setting. The test integrates a blood-based multiplex lateral flow assay (LFA) with clinical decision support (CDS) software, accessible through a Mobile Application (App). The study was registered in the German Clinical Trials Register (DRKS-ID: DRKS00037840).Methods and analysisThis multicenter prospective observational study will include 800 patients with suspected stroke, enrolled within 24 h after symptom onset. Participants will be recruited at three Mobile Stroke Unit (MSU) sites in Berlin, Germany. Prehospital blood samples will be analyzed directly in the ambulance using the LVOCheck device. The test achieves its performance by quantifying the blood levels of the vascular biomarkers (NT-proBNP, D-Dimer, and H-FABP), and inputting these concentrations, along with neurological assessment score and patient-specific medical information such as age and blood pressure, to output predictive information on the probability of LVO stroke, together with all the input data. Additional clinical data, including final diagnoses, will be documented in electronic case report forms (eCRFs). The diagnostic performance of LVOCheck will be evaluated through comprehensive statistical analysis of the combined biomarker and clinical data, including assessment of sensitivity, specificity, and predictive models.DiscussionThis real-world study aims to evaluate the diagnostic accuracy and feasibility (including human factors and usability) of LVOCheck, a portable, non-invasive multiplex POCT at prehospital settings, such as an ambulance, in the prediction of acute LVO diagnosis and triage of suspected acute LVO stroke patients. Utilizing Mobile Stroke Units (MSUs) as recruiting sites enables the analysis of ultra-early biomarker levels from prehospital whole-blood samples combined with patient-specific medical information to provide a predictive risk of LVO stroke. A cost-effective and practical POCT could provide additional biochemical information to support prehospital LVO identification in the future, thereby potentially assisting emergency medical services in transport decisions regarding direct transfer to thrombectomy-capable centers. This may improve triage efficiency, treatment metrics and outcomes in both urban and rural settings.Clinical trial registrationhttps://www.drks.de/search/de/trial/DRKS00037840/details, Identifier DRKS00037840.

INTRODUCTION:In patients with acute intracerebral haemorrhage (ICH) and elevated systolic blood pressure (BP), guidelines suggest that systolic BP reduction to <140 mmHg should be rapidly initiated. Compared with conventional care, Mobile Stroke Units (MSUs) allow for earlier ICH diagnosis through prehospital imaging and earlier BP lowering. PATIENTS AND METHODS:ICH patients were prospectively evaluated as a cohort of the controlled B_PROUD-study in which MSU availability alone determined MSU dispatch in addition to conventional ambulance. We used inverse probability of treatment weighting to adjust for confounding to estimate the effect of additional MSU dispatch in ICH patients. Outcomes of interest were 7-day mortality (primary), systolic BP (sBP) at hospital arrival, dispatch-to-imaging time, largest haematoma volume, anticoagulation reversal, length of in-hospital stay, 3-month functional outcome. RESULTS:Between February 2017 and May 2019, MSUs were dispatched to 95 (mean age: 72 ± 13 years, 45% female) and only conventional ambulances to 78 ICH patients (mean age: 71 ± 12 years, 44% female). After adjusting for confounding, we found shorter dispatch-to-imaging time (mean difference: -17.75 min, 95% CI: -27.16 to -8.21 min) and lower sBP at hospital arrival (mean difference = -16.31 mmHg, 95% CI: -30.64 to -6.19 mmHg) in the MSU group. We found no statistically significant difference for the other outcomes, including 7-day mortality (adjusted odds ratio: 1.43, 95% CI: 0.68 to 3.31) or favourable outcome (adjusted odds ratio = 0.67, 95% CI: 0.27 to 1.67). CONCLUSIONS:Although MSU dispatch led to sBP reduction and lower dispatch-to-imaging time compared to conventional ambulance care, we found no evidence of better outcomes in the MSU dispatch group.

BackgroundTelemedicine provides specialized medical expertise in underserved areas where neurological expertise is frequently not available on a daily basis for hospitalized stroke patients. While tele-consultations are well established in acute stroke assessment, the value of telemedicine-based ward-rounds in the subsequent in-patient stroke management is unknown.MethodsFour telemedicine stroke networks in Germany, implemented in eight out of 16 federal states, participate in this prospective observational multi-center study. We plan to enroll 523 patients hospitalized due to acute (suspected or confirmed) stroke or transient ischemic attack. Each recruited patient will receive both a tele-consultation and an on-site consultation at the same day within the first three days after hospital admission. We will test non-inferiority of telemedicine-based assessments in ward-rounds in terms of quality of medical assessment and recommendations for hospitalized stroke patients. The correctness of the medical assessment and recommendation is defined as positive evaluation (binary, correct vs. in-correct) of six out of six predefined quality indicators by at least two out of three blinded independent raters. The non-inferiority margin for the difference in proportions of correct assessments is set to 5%-points.DiscussionIf non-inferiority of telemedicine-based ward-rounds compared to on-site ward-rounds by a neurologist were demonstrated, telemedicine-based neurological consultation for post-acute stroke patients may contribute to deliver evidence-based high-quality stroke care more easily in underserved regions.Trial registrationDRKS - DRKS00028671 (https://drks.de/search/de/trial/DRKS00028671; registration date 09-27-2022).

BACKGROUND:Clinical data warehouses provide harmonized access to healthcare data for medical researchers. Informatics for Integrating Biology and the Bedside (i2b2) is a well-established open-source solution with the major benefit that data representations can be tailored to support specific use cases. These data representations can be defined and improved via an iterative approach together with domain experts and the medical researchers using the platform. To facilitate these discussions, it is important to understand how users interact with the system. OBJECTIVE:The objective of this work was to develop metrics for describing user interactions with clinical data warehouses in general and i2b2 in particular. Moreover, we aimed to develop a dashboard featuring interactive visualizations that inform data engineers and data stewards about potential improvements. METHODS:We first identified metrics for different data usage dimensions and extracted the relevant metadata about previous user queries from the i2b2 database schema for further analysis. We then implemented associated visualizations in Python and integrated the results into an interactive dashboard using Dash. RESULTS:The identified categories of metrics include frequency of use, session duration, and use of functionality and features. We created a dashboard that extends our local i2b2 data warehouse platform, focusing on the latter category, further broken down into the number of queries, frequently queried concepts, and query complexity. The implementation is available as open-source software. CONCLUSION:A range of metrics can be derived from metadata logged in the i2b2 database schema to provide data engineers and data stewards with a comprehensive understanding of how users interact with the platform. This can help to identify the strengths and limitations of specific instances of the platform for specific use cases and aid their iterative improvement.

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 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|<0.1). Conclusions This study provides easy-to-apply algorithms to convert PROMIS-29 data to well-established SF-36 physical and mental component summary scores in a cardiovascular population. Applied to new data, the agreement between empirical and predicted SF-36 scores was high. However, for SF-36 mental component summary scores, considerably better predictions were found under the correlated (MCSc) than under the original factor model (MCS). Additionally, as a pertinent byproduct, our study confirmed construct validity of the relatively new PROMIS-29 health summary scores in cardiology patients.

Abstract BackgroundPseudonymization has become a best practice to securely manage the identities of patients and study participants in medical research projects and data sharing initiatives. This method offers the advantage of not requiring the direct identification of data to support various research processes while still allowing for advanced processing activities, such as data linkage. Often, pseudonymization and related functionalities are bundled in specific technical and organization units known as trusted third parties (TTPs). However, pseudonymization can significantly increase the complexity of data management and research workflows, necessitating adequate tool support. Common tasks of TTPs include supporting the secure registration and pseudonymization of patient and sample identities as well as managing consent. ObjectiveDespite the challenges involved, little has been published about successful architectures and functional tools for implementing TTPs in large university hospitals. The aim of this paper is to fill this research gap by describing the software architecture and tool set developed and deployed as part of a TTP established at Charité – Universitätsmedizin Berlin. MethodsThe infrastructure for the TTP was designed to provide a modular structure while keeping maintenance requirements low. Basic functionalities were realized with the free MOSAIC tools. However, supporting common study processes requires implementing workflows that span different basic services, such as patient registration, followed by pseudonym generation and concluded by consent collection. To achieve this, an integration layer was developed to provide a unified Representational state transfer (REST) application programming interface (API) as a basis for more complex workflows. Based on this API, a unified graphical user interface was also implemented, providing an integrated view of information objects and workflows supported by the TTP. The API was implemented using Java and Spring Boot, while the graphical user interface was implemented in PHP and Laravel. Both services use a shared Keycloak instance as a unified management system for roles and rights. ResultsBy the end of 2022, the TTP has already supported more than 10 research projects since its launch in December 2019. Within these projects, more than 3000 identities were stored, more than 30,000 pseudonyms were generated, and more than 1500 consent forms were submitted. In total, more than 150 people regularly work with the software platform. By implementing the integration layer and the unified user interface, together with comprehensive roles and rights management, the effort for operating the TTP could be significantly reduced, as personnel of the supported research projects can use many functionalities independently. ConclusionsWith the architecture and components described, we created a user-friendly and compliant environment for supporting research projects. We believe that the insights into the design and implementation of our TTP can help other institutions to efficiently and effectively set up corresponding structures.

Background The severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) pandemic causes a high burden of acute and long-term morbidity and mortality worldwide despite global efforts in containment, prophylaxis, and therapy. With unprecedented speed, the global scientific community has generated pivotal insights into the pathogen and the host response evoked by the infection. However, deeper characterization of the pathophysiology and pathology remains a high priority to reduce morbidity and mortality of coronavirus disease 2019 (COVID-19). Methods NAPKON-HAP is a multi‐centered prospective observational study with a long‐term follow‐up phase of up to 36 months post-SARS-CoV-2 infection. It constitutes a central platform for harmonized data and biospecimen for interdisciplinary characterization of acute SARS-CoV-2 infection and long-term outcomes of diverging disease severities of hospitalized patients. Results Primary outcome measures include clinical scores and quality of life assessment captured during hospitalization and at outpatient follow-up visits to assess acute and chronic morbidity. Secondary measures include results of biomolecular and immunological investigations and assessment of organ-specific involvement during and post-COVID-19 infection. NAPKON-HAP constitutes a national platform to provide accessibility and usability of the comprehensive data and biospecimen collection to global research. Conclusion NAPKON-HAP establishes a platform with standardized high-resolution data and biospecimen collection of hospitalized COVID-19 patients of different disease severities in Germany. With this study, we will add significant scientific insights and provide high-quality data to aid researchers to investigate COVID-19 pathophysiology, pathology, and chronic morbidity.

Clonal hematopoiesis (CH) is common among older people and associated with an increased risk of atherosclerosis, inflammation, and shorter overall survival. Age and inflammation are major risk factors for ischemic stroke, yet the association of CH with risk of secondary vascular events and death is unknown. We investigated CH in peripheral blood DNA from 581 patients with first-ever ischemic stroke from the Prospective Cohort with Incident Stroke-Berlin study (PROSCIS-B) using error-corrected targeted sequencing. The primary composite endpoint (CEP) consisted of recurrent stroke, myocardial infarction, and all-cause mortality. 348 somatic mutations with a variant allele frequency ≥ 1% were identified in 236/581 patients (41%). CH was associated with large-artery atherosclerosis stroke (P = 0.01) and white matter lesion (P < 0.001). CH-positive patients showed increased levels of pro-inflammatory cytokines such as IL-6, IFN-γ, hsCRP, and VCAM-1. CH-positive patients had a higher risk for the primary CEP (HR: 1.55, 95%-CI 1.04 - 2.31, P = 0.03), which was more pronounced in patients with larger clones. CH clone size remained an independent risk factor (HR 1.30, 95%-CI 1.04 - 1.62, P = 0.022) in multivariable Cox regression. While our data show that in particular larger and TET2- or PPM1D-mutated clones are associated with increased risk of recurrent vascular events and death, this risk is partially mitigated by a common germline variant of the IL-6 receptor (IL-6R p.D358A). The CH mutation profile is accompanied by a pro-inflammatory profile opening new avenues for preventive precision medicine approaches to resolve the self-perpetuating cycle of inflammation and clonal expansion.

IntroductionIntravenous thrombolysis (IVT) and mechanical thrombectomy (MT) are well-established, evidence-based, time-critical therapies that reduce morbidity and mortality in acute ischemic stroke (AIS) patients. The exclusion of intracerebral hemorrhage (ICH) is mandatory and has been performed by cerebral imaging to date. Mobile stroke units (MSUs) have been shown to improve functional outcomes by bringing cerebral imaging and IVT directly to the patient, but they have limited coverage. Blood biomarkers clearly distinguishing between AIS, ICH, and stroke mimics (SM) could provide an alternative to cerebral imaging if concentration changes are detectable in the hyperacute phase after stroke with high diagnostic accuracy. In this study, we will take blood samples in a prehospital setting to evaluate potential biomarkers. The study was registered in the German Clinical Trials Register (https://drks.de/search/de) with the identifier DRKS00023063.Methods and analysisWe plan a prospective, observational study involving 300 patients with suspected stroke and symptom onset of ≤4.5 h before the collection of biomarkers. Study participants will be recruited from three sites in Berlin, Germany during MSU deployments. The focus of the study is the collection of blood samples from participants at the prehospital scene and from participants with AIS or ICH at a second-time point. All samples will be analyzed using targeted and untargeted analytical approaches. Study-related information about participants, including medical information and discharge diagnoses from the subsequent treating hospital, will be collected and documented in an electronic case report form (eCRF).DiscussionThis study will evaluate whether a single blood biomarker or a combination of biomarkers can distinguish patients with AIS and ICH from patients with stroke and SM in the early phase after symptom onset in the prehospital setting. In addition, the kinetics of blood biomarkers in AIS and ICH patients will be investigated. Our goal is to evaluate new ways to reliably diagnose stroke in the prehospital setting and thus accelerate the application of evidence-based therapies to stroke patients.

BackgroundMechanical thrombectomy (MT) is highly effective in large vessel occlusion (LVO) stroke. In north-east Germany, many rural hospitals do not have continuous neurological expertise onsite and secondary transport to MT capable comprehensive stroke centers (CSC) is necessary. In metropolitan areas, small hospitals often have neurology departments, but cannot perform MT. Thus, interhospital transport to CSCs is also required. Here, we compare time-to-care metrics and outcomes in patients receiving MT after interhospital transfer from primary stroke centers (PCSs) to CSCs in rural vs. metropolitan areas.MethodsPatients from ten rural telestroke centers (RTCs) and nine CSCs participated in this study under the quality assurance registry for thrombectomies of the Acute Neurological care in North-east Germany with TeleMedicine (ANNOTeM) telestroke network. For the metropolitan area, we included patients admitted to 13 hospitals without thrombectomy capabilities (metropolitan primary stroke centers, MPSCs) and transferred to two CSCs. We compared groups regarding baseline variables, time-to-care metrics, clinical, and technical outcomes.ResultsBetween October 2018 and June 2022, 50 patients were transferred from RTCs within the ANNOTeM network and 42 from MPSCs within the Berlin metropolitan area. RTC patients were older (77 vs. 72 yrs, p = 0.05) and had more severe strokes (NIHSS 17 vs. 10 pts., p < 0.01). In patients with intravenous thrombolysis (IVT; 34.0 and 40.5%, respectively), time from arrival at the primary stroke center to start of IVT was longer in RTCs (65 vs. 37 min, p < 0.01). However, RTC patients significantly quicker underwent groin puncture at CSCs (door-to-groin time: 42 vs. 60 min, p < 0.01). Despite longer transport distances from RTCs to CSCs (55 vs. 22 km, p < 0.001), there was no significant difference of times between arrival at the PSC and groin puncture (210 vs. 208 min, p = 0.96). In adjusted analyses, there was no significant difference in clinical and technical outcomes.ConclusionDespite considerable differences in the setting of stroke treatment in rural and metropolitan areas, overall time-to-care metrics were similar. Targets of process improvement should be door-to-needle times in RTCs, transfer organization, and door-to-groin times in CSCs wherever such process times are above best-practice models.

Pseudonymisation has become a best practice to securely manage the identities of patients and study participants in medical research projects and data sharing initiatives. This method offers the advantage of not requiring directly identifying data to support various research processes, while still allowing for advanced processing activities, such as data linkage. Often, pseudonymization and related functionalities are bundled in specific technical and organization units, the so-called Trusted Third Parties (TTPs). However, pseudonymization can significantly increase the complexity of data management and research workflows, necessitating the need for adequate tool support. Common tasks for TTPs include supporting the secure registration and pseudonymization of patient and sample identities as well as consent management. Despite the challenges involved, little has been published about successful architectures and functional tools for implementing TTPs in large-scale university hospitals. The aim of this manuscript is to bridge this gap by describing the software architecture and tool set developed and deployed as part of a TTP established at Charité – Universitätsmedizin Berlin. The infrastructure for the TTP was designed to provide a modular structure while keeping maintenance requirements low. Basic functionalities were realized with the free MOSAIC tools. However, supporting common study processes required to implement workflows that span different basic services, e.g., patient registration, followed by pseudonym generation and concluded by consent collection. To achieve this, an integration layer was developed that provides a unified RESTful Application Programming Interface (API) as a basis for more complex workflows. Based on this API, a unified Graphical User Interface (GUI) was also implemented, providing an integrated view on information objects and workflows supported by the TTP. The API was implemented using Java and Spring Boot, while the GUI was implemented in PHP and Laravel. Both services use a shared Keycloak instance as a unified management system for roles and rights. By the end of 2022, the TTP has already supported more than 10 research projects since it took up operation in December 2019. Within these projects, more than 3,000 identities were stored, more than 30,000 pseudonyms were generated and more than 1,500 consent forms were submitted. In total, more than 150 people regularly work with the software platform. By implementing the integration layer and the unified user interface together with comprehensive roles and rights management, the effort for operating the TTP could be significantly reduced, since personnel of the supported research projects can use many functionalities independently. With the architecture and components described, a user-friendly and compliant environment for supporting research projects has been created. We believe that the insights into the design and implementation of our TTP can help other institutions to efficiently and effectively set up corresponding structures.

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.