CENTER-TBI: Collaborative European NeuroTrauma Effectiveness Research in TBI

Completed

Conditions: Traumatic Brain Injury

Registration Number: NCT02210221

Lead Sponsor: University Hospital, Antwerp

Brief Summary: The research aims of the CENTER-TBI study are to:

1. better characterize Traumatic Brain Injury (TBI) as a disease and describe it in a European context, and

2. identify the most effective clinical interventions for managing TBI.

Specific aims

1. To collect high quality clinical and epidemiological data with repositories for neuro-imaging, DNA, and serum from patients with TBI.

2. To refine and improve outcome assessment and develop health utility indices for TBI.

3. To develop multidimensional approaches to characterisation and prediction of TBI.

4. To define patient profiles which predict efficacy of specific interventions ("Precision Medicine").

5. To develop performance indicators for quality assurance and quality improvement in TBI care.

6. To validate the common data elements (CDEs) for broader use in international settings, and to develop a user-friendly web based data entry instrument and case report form builder.

7. To develop an open database compatible with Federal Interagency Traumatic Brain Injury Research (FITBIR).

8. To intensify networking activities and international collaborations in TBI.

9. To disseminate study results and management recommendations for TBI to health care professionals, policy makers and consumers, aiming to improve health care for TBI at individual and population levels.

10. To develop a "knowledge commons" for TBI, integrating CENTER-TBI outputs into systematic reviews.

Detailed Description: • Introduction:

CENTER-TBI (Collaborative European NeuroTrauma Effectiveness Research in TBI) (www.center-tbi.eu) is a project embedded within the International Initiative on TBI Research (InTBIR) (http://intbir.nih.gov/), as a collaboration between the European Commission (EC), the US National Institute of Neurological Disorders and Stroke (NIH-NINDS) and the Canadian Institute of Health Research (CIHR).

* Research aims:

The basic concept of this project is to exploit the existing heterogeneity in biology, care and outcome of TBI patients to discover underlying pathophysiology, to refine characterisation, and to identify effective clinical interventions. The key driver of our research plan is to collect data from a large number of European centres and sufficiently large cohort to enable 'Comparative effectiveness research' (CER) analyses of differences in clinical care and management pathways in TBI.

Improved disease characterization will aid Precision Medicine, a concept recently enunciated by the US National Academy of Science. Such improved characterization and stratification will allow for more targeted therapies. Further, CER provides a promising framework to identify best practices and improve outcome after TBI. CER is the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition or to improve the delivery of care. The purpose of CER is to assist consumers, clinicians, purchasers, and policy makers to make informed decisions that will improve health care at both the individual and population levels.

* Cohort:

A large core cohort of patients across the severity spectrum in TBI will be recruited at approximately 77 sites in Europe and Israel (the CENTER-TBI Core Study): 5400 patients differentiated into 3 equal strata of approximately 1800:

* ER stratum: patients seen and discharged from the ER;

* Admission stratum: patients admitted to the hospital but not to the ICU;

* ICU stratum: patients admitted directly to the ICU. Balance in numbers between the strata will be aimed for, but sites will be allowed to arrange recruitment strategies to best suit their local requirements.

The core cohort will be underpinned by comparison with a larger registry (the CENTER-TBI registry) based on pragmatic data collection of all patients with TBI seen in participating centres (to establish the internal generalizability of our study), and by comparison with national trauma registries (to establish the external generalizability of our findings).

In the core cohort, detailed data will be collected on clinical parameters, neuroimaging studies, biomarker analyses, DNA analyses, and longitudinal outcome assessments. In selected centres, extended studies will additionally focus on advanced magnetic resonance (MR) imaging, detailed coagulation profiling and high resolution ICU monitoring.

* Sample size assessment:

The sample size estimate (n=5400) was based on:

* Practical logistic considerations

* Power calculations for the different strata, targeting comparative effectiveness analyses, assuming a between-centre and between-country heterogeneity as identified in previous research (expressed by variance parameter from a random effects model, Tau\^2 of 0.431)

* Postulated odds ratios for intervention effects of approximately 5% improvement in outcome.

Overall, these calculations provided a statistical power to detect odds ratios of \~1.2 associated with differences in process or intervention variables across the core dataset with a power of 80%; and require somewhat larger odds ratios in each of the three individual strata. In the registry we expect to be able to detect differences (predominantly in organizational or system variables) with an odds ratio of 1.2 with a power of 82%.

* Quality control and assurance:

Continuous monitoring of enrolment and completeness of data will be performed by ICON as contract research organization (CRO). Source data verification (SDV) will be performed in 10% of subjects by the CRO. The quality of data collection will be further enhanced by implementing automated data entry checks for impossible/implausible values and implementing data checks for consistency between variables. A task force of study personnel will evaluate the completeness, consistency and validity of submitted data and function as support desk for participating sites.

* Data management:

Prior to upload to the study database, all acquired data will be stored locally. All patients will be allocated a random Global Unique Personal Identification number (GUPI) which will be linked locally to hospital identifiers. All uploaded data will be de-identified and images will be defaced prior to upload. While blood samples and clinical data will be linked, both sets of data will be kept confidential and anonymised beyond the initial stage of correlation for analysis. All imaging and electronic data will be kept on individually password protected servers. All clinical data will be entered into electronic Case Report Forms (eCRFs) and managed by the 'QuesGen data management platform' (http://www.quesgen.com/) which will be developed in collaboration with Karolinska Institutet International Neuroinformatics Coordinating Faculty (KI-INCF). As data is entered into each form, the system will run data validation checks that include conditionally required data, validation across fields, and validation requirements based on subject type. If any validation check fails, the user is alerted immediately that the data does not meet Quality Assurance (QA) criteria and the issue can be addressed and corrected at that point. All de-identified electronic study data in the CENTER-TBI database will be stored securely in the European data space under supervision of KI-INCF for the duration of subject enrolment and follow-up and for a period afterwards for data analysis and preparation of publications. We estimate that the analysis and publication period will last for several years after the conclusion of subject enrolment.

Together with QuesGen Systems, KI-INCF will ensure that data standards are established for the data model e.g. conformity of field formats, field codes and names to ensure consistency across all datasets. Any approved changes will be fully documented with dataset updates to maintain data quality and accuracy. KI-INCF will be responsible for importing cleaned datasets to other analytic platforms as determined by the coordinators.

Where applicable, information relevant to the patient's care will be made available to the physician responsible. Data, including blood samples collected as part of this study will be shared in an anonymised form with collaborators from other European states (this is part of a European Commission Framework7 funded program), and with selected collaborators in other countries who form part of an emerging International Traumatic Brain Injury Research initiative.

* Computing platform and Neuroinformatics Resource:

The KI-INCF will coordinate the establishment of an informatics platform for acquisition, storage and analysis of CDE-based clinical data. The goal is to develop a next generation open standards-based platform to support advanced large-scale analytics and model building. Such a platform also provides a model for future clinical studies on brain diseases and disorders. This development will receive additional support from One Mind for Research.

* Statistical analysis plan:

Statistical analyses for the Comparative Effectiveness Research (CER) questions will primarily apply random effects modelling, in which center is included at the higher level, and patients are considered clustered within centers. In some analyses, higher levels of clustering will also be considered, e.g. country, or European region; or lower levels, e.g. physicians within hospitals. Confounding factors as measured at the individual patient and/or center level, will be considered extensively, and will be targeted to the specific research question.

Statistical analyses for better characterization of TBI will be exploratory, aiming to better understand the complexity of the disease and to discover new associations. In addition to standard statistical descriptive and inferential techniques, we will also employ novel machine learning techniques as appropriate.

Prognostic analyses will consider a range of variables, including genetic, demographic and clinical data, physiological signals, imaging results, and biomarkers as predictors of early endpoints and physiologic derangement (e.g. raised ICP), and late outcome, including mortality, functional outcome, quality of life and neuropsychological performance. Previously and newly developed prediction models will be validated by comparison of observed to predicted outcome risks, with predictive performance summarized by measures for model fit, discrimination, and calibration.

* Missing data:

Every effort will be made to limit the number of missing data in the CENTER-TBI study. Missing values are, however, inherent to any clinical study. Missing values may confound the descriptive, prognostic and CER analyses. Thus, appropriate techniques for dealing with missing values are required. First, we will evaluate the various reasons for missingness per centre. Next, we will explore the use of alternative statistical approaches, including inverse probability weighting and multiple imputation. We will consider missing values in baseline characteristics as well as in short and long term outcomes. Based on simulation studies and practical considerations we will develop standard operating procedures towards the analyses with missing values, respecting the differences in multiple research questions.

* Informed Consent:

Informed consent procedures will follow local and national requirements in all cases. We anticipate that many potential patients will not be able to consent themselves to participate in this project. The nature of TBI means that some patients may lack capacity to decide to participate in this study especially at the earliest time point. It is important to try and include these patients to ensure that representative samples of patients are included to avoid bias in the study findings. Every step will be taken to ensure that a test of capacity is undertaken before a decision on a person's capacity to consent or not to consent to participation in research is taken. If the subject is not capable of self-consent, all efforts will be made to locate a legally acceptable representative to act on behalf of the subject. When a legally acceptable representative (e.g. consultee/proxy) is identified, their opinion will be sought about the potential participant's wishes and feelings in relation to the project, and whether he or she would have wanted to take part in the study.

Subjects are free to withdraw, or be withdrawn by their consultee/proxy if appropriate, at any point in the study, and they need not state a reason.

* Impact:

The CENTER-TBI project will contribute towards the overall goals of InTBIR, by identifying more effective and efficient treatment provision, thus improving outcome and reducing costs. The science in the project will provide novel information on disease processes, treatment, outcome, and prognosis in TBI, identifying new therapeutic targets and therapies; while the CENTER-TBI repositories will ensure opportunities for legacy research. Thus, the project has the potential to improve current health care and its delivery at both population and individual levels, deliver early scientific advances that could improve the care of patients with TBI, and provide a rich investment for future biomedical research.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 4559

Inclusion Criteria

Clinical diagnosis of TBI
Clinical indication for CT scan
Presentation within 24 hours of injury
Informed consent obtained according to local and national requirements

Exclusion Criteria

Severe pre-existing neurological disorder that would confound outcome assessments

Study & Design

Study Type: OBSERVATIONAL

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
SF-12v2 Health Survey (Short-Form Health Survey With 12 Questions) at 6 Months	6 months	The SF-12v2 Health Survey uses 12 questions to measure functional health and well-being from the patient's point of view. The SF-12v2 at 6 months is available in 2300 patients.
Glasgow Outcome Scale - Extended (GOSE) at 6 Months	6 months	The Extended Glasgow Outcome Scale is a global scale for functional outcome that rates patient status into 8 categories, going from dead to good recovery. 1. Death 2. Vegetative sate 3. Lower severe disability 4. Upper severe disability 5. Lower moderate disability 6. Upper moderate disability - some disability but can potentially return to some form of employment 7. Lower good recovery - minor physical or mental defect 8. Upper good recovery - full recovery The 6-month GOSE score is available in 3804 patients (84%).
6 Month Quality of Life in Brain Injury (Qolibri-OS) <52 (Impaired)	6 months	The Quality of Life in Brain Injury (Qolibri-OS) is a 6 item overall scale that provides a profile of health-related quality of life in domains typicality affected by brain injury, such as physical function, cognition, emotional status, ability to perform daily activities, personal life and social relationship, and satisfaction with current situation and future prospects. The QOLIBRI scores are reported on a 0-100 scale , where 0=worst possible quality of life and 100=best possible quality of life.

Secondary Outcome Measures

Name	Time	Method
6 Month Galveston Orientation and Amnesia Test (GOAT) < 75 (Impaired)	6 months	The GOAT is a standardised assessment used to determine whether a participant is in post-traumatic amnesia (PTA). PTA is an early phase of TBI recovery during which the person with injury shows markedly impaired memory, confusion, fluctuation in performance, disorientation, and other neurobehavioral signs and symptoms. GOAT questions assess orientation, memory for the first event that the participant can recall after the injury, and memory for the last event that the participant can recall from before the injury. The GOAT's total score must be achieved by subtracting from 100 the total amount of error scores (Total score = 100 - total amount of error scores). Scores lower than 75 point to the fact that the victim is still experiencing amnesia.
6 Month JK Coma Recovery Scale - Revised <23 (Impaired)	6 months	The Coma Recovery Scale- Revised (CRS-R) is a standardized behavioral assessment instrument designed to measure neurobehavioral function in patients with disorders of consciousness (DOC). The CRS-R is comprised of six subscales addressing auditory, visual, motor, oromotor/verbal, communication and arousal functions. Subscale items are hierarchically-arranged, corresponding to brain stem, subcortical and cortically-mediated functions. Scores range between 0 (deep coma) and 23 (able to follow commands and to use objects purposefully). A total score less than 23 indicates impairment.
6 Month Post-traumatic Stress Disorder (PTSD) Checklist for DSM-5 (PCL-5) <33 (Impaired)	6 months	The PCL-5 is a self-report rating scale intended to assess 20 DSM-5 symptoms of Posttraumatic Stress Disorder. The standard recall period for the PCL-5 is one month. For CENTER-TBI a recall period of one week was used at the 2-3 week assessment, and the standard one month recall period was used at other time points. The sum of scores can range from 0 to 80, where high scores indicate more pronounced PTSD symptoms.
6 Month Rivermead Post Concussion Questionnaire <16 (Impaired)	6 months	The Rivermead PCS Questionnaire (RPQ) was originally developed as a measure of severity of symptoms following MTBI. It consists of 16 post-concussion symptoms including headaches, dizziness, nausea/vomiting, noise sensitivity, sleep disturbance, fatigue, irritability, feeling depressed/tearful, feeling frustrated/ impatient, forgetfulness, poor concentration, taking longer to think, blurred vision, light sensitivity, double vision and restlessness. In the original version of the RPQ, participants are asked to rate the degree (on a scale of 0 to 4) to which a particular symptom has been absent or a mild, moderate or severe problem over the previous 7 days compared with premorbid levels. Total scores range from 0 to 64 with higher scores indicating more severe symptoms. Scores equal to or greater than 16 were considered indicative of persisting post-concussion symptoms.
6 Month Timed up and go Test - Impaired	6 months	In the timed up and go (TUG) test, subjects are asked to rise from a standard armchair, walk to a marker 3 m away, turn, walk back, and sit down again, for quantifying functional mobility. The presence of slowness, hesitancy, abnormal trunk or arm movements, staggering or stumbling is used to grade the patient from 1 (normal) to 5 (severely abnormal). Impaired mobility was defined as taking 14 seconds or longer to perform the TUG test.
6 Month Trail Making Test (TMT) Part A - Impaired	6 months	The Trail Making Test (TMT) is a measure of attention, speed, and mental flexibility. Part A requires the individual to draw lines to connect 25 encircled numbers distributed on a page. Part B is similar except the person must alternate between numbers and letters and is more difficult and takes longer to complete. Both sections are timed and the score represents the amount of time required to complete the task, with shorter times indicating better performance. The maximum time allowed is 100 seconds. Impairment cutoff: \> 55.9 (based on the comparison group as a whole and expressed as raw score). For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be \> or \< than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).
6 Month Rey Auditory Verbal Learning Test (RAVLT) - Impaired	6 months	The Rey Auditory Verbal Learning Test (RAVLT) is a test of verbal memory that assesses the ability to acquire 15 words. Recall is assessed after each presentation of the list, after the recall of an interference list, and again following a 20-minute delay. The total score for recall of the principal list ranges from 0 to 75, with higher scores indicating better performance. Impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers.
6 Month Trail Making Test (TMT) Part B - Impaired	6 months	The TMT is a measure of attention, speed, and mental flexibility. Part A requires the individual to draw lines to connect 25 encircled numbers distributed on a page. Part B is similar except the person must alternate between numbers and letters, is more difficult, takes longer to complete. Both sections are timed, the score represents the amount of time required to complete the task, with shorter times indicating better performance. Impairment cutoff: \> 143.7 (based on the comparison group as a whole and expressed as raw score). For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be \> or \< than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).
6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) PAL (Paired Associate Learning Task) - Impaired	6 months	CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For CANTAB PAL, the individual must remember 1 to 8 patterns displayed in different positions on the screen. The score is the number of incorrect responses adjusted if necessary for trials that have not been completed. Scores ranged from 0-194 with lower score indicating better performance. Impairment cutoff: \> 72.3 (based on the comparison group as a whole and expressed as raw score). For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be \> or \< than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).
6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) SOC (Stockings of Cambridge Task) - Impaired	6 months	The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For the CANTAB SOC, the individual moves circles to match a target in this task based on the Tower of Hanoi game. The score is the number of problems solved in the minimum number of moves, with a maximum of 12. Higher scores indicate better performance. Impairment cutoff: \< 5.7(based on the comparison group as a whole and expressed as raw score). For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be \> or \< than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).
6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) SWM (Spatial Working Memory Task) - Impaired	6 months	The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For the CANTAB SWM, the participant searches for tokens in boxes on the screen. The between errors measure is the number of times the participant queries a box that has already been searched. Errors ranged from 0 to 151, with lower numbers indicating better performance. Impairment cutoff: \> 52.0 (based on the comparison group as a whole and expressed as raw score). For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be \> or \< than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).
6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) AST (Attention Switching Task ) - Impaired	6 months	The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For the CANTAB AST, participants respond either to the position of an arrow or the direction it is pointing, after being cued to the task on each trial. Total correct responses range from 0 to 160, where higher numbers indicate better performance. Impairment cutoff: \<135.5 (based on the comparison group as a whole and expressed as raw score). For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be \> or \< than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).
6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) RTI (Reaction Time Task) - Impaired	6 months	The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For CANTAB RTI, the individual must respond as quickly as possible to a circle presented at one of 5 positions. The outcome measure is the median time for correct responses (ms). Impairment cutoff: \> 470.9 (based on the comparison group as a whole and expressed as raw score). For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be \> or \< than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).
6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) RVP (Rapid Visual Information Processing Task) - Impaired	6 months	The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For the CANTAB RVP, sequences of numbers must be detected as they appear on the screen. The measure of accuracy is A' (A prime) which is derived from hits and correct rejections. The maximum score is 1 and, a higher A' indicates better performance. Impairment cutoff: \< 0.82 (based on the comparison group as a whole and expressed as raw score). For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be \> or \< than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).
Early (2-3 Weeks) MRI Imaging - Traumatic Intracranial Abnormalities	Between 2-3 weeks after enrolment	A selected number of sites performed MRI follow up in a subset of patients that consented for imaging data collection. The CENTER-TBI MR protocols included a high-resolution 3D T1-weighted, a T2-weighted, a FLAIR, a DTI, a T2\* sequence (gradient echo and/or SWI), and (optionally) a resting-state fMRI. Across all stratum the MRI sites performed a follow up MRI at 2-3 weeks after injury. Traumatic Intracranial Abnormalities were assessed according to the TBI-Common Data Elements (CDEs). It indicates whether any of the 12 following imaging abnormalities are present (Mass lesion, Extra-axial Hematoma, Epidural Hematoma, Subdural Hematoma Acute, Subdural Hematoma Subacute Chronic, Subdural Collection Mixed Density, Contusion, TAI, traumatic Subarachnoid Hemorrhage, Intraventricular Hemorrhage, Midline Shift or Cisternal Compression.

Trial Locations

Locations (65): Bufalini Hospital
🇮🇹
Cesena, Italy
S Raffaele University Hospital
🇮🇹
Milan, Italy
Maggiore Della Carità Hospital
🇮🇹
Novara, Italy
Azienda Ospedaliera Università di Padova
🇮🇹
Padova, Italy
Antwerp University Hospital
🇧🇪
Edegem, Belgium
Lille University Hospital
🇫🇷
Lille, France
University Hospital Nancy
🇫🇷
Nancy, France
Hadassah-hebrew University Medical Center
🇮🇱
Jerusalem, Israel
ASST di Monza
🇮🇹
Monza, Italy
Rezekne Hospital
🇱🇻
Rezekne, Latvia
Leiden University Medical Center
🇳🇱
Leiden, Netherlands
Medical Center Haaglanden
🇳🇱
The Hague, Netherlands
Umea University Hospital
🇸🇪
Umea, Sweden
Centre Hospitalier Universitaire Vaudois
🇨🇭
Lausanne, Switzerland
Addenbrookes Hospital
🇬🇧
Cambridge, United Kingdom
University Hospitals Leuven
🇧🇪
Leuven, Belgium
CHU Liege
🇧🇪
Liege, Belgium
Odense University Hospital
🇩🇰
Odense, Denmark
Turku University Hospital
🇫🇮
Turku, Finland
University Hospital Heidelberg
🇩🇪
Heidelberg, Germany
University of Pecs
🇭🇺
Pecs, Hungary
APHP
🇫🇷
Paris, France
University Hospital of Grenoble
🇫🇷
Grenoble, France
University of Szeged
🇭🇺
Szeged, Hungary
Rambam Medical Center
🇮🇱
Haifa, Israel
Fondazione IRCCS Cà Granda Ospedale Maggiore Poloclinico
🇮🇹
Milan, Italy
University Medical Center Groningen
🇳🇱
Groningen, Netherlands
St Olavs Hospital/Norwegian University of science and technology
🇳🇴
Trondheim, Norway
Cruces University Hospital
🇪🇸
Bilbao, Spain
Southmead Hospital
🇬🇧
Bristol, United Kingdom
Lothian Health Board
🇬🇧
Edinburgh, United Kingdom
The Walton centre NHS Foundation Trust
🇬🇧
Liverpool, United Kingdom
Sheffield Teaching Hospitals NHS Foundation Trust
🇬🇧
Sheffield, United Kingdom
Innsbruck Medical University
🇦🇹
Innsbruck, Austria
Medical University Vienna
🇦🇹
Vienna, Austria
CHR Citadelle
🇧🇪
Liege, Belgium
Helsinki University Central Hospital
🇫🇮
Helsinki, Finland
CHU Poitiers
🇫🇷
Poitiers, France
University Hospital Aachen
🇩🇪
Aachen, Germany
Klinikum Ludwigsburg
🇩🇪
Ludwigsburg, Germany
University of Health Sciences
🇱🇹
Kaunas, Lithuania
Center of neurovascular surgery, Clinic of neurology and neurosurgery, Vilnius University
🇱🇹
Vilnius, Lithuania
Erasmus MC
🇳🇱
Rotterdam, Netherlands
Oslo University Hospital
🇳🇴
Oslo, Norway
University Hospital Northern Norway
🇳🇴
Tromso, Norway
Karolinska University Hospital
🇸🇪
Stockholm, Sweden
Charité Campus Virchow
🇩🇪
Berlin, Germany
Kings college London
🇬🇧
London, United Kingdom
Niguarda Hospital
🇮🇹
Milan, Italy
Pauls Stradins Clinical University Hospital
🇱🇻
Riga, Latvia
Kaunas University of technology and Vilnius University
🇱🇹
Vilnius, Lithuania
Radboud University Medical Center
🇳🇱
Nijmegen, Netherlands
Emergency County Hospital Timisoara
🇷🇴
Timisoara, Romania
Queen Elizabeth Hospital
🇬🇧
Birmingham, United Kingdom
Hospital Universitario 12 de Octubre
🇪🇸
Madrid, Spain
Vall d'Hebron University Hospital
🇪🇸
Barcelona, Spain
AOU Città della Salute e della Scienza di Torino
🇮🇹
Torino, Italy
Riga Eastern Clinical University Hospital
🇱🇻
Riga, Latvia
The HAGA Hospital
🇳🇱
The Hague, Netherlands
TweeSteden Ziekenhuis
🇳🇱
Tilburg, Netherlands
Clinical centre of Vojvodina
🇷🇸
Novi Sad, Serbia
Salford Royal Hospital
🇬🇧
Salford, United Kingdom
University Hospitals Southampton NHS Trust
🇬🇧
Southampton, United Kingdom
Clínico Universitario de Valencia
🇪🇸
Valencia, Spain
Region Hovedstaden Rigshospitalet
🇩🇰
Copenhagen, Denmark