How do 66 European institutional review boards approve one protocol for an international prospective observational study on traumatic brain injury? Experiences from the CENTER-TBI study

Background The European Union (EU) aims to optimize patient protection and efficiency of health-care research by harmonizing procedures across Member States. Nonetheless, further improvements are required to increase multicenter research efficiency. We investigated IRB procedures in a large prospective European multicenter study on traumatic brain injury (TBI), aiming to inform and stimulate initiatives to improve efficiency. Methods We reviewed relevant documents regarding IRB submission and IRB approval from European neurotrauma centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI). Documents included detailed information on IRB procedures and the duration from IRB submission until approval(s). They were translated and analyzed to determine the level of harmonization of IRB procedures within Europe. Results From 18 countries, 66 centers provided the requested documents. The primary IRB review was conducted centrally (N = 11, 61%) or locally (N = 7, 39%) and primary IRB approval was obtained after one (N = 8, 44%), two (N = 6, 33%) or three (N = 4, 23%) review rounds with a median duration of respectively 50 and 98 days until primary IRB approval. Additional IRB approval was required in 55% of countries and could increase duration to 535 days. Total duration from submission until required IRB approval was obtained was 114 days (IQR 75-224) and appeared to be shorter after submission to local IRBs compared to central IRBs (50 vs. 138 days, p = 0.0074). Conclusion We found variation in IRB procedures between and within European countries. There were differences in submission and approval requirements, number of review rounds and total duration. Research collaborations could benefit from the implementation of more uniform legislation and regulation while acknowledging local cultural habits and moral values between countries.Peer reviewe

Quality indicators for patients with traumatic brain injury in European intensive care units

Background: The aim of this study is to validate a previously published consensus-based quality indicator set for the management of patients with traumatic brain injury (TBI) at intensive care units (ICUs) in Europe and to study its potential for quality measur

Asthma control in adolescents 10 to 11 y after exposure to the World Trade Center disaster

Background: Little is known about asthma control in adolescents who were exposed to the World Trade Center (WTC) attacks of 11 September 2001 and diagnosed with asthma after 9/11. This report examines asthma and asthma control 10–11 y after 9/11 among exposed adolescents. Methods: The WTC Health Registry adolescent Wave 3 survey (2011–2012) collected data on asthma diagnosed by a physician after 11 September 2001, extent of asthma control based on modified National Asthma Education and Prevention Program criteria, probable mental health conditions, and behavior problems. Parents reported healthcare needs and 9/11-exposures. Logistic regression was used to evaluate associations between asthma and level of asthma control and 9/11-exposure, mental health and behavioral problems, and unmet healthcare needs. Results: Poorly/very poorly controlled asthma was significantly associated with a household income of ≤$75,000 (adjusted odds ratio (AOR): 3.0; 95% confidence interval (CI): 1.1–8.8), having unmet healthcare needs (AOR: 6.2; 95% CI: 1.4–27.1), and screening positive for at least one mental health condition (AOR: 5.0; 95% CI: 1.4–17.7), but not with behavioral problems. The impact of having at least one mental health condition on the level of asthma control was substantially greater in females than in males. Conclusions: Comprehensive care of post-9/11 asthma in adolescents should include management of mental health-related comorbidities. The collapse and burning of the World Trade Center (WTC) towers on 11 September 2001 (9/11) exposed hundreds of thousands of people to a complex mixture of dust, debris, and jet fuel combustion byproducts (1). It is estimated that over 25,000 persons in lower Manhattan developed asthma symptoms after exposure to the WTC terrorist attacks and the subsequent rescue and recovery efforts (1). In the years immediately following 9/11, new-onset asthma rates were elevated among exposed adults and many of those affected continued to experience respiratory symptoms (i.e., coughing, shortness of breath) years later (1,2). An estimated 25,000 children were living or attending school in lower Manhattan near the WTC on 9/11, and potentially were in the path of the dust cloud of building debris and smoke after the collapse of the towers, as well as for several months following the attacks, and could have inhaled particulate matter and toxic substances (3,4). Associations between 9/11-related exposures and both asthma diagnosis and persistent respiratory symptoms among children and adolescents have been documented (4,5,6). A previous report found that 2 to 3 y after 9/11, over half of children under 18 y of age who were enrolled in the World Trade Center Health Registry (Registry) reported new or worsening respiratory symptoms (53%), and 5.7% reported a post-9/11 diagnosis of asthma, both of which were associated with exposure to the dust cloud that resulted from the collapse of buildings on 9/11 (4). A subsequent study of Registry enrollees under 18 y old found that respiratory symptoms persisted up to 7 y post-9/11 (5). The WTC Environmental Health Center which collected clinical data on a sample of children an average of 7.8 y after 9/11, reported new onset provider-diagnosed asthma in 21.4% of children, and found that dust cloud exposure was associated with pulmonary function abnormalities, such as isolated low forced vital capacity pattern and an obstructive pattern consistent with asthma (6). Although the association between asthma and 9/11-exposure in children and adolescents has been documented, little is known about asthma control in this population. Large population-based surveys consistently show that poor asthma control is common in many children with asthma (7,8). Asthma control is affected by many factors, including healthcare access (9,10), socioeconomic status (9,10), and comorbid mental health conditions (11,12,13). It has been observed that adolescents with symptomatic asthma are more likely than adolescents without asthma to have lower perceived well-being, more negative behaviors, and a greater number of physical and mental health comorbidities (14). Several studies found that depression has been associated with uncontrolled asthma (11,12). In adults with 9/11-related asthma, having at least one mental health condition has been associated with poorly controlled asthma (15). However, little is known about the association between mental health conditions and the level of asthma control especially among 9/11-exposed adolescents. Previous studies of adult Registry enrollees found that those with unmet healthcare needs are more likely to have severe mental health symptoms, comorbid mental and physical health problems, and have lower quality of life (1,16). Unmet healthcare needs among adolescents have been shown to be associated with poorer health status and functioning, including asthma control (17). Poorly controlled asthma has also been associated with unmet healthcare needs related to cost or access barriers (18), such as an inability to pay for asthma medications and not having access to asthma specialists (19). The goal of this study was to evaluate asthma control 10–11 y after 9/11 among Registry as children, and to determine whether poor asthma control is associated with specific factors including adolescent 9/11-exposure, adverse mental health, behavior problems, and unmet healthcare needs

Changing care pathways and between-center practice variations in intensive care for traumatic brain injury across Europe

Purpose: To describe ICU stay, selected management aspects, and outcome of Intensive Care Unit (ICU) patients with traumatic brain injury (TBI) in Europe, and to quantify variation across centers. Methods: This is a prospective observational multicenter study conducted across 18 countries in Europe and Israel. Admission characteristics, clinical data, and outcome were described at patient- and center levels. Between-center variation in the total ICU population was quantified with the median odds ratio (MOR), with correction for case-mix and random variation between centers. Results: A total of 2138 patients were admitted to the ICU, with median age of 49 years; 36% of which were mild TBI (Glasgow Coma Scale; GCS 13–15). Within, 72 h 636 (30%) were discharged and 128 (6%) died. Early deaths and long-stay patients (> 72 h) had more severe injuries based on the GCS and neuroimaging characteristics, compared with short-stay patients. Long-stay patients received more monitoring and were treated at higher intensity, and experienced worse 6-month outcome compared to short-stay patients. Between-center variations were prominent in the proportion of short-stay patients (MOR = 2.3, p < 0.001), use of intracranial pressure (ICP) monitoring (MOR = 2.5, p < 0.001) and aggressive treatme

Machine learning algorithms performed no better than regression models for prognostication in traumatic brain injury

Objective: We aimed to explore the added value of common machine learning (ML) algorithms for prediction of outcome for moderate and severe traumatic brain injury. Study Design and Setting: We performed logistic regression (LR), lasso regression, and ridge regression with key baseline predictors in the IMPACT-II database (15 studies, n = 11,022). ML algorithms included support vector machines, random forests, gradient boosting machines, and artificial neural networks and were trained using the same predictors. To assess generalizability of predictions, we performed internal, internal-external, and external validation on the recent CENTER-TBI study (patients with Glasgow Coma Scale <13, n = 1,554). Both calibration (calibration slope/intercept) and discrimination (area under the curve) was quantified. Results: In the IMPACT-II database, 3,332/11,022 (30%) died and 5,233(48%) had unfavorable outcome (Glasgow Outcome Scale less than 4). In the CENTER-TBI study, 348/1,554(29%) died and 651(54%) had unfavorable outcome. Discrimination and calibration varied widely between the studies and less so between the studied algorithms. The mean area under the curve was 0.82 for mortality and 0.77 for unfavorable outcomes in the CENTER-TBI study. Conclusion: ML algorithms may not outperform traditional regression approaches in a low-dimensional setting for outcome prediction after moderate or severe traumatic brain injury. Similar to regression-based prediction models, ML algorithms should be rigorously validated to ensure applicability to new populations

Variation in Structure and Process of Care in Traumatic Brain Injury: Provider Profiles of European Neurotrauma Centers Participating in the CENTER-TBI Study.

INTRODUCTION: The strength of evidence underpinning care and treatment recommendations in traumatic brain injury (TBI) is low. Comparative effectiveness research (CER) has been proposed as a framework to provide evidence for optimal care for TBI patients. The first step in CER is to map the existing variation. The aim of current study is to quantify variation in general structural and process characteristics among centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. METHODS: We designed a set of 11 provider profiling questionnaires with 321 questions about various aspects of TBI care, chosen based on literature and expert opinion. After pilot testing, questionnaires were disseminated to 71 centers from 20 countries participating in the CENTER-TBI study. Reliability of questionnaires was estimated by calculating a concordance rate among 5% duplicate questions. RESULTS: All 71 centers completed the questionnaires. Median concordance rate among duplicate questions was 0.85. The majority of centers were academic hospitals (n = 65, 92%), designated as a level I trauma center (n = 48, 68%) and situated in an urban location (n = 70, 99%). The availability of facilities for neuro-trauma care varied across centers; e.g. 40 (57%) had a dedicated neuro-intensive care unit (ICU), 36 (51%) had an in-hospital rehabilitation unit and the organization of the ICU was closed in 64% (n = 45) of the centers. In addition, we found wide variation in processes of care, such as the ICU admission policy and intracranial pressure monitoring policy among centers. CONCLUSION: Even among high-volume, specialized neurotrauma centers there is substantial variation in structures and processes of TBI care. This variation provides an opportunity to study effectiveness of specific aspects of TBI care and to identify best practices with CER approaches

Changing care pathways and between-center practice variations in intensive care for traumatic brain injury across Europe: a CENTER-TBI analysis

peer reviewedPurpose: To describe ICU stay, selected management aspects, and outcome of Intensive Care Unit (ICU) patients with traumatic brain injury (TBI) in Europe, and to quantify variation across centers. Methods: This is a prospective observational multicenter study conducted across 18 countries in Europe and Israel. Admission characteristics, clinical data, and outcome were described at patient- and center levels. Between-center variation in the total ICU population was quantified with the median odds ratio (MOR), with correction for case-mix and random variation between centers. Results: A total of 2138 patients were admitted to the ICU, with median age of 49 years; 36% of which were mild TBI (Glasgow Coma Scale; GCS 13–15). Within, 72 h 636 (30%) were discharged and 128 (6%) died. Early deaths and long-stay patients (> 72 h) had more severe injuries based on the GCS and neuroimaging characteristics, compared with short-stay patients. Long-stay patients received more monitoring and were treated at higher intensity, and experienced worse 6-month outcome compared to short-stay patients. Between-center variations were prominent in the proportion of short-stay patients (MOR = 2.3, p < 0.001), use of intracranial pressure (ICP) monitoring (MOR = 2.5, p < 0.001) and aggressive treatments (MOR = 2.9, p < 0.001); and smaller in 6-month outcome (MOR = 1.2, p = 0.01). Conclusions: Half of contemporary TBI patients at the ICU have mild to moderate head injury. Substantial between-center variations exist in ICU stay and treatment policies, and less so in outcome. It remains unclear whether admission of short-stay patients represents appropriate prudence or inappropriate use of clinical resources. © 2020, The Author(s)

Frequency of fatigue and its changes in the first 6 months after traumatic brain injury: results from the CENTER-TBI study

peer reviewedBackground: Fatigue is one of the most commonly reported subjective symptoms following traumatic brain injury (TBI). The aims were to assess frequency of fatigue over the first 6 months after TBI, and examine whether fatigue changes could be predicted by demographic characteristics, injury severity and comorbidities. Methods: Patients with acute TBI admitted to 65 trauma centers were enrolled in the study Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI). Subjective fatigue was measured by single item on the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), administered at baseline, three and 6 months postinjury. Patients were categorized by clinical care pathway: admitted to an emergency room (ER), a ward (ADM) or an intensive care unit (ICU). Injury severity, preinjury somatic- and psychiatric conditions, depressive and sleep problems were registered at baseline. For prediction of fatigue changes, descriptive statistics and mixed effect logistic regression analysis are reported. Results: Fatigue was experienced by 47% of patients at baseline, 48% at 3 months and 46% at 6 months. Patients admitted to ICU had a higher probability of experiencing fatigue than those in ER and ADM strata. Females and individuals with lower age, higher education, more severe intracranial injury, preinjury somatic and psychiatric conditions, sleep disturbance and feeling depressed postinjury had a higher probability of fatigue. Conclusion: A high and stable frequency of fatigue was found during the first 6 months after TBI. Specific socio-demographic factors, comorbidities and injury severity characteristics were predictors of fatigue in this study. © 2020, The Author(s)

Use and impact of high intensity treatments in patients with traumatic brain injury across Europe: a CENTER-TBI analysis

Abstract: Purpose: To study variation in, and clinical impact of high Therapy Intensity Level (TIL) treatments for elevated intracranial pressure (ICP) in patients with traumatic brain injury (TBI) across European Intensive Care Units (ICUs). Methods: We studied high TIL treatments (metabolic suppression, hypothermia (< 35 °C), intensive hyperventilation (PaCO2 < 4 kPa), and secondary decompressive craniectomy) in patients receiving ICP monitoring in the ICU stratum of the CENTER-TBI study. A random effect logistic regression model was used to determine between-centre variation in their use. A propensity score-matched model was used to study the impact on outcome (6-months Glasgow Outcome Score-extended (GOSE)), whilst adjusting for case-mix severity, signs of brain herniation on imaging, and ICP. Results: 313 of 758 patients from 52 European centres (41%) received at least one high TIL treatment with significant variation between centres (median odds ratio = 2.26). Patients often transiently received high TIL therapies without escalation from lower tier treatments. 38% of patients with high TIL treatment had favourable outcomes (GOSE ≥ 5). The use of high TIL treatment was not significantly associated with worse outcome (285 matched pairs, OR 1.4, 95% CI [1.0–2.0]). However, a sensitivity analysis excluding high TIL treatments at day 1 or use of metabolic suppression at any day did reveal a statistically significant association with worse outcome. Conclusion: Substantial between-centre variation in use of high TIL treatments for TBI was found and treatment escalation to higher TIL treatments were often not preceded by more conventional lower TIL treatments. The significant association between high TIL treatments after day 1 and worse outcomes may reflect aggressive use or unmeasured confounders or inappropriate escalation strategies. Take home message: Substantial variation was found in the use of highly intensive ICP-lowering treatments across European ICUs and a stepwise escalation strategy from lower to higher intensity level therapy is often lacking. Further research is necessary to study the impact of high therapy intensity treatments. Trial registration: The core study was registered with ClinicalTrials.gov, number NCT02210221, registered 08/06/2014, https://clinicaltrials.gov/ct2/show/NCT02210221?id=NCT02210221&draw=1&rank=1 and with Resource Identification Portal (RRID: SCR_015582)