Additional co-authors: Endre Czeiter, Marek Czosnyka, Ramon Diaz-Arrastia, Jens P Dreier, Ann-Christine Duhaime, Ari Ercole, Thomas A van Essen, Valery L Feigin, Guoyi Gao, Joseph Giacino, Laura E Gonzalez-Lara, Russell L Gruen, Deepak Gupta, Jed A Hartings, Sean Hill, Ji-yao Jiang, Naomi Ketharanathan, Erwin J O Kompanje, Linda Lanyon, Steven Laureys, Fiona Lecky, Harvey Levin, Hester F Lingsma, Marc Maegele, Marek Majdan, Geoffrey Manley, Jill Marsteller, Luciana Mascia, Charles McFadyen, Stefania Mondello, Virginia Newcombe, Aarno Palotie, Paul M Parizel, Wilco Peul, James Piercy, Suzanne Polinder, Louis Puybasset, Todd E Rasmussen, Rolf Rossaint, Peter Smielewski, Jeannette Soderberg, Simon J Stanworth, Murray B Stein, Nicole von Steinbuchel, William Stewart, Ewout W Steyerberg, Nino Stocchetti, Anneliese Synnot, Braden Te Ao, Olli Tenovuo, Alice Theadom, Dick Tibboel, Walter Videtta, Kevin K W Wang, W Huw Williams, Kristine Yaffe for the InTBIR Participants and Investigators

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Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research

Additional co-authors: Wilco Peul, Nino Stocchetti, Nicole von Steinbuchel, Thijs Vande Vyvere, Jan Verheyden, Andrew I R Maas, David K Menoni and the CENTER-TBI Participants and Investigators Until 1 November 2019, this article is free to read and download at: https://authors.elsevier.com/c/1ZjYd5FFzKkIst

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Case-mix, care pathways, and outcomes in patients with traumatic brain injury in CENTER-TBI: a European prospective, multicentre, longitudinal, cohort study

Summary China has more patients with traumatic brain injury (TBI) than most other countries in the world, making this condition a major public health concern. Population-based mortality of TBI in China is estimated to be approximately 13 cases per 100 000 people, which is similar to the rates reported in other countries. The implementation of various measures, such as safety legislation for road traffic, establishment of specialised neurosurgical intensive care units, and the development of evidence-based guidelines, have contributed to advancing prevention and care of patients with TBI in China. However, many challenges remain, which are augmented further by regional differences in TBI care. High-level care, such as intracranial pressure monitoring, is not universally available yet. In the past 30 years, the quality of TBI research in China has substantially improved, as evidenced by an increasing number of clinical trials done. The large number of patients with TBI and specialised trauma centres offer unique opportunities for TBI research in China. Furthermore, the formation and development of research collaborations between China and international groups are considered essential to advancing the quality of TBI care and research in China, and to improve quality of life in patients with this condition.

Traumatic brain injury in China.

Brain tissue is not only one of the most important but also the most complex and compliant tissue in the human body. While long underestimated, increasing evidence confirms that mechanics plays a critical role in modulating brain function and dysfunction. Computational simulations–based on the field equations of nonlinear continuum mechanics–can provide important insights into the underlying mechanisms of brain injury and disease that go beyond the possibilities of traditional diagnostic tools. Realistic numerical predictions, however, require mechanical models that are capable of capturing the complex and unique characteristics of this ultrasoft, heterogeneous, and active tissue. In recent years, contradictory experimental results have caused confusion and hindered rapid progress. In this review, we carefully assess the challenges associated with brain tissue testing and modeling, and work out the most important characteristics of brain tissue behavior on different length and time scales. Depending on the application of interest, we propose appropriate mechanical modeling approaches that are as complex as necessary but as simple as possible. This comprehensive review will, on the one hand, stimulate the design of new experiments and, on the other hand, guide the selection of appropriate constitutive models for specific applications. Mechanical models that capture the complex behavior of nervous tissues and are accurately calibrated with reliable and comprehensive experimental data are key to performing reliable predictive simulations. Ultimately, mathematical modeling and computational simulations of the brain are useful for both biomedical and clinical communities, and cover a wide range of applications ranging from predicting disease progression and estimating injury risk to planning surgical procedures.

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Fifty Shades of Brain: A Review on the Mechanical Testing and Modeling of Brain Tissue

Aims Ferroptosis, a new form of iron-dependent programmed cell death, has been shown to be involved in a range of diseases. However, the role of ferroptosis in traumatic brain injury (TBI) has yet to be elucidated. We aimed to investigate whether ferroptosis is induced after TBI and whether the inhibition of ferroptosis would protect against traumatic brain injury in a controlled cortical impact injury (CCI) mouse model. Methods After establishing the TBI model in mice, we determined the biochemical and morphological changes associated with ferroptosis, including iron accumulation with Perl's staining, neuronal cell death with Fluoro-Jade B (FJB) staining, iron metabolism dysfunction with Western blotting, reactive oxygen species (ROS) accumulation with malondialdehyde (MDA) assays, and shrunken mitochondria with transmission electron microscopy. Furthermore, a specific inhibitor of ferroptosis, ferrostatin-1(fer-1), was administrated by cerebral ventricular injection after CCI. We used cresyl violet (CV) staining to assess lesion volume, along with the Morris water maze and beam walk test to evaluate long-term outcomes. Results TBI was followed by iron accumulation, dysfunctional iron metabolism, the upregulation of ferroptosis-related genes, reduced glutathione peroxidase (GPx) activity, and the accumulation of lipid-reactive oxygen species (ROS). Three days (d) after TBI, transmission electron microscopy (TEM) confirmed that the mitochondria had shrunk a typical characteristic of ferroptosis. Importantly, the administration of Fer-1 by cerebral ventricular injection significantly reduced iron deposition and neuronal degeneration while attenuating injury lesions and improving long-term motor and cognitive function. Conclusion This study demonstrated an effective method with which to treat TBI by targeting ferroptosis.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cns.13069

Inhibition of ferroptosis attenuates tissue damage and improves long-term outcomes after traumatic brain injury in mice.

Summary Introduction Traumatic brain injuries (TBI) are a major medical and socioeconomic problem. We aimed to estimate the hospital-based incidence, population-wide mortality, and the contribution of TBI to injury-related mortalities in European countries, and to provide European summary estimates for these indicators. Methods For this cross-sectional analysis, we obtained population data from Eurostat for hospital discharges and causes of death in European countries in 2012. Outcomes of interest were TBIs that required hospital admission or were fatal. We calculated age-adjusted hospital discharge rates and mortality rates and extrapolated data to 28 European Union countries and all 48 states in Europe. We present between-country comparisons, pooled age-adjusted rates, and comparisons with all-injury rates. Findings In 2012, 1 375 974 hospital discharges (data from 24 countries) and 33 415 deaths (25 countries) related to TBI were identified. The pooled age-adjusted hospital discharge rate was 287·2 per 100 000 (95% CI 232·9–341·5) and the pooled age-adjusted mortality rate was 11·7 per 100 000 (9·9–13·6). TBI caused 37% (95% CI 36–38) of all injury-related deaths in the analysed countries. Extrapolating our results, we estimate 56 946 (95% CI 47 286–66 099) TBI-related deaths and 1 445 526 (1 172 996–1 717 039) hospital discharges occurred in 2012 in the European Union (population 508·5 million) and about 82 000 deaths and about 2·1 million hospital discharges in the whole of Europe (population 737 million). We noted substantial between-country differences. Interpretation TBI is an important cause of death and hospital admissions in Europe. The substantial between-country differences observed warrant further study and suggest that the true burden of TBI in Europe has not yet been captured. Rigorous epidemiological studies are needed to fully quantify the effect of TBI on society. Despite a great degree of consistency in data reporting across countries already being achieved, further efforts in this respect could improve the validity of between-country comparisons. Funding European Union, FP7.

Epidemiology of traumatic brain injuries in Europe: a cross-sectional analysis.

Introduction 
Traumatic brain injuries (TBIs) are a major public health, medical, and societal challenge globally. They present a substantial burden to victims, their families, and the society as a whole. Although indicators such as incidence or death rates provide insight into the occurrence and outcome of TBIs in various populations, they fail to quantify the full extent of their public health and societal impact. Measures such as years of life lost (YLLs), which quantifies the number of years of life lost because the person dies prematurely due to a disease or injury, should be employed to better quantify the population impact. The aim of this study was to provide an in-depth analysis of the burden of deaths due to TBI by calculating TBI-specific YLLs in 16 European countries, analyzing their main causes and demographic patterns, using data extracted from death certificates under unified guidelines and collected in a standardized manner.


Methods and findings 
A population-wide, cross-sectional epidemiological study was conducted in 16 European countries to estimate TBI YLLs for the year 2013. The data used for all analyses in this study were acquired from the statistical office of the European Union (Eurostat). A specifically tailored dataset of micro-level data was provided that listed the external cause of death (International Classification of Diseases–10th Revision [ICD-10] codes V01–Y98), the specific nature of injury (ICD-10 codes S00–T98), the age at death, and sex for each death. Overall number of TBI YLLs, crude and age-standardized TBI YLL rates, and TBI YLLs per case were calculated stratified for country, sex, and age. Pooled analyses were performed in order to estimate summary age-standardized rates of TBI YLLs. In order to evaluate the relative importance of TBI in the context of all injuries, proportions of TBI YLLs out of overall injury YLLs were calculated. The total number of TBI YLLs was estimated by extrapolating the pooled crude rate of TBI YLLs in the 16 analyzed countries to the total population of the 28 member states of the EU (EU-28). We found that a total of 17,049 TBI deaths occurred in 2013 in the 16 analyzed countries. These translated into a total of 374,636 YLLs. The pooled age-standardized rate of YLLs per 100,000 people per year was 259.1 (95% CI: 205.8 to 312.3) overall, 427.5 (95% CI: 290.0 to 564.9) in males, and 105.4 (95% CI: 89.1 to 121.6) in females. Males contributed substantially more to TBI YLLs than females (282,870 YLLs, 76% of all TBI YLLs), which translated into a rate ratio of 3.24 (95% CI: 3.22 to 3.27). Each TBI death was on average associated with 24.3 (95% CI: 22.0 to 26.6) YLLs overall, 25.6 (95% CI: 23.4 to 27.8) in males and 20.9 (17.9 to 24.0) in females. Falls and traffic crashes were the most common external causes of TBI YLLs. TBI contributed on average 41% (44% in males and 34% in females) to overall injury YLLs. Extrapolating our findings, about 1.3 million YLLs were attributable to TBI in the EU-28 in 2013 overall, 1.1 million in males and 271,000 in females. This study is based on administratively collected data from 16 countries, and despite the efforts to harmonize them to the greatest possible extent, there may be differences in coding practices or reporting between countries. If present, these would be inherited into our findings without our ability to control for them. The extrapolation of the pooled rates from the 16 countries to the EU-28 should be interpreted with caution.


Conclusions 
Our study showed that TBI-related deaths and YLLs have a substantial impact at the individual and population level in Europe and present an important societal and economic burden that must not be overlooked. We provide information valuable for policy-makers, enabling them to evaluate and plan preventive activities and resource allocation, and to formulate and implement strategic decisions. In addition, our results can serve as a basis for analyzing the overall burden of TBI in the population.

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Years of life lost due to traumatic brain injury in Europe: a cross-sectional analysis of 16 countries

Traumatic spinal cord injuries (TSCI) pose a significant burden globally, while existing epidemiological data–especially on population mortality–are limited. The aim of this study was to calculate the age-standardized population mortality rates attributable to TSCI in 22 European countries, along with the pooled age-standardized mortality rate attributable to TSCI in Europe. A descriptive cross-sectional epidemiological study was conducted. Crude and age-standardized mortality rates attributable to TSCI for the year 2012 for 22 European countries were compared using data from death certificates provided by Eurostat. Pooled age-standardized mortality rates were calculated using the random effects model, and overall number of cases were estimated by extrapolating our findings to the populations of EU and Europe (48 countries), in 2012. A total of 1840 TSCI-related deaths were identified, of which 1084 (59%) were males. The pooled age-standardized TSCI-related mortality rate of 6.7 per million (95% CI: 5.2 to 8.2) overall, 9.4 (95% CI: 7.3 to 11.5) for males, and 4.5 (95% CI: 3.4 to 5.6) for females. Extrapolating our results, 3152 (95% CI: 2441 to 3915) deaths would occur in 2012 in the EU-28 and 4570 (95% CI: 3538 to 5675) deaths in the whole Europe. TSCI-related deaths contributed by 2% (95% CI: 1.8% to 2.2%) to the overall injury related mortality. 61% of fatal TSCI were located in the cervical spine area. To our knowledge, this is the largest study that reports TSCI-related population-based mortalities to date which brings valuable information that can inform further research or prevention strategies. Our study presents a comprehensive and large-scale overview of TSCI-related population mortality in Europe. With an estimated toll of nearly five thousand lives that could be potentially saved by prevention, our findings confirm TSCI as an important cause of injury related deaths in Europe. Further action towards harmonization of case ascertainment and towards prevention strategies targeted mainly on the elderly is warranted.

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Mortality due to traumatic spinal cord injuries in Europe: a cross-sectional and pooled analysis of population-wide data from 22 countries.

Background: Understanding the factors related to traumatic brain injury (TBI)-related mortality is important in obtaining a complete picture of the predictors and burden of injury-related deaths.Ob...

Location of traumatic brain injury-related deaths: epidemiological analysis of 11 European countries.

Children and adolescents are at high risk of traumatic brain injuries (TBI). To identify those most at risk across Europe, a comprehensive epidemiological study on the burden of TBI is needed. Our aim was to estimate the burden of TBI in the pediatric and adolescent population of Europe by calculating rates of hospital-based incidence, death and years of life lost (YLL) due to TBI in 33 countries of Europe in 2014 (most recent available data). We conducted a cross-sectional observational, population-based study. All cases with TBI in the age range 0 to 19, registered in the causes of death databases or hospital discharge databases of 33 European countries were included. Crude and age-standardized rates of hospital discharges, deaths and YLLs due to TBI; and pooled estimates for all countries combined were calculated. TBI caused 2303 deaths (71% in boys), 154,282 YLLs (68% in boys) and 441,368 hospital discharges (61% in boys) in the population of 0–19 year-olds. We estimated pooled age-standardized rates of death (2.8, 95% CI: 2.4–3.3), YLLs (184.4, 95% CI: 151.6–217.2) and hospital discharges (344.6, 95% CI: 250.3–438.9) for the analyzed countries in 2014. The population of 15–19 year-olds had the highest rates of deaths and YLLs, and the population of 0–4 year-olds had the highest rate of hospital discharges. Detailed estimates of hospital discharge, death and YLL rates based on high-quality, standardized data may be used to develop health policies, aid decision-making and plan prevention.

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Dominika Plancikova

Papers

Epidemiology of traumatic brain injuries in Europe: a cross-sectional analysis.

Years of life lost due to traumatic brain injury in Europe: a cross-sectional analysis of 16 countries

Mortality due to traumatic spinal cord injuries in Europe: a cross-sectional and pooled analysis of population-wide data from 22 countries.

Location of traumatic brain injury-related deaths: epidemiological analysis of 11 European countries.

Burden of Traumatic Brain Injuries in Children and Adolescents in Europe: Hospital Discharges, Deaths and Years of Life Lost