Optimized fabrication of high-quality La0.67Sr0.33MnO3 thin films considering all essential characteristics

In this paper, an overview of the fabrication and properties of high-quality La0.67Sr0.33MnO3 (LSMO) thin films is given. A high-quality LSMO film combines a smooth surface morphology with a large magnetization and a small residual resistivity, while avoiding precipitates and surface segregation. In the literature, typically only a few of these issues are adressed. We therefore present a thorough characterization of our films, which were grown by pulsed laser deposition. The films were characterized with reflection high energy electron diffraction, atomic force microscopy, x-ray diffraction, magnetization and transport measurements, x-ray photoelectron spectroscopy and scanning transmission electron microscopy. The films have a saturation magnetization of 4.0 µB/Mn, a Curie temperature of 350 K and a residual resistivity of 60 µΩ cm. These results indicate that high-quality films, combining both large magnetization and small residual resistivity, were realized. A comparison between different samples presented in the literature shows that focussing on a single property is insufficient for the optimization of the deposition process. For high-quality films, all properties have to be adressed. For LSMO devices, the thin-film quality is crucial for the device performance. Therefore, this research is important for the application of LSMO in devices

Variation in Blood Transfusion and Coagulation Management in Traumatic Brain Injury at the Intensive Care Unit: A Survey in 66 Neurotrauma Centers Participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury Study

Our aim was to describe current approaches and to quantify variability between European intensive care units (ICUs) in patients with traumatic brain injury (TBI). Therefore, we conducted a provider profiling survey as part of the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. The ICU Questionnaire was sent to 68 centers from 20 countries across Europe and Israel. For this study, we used ICU questions focused on 1) hemoglobin target level (Hb-TL), 2) coagulation management, and 3) deep venous thromboembolism (DVT) prophylaxis. Seventy-eight participants, mostly intensivists and neurosurgeons of 66 centers, completed the ICU questionnaire. For ICU-patients, half of the centers (N = 34; 52%) had a defined Hb-TL in their protocol. For patients with TBI, 26 centers (41%) indicated an Hb-TL between 70 and 90 g/L and 38 centers (59%) above 90 g/L. To treat trauma-related hemostatic abnormalities, the use of fresh frozen plasma (N = 48; 73%) or platelets (N = 34; 52%) was most often reported, followed by the supplementation of vitamin K (N = 26; 39%). Most centers reported using DVT prophylaxis with anticoagulants frequently or always (N = 62; 94%). In the absence of hemorrhagic brain lesions, 14 centers (21%) delayed DVT prophylaxis until 72 h after trauma. If hemorrhagic brain lesions were present, the number of centers delaying DVT prophylaxis for 72 h increased to 29 (46%). Overall, a lack of consensus exists between European ICUs on blood transfusion and coagulation management. The results provide a baseline for the CENTER-TBI study, and the large between-center variation indicates multiple opportunities for comparative effectiveness research

The burden of traumatic brain injury from low-energy falls among patients from 18 countries in the CENTER-TBI Registry: A comparative cohort study.

BACKGROUND: Traumatic brain injury (TBI) is an important global public health burden, where those injured by high-energy transfer (e.g., road traffic collisions) are assumed to have more severe injury and are prioritised by emergency medical service trauma triage tools. However recent studies suggest an increasing TBI disease burden in older people injured through low-energy falls. We aimed to assess the prevalence of low-energy falls among patients presenting to hospital with TBI, and to compare their characteristics, care pathways, and outcomes to TBI caused by high-energy trauma. METHODS AND FINDINGS: We conducted a comparative cohort study utilising the CENTER-TBI (Collaborative European NeuroTrauma Effectiveness Research in TBI) Registry, which recorded patient demographics, injury, care pathway, and acute care outcome data in 56 acute trauma receiving hospitals across 18 countries (17 countries in Europe and Israel). Patients presenting with TBI and indications for computed tomography (CT) brain scan between 2014 to 2018 were purposively sampled. The main study outcomes were (i) the prevalence of low-energy falls causing TBI within the overall cohort and (ii) comparisons of TBI patients injured by low-energy falls to TBI patients injured by high-energy transfer-in terms of demographic and injury characteristics, care pathways, and hospital mortality. In total, 22,782 eligible patients were enrolled, and study outcomes were analysed for 21,681 TBI patients with known injury mechanism; 40% (95% CI 39% to 41%) (8,622/21,681) of patients with TBI were injured by low-energy falls. Compared to 13,059 patients injured by high-energy transfer (HE cohort), the those injured through low-energy falls (LE cohort) were older (LE cohort, median 74 [IQR 56 to 84] years, versus HE cohort, median 42 [IQR 25 to 60] years; p < 0.001), more often female (LE cohort, 50% [95% CI 48% to 51%], versus HE cohort, 32% [95% CI 31% to 34%]; p < 0.001), more frequently taking pre-injury anticoagulants or/and platelet aggregation inhibitors (LE cohort, 44% [95% CI 42% to 45%], versus HE cohort, 13% [95% CI 11% to 14%]; p < 0.001), and less often presenting with moderately or severely impaired conscious level (LE cohort, 7.8% [95% CI 5.6% to 9.8%], versus HE cohort, 10% [95% CI 8.7% to 12%]; p < 0.001), but had similar in-hospital mortality (LE cohort, 6.3% [95% CI 4.2% to 8.3%], versus HE cohort, 7.0% [95% CI 5.3% to 8.6%]; p = 0.83). The CT brain scan traumatic abnormality rate was 3% lower in the LE cohort (LE cohort, 29% [95% CI 27% to 31%], versus HE cohort, 32% [95% CI 31% to 34%]; p < 0.001); individuals in the LE cohort were 50% less likely to receive critical care (LE cohort, 12% [95% CI 9.5% to 13%], versus HE cohort, 24% [95% CI 23% to 26%]; p < 0.001) or emergency interventions (LE cohort, 7.5% [95% CI 5.4% to 9.5%], versus HE cohort, 13% [95% CI 12% to 15%]; p < 0.001) than patients injured by high-energy transfer. The purposive sampling strategy and censorship of patient outcomes beyond hospital discharge are the main study limitations. CONCLUSIONS: We observed that patients sustaining TBI from low-energy falls are an important component of the TBI disease burden and a distinct demographic cohort; further, our findings suggest that energy transfer may not predict intracranial injury or acute care mortality in patients with TBI presenting to hospital. This suggests that factors beyond energy transfer level may be more relevant to prehospital and emergency department TBI triage in older people. A specific focus to improve prevention and care for patients sustaining TBI from low-energy falls is required.CENTER-TBI was supported by the European Union 7th Framework program (EC grant 602150), recipient A.I.R. Maas. Additional funding was obtained from the Hannelore Kohl Stiftung (Germany) - recipient A.I.R. Maas, from OneMind (USA) - recipient A.I.R. Maas and from Integra LifeSciences Corporation (USA) - recipient A.I.R. Maas. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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 monitoring and treatment policies for intracranial hypertension in traumatic brain injury: A survey in 66 neurotrauma centers participating in the CENTER-TBI

Background: No definitive evidence exists on how intracranial hypertension should be treated in patients with traumatic brain injury (TBI). It is therefore likely that centers and practitioners individually balance potential benefits and risks of different intracranial pressure (ICP) management strategies, resulting in practice variation. The aim of this study was to examine variation in monitoring and treatment policies for intracranial hypertension in patients with TBI. Methods: A 29-item survey on ICP monitoring and treatment was developed based on literature and expert opinion, and pilot-tested in 16 centers. The questionnaire was sent to 68 neurotrauma centers participating in the Collaborative European Neurotrauma Effectiveness Research (CENTER-TBI) study. Results: The survey was completed by 66 centers (97% response rate). Centers were mainly academic hospitals (n = 60, 91%) and designated level I trauma centers (n = 44, 67%). The Brain Trauma Foundation guidelines were used in 49 (74%) centers. Approximately ninety percent of the participants (n = 58) indicated placing an ICP monitor in patients with severe TBI and computed tomography abnormalities. There was no consensus on other indications or on peri-insertion precautions. We found wide variation in the use of first- and second-tier treatments for elevated ICP. Approximately half of the centers were classified as having a relatively aggressive approach to ICP monitoring and treatment (n = 32, 48%), whereas the others were considered more conservative (n = 34, 52%). Conclusions: Substantial variation was found regarding monitoring and treatment policies in patients with traumatic brain injury and intracranial hypertension. The results of this survey indicate a lack of consensus between European neurotrauma centers and provide an opportunity and necessity for comparative effectiveness research

Clustering identifies endotypes of traumatic brain injury in an intensive care cohort: a CENTER-TBI study

Background While the Glasgow coma scale (GCS) is one of the strongest outcome predictors, the current classification of traumatic brain injury (TBI) as ‘mild’, ‘moderate’ or ‘severe’ based on this fails to capture enormous heterogeneity in pathophysiology and treatment response. We hypothesized that data-driven characterization of TBI could identify distinct endotypes and give mechanistic insights. Methods We developed an unsupervised statistical clustering model based on a mixture of probabilistic graphs for presentation (< 24 h) demographic, clinical, physiological, laboratory and imaging data to identify subgroups of TBI patients admitted to the intensive care unit in the CENTER-TBI dataset (N = 1,728). A cluster similarity index was used for robust determination of optimal cluster number. Mutual information was used to quantify feature importance and for cluster interpretation. Results Six stable endotypes were identified with distinct GCS and composite systemic metabolic stress profiles, distinguished by GCS, blood lactate, oxygen saturation, serum creatinine, glucose, base excess, pH, arterial partial pressure of carbon dioxide, and body temperature. Notably, a cluster with ‘moderate’ TBI (by traditional classification) and deranged metabolic profile, had a worse outcome than a cluster with ‘severe’ GCS and a normal metabolic profile. Addition of cluster labels significantly improved the prognostic precision of the IMPACT (International Mission for Prognosis and Analysis of Clinical trials in TBI) extended model, for prediction of both unfavourable outcome and mortality (both p < 0.001). Conclusions Six stable and clinically distinct TBI endotypes were identified by probabilistic unsupervised clustering. In addition to presenting neurology, a profile of biochemical derangement was found to be an important distinguishing feature that was both biologically plausible and associated with outcome. Our work motivates refining current TBI classifications with factors describing metabolic stress. Such data-driven clusters suggest TBI endotypes that merit investigation to identify bespoke treatment strategies to improve care

Rehabilitation and outcomes after complicated vs uncomplicated mild TBI: results from the CENTER-TBI study

Background: Despite existing guidelines for managing mild traumatic brain injury (mTBI), evidence-based treatments are still scarce and large-scale studies on the provision and impact of specific rehabilitation services are needed. This study aimed to describe the provision of rehabilitation to patients after complicated and uncomplicated mTBI and investigate factors associated with functional outcome, symptom burden, and TBI-specific health-related quality of life (HRQOL) up to six months after injury. Methods: Patients (n = 1379) with mTBI from the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study who reported whether they received rehabilitation services during the first six months post-injury and who participated in outcome assessments were included. Functional outcome was measured with the Glasgow Outcome Scale – Extended (GOSE), symptom burden with the Rivermead Post Concussion Symptoms Questionnaire (RPQ), and HRQOL with the Quality of Life after Brain Injury – Overall Scale (QOLIBRI-OS). We examined whether transition of care (TOC) pathways, receiving rehabilitation services, sociodemographic (incl. geographic), premorbid, and injury-related factors were associated with outcomes using regression models. For easy comparison, we estimated ordinal regression models for all outcomes where the scores were classified based on quantiles. Results: Overall, 43% of patients with complicated and 20% with uncomplicated mTBI reported receiving rehabilitation services, primarily in physical and cognitive domains. Patients with complicated mTBI had lower functional level, higher symptom burden, and lower HRQOL compared to uncomplicated mTBI. Rehabilitation services at three or six months and a higher number of TOC were associated with unfavorable outcomes in all models, in addition to pre-morbid psychiatric problems. Being male and having more than 13 years of education was associated with more favorable outcomes. Sustaining major trauma was associated with unfavorable GOSE outcome, whereas living in Southern and Eastern European regions was associated with lower HRQOL. Conclusions: Patients with complicated mTBI reported more unfavorable outcomes and received rehabilitation services more frequently. Receiving rehabilitation services and higher number of care transitions were indicators of injury severity and associated with unfavorable outcomes. The findings should be interpreted carefully and validated in future studies as we applied a novel analytic approach. Trial registration: ClinicalTrials.gov NCT02210221

Serum metabolome associated with severity of acute traumatic brain injury

Complex metabolic disruption is a crucial aspect of the pathophysiology of traumatic brain injury (TBI). Associations between this and systemic metabolism and their potential prognostic value are poorly understood. Here, we aimed to describe the serum metabolome (including lipidome) associated with acute TBI within 24 h post-injury, and its relationship to severity of injury and patient outcome. We performed a comprehensive metabolomics study in a cohort of 716 patients with TBI and non-TBI reference patients (orthopedic, internal medicine, and other neurological patients) from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) cohort. We identified panels of metabolites specifically associated with TBI severity and patient outcomes. Choline phospholipids (lysophosphatidylcholines, ether phosphatidylcholines and sphingomyelins) were inversely associated with TBI severity and were among the strongest predictors of TBI patient outcomes, which was further confirmed in a separate validation dataset of 558 patients. The observed metabolic patterns may reflect different pathophysiological mechanisms, including protective changes of systemic lipid metabolism aiming to maintain lipid homeostasis in the brain

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

Background: 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). Subj

Tracheal intubation in traumatic brain injury

Background: We aimed to study the associations between pre- and in-hospital tracheal intubation and outcomes in traumatic brain injury (TBI), and whether the association varied according to injury severity. Methods: Data from the international prospective pan-European cohort study, Collaborative European NeuroTrauma Effectiveness Research for TBI (CENTER-TBI), were used (n=4509). For prehospital intubation, we excluded self-presenters. For in-hospital intubation, patients whose tracheas were intubated on-scene were excluded. The association between intubation and outcome was analysed with ordinal regression with adjustment for the International Mission for Prognosis and Analysis of Clinical Trials in TBI variables and extracranial injury. We assessed whether the effect of intubation varied by injury severity by testing the added value of an interaction term with likelihood ratio tests. Results: In the prehospital analysis, 890/3736 (24%) patients had their tracheas intubated at scene. In the in-hospital analysis, 460/2930 (16%) patients had their tracheas intubated in the emergency department. There was no adjusted overall effect on functional outcome of prehospital intubation (odds ratio=1.01; 95% confidence interval, 0.79–1.28; P=0.96), and the adjusted overall effect of in-hospital intubation was not significant (odds ratio=0.86; 95% confidence interval, 0.65–1.13; P=0.28). However, prehospital intubation was associated with better functional outcome in patients with higher thorax and abdominal Abbreviated Injury Scale scores (P=0.009 and P=0.02, respectively), whereas in-hospital intubation was associated with better outcome in patients with lower Glasgow Coma Scale scores (P=0.01): in-hospital intubation was associated with better functional outcome in patients with Glasgow Coma Scale scores of 10 or lower. Conclusion: The benefits and harms of tracheal intubation should be carefully evaluated in patients with TBI to optimise benefit. This study suggests that extracranial injury should influence the decision in the prehospital setting, and level of consciousness in the in-hospital setting. Clinical trial registration: NCT02210221