| 1. |
- Bazarian, Jeffrey J., et al.
(författare)
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Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI) : a multicentre observational study
- 2018
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Ingår i: Lancet Neurology. - : Lancet Publishing Group. - 1474-4422 .- 1474-4465. ; 17:9, s. 782-789
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Tidskriftsartikel (refereegranskat)abstract
- Background: More than 50 million people worldwide sustain a traumatic brain injury (TBI) annually. Detection of intracranial injuries relies on head CT, which is overused and resource intensive. Blood-based brain biomarkers hold the potential to predict absence of intracranial injury and thus reduce unnecessary head CT scanning. We sought to validate a test combining ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP), at predetermined cutoff values, to predict traumatic intracranial injuries on head CT scan acutely after TBI.Methods: This prospective, multicentre observational trial included adults (≥18 years) presenting to participating emergency departments with suspected, non-penetrating TBI and a Glasgow Coma Scale score of 9-15. Patients were eligible if they had undergone head CT as part of standard emergency care and blood collection within 12 h of injury. UCH-L1 and GFAP were measured in serum and analysed using prespecified cutoff values of 327 pg/mL and 22 pg/mL, respectively. UCH-L1 and GFAP assay results were combined into a single test result that was compared with head CT results. The primary study outcomes were the sensitivity and the negative predictive value (NPV) of the test result for the detection of traumatic intracranial injury on head CT.Findings: Between Dec 6, 2012, and March 20, 2014, 1977 patients were recruited, of whom 1959 had analysable data. 125 (6%) patients had CT-detected intracranial injuries and eight (<1%) had neurosurgically manageable injuries. 1288 (66%) patients had a positive UCH-L1 and GFAP test result and 671 (34%) had a negative test result. For detection of intracranial injury, the test had a sensitivity of 0·976 (95% CI 0·931-0·995) and an NPV of 0·996 (0·987-0·999). In three (<1%) of 1959 patients, the CT scan was positive when the test was negative.Interpretation: These results show the high sensitivity and NPV of the UCH-L1 and GFAP test. This supports its potential clinical role for ruling out the need for a CT scan among patients with TBI presenting at emergency departments in whom a head CT is felt to be clinically indicated. Future studies to determine the value added by this biomarker test to head CT clinical decision rules could be warranted.Funding: Banyan Biomarkers and US Army Medical Research and Materiel Command.
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| 2. |
- Diener, Hans-Christoph, et al.
(författare)
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Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial : a double-blind, active and placebo-controlled study.
- 2008
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Ingår i: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 7:10, s. 875-884
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The treatment of ischaemic stroke with neuroprotective drugs has been unsuccessful, and whether these compounds can be used to reduce disability after recurrent stroke is unknown. The putative neuroprotective effects of antiplatelet compounds and the angiotensin II receptor antagonist telmisartan were investigated in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial.METHODS: Patients who had had an ischaemic stroke were randomly assigned in a two by two factorial design to receive either 25 mg aspirin (ASA) and 200 mg extended-release dipyridamole (ER-DP) twice a day or 75 mg clopidogrel once a day, and either 80 mg telmisartan or placebo once per day. The predefined endpoints for this substudy were disability after a recurrent stroke, assessed with the modified Rankin scale (mRS) and Barthel index at 3 months, and cognitive function, assessed with the mini-mental state examination (MMSE) score at 4 weeks after randomisation and at the penultimate visit. Analysis was by intention to treat. The study was registered with ClinicalTrials.gov, number NCT00153062.FINDINGS: 20,332 patients (mean age 66 years) were randomised and followed-up for a median of 2.4 years. Recurrent strokes occurred in 916 (9%) patients randomly assigned to ASA with ER-DP and 898 (9%) patients randomly assigned to clopidogrel; 880 (9%) patients randomly assigned to telmisartan and 934 (9%) patients given placebo had recurrent strokes. mRS scores were not statistically different in patients with recurrent stroke who were treated with ASA and ER-DP versus clopidogrel (p=0.38), or with telmisartan versus placebo (p=0.61). There was no significant difference in the proportion of patients with recurrent stroke with a good outcome, as measured with the Barthel index, across all treatment groups. Additionally, there was no significant difference in the median MMSE scores, the percentage of patients with an MMSE score of 24 points or less, the percentage of patients with a drop in MMSE score of 3 points or more between 1 month and the penultimate visit, and the number of patients with dementia among the treatment groups. There were no significant differences in the proportion of patients with cognitive impairment or dementia among the treatment groups.INTERPRETATION: Disability due to recurrent stroke and cognitive decline in patients with ischaemic stroke were not different between the two antiplatelet regimens and were not affected by the preventive use of telmisartan.
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| 3. |
- Galimberti, Stefania, et al.
(författare)
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Effect of frailty on 6-month outcome after traumatic brain injury : a multicentre cohort study with external validation
- 2022
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Ingår i: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 21:2, s. 153-162
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Frailty is known to be associated with poorer outcomes in individuals admitted to hospital for medical conditions requiring intensive care. However, little evidence is available for the effect of frailty on patients' outcomes after traumatic brain injury. Many frailty indices have been validated for clinical practice and show good performance to predict clinical outcomes. However, each is specific to a particular clinical context. We aimed to develop a frailty index to predict 6-month outcomes in patients after a traumatic brain injury.METHODS: A cumulative deficit approach was used to create a novel frailty index based on 30 items dealing with disease states, current medications, and laboratory values derived from data available from CENTER-TBI, a prospective, longitudinal observational study of patients with traumatic brain injury presenting within 24 h of injury and admitted to a ward or an intensive care unit at 65 centres in Europe between Dec 19, 2014, and Dec 17, 2017. From the individual cumulative CENTER-TBI frailty index (range 0-30), we obtained a standardised value (range 0-1), with high scores indicating higher levels of frailty. The effect of frailty on 6-month outcome evaluated with the extended Glasgow Outcome Scale (GOSE) was assessed through a proportional odds logistic model adjusted for known outcome predictors. An unfavourable outcome was defined as death or severe disability (GOSE score ≤4). External validation was performed on data from TRACK-TBI, a prospective observational study co-designed with CENTER-TBI, which enrolled patients with traumatic brain injury at 18 level I trauma centres in the USA from Feb 26, 2014, to July 27, 2018. CENTER-TBI is registered with ClinicalTrials.gov, NCT02210221; TRACK-TBI is registered at ClinicalTrials.gov, NCT02119182.FINDINGS: 2993 participants (median age was 51 years [IQR 30-67], 2058 [69%] were men) were included in this analysis. The overall median CENTER-TBI frailty index score was 0·07 (IQR 0·03-0·15), with a median score of 0·17 (0·08-0·27) in older adults (aged ≥65 years). The CENTER-TBI frailty index score was significantly associated with the probability of an increasingly unfavourable outcome (cumulative odds ratio [OR] 1·03, 95% CI 1·02-1·04; p<0·0001), and the association was stronger for participants admitted to hospital wards (1·04, 1·03-1·06, p<0·0001) compared with those admitted to the intensive care unit (1·02, 1·01-1·03 p<0·0001). External validation of the CENTER-TBI frailty index in data from the TRACK-TBI (n=1667) cohort supported the robustness and reliability of these findings. The overall median TRACK-TBI frailty index score was 0·03 (IQR 0-0·10), with the frailty index score significantly associated with the risk of an increasingly unfavourable outcome in patients admitted to hospital wards (cumulative OR 1·05, 95% CI 1·03-1·08; p<0·0001), but not in those admitted to the intensive care unit (1·01, 0·99-1·03; p=0·43).INTERPRETATION: We developed and externally validated a frailty index specific to traumatic brain injury. Risk of unfavourable outcome was significantly increased in participants with a higher CENTER-TBI frailty index score, regardless of age. Frailty identification could help to individualise rehabilitation approaches aimed at mitigating effects of frailty in patients with traumatic brain injury.FUNDING: European Union, Hannelore Kohl Stiftung, OneMind, Integra LifeSciences Corporation, NeuroTrauma Sciences, NIH-NINDS-TRACK-TBI, US Department of Defense.
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| 4. |
- Helmrich, Isabel R. A. Retel, et al.
(författare)
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Incremental prognostic value of acute serum biomarkers for functional outcome after traumatic brain injury (CENTER-TBI) : an observational cohort study
- 2022
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Ingår i: Lancet Neurology. - : The Lancet Publishing Group. - 1474-4422 .- 1474-4465. ; 21:9, s. 792-802
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Several studies have reported an association between serum biomarker values and functional outcome following traumatic brain injury. We aimed to examine the incremental (added) prognostic value of serum biomarkers over demographic, clinical, and radiological characteristics and over established prognostic models, such as IMPACT and CRASH, for prediction of functional outcome.METHODS: We used data from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) core study. We included patients aged 14 years or older who had blood sampling within 24 h of injury, results from a CT scan, and outcome assessment according to the Glasgow Outcome Scale-Extended (GOSE) at 6 months. Amounts in serum of six biomarkers (S100 calcium-binding protein B, neuron-specific enolase, glial fibrillary acidic protein, ubiquitin C-terminal hydrolase L1 [UCH-L1], neurofilament protein-light, and total tau) were measured. The incremental prognostic value of these biomarkers was determined separately and in combination. The primary outcome was the GOSE 6 months after injury. Incremental prognostic value, using proportional odds and a dichotomised analysis, was assessed by delta C-statistic and delta R2 between models with and without serum biomarkers, corrected for optimism with a bootstrapping procedure.FINDINGS: Serum biomarker values and 6-month GOSE were available for 2283 of 4509 patients. Higher biomarker levels were associated with worse outcome. Adding biomarkers improved the C-statistic by 0·014 (95% CI 0·009-0·020) and R2 by 4·9% (3·6-6·5) for predicting GOSE compared with demographic, clinical, and radiological characteristics. UCH-L1 had the greatest incremental prognostic value. Adding biomarkers to established prognostic models resulted in a relative increase in R2 of 48-65% for IMPACT and 30-34% for CRASH prognostic models.INTERPRETATION: Serum biomarkers have incremental prognostic value for functional outcome after traumatic brain injury. Our findings support integration of biomarkers-particularly UCH-L1-in established prognostic models.
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| 8. |
- Maegele, Marc, et al.
(författare)
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Coagulopathy and haemorrhagic progression in traumatic brain injury : advances in mechanisms, diagnosis, and management
- 2017
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Ingår i: The Lancet Neurology. - : Lancet Publishing Group. - 1474-4422 .- 1474-4465. ; 16:8, s. 630-647
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Forskningsöversikt (refereegranskat)abstract
- Normal haemostasis depends on an intricate balance between mechanisms of bleeding and mechanisms of thrombosis, and this balance can be altered after traumatic brain injury (TBI). Impaired haemostasis could exacerbate the primary insult with risk of initiation or aggravation of bleeding; anticoagulant use at the time of injury can also contribute to bleeding risk after TBI. Many patients with TBI have abnormalities on conventional coagulation tests at admission to the emergency department, and the presence of coagulopathy is associated with increased morbidity and mortality. Further blood testing often reveals a range of changes affecting platelet numbers and function, procoagulant or anticoagulant factors, fibrinolysis, and interactions between the coagulation system and the vascular endothelium, brain tissue, inflammatory mechanisms, and blood flow dynamics. However, the degree to which these coagulation abnormalities affect TBI outcomes and whether they are modifiable risk factors are not known. Although the main challenge for management is to address the risk of hypocoagulopathy with prolonged bleeding and progression of haemorrhagic lesions, the risk of hypercoagulopathy with an increased prothrombotic tendency also warrants consideration.
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| 9. |
- Steyerberg., Ewout W, et al.
(författare)
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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
- 2019
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Ingår i: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 18:10, s. 923-934
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The burden of traumatic brain injury (TBI) poses a large public health and societal problem, but the characteristics of patients and their care pathways in Europe are poorly understood. We aimed to characterise patient case-mix, care pathways, and outcomes of TBI.METHODS: CENTER-TBI is a Europe-based, observational cohort study, consisting of a core study and a registry. Inclusion criteria for the core study were a clinical diagnosis of TBI, presentation fewer than 24 h after injury, and an indication for CT. Patients were differentiated by care pathway and assigned to the emergency room (ER) stratum (patients who were discharged from an emergency room), admission stratum (patients who were admitted to a hospital ward), or intensive care unit (ICU) stratum (patients who were admitted to the ICU). Neuroimages and biospecimens were stored in repositories and outcome was assessed at 6 months after injury. We used the IMPACT core model for estimating the expected mortality and proportion with unfavourable Glasgow Outcome Scale Extended (GOSE) outcomes in patients with moderate or severe TBI (Glasgow Coma Scale [GCS] score ≤12). The core study was registered with ClinicalTrials.gov, number NCT02210221, and with Resource Identification Portal (RRID: SCR_015582).FINDINGS: Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study and from 22 782 patients in the registry. In the core study, 848 (19%) patients were in the ER stratum, 1523 (34%) in the admission stratum, and 2138 (47%) in the ICU stratum. In the ICU stratum, 720 (36%) patients had mild TBI (GCS score 13-15). Compared with the core cohort, the registry had a higher proportion of patients in the ER (9839 [43%]) and admission (8571 [38%]) strata, with more than 95% of patients classified as having mild TBI. Patients in the core study were older than those in previous studies (median age 50 years [IQR 30-66], 1254 [28%] aged >65 years), 462 (11%) had serious comorbidities, 772 (18%) were taking anticoagulant or antiplatelet medication, and alcohol was contributory in 1054 (25%) TBIs. MRI and blood biomarker measurement enhanced characterisation of injury severity and type. Substantial inter-country differences existed in care pathways and practice. Incomplete recovery at 6 months (GOSE <8) was found in 207 (30%) patients in the ER stratum, 665 (53%) in the admission stratum, and 1547 (84%) in the ICU stratum. Among patients with moderate-to-severe TBI in the ICU stratum, 623 (55%) patients had unfavourable outcome at 6 months (GOSE <5), similar to the proportion predicted by the IMPACT prognostic model (observed to expected ratio 1·06 [95% CI 0·97-1·14]), but mortality was lower than expected (0·70 [0·62-0·76]).INTERPRETATION: Patients with TBI who presented to European centres in the core study were older than were those in previous observational studies and often had comorbidities. Overall, most patients presented with mild TBI. The incomplete recovery of many patients should motivate precision medicine research and the identification of best practices to improve these outcomes.FUNDING: European Union 7th Framework Programme, the Hannelore Kohl Stiftung, OneMind, and Integra LifeSciences Corporation.
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| 10. |
- Svenningsson, Anders, et al.
(författare)
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Safety and efficacy of rituximab versus dimethyl fumarate in patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome in Sweden: a rater-blinded, phase 3, randomised controlled trial
- 2022
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Ingår i: Lancet Neurology. - : ELSEVIER SCIENCE INC. - 1474-4422 .- 1474-4465. ; 21:8, s. 693-703
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Tidskriftsartikel (refereegranskat)abstract
- Background B-cell depleting therapies are highly efficacious in relapsing-remitting multiple sclerosis but one such therapy, rituximab, is not approved for multiple sclerosis and no phase 3 trial data are available. We therefore examined the safety and efficacy of rituximab compared with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis to obtain data that might allow inclusion of rituximab in treatment guidelines. Methods RIFUND-MS was a multicentre, rater-blinded, active-comparator, phase 3, randomised controlled trial done at 17 Swedish university and community hospitals. Key inclusion criteria for participants were: age 18-50 years; relapsing-remitting multiple sclerosis or clinically isolated syndrome according to prevailing McDonald criteria; 10 years or less since diagnosis; untreated or only exposed to interferons or glatiramer acetate; and with clinical or neuroradiological disease activity in the past year. Patients were automatically randomly assigned (1:1) by the treating physician using a randomisation module in the Swedish multiple sclerosis registry, without stratification, to oral dimethyl fumarate 240 mg twice daily or to intravenous rituximab 1000 mg followed by 500 mg every 6 months. Relapse evaluation, Expanded Disability Status Scale rating, and assessment of MRI scans were done by examining physicians and radiologists masked to treatment allocation. The primary outcome was the proportion of patients with at least one relapse (defined as subacute onset of new or worsening neurological symptoms compatible with multiple sclerosis with a duration of more than 24 h and preceded by at least 30 days of clinical stability), assessed in an intention-to-treat analysis using log-binomial regression with robust standard errors. This trial is registered at ClinicalTrials.gov, NCT02746744. Findings Between July 1, 2016, and Dec 18, 2018, 322 patients were screened for eligibility, 200 of whom were randomly assigned to a treatment group (100 assigned to rituximab and 100 assigned to dimethyl fumarate). The last patient completed 24-month follow-up on April 21, 2021. 98 patients in the rituximab group and 97 patients in the dimethyl fumarate group were eligible for the primary outcome analysis. Three (3%) patients in the rituximab group and 16 (16%) patients in the dimethyl fumarate group had a protocol-defined relapse during the trial, corresponding to a risk ratio of 0.19 (95% CI 0.06-0.62; p=0.0060). Infusion reactions (105 events [40.9 per 100 patient-years]) in the rituximab group and gastrointestinal reactions (65 events [47.4 per 100 patient-years]) and flush (65 events [47.4 per 100 patient-years]) in the dimethyl fumarate group were the most prevalent adverse events. There were no safety concerns. Interpretation RIFUND-MS provides evidence that rituximab given as 1000 mg followed by 500 mg every 6 months is superior to dimethyl fumarate in preventing relapses over 24 months in patients with early relapsing-remitting multiple sclerosis. Health economic and long-term safety studies of rituximab in patients with multiple sclerosis are needed.
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