IMPORTANCE Dual thrombolytic treatment with small bolus alteplase and mutant prourokinase has the potential to be a safer and more efficacious treatment for ischemic stroke than alteplase alone... Show moreIMPORTANCE Dual thrombolytic treatment with small bolus alteplase and mutant prourokinase has the potential to be a safer and more efficacious treatment for ischemic stroke than alteplase alone because mutant prourokinase is designed to act only on degraded fibrin without affecting circulating fibrinogen.OBJECTIVE To assess the safety and efficacy of this dual thrombolytic treatment compared with alteplase.DESIGN, SETTING, AND PARTICIPANTS This controlled, open-label randomized clinical trial with a blinded end point was conducted from August 10, 2019, to March 26, 2022, with a total follow-up of 30 days. Adult patients with ischemic stroke from 4 stroke centers in the Netherlands were enrolled.INTERVENTIONS Patients were randomized (1:1) to receive a bolus of 5mg of intravenous alteplase and 40mg of an intravenous infusion of mutant prourokinase (intervention) or usual care with 0.9mg/kg of intravenous alteplase (control).MAIN OUTCOMES AND MEASURES The primary outcomewas any intracranial hemorrhage (ICH) on neuroimaging at 24 hours. Secondary outcomes included functional outcome at 30 days, symptomatic ICH, and fibrinogen levels within 24 hours. Analyses were by intention to treat. Treatment effects were adjusted for baseline prognostic factors.RESULTS A total of 268 patients were randomized, and 238 (median [IQR] age, 69 [59-77] years; 147 [61.8%] male) provided deferred consent and were included in the intention-to-treat population (121 in the intervention group and 117 in the control group). The median baseline score on the National Institutes of Health Stroke Scale was 3 (IQR, 2-5). Any ICH occurred in 16 of 121 patients (13.2%) in the intervention group and 16 of 117 patients (13.7%) in the control group (adjusted odds ratio, 0.98; 95% CI, 0.46-2.12). Mutant prourokinase led to a nonsignificant shift toward better modified Rankin Scale scores (adjusted common odds ratio, 1.16; 95% CI, 0.74-1.84). Symptomatic ICH occurred in none of the patients in the intervention group and 3 of 117 patients (2.6%) in the control group. Plasma fibrinogen levels at 1 hour remained constant in the intervention group but decreased in the control group (ss = 65mg/dL; 95% CI, 26-105mg/dL).CONCLUSIONS AND RELEVANCE In this trial, dual thrombolytic treatment with small bolus alteplase and mutant prourokinase was found to be safe and did not result in fibrinogen depletion. Further evaluation of thrombolytic treatment with mutant prourokinase in larger trials to improve outcomes in patients with larger ischemic strokes is needed. Overall, in patients with minor ischemic stroke who met indications for treatment with intravenous thrombolytics but were not eligible for treatment with endovascular therapy, dual thrombolytic therapy with intravenous mutant prourokinase was not superior to treatment with intravenous alteplase alone.TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04256473 Show less
Background Endovascular treatment for anterior circulation ischaemic stroke is effective and safe within a 6 h window. MR CLEAN-LATE aimed to assess efficacy and safety of endovascular treatment... Show moreBackground Endovascular treatment for anterior circulation ischaemic stroke is effective and safe within a 6 h window. MR CLEAN-LATE aimed to assess efficacy and safety of endovascular treatment for patients treated in the late window (6-24 h from symptom onset or last seen well) selected on the basis of the presence of collateral flow on CT angiography (CTA).Methods MR CLEAN-LATE was a multicentre, open-label, blinded-endpoint, randomised, controlled, phase 3 trial done in 18 stroke intervention centres in the Netherlands. Patients aged 18 years or older with ischaemic stroke, presenting in the late window with an anterior circulation large-vessel occlusion and collateral flow on CTA, and a neurological deficit score of at least 2 on the National Institutes of Health Stroke Scale were included. Patients who were eligible for late-window endovascular treatment were treated according to national guidelines (based on clinical and perfusion imaging criteria derived from the DAWN and DEFUSE-3 trials) and excluded from MR CLEAN-LATE enrolment. Patients were randomly assigned (1:1) to receive endovascular treatment or no endovascular treatment (control), in addition to best medical treatment. Randomisation was web based, with block sizes ranging from eight to 20, and stratified by centre. The primary outcome was the modified Rankin Scale (mRS) score at 90 days after randomisation. Safety outcomes included all-cause mortality at 90 days after randomisation and symptomatic intracranial haemorrhage. All randomly assigned patients who provided deferred consent or died before consent could be obtained comprised the modified intention-to-treat population, in which the primary and safety outcomes were assessed. Analyses were adjusted for predefined confounders. Treatment effect was estimated with ordinal logistic regression and reported as an adjusted common odds ratio (OR) with a 95% CI. This trial was registered with the ISRCTN, ISRCTN19922220. Findings Between Feb 2, 2018, and Jan 27, 2022, 535 patients were randomly assigned, and 502 (94%) patients provided deferred consent or died before consent was obtained (255 in the endovascular treatment group and 247 in the control group; 261 [52%] females). The median mRS score at 90 days was lower in the endovascular treatment group than in the control group (3 [IQR 2-5] vs 4 [2-6]), and we observed a shift towards better outcomes on the mRS for the endovascular treatment group (adjusted common OR 1 center dot 67 [95% CI 1 center dot 20-2 center dot 32]). All-cause mortality did not differ significantly between groups (62 [24%] of 255 patients vs 74 [30%] of 247 patients; adjusted OR 0 center dot 72 [95% CI 0 center dot 44-1 center dot 18]). Symptomatic intracranial haemorrhage occurred more often in the endovascular treatment group than in the control group (17 [7%] vs four [2%]; adjusted OR 4 center dot 59 [95% CI 1 center dot 49-14 center dot 10]). Interpretation In this study, endovascular treatment was efficacious and safe for patients with ischaemic stroke caused by an anterior circulation large-vessel occlusion who presented 6-24 h from onset or last seen well, and who were selected on the basis of the presence of collateral flow on CTA. Selection of patients for endovascular treatment in the late window could be primarily based on the presence of collateral flow.Funding Collaboration for New Treatments of Acute Stroke consortium, Dutch Heart Foundation, Stryker, Medtronic, Cerenovus, Top Sector Life Sciences & Health, and the Netherlands Brain Foundation.Copyright (c) 2023 Elsevier Ltd. All rights reserved. Show less
Roumans, C.A.M.; Bogt, R.D. van der; Nieboer, D.; Steyerberg, E.W.; Rizopoulos, D.; Lansdorp-Vogelaar, I.; ... ; ProBar Study Grp 2022
Half of Barrett's esophagus (BE) surveillance endoscopies do not adhere to guideline recommendations. In this multicenter prospective cohort study, we assessed the clinical consequences of... Show moreHalf of Barrett's esophagus (BE) surveillance endoscopies do not adhere to guideline recommendations. In this multicenter prospective cohort study, we assessed the clinical consequences of nonadherence to recommended surveillance intervals and biopsy protocol. Data from BE surveillance patients were collected from endoscopy and pathology reports; questionnaires were distributed among endoscopists. We estimated the association between (non)adherence and (i) endoscopic curability of esophageal adenocarcinoma (EAC), (ii) mortality, and (iii) misclassification of histological diagnosis according to a multistate hidden Markov model. Potential explanatory parameters (patient, facility, endoscopist variables) for nonadherence, related to clinical impact, were analyzed. In 726 BE patients, 3802 endoscopies were performed by 167 endoscopists. Adherence to surveillance interval was 16% for non-dysplastic (ND)BE, 55% for low-grade dysplasia (LGD), and 54% of endoscopies followed the Seattle protocol. There was no evidence to support the following statements: longer surveillance intervals or fewer biopsies than recommended affect endoscopic curability of EAC or cause-specific mortality (P > 0.20); insufficient biopsies affect the probability of NDBE (OR 1.0) or LGD (OR 2.3) being misclassified as high-grade dysplasia/EAC (P > 0.05). Better adherence was associated with older patients (OR 1.1), BE segments <= 2 cm (OR 8.3), visible abnormalities (OR 1.8, all P <= 0.05), endoscopists with a subspecialty (OR 3.2), and endoscopists who deemed histological diagnosis an adequate marker (OR 2.0). Clinical consequences of nonadherence to guidelines appeared to be limited with respect to endoscopic curability of EAC and mortality. This indicates that BE surveillance recommendations should be optimized to minimize the burden of endoscopies. Show less
Roumans, C.A.M.; Bogt, R.D. van der; Nieboer, D.; Steyerberg, E.W.; Rizopoulos, D.; Lansdorp-Vogelaar, I.; ... ; ProBar Study Grp 2022
Half of Barrett's esophagus (BE) surveillance endoscopies do not adhere to guideline recommendations. In this multicenter prospective cohort study, we assessed the clinical consequences of... Show moreHalf of Barrett's esophagus (BE) surveillance endoscopies do not adhere to guideline recommendations. In this multicenter prospective cohort study, we assessed the clinical consequences of nonadherence to recommended surveillance intervals and biopsy protocol. Data from BE surveillance patients were collected from endoscopy and pathology reports; questionnaires were distributed among endoscopists. We estimated the association between (non)adherence and (i) endoscopic curability of esophageal adenocarcinoma (EAC), (ii) mortality, and (iii) misclassification of histological diagnosis according to a multistate hidden Markov model. Potential explanatory parameters (patient, facility, endoscopist variables) for nonadherence, related to clinical impact, were analyzed. In 726 BE patients, 3802 endoscopies were performed by 167 endoscopists. Adherence to surveillance interval was 16% for non-dysplastic (ND)BE, 55% for low-grade dysplasia (LGD), and 54% of endoscopies followed the Seattle protocol. There was no evidence to support the following statements: longer surveillance intervals or fewer biopsies than recommended affect endoscopic curability of EAC or cause-specific mortality (P > 0.20); insufficient biopsies affect the probability of NDBE (OR 1.0) or LGD (OR 2.3) being misclassified as high-grade dysplasia/EAC (P > 0.05). Better adherence was associated with older patients (OR 1.1), BE segments <= 2 cm (OR 8.3), visible abnormalities (OR 1.8, all P <= 0.05), endoscopists with a subspecialty (OR 3.2), and endoscopists who deemed histological diagnosis an adequate marker (OR 2.0). Clinical consequences of nonadherence to guidelines appeared to be limited with respect to endoscopic curability of EAC and mortality. This indicates that BE surveillance recommendations should be optimized to minimize the burden of endoscopies. Show less
Huinink, S.T.; Jong, D.C. de; Nieboer, D.; Thomassen, D.; Steyerberg, E.W.; Dijkgraaf, M.G.W.; ... ; Vries, A.C. de 2022
Background Anti-tumor necrosis factor (TNF) therapy is effective for the treatment of Crohn's disease. Cessation may be considered in patients with a low risk of relapse. We aimed to externally... Show moreBackground Anti-tumor necrosis factor (TNF) therapy is effective for the treatment of Crohn's disease. Cessation may be considered in patients with a low risk of relapse. We aimed to externally validate and update our previously developed prediction model to estimate the risk of relapse after cessation of anti-TNF therapy. Methods We performed a retrospective cohort study in 17 Dutch hospitals. Crohn's disease patients in clinical, biochemical or endoscopic remission were included after anti-TNF cessation. Primary outcome was a relapse necessitating treatment. Discrimination and calibration of the previously developed model were assessed. After external validation, the model was updated. The performance of the updated prediction model was assessed in internal-external validation and by using decision curve analysis. Results 486 patients were included with a median follow-up of 1.7 years. Relapse rates were 35 and 54% after 1 and 2 years. At external validation, the discriminative ability of the prediction model was equal to that found at the development of the model [c-statistic 0.58 (95% confidence interval (CI) 0.54-0.62)], though the model was not well-calibrated on our cohort [calibration slope: 0.52 (0.28-0.76)]. After an update, a c-statistic of 0.60 (0.58-0.63) and calibration slope of 0.89 (0.69-1.09) were reported in internal-external validation. Conclusion Our previously developed and updated prediction model for the risk of relapse after cessation of anti-TNF in Crohn's disease shows reasonable performance. The use of the model may support clinical decision-making to optimize patient selection in whom anti-TNF can be withdrawn. Clinical validation is ongoing in a prospective randomized trial. Show less
Meester, R.G.S.; Schootbrugge-vandermeer, H.J. van de; Breekveldt, E.C.H.; Jonge, L. de; Toes-Zoutendijk, E.; Kooyker, A.; ... ; Dutch colorectal canc screening working group 2022
Objectives: To examine the prognostic potential of repeated faecal haemoglobin (F-Hb) concentration measurements in faecal immunochemical test (FIT)-based screening for colorectal cancer (CRC).... Show moreObjectives: To examine the prognostic potential of repeated faecal haemoglobin (F-Hb) concentration measurements in faecal immunochemical test (FIT)-based screening for colorectal cancer (CRC). Design: Prognostic model. Setting: Dutch biennial FIT-based screening programme during 2014-2018. Participants: 265 881 participants completing three rounds of FIT, with negative test results (F-Hb <47 mu g Hb/g faeces) in rounds 1 and 2. Interventions: Colonoscopy follow-up in participants with a positive FIT (F-Hb >= 47 mu g Hb/g faeces). Main outcomes: We evaluated prognostic models for detecting advanced neoplasia (AN) and CRC in round 3, with as predictors, participant age, sex, F-Hb in rounds 1 and 2, and categories/combinations/non-linear transformations of F-Hb. Primary evaluation criteria included: risk prediction accuracy (calibration), discrimination of participants with versus without AN or CRC (optimism-adjusted C-statistics, range 0.5-1.0), the degree of risk stratification and C-statistics in external validation. Results: Among study participants, 8806 (3.3%) had a positive FIT result, 3254 (1.2%) had AN detected and 557 (0.2%) had cancer. F-Hb concentrations in rounds 1 and 2 were the strongest outcome predictors, with adjusted ORs of up to 9.4 (95% CI 7.5 to 11.7) for the highest F-Hb category. Risk predictions matched the observed risk for most participants (calibration intercept -0.008 to -0.099; slope 0.982-0.998), and discriminated participants with versus without AN or CRC with C-statistics of 0.78 (95% CI 0.77 to 0.79) and 0.73 (95% CI 0.71 to 0.75), respectively. The predicted risk ranged from 0.4% to 36.7% for AN and from 0.0% to 5.5% for CRC across participants. In external validation, the model retained similar discrimination accuracy for AN (C-statistic 0.77, 95% CI 0.66 to 0.87) and CRC (C-statistic 0.78, 95% CI 0.66 to 0.91). Conclusion: Participants at lower versus higher risk of future AN or CRC can be accurately identified based on their age, sex and particularly, prior F-Hb concentrations. Risk stratification should be considered based on this information. Show less
Background Aspirin and unfractionated heparin are often used during endovascular stroke treatment to improve reperfusion and outcomes. However, the effects and risks of anti-thrombotics for this... Show moreBackground Aspirin and unfractionated heparin are often used during endovascular stroke treatment to improve reperfusion and outcomes. However, the effects and risks of anti-thrombotics for this indication are unknown. We therefore aimed to assess the safety and efficacy of intravenous aspirin, unfractionated heparin, both, or neither started during endovascular treatment in patients with ischaemic stroke.Methods We did an open-label, multicentre, randomised controlled trial with a 2 x 3 factorial design in 15 centres in the Netherlands. We enrolled adult patients (ie, >= 18 years) with ischaemic stroke due to an intracranial large-vessel occlusion in the anterior circulation in whom endovascular treatment could be initiated within 6 h of symptom onset. Eligible patients had a score of 2 or more on the National Institutes of Health Stroke Scale, and a CT or MRI ruling out intracranial haemorrhage. Randomisation was done using a web-based procedure with permuted blocks and stratified by centre. Patients were randomly assigned (1:1) to receive either periprocedural intravenous aspirin (300 mg bolus) or no aspirin, and randomly assigned (1:1:1) to receive moderate-dose unfractionated heparin (5000 IU bolus followed by 1250 IU/h for 6 h), low-dose unfractionated heparin (5000 IU bolus followed by 500 IU/h for 6 h), or no unfractionated heparin. The primary outcome was the score on the modified Rankin Scale at 90 days. Symptomatic intracranial haemorrhage was the main safety outcome. Analyses were based on intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. This trial is registered with the International Standard Randomised Controlled Trial Number, ISRCTN76741621.Findings Between Jan 22, 2018, and Jan 27, 2021, we randomly assigned 663 patients; of whom, 628 (95%) provided deferred consent or died before consent could be asked and were included in the modified intention-to-treat population. On Feb 4, 2021, after unblinding and analysis of the data, the trial steering committee permanently stopped patient recruitment and the trial was stopped for safety concerns. The risk of symptomatic intracranial haemorrhage was higher in patients allocated to receive aspirin than in those not receiving aspirin (43 [14%] of 310 vs 23 [7%] of 318; adjusted OR 1.95 [95% CI 1.13-3.35]) as well as in patients allocated to receive unfractionated heparin than in those not receiving unfractionated heparin (44 [13%] of 332 vs 22 [7%] of 296; 1.98 [1.14-3.46]). Both aspirin (adjusted common OR 0.91 [95% CI 0.69-1.21]) and unfractionated heparin (0.81 [0.61-1.08]) led to a non-significant shift towards worse modified Rankin Scale scores.Interpretation Periprocedural intravenous aspirin and unfractionated heparin during endovascular stroke treatment are both associated with an increased risk of symptomatic intracranial haemorrhage without evidence for a beneficial effect on functional outcome. Copyright (C) 2022 Published by Elsevier Ltd. All rights reserved. Show less
Benchmark surveillance tests for detecting disease progression (eg, biopsies, endoscopies) in early-stage chronic noncommunicable diseases (eg, cancer, lung diseases) are usually burdensome. For... Show moreBenchmark surveillance tests for detecting disease progression (eg, biopsies, endoscopies) in early-stage chronic noncommunicable diseases (eg, cancer, lung diseases) are usually burdensome. For detecting progression timely, patients undergo invasive tests planned in a fixed one-size-fits-all manner (eg, annually). We aim to present personalized test schedules based on the risk of disease progression, that optimize the burden (the number of tests) and the benefit (shorter time delay in detecting progression is better) better than fixed schedules, and enable shared decision making. Our motivation comes from the problem of scheduling biopsies in prostate cancer surveillance. Using joint models for time-to-event and longitudinal data, we consolidate patients' longitudinal data (eg, biomarkers) and results of previous tests, into individualized future cumulative-risk of progression. We then create personalized schedules by planning tests on future visits where the predicted cumulative-risk is above a threshold (eg, 5% risk). We update personalized schedules with data gathered over follow-up. To find the optimal risk threshold, we minimize a utility function of the expected number of tests (burden) and expected time delay in detecting progression (shorter is beneficial) for different thresholds. We estimate these two in a patient-specific manner for following any schedule, by utilizing a patient's predicted risk profile. Patients/doctors can employ these quantities to compare personalized and fixed schedules objectively and make a shared decision of a test schedule. Show less
Stoppelenburg, A.; Arslan, M.; Owusuaa, C.; Gunnink, N.; Linden, Y.M. van der; Luelmo, S.A.C.; ... ; Heide, A. van der 2022
Objective This prospective study aimed to evaluate the performance of the 'Surprise Question' (SQ) 'Would I be surprised if this patient died in the next 12 months?' in predicting survival of 12, 6... Show moreObjective This prospective study aimed to evaluate the performance of the 'Surprise Question' (SQ) 'Would I be surprised if this patient died in the next 12 months?' in predicting survival of 12, 6, 3 and 1 month(s), respectively, in hospitalised patients with cancer. Methods In three hospitals, physicians were asked to answer SQs for 12/6/3/1 month(s) for inpatients with cancer. Sensitivity, specificity, positive and negative predictive values were calculated. Results A total of 783 patients were included, of whom 51% died in the 12-month period after inclusion. Sensitivity of the SQ predicting death within 12 months was 0.79, specificity was 0.66, the positive predictive value was 0.71 and the negative predictive value was 0.75. When the SQ concerned a shorter survival period, sensitivities and positive predictive values decreased, whereas specificities and negative predictive values increased. In multivariable logistic regression analysis, the SQ was significantly associated with mortality (OR 3.93, 95% CI 2.70-5.71, p < 0.01). Conclusions The 12-month SQ predicts death in patients with cancer admitted to the hospital reasonably well. Shortening the timeframe decreases sensitivities and increases specificities. The four surprise questions may help to identify patients for whom palliative care is indicated. Show less
LeCouffe, N.E.; Kappelhof, M.; Treurniet, K.M.; Rinkel, L.A.; Bruggeman, A.E.; Berkhemer, O.A.; ... ; MR CLEAN-NO IV Investigators 2021
Alteplase with EVT versus EVT Alone for Stroke Trials involving Asian patients with acute stroke have suggested that endovascular treatment alone is not inferior to the usual practice of... Show moreAlteplase with EVT versus EVT Alone for Stroke Trials involving Asian patients with acute stroke have suggested that endovascular treatment alone is not inferior to the usual practice of thrombolysis before endovascular treatment. This trial involving European patients did not show noninferiority or superiority of endovascular treatment alone.Background The value of administering intravenous alteplase before endovascular treatment (EVT) for acute ischemic stroke has not been studied extensively, particularly in non-Asian populations. Methods We performed an open-label, multicenter, randomized trial in Europe involving patients with stroke who presented directly to a hospital that was capable of providing EVT and who were eligible for intravenous alteplase and EVT. Patients were randomly assigned in a 1:1 ratio to receive EVT alone or intravenous alteplase followed by EVT (the standard of care). The primary end point was functional outcome on the modified Rankin scale (range, 0 [no disability] to 6 [death]) at 90 days. We assessed the superiority of EVT alone over alteplase plus EVT, as well as noninferiority by a margin of 0.8 for the lower boundary of the 95% confidence interval for the odds ratio of the two trial groups. Death from any cause and symptomatic intracerebral hemorrhage were the main safety end points. Results The analysis included 539 patients. The median score on the modified Rankin scale at 90 days was 3 (interquartile range, 2 to 5) with EVT alone and 2 (interquartile range, 2 to 5) with alteplase plus EVT. The adjusted common odds ratio was 0.84 (95% confidence interval [CI], 0.62 to 1.15; P=0.28), which showed neither superiority nor noninferiority of EVT alone. Mortality was 20.5% with EVT alone and 15.8% with alteplase plus EVT (adjusted odds ratio, 1.39; 95% CI, 0.84 to 2.30). Symptomatic intracerebral hemorrhage occurred in 5.9% and 5.3% of the patients in the respective groups (adjusted odds ratio, 1.30; 95% CI, 0.60 to 2.81). Conclusions In a randomized trial involving European patients, EVT alone was neither superior nor noninferior to intravenous alteplase followed by EVT with regard to disability outcome at 90 days after stroke. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. (Funded by the Collaboration for New Treatments of Acute Stroke consortium and others; MR CLEAN-NO IV ISRCTN number, .) Show less
The relation between prostate-specific antigen (PSA) and other relevant prebiopsy information is often combined in a risk calculator (RC). If the setting for RC use differs from that in which it... Show moreThe relation between prostate-specific antigen (PSA) and other relevant prebiopsy information is often combined in a risk calculator (RC). If the setting for RC use differs from that in which it was developed, there is a risk of making clinical decisions based on incorrect estimates of the absolute risk. The ERSPC-MRI RC predicts clinically significant prostate cancer (csPC; Gleason >= 3 + 4) on targeted and systematic biopsy using information on PSA, digital rectal examination, prostate volume, age, previous negative biopsy, and Prostate Imaging-Recording and Data System score. This calculator was developed on a clinical cohort of 961 men (2012-2017) with a csPC prevalence of 36%. Discrimination was good (area under the receiver operating characteristic curve 0.84). With the increasing use of multiparametric magnetic resonance imaging, we foresee that this RC will also be used for men with a lower a priori likelihood of PC. We investigated the effect of such a scenario on individual risk predictions. A small update of the intercept for the calculator can restore the accuracy to support decision-making with locally valid risk estimates.Patient summary: Decisions on who to refer for a prostate biopsy with its risk of sepsis and overdiagnosis require more than a prostate-specific antigen test. A prediction tool may take other relevant prebiopsy information into account, but may need to be updated to contemporary center-specific settings to provide accurate estimates of the risk of having prostate cancer. (C) 2019 Published by Elsevier B.V. on behalf of European Association of Urology. Show less
Lecky, F.E.; Otesile, O.; Marincowitz, C.; Majdan, M.; Nieboer, D.; Lingsma, H.F.; ... ; Moyer, C. 2021
Author summary Why was this study done? Traumatic brain injury (TBI) poses a huge global disease burden, considered to mainly result from high-energy transfer mechanisms such as road traffic... Show moreAuthor summary Why was this study done? Traumatic brain injury (TBI) poses a huge global disease burden, considered to mainly result from high-energy transfer mechanisms such as road traffic collisions, sports, falls from a height, and interpersonal violence.People injured through low-energy transfer (ground- or low-level falls) are considered less likely to sustain significant TBI, so can be given lower priority for acute specialist care within emergency medical services (triage decisions).Recent multinational studies challenge these assumptions by identifying falls as an important TBI causal mechanism-but these studies seldom describe fall height.The lack of clarity concerning the low-energy TBI disease burden hampers effective prevention and clinical management. What did the researchers do and find? We studied 21,681 patients with TBI presenting to 56 hospital emergency departments across Europe and Israel using an efficient registry methodology enabling a real-world approach.We found that the 40% of patients with TBI who were injured through low-energy falls were significantly older, more likely to be female, and more likely to be taking pre-injury drugs that prevent blood clotting than patients with TBI sustained through high-energy transfer.Despite similar rates of significant injury on the CT brain scan and of dying in hospital, patients injured through low-energy falls were half as likely to receive critical care or emergency intervention compared to those injured by high-energy transfer. What do these findings mean? Low-energy falls contribute to a significant portion of the TBI disease burden, which will increase as the global population ages.In older people, the assumption that energy transfer predicts brain injury severity and threat to life appears to lack validity.Factors beyond energy transfer level may be more relevant to prehospital and emergency department TBI triage in older people. The appropriateness of providing less intensive acute hospital care after low-energy TBI requires further study.Reduction of TBI disease burden requires specific prevention and therapy initiatives targeted at low-energy TBI.BackgroundTraumatic 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 findingsWe 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. ConclusionsWe 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. Show less
Statistical models for outcome prediction are central to traumatic brain injury research and critical to baseline risk adjustment. Glasgow coma score (GCS) and pupil reactivity are crucial... Show moreStatistical models for outcome prediction are central to traumatic brain injury research and critical to baseline risk adjustment. Glasgow coma score (GCS) and pupil reactivity are crucial covariates in all such models but may be measured at multiple time points between the time of injury and hospital and are subject to a variable degree of unreliability and/or missingness. Imputation of missing data may be undertaken using full multiple imputation or by simple substitution of measurements from other time points. However, it is unknown which strategy is best or which time points are more predictive. We evaluated the pseudo-R-2 of logistic regression models (dichotomous survival) and proportional odds models (Glasgow Outcome Score-extended) using different imputation strategies on the The Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study dataset. Substitution strategies were easy to implement, achieved low levels of missingness (<< 10%) and could outperform multiple imputation without the need for computationally costly calculations and pooling multiple final models. While model performance was sensitive to imputation strategy, this effect was small in absolute terms and clinical relevance. A strategy of using the emergency department discharge assessments and working back in time when these were missing generally performed well. Full multiple imputation had the advantage of preserving time-dependence in the models: the pre-hospital assessments were found to be relatively unreliable predictors of survival or outcome. The predictive performance of later assessments was model-dependent. In conclusion, simple substitution strategies for imputing baseline GCS and pupil response can perform well and may be a simple alternative to full multiple imputation in many cases. Show less
Sewalt, C.A.; Gravesteijn, B.Y.; Nieboer, D.; Steyerberg, E.W.; Hartog, D. den; Klaveren, D. van 2021
Background Prehospital triage protocols typically try to select patients with Injury Severity Score (ISS) above 15 for direct transportation to a Level-1 trauma center. However, ISS does not... Show moreBackground Prehospital triage protocols typically try to select patients with Injury Severity Score (ISS) above 15 for direct transportation to a Level-1 trauma center. However, ISS does not necessarily discriminate between patients who benefit from immediate care at Level-1 trauma centers. The aim of this study was to assess which patients benefit from direct transportation to Level-1 trauma centers. Methods We used the American National Trauma Data Bank (NTDB), a retrospective observational cohort. All adult patients (ISS > 3) between 2015 and 2016 were included. Patients who were self-presenting or had isolated limb injury were excluded. We used logistic regression to assess the association of direct transportation to Level-1 trauma centers with in-hospital mortality adjusted for clinically relevant confounders. We used this model to define benefit as predicted probability of mortality associated with transportation to a non-Level-1 trauma center minus predicted probability associated with transportation to a Level-1 trauma center. We used a threshold of 1% as absolute benefit. Potential interaction terms with transportation to Level-1 trauma centers were included in a penalized logistic regression model to study which patients benefit. Results We included 388,845 trauma patients from 232 Level-1 centers and 429 Level-2/3 centers. A small beneficial effect was found for direct transportation to Level-1 trauma centers (adjusted Odds Ratio: 0.96, 95% Confidence Interval: 0.92-0.99) which disappeared when comparing Level-1 and 2 versus Level-3 trauma centers. In the risk approach, predicted benefit ranged between 0 and 1%. When allowing for interactions, 7% of the patients (n = 27,753) had more than 1% absolute benefit from direct transportation to Level-1 trauma centers. These patients had higher AIS Head and Thorax scores, lower GCS and lower SBP. A quarter of the patients with ISS > 15 were predicted to benefit from transportation to Level-1 centers (n = 26,522, 22%). Conclusions Benefit of transportation to a Level-1 trauma centers is quite heterogeneous across patients and the difference between Level-1 and Level-2 trauma centers is small. In particular, patients with head injury and signs of shock may benefit from care in a Level-1 trauma center. Future prehospital triage models should incorporate more complete risk profiles. Show less
Objective To assess the value of the Emergency Department-Pediatric Early Warning Score (ED-PEWS) for triage of children with comorbidity.Design Secondary analysis of a prospective cohort.Setting... Show moreObjective To assess the value of the Emergency Department-Pediatric Early Warning Score (ED-PEWS) for triage of children with comorbidity.Design Secondary analysis of a prospective cohort.Setting and patients 53 829 consecutive ED visits of children <16 years in three European hospitals (Netherlands, UK and Austria) participating in the TrIAGE (Triage Improvements Across General Emergency departments) project in different periods (2012-2015).Intervention ED-PEWS, a score consisting of age and six physiological parameters.Main outcome measure A three-category reference standard as proxy for true patient urgency. We assessed discrimination and calibration of the ED-PEWS for children with comorbidity (complex and non-complex) and without comorbidity. In addition, we evaluated the value of adding the ED-PEWS to the routinely used Manchester Triage System (MTS).Results 5053 (9%) children had underlying non-complex morbidity and 5537 (10%) had complex comorbidity. The c-statistic for identification of high-urgency patients was 0.86 (95% prediction interval 0.84-0.88) for children without comorbidity, 0.87 (0.82-0.92) for non-complex and 0.86 (0.84-0.88) for complex comorbidity. For high and intermediate urgency, the c-statistic was 0.63 (0.62-0.63), 0.63 (0.61-0.65) and 0.63 (0.55-0.73) respectively. Sensitivity was slightly higher for children with comorbidity (0.73-0.75 vs 0.70) at the cost of a lower specificity (0.86-0.87 vs 0.92). Calibration was largely similar. Adding the ED-PEWS to the MTS for children with comorbidity improved performance, except in the setting with few high-urgency patients.Conclusions The ED-PEWS has a similar performance in children with and without comorbidity. Adding the ED-PEWS to the MTS for children with comorbidity improves triage, except in the setting with few high-urgency patients. Show less
Bruinsma, S.M.; Nieboer, D.; Roobol, M.J.; Bangma, C.H.; Verbeek, J.F.M.; Gnanapragasam, V.; ... ; Movember Fdn Global Action Plan 2021
Purpose: We sought to identify and validate known predictors of disease reclassification at 1 or 4 years to support risk-based selection of patients suitable for active surveillance.Materials and... Show morePurpose: We sought to identify and validate known predictors of disease reclassification at 1 or 4 years to support risk-based selection of patients suitable for active surveillance.Materials and Methods: An individual participant data meta-analysis using data from 25 established cohorts within the Movember Foundations GAP3 Consortium. In total 5,530 men were included. Disease reclassification was defined as any increase in Gleason grade group at biopsy at 1 and 4 years. Associations were estimated using random effect logistic regression models. The discriminative ability of combinations of predictors was assessed in an internaleexternal validation procedure using the AUC curve.Results: Among the 5,570 men evaluated at 1 year, we found 815 reclassifications to higher Gleason grade group at biopsy (pooled reclassification rate 13%, range 0% to 31%). Important predictors were age, prostate specific antigen, prostate volume, T-stage and number of biopsy cores with prostate cancer. Among the 1,515 men evaluated at 4 years, we found 205 reclassifications (pooled reclassification rates 14%, range 3% to 40%), with similar predictors. The average areas under the receiver operating characteristic curve at internaleexternal validation were 0.68 and 0.61 for 1-year and 4-year reclassification, respectively.Conclusions: Disease reclassification occurs typically in 13% to 14% of biopsies at 1 and 4 years after the start of active surveillance with substantial between-study heterogeneity. Current guidelines might be extended by considering prostate volume to improve individualized selection for active surveillance. Additional predictors are needed to improve patient selection for active surveillance. Show less
In medical research, missing data is common. In acute diseases, such as traumatic brain injury (TBI), even well-conducted prospective studies may suffer from missing data in baseline... Show moreIn medical research, missing data is common. In acute diseases, such as traumatic brain injury (TBI), even well-conducted prospective studies may suffer from missing data in baseline characteristics and outcomes. Statistical models may simply drop patients with any missing values, potentially leaving a selected subset of the original cohort. Imputation is widely accepted by methodologists as an appropriate way to deal with missing data. We aim to provide practical guidance on handling missing data for prediction modeling. We hereto propose a five-step approach, centered around single and multiple imputation: 1) explore the missing data patterns; 2) choose a method of imputation; 3) perform imputation; 4) assess diagnostics of the imputation; and 5) analyze the imputed data sets. We illustrate these five steps with the estimation and validation of the IMPACT (International Mission on Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury) prognostic model in 1375 patients from the CENTER-TBI database, included in 53 centers across 17 countries, with moderate or severe TBI in the prospective European CENTER-TBI study. Future prediction modeling studies in acute diseases may benefit from following the suggested five steps for optimal statistical analysis and interpretation, after maximal effort has been made to minimize missing data. Show less
Objective To evaluate the role of blood pressure (BP) as mediator of the effect of conscious sedation (CS) compared to local anesthesia (LA) on functional outcome after endovascular treatment (EVT)... Show moreObjective To evaluate the role of blood pressure (BP) as mediator of the effect of conscious sedation (CS) compared to local anesthesia (LA) on functional outcome after endovascular treatment (EVT). Methods Patients treated in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry centers with CS or LA as preferred anesthetic approach during EVT for ischemic stroke were analyzed. First, we evaluated the effect of CS on area under the threshold (AUT), relative difference between baseline and lowest procedural mean arterial pressure ( increment LMAP), and procedural BP trend, compared to LA. Second, we assessed the association between BP and functional outcome (modified Rankin Scale [mRS]) with multivariable regression. Lastly, we evaluated whether BP explained the effect of CS on mRS. Results In 440 patients with available BP data, patients treated under CS (n = 262) had larger AUTs (median 228 vs 23 mm Hg*min), larger increment LMAP (median 16% vs 6%), and a more negative BP trend (-0.22 vs -0.08 mm Hg/min) compared to LA (n = 178). Larger increment LMAP and AUTs were associated with worse mRS (adjusted common odds ratio [acOR] per 10% drop 0.87, 95% confidence interval [CI] 0.78-0.97, and acOR per 300 mm Hg*min 0.89, 95% CI 0.82-0.97). Patients treated under CS had worse mRS compared to LA (acOR 0.59, 95% CI 0.40-0.87) and this association remained when adjusting for increment LMAP and AUT (acOR 0.62, 95% CI 0.42-0.92). Conclusions Large BP drops are associated with worse functional outcome. However, BP drops do not explain the worse outcomes in the CS group. Show less
Dijkland, S.A.; Helmrich, I.R.A.R.; Nieboer, D.; Jagt, M. van der; Dippel, D.W.J.; Menon, D.K.; ... ; CENTER-TBI Participants Investig 2020
The International Mission on Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) and Corticoid Randomisation After Significant Head injury (CRASH) prognostic models predict... Show moreThe International Mission on Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) and Corticoid Randomisation After Significant Head injury (CRASH) prognostic models predict functional outcome after moderate and severe traumatic brain injury (TBI). We aimed to assess their performance in a contemporary cohort of patients across Europe. The Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) core study is a prospective, observational cohort study in patients presenting with TBI and an indication for brain computed tomography. The CENTER-TBI core cohort consists of 4509 TBI patients available for analyses from 59 centers in 18 countries across Europe and Israel. The IMPACT validation cohort included 1173 patients with GCS <= 12, age >= 14, and 6-month Glasgow Outcome Scale-Extended (GOSE) available. The CRASH validation cohort contained 1742 patients with GCS <= 14, age >= 16, and 14-day mortality or 6-month GOSE available. Performance of the three IMPACT and two CRASH model variants was assessed with discrimination (area under the receiver operating characteristic curve; AUC) and calibration (comparison of observed vs. predicted outcome rates). For IMPACT, model discrimination was good, with AUCs ranging between 0.77 and 0.85 in 1173 patients and between 0.80 and 0.88 in the broader CRASH selection (n = 1742). For CRASH, AUCs ranged between 0.82 and 0.88 in 1742 patients and between 0.66 and 0.80 in the stricter IMPACT selection (n = 1173). Calibration of the IMPACT and CRASH models was generally moderate, with calibration-in-the-large and calibration slopes ranging between -2.02 and 0.61 and between 0.48 and 1.39, respectively. The IMPACT and CRASH models adequately identify patients at high risk for mortality or unfavorable outcome, which supports their use in research settings and for benchmarking in the context of quality-of-care assessment. Show less
Wijk, R.P.J. van; Dijck, J.T.J.M. van; Timmers, M.; Veen, E. van; Citerio, G.; Lingsma, H.F.; ... ; CENTER-TB1 Investigators 2020
Purpose: Enrolling traumatic brain injury (731) patients with an inability to provide informed consent in research is challenging. Alternatives to patient consent are not sufficiently embedded in... Show morePurpose: Enrolling traumatic brain injury (731) patients with an inability to provide informed consent in research is challenging. Alternatives to patient consent are not sufficiently embedded in European and national legislation, which allows procedural variation and bias. We aimed to quantify variations in informed consent policy and practice.Methods: Variation was explored in the CENTER-TBI study. Policies were reported by using a questionnaire and national legislation. Data on used informed consent procedures were available for 4498 patients from 57 centres across 17 European countries.Results: Variation in the use of informed consent procedures was found between and within EU member states. Proxy informed consent (N = 1377;64%) was the most frequently used type of consent in the ICU, followed by patient informed consent (N 426;20%) and deferred consent (N 334;16%). Deferred consent was only actively used in 15 centres (26%), although it was considered valid in 47 centres (82%).Conclusions: Alternatives to patient consent are essential for TBI research. While there seems to be concordance amongst national legislations, there is regional variability in institutional practices with respect to the use of different informed consent procedures. Variation could be caused by several reasons, including inconsistencies in clear legislation or knowledge of such legislation amongst researchers. (C) 2020 Published by Elsevier Inc. Show less
