Evaluating the feasibility and acceptability of an adapted fencing intervention in breast cancer surgery post-operative care: the RIPOSTE pilot randomized trial.

Background: Adapted physical activity programs have shown promising results in reducing the physical, social and psychological side effects associated with breast cancer, but the extent to which they can be effectively adopted, implemented and maintained is unclear. The aim of this study is to use the framework to guide the planning and evaluation of programs according to the 5 following keys: Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) framework to evaluate a fencing program under the French acronym RIPOSTE (Reconstruction, Image de soi, Posture, Oncologie, Santé, Thérapie, Escrime) literally in English (Reconstruction, Self-Image, Posture, Oncology, Health, Therapy, Fencing). This program is an innovative intervention focused on improving the quality of life (QoL) of breast cancer surgery patients through fencing. Methods: A convergent mixed methods pilot study was conducted to preliminary evaluate the different RE-AIM dimension of the pilot program. Twenty-four participants who have just undergone surgery for invasive breast cancer were randomly allocated in two groups: one group started immediately after their inclusion (Early RIPOSTE group) and the other started 3 months following their inclusion (Delayed RIPOSTE group). Participants answered a questionnaire at inclusion and at the end of the program on QoL, shoulder functional capacity, fatigue, anxiety-depression and physical activity. Results: RIPOSTE program was able to reach mainly young and dynamic participants, attracted by the originality of fencing and keen to improve their physical condition. Regarding effectiveness, our results suggest a trend to the improvement of QoL, shoulder functional capacity, fatigue and anxiety-depression state, even without any significant differences between the Early RIPOSTE group and the Delayed RIPOSTE group. Discussions: The cooperation, exchanges and cohesion within the group greatly facilitated the adoption of the program, whereas interruptions during school vacations were the main barriers. The intervention was moderately well implemented and adherence to the protocol was suitable. Conclusion: RIPOSTE is an acceptable and effective program for involving breast cancer survivors in physical activity, that needs to be tested at a larger scale to investigate its effectiveness, but has the potential to be transferred and scaled up worldwide.

Risk of secondary progression in patients with highly active multiple sclerosis treated with natalizumab: a real-life study.

BACKGROUND: one of the most important therapeutic goals in relapse-onset multiple sclerosis is to preclude conversion to secondary progression. Our objective was to determine the risk of progression associated with natalizumab treatment in an registry-based cohort of patients and to identify determinant factors. METHODS: Patients with relapse-onset multiple sclerosis from the Registre Lorrain des Scléroses en Plaques (ReLSEP) were included if they had received one infusion of natalizumab between 2002 and 2021. The risk of secondary progression was determined using a standardized definition and a multi-state estimator to account for the possibility of stopping natalizumab before progression, and analyzed with multivariate Cox models. RESULTS: 574 patients were followed up for a median of 6.7 years. Of the 304 who stopped NTZ before progression onset, the probabilities (95% confidence interval) to convert to progression after 1, 2, 5 and 10 years were 3.2% (2.0-4.8%), 5.3% (3.6-7.3%), 17.5% (14.3-21.3%) and 28.3% (23.7-33.7%), respectively. Discontinuation of NTZ during follow-up was significantly associated with an increased risk of conversion in case of no resumption of a highly active treatment thereafter (adjusted hazard ratio = 2.7; 95% confidence interval 1.5-4.9; p = 0.001). The use of such a treatment was associated with a lower risk of progression (adjusted hazard ratio = 0.42; 95% confidence interval 0.23-0.79; p = 0.007). CONCLUSION: the risk of conversion to secondary progression associated with natalizumab treatment is relatively low but increases in case of natalizumab discontinuation in the absence of switch to highly active immunosuppressant.

Real-life evaluation of the 2017 McDonald criteria for relapsing-remitting multiple sclerosis after a clinically isolated syndrome confirms a gain in time-to-diagnosis.

BACKGROUND: Previous cohort studies evaluating the performances of the McDonald criteria suffered from bias regarding real-life conditions. We aimed to evaluate the probability of diagnosing relapsing-remitting multiple sclerosis (MS) at several timepoints from the first medical evaluation and the gain in time-to-diagnosis with the 2017 McDonald criteria compared with the 2001, 2005 and 2010 versions in real life. METHODS: Patients with a first demyelinating event suggestive of MS between 2002 and 2020 were included in the ReLSEP, an exhaustive and prospectively incremented registry of MS patients in North-Eastern France. We estimated the probability of being positive at the first medical evaluation and at five timepoints according to the four versions of criteria using Kaplan-Meier estimators and Cox models. RESULTS: A total of 2220 patients were followed up for a median of 7.1 years. At baseline, 31.7%, 32.1%, 36.6% and 54.0% of patients, respectively, fulfilled the 2001, 2005, 2010 and 2017 McDonald criteria. Using the 2017 criteria, the gain in time-to-diagnosis was 3.7 months compared with the 2010 criteria. The presence of intrathecal synthesis of immunoglobulin G in the McDonald 2017 criteria led to a 1.8-month reduction in median time-to-diagnosis compared to a version of McDonald 2017 without this criteria. CONCLUSIONS: In real-life, the 2017 McDonald criteria revision undoubtedly shortened time-to-diagnosis.

Fluid balance control in critically ill patients: results from as-treated analyses of POINCARE-2 randomized trial.

BACKGROUND: Intention-to-treat analyses of POINCARE-2 trial led to inconclusive results regarding the effect of a conservative fluid balance strategy on mortality in critically ill patients. The present as-treated analysis aimed to assess the effectiveness of actual exposure to POINCARE-2 strategy on 60-day mortality in critically ill patients. METHODS: POINCARE­2 was a stepped wedge randomized controlled trial. Eligible patients were ≥ 18 years old, under mechanical ventilation and had an expected length of stay in ICU > 24 h. POINCARE-2 strategy consisted of daily weighing over 14 days, and subsequent restriction of fluid intake, administration of diuretics, and/or ultrafiltration. We computed a score of exposure to the strategy based on deviations from the strategy algorithm. We considered patients with a score ≥ 75 as exposed to the strategy. We used logistic regression adjusted for confounders (ALR) or for an instrumental variable (IVLR). We handled missing data using multiple imputations. RESULTS: A total of 1361 patients were included. Overall, 24.8% of patients in the control group and 69.4% of patients in the strategy group had a score of exposure ≥ 75. Exposure to the POINCARE-2 strategy was not associated with 60-day all-cause mortality (ALR: OR 1.2, 95% CI 0.85-1.55; IVLR: OR 1.0, 95% CI 0.76-1.33). CONCLUSION: Actual exposure to POINCARE-2 conservative strategy was not associated with reduced mortality in critically ill patients. Trial registration POINCARE-2 trial is registered at ClinicalTrials.gov (NCT02765009). Registered 29 April 2016.

Performance of administrative databases for identifying individuals with multiple sclerosis.

Administrative databases are an alternative to disease registries as a research tool to study multiple sclerosis. However, they are not initially designed to fulfill research purposes. Therefore, an evaluation of their performance is necessary. Our objective was to assess the performance of the French administrative database comprising hospital discharge records and national health insurance databases in identifying individuals with multiple sclerosis, in comparison with a registry that exhaustively compiles resident multiple sclerosis cases in Lorraine, northeastern France, as reference. We recorded all individuals residing in the Lorraine region who were identified by the administrative database or the registry as having multiple sclerosis from 2011 to 2016. We calculated the Matthews correlation coefficient and other concordance indicators. For identifying individuals with multiple sclerosis, the Matthews correlation coefficient by the administrative database was 0.79 (95% CI 0.78-0.80), reflecting moderate performance. The mean time to identification was 5.5 years earlier with the registry than the administrative database. Administrative databases, although useful to study multiple sclerosis, should be used with caution because results of studies based on them may be biased. Our study highlights the value of regional registries that allow for a more exhaustive and rapid identification of cases.

Prognostic factors of readmission and mortality after first heart failure hospitalization: results from EPICAL2 cohort.

AIMS: We aimed to identify prognostic individual factors in patients with first acute heart failure (HF) hospitalization, considering both death and readmission as part of the natural history of HF. METHODS AND RESULTS: We used data from the observational, prospective, multicentre EPICAL2 cohort study from which we selected incident cases of acute HF alive at discharge. We relied on an illness-death model to identify prognostic factors on first readmission and on mortality before and after readmission. In 451 patients hospitalized for first acute HF, we observed within the year after discharge, 23 (5.1%) deaths before readmission and 270 (59.9%) first readmissions, of which 60 (22.2%) were followed by death of any cause. First, among patient characteristics, only Charlson index ≥ 8 was associated with first readmission [adjusted hazard ratio (aHR) = 1.6, 95% confidence interval (CI) (1.1-2.3), P = 0.011]. Second, Charlson index ≥ 8 [aHR = 4.2, 95% CI (1.2-14.8), P = 0.025], low blood pressure (BP) [aHR = 12.2, 95% CI (1.9-79.6), P = 0.009], high BP [aHR = 6.9, 95% CI (1.3-36.4), P = 0.023], and prescription of recommended dual or triple HF therapy at index discharge [aHR = 0.2, 95% CI (0.1-0.7), P = 0.014] were associated with mortality before any readmission. Third, Charlson index ≥ 8 [aHR = 2.4, 95% CI (1.1-5.6), P = 0.037] and the time to first readmission (per 30 days additional) [aHR = 1.2; 95% CI (1.1-1.4), P = 0.007] were associated with mortality after readmission. CONCLUSIONS: Regardless of the prognostic state considered, we showed that comorbidities are of critical prognostic value in a real-world cohort of incident HF cases. This argues in favour of multidisciplinary care in HF.

Prognostic impact of epileptic seizures in multiple sclerosis varies according to time of occurrence and etiology.

BACKGROUND AND PURPOSE: Epileptic seizures occur more often in patients with multiple sclerosis (MS) than in the general population. Their association with the prognosis of MS remains unclear. This study was undertaken to evaluate whether epileptic seizures may be a prognostic marker of MS disability, according to when the seizure occurs and its cause. METHODS: Data were extracted from a population-based registry of MS in Lorraine, France. Kaplan-Meier curves and log-rank tests were used to compare the probability of different levels of irreversible handicap during the course of MS in patients who experience epileptic seizures or do not, according to the chronology and the cause of the first epileptic seizure. RESULTS: Among 6238 patients, 134 had experienced at least one epileptic seizure (2.1%), and 82 (1.2%) had seizures secondary to MS. Patients with epileptic seizure as a first symptom of MS (14 patients) had the same disease progression as other relapsing-remitting MS patients. Patients who developed epileptic seizures during the course of MS (68 patients) had a higher probability of reaching Expanded Disability Status Scale = 3.0 (p = 0.006), 6.0 (p = 0.003), and 7.0 (p = 0.004) than patients without an epileptic background. Patients with a history of epileptic seizures unrelated to MS also had a worse prognosis than patients without an epileptic background. CONCLUSIONS: Epileptic seizures might be viewed as a "classic MS relapse" in terms of prognosis if occurring early in MS, or as a marker of MS severity if developing during the disease. Epileptic diseases other than MS may worsen the course of MS.

Age-period-cohort analysis of the incidence of multiple sclerosis over twenty years in Lorraine, France.

Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system. An increase in MS incidence over time is reported in several regions of the world. We aimed to describe the evolution of the annual MS incidence in the Lorraine region, France, from 1996 to 2015 and to analyze potential components of a possible change by a temporal effect of age at MS onset, MS onset period, and birth cohort, overall and for each sex. Cases were identified from ReLSEP, a population-based registry of MS cases living in Lorraine, northeastern France, with MS onset between 1996 and 2015. Age-period-cohort modeling was used to describe trends in MS incidence. Annual age- and sex-standardized incidences were relatively stable: 6.76/100 000 population (95%CI [5.76-7.91]) in 1996 and 6.78/100 000 (95%CI [5.72-7.97]) in 2015. The incidence ratio between women and men was 2.4. For all time periods, the peak incidence occurred between ages 25 and 35 years. Age-period-adjusted cohort and age-cohort-adjusted period analyses did not reveal a period or cohort effect. The incidence of MS remained stable over the study period in Lorraine, and we could not identify any particular effect of disease onset period or birth period on this evolution.

Impact of Pretreatment Ischemic Location on Functional Outcome after Thrombectomy.

Pretreatment ischemic location may be an important determinant for functional outcome prediction in acute ischemic stroke. In total, 143 anterior circulation ischemic stroke patients in the THRACE study were included. Ischemic lesions were semi-automatically segmented on pretreatment diffusion-weighted imaging and registered on brain atlases. The percentage of ischemic tissue in each atlas-segmented region was calculated. Statistical models with logistic regression and support vector machine were built to analyze the predictors of functional outcome. The investigated parameters included: age, baseline National Institutes of Health Stroke Scale score, and lesional volume (three-parameter model), together with the ischemic percentage in each atlas-segmented region (four-parameter model). The support vector machine with radial basis functions outperformed logistic regression in prediction accuracy. The support vector machine three-parameter model demonstrated an area under the curve of 0.77, while the four-parameter model achieved a higher area under the curve (0.82). Regions with marked impacts on outcome prediction were the uncinate fasciculus, postcentral gyrus, putamen, middle occipital gyrus, supramarginal gyrus, and posterior corona radiata in the left hemisphere; and the uncinate fasciculus, paracentral lobule, temporal pole, hippocampus, inferior occipital gyrus, middle temporal gyrus, pallidum, and anterior limb of the internal capsule in the right hemisphere. In conclusion, pretreatment ischemic location provided significant prognostic information for functional outcome in ischemic stroke.

Clinical imaging factors of excellent outcome after thrombolysis in large-vessel stroke: a THRACE subgroup analysis.

BACKGROUND: For patients with stroke with large-vessel occlusion (LVO), study of factors predicting response to intravenous thrombolysis (IVT) would allow identifying subgroups with high expected gain, and those for whom it could be considered as futile, and even detrimental. From patients included in the Mechanical Thrombectomy After Intravenous Alteplase vs Alteplase Alone After Stroke trial, we investigated clinical-imaging factors associated with optimal response to IVT. METHODS: We included patients receiving IVT alone. Excellent outcome was defined by a 3-month modified Rankin Scale (mRS) score ≤1. Clinical-imaging predictors were assessed on multivariate analysis after multiple imputations. The predictive performance of the model was assessed with the C-statistic. RESULTS: Among 247 patients with LVO treated with IVT alone, 77 (31%) showed 3-month mRS ≤1. Predictors of 3-month mRS ≤1 were no medical history of hypertension (OR 2.43; 95% CI 1.74 to 3.38; p=0.007); no current smoking (OR 2.76; 95% CI 1.79 to 4.26; p=0.02); onset-to-IVT time (OR 0.47 per hour increase; 95% CI 0.23 to 0.78; p=0.003); diffusion-weighted imaging (DWI) volume (OR 0.78 per 10 mL increase; 95% CI 0.68 to 0.89; p=0.0004); presence of susceptibility vessel sign (SVS) (OR 7.89; 95% CI 1.65 to 37.78; p=0.01) and SVS length (OR 0.87 per mm increase; 95% CI 0.80 to 0.94; p=0.001). The prediction models showed a C-statistic=0.79 (95% CI 0.79 to 0.80). CONCLUSIONS: In patients with stroke with anterior-circulation LVO treated with IVT alone, predictors of excellent outcome at 3 months were no medical history of hypertension or current smoking, reduced onset-to-IVT time, small DWI volume, presence of SVS and short SVS length. These predictive factors could help practitioners in decision-making for IVT implementation in reperfusion strategies, all the more for the drip and ship paradigm. TRIAL REGISTRATION NUMBER: NCT01062698.

Long-term analysis of patients with benign multiple sclerosis: new insights about the disability course.

OBJECTIVE: To describe the course of disability in patients with benign multiple sclerosis-i.e., with an expanded disability status scale score < 3 10 years after disease onset-for up to 30 years after disease onset. We evaluated the proportion of patients remaining in the benign state on the long term and the factor associated with this favorable outcome and determined the pattern of disability course after the loss of the benign status. METHODS: Patients were selected from the ReLSEP, a French population-based registry. We studied the probability (Kaplan-Meier method) and predictors (multivariate Cox model) of remaining < 3 after year 10, and the course of disability after score 3 according to the duration of the benign phase in patients with ≥ 30 years of follow-up (graphs of the course of the mean expanded disability status scale scores in subgroups of patients). RESULTS: 2295/3440 patients had benign multiple sclerosis (66.7%). The probability of remaining benign at year 30 was 0.26 (95% CI 0.26-0.32). A young age at disease onset and a good recovery after the first relapse were associated with remaining benign. Graphs illustrate that those who lost their benign status between years 10 and 30 follow a two-stage course. Beyond score 3, disability accumulation is similar in all but lower disability scores at advanced age are associated with longer benign periods. CONCLUSION: The longer a patient remains in the benign state, the lower the final EDSS at advanced age.

Clinical and radiological activity of secondary progressive multiple sclerosis in a population-based cohort.

BACKGROUND AND PURPOSE: Patients with secondary progressive multiple sclerosis (SP MS) and clinical and/or radiological activity could be the more likely to benefit from disease-modifying treatments. To evaluate the proportions each year after progression onset, patients with SP MS onset between 2002 and 2012 from a population-based multiple sclerosis registry in northeastern France were studied. METHODS: Progression onset was first identified by the neurologist's diagnosis (N cohort), and then by using an automated data-driven definition (D cohort). In a given year after onset of progression, clinical activity was defined as at least one relapse, and radiological activity as at least one new T2 and/or gadolinium-enhancing lesion. A multivariate mixed logistic regression was used to assess factors associated with activity during the year. RESULTS: In the N cohort, amongst 833 patients with SP MS with a median follow-up of 8 years, 10.0%-14.8% had at least one relapse in a year during the first 5 years of progression. Including both clinical and radiological activity increased these proportions to 11.9%-23.7%, with the proportion having a magnetic resonance imaging scan in the year ranging from 29.8% to 40.5%. The first year of progression, a young age and a high relapse rate during the 5 years before progression were associated with activity in a given year. The D cohort results confirmed these findings. CONCLUSIONS: A substantial proportion of patients with SP MS present disease activity. Further studies should evaluate the impact of disease-modifying treatments on the disease course of these patients.

Safety and efficacy of intra-arterial fibrinolytics as adjunct to mechanical thrombectomy: a systematic review and meta-analysis of observational data.

BACKGROUND: Achieving the best possible reperfusion is a key determinant of clinical outcome after mechanical thrombectomy (MT). However, data on the safety and efficacy of intra-arterial (IA) fibrinolytics as an adjunct to MT with the intention to improve reperfusion are sparse. METHODS: We performed a PROSPERO-registered (CRD42020149124) systematic review and meta-analysis accessing MEDLINE, PubMed, and Embase from January 1, 2000 to January 1, 2020. A random-effect estimate (Mantel-Haenszel) was computed and summary OR with 95% CI were used as a measure of added IA fibrinolytics versus control on the risk of symptomatic intracranial hemorrhage (sICH) and secondary endpoints (modified Rankin Scale ≤2, mortality at 90 days). RESULTS: The search identified six observational cohort studies and three observational datasets of MT randomized-controlled trial data reporting on IA fibrinolytics with MT as compared with MT alone, including 2797 patients (405 with additional IA fibrinolytics (100 urokinase (uPA), 305 tissue plasminogen activator (tPA)) and 2392 patients without IA fibrinolytics). Of 405 MT patients treated with additional IA fibrinolytics, 209 (51.6%) received prior intravenous tPA. We did not observe an increased risk of sICH after administration of IA fibrinolytics as adjunct to MT (OR 1.06, 95% CI 0.64 to 1.76), nor excess mortality (0.81, 95% CI 0.60 to 1.08). Although the mode of reporting was heterogeneous, some studies observed improved reperfusion after IA fibrinolytics. CONCLUSION: The quality of evidence regarding peri-interventional administration of IA fibrinolytics in MT is low and limited to observational data. In highly selected patients, no increase in sICH was observed, but there is large uncertainty.

Effect of emergent carotid stenting during endovascular therapy for acute anterior circulation stroke patients with tandem occlusion: A multicenter, randomized, clinical trial (TITAN) protocol.

BACKGROUND AND HYPOTHESIS: There is no consensus on the optimal endovascular management of the extracranial internal carotid artery steno-occlusive lesion in patients with acute ischemic stroke due to tandem occlusion. We hypothesized that intracranial mechanical thrombectomy plus emergent internal carotid artery stenting (and at least one antiplatelet therapy) is superior to intracranial mechanical thrombectomy alone in patients with acute tandem occlusion. STUDY DESIGN: TITAN is an investigator-initiated, multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE) study. Eligibility requires a diagnosis of acute ischemic stroke, pre-stroke modified Rankin Scale (mRS)≤2 (no upper age limit), National Institutes of Health Stroke Scale (NIHSS)≥6, Alberta Stroke Program Early Computed Tomography Score (ASPECTS)≥6, and tandem occlusion on the initial catheter angiogram. Tandem occlusion is defined as large vessel occlusion (intracranial internal carotid artery , M1 and/or M2 segment) and extracranial severe internal carotid artery stenosis ≥90% (NASCET) or complete occlusion. Patients are randomized in two balanced parallel groups (1:1) to receive either intracranial mechanical thrombectomy plus internal carotid artery stenting (and at least one antiplatelet therapy) or intracranial mechanical thrombectomy alone within 8 h of stroke onset. Up to 432 patients are randomized after tandem occlusion confirmation on angiogram. STUDY OUTCOMES: The primary outcome measure is complete reperfusion rate at the end of endovascular procedure, assessed as a modified Thrombolysis in Cerebral Infarction (mTICI) 3, and ≥4 point decrease in NIHSS at 24 h. Secondary outcomes include infarct growth, recurrent clinical ischemic event in the ipsilateral carotid territory, type and dose of antiplatelet therapy used, mRS at 90 (±15) days and 12 (±1) months. Safety outcomes are procedural complications, stent patency, intracerebral hemorrhage, and death. Economics analysis includes health-related quality of life, and costs utility comparison, especially with the need or not of endarterectomy. DISCUSSION: TITAN is the first randomized trial directly comparing two types of treatment in patients with acute ischemic stroke due to anterior circulation tandem occlusion, and especially assessing the safety and efficacy of emergent internal carotid artery stenting associated with at least one antiplatelet therapy in the acute phase of stroke reperfusion. TRIAL REGISTRATION: ClinicalTrials.gov NCT03978988.

Discontinuation of disease-modifying treatments for multiple sclerosis in patients aged over 50 with disease Inactivity.

BACKGROUND: Treatments may become redundant in older patients with multiple sclerosis (MS). Our aim was to explore whether stopping treatments might be possible in patients aged over 50 with disease inactivity. METHODS: Patients over 50 were included from the population-based MS Lorraine registry if they had a relapsing-remitting course at onset and had experienced no relapse for ≥ 3 years. Patients who stopped treatments were defined as "stoppers", and the others as "stayers". The outcomes were the time to first relapse, to first disability progression, and to the occurrence of EDSS score of 6, assessed by multivariate analysis using a propensity score. RESULTS: 132 stoppers and 366 stayers had a median follow-up of 7 years. There was no difference in Log-rank tests for the times to first relapse (p = 0.61) and to first disability progression (p = 0.22). In Cox models, stopping treatments was not associated with an increased risk of relapse (adjusted Hazard ratio (aHR) = 0.92 [0.72-1.16; p = 0.47]) or of an increase in EDSS score (aHR = 0.89 [0.71-1.13; p = 0.34]). However, stopping was associated with a higher risk of occurrence of EDSS score of 6 (aHR = 3.29 [2.22-4.86; p < 0.0001]), with a significant difference for the time to occurrence of EDSS score of 6 (p = 0.003). CONCLUSION: Our study suggests that stopping injectable disease-modifying treatments, in patients over 50 with disease inactivity, is not associated with an increased risk of relapse or EDSS progression, but there might be a higher risk of reaching EDSS 6. These results have to be confirmed by interventional studies.

Effects of Statins to Reduce All-Cause Mortality in Heart Failure Patients: Findings from the EPICAL2 Cohort Study.

INTRODUCTION: The addition of statins to standard care in heart failure (HF) patients remains controversial in clinical practice. Large-scale clinical trials failed to show mortality benefits, but uncertainty persists in real-world settings. OBJECTIVE: We evaluated whether the prescription of statins at hospital discharge is associated with a reduction in all-cause mortality at up to 1 year of follow-up in HF patients. METHODS: We analyzed data from Epidémiologie et Pronostic de l'Insuffisance Cardiaque Aiguë en Lorraine (EPICAL2) cohort study of 2254 hospitalized acute HF patients who were admitted to 21 hospitals located in northeast France for acute HF between October 2011 and October 2012 and who received statins at discharge compared with patients who did not. We used propensity score matching and instrumental variable analyses to estimate the treatment effects of statins, and a multivariable Cox proportional-hazards model to examine survival with statin use, adjusting for patient demographics, HF characteristics, medical history, comorbidities, drug treatment and other known potential confounders. We plotted Kaplan-Meier survivor curves, and used log-rank test to determine the equality of survivor functions. RESULTS: We included 2032 patients in this investigation: 919 (45%) in the statin-treated group and 1113 (55%) in the control group. The estimated average statin-treatment effects for all-cause mortality in HF failed to demonstrate a significant effect on mortality [Z = - 1.73, 95% confidence interval (CI) - 0.11 to 0.007, p value = 0.083, and Z = - 0.95, 95% CI - 1.34 to 0.46, p value = 0.34] for propensity score matching and instrumental variable analyses, respectively. Moreover, the Cox proportional-hazards model showed that statin prescription was not significantly associated with the rate of death (hazard ratio = 0.85, 95% CI 0.66-1.11, p value = 0.26), adjusted for all confounders. CONCLUSION: In patients with HF (and reduced or preserved ejection fraction), the prescription of statins did not appear to be associated with better survival after 1 year of follow-up in the EPICAL2 cohort. We cannot exclude that a subpopulation of HF patients may have some benefits compared with the whole HF population or that there might be a lack of power to show such effect. CLINICAL TRIAL REGISTRATION: NCT02880358.

Magnetic Resonance Imaging or Computed Tomography Before Treatment in Acute Ischemic Stroke.

Background and Purpose- The acute management of stroke patients requires a fast and efficient screening imaging modality. We compared workflow and functional outcome in acute ischemic stroke patients screened by magnetic resonance imaging (MRI) or computed tomography (CT) before treatment in the THRACE trial (Thrombectomie des Artères Cérébrales), with the emphasis on the duration of the imaging step. Methods- The THRACE randomized trial (June 2010 to February 2015) evaluated the efficacy of mechanical thrombectomy after intravenous tPA (tissue-type plasminogen activator) in ischemic stroke patients with proximal occlusion. The choice of screening imaging modality was left to each enrolling center. Differences between MRI and CT groups were assessed using univariable analysis and the impact of imaging modality on favorable 3-month functional outcome (modified Rankin Scale score of ≤2) was tested using multivariable logistic regression. Results- Four hundred one patients were included (25 centers), comprising 299 MRI-selected and 102 CT-selected patients. Median baseline National Institutes of Health Stroke Scale score was 18 in both groups. MRI scan duration (median [interquartile range]) was longer than CT (MRI: 13 minutes [10-16]; CT: 9 minutes [7-12]; P<0.001). Stroke-onset-to-imaging time (MRI: median 114 minutes [interquartile range, 89-138]; CT: 107 minutes [88-139]; P=0.19), onset-to-intravenous tPA time (MRI: 150 minutes [124-179]; CT: 150 minutes [123-180]; P=0.38) and onset-to-angiography-suite time (MRI: 200 minutes [170-250]; CT: 213 minutes [180-246]; P=0.57) did not differ between groups. Imaging modality was not significantly associated with functional outcome in the multivariable analysis. Conclusions- Although MRI scan duration is slightly longer than CT, MRI-based selection for acute ischemic stroke patients is accomplished within a timeframe similar to CT-based selection, without delaying treatment or impacting functional outcome. This should help to promote wider use of MRI, which has inherent imaging advantages over CT. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01062698.

Does Clot Burden Score on Baseline T2*-MRI Impact Clinical Outcome in Acute Ischemic Stroke Treated with Mechanical Thrombectomy?

BACKGROUND AND PURPOSE: A long clot, defined by a low (0-6) clot burden score (CBS) assessed by T2*-MR sequence, is associated with worse clinical outcome after intravenous thrombolysis (IVT) for acute ischemic stroke than is a small clot (CBS, 7-10). The added benefit of mechanical thrombectomy (MT) might be higher in patients with long clot. The aim of this pre-specified post hoc analysis of the THRombectomie des Artères CErebrales (THRACE) trial was to assess the association between T2*-CBS, successful recanalization and clinical outcome. METHODS: Of 414 patients randomized in the THRACE trial, 281 patients were included in this analysis. Associations between T2*-CBS and clinical outcome on the modified Rankin Scale (mRS) at 3 months were tested. RESULTS: High T2*-CBS, i.e., small clot, was associated with a shift toward better outcome on the mRS; proportional odds ratio (POR) per point CBS was 1.19 (95% confidence interval [CI], 1.05 to 1.34) in the whole population, 1.34 (95% CI, 1.13 to 1.59) in IVT group, and 1.04 (95% CI, 0.87 to 1.23) in IVTMT group. After adjustment for baseline prognostic variables, the effect of the full scale T2*-CBS was not statistically significant in the whole population and for the IVTMT group but remains significant for the IVT group (POR, 1.32; 95% CI, 1.11 to 1.58). CONCLUSION: s A small clot, as assessed using T2*-CBS, is associated with improved outcome and may be used as a prognostic marker. Despite the worst outcome with long clot, the relative benefit of MT over IVT seemed to increase with low T2*-CBS and longer clot.

Penumbral imaging and functional outcome in patients with anterior circulation ischaemic stroke treated with endovascular thrombectomy versus medical therapy: a meta-analysis of individual patient-level data.

BACKGROUND: CT perfusion (CTP) and diffusion or perfusion MRI might assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of irreversibly injured ischaemic core and potentially salvageable penumbra volumes were associated with functional outcome and whether they interacted with the treatment effect of endovascular thrombectomy on functional outcome. METHODS: In this systematic review and meta-analysis, the HERMES collaboration pooled patient-level data from all randomised controlled trials that compared endovascular thrombectomy (predominantly using stent retrievers) with standard medical therapy in patients with anterior circulation ischaemic stroke, published in PubMed from Jan 1, 2010, to May 31, 2017. The primary endpoint was functional outcome, assessed by the modified Rankin Scale (mRS) at 90 days after stroke. Ischaemic core was estimated, before treatment with either endovascular thrombectomy or standard medical therapy, by CTP as relative cerebral blood flow less than 30% of normal brain blood flow or by MRI as an apparent diffusion coefficient less than 620 µm2/s. Critically hypoperfused tissue was estimated as the volume of tissue with a CTP time to maximum longer than 6 s. Mismatch volume (ie, the estimated penumbral volume) was calculated as critically hypoperfused tissue volume minus ischaemic core volume. The association of ischaemic core and penumbral volumes with 90-day mRS score was analysed with multivariable logistic regression (functional independence, defined as mRS score 0-2) and ordinal logistic regression (functional improvement by at least one mRS category) in all patients and in a subset of those with more than 50% endovascular reperfusion, adjusted for baseline prognostic variables. The meta-analysis was prospectively designed by the HERMES executive committee, but not registered. FINDINGS: We identified seven studies with 1764 patients, all of which were included in the meta-analysis. CTP was available and assessable for 591 (34%) patients and diffusion MRI for 309 (18%) patients. Functional independence was worse in patients who had CTP versus those who had diffusion MRI, after adjustment for ischaemic core volume (odds ratio [OR] 0·47 [95% CI 0·30-0·72], p=0·0007), so the imaging modalities were not pooled. Increasing ischaemic core volume was associated with reduced likelihood of functional independence (CTP OR 0·77 [0·69-0·86] per 10 mL, pinteraction=0·29; diffusion MRI OR 0·87 [0·81-0·94] per 10 mL, pinteraction=0·94). Mismatch volume, examined only in the CTP group because of the small numbers of patients who had perfusion MRI, was not associated with either functional independence or functional improvement. In patients with CTP with more than 50% endovascular reperfusion (n=186), age, ischaemic core volume, and imaging-to-reperfusion time were independently associated with functional improvement. Risk of bias between studies was generally low. INTERPRETATION: Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome. Combining ischaemic core volume with age and expected imaging-to-reperfusion time will improve assessment of prognosis and might inform endovascular thrombectomy treatment decisions. FUNDING: Medtronic.

Generational changes in multiple sclerosis phenotype in North African immigrants in France: A population-based observational study.

BACKGROUND: The incidence of multiple sclerosis (MS) changes from generation to generation in ethnically different immigrants compared with native-born people. We aimed to determine whether there are generational changes in MS phenotypes among North African immigrants in France. METHODS: Cohort study with data from a population-based MS registry to compare the clinical characteristics of 80 first (NAG1) and 167 second (NAG2) generation North Africans with MS living in France with 5200 native-born Europeans. Adjusted Cox models were used to test the association between scores of 3 and 6 on the expanded disability status scale (EDSS) and the "origin/generation" variable. RESULTS: Cox models for EDSS scores 3 and 6 showed a higher risk of score 3 (hazard ratio = 1.738, 95% confidence interval 1.237 to 2.444; P = .002) and 6 (hazard ratio = 2.372, 95% confidence interval 1.626 to 3.462; P<.0001) for NAG1 than Europeans. Being NAG2 was not significantly associated with higher hazards of scores 3 and 6. CONCLUSIONS: We found two different phenotypes among NAG1 and NAG2 MS patients in France. NAG1, but not NAG2, have a higher risk of disability than Europeans. This raises the question of environmental factors in MS expression, and advocates appropriate patient management according to generation in immigrants.