Comparison of Incidence and Prognostic Impact of Ischemic, Major Bleeding and Heart Failure Events in Patients With Chronic Coronary Syndrome: Insights From the CORONOR Registry.

BACKGROUND: Evaluation of the residual risk in patient with chronic coronary syndrome is challenging in daily practice. Several types of events (myocardial infarction, ischemic stroke, bleeding, and heart failure [HF]) may occur, and their impact on subsequent mortality is unclear in the era of modern evidence-based pharmacotherapy. METHODS: CORONOR (Suivi d'une cohorte de patients Coronariens stables en région Nord-pas-de-Calais) is a prospective multicenter cohort that enrolled 4184 consecutive unselected outpatients with chronic coronary syndrome. We analyzed the incidence, correlates, and impact of ischemic events (a composite of myocardial infarction and ischemic stroke), major bleeding (Bleeding Academic Research Consortium 3 or higher), and hospitalization for HF on subsequent patient mortality. RESULTS: During follow-up (median, 4.9 years), 677 patients (16.5%) died. The 5-year cumulative incidences (death as competing event) of ischemic events, major bleeding, and HF hospitalization were 6.3% (5.6%-7.1%), 3.1% (2.5%-3.6%), and 8.1% (7.3%-9%), respectively. Ischemic events, major bleeding, and HF hospitalization were each associated with all-cause mortality. Major bleeding and hospitalization for HF were associated with the highest mortality rates in the postevent period (42.4%/y and 34.7%/y, respectively) compared with incident ischemic events (13.1%/y). The age- and sex-adjusted hazard ratios for all-cause mortality were 3.57 (95% CI, 2.77-4.61), 9.88 (95% CI, 7.55-12.93), and 8.60 (95% CI, 7.15-10.35) for ischemic events, major bleeding, and hospitalization for HF, respectively (all P<0.001). CONCLUSIONS: Hospitalization for HF has become both the most frequent and one of the most ominous events among patients with chronic coronary syndrome. Although less frequent, major bleeding is strongly associated with worse patient survival. Secondary prevention should not be limited to preventing ischemic events. Minimizing bleeding and preventing HF may be at least as important.

Trial of Deferiprone in Parkinson's Disease.

BACKGROUND: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. METHODS: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. RESULTS: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants. CONCLUSIONS: In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).

Shear Forces Induced Platelet Clearance Is a New Mechanism of Thrombocytopenia.

BACKGROUND: Thrombocytopenia has been consistently described in patients with extracorporeal membrane oxygenation (ECMO) and associated with poor outcome. However, the prevalence and underlying mechanisms remain largely unknown, and a device-related role of ECMO in thrombocytopenia has been hypothesized. This study aims to investigate the mechanisms underlying thrombocytopenia in ECMO patients. METHODS: In a prospective cohort of 107 ECMO patients, we investigated platelet count, functions, and glycoprotein shedding. In an ex vivo mock circulatory ECMO loop, we assessed platelet responses and VWF (von Willebrand factor)-GP Ibα (glycoprotein Ibα) interactions at low- and high-flow rates, in the presence or absence of red blood cells. The clearance of human platelets subjected or not to ex vivo perfusion was studied using an in vivo transfusion model in NOD/SCID (nonobese diabetic/severe combined Immunodeficient) mice. RESULTS: In ECMO patients, we observed a time-dependent decrease in platelet count starting 1 hour after device onset, with a mean drop of 7%, 35%, and 41% at 1, 24, and 48 hours post-ECMO initiation (P=0.00013, P<0.0001, and P<0.0001, respectively), regardless of the type of ECMO. This drop in platelet count was associated with a decrease in platelet GP Ibα expression (before: 47.8±9.1 versus 24 hours post-ECMO: 42.3±8.9 mean fluorescence intensity; P=0.002) and an increase in soluble GP Ibα plasma levels (before: 5.6±3.3 versus 24 hours post-ECMO: 10.8±4.1 µg/mL; P<0.0001). GP Ibα shedding was also observed ex vivo and was unaffected by (1) red blood cells, (2) the coagulation potential, (3) an antibody blocking VWF-GP Ibα interaction, (4) an antibody limiting VWF degradation, and (5) supraphysiological VWF plasma concentrations. In contrast, GP Ibα shedding was dependent on rheological conditions, with a 2.8-fold increase at high- versus low-flow rates. Platelets perfused at high-flow rates before being transfused to immunodeficient mice were eliminated faster in vivo with an accelerated clearance of GP Ibα-negative versus GP Ibα-positive platelets. CONCLUSIONS: ECMO-associated shear forces induce GP Ibα shedding and thrombocytopenia due to faster clearance of GP Ibα-negative platelets. Inhibiting GP Ibα shedding could represent an approach to reduce thrombocytopenia during ECMO.

Combined Technique for Internal Carotid Artery Terminus or Middle Cerebral Artery Occlusions in the ASTER2 Trial.

BACKGROUND: The aim of this study was to report the results of a subgroup analysis of the ASTER2 trial (Effect of Thrombectomy With Combined Contact Aspiration and Stent Retriever vs Stent Retriever Alone on Revascularization in Patients With Acute Ischemic Stroke and Large Vessel Occlusion) comparing the safety and efficacy of the combined technique (CoT) and stent retriever as a first-line approach in internal carotid artery (ICA) terminus±M1-middle cerebral artery (M1-MCA) and isolated M1-MCA occlusions. METHODS: Patients enrolled in the ASTER2 trial with ICA terminus±M1-MCA and isolated M1-MCA occlusions were included in this subgroup analysis. The effect of first-line CoT versus stent retriever according to the occlusion site was assessed on angiographic (first-pass effect, expanded Treatment in Cerebral Infarction score ≥2b50, and expanded Treatment in Cerebral Infarction score ≥2c grades at the end of the first-line strategy and at the end of the procedure) and clinicoradiological outcomes (24-hour National Institutes of Health Stroke Scale, ECASS-III [European Cooperative Acute Stroke Study] grades, and 3-month modified Rankin Scale). RESULTS: Three hundred sixty-two patients were included in the postsubgroup analysis according to the occlusion site: 299 were treated for isolated M1-MCA occlusion (150 with first-line CoT) and 63 were treated for ICA terminus±M1-MCA occlusion (30 with first-line CoT). Expanded Treatment in Cerebral Infarction score ≥2b50 (odds ratio, 11.83 [95% CI, 2.32-60.12]) and expanded Treatment in Cerebral Infarction score ≥2c (odds ratio, 4.09 [95% CI, 1.39-11.94]) were significantly higher in first-line CoT compared with first-line stent retriever in patients with ICA terminus±M1-MCA occlusion but not in patients with isolated M1-MCA. CONCLUSIONS: First-line CoT was associated with higher reperfusion grades in patients with ICA terminus±M1-MCA at the end of the procedure. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03290885.

Long-term outcome following liver transplantation of patients with ACLF grade 3.

BACKGROUND & AIMS: Utility, a major principle for allocation in the context of transplantation, is questioned in patients with acute-on chronic liver failure grade 3 (ACLF-3) who undergo liver transplantation (LT). We aimed to explore long-term outcomes of patients included in a three-centre retrospective French study published in 2017. METHOD: All patients with ACLF-3 (n = 73), as well as their transplanted matched controls with ACLF-2 (n = 145), 1 (n = 119) and no ACLF (n = 292), who participated in the Princeps study published in 2017 were included. We explored 5- and 10-year patient and graft survival rates, causes of death and their predictive factors. RESULTS: Median follow-up of patients with ACLF-3 was 7.5 years. At LT, median MELD was 40. In patients with ACLF-3, 2, 1 and no ACLF, 5-year patient survival rates were 72.6% vs. 69.7% vs. 76.4% vs. 77.0%, respectively (p = 0.31). Ten-year patient survival for ACLF-3 was 56.8% and was not different to other groups (p = 0.37). Leading causes of death in patients with ACLF-3 were infections (33.3%) and cardiovascular events (23.3%). After exclusion of early death, UCLA futility risk score, age-adjusted Charlson comorbidity index and CLIF-C ACLF score were independently associated with 10-year patient survival. Long-term graft survival rates were not different across the groups. Clinical frailty scale and WHO performance status improved over time in patients alive after 5 years. CONCLUSION: 5- and 10-year patient and graft survival rates were not different in patients with ACLF-3 compared to matched controls. 5-year patient survival is higher than the 50%-70% threshold defining the utility of a liver graft. Efforts should focus on candidate selection based on comorbidities, as well as the prevention of infection and cardiovascular events. IMPACT AND IMPLICATIONS: While short-term outcomes following liver transplantation in the most severely ill patients with cirrhosis (acute-on-chronic liver failure grade 3 [ACLF-3]) are known, long-term data are limited, raising questions about the utility of graft allocation in the context of scarce medical resources. This study provides a favourable long-term update, confirming no differences in 5- and 10-year patient and graft survival following liver transplantation in patients with ACLF-3 compared to matched patients with ACLF-2, ACLF-1, and no-ACLF. The study highlights the risk of dying from infection and cardiovascular causes in the long-term and identifies scores including comorbidity evaluation, such as the age-adjusted Charlson comorbidity index, as independently associated with long-term survival. Therefore, physicians should consider the cumulative burden of comorbidities when deciding whether to transplant these patients. Additionally, after transplantation, the study encourages mitigating infectious risk with tailored immunosuppressive regimens and tightly managing cardiovascular risk over time.

Inter-hospital transfer for thrombectomy: transfer time is brain.

BACKGROUND AND PURPOSE: Patients with acute ischaemic stroke and a large vessel occlusion who present to a non-endovascular-capable centre often require inter-hospital transfer for thrombectomy. Whether the inter-hospital transfer time is associated with 3-month functional outcome is poorly known. METHODS: Acute stroke patients enrolled between January 2015 and December 2022 in the prospective French multicentre Endovascular Treatment of Ischaemic Stroke registry were retrospectively analysed. Patients with an anterior circulation large vessel occlusion transferred from a non-endovascular to a comprehensive stroke centre for thrombectomy were eligible. Inter-hospital transfer time was defined as the time between imaging in the referring hospital and groin puncture for thrombectomy. The relationship between transfer time and favourable 3-month functional outcome (modified Rankin Scale 0-2) was assessed through a mixed logistic regression model adjusting for centre and symptom-onset-to-referring-hospital imaging time, age, sex, diabetes, referring hospital National Institutes of Health Stroke Scale score, Alberta Stroke Programme Early Computed Tomography Score, occlusion site and intravenous thrombolysis use. RESULTS: Overall, 3769 patients were included (median inter-hospital transfer time 161 min, interquartile range 128-195; 46% with favourable outcome). A longer transfer time was independently associated with lower rates of favourable outcome (p < 0.001). Compared to patients with transfer time below 120 min, there was a 15% reduction in the odds of achieving favourable outcome for transfer times between 120 and 180 min (adjusted odds ratio 0.85; 95% confidence interval 0.67-1.07), and a 36% reduction for transfer times beyond 180 min (adjusted odds ratio 0.64; 95% confidence interval 0.50-0.81). CONCLUSIONS: A shorter inter-hospital transfer time is strongly associated with favourable 3-month functional outcome. A speedier inter-hospital transfer is of critical importance to improve outcome.

Iatrogenic arterial vasospasm during mechanical thrombectomy requiring treatment with intra-arterial nimodipine might be associated with worse outcomes.

BACKGROUND AND PURPOSE: Vasospasm is a common iatrogenic event during mechanical thrombectomy (MT). In such circumstances, intra-arterial nimodipine administration is occasionally considered. However, its use in the treatment of iatrogenic vasospasm during MT has been poorly studied. We investigated the impact of iatrogenic vasospasm treated with intra-arterial nimodipine on outcomes after MT for large vessel occlusion stroke. METHODS: We conducted a retrospective analysis of the multicenter observational registry Endovascular Treatment in Ischemic Stroke (ETIS). Consecutive patients treated with MT between January 2015 and December 2022 were included. Patients treated with medical treatment alone, without MT, were excluded. We also excluded patients who received another in situ vasodilator molecule during the procedure. Outcomes were compared according to the occurrence of cervical and/or intracranial arterial vasospasm requiring intraoperative use of in situ nimodipine based on operator's decision, using a propensity score approach. The primary outcome was a modified Rankin Scale (mRS) score of 0-2 at 90 days. Secondary outcomes included excellent outcome (mRS score 0-1), final recanalization, mortality, intracranial hemorrhage and procedural complications. Secondary analyses were performed according to the vasospasm location (intracranial or cervical). RESULTS: Among 13,678 patients in the registry during the study period, 434 received intra-arterial nimodipine for the treatment of MT-related vasospasm. In the main analysis, comparable odds of favorable outcome were observed, whereas excellent outcome was significantly less frequent in the group with vasospasm requiring nimodipine (adjusted odds ratio [aOR] 0.78, 95% confidence interval [CI] 0.63-0.97). Perfect recanalization, defined as a final modified Thrombolysis In Cerebral Infarction score of 3 (aOR 0.63, 95% CI 0.42-0.93), was also rarer in the vasospasm group. Intracranial vasospasm treated with nimodipine was significantly associated with worse clinical outcome (aOR 0.64, 95% CI 0.45-0.92), in contrast to the cervical location (aOR 1.37, 95% CI 0.54-3.08). CONCLUSION: Arterial vasospasm occurring during the MT procedure and requiring intra-arterial nimodipine administration was associated with worse outcomes, especially in case of intracranial vasospasm. Although this study cannot formally differentiate whether the negative consequences were due to the vasospasm itself, or nimodipine administration or both, there might be an important signal toward a substantial clinical impact of iatrogenic vasospasm during MT.

Definitions of major bleeding for predicting mortality in critically ill adult patients who survived 24 hours while supported with peripheral veno-arterial extracorporeal membrane oxygenation for cardiogenic shock: a comparative historical cohort study.

PURPOSE: The severity of bleeding events is heterogeneously defined during peripheral veno-arterial extracorporeal membrane oxygenation (pVA-ECMO). We studied three bleeding definitions in pVA-ECMO: the Extracorporeal Life Support Organization (ELSO)-serious bleeding, the Bleeding Academic Research Consortium (BARC), and the universal definition of postoperative bleeding (UPDB) classifications. METHODS: We included consecutive adult patients supported by pVA-ECMO for refractory cardiogenic shock admitted to Lille academic hospitals between January 2013 and December 2019. We assessed the association of bleeding definitions with the primary endpoint of 28-day all-cause mortality with the use of multivariate models accounting for time-dependent and competing variables. We compared models' performances using the Harrell's C-Index and the Akaike information criteria. RESULTS: Twenty-eight-day mortality occurred in 128/308 (42%) 308 patients. The ELSO-serious bleeding (hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.09 to 2.56) and BARC ≥ type 2 (HR, 1.55; 95% CI, 1.01 to 2.37) were associated with 28-day mortality (Harrell's C-index, 0.69; 95% CI, 0.63 to 0.74 for both). Predictors of ELSO-serious bleeding were postcardiotomy, body mass index, baseline platelets count, fibrinogen, and hemoglobin levels. CONCLUSION: Extracorporeal Life Support Organization-serious bleeding and BARC ≥ type 2 are relevant definitions of major bleeding regarding their association with mortality in critically ill patients who survived the first 24 hr while supported with pVA-ECMO for cardiogenic shock. STUDY REGISTRATION: CERAR (IRB 00010254-2022-050, Paris, France); first submitted on 18 April 2022.

RéSUMé: OBJECTIF: La gravité des événements hémorragiques est définie de manière hétérogène pendant une oxygénation par membrane extracorporelle veino-artérielle périphérique (ECMO-VA périphérique). Nous avons étudié trois définitions du saignement sous ECMO-VA périphérique : les classifications des saignements graves selon l'Extracorporeal Life Support Organization (ELSO), celles du Bleeding Academic Research Consortium (BARC) et la définition universelle du saignement postopératoire (UPDB). MéTHODE: Nous avons inclus des patient·es adultes pris·es en charge de manière consécutive par ECMO-VA périphérique à la suite d'un choc cardiogénique réfractaire et admis·es dans les centres hospitaliers universitaires de Lille entre janvier 2013 et décembre 2019. Nous avons évalué l'association des définitions du saignement avec le critère d'évaluation principal de mortalité toutes causes confondues à 28 jours à l'aide de modèles multivariés tenant compte des variables dépendantes du temps et concurrentes. Nous avons comparé les performances des modèles à l'aide de l'indice C de Harrell et du critère d'information d'Akaike. RéSULTATS: La mortalité à 28 jours est survenue chez 128/308 (42 %) patient·es. Le saignement grave selon l'ELSO (rapport de risque [RR], 1,67; intervalle de confiance [IC] à 95 %, 1,09 à 2,56) et une classification BARC ≥ type 2 (RR, 1,55; IC 95 %, 1,01 à 2,37) étaient associés à une mortalité à 28 jours (indice C de Harrell, 0,69; IC 95 %, 0,63 à 0,74 pour les deux). Les prédicteurs d'hémorragie grave selon l'ELSO étaient la postcardiotomie, l'indice de masse corporelle, la numération plaquettaire initiale, le taux de fibrinogène et les taux d'hémoglobine. CONCLUSION: Les définitions du saignement grave de l'Extracorporeal Life Support Organization et une classification BARC ≥ type 2 sont des définitions pertinentes des saignements majeurs en ce qui touche à leur association avec la mortalité chez les personnes gravement malades qui ont survécu aux premières 24 heures alors qu'elles étaient prises en charge par ECMO-VA périphérique à la suite d'un choc cardiogénique. ENREGISTREMENT DE L'éTUDE: CERAR (IRB 00010254-2022-050, Paris, France); soumis pour la première fois le 18 avril 2022.

Can we predict the risk of esophageal stricture after caustic injury?

Nonoperative management of severe caustic injuries has demonstrated its feasibility, avoiding the need for emergency esogastric resection and resulting in low mortality rates. However, leaving superficial necrosis in place could increase the risk of esophageal stricture development. Data on the risk factors of esophageal stricture secondary to caustic ingestion are scarce. The aim of our study was to identify the risk factors for esophageal strictures after caustic ingestion at admission. From February 2015 to March 2021, all consecutive patients with esophageal or gastric caustic injury score ≥ II according to the Zargar classification were retrospectively analyzed. For each patient, we collected over 50 criteria at admission to the emergency room and then selected among them 20 criteria with the best clinical relevance and limited missing data for risk factor analyses. Among the 184 patients included in this study, 37 developed esophageal strictures (cumulative rate 29.4%). All esophageal strictures occurred within 3 months. In multivariate analyses, the risk factors for esophageal strictures were voluntary ingestion (cause-specific hazard ratio 5.92; 95% confidence interval 1.76-19.95, P = 0.004), Zargar's esophageal score ≥ III (cause-specific hazard ratio 14.30; 95% confidence interval 6.07-33.67, P < 0.001), and severe ear, nose, and throat lesions (cause-specific hazard ratio 2.15; 95% confidence interval 1.09-4.22, P = 0.027). Intentional ingestion, severe endoscopic grade, and severe ENT lesions were identified as risk factors for esophageal stricture following caustic ingestion. Preventive measures for this population require further evaluation.

Comparison Between Ultrasonography and Radiography in the Detection of Epiphyseal Ossification Centers of the Knee in Infants With Permanent Congenital Hypothyroidism.

OBJECTIVE: To demonstrate the usefulness of ultrasonography in detecting knee ossification centers in infants with permanent congenital hypothyroidism (PCH). METHODS: From 2011 to 2021, all infants with PCH referred for thyroid ultrasound also underwent left knee ultrasound and radiography on the same day. Knee radiographs were compared with knee sonograms. Two pediatric radiologists reviewed the consensus knee radiographs and sonograms to identify femoral and tibial epiphyseal ossification centers (presence/absence). The concordance between ultrasonography and radiography was assessed. Another radiologist conducted a second late review to evaluate interobserver agreement. RESULTS: We identified 125 patients (65 girls, 60 boys) with a mean age of 24 days (5 days-5 months). On scintigraphy, the thyroid was in place in 66.4%, ectopic in 24%, and absent in 9.6% of patients. The femoral center was observed in 108 patients (86.4%) via sonography and 106 patients (84.8%) via radiography. The tibial center was observed in 84 patients (67.2%) via sonography and radiography. Both femoral and tibial centers were present on sonography and radiography in 84 patients (67.2%). A single nucleus was present in 24 patients (19.2%) on sonography and 22 patients (17.6%) on radiography; it corresponded to the femoral center in all patients. The concordance between ultrasonography and radiography was 99% and 100%, respectively, for the detection of the femoral and tibial centers. Interobserver agreement was substantial to almost perfect for both ultrasonography and radiography. CONCLUSION: Ultrasonography is as effective as radiography in detecting knee ossification centers in PCH. It can be performed at the same time as thyroid examination, in place of radiography.

Impact of Day 1 carotid patency on outcome in dissection-related tandem occlusions treated with mechanical thrombectomy.

BACKGROUND: The clinical benefit of mechanical thrombectomy(MT) for stroke patients with tandem occlusion is similar to that of isolated intracranial occlusions. However, the management of cervical internal carotid artery(ICA) occlusion during the MT, particularly in the setting of carotid dissection, remains controversial. We aimed to investigate the clinical impact of cervical ICA patency at day 1 on 3-month functional outcome. METHODS: We collected data from the Endovascular Treatment in Ischemic Stroke, a prospective national registry in 30 French centers performing MT between January 2015 and January 2022. Inclusion criteria were consecutive tandem occlusions related to cervical ICA dissection treated with MT. Tandem occlusions of other etiology, isolated cervical ICA occlusions without intracranial thrombus and patients without day-1 ICA imaging were excluded. Primary endpoint was the 3-month functional outcome. Secondary endpoints included intracranial hemorrhage(ICH), excellent outcome, mortality and early neurological improvement. A sensitivity analysis was performed in patients with intracranial favorable recanalization after MT. RESULTS: During the study period, 137 patients were included of which 89(65%) presented ICA patency at day 1. The odds of favorable outcome did not significantly differ between patients with patent and occluded ICA at day 1(68.7 vs 59.1%;aOR=1.30;95%CI 0.56-3.00,p=0.54). Excellent outcome, early neurological improvement, mortality and ICH were also comparable between groups. Sensitivity analysis showed similar results. CONCLUSION: ICA patency at day 1 in patients with tandem occlusions related to dissection did not seem to influence functional outcome. Endovascular recanalization of the cervical ICA including stenting might not be systematically required in this setting.

Cerebral Microbleeds During Transcatheter Aortic Valve Replacement: A Prospective Magnetic Resonance Imaging Cohort.

BACKGROUND: Cerebral microbleeds (CMBs) have been observed in healthy elderly people undergoing systematic brain magnetic resonance imaging. The potential role of acute triggers on the appearance of CMBs remains unknown. We aimed to describe the incidence of new CMBs after transcatheter aortic valve replacement (TAVR) and to identify clinical and procedural factors associated with new CMBs including hemostatic measures and anticoagulation management. METHODS: We evaluated a prospective cohort of patients with symptomatic aortic stenosis referred for TAVR for CMBs (METHYSTROKE [Identification of Epigenetic Risk Factors for Ischemic Complication During the TAVR Procedure in the Elderly]). Standardized neurologic assessment, brain magnetic resonance imaging, and analysis of hemostatic measures including von Willebrand factor were performed before and after TAVR. Numbers and location of microbleeds on preprocedural magnetic resonance imaging and of new microbleeds on postprocedural magnetic resonance imaging were reported by 2 independent neuroradiologists blinded to clinical data. Measures associated with new microbleeds and postprocedural outcome including neurologic functional outcome at 6 months were also examined. RESULTS: A total of 84 patients (47% men, 80.9±5.7 years of age) were included. On preprocedural magnetic resonance imaging, 22 patients (26% [95% CI, 17%-37%]) had at least 1 microbleed. After TAVR, new microbleeds were observed in 19 (23% [95% CI, 14%-33%]) patients. The occurrence of new microbleeds was independent of the presence of microbleeds at baseline and of diffusion-weighted imaging hypersignals. In univariable analysis, a previous history of bleeding (P=0.01), a higher total dose of heparin (P=0.02), a prolonged procedure (P=0.03), absence of protamine reversion (P=0.04), higher final activated partial thromboplastin time (P=0.05), lower final von Willebrand factor high-molecular-weight:multimer ratio (P=0.007), and lower final closure time with adenosine-diphosphate (P=0.02) were associated with the occurrence of new postprocedural microbleeds. In multivariable analysis, a prolonged procedure (odds ratio, 1.22 [95% CI, 1.03-1.73] for every 5 minutes of fluoroscopy time; P=0.02) and postprocedural acquired von Willebrand factor defect (odds ratio, 1.42 [95% CI, 1.08-1.89] for every lower 0.1 unit of high-molecular-weight:multimer ratio; P=0.004) were independently associated with the occurrence of new postprocedural microbleeds. New CMBs were not associated with changes in neurologic functional outcome or quality of life at 6 months. CONCLUSIONS: One out of 4 patients undergoing TAVR has CMBs before the procedure and 1 out of 4 patients develops new CMBs. Procedural or antithrombotic management and persistence of acquired von Willebrand factor defect were associated with the occurrence of new CMBs. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02972008.

24-Hour Carotid Stent Patency and Outcomes After Endovascular Therapy: A Multicenter Study.

BACKGROUND: Management of extracranial internal carotid artery steno-occlusive lesion during endovascular therapy remains debated. Stent occlusion within 24 hours of endovascular therapy is a frequent event after acute carotid artery stenting, and we currently lack large population results. We investigated the incidence, predictors, and clinical impact of stent occlusion after acute carotid artery stenting in current clinical practice. METHODS: Patients treated by endovascular therapy with acute carotid artery stenting between 2015 and 2019 in 5 large-volume endovascular-capable centers were retrospectively analyzed. Patients were separated in 2 groups according to the stent patency at 24 hours after carotid artery stenting. We compared baseline characteristics, treatment modalities, and clinical outcome depending on 24-hour stent patency. Primary end point was favorable outcome, defined as a modified Rankin Scale score 0-2 at 3 months. RESULTS: A stent occlusion was observed in 47/225 patients (20.9%). Patients with stent patency had a lower baseline National Institutes of Health Stroke Scale (median [interquartile range]: 13 [7-17] versus 18 [12-21]) and had more often stroke of atherothrombotic origin (77.0% versus 53.2%). A higher stent patency rate was found for patients treated with P2Y12 antagonists at the acute phase (odds ratio [OR]' 2.95 [95% CI' 1.10-7.91]; P=0.026) and treated with angioplasty (OR' 2.42 [95% CI' 1.24-4.67]; P=0.008). A better intracranial angiographic reperfusion was observed in patients with 24-hour stent patency compared with patients without stent patency (OR' 8.38 [95% CI' 3.07-22.78]; P<0.001). Patients with a stent patency at 24 hours had a higher chance of favorable outcome (OR' 3.29 [95% CI, 1.66-6.52]; P<0.001) and a lower risk of death (OR' 0.32 [95% CI, 0.13-0.76]; P=0.009). CONCLUSIONS: One out of 5 patients treated with carotid artery stenting during endovascular therapy presented a stent occlusion within 24 hours. This event was associated with worse functional outcome. Stroke etiology, P2Y12 antagonist administration, quality of intracranial reperfusion, and angioplasty were associated with 24-hour stent patency.

More Than 50 Percent Reduction in LDL Cholesterol in Patients With Target LDL <70 mg/dL After a Stroke.

BACKGROUND: Whether a strategy to target an LDL (low-density lipoprotein) cholesterol <70 mg/dL is more effective when LDL is reduced >50% from baseline rather than <50% from baseline has not been investigated. METHODS: The Treat Stroke to Target trial was conducted in France and South Korea in 61 sites between March 2010 and December 2018. Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned to a target LDL cholesterol of <70 mg/dL or 100±10 mg/dL, using statin and/or ezetimibe as needed. We used the results of repeated LDL measurements (median, 5 [2-6] per patient) during 3.9 years (interquartile range, 2.1-6.8) of follow-up. The primary outcome was the composite of ischemic stroke, myocardial infarction, new symptoms requiring urgent coronary or carotid revascularization, and vascular death. Cox regression model including lipid-lowering therapy as a time-varying variable, after adjustment for randomization strategy, age, sex, index event (stroke or transient ischemic attack), and time since the index event. RESULTS: Among 2860 patients enrolled, patients in the lower target group who had >50% LDL cholesterol reduction from baseline during the trial had a higher baseline LDL cholesterol and a lower LDL cholesterol achieved as compared to patients who had <50% LDL cholesterol reduction (155±32 and 62 mg/dL versus 121±34 and 74 mg/dL, respectively, P<0.001 for both). In the <70 mg/dL target group, patients with >50% LDL reduction had a significant reduction in the primary outcome as compared to the higher target group (hazard ratio, 0.61 [95% CI, 0.43-0.88]; P=0.007) and patients with <50% LDL reduction from baseline had little reduction (hazard ratio, 0.96 [95% CI, 0.73-1.26]; P=0.75). CONCLUSIONS: In this post hoc analysis of the TST trial, targeting an LDL cholesterol of <70 mg/dL reduced the risk of primary outcome compared with 100±10 mg/dL provided LDL cholesterol reduction from baseline was superior to 50%, thereby suggesting that the magnitude of LDL cholesterol reduction was as important to consider as the target level to achieve. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01252875. URL: https://clinicaltrialsregister.eu; Unique identifier: EUDRACT2009-A01280-57.

A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke.

BACKGROUND: The use of intensive lipid-lowering therapy by means of statin medications is recommended after transient ischemic attack (TIA) and ischemic stroke of atherosclerotic origin. The target level for low-density lipoprotein (LDL) cholesterol to reduce cardiovascular events after stroke has not been well studied. METHODS: In this parallel-group trial conducted in France and South Korea, we randomly assigned patients with ischemic stroke in the previous 3 months or a TIA within the previous 15 days to a target LDL cholesterol level of less than 70 mg per deciliter (1.8 mmol per liter) (lower-target group) or to a target range of 90 mg to 110 mg per deciliter (2.3 to 2.8 mmol per liter) (higher-target group). All the patients had evidence of cerebrovascular or coronary-artery atherosclerosis and received a statin, ezetimibe, or both. The composite primary end point of major cardiovascular events included ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid revascularization, or death from cardiovascular causes. RESULTS: A total of 2860 patients were enrolled and followed for a median of 3.5 years; 1430 were assigned to each LDL cholesterol target group. The mean LDL cholesterol level at baseline was 135 mg per deciliter (3.5 mmol per liter), and the mean achieved LDL cholesterol level was 65 mg per deciliter (1.7 mmol per liter) in the lower-target group and 96 mg per deciliter (2.5 mmol per liter) in the higher-target group. The trial was stopped for administrative reasons after 277 of an anticipated 385 end-point events had occurred. The composite primary end point occurred in 121 patients (8.5%) in the lower-target group and in 156 (10.9%) in the higher-target group (adjusted hazard ratio, 0.78; 95% confidence interval, 0.61 to 0.98; P = 0.04). The incidence of intracranial hemorrhage and newly diagnosed diabetes did not differ significantly between the two groups. CONCLUSIONS: After an ischemic stroke or TIA with evidence of atherosclerosis, patients who had a target LDL cholesterol level of less than 70 mg per deciliter had a lower risk of subsequent cardiovascular events than those who had a target range of 90 mg to 110 mg per deciliter. (Funded by the French Ministry of Health and others; Treat Stroke to Target ClinicalTrials.gov number, NCT01252875.).

Dual-energy CT lung perfusion in systemic sclerosis: preliminary experience in 101 patients.

OBJECTIVES: To investigate lung perfusion in systemic sclerosis (SSc). METHODS: The study population included 101 patients who underwent dual-energy CT (DECT) in the follow-up of SSc with pulmonary function tests obtained within 2 months. Fifteen patients had right heart catheterization-proven PH. RESULTS: Thirty-seven patients had no SSc-related lung involvement (Group A), 56 patients had SSc-related interstitial lung disease (Group B) of variable extent (Group B mild: ≤ 10% of lung parenchyma involved: n = 17; Group B moderate: between 11 and 50%: n = 31; Group B severe: > 50%: n = 8), and 8 patients had PVOD/PCH (Group C). Lung perfusion was abnormal in 8 patients in Group A (21.6%), 14 patients in Group B (25%), and 7 patients in Group C (87.5%). In Group A and Group B mild (n = 54), (a) patients with abnormal lung perfusion (n = 14; 26%) had a higher proportion of NYHA III/IV scores of dyspnea (7 [50%] vs 7 [17.5%]; p = 0.031) and a shorter mean walking distance at the 6MWT (397.0 [291.0; 466.0] vs 495.0 [381.0; 549.0]; p = 0.042) but no evidence of difference in the DLCO% predicted (61.0 [53.0; 67.0] vs 68.0 [61.0; 78.0]; p = 0.055) when compared to patients with normal lung perfusion (n = 40; 74%); (b) a negative correlation was found between the iodine concentration in both lungs and the DLCO% predicted but it did not reach statistical significance (r = -0.27; p = 0.059) and no correlation was found with the PAPs (r = 0.16; p = 0.29) and walking distance during the 6MWT (r = -0.029; p = 0.84). CONCLUSIONS: DECT lung perfusion provides complementary information to standard HRCT scans, depicting perfusion changes in SSc patients with normal or minimally infiltrated lung parenchyma. KEY POINTS: • In a retrospective observational study of 101 consecutive patients with SSc, dual-energy CT pulmonary angiography was obtained to evaluate lung perfusion. • Lung perfusion was abnormal in 14 out of 54 patients (26%) with no or mild SSc-related lung infiltration. • Patients with abnormal perfusion and no or mild SSc-related lung infiltration had more severe scores of dyspnea and shorter walking distance than patients with similar lung findings and normal perfusion, suggesting the presence of small vessel vasculopathy.

Effect of small vessel disease severity on blood pressure management after endovascular therapy in the BP TARGET trial.

BACKGROUND AND PURPOSE: Acute ischaemic stroke patients with cerebral small vessel disease (CSVD), including cerebral microbleeds (CMBs) and white matter hyperintensities (WMHs), have worse outcomes. The effect was investigated of two blood pressure strategies (intensive vs. standard) and blood pressure variability (BPV) after reperfusion according to CSVD burden in the BP TARGET trial. METHODS: Patients with available magnetic resonance imaging at baseline were included. CMBs were described as absent or present and WMH severity was described according to the Fazekas classification (0-1, absent-mild; 2-3, moderate to severe). Outcomes consisted of any intracerebral hemorrhage (ICH) at 24 h and favorable outcome at 90 days (modified Rankin Scale score between 0 and 2). RESULTS: In all, 246 patients were included. The intensive systolic blood pressure target was not associated with lower rates of ICH or favorable outcome according to CSVD subgroups (all p values >0.35). Several BPV parameters were associated with increased odds of ICH in patients with CMBs but not in patients without CMBs (diastolic blood pressure coefficient of variation, odds ratio 2.06, 95% confidence interval [CI] 1.13-3.77, in patients with ≥1 CMB vs. 0.94, 95% CI 0.68-1.31, in patients without CMBs, phet  = 0.026). Several diastolic BPV parameters were associated with worse outcomes in patients with severe WMHs but not in patients without WMHs (diastolic blood pressure coefficient of variation, odds ratio 0.32, 95% CI 0.17-0.61, in patients with severe WMHs vs. 1.09, 95% CI 0.67-1.79, in patients without WMHs; phet  = 0.003). CONCLUSION: No effect of the intensive systolic blood pressure management strategy was found on ICH occurrence or functional outcome according to CSVD burden. BPV was associated with higher odds of ICH in patients with CMBs and worse outcome in patients with moderate-to-severe WMHs.

Etiologic and prognostic value of external carotid artery thrombus detection during endovascular therapy for anterior circulation proximal occlusions.

BACKGROUND AND PURPOSE: An early understanding of stroke mechanism may improve treatment and outcome in patients presenting with large vessel occlusion stroke (LVOS) treated with mechanical thrombectomy (MT). We aimed to investigate whether spontaneous external carotid artery (ECA) embolism detection during MT is associated with stroke etiology and clinical outcome. METHODS: We retrospectively reviewed our prospectively maintained institutional database including consecutive patients with anterior circulation LVOS treated with MT between January 2015 and August 2020. RESULTS: An ECA embolus was detected in 68 of 1298 patients (5.2%). The kappa coefficient for interobserver agreement was 0.89 (95% confidence interval [CI] 0.82-0.95). ECA embolism was significantly associated with intracranial internal carotid artery (ICA) occlusion (p < 0.001), cardioembolic etiology (p < 0.001) and a lower clot burden score (p < 0.001). Day-1 variation of National Institutes of Health Stroke Scale score (adjusted odds ratio [OR] -2.7, 95% CI -4.9 to 0.3; p = 0.021) and delta Alberta Stroke Program Early Computed Tomography Score (adjusted OR 0.9, 95% CI 0.2 to 1.5; p = 0.004) were worse among patients with ECA emboli. There was no significant difference in 90-day functional outcome between groups (adjusted OR 0.8, 95% CI 0.42 to 1.52; p = 0.50). CONCLUSION: In patients with anterior circulation LVOS treated with MT, ECA embolism was significantly associated with cardioembolic etiology, high thrombus burden and proximal intracranial ICA occlusions. This underexplored angiographic pattern might provide a valuable etiologic clue to the underlying cause of anterior circulation LVOS and may also help determine the appropriate revascularization strategy.

Changes in physical activity patterns from adolescence to young adulthood: the BELINDA study.

Physical activity (PA) is recognized as a marker of health. The aim was to investigate PA differences from adolescence to young adulthood. European adolescents included in the HELENA study were invited to participate in a follow-up study, 10 years later. The present study included 141 adults (25.0 ± 1.4 years) for whom valid accelerometer data were available in adolescence and adulthood. Changes in PA by sex, weight and maternal education level were explored with interactions. Time spent in sedentary activity, light PA (LPA) and moderate PA (MPA) increased by 39.1, 59.6 and 6.6 min/day, respectively, whereas the time spent in vigorous PA (VPA) decreased by 11.3 min/day compared with adolescent VPA (p < 0.05). Increases in MPA were greater on weekends compared with weekdays, but we found a greater decrease in VPA on weekdays compared with weekends. Moderate-to-vigorous PA (MVPA) decreased significantly on weekdays (-9.6 min/day; 95%CI, -15.9 to -3.4), while it increased on weekends (8.4 min/day; 95%CI, 1.9 to 14.8). Significant heterogeneity was found across sexes for VPA and MVPA, with a stronger decrease in VPA in males compared with females and a significant decrease in MVPA (-12.5 min/day; 95%CI, -20.4 to -4.5) in males but not in females (1.9 min/day; 95%CI, -5.5 to 9.2). No significant heterogeneity was found to be linked to maternal education level or weight, irrespective of PA level.  Conclusion: Our data suggest that the transition from adolescence to young adulthood is a critical period for lifestyle PA habits. A decline in VPA and an increasingly sedentary time were observed. The observed changes are worrying and may increase the risk of developing adverse health consequences later in life. What is Known: • The transition from adolescence to adulthood is marked by many life changes affecting lifestyle habits. Most studies tracking physical activity from adolescence to adulthood were done using PA questionnaires, which is a subjective method. What is New: • Our study bring first data on objective changes in PA patterns between adolescence and young adulthood, taking account of BMI, sex and maternal educational level. Our results suggest that the transition from adolescence to young adulthood is a critical period for lifestyle PA habits, especially for time spent on sedentary activities.

Factors associated with a maternal lower-limb neurological deficit after vaginal delivery.

INTRODUCTION: The etiology of lower-limb neurological deficit after vaginal delivery remains poorly understood. The objective herein was to identify factors associated with this maternal nerve injury after vaginal delivery. MATERIAL AND METHODS: A single-center, case-control (matching 1:4) study. Cases were women with a lower-limb neurological deficit that appeared immediately after vaginal delivery. Controls were randomly selected women who gave birth vaginally during the same period, without any deficit. Finally, to assess the rates of factors associated with these deficits, we studied them using a randomly selected 5% sample of the population with vaginal deliveries. RESULTS: During the 30-month study period, 31 cases were identified among 10 333 women who gave birth vaginally (0.3%, 95% CI 0.20-0.43); 124 controls were also included. After logistic regression, the presence of a neurological deficit after delivery was associated with second-stage labor duration (per hour odds ratio [OR] 3.67, 95% CI 2.09-6.44; OR per standard deviation increase 2.73, 95% CI 1.75-4.25, p < 0.001) and instrumental delivery (OR = 3.24, 95% CI 1.29-8.14, p = 0.012), with no interaction effect (p = 0.56). Extrapolation of these factors to a 5% sample of the overall population of women with vaginal births showed that the rate of these deficits would be very low for women with second-stage labor lasting up to 90 min without instrumental delivery (0.05%) but increased to 1.52% when these factors were combined (OR 33.1, 95% CI 9.4-116.9). CONCLUSIONS: Following vaginal delivery, the onset of a neurological deficit is principally associated with the duration of second-stage labor and instrumental delivery.