Anti-CD20 Therapies in Drug-Naive Patients With Primary Progressive Multiple Sclerosis: A Multicenter Real-Life Study.

BACKGROUND AND OBJECTIVES: Although rituximab failed to demonstrate a significant effect on disability progression in primary progressive multiple sclerosis (PPMS), ocrelizumab succeeded. Our main objective was to analyze confirmed disability progression (CDP) in a cohort of patients with PPMS treated with anti-CD20 therapies compared with a weighted untreated control cohort. METHODS: This was a retrospective study using data from the French MS registry (Observatoire Français de la Sclérose En Plaques). We included patients with PPMS treated or never treated with anti-CD20 therapies from 2016 to 2021, with an Expanded Disability Status Scale score of ≤6.5 at baseline. The primary outcome was time to first CDP. The secondary outcomes were time to first relapse, MRI activity at 2 years, identification of risk factors associated with CDP, and serious infection incidence rates (IIRs). Each outcome was studied using an inverse probability of treatment weighting method. The outcomes were modeled using a weighted proportional Cox model for the time-to-event outcomes and by a logistic regression regarding the MRI activity. RESULTS: A total of 1,184 patients (426 treated and 758 untreated) fulfilled the inclusion criteria. Median age (Q1-Q3) was 56 years (49.3-63.8), and 52.7% were female. Among treated patients, 295 received rituximab, whereas 131 received ocrelizumab. At baseline, anti-CD20-treated patients were younger (median 51.9 vs 58.6 years, Cohen d = 0.683) and had more active disease (54.5 vs 27.8%, Cohen d = 0.562). 91.6% were drug-naive at inclusion. In time to first CDP analysis, no statistical significance was observed (hazard ratio [HR], 1.13; 95% CI 0.93-1.36, p = 0.2113). In time to first relapse analysis, a nonsignificant trend toward fewer patients relapsing in the treated group was observed (HR 0.83; 95% CI 0.48-1.28, p = 0.0809). For MRI activity, no significant difference was found between the 2 groups. Risk factors associated with CDP in the treated group were male sex and MS duration. IIR was 6.67 (95% CI 3.12-14.25) per 100 person-years in the treated group vs 2.67 (95% CI 0.80-8.86) in the untreated group. DISCUSSION: Time to first CDP was not different between anti-CD20 treated and untreated patients with PPMS. Although our study is retrospective and mainly included patients treated by rituximab, our results indicate that there should be a constant evaluation of all available data to ascertain the best risk/benefit ratio for patients with PPMS. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that anti-CD20 therapy of previously untreated patients with PPMS was not superior to no therapy in delaying time to first CDP.

Depressive symptoms profile and dementia risk after spontaneous intracerebral haemorrhage.

INTRODUCTION: Depressive symptoms are commonly reported after spontaneous intracerebral haemorrhage (ICH) and frequently associated with cognitive decline. Using hierarchical clustering analysis (HCA), we aimed to identify different post-ICH depressive symptoms profiles and to evaluate their association with dementia risk. METHODS: We included consecutive patients from the prospective Prognosis of Intracerebral Haemorrhage (PITCH) study who survived 6 months after the ICH. We performed HCA using depressive symptoms severity (assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS)), along with the presence of apathy and anxiety (screened using Neuropsychiatric Inventory questionnaire). Baseline clinical/neuroimaging characteristics and risk of incident dementia were compared between different profiles using univariate and multivariable models. RESULTS: Of 265 six-month ICH survivors, 221 (83%) underwent neuropsychiatric screening (mean age 65.5 years; 57% male). Using HCA, 3 profiles were identified: (1) without significant depressive symptoms (n = 152; median MADRS score = 2 [IQR 0-4]); (2) depressive symptoms with predominant apathy (n = 41; median MADRS score = 15 [IQR 5-20], 68% with apathy); (3) depressive symptoms profile with predominant anxiety (n = 28; median MADRS score = 17 [IQR 9-25]; 100% with anxiety). Compared to patients without depressive symptoms, patients with depressive symptoms and predominant apathy (but not those with predominant anxiety) were more likely to have cerebral atrophy (OR = 2.4, 95% CI = 1.4-4.2) and had significantly higher long-term new-onset dementia risk (adjusted hazard ratio = 2.2, 95% CI = 1.3-3.8). CONCLUSION: Screening for apathy and anxiety on top of depressive symptoms might help identifying patients at risk for dementia. Future studies on treatment should account for different post-ICH depressive symptoms profiles that may impact on cognitive function.

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.

Genomes of nitrogen-fixing eukaryotes reveal a non-canonical model of organellogenesis.

Endosymbiont gene transfer and import of host-encoded proteins are considered hallmarks of organelles necessary for stable integration of two cells. However, newer endosymbiotic models have challenged the origin and timing of such genetic integration during organellogenesis. Epithemia diatoms contain diazoplasts, closely related to recently-described nitrogen-fixing organelles, that are also stably integrated and co-speciating with their host algae. We report genomic analyses of two species, freshwater E.clementina and marine E.pelagica, which are highly divergent but share a common endosymbiotic origin. We found minimal evidence of genetic integration: nonfunctional diazoplast-to-nuclear DNA transfers in the E.clementina genome and 6 host-encoded proteins of unknown function in the E.clementina diazoplast proteome, far fewer than in other recently-acquired organelles. Epithemia diazoplasts are a valuable counterpoint to existing organellogenesis models, demonstrating that endosymbionts can be stably integrated and inherited absent significant genetic integration. The minimal genetic integration makes diazoplasts valuable blueprints for bioengineering endosymbiotic compartments de novo.

Acute Clinical Events Identified as Relapses With Stable Magnetic Resonance Imaging in Multiple Sclerosis.

Importance: Understanding the association between clinically defined relapses and radiological activity in multiple sclerosis (MS) is essential for patient treatment and therapeutic development. Objective: To investigate clinical events identified as relapses but not associated with new T2 lesions or gadolinium-enhanced T1 lesions on brain and spinal cord magnetic resonance imaging (MRI). Design, Setting, and Participants: This multicenter observational cohort study was conducted between January 2015 and June 2023. Data were extracted on June 8, 2023, from the French MS registry. All clinical events reported as relapses in patients with relapsing-remitting MS were included if brain and spinal cord MRI was performed within 12 and 24 months before the event, respectively, and 50 days thereafter with gadolinium injection. Exposures: Events were classified as relapses with active MRI (RAM) if a new T2 lesion or gadolinium-enhanced T1 lesion appeared on brain or spinal cord MRI or as acute clinical events with stable MRI (ACES) otherwise. Main Outcomes and Measures: Factors associated with ACES were investigated; patients with ACES and RAM were compared regarding Expanded Disability Status Scale (EDSS) course, relapse rate, confirmed disability accrual (CDA), relapse-associated worsening (RAW), progression independent of relapse activity (PIRA), and transition to secondary progressive (SP) MS, and ACES and RAM rates under each disease-modifying therapy (DMT) were estimated. Results: Among 31 885 clinical events, 637 in 608 patients (493 [77.4%] female; mean [SD] age, 35.8 [10.7] years) were included. ACES accounted for 166 (26.1%) events and were more likely in patients receiving highly effective DMTs, those with longer disease duration (odds ratio [OR], 1.04; 95% CI, 1.01-1.07), or those presenting with fatigue (OR, 2.14; 95% CI, 1.15-3.96). ACES were associated with significant EDSS score increases, lower than those found for RAM. Before the index event, patients with ACES experienced significantly higher rates of relapse (relative rate [RR], 1.21; 95% CI, 1.01-1.46), CDA (hazard ratio [HR], 1.54; 95% CI, 1.13-2.11), and RAW (HR, 1.72; 95% CI, 1.20-2.45). Patients with ACES were at significantly greater risk of SP transition (HR, 2.58; 95% CI, 1.02-6.51). Although RAM rate decreased with DMTs according to their expected efficacy, ACES rate was stable across DMTs. Conclusions and Relevance: The findings in this study introduce the concept of ACES in MS, which accounted for one-fourth of clinical events identified as relapses.

Clinical and safety outcomes of acute stenting plus thrombectomy for carotid tandem lesions with large ischemic core.

BACKGROUND: We evaluated the clinical and safety outcomes of emergent carotid artery stenting (eCAS) plus endovascular thrombectomy (EVT) among patients with anterior tandem lesion (TL) and large ischemic core (LIC). METHODS: This retrospective study included consecutive stroke patients enrolled in the Endovascular Treatment in Ischemic Stroke Registry in France between January 2015 and June 2023. We compared the outcomes of carotid stenting vs no stenting in tandem lesion with pre-treatment LIC (Alberta Stroke Program Early CT Score (ASPECTS) 3-5) and stenting in tandem lesion vs thrombectomy alone for isolated intracranial occlusions with pre-treatment LIC. Primary outcome was a score of 0 to 3 on the modified Rankin scale (mRS) at 90 days. Multivariable mixed-effects logistic regression was performed. RESULTS: Among 218 tandem patients with LIC, 55 were treated with eCAS plus EVT. The eCAS group had higher odds of 90-day mRS 0-3 (adjusted Odds Ratio (aOR) 2.40, 95% confidence interval (CI) 1.10 to 5.21; p=0.027). There were no differences in the risk of any intracerebral hemorrhage (OR 1.41, 95% CI 0.69 to 2.86; p=0.346), parenchymal hematoma (aOR 1.216, 95% CI 0.49 to 3.02; p=0.675), symptomatic intracerebral hemorrhage (aOR 1.45, 95% CI 0.60 to 3.48; p=0.409), or 90-day mortality (aOR 0.74, 95% CI 0.33 to 1.68; p=0.472). eCAS was associated with a higher rate of carotid patency at day 1 (aOR 3.54, 95% CI 1.14 to 11.01; p=0.028). Safety outcomes were similar between EVT+eCAS group in TL-LIC and EVT alone group in isolated intracranial occlusions with LIC. CONCLUSION: eCAS appears to be a safe and effective strategy in patients with TL and LIC volume.

The endosymbiont of Epithemia clementina is specialized for nitrogen fixation within a photosynthetic eukaryote.

Epithemia spp. diatoms contain obligate, nitrogen-fixing endosymbionts, or diazoplasts, derived from cyanobacteria. These algae are a rare example of photosynthetic eukaryotes that have successfully coupled oxygenic photosynthesis with oxygen-sensitive nitrogenase activity. Here, we report a newly-isolated species, E. clementina, as a model to investigate endosymbiotic acquisition of nitrogen fixation. We demonstrate that the diazoplast, which has lost photosynthesis, provides fixed nitrogen to the diatom host in exchange for fixed carbon. To identify the metabolic changes associated with this endosymbiotic specialization, we compared the Epithemia diazoplast with its close, free-living cyanobacterial relative, Crocosphaera subtropica. Unlike C. subtropica, in which nitrogenase activity is temporally separated from photosynthesis, we show that nitrogenase activity in the diazoplast is continuous through the day (concurrent with host photosynthesis) and night. Host and diazoplast metabolism are tightly coupled to support nitrogenase activity: Inhibition of photosynthesis abolishes daytime nitrogenase activity, while nighttime nitrogenase activity no longer requires cyanobacterial glycogen storage pathways. Instead, import of host-derived carbohydrates supports nitrogenase activity throughout the day-night cycle. Carbohydrate metabolism is streamlined in the diazoplast compared to C. subtropica with retention of the oxidative pentose phosphate pathway and oxidative phosphorylation. Similar to heterocysts, these pathways may be optimized to support nitrogenase activity, providing reducing equivalents and ATP and consuming oxygen. Our results demonstrate that the diazoplast is specialized for endosymbiotic nitrogen fixation. Altogether, we establish a new model for studying endosymbiosis, perform a functional characterization of this diazotroph endosymbiosis, and identify metabolic adaptations for endosymbiotic acquisition of a critical biological function.

High-Efficacy Therapy Discontinuation vs Continuation in Patients 50 Years and Older With Nonactive MS.

Importance: A recent randomized clinical trial concluded that discontinuing medium-efficacy therapy might be a reasonable option for older patients with nonactive multiple sclerosis (MS), but there is a lack of data on discontinuing high-efficacy therapy (HET). In younger patients, the discontinuation of natalizumab and fingolimod is associated with a risk of rebound of disease activity. Objective: To determine whether discontinuing HET in patients 50 years and older with nonactive MS is associated with an increased risk of relapse compared with continuing HET. Design, Setting, and Participants: This observational cohort study used data from 38 referral centers from the French MS registry (Observatoire Français de la Sclérose en Plaques [OFSEP] database). Among 84704 patients in the database, data were extracted for 1857 patients 50 years and older with relapsing-remitting MS treated by HET and with no relapse or magnetic resonance imaging activity for at least 2 years. After verification of the medical records, 1620 patients were classified as having discontinued HET or having remained taking treatment and were matched 1:1 using a dynamic propensity score (including age, sex, disease phenotype, disability, treatment of interest, and time since last inflammatory activity). Patients were included from February 2008 to November 2021, with a mean (SD) follow-up of 5.1 (2.9) years. Data were extracted in June 2022. Exposures: Natalizumab, fingolimod, rituximab, and ocrelizumab. Main Outcomes and Measures: Time to first relapse. Results: Of 1620 included patients, 1175 (72.5%) were female, and the mean (SD) age was 54.7 (4.8) years. Among the 1452 in the HET continuation group and 168 in the HET discontinuation group, 154 patients in each group were matched using propensity scores (mean [SD] age, 57.7 [5.5] years; mean [SD] delay since the last inflammatory activity, 5.6 [3.8] years; mean [SD] follow-up duration after propensity score matching, 2.5 [2.1] years). Time to first relapse was significantly reduced in the HET discontinuation group compared with the HET continuation group (hazard ratio, 4.1; 95% CI, 2.0-8.5; P < .001) but differed between HETs, with a hazard ratio of 7.2 (95% CI, 2.1-24.5; P = .001) for natalizumab, 4.5 (95% CI, 1.3-15.5; P = .02) for fingolimod, and 1.1 (95% CI, 0.3-4.8; P = .85) for anti-CD20 therapy. Conclusion and Relevance: As in younger patients, in patients 50 years and older with nonactive MS, the risk of relapse increased significantly after stopping HETs that impact immune cell trafficking (natalizumab and fingolimod). There was no significant increase in risk after stopping HETs that deplete B-cells (anti-CD20 therapy). This result may inform decisions about stopping HETs in clinical practice.

Cross-border forensic profiling of fraudulent identity and travel documents: A pilot project between France and Switzerland.

The serial character of document fraud and its connection to organised crime groups who produce, sell and/or use fraudulent documents is a challenge for security and crime fighting. As a response, the added value of forensic intelligence is increasingly recognised. Using a forensic profiling method and a dedicated system deployed in Switzerland, document examiners can detect series (i.e., documents that share a common source) of fraudulent documents conveniently and efficiently. This detection can trigger or orientate investigations, supports crime intelligence efforts, and facilitates cross-jurisdictional cooperation. This study aims to assess the suitability of the forensic profiling system for international purpose and the efficiency of the method to detect cross-border series. The forensic profiling system has been deployed in France in the framework of a cross-border pilot project conducted by the School of Criminal Justice from the University of Lausanne and the French National Police (Division Nationale de Lutte contre la Fraude Documentaire et à l'Identité) over the period July 2019-May 2020. Data from the Swiss and French forensic profiling systems were compared to each other to detect cross-border series. The study sought to create operating conditions as close as possible to the real-life conditions of the profiling systems. The results are extremely positive both quantitatively and qualitatively. They demonstrate the benefit of setting up a systematic exchange of forensic data issued from profiling systems for fraudulent identity documents between France and Switzerland, let alone between any other countries. The results open up a very promising prospect for a sustained operational implementation by the police services of both countries and the extension of the exchanges internationally.

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.

Brush Sign on pre-treatment imaging is associated with good functional outcome in stroke patients treated with mechanical thrombectomy: A prospective monocentric study.

BACKGROUND: The Brush Sign (BrS) is a radiological biomarker (MRI) showing signal decrease of subependymal and deep medullary veins on paramagnetic-sensitive magnetic resonance sequences. Previous studies have shown controversial results regarding the prognostic value of BrS. We aimed to assess whether BrS on T2*-weighted sequences could predict functional prognosis in patients treated with mechanical thrombectomy (MT). METHODS: We included all consecutive patients with large artery occlusion related stroke in anterior circulation treated with MT between February 2020 and August 2022 at Reims University Hospital. Multivariable logistic regression models were used to investigate factors associated with BrS and its impact on outcomes. RESULTS: Of the 327 included patients, 124 (37,9%) had a BrS on baseline MRI. Mean age was 72 ± 16 years and 184 (56,2 %) were female. In univariate analysis, BrS was associated with a younger age (67 vs 74; p<0.001), a higher NIHSS score (16(10-20) vs 13(8-19); p = 0.047) history of diabetes (15.3% vs 26.1 %; p = 0.022) and a shorter onset to MRI time (145.5 (111.3-188.5) vs 162 (126-220) p = 0.008). In multivariate analyses, patients with a BrS were younger (OR:0.970 (0.951 - 0.989)), tend to have a higher NIHSS score at baseline (OR:1.046 (1.000 - 1.094) and were less likely to have diabetes (OR: 0.433; 0.214-0.879). The presence of BrS was independently associated with functional independence (OR: 2.234(1.158-4,505) at 3 months but not with mortality nor with symptomatic intracerebral hemorrhage. CONCLUSION: BrS on pre-treatment imaging could be considered as a biomarker of physiological adaptation to cerebral ischemia, allowing prolonged viability of brain tissue and might participate in the therapeutic decision.

Evaluation of mechanical thrombectomy in acute ischemic stroke related to a distal arterial occlusion: A randomized controlled trial.

RATIONALE: Mechanical thrombectomy (MT) associated with the best medical treatment (BMT) has recently shown efficacy for the management of acute ischemic stroke (AIS) secondary to a large vessel occlusion. However, evidence is lacking regarding the benefit of MT for more distal occlusions. AIM: To evaluate the efficacy in terms of good clinical outcome at 3 months of MT associated with the BMT over the BMT alone in AIS related to a distal occlusion. METHODS: The DISCOUNT trial is a multicenter open-label randomized controlled trial involving French University hospitals. Adult patients (⩾18 years) with an AIS involving the anterior or posterior circulation secondary to a distal vessel occlusion within 6 h of symptom onset or within 24 h if no hyperintense signal on fluid attenuation inversion recovery acquisition will be randomized 1:1 to receive either MT associated with the BMT (experimental group) or BMT alone (control group). The number of patients to be included is 488. STUDY OUTCOMES: The primary outcome is the rate of good clinical outcome at 3 months defined as a modified Rankin scale (mRS) ⩽2 and evaluated by an independent assessor blinded to the intervention arm. Secondary outcomes include recanalization of the occluded vessel within 48 h, angiographic reperfusion in the experimental group, 3-month excellent clinical outcome (mRS ⩽ 1), all adverse events, and death. A cost utility analysis will estimate the incremental cost per quality-adjusted life year (QALY) gained. DISCUSSION: If positive, this study will open new insights in the management of AISs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05030142 registered on 1 September 2021.

Intravenous thrombolysis with tenecteplase versus alteplase combined with endovascular treatment of anterior circulation tandem occlusions: A pooled analysis of ETIS and TETRIS.

BACKGROUND: Tandem occlusions are a singular large vessel occlusion entity involving specific endovascular and perioperative antithrombotic management. In this context, data on safety and efficacy of prior intravenous thrombolysis (IVT) with tenecteplase is scarce. We aimed to compare IVT with tenecteplase or alteplase in patients with acute tandem occlusions intended for endovascular treatment. PATIENTS AND METHODS: A retrospective pooled analysis of two large observational registries (ETIS (Endovascular Treatment of Ischemic Stroke) and TETRIS (Tenecteplase Treatment in Ischemic Stroke)) was performed on consecutive patients presenting with anterior circulation tandem occlusion treated with IVT using either alteplase (ETIS) or tenecteplase (TETRIS) followed by endovascular treatment between January 2015 and June 2022. Sensitivity analyses on atherosclerosis related tandem occlusions and on patient treated with emergent carotid stenting were conducted. Propensity score overlap weighting analyses were performed. RESULTS: We analyzed 753 patients: 124 in the tenecteplase and 629 in the alteplase group. The overall odds of favorable outcome (3-month modified Rankin score 0-2) were comparable between both groups (49.4% vs 47.1%; OR = 1.10, 95%CI 0.85-1.41). Early recanalization, final successful recanalization and mortality favored the use of tenecteplase. The occurrence of any intracranial hemorrhage (ICH) was more frequent after tenecteplase use (OR = 2.24; 95%CI 1.75-2.86). However, risks of symptomatic ICH and parenchymal hematoma remained similar. In atherosclerotic tandems, favorable outcome, mortality, parenchymal hematoma, early recanalization, and final successful recanalization favored the tenecteplase group. In the carotid stenting subgroup, PH were less frequent in the tenecteplase group (OR = 0.18; 95%CI 0.05-0.69). CONCLUSION: In patients with tandem occlusions, IVT with tenecteplase seemed reasonably safe in particular with increased early recanalization rates. These findings remain preliminary and should be further confirmed in randomized trials.

Fatigue after spontaneous intracerebral haemorrhage: prevalence and associated factors.

BACKGROUND: Fatigue is a major complaint in stroke survivors, but data focusing on intracerebral haemorrhage (ICH) survivors are scarce. In a cohort of spontaneous ICH survivors, we assessed the long-term prevalence of fatigue and its associated factors. METHODS: We included consecutive 1-year ICH survivors from the prospective, observational, single-centre Prognosis of Intracerebral Haemorrhage (PITCH) study. We evaluated fatigue (defined as a score ≥ 4 in Chalder Fatigue Scale); the severity of neurological, depressive, and anxiety symptoms; and functional disability 1, 3, and 6 years after ICH. We performed univariable and multivariable models to evaluate clinical factors and brain magnetic resonance imaging (MRI) small vessel disease (SVD) markers associated with fatigue. RESULTS: Of 255 1-year ICH survivors, 153 (60%) underwent fatigue screening and were included in this study. Seventy-eight patients (51%) reported fatigue at 1-year, 56/110 (51%) at 3-year, and 27/67 (40%) at 6-year follow-up. Patients with fatigue exhibited more severe concomitant depressive/anxiety symptoms, but the severity of depressive symptoms was the only clinical factor significantly associated with 1-year fatigue in multivariable analysis (adjusted odds ratio 1.4 for one-point increase; 95% confidence interval 1.2-1.6). Patients with severe cortical atrophy at baseline had increased risk of fatigue at 1-year follow-up compared to patients with mild/no cortical atrophy (adjusted odds ratio 2.5; 95% confidence interval 1.1-5.8). CONCLUSIONS: Fatigue after ICH is frequent and long-lasting, and it is associated with cortical atrophy (but not with other MRI markers of cerebral SVD). The link between fatigue and depressive symptoms may represent a potential therapeutic target.

Endovascular Thrombectomy Outcomes with and without Intravenous Thrombolysis for Large Ischemic Cores Identified with CT or MRI.

Background Whether intravenous thrombolysis (IVT) prior to endovascular thrombectomy (EVT) provides additional benefits in patients with acute ischemic stroke (AIS) and a large infarct core (LIC) remains unclear. Purpose To examine whether treatment with IVT before EVT is beneficial in patients with LIC identified with CT or MRI (Alberta Stroke Program Early CT score 0-5). Materials and Methods This retrospective study included consecutive adult patients diagnosed with AIS due to large vessel occlusion (LVO) and LIC treated with EVT who were enrolled in the ETIS (Endovascular Treatment in Ischemic Stroke) Registry in France between January 2015 and January 2022. The primary outcome measure was a favorable outcome (modified Rankin Scale [mRS] score 0-3) at 90 days. Secondary outcomes included functional independence (mRS score 0-2) at 90 days, improvement in degree of disability (ordinal shift in mRS score toward a better outcome) at 90 days, early neurologic improvement at 24 hours, and successful reperfusion (modified Thrombolysis in Cerebral Infarction score of 2b or higher). Safety outcomes included symptomatic intracerebral hemorrhage within 24 hours and mortality at 90 days. Inverse probability of treatment weighting (IPTW)-adjusted analysis was used to assess the treatment effect of IVT adjusted for baseline variables. Results Of 1408 patients (mean age, 68.3 years ± 15.4 [SD]; 789 men), 654 (46.4%) were treated with IVT prior to EVT. In the IPTW-adjusted data set, IVT plus EVT was associated with a higher rate of favorable outcome at 90 days (odds ratio [OR], 1.24 [95% CI: 1.05, 1.46]; P = .01), functional independence at 90 days (OR, 1.47 [95% CI: 1.22, 1.77]; P < .001), improvement in degree of disability at 90 days (common OR, 1.30 [95% CI: 1.13, 1.49]; P < .001), early neurologic improvement (OR, 1.26 [95% CI: 1.07, 1.49]; P = .005), and successful reperfusion (OR, 1.43 [95% CI: 1.14, 1.79]; P = .002) than EVT alone. Rates of brain hemorrhage within 24 hours and mortality at 90 days were similar between groups. Conclusion In patients with AIS due to LVO with LIC identified with CT or MRI, treatment with IVT before EVT appeared to provide a clinical benefit over EVT alone. Clinical trial registration no. NCT03776877 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Kallmes and Rabinstein in this issue.

Successful Thrombectomy Improves Functional Outcome in Tandem Occlusions with a Large Ischemic Core.

BACKGROUND: Emergent stenting in tandem occlusions and mechanical thrombectomy (MT) of acute ischemic stroke related to large vessel occlusion (LVO-AIS) with a large core are tested independently. We aim to assess the impact of reperfusion with MT in patients with LVO-AIS with a large core and a tandem occlusion and to compare the safety of reperfusion between large core with tandem and nontandem occlusions in current practice. METHODS: We analyzed data of all consecutive patients included in the prospective Endovascular Treatment in Ischemic Stroke Registry in France between January 2015 and March 2023 who presented with a pretreatment ASPECTS (Alberta Stroke Program Early CT Score) of 0-5 and angiographically proven tandem occlusion. The primary end point was a favorable outcome defined by a modified Rankin Scale (mRS) score of 0-3 at 90 days. RESULTS: Among 262 included patients with a tandem occlusion and ASPECTS 0-5, 203 patients (77.5%) had a successful reperfusion (modified Thrombolysis in Cerebral Infarction grade 2b-3). Reperfused patients had a favorable shift in the overall mRS score distribution (adjusted odds ratio [aOR], 1.57 [1.22-2.03]; P < 0.001), higher rates of mRS score 0-3 (aOR, 7.03 [2.60-19.01]; P < 0.001) and mRS score 0-2 at 90 days (aOR, 3.85 [1.39-10.68]; P = 0.009) compared with nonreperfused. There was a trend between the occurrence of successful reperfusion and a decreased rate of symptomatic intracranial hemorrhage (aOR, 0.5 [0.22-1.13]; P = 0.096). Similar safety outcomes were observed after large core reperfusion in tandem and nontandem occlusions. CONCLUSIONS: Successful reperfusion was associated with a higher rate of favorable outcome in large core LVO-AIS with a tandem occlusion, with a safety profile similar to nontandem occlusion.

The endosymbiont of Epithemia clementina is specialized for nitrogen fixation within a photosynthetic eukaryote.

Epithemia spp. diatoms contain obligate, nitrogen-fixing endosymbionts, or "diazoplasts", derived from cyanobacteria. These algae are a rare example of photosynthetic eukaryotes that have successfully coupled oxygenic photosynthesis with oxygen-sensitive nitrogenase activity. Here, we report a newly-isolated species, E. clementina, as a model to investigate endosymbiotic acquisition of nitrogen fixation. To detect the metabolic changes associated with endosymbiotic specialization, we compared nitrogen fixation, associated carbon and nitrogen metabolism, and their regulatory pathways in the Epithemia diazoplast with its close, free-living cyanobacterial relative, Crocosphaera subtropica. Unlike C. subtropica, we show that nitrogenase activity in the diazoplast is concurrent with, and even dependent on, host photosynthesis and no longer associated with cyanobacterial glycogen storage suggesting carbohydrates are imported from the host diatom. Carbohydrate catabolism in the diazoplast indicates that the oxidative pentose pathway and oxidative phosphorylation, in concert, generates reducing equivalents and ATP and consumes oxygen to support nitrogenase activity. In contrast to expanded nitrogenase activity, the diazoplast has diminished ability to utilize alternative nitrogen sources. Upon ammonium repletion, negative feedback regulation of nitrogen fixation was conserved, however ammonia assimilation showed paradoxical responses in the diazoplast compared with C. subtropica. The altered nitrogen regulation likely favors nitrogen transfer to the host. Our results suggest that the diazoplast is specialized for endosymbiotic nitrogen fixation. Altogether, we establish a new model for studying endosymbiosis, perform the first functional characterization of this diazotroph endosymbiosis, and identify metabolic adaptations for endosymbiotic acquisition of a critical biological function.