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.

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.

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.

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.

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.

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.

Aspirin versus aggressive antiplatelet therapy for acute carotid stenting plus thrombectomy in tandem occlusions: ETIS Registry results.

BACKGROUND: Patients treated with acute carotid stenting (CAS) may have higher odds of a favorable outcome than those treated without CAS during thrombectomy in tandem occlusions. Antiplatelet therapy is associated with CAS to avoid stent thrombosis, which occurs in around 20% of patients and negatively impacts outcomes. In this study we compared two antiplatelet strategies in tandem occlusion strokes treated with CAS and intracranial thrombectomy in clinical practice. METHODS: The Endovascular Treatment in Ischemic Stroke Registry is an ongoing prospective observational study involving 21 comprehensive stroke centers performing thrombectomy in France. We analyzed patients with atherosclerotic tandem occlusions treated with acute CAS and intracranial thrombectomy who received at least one antiplatelet agent. Aggressive antiplatelet therapy included oral or intravenous glycoprotein (GP) IIb/IIIa or P2Y12 inhibitors. The primary outcome was cervical carotid artery patency at day 1 imaging follow-up. RESULTS: Among the 187 included patients, 124 (66.3%) received aspirin alone and 63 (33.7%) received aggressive antiplatelet therapy. There was no significant difference regarding safety outcomes, especially in symptomatic intracerebral hemorrhage, parenchymal hematoma, and procedural complications. There was a significantly higher rate of carotid stent patency at day 1 in the aggressive antiplatelet therapy group (81.7% vs 97.1%, aOR 17.49, 95% CI 1.10 to 277.2, p=0.042). Odds of favorable functional outcome (90-day modified Rankin Scale score 0-2) were similar between the groups (OR 3.04, 95% CI 0.64 to 14.25, p=0.158). CONCLUSIONS: In tandem occlusions treated with CAS plus thrombectomy, an aggressive antiplatelet regimen was associated with an increased rate of carotid stent patency at day 1 without safety concerns. Randomized trials are warranted to confirm these findings.

Influence of prior intravenous thrombolysis in patients treated with mechanical thrombectomy for M2 occlusions: insight from the Endovascular Treatment in Ischemic Stroke (ETIS) registry.

BACKGROUND: Intravenous thrombolysis (IVT) for patients treated with mechanical thrombectomy (MT) for proximal occlusions has recently been questioned through randomized trials. However, few patients with M2 occlusions were included. We investigated the influence of prior IVT for patients presenting M2 occlusions treated with MT in comparison with MT alone. METHODS: We conducted a retrospective analysis of the Endovascular Treatment in Ischemic Stroke (ETIS) registry, a multicenter observational study. Data from consecutive patients treated with MT for M2 occlusions between January 2015 and January 2022 at 26 comprehensive stroke centers were analyzed. The primary endpoint was 90-day modified Rankin Scale score of 0-2. Outcomes were compared using propensity score approaches. We also performed sensitivity analysis in relevant subgroups of patients. RESULTS: Among 1132 patients with M2 occlusions treated with MT, 570 received prior IVT. The two groups were comparable after propensity analysis. The rate of favorable functional outcome was significantly higher in the IVT+MT group compared with the MT alone group (59.8% vs 44.7%; adjusted OR 1.38, 95% CI 1.10 to 1.75, P=0.008). Hemorrhagic and procedural complications were similar in both groups. In sensitivity analysis excluding patients with anticoagulation treatment, favorable recanalization was more frequent in the IVT+MT group (OR 1.37, 95% CI 1.11 to 1.70, P=0.004). CONCLUSIONS: In cases of M2 occlusions, prior IVT combined with MT resulted in better functional outcome than MT alone, without increasing the rate of hemorrhagic or procedural complications. These results suggest the benefit of IVT in patients undergoing MT for M2 occlusions.

Investigating the Long-term Effect of Pregnancy on the Course of Multiple Sclerosis Using Causal Inference.

BACKGROUND AND OBJECTIVES: The question of the long-term safety of pregnancy is a major concern in patients with multiple sclerosis (MS), but its study is biased by reverse causation (women with higher disability are less likely to experience pregnancy). Using a causal inference approach, we aimed to estimate the unbiased long-term effects of pregnancy on disability and relapse risk in patients with MS and secondarily the short-term effects (during the perpartum and postpartum years) and delayed effects (occurring beyond 1 year after delivery). METHODS: We conducted an observational cohort study with data from patients with MS followed in the Observatoire Français de la Sclérose en Plaques registry between 1990 and 2020. We included female patients with MS aged 18-45 years at MS onset, clinically followed up for more than 2 years, and with ≥3 Expanded Disease Status Scale (EDSS) measurements. Outcomes were the mean EDSS score at the end of follow-up and the annual probability of relapse during follow-up. Counterfactual outcomes were predicted using the longitudinal targeted maximum likelihood estimator in the entire study population. The patients exposed to at least 1 pregnancy during their follow-up were compared with the counterfactual situation in which, contrary to what was observed, they would not have been exposed to any pregnancy. Short-term and delayed effects were analyzed from the first pregnancy of early-exposed patients (who experienced it during their first 3 years of follow-up). RESULTS: We included 9,100 patients, with a median follow-up duration of 7.8 years, of whom 2,125 (23.4%) patients were exposed to at least 1 pregnancy. Pregnancy had no significant long-term causal effect on the mean EDSS score at 9 years (causal mean difference [95% CI] = 0.00 [-0.16 to 0.15]) or on the annual probability of relapse (causal risk ratio [95% CI] = 0.95 [0.93-1.38]). For the 1,253 early-exposed patients, pregnancy significantly decreased the probability of relapse during the perpartum year and significantly increased it during the postpartum year, but no significant delayed effect was found on the EDSS and relapse rate. DISCUSSION: Using a causal inference approach, we found no evidence of significantly deleterious or beneficial long-term effects of pregnancy on disability. The beneficial effects found in other studies were probably related to a reverse causation bias.

Time to treatment with bridging intravenous alteplase before endovascular treatment:subanalysis of the randomized controlled SWIFT-DIRECT trial.

BACKGROUND: We hypothesized that treatment delays might be an effect modifier regarding risks and benefits of intravenous thrombolysis (IVT) before mechanical thrombectomy (MT). METHODS: We used the dataset of the SWIFT-DIRECT trial, which randomized 408 patients to IVT+MT or MT alone. Potential interactions between assignment to IVT+MT and expected time from onset-to-needle (OTN) as well as expected time from door-to-needle (DTN) were included in regression models. The primary outcome was functional independence (modified Rankin Scale (mRS) 0-2) at 3 months. Secondary outcomes included mRS shift, mortality, recanalization rates, and (symptomatic) intracranial hemorrhage at 24 hours. RESULTS: We included 408 patients (IVT+MT 207, MT 201, median age 72 years (IQR 64-81), 209 (51.2%) female). The expected median OTN and DTN were 142 min and 54 min in the IVT+MT group and 129 min and 51 min in the MT alone group. Overall, there was no significant interaction between OTN and bridging IVT assignment regarding either the functional (adjusted OR (aOR) 0.76, 95% CI 0.45 to 1.30) and safety outcomes or the recanalization rates. Analysis of in-hospital delays showed no significant interaction between DTN and bridging IVT assignment regarding the dichotomized functional outcome (aOR 0.48, 95% CI 0.14 to 1.62), but the shift and mortality analyses suggested a greater benefit of IVT when in-hospital delays were short. CONCLUSIONS: We found no evidence that the effect of bridging IVT on functional independence is modified by overall or in-hospital treatment delays. Considering its low power, this subgroup analysis could have missed a clinically important effect, and exploratory analysis of secondary clinical outcomes indicated a potentially favorable effect of IVT with shorter in-hospital delays. Heterogeneity of the IVT effect size before MT should be further analyzed in individual patient meta-analysis of comparable trials. TRIAL REGISTRATION NUMBER: URL: https://www. CLINICALTRIALS: gov ; Unique identifier: NCT03192332.