Case report: Chronic Candida albicans meningitis: a rare entity diagnosed by metagenomic next-generation sequencing.

The aetiology of chronic aseptic meningitis is difficult to establish. Candida meningitis in particular is often diagnosed late, as cerebrospinal fluid (CSF) work-up and imaging findings are nonspecific. A 35-year-old patient with chronic aseptic meningitis, for which repeated microbiological testing of CSF was unrevealing, was finally diagnosed with Candida albicans (C. albicans) meningitis with cauda equina involvement using metagenomic next-generation sequencing (mNGS). This report highlights the diagnostic challenges and the difficulties of treating shunt-associated fungal meningitis.

Baseline characteristics and outcome of stroke patients after endovascular therapy according to previous symptomatic vascular disease and sex.

Aim: The aim of this study was to investigate baseline characteristics and outcome of patients after endovascular therapy (EVT) for acute large vessel occlusion (LVO) in relation to their history of symptomatic vascular disease and sex. Methods: Consecutive EVT-eligible patients with LVO in the anterior circulation admitted to our stroke center between 04/2015 and 04/2020 were included in this observational cohort study. All patients were treated according to a standardized acute ischaemic stroke (AIS) protocol. Baseline characteristics and successful reperfusion, recurrent/progressive in-hospital ischaemic stroke, symptomatic in-hospital intracranial hemorrhage, death at discharge and at 3 months, and functional outcome at 3 months were analyzed according to previous symptomatic vascular disease and sex. Results: 995 patients with LVO in the anterior circulation (49.4% women, median age 76 years, median admission NIHSS score 14) were included. Patients with multiple vs. no previous vascular events showed higher mortality at discharge (20% vs. 9.3%, age/sex - adjustedOR = 1.43, p = 0.030) and less independency at 3 months (28.8% vs. 48.8%, age/sex - adjustedOR = 0.72, p = 0.020). All patients and men alone with one or multiple vs. patients and men with no previous vascular events showed more recurrent/progressive in-hospital ischaemic strokes (19.9% vs. 6.4% in all patients, age/sex - adjustedOR = 1.76, p = 0.028) (16.7% vs. 5.8% in men, age-adjustedOR = 2.20, p = 0.035). Men vs. women showed more in-hospital symptomatic intracranial hemorrhage among patients with one or multiple vs. no previous vascular events (23.7% vs. 6.6% in men and 15.4% vs. 5.5% in women, OR = 2.32, p = 0.035/age - adjustedOR = 2.36, p = 0.035). Conclusions: Previous vascular events increased the risk of in-hospital complications and poorer outcome in the analyzed patients with EVT-eligible LVO-AIS. Our findings may support risk assessment in these stroke patients and could contribute to the design of future studies.

A Balancing Act: The Viral-Host Battle over RNA Binding Proteins.

A defining feature of a productive viral infection is the co-opting of host cell resources for viral replication. Despite the host repertoire of molecular functions and biological counter measures, viruses still subvert host defenses to take control of cellular factors such as RNA binding proteins (RBPs). RBPs are involved in virtually all steps of mRNA life, forming ribonucleoprotein complexes (mRNPs) in a highly ordered and regulated process to control RNA fate and stability in the cell. As such, the hallmark of the viral takeover of a cell is the reshaping of RNA fate to modulate host gene expression and evade immune responses by altering RBP interactions. Here, we provide an extensive review of work in this area, particularly on the duality of the formation of RNP complexes that can be either pro- or antiviral. Overall, in this review, we highlight the various ways viruses co-opt RBPs to regulate RNA stability and modulate the outcome of infection by gathering novel insights gained from research studies in this field.

Training Performance Assessment for Intracranial Aneurysm Clipping Surgery Using a Patient-Specific Mixed-Reality Simulator: A Learning Curve Study.

BACKGROUND AND OBJECTIVES: The value of simulation-based training in medicine and surgery has been widely demonstrated. This study investigates the introduction and use of a new mixed-reality neurosurgical simulator in aneurysm clipping surgery, focusing on the learning curve and performance improvement. METHODS: Five true-scale craniotomy head models replicating patient-specific neuroanatomy, along with a mixed-reality simulator, a neurosurgical microscope, and a set of microsurgical instruments and clips, were used in the operation theater to simulate aneurysm microsurgery. Six neurosurgical residents participated in five video-recorded simulation sessions over 4 months. Complementary learning modalities were implemented between sessions. Thereafter, three blinded analysts reported on residents' use of the microscope, quality of manipulation, aneurysm occlusion, clipping techniques, and aneurysm rupture. Data were also captured regarding training time and clipping attempts. RESULTS: Over the course of training, clipping time and number of clipping attempts decreased significantly (P = .018, P = .032) and the microscopic skills improved (P = .027). Quality of manipulation and aneurysm occlusion scoring improved initially although the trend was interrupted because the spacing between sessions increased. Significant differences in clipping time and attempts were observed between the most and least challenging patient models (P = .005, P = .0125). The least challenging models presented higher rates of occlusion based on indocyanine green angiography evaluation from the simulator. CONCLUSION: The intracranial aneurysm clipping learning curve can be improved by implementing a new mixed-reality simulator in dedicated training programs. The simulator and the models enable comprehensive training under the guidance of a mentor.

The antiviral protein Shiftless blocks p-body formation during KSHV infection.

P-bodies (PB) are non-membranous foci involved in determining mRNA fate by affecting translation and mRNA decay. In this study, we identify the anti-viral factor SHFL as a potent disassembly factor of PB. We show that PBs remain sparse in the presence of SHFL even in the context of oxidative stress, a major trigger for PB induction. Mutational approaches revealed that SHFL RNA binding activity is not required for its PB disassembly function. However, we have identified a new region of SHFL which bridges two distant domains as responsible for PB disassembly. Furthermore, we show that SHFL ability to disrupt PB formation is directly linked to its anti-viral activity during KSHV infection. While WT SHFL efficiently restricts KSHV lytic cycle, PB disruption defective mutants no longer lead to reactivation defects. SHFL-mediated PB disassembly also leads to increased expression of key anti-viral cytokines, further expanding SHFL dependent anti-viral state. Taken together, our observations suggest a role of SHFL in PB disassembly, which could have important anti-viral consequences during infection.

Intraoperative Laser Speckle Contrast Imaging to Assess Vessel Flow in Neurosurgery: A Pilot Study.

BACKGROUND AND OBJECTIVES: Laser speckle contrast imaging (LSCI) has emerged as a promising tool for assessment of vessel flow during neurosurgery. We aimed to investigate the feasibility of visualizing vessel flow in the macrocirculation with a new fully microscope-integrated LSCI system and assess the validity and objectivity of findings compared with fluorescence angiography (FA). METHODS: This is a single-center prospective observational study enrolling adult patients requiring microsurgical treatment for brain vascular pathologies or brain tumors. Three independent raters, blinded toward findings of FA, reviewed regions of interest (ROIs) placed in exposed vessels and target structures. The primary end point was the validity of LSCI for assessment of vessel flow as measured by the agreement with FA. The secondary end point was objectivity, measured as the inter-rater agreement of LSCI findings. RESULTS: During 18 surgical procedures, 23 observations using FA and LSCI were captured simultaneously. Using LSCI, vessel flow was assessable in 62 (86.1%) and not assessable in 10 (13.9%) ROIs. The agreement between LSCI and FA was 86.1%, with an agreement coefficient of 0.85 (95% CI: 0.75-0.94). Disagreement between LSCI and FA was observed in the 10 ROIs that were not assessable. The agreement between ROIs that were assessable using LSCI and FA was 100%. The inter-rater agreement of LSCI findings was 87.9%, with an agreement coefficient of 0.86 (95% CI: 0.79-0.94). CONCLUSION: Fully microscope-integrated LSCI is feasible and has a high potential for clinical utility. Because of its characteristics, LSCI can be viewed as a full-field visual micro-Doppler that can be used as a complementary method to FA for assessing vessel flow during neurosurgery. Despite technical limitations related to the early development phase of the fully microscope-integrated system, we demonstrated reasonable validity and objectivity of findings compared with FA. Further research and refinement of the system may enhance its value in neurosurgical applications.

Nonstructural protein 1 widespread RNA decay phenotype varies among coronaviruses.

Extensive remodeling of host gene expression by nonstructural protein 1 (nsp1) of coronaviruses is a well-documented and conserved aspect of coronavirus-host takeover. Using comparative transcriptomics we investigated the diversity of transcriptional targets between various nsp1 proteins. Additionally, affinity purification followed by mass spectrometry was implemented to identify common interactors between the different nsp1 proteins. Although we detected widespread RNA destabilization, closely related nsp1 showed little similarities in clustering of targeted genes. We observed a partial overlap in transcriptional targeting between α-CoV 229E and MERS nsp1, which may suggest a common targeting mechanism, as MERS nsp1 preferentially targets nuclear transcripts. Our interactome data show great variability between nsp1 interactions, with 229E nsp1, the smallest nsp1 tested here, interacting with the most number of host proteins. Although nsp1 is a rather well-conserved protein with conserved functions across different coronaviruses, our data indicate that its precise effects on the host cell are virus specific.

Shiftless Restricts Viral Gene Expression and Influences RNA Granule Formation during Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication.

Herpesviral infection reflects thousands of years of coevolution and the constant struggle between virus and host for control of cellular gene expression. During Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication, the virus rapidly seizes control of host gene expression machinery by triggering a massive RNA decay event via a virally encoded endoribonuclease, SOX. This virus takeover strategy decimates close to 80% of cellular transcripts, reallocating host resources toward viral replication. The host cell, however, is not entirely passive in this assault on RNA stability. A small pool of host transcripts that actively evade SOX cleavage has been identified over the years. One such "escapee," C19ORF66 (herein referred to as Shiftless [SHFL]), encodes a potent antiviral protein capable of restricting the replication of multiple DNA and RNA viruses and retroviruses, including KSHV. Here, we show that SHFL restricts KSHV replication by targeting the expression of critical viral early genes, including the master transactivator protein, KSHV ORF50, and thus subsequently the entire lytic gene cascade. Consistent with previous reports, we found that the SHFL interactome throughout KSHV infection is dominated by RNA-binding proteins that influence both translation and protein stability, including the viral protein ORF57, a crucial regulator of viral RNA fate. We next show that SHFL affects cytoplasmic RNA granule formation, triggering the disassembly of processing bodies. Taken together, our findings provide insights into the complex relationship between RNA stability, RNA granule formation, and the antiviral response to KSHV infection. IMPORTANCE In the past 5 years, SHFL has emerged as a novel and integral piece of the innate immune response to viral infection. SHFL has been reported to restrict the replication of multiple viruses, including several flaviviruses and the retrovirus HIV-1. However, to date, the mechanism(s) by which SHFL restricts DNA virus infection remains largely unknown. We have previously shown that following its escape from KSHV-induced RNA decay, SHFL acts as a potent antiviral factor, restricting nearly every stage of KSHV lytic replication. In this study, we set out to determine the mechanism by which SHFL restricts KSHV infection. We demonstrate that SHFL impacts all classes of KSHV genes and found that SHFL restricts the expression of several key early genes, including KSHV ORF50 and ORF57. We then mapped the interactome of SHFL during KSHV infection and found several host and viral RNA-binding proteins that all play crucial roles in regulating RNA stability and translation. Lastly, we found that SHFL expression influences RNA granule formation both outside and within the context of KSHV infection, highlighting its broader impact on global gene expression. Collectively, our findings highlight a novel relationship between a critical piece of the antiviral response to KSHV infection and the regulation of RNA-protein dynamics.

Natural history of carotid artery free-floating thrombus-A single center, consecutive cohort analysis.

Introduction: Carotid free-floating thrombus (CFFT) is a rare cause of stroke and is thought to be associated with a high risk of recurrent cerebrovascular ischaemic events. The existing data on the natural history and optimal treatment modalities of CFFT is scanty and no clear recommendations exist. Objective: A retrospective analysis, single-center cohort of consecutive patients diagnosed with CFFT was conducted, investigating the risk for recurrent cerebrovascular ischaemic events. Methods: We performed a single-center retrospective analysis including all patients presenting at our tertiary center between January 2005 and December 2020 with symptoms consistent with ischaemic stroke and/or transient ischaemic attack. Digital subtraction angiography (DSA), computed tomography angiography (CTA) or magnetic resonance angiography (MRA) were used to diagnose CFFT. In all included patients, CFFT was confirmed with a second imaging modality. CFFT was defined on imaging as a defect in contrast filling extending into the carotid lumen. We gathered information on vascular risk factors, diagnosis and follow-up methods, modality of treatment and neurological outcome. A survival analysis was performed, assessing the risk for recurrent cerebrovascular events. Results: In total, N = 62 patients presenting with symptomatic CFFT were included. Mean age was 68 years, 69% (43/62) of patients were male, 52% (32/62) current or previous smokers, 76% (47/62) suffered from arterial hypertension, 68% (42/62) from dyslipidaemia, and 31% (19/62) from diabetes mellitus. Overall, 71% (44/62) of patients received any kind of intervention [endovascular or surgical carotid thrombo-endartectomy (CEA)] at any time point during follow-up. Sixteen percent of patients (10/62) received intervention within 48 h after diagnosis of CFFT. The survival analysis and Kaplan-Meier model censoring patients at the time of intervention or last follow-up showed that the risk for any recurrent ischaemic stroke was 19.7% within the first 7 days and 27.4% within 3 months after diagnosis. No patients experienced a new ischaemic stroke beyond 11 days after diagnosis of CFTT (n = 17). Conclusion: The risk of recurrent ischaemic events in patients with CFFT is high, especially in the first week after diagnosis. Prospective studies are needed to further investigate the optimal management of these patients.

Shiftless, a Critical Piece of the Innate Immune Response to Viral Infection.

Since its initial characterization in 2016, the interferon stimulated gene Shiftless (SHFL) has proven to be a critical piece of the innate immune response to viral infection. SHFL expression stringently restricts the replication of multiple DNA, RNA, and retroviruses with an extraordinary diversity of mechanisms that differ from one virus to the next. These inhibitory strategies include the negative regulation of viral RNA stability, translation, and even the manipulation of RNA granule formation during viral infection. Even more surprisingly, SHFL is the first human protein found to directly inhibit the activity of the -1 programmed ribosomal frameshift, a translation recoding strategy utilized across nearly all domains of life and several human viruses. Recent literature has shown that SHFL expression also significantly impacts viral pathogenesis in mouse models, highlighting its in vivo efficacy. To help reconcile the many mechanisms by which SHFL restricts viral replication, we provide here a comprehensive review of this complex ISG, its influence over viral RNA fate, and the implications of its functions on the virus-host arms race for control of the cell.

The m6A reader YTHDC2 is essential for escape from KSHV SOX-induced RNA decay.

The role of N6-methyladenosine (m6A) modifications has increasingly been associated with a diverse set of roles in modulating viruses and influencing the outcomes of viral infection. Here, we report that the landscape of m6A deposition is drastically shifted during Kaposi's sarcoma-associated herpesvirus (KSHV) lytic infection for both viral and host transcripts. In line with previous reports, we also saw an overall decrease in host methylation in favor of viral messenger RNA (mRNA), along with 5' hypomethylation and 3' hypermethylation. During KSHV lytic infection, a major shift in overall mRNA abundance is driven by the viral endoribonuclease SOX, which induces the decay of greater than 70% of transcripts. Here, we reveal that interlukin-6 (IL-6) mRNA, a well-characterized, SOX-resistant transcript, is m6A modified during lytic infection. Furthermore, we show that this modification falls within the IL-6 SOX resistance element, an RNA element in the IL-6 3' untranslated region (UTR) that was previously shown to be sufficient for protection from SOX cleavage. We show that the presence of this m6A modification is essential to confer SOX resistance to the IL-6 mRNA. We next show that this modification recruits the m6A reader YTHDC2 and found that YTHDC2 is necessary for the escape of the IL-6 transcript. These results shed light on how the host cell has evolved to use RNA modifications to circumvent viral manipulation of RNA fate during KSHV infection.

[Atherosclerosis of the intracranial arteries and of the extracranial carotid artery.] / Atherosklerose der intrakraniellen Arterien und der extrakraniellen Karotis.

Atherosclerosis of the intracranial arteries and of the extracranial carotid artery. Abstract. Intracranial atherosclerotic stenoses are the most common cause of ischemic stroke worldwide. Nowadays, three therapeutic approaches are available for consideration for patients with intracranial atherosclerotic stenoses: A conservative therapy (best medical treatment, management of vascular risk factors and healthy lifestyle), endovascular and surgical therapy. Conservative approach has been recommended for patients with asymptomatic intracranial atherosclerotic stenoses, as well as for those with symptomatic stenoses. Endovascular therapy should be considered as a treatment option for carefully selected patients with recurrent ischemic strokes attributed to the stenotic artery while receiving best medical therapy. Surgical revascularisation is rarely favored in patients with intracranial stenoses. In patients with extracranial atherosclerotic stenoses, carotid endarterectomy (CEA) has been associated with a lower risk of death and recurrent stroke when compared to carotid angioplasty and stenting (CAS). Especially in elderly patients over 70 years of age CEA is preferred over CAS due to the twofold increased 30-day risk of recurrent stroke or death in patients treated with CAS. Results from contemporary studies using modern techniques and devices are expected. It remains unclear whether patients with asymptomatic extracranial atherosclerotic stenoses receiving best medical treatment would benefit of invasive procedures such as CEA or CAS.

Lipoprotein(a) is associated with large artery atherosclerosis stroke aetiology and stroke recurrence among patients below the age of 60 years: results from the BIOSIGNAL study.

AIMS: Lipoprotein(a) [Lp(a)] is a recognized causal risk factor for atherosclerotic cardiovascular disease but its role for acute ischaemic stroke (AIS) is controversial. In this study, we evaluated the association of Lp(a) with large artery atherosclerosis (LAA) stroke and risk of recurrent cerebrovascular events in AIS patients. METHODS AND RESULTS: For this analysis of the prospective, observational, multicentre BIOSIGNAL cohort study we measured Lp(a) levels in plasma samples of 1733 primarily Caucasian (98.6%) AIS patients, collected within 24 h after symptom onset. Primary outcomes were LAA stroke aetiology and recurrent cerebrovascular events (ischaemic stroke or transient ischaemic attack) within 1 year. We showed that Lp(a) levels are independently associated with LAA stroke aetiology [adjusted odds ratio 1.48, 95% confidence interval (CI) 1.14-1.90, per unit log10Lp(a) increase] and identified age as a potent effect modifier (Pinteraction =0.031) of this association. The adjusted odds ratio for LAA stroke in patients aged <60 years was 3.64 (95% CI 1.76-7.52) per unit log10Lp(a) increase and 4.04 (95% CI 1.73-9.43) using the established cut-off ≥100 nmol/l. For 152 recurrent cerebrovascular events, we did not find a significant association in the whole cohort. However, Lp(a) levels ≥100 nmol/l were associated with an increased risk for recurrent events among patients who were either <60 years [adjusted hazard ratio (HR) 2.40, 95% CI 1.05-5.47], had evident LAA stroke aetiology (adjusted HR 2.18, 95% CI 1.08-4.40), or had no known atrial fibrillation (adjusted HR 1.60, 95% CI 1.03-2.48). CONCLUSION: Elevated Lp(a) was independently associated with LAA stroke aetiology and risk of recurrent cerebrovascular events among primarily Caucasian individuals aged <60 years or with evident arteriosclerotic disease.

Fated for decay: RNA elements targeted by viral endonucleases.

For over a decade, studies of messenger RNA regulation have revealed an unprecedented level of connectivity between the RNA pool and global gene expression. These connections are underpinned by a vast array of RNA elements that coordinate RNA-protein and RNA-RNA interactions, each directing mRNA fate from transcription to translation. Consequently, viruses have evolved an arsenal of strategies to target these RNA features and ultimately take control of the pathways they influence, and these strategies contribute to the global shutdown of the host gene expression machinery known as "Host Shutoff". This takeover of the host cell is mechanistically orchestrated by a number of non-homologous virally encoded endoribonucleases. Recent large-scale screens estimate that over 70 % of the host transcriptome is decimated by the expression of these viral nucleases. While this takeover strategy seems extraordinarily well conserved, each viral endonuclease has evolved to target distinct mRNA elements. Herein, we will explore each of these RNA structures/sequence features that render messenger RNA susceptible or resistant to viral endonuclease cleavage. By further understanding these targeting and escape mechanisms we will continue to unravel untold depths of cellular RNA regulation that further underscores the integral relationship between RNA fate and the fate of the cell.

Arterial collateral anatomy predicts the risk for intra-operative changes in somatosensory evoked potentials in patients undergoing carotid endarterectomy: a prospective cohort study.

BACKGROUND: During carotid endarterectomy (CEA), significant amplitude decrement of somatosensory evoked potentials (SEPs) is associated with post-operative neurological deficits. OBJECTIVE: To investigate the association between an incomplete circle of Willis and/or contralateral ICA occlusion and subsequent changes in intra-operatively monitored SEPs. METHODS: We performed a retrospective analysis of a single center, prospective cohort of consecutive patients undergoing CEA over a 42-month period after reviewing the collateral arterial anatomy on pre-operative radiological imaging. The primary endpoint was an intra-operative decline in SEPs > 50% compared to the baseline value during arterial cross-clamping. Univariate and multivariate logistic regression analyses were performed to investigate a potential association between contralateral ICA occlusion, incomplete circle of Willis, and subsequent alteration in SEPs. RESULTS: A total of 140 consecutive patients were included, of which 116 patients (82.9%) had symptomatic carotid stenosis of at least 50% according to the classification used in the North American Carotid Surgery Trial (NASCET) (Stroke 22:711-720, 1991). Six patients (4.3%) showed contralateral ICA occlusion, 22 patients (16%) a missing/hypoplastic anterior communicating artery (Acom) or A1 segment, and 79 patients (56%) a missing ipsilateral posterior communicating artery (Pcom) or P1 segment. ICA occlusion and missing segments of the anterior circulation (missing A1 and/or missing Acom) were associated with the primary endpoint (p = 0.003 and p = 0.022, respectively). CONCLUSION: Contralateral ICA occlusion and missing anterior collaterals of the circle of Willis increase the risk of intra-operative SEP changes during CEA. Pre-operative assessment of collateral arterial anatomy might help identifying patients with an increased intra-operative risk.

Stealing the Show: KSHV Hijacks Host RNA Regulatory Pathways to Promote Infection.

Kaposi's sarcoma-associated herpesvirus (KSHV) induces life-long infections and has evolved many ways to exert extensive control over its host's transcriptional and post-transcriptional machinery to gain better access to resources and dampened immune sensing. The hallmark of this takeover is how KSHV reshapes RNA fate both to control expression of its own gene but also that of its host. From the nucleus to the cytoplasm, control of RNA expression, localization, and decay is a process that is carefully tuned by a multitude of factors and that can adapt or react to rapid changes in the environment. Intriguingly, it appears that KSHV has found ways to co-opt each of these pathways for its own benefit. Here we provide a comprehensive review of recent work in this area and in particular recent advances on the post-transcriptional modifications front. Overall, this review highlights the myriad of ways KSHV uses to control RNA fate and gathers novel insights gained from the past decade of research at the interface of RNA biology and the field of KSHV research.

Carotid artery stenting versus endarterectomy for treatment of carotid artery stenosis.

BACKGROUND: Carotid artery stenting is an alternative to carotid endarterectomy for the treatment of atherosclerotic carotid artery stenosis. This review updates a previous version first published in 1997 and subsequently updated in 2004, 2007, and 2012. OBJECTIVES: To assess the benefits and risks of stenting compared with endarterectomy in people with symptomatic or asymptomatic carotid stenosis. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched August 2018) and the following databases: CENTRAL, MEDLINE, Embase, and Science Citation Index to August 2018. We also searched ongoing trials registers (August 2018) and reference lists, and contacted researchers in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing stenting with endarterectomy for symptomatic or asymptomatic atherosclerotic carotid stenosis. In addition, we included RCTs comparing carotid artery stenting with medical therapy alone. DATA COLLECTION AND ANALYSIS: One review author selected trials for inclusion, assessed trial quality and risk of bias, and extracted data. A second review author independently validated trial selection and a third review author independently validated data extraction. We calculated treatment effects as odds ratios (OR) and 95% confidence intervals (CI), with endarterectomy as the reference group. We quantified heterogeneity using the I² statistic and used GRADE to assess the overall certainty of evidence. MAIN RESULTS: We included 22 trials involving 9753 participants. In participants with symptomatic carotid stenosis, compared with endarterectomy stenting was associated with a higher risk of periprocedural death or stroke (the primary safety outcome; OR 1.70, 95% CI 1.31 to 2.19; P < 0.0001, I² = 5%; 10 trials, 5396 participants; high-certainty evidence); and periprocedural death, stroke, or myocardial infarction (OR 1.43, 95% CI 1.14 to 1.80; P = 0.002, I² = 0%; 6 trials, 4861 participants; high-certainty evidence). The OR for the primary safety outcome was 1.11 (95% CI 0.74 to 1.64) in participants under 70 years old and 2.23 (95% CI 1.61 to 3.08) in participants 70 years old or more (interaction P = 0.007). There was a non-significant increase in periprocedural death or major or disabling stroke with stenting (OR 1.36, 95% CI 0.97 to 1.91; P = 0.08, I² = 0%; 7 trials, 4983 participants; high-certainty evidence). Compared with endarterectomy, stenting was associated with lower risks of myocardial infarction (OR 0.47, 95% CI 0.24 to 0.94; P = 0.03, I² = 0%), cranial nerve palsy (OR 0.09, 95% CI 0.06 to 0.16; P < 0.00001, I² = 0%), and access site haematoma (OR 0.32, 95% CI 0.15 to 0.68; P = 0.003, I² = 27%). The combination of periprocedural death or stroke or ipsilateral stroke during follow-up (the primary combined safety and efficacy outcome) favoured endarterectomy (OR 1.51, 95% CI 1.24 to 1.85; P < 0.0001, I² = 0%; 8 trials, 5080 participants; high-certainty evidence). The rate of ipsilateral stroke after the periprocedural period did not differ between treatments (OR 1.05, 95% CI 0.75 to 1.47; P = 0.77, I² = 0%). In participants with asymptomatic carotid stenosis, there was a non-significant increase in periprocedural death or stroke with stenting compared with endarterectomy (OR 1.72, 95% CI 1.00 to 2.97; P = 0.05, I² = 0%; 7 trials, 3378 participants; moderate-certainty evidence). The risk of periprocedural death or stroke or ipsilateral stroke during follow-up did not differ significantly between treatments (OR 1.27, 95% CI 0.87 to 1.84; P = 0.22, I² = 0%; 6 trials, 3315 participants; moderate-certainty evidence). Moderate or higher carotid artery restenosis (50% or greater) or occlusion during follow-up was more common after stenting (OR 2.00, 95% CI 1.12 to 3.60; P = 0.02, I² = 44%), but the difference in risk of severe restenosis was not significant (70% or greater; OR 1.26, 95% CI 0.79 to 2.00; P = 0.33, I² = 58%; low-certainty evidence). AUTHORS' CONCLUSIONS: Stenting for symptomatic carotid stenosis is associated with a higher risk of periprocedural stroke or death than endarterectomy. This extra risk is mostly attributed to an increase in minor, non-disabling strokes occurring in people older than 70 years. Beyond the periprocedural period, carotid stenting is as effective in preventing recurrent stroke as endarterectomy. However, combining procedural safety and long-term efficacy in preventing recurrent stroke still favours endarterectomy. In people with asymptomatic carotid stenosis, there may be a small increase in the risk of periprocedural stroke or death with stenting compared with endarterectomy. However, CIs of treatment effects were wide and further data from randomised trials in people with asymptomatic stenosis are needed.

Outcome of endovascular therapy in stroke with large vessel occlusion and mild symptoms.

OBJECTIVE: To compare outcomes after endovascular therapy (EVT) and IV thrombolysis (IVT) in patients with stroke with emergent large vessel occlusion (LVO) and mild neurologic deficits. METHODS: This was a retrospective analysis of patients from the Swiss Stroke Registry with admission NIH Stroke Scale score ≤5 and LVO treated by EVT (± IVT) vs IVT alone. The primary endpoint was favorable functional outcome (modified Rankin Scale [mRS] score 0-1) at 3 months. Secondary outcomes were independence (mRS score 0-2), mRS score (ordinal shift analysis), and survival with high disability (mRS score 4-5). Safety endpoints were mortality and symptomatic hemorrhage. RESULTS: Of 11,356 patients, 312 met the criteria and propensity score method matched 108 in each group. A comparably large proportion of patients with EVT and IVT had favorable outcome (63% vs 65.7% respectively; odds ratio 0.94, 95% confidence interval 0.51-1.72; p = 0.840). Patients with EVT showed a nonsignificant trend toward higher mRS score at 3 months (p = 0.717), while the proportion of surviving patients with high disability was comparably very low in both groups (p = 0.419). Mortality was slightly higher among those with EVT (9.3% vs 2.8%; p = 0.06), and symptomatic intracranial hemorrhage was a rare event in both groups (2.8% vs 0%; p = 0.997). CONCLUSIONS: In acute ischemic stroke, EVT and IVT appear similarly effective in achieving favorable outcome at 3 months for patients with LVO and mild neurologic symptoms. EVT might be marginally inferior to IVT regarding outcome across all levels of disability and mortality. Further studies are required to determine whether certain subgroups of patients with LVO and mild symptoms benefit from EVT. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that patients with LVO and mild symptoms receiving either EVT or IVT had similar favorable functional outcomes at 3 months.