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In-stent stenosis (ISS) is a delayed complication that can occur after pipeline embolization device use when treating intracranial aneurysms (IAs).To assess the incidence, predictors, and outcomes of ISS.This was a retrospective, multicenter, observational study. All patient data were collected from a PLUS registry study. We collected data from patients with IA who completed digital subtraction angiography at follow-up and divided patients into "non-ISS," "mild ISS," or "severe ISS" groups. Multivariate logistic regression analysis was conducted to determine predictors of ISS.A total of 1171 consecutive patients with 1322 IAs participated in this study. Angiographic follow-up was available for 662 patients with 728 IAs, and the mean follow-up time was 9 months. ISS was detected in 73 cases (10.03%), including 61 mild ISS cases and 12 severe ISS cases. Univariate and multivariable analysis demonstrated that current smoking history (mild ISS: OR 2.15, 95% CI 1.122-4.118, P = .021; severe ISS: OR 5.858, 95% CI 1.186-28.93, P = .030) and cerebral atherosclerosis (mild ISS: OR 5.694, 95% CI 3.193-10.15, P = .001; severe ISS: OR 6.103, 95% CI 1.384-26.91, P = .017) were independent predictors of ISS. Compared with the other groups, the severe ISS group had higher rate of ischemic stroke (33.3%).ISS occurs in approximately 10.03% of cases at a mean follow-up of 9 months. Statistically, current smoking history and cerebral atherosclerosis are the main predictors of ISS. Severe ISS may be associated with higher risk of neurological ischemic events in patients with IA after pipeline embolization device implantation.

In this paper, the deformation characteristics of silty clay after immersion in water were studied. The wetting test of silty clay in a stratum in Chongqing under different confining pressures and different stress levels was carried out by using multi functional triaxial apparatus. Through the single line method and double line method experiments, the law of wetting deformation of silty clay was obtained and a new curve formula was fitted.

Peri-ophthalmic aneurysm is a special type of aneurysm. We assessed the relationship between ophthalmic artery (OA) origin and aneurysm and examined the effect of a pipeline embolization device (PED, Covidien/Medtronic) with or without coils on aneurysm occlusion rate and visual outcomes.We retrospectively analyzed 194 peri-ophthalmic aneurysms in 189 patients among 1171 patients treated with a PED in a Chinese post-market multi-center registry study from November 2014 to October 2019. Peri-ophthalmic aneurysms were defined as carotid-ophthalmic segment aneurysms arising from the internal carotid artery dorsal wall at, or distal to, the OA origin, with a superior or superomedial projection. The relationship between OA origin and the aneurysm was classified as follows: type A, OA originating separate from the aneurysm; type B, OA originating from the aneurysm neck or dome. Patients with aneurysm were divided into the PED-only group and the PED + coils group according to treatment.The median follow-up time was 6.8 months (range, 5.3-20.2 months). There were 163 occluded aneurysms (84%) and 31 aneurysms with incomplete occlusion (16%). A multivariate analysis showed that type B aneurysm was a risk factor for incomplete occlusion in the PED-only group (odds ratio [OR] 4.854, 95% confidence interval [CI] 1.878-12.548, P = 0.001). Visual symptoms at final follow-up correlated with preoperative visual symptoms (OR 22.777, 95% CI 3.115-166.555, P = 0.002).Type B aneurysm is associated with a lower occlusion rate after PED-only treatment. Patients with preoperative visual symptoms should be treated promptly to avoid permanent visual symptoms.

BackgroundIntracranial fusiform aneurysms are less common than saccular aneurysms, but are associated with higher mortality and morbidity. We conducted this study to determine the safety and efficacy of the pipeline embolization device (PED) to treat intracranial fusiform aneurysms.MethodsThis was a multicenter, retrospective, and observational study. Data for this study came from the PLUS study conducted from 2014 to 2019 across 14 centers in China. Univariate and multivariable logistic regression analyses were performed to evaluate predictors of the occlusion rate and complication.ResultsA total of 1171 consecutive patients with 1322 intracranial aneurysms participated in this study. Among the participants, 104 patients with 109 fusiform aneurysms were eligible for this analysis (mean age 49 years, 36.5% women, aneurysm mean size 14.7 mm, 55% in the posterior circulation, and 6% in the basilar artery). Mean follow-up time was 9.0 months (range 3–36 months). The last DSA angiographic follow-up was available for 85 patients, and 58 aneurysms (68.2%) were completely occluded. The overall complication rate and mortality were 17.3% and 2.8%, respectively. Multivariate analysis demonstrated that age (OR=1.007, p=0.037) and cerebral atherosclerosis (OR=1.441, p=0.002) were associated with incomplete occlusion of fusiform aneurysms after PED treatment.ConclusionPEDs may be an effective treatment for intracranial fusiform aneurysms, with a favorable occlusion rate. However, because these treatments have a relatively high rate of complications, PED treatment for fusiform aneurysms should be carefully and strictly controlled. Our analysis showed that PEDs with adjunctive coiling did not significantly improve the occlusion rate of fusiform aneurysms.

Background and ObjectivesBrain arteriovenous malformation (bAVM) is a congenital disorder and a leading cause of hemorrhagic stroke. Germline genetic variants play an essential role in the pathogenesis of bAVM. However, the biological relevance of disease-associated genes identified in previous studies is elusive. In this study, we aim to systematically investigate the contribution of germline variants to bAVM and explore the critical molecular pathways underlying the pathogenesis of bAVM.MethodsProbands with sporadic bAVM were consecutively recruited into this study from November 2015 to November 2018 and underwent exome sequencing. The controls were aggregated from individuals who were not known to have vascular malformation and underwent exome sequencing for clinical or research purposes. The retained control dataset included 4,609 individuals, including 251 individuals with parental samples sequenced. We first analyzed de novo variants in cases and controls and performed a pathway enrichment analysis. A gene-based rare variant association analysis was then performed to identify genes whose variants were significantly enriched in cases.ResultsWe collected an exome-sequenced bAVM cohort consisting of 152 trios and 40 singletons. By first focusing on de novo variants, we observed a significant mutational burden of likely gene-disrupting variants in cases vs controls. By performing a pathway enrichment analysis of all nonsynonymous de novo variants identified in cases, we found the angiopoietin-like protein 8 (ANGPTL8) regulatory pathway to be significantly enriched in patients with bAVM. Through an exome-wide rare variant association analysis utilizing 4,394 in-house exome data as controls, we identifiedSLC19A3as a disease-associated gene for bAVM. In addition, we found that theSLC19A3variants in cases are preferably located at the N′ side of the SLC19A3 protein. These findings implicate a phenotypic expansion ofSLC19A3-related disorders with a domain-specific effect.DiscussionThis study provides insights into the biological basis of bAVM by identifying novel molecular pathways and candidate genes.

BackgroundPipeline embolization device (PED) deployment combined with coil therapy for large complex intracranial aneurysms is effective and considered superior to PED deployment alone. However, the optimal strategy for use of coils remains unclear. We used patient-specific aneurysm models and finite element analysis to determine the ideal packing density of coils after PED placement.MethodsFinite element analysis was used to provide a higher-fidelity model for accurate post-treatment computational fluid dynamics analysis to simulate the real therapeutic process of PED and all coils. We then calculated and analyzed the reduction ratio of velocity to identify the hemodynamic change during PED deployment and each coil embolization.ResultsSixteen consecutive patients underwent PED plus coil procedures to treat internal carotid artery intracranial aneurysms. After PED deployment, the intra-aneurysmal flow velocity significantly decreased (15.3 vs 10.0 cm/s; pConclusionAdjunct coiling could improve the post-PED hemodynamic environment in treated intracranial aneurysms. However, dense packing is not necessary because the intra-aneurysmal hemodynamics tend to stabilize as the packing density reaches an average of 7.06% or after insertion of the second coil.

Multidrug resistance (MDR) of tumors has been recognized as an important cause of chemotherapy failure, which is responsible for about 90% of cancer deaths. Therefore, it is desirable to develop a highly effective strategy to reverse tumor MDR for rebuilding the sensitivity of tumor cells towards chemodrugs. Here, self-assembled DNAzyme nanoflowers (NFs) constructed by rolling circle amplification (RCA) strategy were applied in doxorubicin (Dox) delivery for efficiently ablating Dox-resistant breast cancer. The encoded multiple DNAzymes could catalytically cleave P-glycoprotein (P-gp) mRNA which assists the efflux of chemodrugs, for reversing the MDR. The in vitro and in vivo results showed that the P-gp DNAzymes NFs not only had a high drug-loading capacity (69.21%) and acid-triggered biodegrade ability, but also effectively suppressed the expression of P-gp for reversing MDR of the tumor. Therefore, the DNAzyme-based drug delivery nanoplatform would be a promisingstrategyfor reversing MDR in cancer therapy.

Cuprous oxide (Cu2O) is a p-type semiconductor with excellent catalytic activity and stability that has gained much attention because it is non-toxic, abundant, and inexpensive. Porous carbon materials have large specific surface areas, which offer abundant electroactive sites, enhance the electrical conductivity of materials, and prevent the aggregation of Cu2O nanocubes. In this study, a composite with high electrocatalytic activity was prepared based on Cu2O nanocubes anchored onto three-dimensional macroporous carbon (MPC) by a simple, eco-friendly, and cheap method for hydrazine detection. Due to the synergistic effect of MPC and Cu2O, the sensor exhibited high electrocatalytic activity, sensitivity, better selectivity, and low limit of detection. The resulting sensor could be a sensitive and effective platform for detecting hydrazine and promising practical applications.

Background and Purpose: This study tests whether patients with unruptured intracranial aneurysm who underwent stent placement benefitted from platelet function monitoring–guided adjustment of antiplatelet therapy. Methods: We conducted a randomized, open-label, parallel group, assessor-blinded trial. Patients with unruptured intracranial aneurysm who underwent stent placement were assigned in a 1:1 ratio to receive either drug adjustment (patients who had high on-treatment platelet reactivity to antiplatelet therapy on the basis of platelet function monitoring [monitoring group]) or conventional therapy (without monitoring and drug adjustment [conventional group]). The second monitoring was performed 14 days after randomization in patients with drug adjustment. The primary outcome was the composite frequency of ischemic stroke, transient ischemic attack, stent thrombosis, urgent revascularization, and cerebrovascular death within 7 days after stent implantation. The safety outcome was the composite frequency of major, minor, or minimal bleeding within 1 month after stent implantation. Results: In total, 314 patients were included (n=157 per group). The primary combined outcome occurred in 19 patients (12.1%) in the conventional group and 8 patients (5.1%) in the monitoring group (hazard ratio, 0.39 [95% CI, 0.17–0.92]; P =0.03). Ischemic stroke occurred at a lower frequency in the monitoring group compared with that in the conventional group (4.5% versus 12.1%; hazard ratio, 0.34 [95% CI, 0.14–0.83]; P =0.01), which drove the overall primary combined outcome. The safety outcome occurred in the monitoring group (7.0%) and in the conventional group (1.9%; hazard ratio, 3.87 [95% CI, 1.06–14.14]; P =0.03). A significant difference was observed in the frequency of minor or minimal bleeding events between the two groups (monitoring group versus conventional group, 6.4% versus 1.3%; P =0.02) but not in the frequency of major bleeding events between the two groups. Conclusions: Platelet function monitoring–guided antiplatelet therapy reduces thromboembolic events in patients with unruptured intracranial aneurysm after stent placement, significantly enhancing minor or minimal bleeding events but not major bleeding events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03989557.

BackgroundAneurysm recurrence after coil embolization remains a challenging problem.ObjectiveTo determine the histopathological features of recurrent aneurysm specimens and explore the mechanism of aneurysm recurrence.MethodsNine aneurysm specimens were collected from eight patients who underwent clipping for aneurysm recurrence within 2 years after embolization. All specimens were sectioned and embedded in resin, stained with hematoxylin-eosin (H&E), Masson stain, and immunohistochemical staining for smooth muscle actin (SMA) and CD68+ antibodies, and were examined under light microscopy.ResultsFive aneurysms were surgically clipped owing to post-embolic subarachnoid hemorrhage, while the other four aneurysms had dangerous recanalization detected on follow-up imaging. Five aneurysms had self-growth and four aneurysms had coil compactions. Gross observation showed that each recurrent aneurysm was wrapped by a thrombus and the aneurysm wall; some coils protruded from the pseudocapsule in some ruptured aneurysms. Microscopically, H&E staining showed that three types of thrombi (fresh thrombus, granulation tissue, and scar tissue) coexisted in one section. In addition, characteristic unstable and unorganized thrombi with empty spaces were found in the neck cavity. Immunohistochemical staining showed that the SMA stain was discontinued and incomplete, and CD68+ antibody and H&E staining revealed inflammatory infiltrate in the aneurysm wall.ConclusionThe coexistence of three types of thrombi is the main characteristic of recurrent aneurysms. The formation of stable thrombus may be one of the key points of aneurysm recurrence. Smooth muscle cell damage and infiltration of inflammatory cells in the aneurysm wall probably contribute to the recanalization.

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BackgroundVertebrobasilar dissecting aneurysms (VBDAs) with an intramural hematoma (IMH) usually cause symptoms because of mass effect and grow in size over time. Clinical outcomes are generally poor.ObjectiveThis study aimed to examine outcomes of reconstructive endovascular treatment (EVT) in patients with VBDAs with IMH. Safety and effectiveness were compared between flow diverters (FDs) and conventional stents.MethodsWe retrospectively analyzed the clinical and radiological data of 36 VBDAs with IMH in 36 patients who underwent EVT with either FDs or conventional stents from January 2012 to December 2020 at our institution.ResultsAmong the 36 study patients, 20 were treated with FDs and 16 with conventional stents. Incidence of procedure-related complications did not significantly differ between the two stents. IMH growth occurred after EVT in a significantly higher proportion of conventional stent group aneurysms (zero vs. 31.3% [5/16]; p = 0.012). Among the five aneurysms with IMHs that grew, all recurred. Change in IMH size after EVT was significantly lower in the FD group (−2.7 vs. +8.1%, p = 0.036). However, after the recurrent aneurysms were removed from the conventional stent group, change in IMH size did not significantly differ between the two groups (−2.7 vs. +1.0%, p = 0.332). The proportion of patients who experienced an improvement in mRS score after EVT was significantly higher in the FD group (60 vs. 25%, p = 0.036).ConclusionIMHs in VBDAs stop growing after successful reconstructive EVT. Although both FD and conventional stent treatment are effective, FD treatment may be superior based on clinical outcomes and effect on IMH size.

To investigate the predictors of the improvement for patients with isolated intracranial vasculitis stenoses using high-resolution vessel wall magnetic resonance imaging (HR VW-MRI).We retrospectively reviewed data from consecutive patients with confirmed intracranial vasculitis under the same conventional conservative treatment based on a prospectively established HR VW-MRI database between December 2016 and December 2020. According to the changes between the degree of stenosis at baseline compared to follow-up MR angiography, the patients were divided into an improvement group and a non-improvement group. A multivariate analysis was performed to identify the predictive factors associated with the improvement of stenoses secondary to intracranial vasculitis.Overall, 41 patients (mean age 32.0 ± 10.1 years, 16 females) with isolated intracranial vasculitis stenoses were included (41.5 % [17/41] in the improvement group, and 58.5 % [24/41] were in the non-improvement group). The degree of wall enhancement on follow-up imaging was significantly reduced compared with that on the baseline imaging in the improvement group (P = 0.004). The multivariate analysis showed that the degree of enhancement (OR, 0.219, 95 % CI, 0.054 to 0.881; P = 0.033) at baseline was an independent predictive factor associated with the improvement in the intracranial vasculitis stenoses.In patients with isolated intracranial vasculitis stenoses, the less enhancement the vessel wall was, the more likely the degree of stenosis would be reduced by conventional conservative therapy.

BackgroundAlthough coiling with a flow diverter may provide immediate dome protection, no studies have evaluated the effect on complications of postoperative occlusion degree immediately postoperatively. The purpose of this study was to determine whether postoperative occlusion degree immediately after flow-diverter placement with adjunctive coiling was associated with complications.MethodsAll patients’ data were collected from the post-market multi-center cohort study of embolization of intracranial aneurysms with a pipeline embolization device (PED) in China (PLUS) registry. We divided patients into those treated with a PED alone (PED-only (PO) group), those treated with a PED with coils and incomplete occlusion (PED + coils + incomplete occlusion (PCIO) group), and those treated with a PED with coils and complete occlusion (PED + coils + complete occlusion (PCCO) group).ResultsWe evaluated 1171 consecutive patients with 1322 aneurysms treated with a PED: 685 aneurysms were treated with PO, 444 with PCIO, and 193 with PCCO. The PCCO group had a higher rate of aneurysm occlusion at the last follow-up than the PCIO and PO groups (PConclusionsAlthough postoperative complete occlusion with a PED and adjunctive coiling can increase the rate of aneurysm occlusion, this approach may also increase the risk of ischemic stroke and lead to poor postoperative functional outcomes.

BackgroundStent assisted coiling (SAC) and flow diverters (FDs) are common endovascular treatments for wide necked cerebral aneurysms, but studies comparing the new generation Atlas SAC and FDs are scarce. We performed a propensity score matched (PSM) cohort study to compare the Atlas SAC and the pipeline embolization device (PED) for proximal internal carotid artery (ICA) aneurysms.MethodsConsecutive ICA aneurysms treated at our institution with either the Atlas SAC or PED were studied. PSM was used to control for age, sex, smoking, hypertension, and hyperlipidemia, and the rupture status, maximal diameter, and neck size of the aneurysm (aneurysms >15 mm and non-saccular aneurysms were excluded). Midterm outcomes and hospital costs were compared between these two devices.ResultsA total of 309 patients with 316 ICA aneurysms were included. Following PSM, 178 aneurysms treated with the Atlas SAC and PED were matched (n=89 in each group). Aneurysms treated with the Atlas SAC required a slightly longer procedure time, but had lower hospital costs than those treated with the PED (115.2±24.6 vs 102.4±40.8 min, P=0.012; $27 650.2±$6961.4 vs $34 107.0±$3707.2, PConclusionIn this PSM study, midterm outcomes of the PED and Atlas SAC in the treatment of ICA aneurysms were similar. However, SAC required a longer operation time, and the PED may increase the economic cost of inpatients in Beijing, China.

During intracranial aneurysm embolization with the Pipeline embolization device (PED), ischemic and hemorrhagic complications have been observed in cases among Western populations. The postmarket multicenter registry study on the embolization of intracranial aneurysms with the PED in China, i.e., the PLUS study, was performed to assess real-world predictors of complications and functional outcomes in patients treated with the PED in a Chinese population. All patients with intracranial aneurysms who underwent embolization using the PED between November 2014 and October 2019 across 14 centers in China were included. The study endpoints included preoperative and early postoperative ( 10 mm, distal anterior circulation aneurysms, and adjunctive coiling were found to be independent predictors of delayed aneurysm rupture, distal intraparenchymal hemorrhage, and neurological compression symptoms, respectively. The rate of PED-related complications in the PLUS study was similar to that in Western populations. The PLUS study identified successful deployment after adjustment or unsuccessful device deployment and the degree of immediate postoperative occlusion as novel independent predictors of PED-related ischemic stroke in a Chinese population. ClinicalTrial.gov Identifier: NCT03831672 SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-020-00990-8.

ObjectiveThe purpose of this work was to summarize the real-world safety and efficacy of Pipeline Embolization Device (PED) therapy for small and medium-sized intracranial aneurysms in China.MethodsPatients from the PED in China post-market multi-center registry study (PLUS) with aneurysms smaller than 12 mm were selected. Radiographic outcomes were assessed using digital subtraction angiography. Clinical outcomes included functional outcomes (modified Rankin Scale, MRS) in the early postoperative period ( ≤ 30 days) and early postoperative complications associated with PED therapy.ResultsA total of 652 patients with a combined 754 aneurysms were included in this study (mean age of 53.9 ± 10.3 years, 68.7% women). Mean aneurysm diameter was 6.78 ± 2.67 mm. Of the 687 stents deployed, 99.7% (685/689) were successfully deployed. In this study, 64.7% (488/754) of aneurysms were treated with only the PED, whereas 35.3% (266/754) were subjected to PED-assisted therapy. Radiographic outcome at the last follow-up (median time: seven months) was available for 64.3% (485/754) of the aneurysms. 82.5% (400/485) of aneurysms demonstrated complete occlusion (Raymond Roy Grade I). 81.4% (395/485) of aneurysms were found to meet the study's primary effectiveness outcome. At the early postoperative period, the mRS score was determined to be 0–2 vs. 3-6 in 98.2% (640/652) vs. 1.8% (12/652) of the cases, respectively. The combined major morbidity and mortality rate was 3.2% (21/652).ConclusionIn the largest study of PED therapy for small and medium-sized intracranial aneurysms to date, pipeline-assisted coil embolization was chosen more often than multiple stent implantation for aneurysm treatment, demonstrating good results, high surgical success rates, high occlusion rates, and low morbidity and mortality.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier: NCT03831672.

Contrast-induced encephalopathy (CIE) was defined as new onset of neurological deficits after exposure to contrast media, which could be observed after the endovascular treatment for intracranial aneurysms.We enrolled a consecutive cohort of patients who underwent endovascular treatment for unruptured intracranial aneurysms. CIE was defined as a reversible neuropathic syndrome that occurred after interventional therapy, accompanied by imaging abnormalities and excluding other diseases. Multivariable Poisson regression analysis was performed to show risk factors by incidence rate ratio (IRR) and a clinical strategy was proposed.Among the 579 patients who underwent interventional therapy for intracranial aneurysms, the crude incidence rate of CIE was 2.4% (95% CI, 1.2-3.6%) at our center. Headache, hemiplegia, and disorientation could be initial symptoms, and cortical blindness was the most common localized deficit. Cerebral edema and sulci effacement on CT were observed, and re-revaluation after treatments on CT/MRI showed absent lesions. The risk factors were history of stroke (IRR, 7.752; P = 0.007), history of hypertension (IRR, 1.064; P = 0.042), posterior circulation aneurysms (IRR, 9.412; P = 0.004) and higher dosage of contrast agents (IRR, 1.018; P = 0.007). After the strategy of accelerating excretion of contrast agents, reduction of intracranial pressure and anti-inflammation/vasospasm therapy, the prognosis was favorable with most patients fully recovered within 72 h.History of stroke and posterior circulation aneurysms were main risk factors for CIE. A higher dosage of contrast agents might induce CIE, and the history of hypertension should be considered as well.

Objective:Intracranial fusiform aneurysms are uncommon and can occur in vessels of the anterior circulation (AC) or posterior circulation (PC). While flow diversion is one treatment option, research into Pipeline Embolization Device (PED) treatment is lacking. This study explored the efficacy and safety of PED treatment for intracranial fusiform aneurysms, and compared therapeutic effects between AC and PC aneurysms.MethodsIn the post-market multi-center cohort study of embolization of intracranial aneurysms with PED in China (PLUS) registry study, we retrospectively analyzed 71 fusiform aneurysms in 67 patients among 1,171 patients treated with a PED from November 2014 to October 2019. The general characteristics, perioperative status, aneurysm occlusion rate at the last follow-up angiography, and changes in modified Rankin Scale scores were analyzed. Aneurysms were divided into AC and PC groups, and univariate and multivariate analyses were conducted.ResultsThe study included 26 AC (25 patients) and 45 PC (42 patients) aneurysms. A total of 75 PEDs were used, an average of 1.1 PEDs were used, and the median follow-up was 6.7 months. Fifty aneurysms (71.4%) were occluded and twenty (28.5%) were incompletely occluded. There were significantly more occluded aneurysms in the PC group than in the AC group (12 vs. 38; P = 0.001). Risk factors for incomplete occlusion were AC aneurysms (P = 0.001) and a perforating artery originating from the aneurysm (P = 0.006). The mean modified Rankin Scale score was significantly lower at the last follow up than preoperatively (0.58 vs. 0.21; P = 0.0001).ConclusionNon-overlapping PED is a safe and effective treatment for both AC and PC fusiform aneurysms. The occlusion rate of AC fusiform aneurysms is lower than that of PC.

The postoperative recurrence and metastasis of triple negative breast cancer (TNBC) remain one fatal reason for the failure of clinical treatments. Although the rise of immunotherapy has brought hopes for reducing postoperative recurrence and potential metastasis, the low immune response and immunosuppression of tumor microenvironment (TME) still restrain its extensive application. Herein, we reported a boosting strategy by improving immunogenicity and reversing suppressive TME to realize efficient immunotherapy of TNBC. In this work, a CaCO

BackgroundThe Pipeline for Uncoilable or Failed Aneurysms (PUFS) trial primarily demonstrated the safety and efficacy of the implantation of multiple pipeline embolization devices (multi-PEDs) for large/giant intracranial aneurysms. However, no study has focused on when, why, or how to apply multi-PEDs.ObjectiveThe purpose of this study was to investigate the indications and strategies of using multi-PEDs for complex intracranial aneurysms.MethodsPatients who had been treated with two or more PEDs were included in the post-market multicenter registry study from 2014 to 2019, across 14 centers in China. Indications, strategies, perioperative safety, and clinical outcomes were retrospectively analyzed. The modified Rankin scale (mRS) score was used to evaluate clinical outcomes comprehensively, and the O’Kelly–Marotta (OKM) grading scale was used to evaluate aneurysm healing results.ResultsA total of 55 intracranial aneurysms were treated with multi-PEDs. There were 20 fusiform aneurysms with a large range, 25 large/giant saccular aneurysms, six aneurysms with failed treatment, and four aneurysms with greatly varied diameters of the parent artery. The strategies included telescope techniques in 40 patients and overlap techniques in 15 patients. In total, 120 stents were deployed in 55 patients. The operation styles included 25 patients (55.6%) with two PEDs, 21 patients (38.2%) with two PEDs combined with coiling, four patients (7.3%) with three PEDs, four patients (7.3%) with three PEDs combined with coiling, and one patient (1.8%) with four PEDs. Angiography revealed OKM D in two, OKM C in seven, and OKM A and B in 46 cases after surgery. During the perioperative period, eight patients developed neurological dysfunction, three of whom died. A total of thirty-four patients were followed up with digital subtraction angiography for 2–45 (8.2 ± 8.0) months. Angiography revealed OKM D in 26, OKM C in five, and OKM B in three. At the last follow-up, the mRS score was 0–1 in 52 patients.ConclusionThe treatment of anterior circulation aneurysms with multi-PEDs is safe and effective. The implantation of multi-PEDs could be considered for large-scale fusiform aneurysms, large/giant saccular aneurysms with a jet-sign, salvage of failed PED treatments, and in cases where the diameter of the parent artery varies greatly.

Hypoxia can increase the resistance of tumor cells to radiotherapy and chemotherapy. However, the dense extracellular matrix, high interstitial fluid pressure, and irregular blood supply often serve as physical barriers to inhibit penetration of drugs or nanodrugs across tumor blood microvessels into hypoxic regions. Therefore, it is of great significance and highly desirable to improve the efficiency of hypoxia-targeted therapy. In this work, living photosynthetic bacteria (PSB) are utilized as hypoxia-targeted carriers for hypoxic tumor therapy due to their near-infrared (NIR) chemotaxis and their physiological characteristics as facultative aerobes. More interestingly, we discovered that PSB can serve as a kind of photothermal agent to generate heat through nonradiative relaxation pathways due to their strong photoabsorption in the NIR region. Therefore, PSB integrate the properties of hypoxia targeting and photothermal therapeutic agents in an "all-in-one" manner, and no postmodification is needed to achieve hypoxia-targeted cancer therapy. Moreover, as natural bacteria, noncytotoxic PSB were found to enhance immune response that induced the infiltration of cytotoxicity T lymphocyte. Our results indicate PSB specifically accumulate in hypoxic tumor regions, and they show a high efficiency in the elimination of cancer cells. This proof of concept may provide a smart therapeutic system in the field of hypoxia-targeted photothermal therapeutic platforms.

Deoxyribozyme (or denoted as DNAzyme), which is produced by in vitro screening technology, has gained extensive research interest in the field of biomedicine due to its high catalytic activity and structure identification. This review introduces the structural characteristics of RNA-cleaving DNAzyme and its application potential in cancer gene therapy, which plays a significant role in cancer-related gene inactivation by specifically cleaving target mRNA and inhibiting the expression of the corresponding protein. However, the low delivery efficiency and cellular uptake hindered the widespread usage of DNAzyme in gene therapy of cancers. Emerging nanotechnology holds great promise for DNAzyme to overcome these obstacles. This review mainly focuses on DNAzyme-based nanotherapeutic platforms in gene therapy of cancers, including oncogene antagonism therapy, treatment resistance gene therapy, immunogene therapy, and antiangiogenesis gene therapy. We also revealed the potential of DNAzyme-based nanotherapeutic platforms as emerging cancer therapy approaches and their security issues.

Background The Low-profile Visualized Intraluminal Support device (LVIS) has been successfully used to treat cerebral aneurysm, and the push-pull technique has been used clinically to compact the stent across aneurysm orifice. Our aim was to exhibit the hemodynamic effect of the compacted LVIS stent. Methods Two patient-specific aneurysm models were constructed from three-dimensional angiographic images. The uniform LVIS stent, compacted LVIS and Pipeline Embolization Device (PED) with or without coil embolization were virtually deployed into aneurysm models to perform hemodynamic analysis. Intra-aneurysmal flow parameters were calculated to assess hemodynamic differences among different models. Results The compacted LVIS had the highest metal coverage across the aneurysm orifice (case 1, 46.37%; case 2, 67.01%). However, the PED achieved the highest pore density (case 1, 19.56 pores/mm2; case 2, 18.07 pores/mm2). The compacted LVIS produced a much higher intra-aneurysmal flow reduction than the uniform LVIS. The PED showed a higher intra-aneurysmal flow reduction than the compacted LVIS in case 1, but the results were comparable in case 2. After stent placement, the intra-aneurysmal flow was further reduced as subsequent coil embolization. The compacted LVIS stent with coils produced a similar reduction in intra-aneurysmal flow to that of the PED. Conclusions The combined characteristics of stent metal coverage and pore density should be considered when assessing the flow diversion effects of stents. More intra-aneurysmal flow reductions could be introduced by compacted LVIS stent than the uniform one. Compared with PED, compacted LVIS stent may exhibit a flow-diverting effect comparable to that of the PED.

Efficient drug delivery into tumor cells while bypassing many biological barriers is still a challenge for cancer therapy. By taking advantage of the palladium (Pd)-mediated in situ activation of a prodrug and the glucose oxidase (GOD)-based β-d-glucose oxidation reaction, we developed a multisynergistic cancer therapeutic platform that combined doxorubicin (DOX)-induced chemotherapy with GOD-mediated cancer-orchestrated oxidation therapy and cancer starvation therapy. In the present work, we first synthesized DOX prodrugs (pDOXs) and temporarily assembled them with β-cyclodextrins to reduce their toxic side effects. Then, a nanoreactor was constructed by synthesizing Pd0 nanoparticles in situ within the pores of mesoporous silica nanoparticles for the conversion of pDOX into the active anticancer drug. Furthermore, GOD was introduced to decrease the pH of the tumor microenvironment and induce cancer-orchestrated oxidation/starvation therapy by catalyzing β-d-glucose oxidation to form hydrogen peroxide (H2O2) and gluconic acid. Our study provides a new strategy that employs a cascade chemical reaction to achieve combined orchestrated oxidation/starvation/chemotherapy for the synergistic killing of cancer cells and the suppression of tumor growth.

Although considerable clinical attempts on various kinds of cancers have been made, photodynamic therapy (PDT) still suffers from attenuated therapeutic effects because of the developed resistance of cancer cells. As a novel antiapoptosis protein, survivin has been demonstrated to be selectively overexpressed in a great number of human malignancies and plays a significant part in cancer progression and therapeutic resistance. Herein, we present an upconversion nanoplatform for enhanced PDT by DNAzyme-mediated gene silencing of survivin. In our system, a long single-stranded DNA (ssDNA) with a repetitive aptamer (AS1411) and survivin-targeted DNAzyme was fabricated by rolling circle amplification (RCA) and adsorbed on the upconversion nanoparticles (UCNPs) by electrostatic attraction. The multivalence of the ssDNA endows the upconversion nanoplatform with high recognition and loading capacity of photosensitizers and DNAzymes. When the nanoplatform is targeted internalized into cancer cells, PDT can be triggered by near-infrared (NIR) light to generate reactive oxygen species (ROS) for killing the cancer cells. Moreover, the encoded DNAzyme can efficiently inhibit the gene expression of survivin, providing the potential to enhance the efficiency of PDT. This study thus highlights the promise of an upconversion photodynamic nanoplatform for admirable combination therapy in cancer.

Machine learning (ML) as a novel approach could help clinicians address the challenge of accurate stability assessment of unruptured intracranial aneurysms (IAs). We developed multiple ML models for IA stability assessment and compare their performances. We enrolled 1897 consecutive patients with unstable (n = 528) and stable (n = 1539) IAs. Thirteen patient-specific clinical features and eighteen aneurysm morphological features were extracted to generate support vector machine (SVM), random forest (RF), and feed-forward artificial neural network (ANN) models. The discriminatory performances of the models were compared with statistical logistic regression (LR) model and the PHASES score in IA stability assessment. Based on the receiver operating characteristic (ROC) curve and area under the curve (AUC) values for each model in the test set, the AUC values for RF, SVM, and ANN were 0.850 (95% CI 0.806–0.893), 0.858 (95 %CI 0.816–0.900), and 0.867 (95% CI 0.828–0.906), demonstrating good discriminatory ability. All ML models exhibited superior performance compared with the statistical LR and the PHASES score (the AUC values were 0.830 and 0.589, respectively; RF versus PHASES, P

Excessive reactive oxygen species (ROS) would attack living cells and cause a series of oxidative stress related diseases, such as liver damage. Hydroxyl radicals (·OH) are currently known as one of the most toxic and harmful free radicals to organisms. Therefore, studies involving hydroxyl radicals have become important research topics in the fields of biology, biochemistry, and biomedicine. In addition, imaging of analytes using upconversion nanoparticles (UCNPs) possesses significant advantages over that using general fluorescent dyes or nanoparticles due to its high spatial resolution, reduced photodamage, and deep tissue penetration properties. Herein, we designed a highly selective and sensitive hydroxyl radical nanoprobe based on the luminescence resonance energy transfer between upconversion nanoparticles and methylene blue (MB). The concentration of ·OH could be determined by the fluorescence recovery of the UCNPs due to the oxidative damage of MB. Using this nanoprobe, the ·OH in living cells or in liver tissues could be monitored with high sensitivity and selectivity.

Glucose is a popular biosensor target due to its closely with diabetes or hypoglycemia in blood. Designing efficiency electrocatalysts for the determination of glucose is vital to develop glucose detection devices. CoMoO4, as a kind of bimetallic oxide material, exhibits unique electrochemical properties. 3D macroporous carbon (MPC) has large specific surface area and excellent electrical conductivity, providing an effective support for loading other nano-entities to form novel composite with good synergetic effects. Herein, nanorod-like CoMoO4 anchored onto MPC support was synthesized for the development of a promising electrochemical sensing platform for glucose. Attributing to the synergic effects between the good electrocatalytic performance of CoMoO4 nanorods and the extraordinary electrical conductivity of 3D layered MPC, the novel CoMoO4/MPC composites non-enzymatic sensor shows excellent electrocatalytic performance for oxidation of glucose. Under the optimum conditions, the proposed CoMoO4/MPC hybrids provided a reliable linear range of 5 × 10−7 to 1.08 × 10−4 M with a low limit of detection (0.13 μM) for the detection of glucose. Meanwhile, the CoMoO4/MPC sensing platform shows fast response time of 1.76 s, good stability and selectivity for detecting glucose. Moreover, this non-enzymatic sensor also has been successfully applied to measure glucose level in human blood samples. Therefore, the developed sensor holds a new promise for the construction of facile and sensitive non-enzymatic glucose analytical platform.

Sulfur is not normally considered a light-emitting material, even though there have been reports of a dim luminescence of this compound in the blue-to-green spectral region. Now, it is shown how to make red-emissive sulfur by a two-step oxidation approach using elemental sulfur and Na2 S as starting materials, with a high photoluminescence quantum yield of 7.2 %. Polysulfide is formed first and is partially transformed into Na2 S2 O3 in the first step, and then turns back to elemental S in the second step. The elevated temperature and relatively oxygen-deficient environment during the second step transforms Na2 S2 O3 into Na2 SO3 incorporated with oxygen vacancies, thus resulting in the formation of a solid-state powder consisting of elemental S embedded in Na2 SO3 . It shows aggregation-induced emission properties, attributed to the influence of oxygen vacancies on the emission dynamics of sulfur by providing additional lower energy states that facilitate the radiative relaxation of excitons.

Background Brain arteriovenous malformations (BAVMs) are abnormal vessels that are apt to rupture, causing life-threatening intracranial hemorrhage (ICH). The estimated prevalence of BAVMs is 0.05% among otherwise healthy individuals. In this study, we aim to investigate the mutational spectrum of syndromic genes in sporadic BAVM. Methods We recruited a cohort of 150 patients with BAVM and performed whole-exome sequencing on their peripheral blood DNA. To explore the mutational spectrum of syndromic genes in sporadic brain arteriovenous malformation, we selected six genes according to the Online Mendelian Inheritance in Man (OMIM) and literature. All variants in the six candidate genes were extracted and underwent filtering for qualifying variants. Results There are a total of four patients with rare variants in hereditary hemorrhagic telangiectasia-related genes. In addition, we identified two patients have the variant of RASA1 gene in our database, which are also rare mutations that are absent from population databases. However, we did not find any patients with GNAQ mutations in our database. Conclusions In conclusion, we demonstrated that variants in syndromic vascular malformations play important roles in the etiology of sporadic BAVM.

Band-Aids have been widely used for wound care. For most adhesive bandages, however, they have a limited capacity to speed up the wound healing process, which in turn may cause serious wound infections. In this study, antibacterial Band-Aids, combining porphyrin-based porous organic polymers (POPs) with commercial antibiotic-free Band-Aids, are designed. Under white light irradiation, POPs can produce effective photothermal heat, as well as highly reactive oxygen species (ROS), thereby triggering the potent hyperthermia and simultaneous ROS increase on wounds. Additionally, white light is similar to sunlight, which makes POP-based Band-Aids (PBAs) ideal wound dressings for wound disinfection.

Background and purposeLight transmission aggregometry (LTA) and CYP2C19 genotype analysis are commonly used to evaluate the antiplatelet effects of clopidogrel during the interventional treatment of intracranial aneurysms. The aim of this study was to determine which test can predict ischaemic events during these treatments.MethodsPatient demographic information, imaging data, laboratory data and ischaemic complications were recorded. LTA and CYP2C19 genotype results were compared, and multiple linear regression was performed to examine factors related to platelet reactivity. Multivariate regression analysis was performed to determine whether LTA and CYP2C19 could predict ischaemic complications and to identify other clinical risk factors. Receiver operating characteristic curve analysis was conducted to calculate the cut-off value for predicting ischaemic complications. A subgroup analysis was also performed for different CYP2C19 genotype metabolisers, as well as for patients with flow diverters and traditional stents.ResultsA total of 379 patients were included, of which 22 developed ischaemic events. Maximum platelet aggregation induced by ADP (ADP-MPA) could predict ischaemic events (p10 years (p=0.022) were independent risk factors for ischaemic events, while the CYP2C19 genotype was not associated with ischaemic events. In the subgroup analysis, ADP-MPA could predict ischaemic events in fast metabolisers (p=0.004) and intermediate metabolisers (p=0.003). The cut-off value for ischaemic events was lower in patients with flow diverters (ADP-MPA=36.4%) than in patients with traditional stents (ADP-MPA=42.9%).ConclusionsADP-MPA can predict ischaemic complications during endovascular treatment of intracranial aneurysms. Patients with flow diverters require stronger antiplatelet medication than patients with traditional stents.

Hypoxia is a prominent feature of malignant tumors and contributes to tumor proliferation, metastasis, and drug resistance in various solid tumors. Therefore, improving tumor oxygenation is crucial for curing tumors. To date, multiple strategies, including oxygen delivering and producing materials, have been designed to increase the oxygen concentration in hypoxic tumors. However, the unsustainable supply of oxygen is still the main obstacle, resulting in a suboptimal outcome in treating oxygen-deprived tumors. Thus, a sufficient oxygen supply is highly desirable in the treatment of hypoxic tumors. Photosynthesis, as the main source of oxygen in nature through the conversion of light energy into chemical energy and oxygen, has been widely studied in scientific research. Moreover, photosynthetic microorganisms have been increasingly applied in cancer therapy by increasing oxygenation, which improves the therapeutic effect of oxygen-consuming tumor therapeutic tools such as radiotherapy and photodynamic therapy. In this review, we summarize recent advances in the design and manufacture of live bacteria as oxygen shuttles for a new generation of hypoxic tumor treatment strategies. Finally, current challenges and future directions are also discussed for successfully addressing hypoxic tumor issues.

Background: Several pharmacological pathways have revealed statin to have a positive role in patients with for intracranial aneurysms. However, prior studies regarding the association between statin use and patients’ outcomes after pipeline embolization device (PED) treatment were not completely supportive. Objectives: To investigate whether statin medication following PED treatment would improve the outcomes of intracranial aneurysm patients in a real-world setting. Design: A retrospective multicenter cohort study. Methods: Patients were selected from the PLUS registry study conducted from November 2014 to October 2019 across 14 centers in China. The population was divided into two groups: those who received statin medication after the PED treatment and those who did not receive statin medication after PED treatment. Study outcomes included angiographic evaluation of aneurysm occlusion, parent arteries stenosis, ischemic and hemorrhage complications, all-cause mortality, neurologic mortality, and functional outcome. Results: 1087 patients with 1168 intracranial aneurysms were eligible; 232 patients were in the statin user group and the other 855 were in the non-statin user group. For the statin user group versus the non-statin user group, no significant difference was found for the primary outcomes of complete occlusion of aneurysm (82.4% versus 84.2%; p = 0.697). Of the secondary outcomes, none had a significant difference including stenosis of parent arteries ≥ 50% (1.4% versus 2.3%; p = 0.739), total subarachnoid hemorrhage (0.9% versus 2.5%; p = 0.215), all-cause mortality (0.0% versus 1.9%; p = 0.204), neurologic mortality (0.0% versus 1.6%; p = 0.280), excellent (95.5% versus 97.2%; p = 0.877), and favorable (98.9% versus 98.4%; p = 0.933) functional outcomes. The total ischemic complication rate (9.0% versus 7.1%; p = 0.401) was higher but not significant in the statin user group. The propensity score-matched cohort showed similar results. Results of binary multivariable logistic regression analysis and propensity score-matched analysis both showed that statin usage was not independently associated with an increased rate of complete occlusion or any other secondary outcomes. Subgroup analysis found the same result in patients who did not use statin before the procedure. Conclusion: Among patients with intracranial aneurysms, statin use after the PED treatment was not significantly associated with better angiographic and clinical outcomes. Well-designed studies are needed to further confirm this finding.

Background As an antioxidant, hydrogen (H2) can selectively react with the highly toxic hydroxyl radical (·OH) in tumor cells to break the balance of reactive oxygen species (ROS) and cause oxidative stress. However, due to the high diffusibility and storage difficulty of hydrogen, it is impossible to achieve long-term release at the tumor site, which highly limited their therapeutic effect. Results Photosynthetic bacteria (PSB) release a large amount of hydrogen to break the balance of oxidative stress. In addition, as a nontoxic bacterium, PSB could stimulate the immune response and increase the infiltration of CD4+ and CD8+ T cells. More interestingly, we found that hydrogen therapy induced by our live PSB did not lead to the up-regulation of PD-L1 after stimulating the immune response, which could avoid the tumor immune escape. Conclusion Hydrogen-immunotherapy significantly kills tumor cells. We believe that our live microbial hydrogen production system provides a new strategy for cancer hydrogen treatment combining with enhanced immunotherapy without up-regulating PD-L1. Graphical Abstract

BackgroundAssessing rupture risk in patients with unruptured intracranial aneurysms (UIAs) remains challenging. Hemodynamics plays an important role in the natural history of intracranial aneurysms. This study aimed to compare aneurysmal hemodynamic features between patients with different rupture risk as determined by PHASES score.MethodsWe retrospectively examined 238 patients who harbored a solitary saccular UIA. Patients were stratified by rupture risk into low-, intermediate-, and high-risk groups according to PHASES score. Flow simulations were performed to compare differences in hemodynamics among the groups.ResultsAneurysmal time-averaged wall shear stress (WSSa) and normalized WSS (WSSn) decreased progressively as PHASES score increased. WSSa and WSSn significantly differed among the low-, intermediate-, and high-risk groups (p < 0.001). WSSa was significantly lower in the high-risk group than the low-risk group (p < 0.001) and the intermediate-risk group (p = 0.004). WSSn was also significantly lower in the high-risk group than the low-risk group (p < 0.001) and the intermediate-risk group (p = 0.001).ConclusionsLow WSS was significantly associated with higher risk of intracranial aneurysm rupture as determined by PHASES score, indicating that hemodynamics may play an important role in aneurysmal rupture. In the future, a multidimensional rupture risk prediction model that includes hemodynamic parameters should be investigated.

Chimeric antigen receptor T (CAR T) cell therapy has achieved remarkable results treating patients with hematological malignancies in clinical studies. Although promising, extensive research has also revealed that CAR T therapy is unsatisfactory for the treatment of solid tumors. In addition, the production of CAR T cells is time-consuming and it's hard for storage and transportation. In this work, inspired by the construction of CAR T cell, we developed an antibody-engineered exosomes from antigen-feeding dendritic cells for beyond CAR T therapy of solid tumor by in situ T cells activation and cancer cell targeting. We have confirmed that tumor antigen-stimulated dendritic cell-derived exosomes (tDC-Exo) provided major histocompatibility (MHC)-antigen complexes and CD86 co-stimulating molecules, which were the same as CAR of CAR T cell acting as the necessary signals for T cell activation. Furthermore, anti-CD3 and anti-EGFR were then engineered on tDC-Exo to promote the binding of T cell to cancer cells for precise therapy. Our CAR T cell therapy-mimicking system have shown an efficient endogenous T cells activation and their crosslinking with cancer cells for enhanced solid tumor therapy. More interestingly, we found that immune activation significantly up-regulated PD-L1 expression, and thus we confirmed the combination with anti-PD-L1 antibodies further enhanced the efficacy of our CAR T cell therapy-mimicking platform.

Objective: Peri-ophthalmic aneurysm is a special type of aneurysm. We assessed the relationship between ophthalmic artery (OA) origin and aneurysm and examined the effect of a pipeline embolization device (PED, Covidien/Medtronic) with or without coils on aneurysm occlusion rate and visual outcomes.Methods: We retrospectively analyzed 194 peri-ophthalmic aneurysms in 189 patients among 1,171 patients treated with a PED in a Chinese post-market multi-center registry study from November 2014 to October 2019. Peri-ophthalmic aneurysms were defined as carotid–ophthalmic segment aneurysms arising from the internal carotid artery dorsal wall at, or distal to, the OA origin, with a superior or superomedial projection. The relationship between OA origin and the aneurysm was classified as follows: Type A, OA originating separate from the aneurysm; Type B, OA originating from the aneurysm neck or dome. Patients with aneurysm were divided into the PED-only group and the PED + coils group according to treatment. Results: The median follow-up time was 6.8 months (range, 5.3–20.2 months). There were 163 occluded aneurysms (84%) and 31 aneurysms with incomplete occlusion (16%). A multivariate analysis showed that Type B aneurysm was a risk factor for incomplete occlusion in the PED-only group (odds ratio [OR] 4.951, 95% confidence interval [CI] 1.904-12.875, p = 0.001). Visual symptoms at final follow up correlated with preoperative visual symptoms (OR 16.005, 95% CI 2.505-102.273, p = 0.003).Conclusions: Type B aneurysm is associated with a lower occlusion rate after PED-only treatment. Patients with preoperative visual symptoms should be treated promptly to avoid permanent visual symptoms.

Background The aim of this study was to comprehensively evaluate the risk factors of periprocedural ischemic stroke associated with endovascular treatment of intracranial aneurysms using a real-world database. Methods From August 2016 to March 2017, 167 patients were enrolled. Univariate analysis and multivariate logistic regression analysis were used to examine the risk factors for periprocedural ischemic stroke. Results Among the 167 cases, periprocedural ischemic stroke occurred in 20 cases (11.98%). After univariate analysis, the ischemic group had a higher proportion of large (≥ 10 mm) aneurysms than the control group (45.0% vs. 23.1%, p = 0.036). The incidence of periprocedural ischemic stroke was higher in cases treated by flow diverter (21.6%) or stent-assisted coiling (11.8%) than in cases treated by coiling only (2.7%), and the differences were statistically significant (p = 0.043). After multivariate logistic regression analysis, treatment modality was the independent risk factor for periprocedural ischemic stroke. Compared with the coiling-only procedure, flow diverter therapy was associated with a significantly higher rate of periprocedural ischemic stroke (OR 9.931; 95% CI 1.174–84.038; p = 0.035). Conclusions Aneurysm size and treatment modality were associated with periprocedural ischemic stroke. Larger aneurysms were associated with increased risk of periprocedural ischemic stroke. Flow diverter therapy was associated with significantly more periprocedural ischemic stroke than the coiling procedure alone.