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Spatiotemporal manipulation of biological processes in living animals using non-invasive, remote-controlled stimuli is a captivating but challenging endeavor. Herein, we present the development of a bioorthogonal photocatalytic technology termed CAT-NIR, which uses external near infrared light (NIR, 740 nm) to trigger bioorthogonal chemical decaging reactions in living mice. The Os(tpy)2 complex was identified as an efficient NIR photocatalyst for promoting deboronative hydroxylation reactions in the presence of NIR lights, resulting in the deprotection of phenol groups and the release of bioactive molecules under bioorthogonal conditions. The validation of the CAT-NIR system was demonstrated through the NIR-triggered rescue of fluorophores, prodrugs as well as biomolecules ranging from amino acids, peptides to proteins in living cells. Furthermore, by combining genetic code expansion and computer-aided screening, CAT-NIR was able to regulate affibody binding to the cell surface receptor Her2 in living cells, providing a highly selective cell tagging technology with spatiotemporal precision through external NIR light. Most significantly, the tissue-penetrating ability of NIR light allowed for smooth prodrug activation in living mice using external NIR light, enabling non-invasive, remote-controlled rescue of bioactive molecules. This opens up new opportunities for in vivo investigations and manipulations given the broad adaptability of the decaging chemistry and the high spatiotemporal resolution potential of such photocatalytic tools.

Introduction: Brain arteriovenous malformations (bAVMs) are a major risk factor for cerebral hemorrhages in young patients. Recent clinical studies have identified somatic activating KRAS mutations in human bAVMs (~76%), and we confirmed the causal role of endothelial KRAS G12V mutation in bAVM development using a mouse model. However, the pathomechanisms underlying bAVM pathology remain to be determined. CD36 is highly expressed in microglia/macrophages (MMs) and microvascular endothelial cells (ECs) and plays various roles in inflammation and angiogenesis, closely related to vascular development and functions. In this study, we determined if CD36 is involved in bAVM pathophysiology. Methods: Mice were injected with either AAV-BR1 carrying GFP (control) or KRAS G12V . We determined CD36 expression in the control or bAVM tissues dissected from the mouse brains. We also determined CD36 levels in the in vitro cultured ECs overexpressing KRAS G12V . Finally, we determined bAVM numbers and size in CD36 knock-out (ko) mice injected with AAV-BR1-KRAS G12V . Results: We found that gene expression of CD36 and the ligands, thrombospondin-1 and -2 were significantly increased in the KRAS G12V -induced bAVMs. However, the CD36 levels were slightly but significantly reduced in KRAS G12V transfected ECs. In the CD36 ko mice, we found that the number of large bAVMs was significantly reduced compared to the control (C57BL/6). Conclusion: Our results indicate that CD36 expression is dysregulated in KRAS G12V -induced bAVMs and contributes to bAVM development. As CD36 has distinctive roles depending on cell types, the role of CD36 in each cell type (e.g., MMs or ECs) on bAVM pathology should be further determined.

Introduction: Plavix resistance is an independent risk factor for thromboembolic complications following carotid artery stent (CAS) placements. The VerifyNow P2Y12 assay is the best studied in gauging for Plavix responsiveness. Its performance is affected when hematocrit (HCT) value is Methods: We included symptomatic carotid artery patients who suffered ischemic strokes and received CAS during the same hospitalization with PRU measured via VerifyNow assay. Therapeutic PRU is defined as ≤180. Primary outcomes were the comparisons of PRU and the proportion of non-responders between low ( Results: 78 of 127 symptomatic carotid artery patients met inclusion criteria. Mean age was 70.5 with 38.5% females. 23 of 78 had HCT < 33. Baseline characteristics between low and high HCT groups were similar except for hemoglobin (9.4 vs. 12.7, p Conclusion: In symptomatic carotid patients receiving CAS, low HCT is associated with increased PRU, resulting in some to be falsely categorized as non-responders receiving more aggressive therapy unnecessarily.

Pyroptosis is an inflammatory cell death form triggered by protease-mediated truncation and release of the N-terminal pore-forming domain of the gasdermin (GSDM) family proteins in various cell types. We report a Bioorthogonally ACtivatable Base editor (BaseBAC) for

The rapid emergence and spread of escaping mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has significantly challenged our efforts in fighting against the COVID-19 pandemic. A broadly neutralizing reagent against these concerning variants is thus highly desirable for the prophylactic and therapeutic treatments of SARS-CoV-2 infection. We herein report a covalent engineering strategy on protein minibinders for potent neutralization of the escaping variants such as B.1.617.2 (Delta), B.1.617.1 (Kappa), and B.1.1.529 (Omicron) through in situ cross-linking with the spike receptor binding domain (RBD). The resulting covalent minibinder (GlueBinder) exhibited enhanced blockage of RBD-human angiotensin-converting enzyme 2 (huACE2) interaction and more potent neutralization effect against the Delta variant than its noncovalent counterpart as demonstrated on authentic virus. By leveraging the covalent chemistry against escaping mutations, our strategy may be generally applicable for restoring and enhancing the potency of neutralizing antibodies to SARS-CoV-2 and other rapidly evolving viral targets.

Identification of the tyrosine phosphorylation (pY)-dependent interactome of immune co-receptors is crucial for understanding signal pathways involved in immunotherapy. However, identifying the motif-specific interactome for each pY commonly found on these multi-phosphorylated membrane proteins remains challenging. Here, we describe a photoaffinity-based chemical proteomic approach to dissect the motif-specific cytoplasmic interactomes of the critical immune co-receptor CD28. Various full-length CD28 cytoplasmic tails (CD28cyto) with defined pY and selectively replaced photo-methionine were synthesized and applied to explore three pY-motif-dependent CD28cyto interactomes. We identified a stand-alone interaction of phospholipase PLCG1 with the Y191 motif with enhanced affinity for the sequence neighboring the transmembrane domain. Importantly, taking advantage of native top-down mass spectrometry with a 193-nm laser, we discovered the direct association of a previously undefined pY218 motif with the kinase PKCθ through its C2 domain. This synthetic CD28cyto-based photoaffinity proteomic approach is generically applicable to the study of other immune co-receptors with multiple pY sites on their linear cytoplasmic tail.

The dynamic interactions between RNAs and proteins play crucial roles in regulating diverse cellular processes. Proteome-wide characterization of these interactions in their native cellular context remains desirable but challenging. Herein, we developed a photocatalytic crosslinking (PhotoCAX) strategy coupled with mass spectrometry (PhotoCAX-MS) and RNA sequencing (PhotoCAX-seq) for the study of the composition and dynamics of protein-RNA interactions. By integrating the blue light-triggered photocatalyst with a dual-functional RNA-protein crosslinker (RP-linker) and the phase separation-based enrichment strategy, PhotoCAX-MS revealed a total of 2044 RBPs in human HEK293 cells. We further employed PhotoCAX to investigate the dynamic change of RBPome in macrophage cells upon LPS-stimulation, as well as the identification of RBPs interacting directly with the 5' untranslated regions of SARS-CoV-2 RNA.

Objective A high rate of cerebral aneurysm recurrence following endovascular coiling has prompted the use of digital subtraction angiography (DSA) for interval follow-up. However, the utility of skull x-rays as an alternative screening method for aneurysm recurrence is unproperly characterized. Methods Retrospective review of a prospective registry of ruptured and unruptured cerebral aneurysms. Anteroposterior and lateral skull x-rays were obtained immediately at the end of the procedure and at 6-month follow-up. Aneurysm recurrence was defined by comparing post-procedure and 6-month DSA imaging. A true positive was defined as a change in coil mass morphology on at least one projection with aneurysm recurrence on DSA, and a true negative defined as a stable coil mass on both projections and no recurrence on DSA. Receiver operating characteristic area under the curve (AUC) statistics was used to assess the performance of skull x-rays in identifying aneurysm recurrence. Results A total of 118 cerebral aneurysms were evaluated with DSA imaging and skull x-rays. A change in coil mass morphology on one projection of skull x-rays correctly detected all true recurrences with a sensitivity of 100% (95% confidence interval [CI], 91-100%). Skull x-rays failed to identify a stable aneurysm coil mass in 15 cases, with a specificity of 79% (68-88%). Skull x-rays performed with AUC 0.8958 (95% CI, 0.8490-0.9431) in identifying aneurysm recurrence. Conclusions The findings of our study suggest that skull x-rays may represent a low-cost, non-invasive screening tool to rule out aneurysm recurrence, which can potentially aid in decreasing the utilization of DSA in the follow-up of patients with coiled cerebral aneurysms.

Objective Brain arteriovenous malformations (bAVMs) are a leading cause of hemorrhagic stroke and neurological deficits in children and young adults, however, no pharmacological intervention is available to treat these patients. Although more than 95% of bAVMs are sporadic without family history, the pathogenesis of sporadic bAVMs is largely unknown, which may account for the lack of therapeutic options. KRAS mutations are frequently observed in cancer, and a recent unprecedented finding of these mutations in human sporadic bAVMs offers a new direction in the bAVM research. Using a novel adeno-associated virus targeting brain endothelium (AAV-BR1), the current study tested if endothelial KRASG12V mutation induces sporadic bAVMs in mice. Methods Five-week-old mice were systemically injected with either AAV-BR1-GFP or -KRASG12V . At 8 weeks after the AAV injection, bAVM formation and characteristics were addressed by histological and molecular analyses. The effect of MEK/ERK inhibition on KRASG12V -induced bAVMs was determined by treatment of trametinib, a US Food and Drug Administration (FDA)-approved MEK/ERK inhibitor. Results The viral-mediated KRASG12V overexpression induced bAVMs, which were composed of a tangled nidus mirroring the distinctive morphology of human bAVMs. The bAVMs were accompanied by focal angiogenesis, intracerebral hemorrhages, altered vascular constituents, neuroinflammation, and impaired sensory/cognitive/motor functions. Finally, we confirmed that bAVM growth was inhibited by trametinib treatment. Interpretation Our innovative approach using AAV-BR1 confirms that KRAS mutations promote bAVM development via the MEK/ERK pathway, and provides a novel preclinical mouse model of bAVMs which will be useful to develop a therapeutic strategy for patients with bAVM. ANN NEUROL 2021;89:926-941.

Background and Purpose: The optimal endovascular stroke therapy (EVT) care delivery structure is unknown. Here, we present our experience in creating an integrated stroke system (ISS) to expand EVT availability throughout our region while maintaining hospital and physician quality standards. Methods: We identified all consecutive patients with large vessel occlusion acute ischemic stroke treated with EVT from January 2014 to February 2019 in our health care system. In October 2017, we implemented the ISS, in which 3 additional hospitals (4 total) became EVT-performing hospitals (EPHs) and physicians were rotated between all centers. The cohort was divided by time into pre-ISS and post-ISS, and the primary outcome was time from stroke onset to EPH arrival. Secondary outcomes included hospital and procedural quality metrics. We performed an external validation using data from the Southeast Texas Regional Advisory Council. Results: Among 513 patients with large vessel occlusion acute ischemic stroke treated with EVT, 58% were treated pre-ISS and 43% post-ISS. Over the study period, EVT procedural volume increased overall but remained relatively low at the 3 new EPHs (P P P Conclusions: In our system, increasing EVT availability decreased time from stroke onset to EPH arrival. The ISS provides a framework to maintain quality in lower volume hospitals.

OBJECTIVETraditionally, stent-assisted coiling and balloon remodeling have been the primary endovascular treatments for wide-necked intracranial aneurysms with complex morphologies. PulseRider is an aneurysm neck reconstruction device that provides parent vessel protection for aneurysm coiling. The objective of this study was to report early postmarket results with the PulseRider device.METHODSThis study was a prospective registry of patients treated with PulseRider at 13 American neurointerventional centers following FDA approval of this device. Data collected included clinical presentation, aneurysm characteristics, treatment details, and perioperative events. Follow-up data included degree of aneurysm occlusion and delayed (> 30 days after the procedure) complications.RESULTSA total of 54 aneurysms were treated, with the same number of PulseRider devices, across 13 centers. Fourteen cases were in off-label locations (7 anterior communicating artery, 6 middle cerebral artery, and 1 A1 segment anterior cerebral artery aneurysms). The average dome/neck ratio was 1.2. Technical success was achieved in 52 cases (96.2%). Major complications included the following: 3 procedure-related posterior cerebral artery strokes, a device-related intraoperative aneurysm rupture, and a delayed device thrombosis. Immediately postoperative Raymond-Roy occlusion classification (RROC) class 1 was achieved in 21 cases (40.3%), class 2 in 15 (28.8%), and class 3 in 16 cases (30.7%). Additional devices were used in 3 aneurysms. For those patients with 3- or 6-month angiographic follow-up (28 patients), 18 aneurysms (64.2%) were RROC class 1 and 8 (28.5%) were RROC class 2.CONCLUSIONSPulseRider is being used in both on- and off-label cases following FDA approval. The clinical and radiographic outcomes are comparable in real-world experience to the outcomes observed in earlier studies. Further experience is needed with the device to determine its role in the neurointerventionalist’s armamentarium, especially with regard to its off-label use.

Quantitative detection and characterization of antigen-specific T cells are crucial to our understanding of immune responses as well as the development of new immunotherapies. Herein, we report a spatiotemporally resolved method for the detection and quantification of cell-cell interactions via

Introduction: Brain arteriovenous malformations (bAVMs) is a high risk factor for intracerebral hemorrhage (ICH). We recently confirmed that KRAS G12V mutation is sufficient to induce sporadic bAVMs that recapitulate the characteristics of human bAVMs including a tangled vasculature and ICH. However, the bAVMs form in random location in the mouse brain. Therefore, it will be important to establish non-invasive methods to detect bAVMs and bAVM-associated ICH for further studies identifying pathophysiology of bAVMs and testing drug efficacy on bAVM pathology. Methods: We induced bAVMs in mice by adeno-associated virus (AAV)-BR1 carrying KRAS G12V . Magnetic resonance angiography (MRA) and T2*-weighted MR imaging (MRI) were performed to assess bAVM and ICH. The bAVM and ICH were graded by the volume (e.g., for bAVMs, grade 13 , 1mm 3 3 ...grade 9>9mm 3 ; for ICH, grade 13 , 0.5mm 3 3 ...grade 9>4.5mm 3 ). The ICHs smaller than 0.5 mm 3 and round shape were considered as microbleeding (ITK-SNAP and ImageJ). The MRI/MRA-visualized bAVM and ICHs were confirmed by histological analyses (latex casting and H&E and Ter-119 immunostaining). Results: By MRA, bAVMs were first detected at 7 weeks after AAV-BR1-KRAS G12V injection and showed robust growth between 7 to 8 weeks. Various size of bAVMs were detected at 9 weeks after the AAV injection. The grade 1 of microbleeding preceded bAVM formation and was detected 2-3 weeks after AAV-BR1-KRAS G12V injection. We confirmed that the locations of bAVM/ICH detected by MRI/MRA imaging overlapped with the ones detected by vascular casting and histological analysis. Conclusions: We successfully established the non-invasive protocol for detecting bAVM growth and ICH in our sporadic bAVM mice model using MRI/MRA technique. With further improvement of the imaging resolution to detect smaller and earlier bAVMs, our non-invasive bAVM/ICH imaging methods will be a useful tool for bAVM study.

Introduction: Brain arteriovenous malformations (bAVMs) are a major risk factor of cerebral hemorrhages in young patients. Recently, somatic KRAS mutation has identified ~60% of human bAVMs, and we confirmed the causal role of endothelial KRAS G12V mutation in bAVM development using a mouse model. Excessive uncontrolled angiogenesis is associated with the abnormal vascular outgrowth in bAVMs. While abnormal VEGF signaling is involved in pathologic angiogenesis, the role in mutant KRAS-induced bAVMs has not been studied. Here, we hypothesized that KRAS mutation induces bAVMs via activation of VEGF signaling, and tested if VEGF inhibition prevents KRAS G12V -induced bAVM development. Methods: We induced bAVMs in mice by systemic injection of AAV-BR1 carrying KRAS G12V mutation (KRAS G12V mice). To determine the effect of KRAS mutation on VEGF signaling, we tested the expression of VEGF-A and VEGFR2 in KRAS G12V -induced bAVMs in vivo and cultured mouse endothelial cells (ECs) overexpressing KRAS G12V in vitro . Furthermore, we performed the tube formation assay to test angiogenesis by KRAS G12V mutation in the cultured EC. Finally, we treated VEGFR2 inhibitor (SU5416) in the KRAS G12V mice and measured the bAVM size and numbers in the latex-casted brains. Results: We found that the expression of VEGF-A, VEGFR2, and phospho(p)-VEGFR2 were significantly increased in KRAS G12V -induced bAVMs in mice. We also found that KRAS G12V transfection up-regulates expression of VEGF-A, VEGFR2, and p-VEGFR2, and increased tube formation in cultured ECs. Finally, we confirmed that SU5416 treatment significantly reduced the numbers and size of bAVMs in KRAS G12V mice. Conclusions: Our data show that endogenous VEGF signaling is activated by KRAS mutation. The VEGF inhibition study suggests that the endogenously activated VEGF signaling would be essential to mediate the mutant KRAS-induced bAVM development.

Despite the increasing evidence of the association between breast cancer and meningioma in women, the relationship between these tumors remains improperly examined. In this study, we aim to identify the sociodemographic and clinicopathologic features of women with breast cancer associated with a higher risk of developing a meningioma.The SEER (Surveillance Epidemiology and End Results) database (18 registries) was used to identify women with breast cancer as their first neoplasm. The risk of subsequent meningioma was reported as the standardized incidence ratio (SIR) and was analyzed by sociodemographic and clinicopathologic subgroups. Results are given as SIR (95% confidence interval [CI]).A total of 564,516 women diagnosed with breast cancer between 2004 and 2016 were included for analysis. A 26% increased risk of meningioma development (SIR, 1.26; 95% CI, 1.19-1.33; P0.05) was found in the cohort compared with the general population. Patients aged between 18 and 49 years (SIR, 2.16; 95% CI, 1.78-2.61; P0.05) and those with a more advanced tumor stage (stage IV; SIR, 2.39; 95% CI, 1.71-3.25; P0.05) were at a higher risk. Hormone receptor expression and treatment modality subgroups were at a similar risk compared with the general population.Our study corroborated the known association between these tumors and found a 26% risk of meningioma development in women with breast cancer, with younger patients and those with a more aggressive disease having a higher than expected risk.

Patients with cerebral vasospasm caused by aneurysmal subarachnoid hemorrhage (aSAH) are often treated with intra-arterial (IA) vasodilator infusion. However, the optimal drug regimen is yet to be elucidated. A retrospective review of patients with aSAH and cerebral vasospasm treated with IA vasodilator infusion was performed. Patients in group 1 (2008–2011) were treated with a single agent, either nicardipine or verapamil, and patients in group 2 (2010–2016) were treated with a regimen of nitroglycerin, verapamil, and nicardipine. The post-infusion improvement ratio (PIIR) was compared between groups. Adjusted multivariate logistic regression models were utilized to determine whether patients treated with multiple vasodilators had an improved functional outcome, defined by the modified Rankin Scale, at discharge and 90-day follow-up. Among 116 patients from group 1 (N = 47) and group 2 (N = 69), the median age was 54.5 years [IQR, 46–53 years] and 78% were female. Use of multiple-agent therapy resulted in a 24.36% improvement in vessel diameter over single-agent therapy (median PIIR: group 1, 10.5% [IQR, 5.3–21.1%] vs group 2, 34.9% [IQR, 21.4–66.0%]; p < 0.0001). In the adjusted multivariate logistic regression, the use of multiple-agent therapy was associated with a better functional outcome at discharge (OR 0.15, 95% CI [0.04–0.55]; p < 0.01) and at 90-day follow-up (OR 0.20, 95% CI [0.05–0.77]; p < 0.05) when compared to single-agent therapy. In this study, we found that patients treated for cerebral vasospasm with IA infusion of multiple vasodilators had an increased vessel response and better functional outcomes compared to those treated with a single agent.

Objective Carotid blister aneurysms remain a formidable surgical challenge with varied surgical options. There have been significant advancements in the endovascular management of these aneurysms with the introduction of flow diverters. The comparative risk profiles for different endovascular options compared to surgical management of these lesions is not completely understood. Methods The study is a comprehensive systematic review and meta-analysis on the treatment of carotid blood blister aneurysms. Pubmed searches were used to identify relevant articles and patient level data was extracted. Two and three group analyses were conducted comparing surgical and endovascular strategies and surgical, stent coil and flow diversion techniques respectively. Patient outcomes were graded on the modified Rankin Scale with a score of 2 or less defined as favorable. Results In total, 83 studies (41 and 42 studies on surgical and endovascular interventions, respectively) with 1119 patients met our inclusion criteria. A statistically significant difference (at the 5% level of significance) in the effect among three different interventions was not found (Q = 3.41, p = 0.1815) under the random-effect model. Our results did show summary proportions of favorable outcomes were higher in the stent coil (0.87, 95% CI: 0.79 – 0.94) and flow diversion (0.87, 95% CI: 0.75 – 0.96) than that of surgery (0.76, 95% CI: 0.71 – 0.83). Conclusions Our results suggest a trend towards improved patient outcomes with endovascular techniques compared to surgical strategies but statistical significance was not achieved. We also found that endovascular techniques compare favorably. Increasing retreatments were found to negatively affect patient outcomes.

Brain arteriovenous malformations (bAVMs) have long been considered to be congenital, developing between the third and eighth weeks of embryogenesis. However, cases reporting their de novo formation suggest that these lesions can develop after birth and have challenged this concept. We present a case of a 6-year-old boy with a history of a brainstem cavernous malformation diagnosed after birth who later developed a de novo bAVM. The de novo occurrence of this bAVM distant to the site of the cavernous malformation and a prior negative catheter angiography contributes to the uncertainty of the dynamics and pathophysiology of bAVMs.

Background and Purpose— Mechanical thrombectomy (MT) devices have led to improved reperfusion and clinical outcomes in acute ischemic stroke patients with emergent large vessel occlusions; however, less than one-third of patients achieve complete reperfusion. Use of intraarterial thrombolysis in the context of MT may provide an opportunity to enhance these results. Here, we evaluate the use of intraarterial rtPA (recombinant tissue-type plasminogen activator) as rescue therapy (RT) after failed MT in the North American Solitaire Stent-Retriever Acute Stroke registry. Methods— The North American Solitaire Stent-Retriever Acute Stroke registry recruited sites within North America to submit data on acute ischemic stroke patients treated with the Solitaire device. After restricting the population of 354 patients to use of RT and anterior emergent large vessel occlusions, we compared patients who were treated with and without intraarterial rtPA after failed MT. Results— A total of 37 and 44 patients was in the intraarterial rtPA RT and the no intraarterial rtPA RT groups, respectively. Revascularization success (modified Thrombolysis in Cerebral Infarction ≥2b) was achieved in more intraarterial rtPA RT patients (61.2% versus 46.6%; P =0.13) with faster times to recanalization (100±85 versus 164±235 minutes; P =0.36) but was not statistically significant. The rate of symptomatic intracranial hemorrhage (13.9% versus 6.8%; P =0.29) and mortality (42.9% versus 44.7%; P =0.87) were similar between the groups. Good functional outcome (modified Rankin Scale score of ≤2) was numerically higher in intraarterial rtPA patients (22.9% versus 18.4%; P =0.64). Further restriction of the RT population to M1 occlusions only and time of onset to groin puncture ≤8 hours, resulted in significantly higher successful revascularization rates in the intraarterial rtPA RT cohort (77.8% versus 38.9%; P =0.02). Conclusions— Intraarterial rtPA as RT demonstrated a similar safety and clinical outcome profile, with higher reperfusion rates achieved in patients with M1 occlusions. Prospective studies are needed to delineate the role of intraarterial thrombolysis in MT.

Background and Purpose— Mechanical thrombectomy has been shown to improve clinical outcomes in patients with acute ischemic stroke. However, the impact of balloon guide catheter (BGC) use is not well established. Methods— STRATIS (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) was a prospective, multicenter study of patients with large vessel occlusion treated with the Solitaire stent retriever as first-line therapy. In this study, an independent core laboratory, blinded to the clinical outcomes, reviewed all procedures and angiographic data to classify procedural technique, target clot location, recanalization after each pass, and determine the number of stent retriever passes. The primary clinical end point was functional independence (modified Rankin Scale, 0–2) at 3 months as determined on-site, and the angiographic end point was first-pass effect (FPE) success rate from a single device attempt (modified Thrombolysis in Cerebral Infarction, ≥2c) as determined by a core laboratory. Achieving modified FPE (modified Thrombolysis in Cerebral Infarction, ≥2b) was also assessed. Comparisons of clinical outcomes were made between groups and adjusted for baseline and procedural characteristics. All participating centers received institutional review board approval from their respective institutions. Results— Adjunctive technique groups included BGC (n=445), distal access catheter (n=238), and conventional guide catheter (n=62). The BGC group had a higher rate of FPE following first pass (212/443 [48%]) versus conventional guide catheter (16/62 [26%]; P =0.001) and distal access catheter (83/235 [35%]; P =0.002). Similarly, the BGC group had a higher rate of modified FPE (294/443 [66%]) versus conventional guide catheter (26/62 [42%]; P P =0.003). The BGC group achieved the highest rate of functional independence (253/415 [61%]) versus conventional guide catheter (23/55 [42%]; P =0.007) and distal access catheter (113/218 [52%]; P =0.027). Final revascularization and mortality rates did not differ across the groups. Conclusions— BGC use was an independent predictor of FPE, modified FPE, and functional independence, suggesting that its routine use may improve the rates of early revascularization success and good clinical outcomes. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT02239640.

Background: Ischemic stroke has no approved treatments to enhance recovery. ALD-401 is an enriched population of aldehyde dehydrogenase-bright stem cells, capable of reducing neurological deficits in animal models. The primary objective of this trial was to determine the safety of internal carotid artery, intra-arterially delivered autologous bone marrow–derived ALD-401 in patients with disabling middle cerebral artery stroke in comparison with sham harvest with sham infusion. Secondary objectives were to determine feasibility and efficacy. Methods: This was a prospective phase 2, industry-funded, randomized, sham-controlled, parallel-group, multicenter study with blinded assessments. One hundred subjects were planned, aged 30 to 83 years, with confirmed first-time middle cerebral artery ischemic stroke with modified Rankin scale ≥3. Study patients were randomly assigned 3:2 to bone marrow harvest at 11 to 17 days after stroke followed 2 days later by intracarotid infusion of ALD-401 versus sham harvest and then sham infusion in the same timeframe. The primary study outcome was safety based on the incidence of a 4-point National Institutes of Health Stroke Scale worsening and the proportion of serious adverse events. Efficacy was based on modified Rankin scale change at 90 days. Other secondary outcomes were the proportions of patients experiencing adverse events, disability by Barthel Index, quality of life using EQ-5D, rehabilitation utilization, disability at 1 year, and MRI evidence of complications. Results: There were no infusional or allergic reactions and no difference in treatment emergent adverse events. Four patients had small areas of asymptomatic restricted diffusion on MRI in the treatment group. There was no significant difference between the ALD-401 and placebo groups on the modified Rankin scale for the intent-to-treat population at day 90 (mean difference, 0.3; 95% CI, –0.3 to 0.8; P =0.330). There were no significant differences between the groups on any of the secondary efficacy measures. Conclusions: Intracarotid infusion of ALD-401 does not lead to clinical adverse events in patients with subacute ischemic stroke, although there was a higher incidence of small lesions on MRI in the treatment group. There was no difference in the primary efficacy end point between the groups. The study provides a framework for the design and conduct of future intra-arterial cell therapy trials in stroke. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01273337.

Endovascular coiling (EC) is a vital procedure that treats intracranial aneurysms (IA) but a common complication is aneurysm recurrence as a result of coil compaction, when the implanted coil fails to isolate IA from cerebrovascular circulation. Such an event may lead to devastating hemorrhages. Hence, frequent follow-up imaging sessions using Digital Subtraction Angiography (DSA) are critical. However, DSA is invasive, expensive and not widely available. Recently, it has been shown that skull X-rays could be used as a proxy. In this work, we present a new pipeline that enables the semi-automatic evaluation of coil compaction based on X-ray images. Our pipeline involves coil segmentation with GrabCut and an autoencoder that learns image embeddings with a location-sensitive loss function. This approach generates efficient representations without training on image labels. We show that the image embeddings capture information relevant to coil compaction and that a simple distance measure between embeddings outperforms other baseline methods including a Siamese network.

INTRODUCTION: Prior retrospective and case-control studies have shown that the use of general anesthesia (GA) during endovascular therapy (EVT) for acute ischemic stroke with large vessel occlusion (AIS-LVO) was independently associated with poor clinical outcomes compared with cases performed under conscious sedation (CS). Conversely, recent small randomized clinical trials (RCT) demonstrated a trend toward better outcome in cases performed under GA. METHODS: We submitted an online survey to 193 Society of Vascular Interventional Neurology and 78 American Association of Neurological Surgeons and Congress of Neurological Surgeons – Cerebrovascular Section neuroendovascular practitioners. Questions were aimed at understanding the current state of anesthesia practice during EVT, and to determine if there is clinical equipoise for a large multicenter RCT comparing GA versus CS during EVT. RESULTS: Between March and May of 2017, we received 116 (43%) responses. Anesthesiologists were responsible for managing 96% of the GA cases as compared to only 51% of the CS cases (P < 0.0001). Notable 56% of providers reported performing less than a quarter of their cases under GA. Only 7% performed all cases under GA compared with 17% who used solely CS (P = 0.048). More than half of respondents thought a new RCT was necessary, of whom 61% were interested in participating. Among interested responders, 59% were located in centers with 3 or more neurointerventionalists. CONCLUSION: The significant variation among neuroendovascular providers, added with the lack of consensus among recent trials and meta-analyses, demonstrate clinical equipoise for further studies to explore the effects of anesthesia during EVT in AIS-LVO.

Introduction: Although stroke severity is increased in patients with diabetes (e.g., higher mortality, larger infarcts, and worse neurological deficits), the underlying mechanism(s) of the worse outcomes is not clear. Evidence shows that hypothalamic-pituitary-adrenal (HPA) axis is dysregulated and cortisol levels are increased in diabetes. Based on the role of HPA axis in immunity, we hypothesized that diabetes-enhanced stress response contributes to stroke injury via regulating inflammation. Methods: Diabetes was induced in C57BL/6 mice by feeding a diabetogenic diet and injecting streptozotocin. Mice were subjected to 30 min middle cerebral artery occlusion. Infarct volume and neurological scores were measured at 24h-post stroke. We measured expression of factors related to stress response, plasma corticosterone, c-Fos and corticotropin-releasing factor (CRH) in hypothalamus, and proopiomelanocortin (POMC) and corticotropin-releasing hormone receptor 1 (CRHR1) in pituitary. Inflammatory cytokine levels were also determined in the ischemic brain. Results: Diabetic mice showed hyperglycemia and delayed glucose clearance in blood. At 1d-post stroke, diabetic mice showed larger infarct and worse neurological score. Plasma corticosterone levels were significantly increased in diabetic mice. We also found increased c-Fos in hypothalamus, and CRHR1 and POMC in pituitary. These were accompanied by increased IL-1β, TNF-α, and IL-6 mRNA in the ischemic brain. Conclusion: Our results indicate that stress response is enhanced in diabetic conditions, and associated with increased inflammation in ischemic brain and worse stroke outcomes. It suggests that regulation of stress response may improve stroke outcomes in diabetic conditions.

Background Venous stenting (VS) for venous sinus stenosis in the setting of idiopathic intracranial hypertension has been increasing in acceptance by neurointerventionalists. Stent-adjacent stenosis (SAS) and in-stent stenosis leading to symptom recurrence and the need for retreatment are known delayed complications. However, the effect of the dual antiplatelet therapy (DAPT) duration on these complications has remained poorly characterized. Methods An extensive literature search was performed to identify reports of VS for patients with idiopathic intracranial hypertension from 2000 to 2020. The primary outcome was the occurrence of SAS. The secondary outcomes included the occurrence of composite stenosis (in-stent stenosis and SAS) and stent survival, defined as the need for retreatment or other surgical management. Generalized linear mixed models were used to explore the effects of DAPT duration (3 vs ≥6 months) on the primary and secondary outcomes. Results A total of 325 patients met the inclusion criteria and were included in our analysis. SAS occurred in 9% (95% confidence interval, 6%-15%) of the patients, and stent survival was 90% (95% confidence interval, 84%-93%) in the cohort. With every 1-mm Hg increase in the venous pressure gradient, an 8% decrease was found in the odds of stent survival (P = 0.043). The meta-regression revealed no association between the DAPT duration and the primary outcome or the odds of composite stenosis and stent survival. Conclusions We found no differences between 3 and ≥6 months of DAPT in terms of the risk of stent stenosis or stent survival. However, patients with a higher venous pressure gradient before VS had a greater risk of stent failure.

BackgroundPrior studies on rupture risk of brain arteriovenous malformations (AVMs) in women undergoing pregnancy and delivery have reported conflicting findings, but also have not accounted for AVM morphology and heterogeneity. Here, we assess the association between pregnancy and the risk of intracranial hemorrhage (ICH) in women with AVMs using a cohort-crossover design in which each woman serves as her own control.MethodsWomen who underwent pregnancy and delivery were identified using DRG codes from the Healthcare Cost and Utilization Project State Inpatient Databases for California (2005–2011), Florida (2005–2014), and New York (2005–2014). The presence of AVM and ICH was determined using ICD 9 codes. Pregnancy was defined as the 40 weeks prior to delivery, and postpartum as 12 weeks after. We defined a non-exposure control period as a 52-week period prior to pregnancy. The relative risks of ICH during pregnancy were compared against the non-exposure period using conditional Poisson regression.ResultsAmong 4 022 811 women identified with an eligible delivery hospitalization (median age, 28 years; 7.3% with gestational diabetes; 4.5% with preeclampsia/eclampsia), 568 (0.014%) had an AVM. The rates of ICH during pregnancy and puerperium were 6355.4 (95% CI 4279.4 to 8431.5) and 14.4 (95% CI 13.3 to 15.6) per 100 000 person-years for women with and without AVM, respectively. In cohort-crossover analysis, in women with AVMs the risk of ICH increased 3.27-fold (RR, 95% CI 1.67 to 6.43) during pregnancy and puerperium compared with a non-pregnant period.ConclusionsAmong women with AVM, pregnancy and puerperium were associated with a greater than 3-fold risk of ICH.

Background and Purpose: Noncontrast head CT and CT perfusion (CTP) are both used to screen for endovascular stroke therapy (EST), but the impact of imaging strategy on likelihood of EST is undetermined. Here, we examine the influence of CTP utilization on likelihood of EST in patients with large vessel occlusion (LVO). Methods: We identified patients with acute ischemic stroke at 4 comprehensive stroke centers. All 4 hospitals had 24/7 CTP and EST capability and were covered by a single physician group (Neurology, NeuroIntervention, NeuroICU). All centers performed noncontrast head CT and CT angiography in the initial evaluation. One center also performed CTP routinely with high CTP utilization (CTP-H), and the others performed CTP optionally with lower utilization (CTP-L). Primary outcome was likelihood of EST. Multivariable logistic regression was used to determine whether facility type (CTP-H versus CTP-L) was associated with EST adjusting for age, prestroke mRS, National Institutes of Health Stroke Scale, Alberta Stroke Program Early CT Score, LVO location, time window, and intravenous tPA (tissue-type plasminogen activator). Results: Among 3107 patients with acute ischemic stroke, 715 had LVO, of which 403 (56%) presented to CTP-H and 312 (44%) presented to CTP-L. CTP utilization among LVO patients was greater at CTP-H centers (72% versus 18%, CTP-H versus CTP-L, P Conclusions: We identified an increased likelihood for undergoing EST in centers with lower CTP utilization, which was not associated with worse clinical outcomes or increased hemorrhage. These findings suggest under-treatment bias with routine CTP.

Background Ischemic stroke is increasingly being realized to be an inflammatory disease. Post stroke peripheral leukocyte recruitment to the brain has been well studied in preclinical models of ischemic stroke. Limited studies have examined the intravascular inflammatory milieu in the brain during ischemia. Thrombi collected from ischemic stroke thrombectomy patients can be valuable resources for these studies. There are a handful of studies focusing on the role of inflammation in clot pathology. Small studies have demonstrated that higher thrombus leukocyte fraction and neutrophil to lymphocyte ratios are associated with technically challenging procedures and a trend to worse long term outcomes. Methods We prospectively collected 44 thrombi obtained during mechanical thrombectomy in patients with LVO ischemic strokes. Data on demographics, clinical, procedural and clot composition were collected. These thrombi were paraffin embedded, sliced and stained with Hematoxylin and Eosin. Images were taken using a light microscope,20 and 40x magnification. Image J was used to quantify the leukocytes using previously described methods. The median and maximum leukocyte count of the 5 analyzed images for each patient was used for analysis. Outcome was defined as location at discharge with discharge to home or rehab considered favorable. Fisher’s exact and Mann-Whitney U tests were used for comparison of categorical and continuous variables, respectively. Multivariate logistic regression was then performed. Pearson’s correlation coefficient was used to assess the relationship of leukocytes to NIHSS and time from symptom onset to groin puncture. Results Among 44 patients with large vessel occlusion, median age was 65.5 years [59–73 years], 15 (35%) were women, 84% had hypertension, 43% had atrial fibrillation, and 24% had hyperlipidemia. Median NIHSS was 18 [14–22] and median leukocyte count in the thrombi was 537 [397–794.5]. NIHSS on admission had a negative correlation with favorable discharge outcome as defined by discharge to home or rehab (OR=0.44, p=0.021). Total leukocyte count did not correlate with NIHSS at arrival (r=-0.0086; P=0.9560), number of passes, TICI score nor with time from last seen well to groin puncture (r=0.1937; P=0.2134). On multivariate analysis, there was a negative correlation between maximum thrombus leukocyte count and discharge outcome (OR=0.066, p=0.048) after accounting for age and NIHSS on admission. Conclusion Leukocyte count in thrombi retrieved post mechanical thrombectomy shows a significant negative correlation with discharge outcome in patients with ischemic stroke. Our study focused on total leukocyte count and corroborates with previous studies which focused on leukocyte fraction. Further studies using flow cytometry and concomitant peripheral blood analysis along with long term outcome measures are necessary to better define this relationship and understand role of inflammation in LVO stroke. Disclosures P. Chen: None. F. Sheriff: None. M. Inam: None. V. Lopez-Rivera: None. E. Lekka: None. A. Oni-Orisan: None. C. Finger: None. J. Hudobenko: None. D. Morales: None. S. Seth: None. B. Manwani: None.

Treatment of ependymoma (EPN) is guided by associated tumor features, such as grade and location. However, the relationship between these features with treatments and overall survival in EPN patients remains uncharacterized. Here, we describe the change over time in treatment strategies and identify tumor characteristics that influence treatment and survival in EPN.Using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) 18 Registries (1973-2016) database, we identified patients with EPN microscopically confirmed to be grade II (EPN-GII) or III (EPN-GIII) tumors between 2004-2016. Overall survival (OS) was analyzed using Kaplan-Meier survival estimates and multivariable Cox proportional hazard models. A sub-analysis was performed by tumor location (supratentorial, posterior fossa, and spine). Change over time in rates of gross total resection (GTR), radiotherapy (RT), and chemotherapy (CS) were analyzed using linear regression, and predictors of treatment were identified using multivariable logistic regression models.Between 2004-2016, 1,671 patients were diagnosed with EPN, of which 1,234 (74 %) were EPN-GII and 437 (26 %) EPN-GIII. Over the study period, EPN-GII patients underwent a less aggressive treatment (48 % vs 27 %, GTR; 60 % vs 30 %, RT; 22 % vs 2%, CS; 2004 vs 2016; p 0.01 for all). Age, tumor size, location, and grade were positive predictors of undergoing treatment. Univariate analysis revealed that tumor grade and location were significantly associated with OS (p 0.0001 for both). In multivariable Cox regression, tumor grade was an independent predictor of OS among patients in the cohort (grade III, HR 3.89 [2.84-5.33]; p 0.0001), with this finding remaining significant across all tumor locations.In EPN, tumor grade and location are predictors of treatment and overall survival. These findings support the importance of histologic WHO grade and location in the decision-making for treatment and their role in individualizing treatment for different patient populations.