Covalent Fragment Inhibits RhoA Activation by Guanine Exchange Factors.

Ras homolog gene family member (RhoA) is a GTPase and a member of the RAS superfamily of GTPases. RhoA is a master regulator of the actin cytoskeleton. It inhibits axon growth preventing repair and recovery following spinal cord and traumatic brain injuries. Despite decades of research into the biological function of Rho GTPases, there exist no small-molecule Rho inhibitors. Here, we screen a library of cysteine electrophiles to explore whether covalent bond formation at Cys-107 leads to inhibition of RhoA activation by guanine exchange factor Trio. Two fragments, propiolamide 1 (ACR-895) and acrylamide 2 (ACR-917), inhibited RhoA nucleotide exchange by Trio in a time-dependent manner. The fragments formed a covalent bond with wild-type RhoA but not Cys107Ser RhoA mutant. Time- and concentration-dependent studies led to equilibrium constants KIs and reaction rates that correspond to t1/2 values in the single-digit hour range. One fragment was selective for RhoA over Rac1 GTPase and had no effect on KRAS nucleotide exchange by SOS1. The fragments did not inhibit RhoA binding to ROCK effector protein. This work establishes Cys-107 as a suitable site for Rho GTPase inhibition and provides fragment starting points for the future development of Rho GTPase covalent inhibitors that could have profound implications in the treatment of patients with injuries of the central nervous system.

Correction: Click functionalized biocompatible gadolinium oxide core-shell nanocarriers for imaging of breast cancer cells.

[This corrects the article DOI: 10.1039/D2RA00347C.].

Click functionalized biocompatible gadolinium oxide core-shell nanocarriers for imaging of breast cancer cells.

Site-specific delivery using functionalized nanocarriers is in high demand in imaging applications of modern clinical research. To improve the imaging capabilities of conventionally used contrast agents and expand the targeting accuracy, functional gadolinium oxide based nanocarriers originated from homogeneous core shells structures (Gd2O3@SiO2@Fe3O4) were developed using a multilayer formation approach. The synthesis and chemical configuration for the covalent binding of macrocyclic chelating agents and estrogen targeting molecules on these nanocarriers were designed by a two-step chemical synthesis method. Initially, SiO2@Fe3O4 structures were prepared and encapsulated with a homogenous thin Gd2O3 overlayer. The exterior surface of the as-prepared carriers offered chemical binding with a breast cancer specific estrogen molecule, covalently grafted through a Click-Chemistry protocol. In the next step, to enhance the diagnostic imaging capabilities of these carriers, thiocyanate-linked chelator molecule, DOTA, was attached to the surface of estrogen bound Gd2O3@SiO2@Fe3O4 using basic reaction conditions. The active amino groups before and after conjugation of estrogen molecules on the surface were quantified using a fluorescamine based approach. Due to the covalent binding of the macrocyclic chelator to the Gd2O3@SiO2@Fe3O4 surface, core shell carriers showed potential radiolabeling efficiency using positron emitter radionuclide, gallium-68 (68Ga). Intracellular uptake of estrogen-conjugated carriers was evaluated with MCF7 breast cancer cell lines using confocal laser scanning microscopy and fluorescent flow cytometry. In addition, in vitro cytotoxicity studies of functional nanocarriers as compared to bare nanoparticles showed reduced toxicity to HEK-293 cells demonstrating the role of surface attached molecules in preventing direct exposure of the Gd2O3 surface to the cells. The as-developed gadolinium based nanocarriers presented excellent capabilities as biocompatible target-specific imaging probes which indicates great potential in the field of dual-mode contrast agents.

Comparison of Mobile Stroke Unit With Usual Care for Acute Ischemic Stroke Management: A Systematic Review and Meta-analysis.

IMPORTANCE: So far, uncertainty remains as to whether there is sufficient cumulative evidence that mobile stroke unit (MSU; specialized ambulance equipped with computed tomography scanner, point-of-care laboratory, and neurological expertise) use leads to better functional outcomes compared with usual care. OBJECTIVE: To determine with a systematic review and meta-analysis of the literature whether MSU use is associated with better functional outcomes in patients with acute ischemic stroke (AIS). DATA SOURCES: MEDLINE, Cochrane Library, and Embase from 1960 to 2021. STUDY SELECTION: Studies comparing MSU deployment and usual care for patients with suspected stroke were eligible for analysis, excluding case series and case-control studies. DATA EXTRACTION AND SYNTHESIS: Independent data extraction by 2 observers, following the PRISMA and MOOSE reporting guidelines. The risk of bias in each study was determined using the ROBINS-I and RoB2 tools. In the case of articles with partially overlapping study populations, unpublished disentangled results were obtained. Data were pooled in random-effects meta-analyses. MAIN OUTCOMES AND MEASURES: The primary outcome was excellent outcome as measured with the modified Rankin Scale (mRS; score of 0 to 1 at 90 days). RESULTS: Compared with usual care, MSU use was associated with excellent outcome (adjusted odds ratio [OR], 1.64; 95% CI, 1.27-2.13; P < .001; 5 studies; n = 3228), reduced disability over the full range of the mRS (adjusted common OR, 1.39; 95% CI, 1.14-1.70; P = .001; 3 studies; n = 1563), good outcome (mRS score of 0 to 2: crude OR, 1.25; 95% CI, 1.09-1.44; P = .001; 6 studies; n = 3266), shorter onset-to-intravenous thrombolysis (IVT) times (median reduction, 31 minutes [95% CI, 23-39]; P < .001; 13 studies; n = 3322), delivery of IVT (crude OR, 1.83; 95% CI, 1.58-2.12; P < .001; 7 studies; n = 4790), and IVT within 60 minutes of symptom onset (crude OR, 7.71; 95% CI, 4.17-14.25; P < .001; 8 studies; n = 3351). MSU use was not associated with an increased risk of all-cause mortality at 7 days or at 90 days or with higher proportions of symptomatic intracranial hemorrhage after IVT. CONCLUSIONS AND RELEVANCE: Compared with usual care, MSU use was associated with an approximately 65% increase in the odds of excellent outcome and a 30-minute reduction in onset-to-IVT times, without safety concerns. These results should help guideline writing committees and policy makers.

Mitogen and Stress-Activated Kinases 1 and 2 Mediate Endothelial Dysfunction.

Inflammation promotes endothelial dysfunction, but the underlying mechanisms remain poorly defined in vivo. Using translational vascular function testing in myocardial infarction patients, a situation where inflammation is prevalent, and knock-out (KO) mouse models we demonstrate a role for mitogen-activated-protein-kinases (MAPKs) in endothelial dysfunction. Myocardial infarction significantly lowers mitogen and stress kinase 1/2 (MSK1/2) expression in peripheral blood mononuclear cells and diminished endothelial function. To further understand the role of MSK1/2 in vascular function we developed in vivo animal models to assess vascular responses to vasoactive drugs using laser Doppler imaging. Genetic deficiency of MSK1/2 in mice increased plasma levels of pro-inflammatory cytokines and promoted endothelial dysfunction, through attenuated production of nitric oxide (NO), which were further exacerbated by cholesterol feeding. MSK1/2 are activated by toll-like receptors through MyD88. MyD88 KO mice showed preserved endothelial function and reduced plasma cytokine expression, despite significant hypercholesterolemia. MSK1/2 kinases interact with MAPK-activated proteins 2/3 (MAPKAP2/3), which limit cytokine synthesis. Cholesterol-fed MAPKAP2/3 KO mice showed reduced plasma cytokine expression and preservation of endothelial function. MSK1/2 plays a significant role in the development of endothelial dysfunction and may provide a novel target for intervention to reduce vascular inflammation. Activation of MSK1/2 could reduce pro-inflammatory responses and preserve endothelial vasodilator function before development of significant vascular disease.

Engineering of a critical membrane-anchored enzyme for high solubility and catalytic activity.

Membrane-associated proteins carry out a wide range of essential cellular functions but the structural characterization needed to understand these functions is dramatically underrepresented in the Protein Data Bank. Producing a soluble, stable and active form of a membrane-associated protein presents formidable challenges, as evidenced by the variety of approaches that have been attempted with a multitude of different membrane proteins to achieve this goal. Aspartate N-acetyltransferase (ANAT) is a membrane-anchored enzyme that performs a critical function, the synthesis of N-acetyl-l-aspartate (NAA), the second most abundant amino acid in the brain. This amino acid is a precursor for a neurotransmitter, and alterations in brain NAA levels have been implicated as a causative effect in Canavan disease and has been suggested to be involved in other neurological disorders. Numerous prior attempts have failed to produce a soluble form of ANAT that is amenable for functional and structural investigations. Through the application of a range of different approaches, including fusion partner constructs, linker modifications, membrane-anchor modifications, and domain truncations, a highly soluble, stable and fully active form of ANAT has now been obtained. Producing this modified enzyme form will accelerate studies aimed at structural characterization and structure-guided inhibitor development.

RRP7A links primary microcephaly to dysfunction of ribosome biogenesis, resorption of primary cilia, and neurogenesis.

Primary microcephaly (MCPH) is characterized by reduced brain size and intellectual disability. The exact pathophysiological mechanism underlying MCPH remains to be elucidated, but dysfunction of neuronal progenitors in the developing neocortex plays a major role. We identified a homozygous missense mutation (p.W155C) in Ribosomal RNA Processing 7 Homolog A, RRP7A, segregating with MCPH in a consanguineous family with 10 affected individuals. RRP7A is highly expressed in neural stem cells in developing human forebrain, and targeted mutation of Rrp7a leads to defects in neurogenesis and proliferation in a mouse stem cell model. RRP7A localizes to centrosomes, cilia and nucleoli, and patient-derived fibroblasts display defects in ribosomal RNA processing, primary cilia resorption, and cell cycle progression. Analysis of zebrafish embryos supported that the patient mutation in RRP7A causes reduced brain size, impaired neurogenesis and cell proliferation, and defective ribosomal RNA processing. These findings provide novel insight into human brain development and MCPH.

Discovery of Novel Inhibitors of a Critical Brain Enzyme Using a Homology Model and a Deep Convolutional Neural Network.

Rare neglected diseases may be neglected but are hardly rare, affecting hundreds of millions of people around the world. Here, we present a hit identification approach using AtomNet, the world's first deep convolutional neural network for structure-based drug discovery, to identify inhibitors targeting aspartate N-acetyltransferase (ANAT), a promising target for the treatment of patients suffering from Canavan disease. Despite the lack of a protein structure or high sequence identity homologous templates, the approach successfully identified five low-micromolar inhibitors with drug-like properties.

Mediating the Fate of Cancer Cell Uptake: Dual-Targeted Magnetic Nanovectors with Biotin and Folate Surface Ligands.

Recognition of folate and biotin surface receptors by dual-functionalized nanoparticles (NPs) is key for site-selective receptor-mediated transport of anticancer drugs to cancer cells. We present here dopamine-capped iron oxide nanoprobes (Fe3O4, 10 ± 2 nm) containing two surface-grafted biologically relevant ligands, namely, folic acid (FA) and biotin (BT). The covalent attachment of both FA and BT on Fe3O4 nanoparticles was achieved by following carbodiimide coupling and click-chemistry protocols. The dual-function Fe3O4 probes were delivered into E-G7 and human HeLa cancer cell lines and tested toward their cellular uptake by immunofluorescence and flow cytometry analysis. Owing to receptor-mediated endocytosis, enhanced accumulation of nanoprobes in cancer cells was successfully monitored by confocal laser microscopy. When compared to dual-function probes, single-functionalized nanoparticles possessing either FA or BT ligands showed significantly reduced uptake in the tested cell lines, underlining the superior interaction potential of dual-purpose probes. A time-dependent receptor-mediated endocytosis of FA-Fe3O4-BT nanovectors was demonstrated by flow cytometry analysis, whereas the unfunctionalized NPs did not show any specificity in terms of uptake. Besides their specific uptake, the surface-functionalized nanoparticles exhibited promising cytotoxicity profiles by demonstrating good viability of more than 95% with analogous cancer cell lines. Our results demonstrate that dual and/or multivariate conjugation of receptor-specific ligands on NPs is highly effective in molecular recognition of surface biomarkers that enhances their potential in anticancer treatment for pretargeting-radio strategies based on biotin/avidin interactions.

A randomized controlled trial of metformin on left ventricular hypertrophy in patients with coronary artery disease without diabetes: the MET-REMODEL trial.

AIM: We tested the hypothesis that metformin may regress left ventricular hypertrophy (LVH) in patients who have coronary artery disease (CAD), with insulin resistance (IR) and/or pre-diabetes. METHODS AND RESULTS: We randomly assigned 68 patients (mean age 65 ± 8 years) without diabetes who have CAD with IR and/or pre-diabetes to receive either metformin XL (2000 mg daily dose) or placebo for 12 months. Primary endpoint was change in left ventricular mass indexed to height1.7 (LVMI), assessed by magnetic resonance imaging. In the modified intention-to-treat analysis (n = 63), metformin treatment significantly reduced LVMI compared with placebo group (absolute mean difference -1.37 (95% confidence interval: -2.63 to -0.12, P = 0.033). Metformin also significantly reduced other secondary study endpoints such as: LVM (P = 0.032), body weight (P = 0.001), subcutaneous adipose tissue (P = 0.024), office systolic blood pressure (BP, P = 0.022) and concentration of thiobarbituric acid reactive substances, a biomarker for oxidative stress (P = 0.04). The glycated haemoglobin A1C concentration and fasting IR index did not differ between study groups at the end of the study. CONCLUSION: Metformin treatment significantly reduced LVMI, LVM, office systolic BP, body weight, and oxidative stress. Although LVH is a good surrogate marker of cardiovascular (CV) outcome, conclusive evidence for the cardio-protective role of metformin is required from large CV outcomes trials.

Cost-Consequence Analysis of Mobile Stroke Units vs. Standard Prehospital Care and Transport.

Background: Mobile stroke units (MSUs) are the latest approach to improving time-sensitive stroke care delivery. Currently, there are no published studies looking at the expanded value of the MSU to diagnose and transport patients to the closest most appropriate facility. The purpose of this paper is to perform a cost consequence analysis of standard transport (ST) vs. MSU. Methods and Results: A cost consequence analysis was undertaken within a decision framework to compare the incremental cost of care for patients with confirmed stroke that were served by the MSU vs. their simulated care had they been served by standard emergency medical services between July 2014 and October 2015. At baseline values, the incremental cost between MSU and ST was $70,613 ($856,482 vs. $785,869) for 355 patient transports. The MSU avoided 76 secondary interhospital transfers and 76 emergency department (ED) encounters. Sensitivity analysis identified six variables that had measurable impact on the model's variability and a threshold value at which MSU becomes the optimal strategy: number of stroke patients (>391), probability of requiring transfer to a comprehensive stroke center (CSC, >0.52), annual cost of MSU operations (<$696,053), cost of air transfer (>$8,841), probability initial receiving hospital is a CSC (<0.32), and probability of ischemic stroke with ST (<0.76). Conclusions: MSUs can avert significant costs in the administration of stroke care once optimal thresholds are achieved. A comprehensive cost-effectiveness analysis is required to determine not just the operational value of an MSU but also its clinical value to patients and the society.

Cerebrospinal fluid drainage and blood pressure elevation to treat acute spinal cord infarct.

BACKGROUND: Current management of acute spinal cord infarction (SCI) is limited. Lumbar cerebrospinal fluid drainage (CSFD) with blood pressure augmentation is utilized in the thoracic/thoracoabdominal aortic repair and thoracic endovascular aortic repair (TEVAR) populations to increase spinal perfusion pressure. CASE DESCRIPTION: We identified 3 patients who sustained acute SCI and underwent CSFD and maintenance of elevated mean arterial pressure (MAP) within 24 hours of injury. The first patient exhibited delayed-onset ischemia after a TEVAR. The second patient presented with an acute type B aortic intramural hematoma. The third patient developed spinal cord ischemia following bronchial artery embolization. There was significant improvement in the motor examination (e.g., ASIA impairment scale grade B or C) to grade D utilizing both blood pressure augmentation and CSFD. CONCLUSIONS: Lumbar CSFD with MAP elevation benefited 3 patients with acute SCI of varying etiologies.

Interhospital Transfer Before Thrombectomy Is Associated With Delayed Treatment and Worse Outcome in the STRATIS Registry (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke).

BACKGROUND: Endovascular treatment with mechanical thrombectomy (MT) is beneficial for patients with acute stroke suffering a large-vessel occlusion, although treatment efficacy is highly time-dependent. We hypothesized that interhospital transfer to endovascular-capable centers would result in treatment delays and worse clinical outcomes compared with direct presentation. METHODS: STRATIS (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) was a prospective, multicenter, observational, single-arm study of real-world MT for acute stroke because of anterior-circulation large-vessel occlusion performed at 55 sites over 2 years, including 1000 patients with severe stroke and treated within 8 hours. Patients underwent MT with or without intravenous tissue plasminogen activator and were admitted to endovascular-capable centers via either interhospital transfer or direct presentation. The primary clinical outcome was functional independence (modified Rankin Score 0-2) at 90 days. We assessed (1) real-world time metrics of stroke care delivery, (2) outcome differences between direct and transfer patients undergoing MT, and (3) the potential impact of local hospital bypass. RESULTS: A total of 984 patients were analyzed. Median onset-to-revascularization time was 202.0 minutes for direct versus 311.5 minutes for transfer patients (P<0.001). Clinical outcomes were better in the direct group, with 60.0% (299/498) achieving functional independence compared with 52.2% (213/408) in the transfer group (odds ratio, 1.38; 95% confidence interval, 1.06-1.79; P=0.02). Likewise, excellent outcome (modified Rankin Score 0-1) was achieved in 47.4% (236/498) of direct patients versus 38.0% (155/408) of transfer patients (odds ratio, 1.47; 95% confidence interval, 1.13-1.92; P=0.005). Mortality did not differ between the 2 groups (15.1% for direct, 13.7% for transfer; P=0.55). Intravenous tissue plasminogen activator did not impact outcomes. Hypothetical bypass modeling for all transferred patients suggested that intravenous tissue plasminogen activator would be delayed by 12 minutes, but MT would be performed 91 minutes sooner if patients were routed directly to endovascular-capable centers. If bypass is limited to a 20-mile radius from onset, then intravenous tissue plasminogen activator would be delayed by 7 minutes and MT performed 94 minutes earlier. CONCLUSIONS: In this large, real-world study, interhospital transfer was associated with significant treatment delays and lower chance of good outcome. Strategies to facilitate more rapid identification of large-vessel occlusion and direct routing to endovascular-capable centers for patients with severe stroke may improve outcomes. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02239640.

Flow Diverter Treatment of Tandem Intracranial Aneurysms.

OBJECTIVE: To assess technical success and clinical and imaging outcomes of flow diversion (FD) treatment of multiple, tandem intracranial aneurysms. METHODS: Retrospective analysis was performed of patients treated with FD for tandem intracranial aneurysms. RESULTS: Twenty female patients with a mean (±SD) age of 60 (±12) years were included. One patient was treated after subarachnoid hemorrhage. In 22 separate procedures, 47 aneurysms, all located in the intracranial internal carotid artery, were treated. In 3 cases, treatment was performed for aneurysm recurrence after previous endovascular treatment. All aneurysms were successfully treated in 1 session. A single stent was used in most (82%) cases, with no adjunctive coiling. There were no intraprocedural complications. Three patients experienced mild, transient neurologic symptoms after the procedure with no long-term neurologic deficits. Follow-up imaging with digital subtraction angiography and/or contrast-enhanced magnetic resonance angiography was available in 18/20 (90%) patients at an average (±SD) of 18.8 (±11.2) months. Of 40 aneurysms with follow-up imaging, 34 (85%) were completely occluded. Clinical follow-up, available in 20/20 (100%) patients, showed that 19/20 (95%) achieved a modified Rankin Scale score of 0-2. There were no cases of aneurysm rupture after treatment, and no patients required retreatment at last available follow-up. CONCLUSIONS: FD appears technically feasible, safe, and effective for treatment of tandem intracranial aneurysms, with potential advantages over traditional endovascular or surgical treatment modalities. Larger studies are needed to confirm these findings.

Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke: Primary Results of the STRATIS Registry.

BACKGROUND AND PURPOSE: Mechanical thrombectomy with stent retrievers has become standard of care for treatment of acute ischemic stroke patients because of large vessel occlusion. The STRATIS registry (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) aimed to assess whether similar process timelines, technical, and functional outcomes could be achieved in a large real world cohort as in the randomized trials. METHODS: STRATIS was designed to prospectively enroll patients treated in the United States with a Solitaire Revascularization Device and Mindframe Capture Low Profile Revascularization Device within 8 hours from symptom onset. The STRATIS cohort was compared with the interventional cohort of a previously published SEER patient-level meta-analysis. RESULTS: A total of 984 patients treated at 55 sites were analyzed. The mean National Institutes of Health Stroke Scale score was 17.3. Intravenous tissue-type plasminogen activator was administered in 64.0%. The median time from onset to arrival in the enrolling hospital, door to puncture, and puncture to reperfusion were 138, 72, and 36 minutes, respectively. The Core lab-adjudicated modified Thrombolysis in Cerebral Infarction ≥2b was achieved in 87.9% of patients. At 90 days, 56.5% achieved a modified Rankin Scale score of 0 to 2, all-cause mortality was 14.4%, and 1.4% suffered a symptomatic intracranial hemorrhage. The median time from emergency medical services scene arrival to puncture was 152 minutes, and each hour delay in this interval was associated with a 5.5% absolute decline in the likelihood of achieving modified Rankin Scale score 0 to 2. CONCLUSIONS: This largest-to-date Solitaire registry documents that the results of the randomized trials can be reproduced in the community. The decrease of clinical benefit over time warrants optimization of the system of care. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02239640.

Reduction in time to treatment in prehospital telemedicine evaluation and thrombolysis.

OBJECTIVE: To compare the times to evaluation and thrombolytic treatment of patients treated with a telemedicine-enabled mobile stroke treatment unit (MSTU) vs those among patients brought to the emergency department (ED) via a traditional ambulance. METHODS: We implemented a MSTU with telemedicine at our institution starting July 18, 2014. A vascular neurologist evaluated each patient via telemedicine and a neuroradiologist and vascular neurologist remotely assessed images obtained by the MSTU CT. Data were entered in a prospective registry. The evaluation and treatment of the first 100 MSTU patients (July 18, 2014-November 1, 2014) was compared to a control group of 53 patients brought to the ED via a traditional ambulance in 2014. Times were expressed as medians with their interquartile ranges. RESULTS: Patient and stroke severity characteristics were similar between 100 MSTU and 53 ED control patients (initial NIH Stroke Scale score 6 vs 7, p = 0.679). There was a significant reduction of median alarm-to-CT scan completion times (33 minutes MSTU vs 56 minutes controls, p < 0.0001), median alarm-to-thrombolysis times (55.5 minutes MSTU vs 94 minutes controls, p < 0.0001), median door-to-thrombolysis times (31.5 minutes MSTU vs 58 minutes controls, p = 0.0012), and symptom-onset-to-thrombolysis times (97 minutes MSTU vs 122.5 minutes controls, p = 0.0485). Sixteen patients evaluated on MSTU received thrombolysis, 25% of whom received it within 60 minutes of symptom onset. CONCLUSION: Compared with the traditional ambulance model, telemedicine-enabled ambulance-based thrombolysis resulted in significantly decreased time to imaging and treatment.

Timeline of blood pressure changes after intra-arterial therapy for acute ischemic stroke based on recanalization status.

BACKGROUND: There is sparse literature on the natural history of blood pressure (BP) after intra-arterial therapy (IAT) for acute ischemic stroke (AIS). METHODS: A retrospective analysis was performed of patients with AIS who underwent IAT without endotracheal intubation for internal carotid artery terminus (ICA-T) or M1 middle cerebral artery occlusion from January 2008 to February 2012. Systolic BP (SBP) values at the beginning (First) and end (End) of IAT and for 36 h after the procedure were collected. Successful recanalization was defined as Thrombolysis In Cerebral Infarction (TICI) 2b-3. RESULTS: Sixty-two patients (14 (22.5%) ICA-T, 46 (74.2%) M1, 2 (3.2%) ICA-T+M1) met the study criteria and 37 (59.7%) achieved successful recanalization. The First and End SBP values were similar in the successful (Group R) and unsuccessful (Group NR) recanalization groups. Taking the whole cohort, End SBP was significantly lower than First SBP, but this decline was significant only in Group R. Subsequently, absolute SBP values in Group R were not significantly different from Group NR. However, when comparing the hourly decline of SBP with First SBP, Group R demonstrated a greater fall than Group NR and the decline was significantly different from hours 8 to 12 post-procedure. The SBP in Group NR then decreased further, and its difference from baseline was similar to Group R from hour 14 onwards. Mean SBP and SBP variability over 36 h were similar between the two groups. CONCLUSIONS: SBP falls significantly in patients with AIS with large vessel occlusion who recanalize with IAT. While SBP in non-recanalized patients also drops from baseline, it occurs to a lesser degree and stays higher only for a short period of time before falling to similar levels as in recanalized patients.

Safety and outcomes of simultaneous vasospasm and endovascular aneurysm treatment (SVAT) in subarachnoid hemorrhage.

BACKGROUND: Simultaneous vasospasm and endovascular aneurysm treatment (SVAT) has been shown to be effective with good clinical outcomes in small series, but these studies have not examined predictive factors for clinical outcome after treatment. OBJECTIVE: To identify the safety and efficacy of SVAT in a large multicenter patient cohort and evaluate prognostic markers of clinical outcome following SVAT. METHODS: This study retrospectively enrolled 50 consecutive patients undergoing SVAT at 11 different centers. We analyzed Hunt and Hess and Fisher grades, aneurysm location, angiographic vasospasm grade, Glasgow Outcome Scale (GOS) at discharge, and 90-day modified Rankin Scale (mRS) scores. RESULTS: A total of 50 patients undergoing SVAT between the years 2003 and 2009 were identified. Patients presented, on average, 6.48±4.45 days after subarachnoid hemorrhage. Hunt and Hess and Fisher grades were 1 (n=7), 2 (n=12), 3 (n=14), 4 (n=15), 5 (n=2), and 3 and 4 (n=33), respectively. Aneurysm location was distributed as follows: anterior (n=32), posterior (n=16), anterior and posterior (n=2). Patients with good clinical condition (Hunt and Hess score 1-3) had significantly higher odds of surviving (OR=17.5, 95% CI 1.9 to 161.5), favorable GOS (OR=4.2, 95% CI 1.2 to 14.8), and favorable 90-day mRS (OR=4.2, 95% CI 1.2 to 14.8). CONCLUSIONS: SVAT is safe, with the majority of patients achieving good clinical outcome. Patients with lower Hunt and Hess grades have higher odds of surviving and favorable clinical prognosis.