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Objective: Mobile stroke units offer improved time to administration of thrombolytics for ischemic stroke patients. Acquisition of intravenous (IV) access, however, can be challenging in the prehospital environment leading to treatment delays. Intraosseous (IO) access is commonly used in the prehospital setting for a variety of conditions and may serve as a viable means for tPA (tissue plasminogen activator) administration. Methods/Results: We describe 3 cases in which tPA was administered via IO access on a mobile stroke unit as part of the Benefits of Stroke Treatment Delivered Using a Mobile Stroke Unit Compared to Standard Management by Emergency Medical Services (BEST-MSU) trial. Conclusion: No adverse events were observed in the process of obtaining IO access or administering tPA. [ABSTRACT FROM AUTHOR]

Background: Rapid dissemination and coordination of clinical and imaging data among multidisciplinary team members are essential for optimal acute stroke care. Aim: To characterize the feasibility and utility of the Synapse Emergency Room mobile (Synapse ERm) informatics system. Methods: We implemented the Synapse ERm system for integration of clinical data, computerized tomography, magnetic resonance, and catheter angiographic imaging, and real-time stroke team communications, in consecutive acute neurovascular patients at a Comprehensive Stroke Center. Results: From May 2014 to October 2014, the Synapse ERm application was used by 33 stroke team members in 84 Code Stroke alerts. Patient age was 69.6 (±17.1), with 41.5% female. Final diagnosis was: ischemic stroke 64.6%, transient ischemic attack 7.3%, intracerebral hemorrhage 6.1%, and cerebrovascular-mimic 22.0%. Each patient Synapse ERm record was viewed by a median of 10 (interquartile range 6-18) times by a median of 3 (interquartile range 2-4) team members. The most used feature was computerized tomography, magnetic resonance, and catheter angiography image display. In-app tweet team, communications were sent by median 1 (interquartile range 0-1, range 0-13) users per case and viewed by median 1 (interquartile range 0-3, range 0-44) team members. Use of the system was associated with rapid treatment times, faster than national guidelines, including median door-to-needle 51.0 min (interquartile range 40.5-69.5) and median door-to-groin 94.5 min (interquartile range 85.5-121.3). In user surveys, the mobile information platform was judged easy to employ in 91% (95% confidence interval 65%-99%) of uses and of added help in stroke management in 50% (95% confidence interval 22%-78%). Conclusion: The Synapse ERm mobile platform for stroke team distribution and integration of clinical and imaging data was feasible to implement, showed high ease of use, and moderate perceived added utility in therapeutic management. [ABSTRACT FROM AUTHOR]

Objective Methods Results Interpretation Given the high disease and cost burden of ischemic stroke, evaluating the clinical efficacy and cost‐effectiveness of new approaches to prevent and treat ischemic stroke is critical. Effective ischemic stroke management depends on timely administration of thrombolytics after stroke onset. This study evaluates the cost‐effectiveness associated with the use of mobile stroke units (MSUs) to expedite tissue plasminogen activator (tPA) administration, as compared with standard management through emergency medical services (EMS).This study is a prospective, multicenter, alternating‐week, cluster‐controlled trial of MSU versus EMS. One‐year and life‐time cost‐effectiveness analyses, using the incremental cost‐effectiveness ratio (ICER) method, were performed from the perspective of CMS's Medicare. Quality‐adjusted life years (QALYs) estimated using patient‐reported EQ‐5D‐5L data were used as the effectiveness measure. Health care utilizations were converted to costs using average national Medicare reimbursements. ICERs excluding patients with pre‐existing disability, and limited to stroke‐related costs were also calculated.The first‐year ICER for all tPA‐eligible patients using total cost differences between MSU and EMS groups was $238,873/QALY; for patients without pre‐existing disability was $61,199/QALY. The lifetime ICERs for all tPA‐eligible patients and for those without pre‐existing disability were $94,710 and $31,259/QALY, respectively. All ICERs were lower when restricted to stroke‐related costs and were highly dependent on the number of patients treated per year in an MSU.MSUs' cost‐effectiveness is borderline if we consider total first‐year costs and outcomes in all tPA‐eligible patients. MSUs are cost‐effective to highly cost‐effective when calculations are based on patients without pre‐existing disability, patients' lifetime horizon, stroke‐related costs, and more patients treated per year in an MSU. ANN NEUROL 2024 [ABSTRACT FROM AUTHOR]

Background and Purpose Methods Results Conclusions Investigating the cost‐effectiveness of future mobile stroke unit (MSU) services with respect to local idiosyncrasies is essential for enabling large‐scale implementation of MSU services. The aim of this study was to assess the cost‐effectiveness for varying urban German settings and modes of operation.Costs of different operating times together with different personnel configurations were simulated. Different possible catchment zones, ischemic stroke incidence, circadian distribution, rates of alternative diagnoses, as well as missed cases were incorporated to model case coverage and patient numbers. Based on internationally reported clinical outcomes of MSUs, a 5‐year Markov model was applied to analyze the cost‐effectiveness for the different program setups.Compared with standard stroke care, MSUs achieved an additional 0.06 quality‐adjusted life years (QALYs) over a 5‐year time horizon. Assuming a catchment zone of 750,000 inhabitants and 8 h/7 day operation resulted in an incremental cost‐effectiveness ratio (ICER) of €37,182 per QALY from a societal perspective and €45,104 per QALY from a healthcare perspective. Lower ICERs were possible when coverage was expanded to 16 h service on 7 days per week and larger populations. Sensitivity analyses revealed that missing ischemic strokes significantly deteriorated economic performance of MSU.Major determinants of cost‐effectiveness should be addressed when setting up novel MSU programs. Catchment zones of more than 500,000–700,000 inhabitants and operating times of at least 12–16 h per day, 7 days per week could enable the most cost‐effective MSU services in the German healthcare system. [ABSTRACT FROM AUTHOR]

Background: MRI and CT modalities are both current standard-of-care options for initial imaging in patients with acute ischemic stroke due to large vessel occlusion (AIS-LVO). MR provides greater lesion conspicuity and spatial resolution, but few series have demonstrated multimodal MR may be performed efficiently.Methods: In a prospective comprehensive stroke center registry, we analyzed all anterior circulation LVO thrombectomy patients between 2012-2017 who: (1) arrived directly by EMS from the field, and (2) had initial NIHSS ≥6. Center imaging policy was multimodal MRI (including DWI/GRE/MRA w/wo PWI) as the initial evaluation in all patients without contraindications, and multimodal CT (including CT with CTA, w/wo CTP) in the remainder.Results: Among 106 EMS-arriving endovascular thrombectomy patients, initial imaging was MRI 62.3%, CT in 37.7%. MRI and CT patients were similar in age (72.5 vs 71.3), severity (NIHSS 16.4 v 18.2), and medical history, though MRI patients had longer onset-to-door times. Overall, door-to-needle (DTN) and door-to-puncture (DTP) times did not differ among MR and CT patients, and were faster for both modalities in 2015-2017 versus 2012-2014. In the 2015-2017 period, for MR-imaged patients, the median DTN 42m (IQR 34-55) surpassed standard (60m) and advanced (45m) national targets and the median DTP 86m (IQR 71-106) surpassed the standard national target (90m).Conclusions: AIS-LVO patients can be evaluated by multimodal MR imaging with care speeds faster than national recommendations for door-to-needle and door-to-puncture times. With its more sensitive lesion identification and spatial resolution, MRI remains a highly viable primary imaging strategy in acute ischemic stroke patients, though further workflow efficiency improvements are desirable. [ABSTRACT FROM AUTHOR]

Complex middle cerebral artery (MCA) aneurysms incorporating parent or branching vessels are often not amenable to standard microsurgical clipping or endovascular embolization treatments. We aim to discuss the treatment of such aneurysms via a combination of surgical revascularization and aneurysm exclusion based on our institutional experience. Thirty-four patients with complex MCA aneurysms were treated with bypass and aneurysm occlusion, 5 with surgical clipping or wrapping only, and 1 with aneurysm excision and primary reanastomosis. Bypasses included superficial temporal artery (STA)-MCA, double-barrel STA-MCA, occipital artery-MCA, and external carotid artery-MCA. After bypass, aneurysms were treated by surgical clipping, Hunterian ligation, trapping, or coil embolization. The average age at diagnosis was 46 years. Of the aneurysms, 67% were large and most involved the MCA bifurcation. Most bypasses performed were STA-MCA bypasses, 12 of which were double-barrel. There were 2 wound-healing complications. All but 2 of the aneurysms treated showed complete occlusion at the last follow-up. There were 3 hemorrhagic complications, 3 graft thromboses, and 4 ischemic insults. The mean follow-up was 73 months. Of patients, 83% reported stable or improved symptoms from presentation and 73% reported a functional status (Glasgow Outcome Scale score 4 or 5) at the latest available follow-up. Cerebral revascularization by bypass followed by aneurysm or parent artery occlusion is an effective treatment option for complex MCA aneurysms that cannot be safely treated by standard microsurgical or endovascular techniques. Double-barrel bypass consisting of 2 STA branches to 2 MCA branches yields adequate flow replacement in most cases. [ABSTRACT FROM AUTHOR]

To discuss the treatment of intracranial fusiform and giant internal carotid artery (ICA) aneurysms via revascularization based on our institutional experience. An institutional review board–approved retrospective analysis was performed of patients with unruptured fusiform and giant intracranial ICA aneurysms treated from November 1991 to May 2020. All patients were evaluated for extracranial-intracranial (EC-IC) bypass and ICA occlusion. Thirty-eight patients were identified. Initially, patients failing preoperative balloon test occlusion were treated with superficial temporal artery (STA)-middle cerebral artery (MCA) bypass and concurrent proximal ICA ligation. We then treated them with STA-MCA bypass, followed by staged balloon test occlusion, and, if they passed, endovascular ICA coil occlusion. We treat all surgical medically uncomplicated patients with double-barrel STA-MCA bypass and concurrent proximal ICA ligation. The mean length of follow-up was 99 months. Symptom stability or improvement was noted in 85% of patients. Bypass graft patency was 92.1%, and all surviving patients had patent bypasses at their last angiogram. Aneurysm occlusion was complete in 90.9% of patients completing proximal ICA ligation. Three patients experienced ischemic complications and 4 patients experienced hemorrhagic complications. Not all fusiform intracranial ICA aneurysms require intervention, except when life-threatening rupture risk is high or symptomatic management is necessary to preserve function and quality of life. EC-IC bypass can augment the safety of proximal ICA occlusion. The rate of complete aneurysm occlusion with this treatment is 90.9%, and long-term bypass graft–related complications are rare. Perioperative stroke is a major risk, and continued evolution of treatment is required. [ABSTRACT FROM AUTHOR]

Introduction: Aneurysmal subarachnoid hemorrhage (aSAH) is a rare event associated with significant pregnancy-associated maternal and neonatal morbidity and mortality. The optimal treatment strategy and clinical outcome of aSAH in pregnancy remains unclear. We aimed to investigate the treatment utilizations and outcomes of aSAH in pregnant people. Methods: Using the 2010–2018 National Inpatient Sample, we identified all birth hospitalizations of women between ages of 18 to 45 associated with subarachnoid hemorrhage and aneurysm treatment were included. Multivariate analyses were used to evaluate the effect of pregnancy state, mode of treatment of aneurysms, severity of subarachnoid hemorrhage on mortality and discharge destination of this cohort. Trends in mode of treatment utilized for aneurysmal treatment in this time interval was evaluated. Results: 13,351 aSAH with treatment were identified, of which 440 were associated with pregnancy. There was no significant difference in mortality or rate of discharge to home in pregnancy related hospitalization. Worse aSAH severity, chronic hypertension, and smaller hospital size was associated with significantly higher rate of mortality from aSAH during pregnancy. Worse aSAH severity was associated with lower rate of discharge to home. Like the non-pregnant cohort, the treatment of ruptured aneurysms in pregnancy are increasingly through endovascular approaches. The mode of treatment does not change the mortality or discharge destination. Conclusions: Pregnancy does not alter mortality or the discharge destination for aSAH. Ruptured aneurysms during pregnancy are increasingly treated endovascularly. Mode of aneurysm treatment does not affect mortality or discharge destination in pregnancy. [ABSTRACT FROM AUTHOR]

The goal of the present study was to determine the safety and efficacy of intravenous tissue plasminogen activator (IVT) in patients with acute ischemic stroke (AIS) with large vessel occlusion (LVO) undergoing mechanical thrombectomy (MT). We performed a retrospective analysis of prospectively collected data gathered during a 3-year period for all our patients with AIS and LVO. We analyzed the stroke outcomes and complications between patients who had received a combination of IVT and MT and those who had undergone MT only. Standardized selection criteria, including the uniform use of perfusion imaging, were used for selection for MT, irrespective of IVT administration. Of the patients who had received IVT, 10% had had successful reperfusion found at initial angiography and did not require MT. A door-to-puncture time within 1 hour of presentation was achieved in 19% of both groups. IVT+MT was not associated with an increased incidence of intracranial hemorrhage (IVT+MT, 47.1%; MT, 49%). Of the 73 patients in IVT+MT group, 8 had developed access-site hematomas compared with 9 of the 95 patients in the MT group (28.6% vs. 26.5%; P = 0.85). The IVT+MT group had a lower proportion of patients with a modified Rankin scale score of 5–6 at 90 days compared with the MT group (36% vs. 56%; P = 0.024). Both groups showed statistically similar proportions of patients with a Thrombolysis in Cerebral Infarction scale score of ≥2c (IVT+MT, 50%; MT, 43%; P = 0.58). The IVT+MT group had a greater proportion of patients with Thrombolysis in Cerebral Infarction scale score of 2c (IVT+MT, 29.6%; MT, 16.8%; P = 0.068). Administration of IVT before MT to patients with AIS with LVO resulted in reperfusion before MT in 10% of patients, reduced the incidence of mortality and severe disability at 90 days, did not affect the door-to-puncture time, and was associated with a similar incidence of systemic and intracranial hemorrhage compared with MT only. [ABSTRACT FROM AUTHOR]

Current in vitro models for human brain arteriovenous malformation (AVM) analyzing the efficacy of embolic materials or flow conditions are limited by a lack of realistic anatomic features of complex AVM nidus. The purpose of this study was to evaluate a newly developed in vitro AVM model for embolic material testing, preclinical training, and flow analysis. Three-dimensional (3D) images of the AVM nidus were extracted from 3D rotational angiography from a patient. Inner vascular mold was printed using a 3D printer, coated with polydimethylsiloxanes, and then was removed by acetone, leaving a hollow AVM model. Injections of liquid embolic material and 4-dimensional (4D) flow magnetic resonance imaging (MRI) were performed using the AVM models. Additionally, computational fluid dynamics analysis was performed to examine the flow volume rate as compared with 4D flow MRI. The manufacture of 3D in vitro AVM models delivers a realistic representation of human nidus vasculature and complexity derived from patients. The injection of liquid embolic agents performed in the in vitro model successfully replicated real-life treatment conditions. The model simulated the plug and push technique before penetration of the liquid embolic material into the AVM nidus. The 4D flow MRI results were comparable to computational fluid dynamics analysis. An in vitro human brain AVM model with realistic geometric complexities of nidus was successfully created using 3D printing technology. This AVM model offers a useful tool for training of embolization techniques and analysis of hemodynamics analysis, and development of new devices and materials. [ABSTRACT FROM AUTHOR]

Mechanical thrombectomy (MT) is the standard of care for the treatment of acute ischemic stroke (AIS) caused by anterior circulation large-vessel occlusion. However, the true safety and efficacy of MT in medium-size vessel occlusions such as the M2 segment of the middle cerebral artery have yet to be completely defined. In this study, we analyze the safety and efficacy of MT in M2 occlusions compared with M1 occlusions. A retrospective analysis was performed of patients with AIS secondary to M1 and M2 occlusions between 2011 and 2018. The inclusion criteria were 1) AIS secondary to M1 or M2 occlusion, 2) MT performed by stentrieval technique alone, aspiration technique, or combined stentrieval–aspiration techniques. Basic patient characteristics, number of passages, first passage recanalization success (≥TICI [Thrombolysis in Cerebral Ischemia] grade 2b), total recanalization success, hemorrhagic complications (including intracerebral hemorrhage [ICH] and subarachnoid hemorrhage), and clinical outcomes were compared between both groups. Two hundred and sixty patients met the inclusion criteria; 171 patients had M1 occlusion versus 89 with M2 occlusion. First passage recanalization success rate was significantly higher in the M2 group (55.1% vs. 39.2%; P = 0.015). Total recanalization success rate was higher in the M2 group but did not reach significance (83% vs. 75%; P = 0.128). Subarachnoid hemorrhage rate was significantly higher in the M2 group (25% vs. 12%; P = 0.010) but there was no difference for ICH complications (14.6% vs. 16.4%; P = 0.711). MT for M2 occlusions has similar overall efficacy to that for M1 occlusions, but with higher first-pass successful recanalization rates. MT for M2 occlusions has a higher risk of associated subarachnoid hemorrhage. [ABSTRACT FROM AUTHOR]

Background and Purpose: Investigating the cost-effectiveness of future mobile stroke unit (MSU) services with respect to local idiosyncrasies is essential for enabling large-scale implementation of MSU services. The aim of this study was to assess the cost-effectiveness for varying urban German settings and modes of operation., Methods: Costs of different operating times together with different personnel configurations were simulated. Different possible catchment zones, ischemic stroke incidence, circadian distribution, rates of alternative diagnoses, as well as missed cases were incorporated to model case coverage and patient numbers. Based on internationally reported clinical outcomes of MSUs, a 5-year Markov model was applied to analyze the cost-effectiveness for the different program setups., Results: Compared with standard stroke care, MSUs achieved an additional 0.06 quality-adjusted life years (QALYs) over a 5-year time horizon. Assuming a catchment zone of 750,000 inhabitants and 8 h/7 day operation resulted in an incremental cost-effectiveness ratio (ICER) of €37,182 per QALY from a societal perspective and €45,104 per QALY from a healthcare perspective. Lower ICERs were possible when coverage was expanded to 16 h service on 7 days per week and larger populations. Sensitivity analyses revealed that missing ischemic strokes significantly deteriorated economic performance of MSU., Conclusions: Major determinants of cost-effectiveness should be addressed when setting up novel MSU programs. Catchment zones of more than 500,000-700,000 inhabitants and operating times of at least 12-16 h per day, 7 days per week could enable the most cost-effective MSU services in the German healthcare system., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

We introduce a multicore DNA nanomachine (MDNM), utilizing four binary DNAzymes for nucleic acid detection without the need for a preamplification step. This innovation remarkably yields a reduction in limit of detection (LOD), over 5-fold, as compared to single-core systems. This reduces the required test time thus highlighting the potential of MDNM in advancing nucleic acid detection., (© 2024 Wiley-VCH GmbH.)

Introduction: Intracranial artery calcification (ICAC) is a common finding on computed tomography (CT) in patients presenting with large vessel occlusion acute ischemic stroke (LVO-AIS) and could serve as a useful biomarker of intracranial atherosclerosis and altered intracranial vessel pliability in patients undergoing endovascular thrombectomy (EVT)., Methods: This was a retrospective cohort study analyzing consecutive patients undergoing CT head prior to EVT between 2016 and 2020. Extent of ICAC proximal to the target vessel was scored using a validated grading scale examining thickness and circumferential extent of calcifications. The relationship between 3 levels of ICAC burden and procedural, clinical, and safety outcomes was analyzed., Results: Among 86 patients meeting inclusion criteria, ICAC of any degree was present in 72.1 %. Median ICAC score was 3 [IQR 0-4]. There was a U-shaped association between ICAC score and successful reperfusion: 90.9 %, 65.7 %, and 94.4 % in the low, intermediate, and high ICAC score groups, respectively (p = 0.008). Use of rescue intervention, most often angioplasty and stenting, was greatest in the high ICAC score group: 3.0 % vs. 5.7 % vs. 22.2 % (p = 0.05). Functional independence at 90 days did not differ significantly among groups (41.7 % vs. 31.0 % vs. 15.4 %, p = 0.26), nor did rates of symptomatic intracranial hemorrhage (15.2 % vs. 14.3 % vs. 16.7 %, p = 0.97)., Conclusions: ICAC is seen on CT in nearly three-quarters of patients with LVO-AIS. Extent of ICAC has a U-shaped association with successful reperfusion, in part due to more frequent use of rescue interventions in patients with extensive ICAC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: David S. Liebeskind reports a relationship with Cerenovus that includes: consulting or advisory. David S. Liebeskind reports a relationship with Genentech that includes: consulting or advisory. David S. Liebeskind reports a relationship with Medtronic that includes: consulting or advisory. David S. Liebeskind reports a relationship with Stryker that includes: consulting or advisory. David S. Liebeskind reports a relationship with Rapid Medical that includes: consulting or advisory. Geoffrey P. Colby reports a relationship with Stryker Neurovascular that includes: consulting or advisory. Geoffrey P. Colby reports a relationship with Medtronic that includes: consulting or advisory. Geoffrey P. Colby reports a relationship with MicroVention Inc that includes: consulting or advisory. Geoffrey P. Colby reports a relationship with Cerenovus that includes: consulting or advisory. Geoffrey P. Colby reports a relationship with Rapid Medical that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Purpose: To simulate patient-level costs, analyze the economic potential of telemedicine-based mobile stroke units for acute prehospital stroke care, and identify major determinants of cost-effectiveness, based on two recent prospective trials from the United States and Germany., Methods: A Markov decision model was developed to simulate lifetime costs and outcomes of mobile stroke unit. The model compares diagnostic and therapeutic pathways of ischemic stroke, hemorrhagic stroke, and stroke mimic patients by conventional care or by mobile stroke units. The treatment outcomes were derived from the B_PROUD and the BEST-mobile stroke unit trials and further input parameters were derived from recent literature. Uncertainty was addressed by deterministic and probabilistic sensitivity analyses. A lifetime horizon based on the US healthcare system was adopted to evaluate different cost thresholds for mobile stroke unit and the resulting cost-effectiveness. Willingness-to-pay thresholds were set at 1x and 3x gross domestic product per capita, as recommended by the World Health Organization., Results: In the base case scenario, mobile stroke unit care yielded an incremental gain of 0.591 quality-adjusted life years per dispatch. Mobile stroke unit was highly cost-effective up to a maximum average cost of 43,067 US dollars per patient. Sensitivity analyses revealed that MSU cost-effectiveness is mainly affected by reduction of long-term disability costs. Also, among other parameters, the rate of stroke mimics patients diagnosed by MSU plays an important role., Conclusion: This study demonstrated that mobile stroke unit can possibly be operated on an excellent level of cost-effectiveness in urban areas in North America with number of stroke mimic patients and long-term stroke survivor costs as major determinants of lifetime cost-effectiveness., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JSR, MFF, SOS, and FT: The Department of Radiology and Nuclear Medicine has research agreements with Siemens Healthineers. KS, CH, MN, and KCF: The authors declare that there is no conflict of interest.JLS: Contracted hourly payments from Medtronic, Cerenovus, Phillips, Neurovasc, Boehringer Ingelheim (prevention only), and Rapid Medical for service on Trial Steering Committee/DSMBs advising on rigorous study design and conduct.

Background: The prevalence of anticoagulation treatment is increasing as an aging global population faces a high burden of cardiovascular comorbidities. Direct oral anticoagulants, including factor Xa inhibitors (FXai), are replacing vitamin K antagonists as the most commonly prescribed treatment for reducing risk of thrombotic events. While the risk of FXai-associated spontaneous bleeds is established, less is understood about their management and the effect of treatment on clinical and patient-reported outcomes. The primary objectives of the REVERXaL study are to describe patient characteristics, health care interventions during the acute-care phase, in-hospital outcomes, and associations between timing of reversal/replacement agent administration and in-hospital outcomes. Secondary/exploratory objectives focus on clinical assessments and patient-reported outcome measures (PROMs) at 30 and 90 days., Methods: REVERXaL is a multinational, observational study of hospitalized patients with FXai-associated major bleeds in Germany, Japan, the United Kingdom, and the United States. The study includes 2 cohorts of approximately 2000 patients each. Cohort A is a historic cohort for whom medical chart data will be collected from hospitalization to discharge for patients admitted for major bleeds during FXai use within 2 years prior to enrollment of Cohort B. Cohort B will prospectively enroll patients administered any reversal/replacement agent during hospitalization to manage FXai-associated major bleeds and will include the collection of clinical outcomes and PROMs data over 3 months., Conclusions: REVERXaL will generate insights on patient characteristics, treatment approaches, and associated outcomes in patients hospitalized with FXai-associated major bleeds. These data may inform clinical practice and streamline treatment pathways in this population., Registration: URL: https://www., Clinicaltrials: gov; unique identifier: NCT06147830., Competing Interests: Declaration of competing interest MN and SY have no conflicts of interest to disclose. RA has received fees for consulting work from AstraZeneca, Alexion, Bristol Myers Squibb, Pfizer, Bayer, and Daiichi. RO-A, SA-C, HC, and BK are employees of AstraZeneca. MY has received lecture, advisory, and travel fees from AstraZeneca, Bristol Myers Squibb, Nippon Boehringer Ingelheim, Bayer, Daiichi Sankyo, and CSL Behring; and scholarship funds or nonrestricted grants from Nippon Boehringer Ingelheim. VS has served as a consultant for Apollo Endosurgery, Pentax, Medtronic, Pharmacosmos, Microtech, and AstraZeneca; has served on advisory boards for Pharmacosmos and Microtech; and has received educational grants from Apollo Endosurgery, Pentax, and Medtronic. AT has received consulting fees from Bayer, Biomarin, Biotest, Chugai, Roche, Takeda, CSL Behring, Novo Nordisk, Octapharma, Pfizer, and Sobi; has received payment or honoraria for lectures, presentations, speakers bureaus, or educational events from Bayer, Biomarin, Biotest, Chugai, Roche, Takeda, CSL Behring, Novo Nordisk, Octapharma, Pfizer, and Sobi; and has received support for attending meetings and/or travel from Bayer, Biomarin, Biotest, Chugai, Roche, Takeda, CSL Behring, Novo Nordisk, Octapharma, Pfizer, and Sobi. BDC has served as a consultant for AstraZeneca. MM has received lecture honoraria, payment for participation in expert and advisory panels, and financial support for scientific meeting participation from AstraZeneca, Baxter, Bayer, Biotest, CSL Behring, IL-Werfen/TEM-International, LFB Biomedicaments France, Octapharma, and Portola. AJS has served on an advisory board for Alexion and AstraZeneca; has served on the speakers bureau of Alexion and AstraZeneca; and his institution has received research funding from Alexion., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Intravenous thrombolysis (IVT) may be administered to stroke patients requiring immediate treatment more quickly than emergency medical services if certain conditions are met. These conditions include the presence of mobile stroke units (MSUs) with on-site treatment teams and a computed tomography scanner. We compared clinical outcomes of MSU conventional therapy by emergency medical services through a systematic review and meta-analysis. We searched key electronic databases from inception till September 2021. The primary outcomes were mortality at 7 and 90 days. The secondary outcomes included the modified Rankin Scale score at 90 days, alarm to IVT or intra-arterial recanalization, and time from symptom onset or last known well to thrombolysis. We included 19 controlled trials and cohort studies to conduct our final analysis. Our comparison revealed that 90-day mortality significantly decreased in the MSU group compared with the conventional care group [risk ratio = 0.82; 95% confidence interval (CI), 0.71-0.95], while there was no significant difference at 7 days (risk ratio = 0.89; 95% CI, 0.69-1.15). MSU achieved greater functional independence (modified Rankin Scale = 0-2) at 90 days (risk ratio = 1.08; 95% CI, 1.01-1.16). MSU was associated with shorter alarm to IVT or intra-arterial recanalization time (mean difference = -29.69; 95% CI, -34.46 to -24.92), treating patients in an earlier time window, as shown through symptom onset or last known well to thrombolysis (mean difference = -36.79; 95% CI, -47.48 to -26.10). MSU-treated patients had a lower rate of 90-day mortality and better 90-day functional outcomes by earlier initiation of IVT compared with conventional care., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Threshold antisense oligonucleotide constructs were designed to cleave mRNA within different biomarker concentrations. The mRNA cleavage is activated by 2.6, 7.5 or 39.5 nM of biomarker depending on the construct design. The constructs can be used to differentiate cancer from normal cells by the level of oncogene expression followed by silencing of a targeted gene.

Background: Spinal epidural arteriovenous fistulas (SEDAVFs) are rarely diagnosed vascular malformations that can cause spinal cord compression and congestive myelopathy., Methods: This is a single-center, retrospective case series of patients with SEDAVFs who underwent observation or treatment at UCLA medical center between 1993 and 2023., Results: Between 1993 and 2023 a total of 26 patients at UCLA were found to have a SEDAVF. The median age at treatment was 59 years (range 4 months to 91 years). Compared with sacral, lumbar, and thoracic SEDAVFs, patients with cervical SEDAVF were younger (41 years vs 63 years, P=0.016) and more likely to be female (66.7% vs 14.3%, P=0.006). Possible triggers for development of SEDAVFs may be prior spinal surgery or trauma (n=4), turning the neck (n=1), lifting a heavy box (n=1), a prolonged period of bending over (n=1), and neurofibromatosis type 1 (n=1). Of the 22 patients treated endovascularly, 18 (82%) were angiographically cured on the first attempt without complications. One patient underwent surgical treatment alone and had a failed surgery on the first attempt, and developed a surgical site infection after the second successful attempt at treatment. Of the 16 patients with adequate clinical follow-up, 11 (69%) demonstrated early improved clinical outcome (eg, improved strength on examination, absent bruit)., Conclusions: SEDAVFs are a rarely diagnosed disease that can be treated effectively and safely with endovascular embolization in most cases. Patients with sacral, lumbar, and thoracic SEDAVFs were older and more often male compared to patients with cervical SEDAVFs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Advancements in DNA computation have unlocked molecular-scale information processing possibilities, utilizing the intrinsic properties of DNA for complex logical operations with transformative applications in biomedicine. DNA computation shows promise in molecular diagnostics, enabling precise and sensitive detection of genetic mutations and disease biomarkers. Moreover, it holds potential for targeted gene regulation, facilitating personalized therapeutic interventions with enhanced efficacy and reduced side effects. Herein, we have developed six DNAzyme-based logic gates able to process YES, AND, and NOT Boolean logic. The novelty of this work lies in their additional functionalization with a common DNA scaffold for increased cooperativity in input recognition. Moreover, we explored hierarchical input binding to multi-input logic gates, which helped gate optimization. Additionally, we developed a new design of an allosteric hairpin switch used to implement NOT logic. All DNA logic gates achieved the desired true-to-false output signal when detecting a panel of miRNAs, known for their important role in malignancy regulation. This is the first example of DNAzyme-based logic gates having all input-recognizing elements integrated in a single DNA nanostructure, which provides new opportunities for building DNA automatons for diagnosis and therapy of human diseases.

Cleavage of biological mRNA by DNAzymes (Dz) has been proposed as a variation of oligonucleotide gene therapy (OGT). The design of Dz-based OGT agents includes computational prediction of two RNA-binding arms with low affinity (melting temperatures (T m ) close to the reaction temperature of 37 °C) to avoid product inhibition and maintain high specificity. However, RNA cleavage might be limited by the RNA binding step especially if the RNA is folded in secondary structures. This calls for the need for two high-affinity RNA-binding arms. In this study, we optimized 10-23 Dz-based OGT agents for cleavage of three RNA targets with different folding energies under multiple turnover conditions in 2 mM Mg 2+ at 37 °C. Unexpectedly, one optimized Dz had each RNA-binding arm with a T m ≥60 °C, without suffering from product inhibition or low selectivity. This phenomenon was explained by the folding of the RNA cleavage products into stable secondary structures. This result suggests that Dz with long (high affinity) RNA-binding arms should not be excluded from the candidate pool for OGT agents. Rather, analysis of the cleavage products' folding should be included in Dz selection algorithms. The Dz optimization workflow should include testing with folded rather than linear RNA substrates., (© 2023 Wiley-VCH GmbH.)

We have developed a hook-equipped DNA nanomachine (HDNM) for the rapid detection of specific nucleic acid sequences without a preamplification step. HDNM efficiently unwinds RNA structures and improves the detection sensitivity. Compared to the hookless system, HDNM offers an 80-fold and 13-fold enhancement in DNA and RNA detection, respectively, reducing incubation time from 3 to 1 h.

Background and Purpose: Perfusion-based collateral indices such as the perfusion collateral index and the hypoperfusion intensity ratio have shown promise in the assessment of collaterals in patients with acute ischemic stroke. We aimed to compare the diagnostic performance of the perfusion collateral index and the hypoperfusion intensity ratio in collateral assessment compared with angiographic collaterals and outcome measures, including final infarct volume, infarct growth, and functional independence., Materials and Methods: Consecutive patients with acute ischemic stroke with anterior circulation proximal arterial occlusion who underwent endovascular thrombectomy and had pre- and posttreatment MRI were included. Using pretreatment MR perfusion, we calculated the perfusion collateral index and the hypoperfusion intensity ratio for each patient. The angiographic collaterals obtained from DSA were dichotomized to sufficient (American Society of Interventional and Therapeutic Neuroradiology [ASITN] scale 3-4) versus insufficient (ASITN scale 0-2). The association of collateral status determined by the perfusion collateral index and the hypoperfusion intensity ratio was assessed against angiographic collaterals and outcome measures., Results: A total of 98 patients met the inclusion criteria. Perfusion collateral index values were significantly higher in patients with sufficient angiographic collaterals ( P < .001), while there was no significant ( P = .46) difference in hypoperfusion intensity ratio values. Among patients with good (mRS 0-2) versus poor (mRS 3-6) functional outcome, the perfusion collateral index of ≥ 62 was present in 72% versus 31% ( P = .003), while the hypoperfusion intensity ratio of ≤0.4 was present in 69% versus 56% ( P = .52). The perfusion collateral index and the hypoperfusion intensity ratio were both significantly predictive of final infarct volume, but only the perfusion collateral index was significantly ( P = .03) associated with infarct growth., Conclusions: Results show that the perfusion collateral index outperforms the hypoperfusion intensity ratio in the assessment of collateral status, infarct growth, and determination of functional outcomes., (© 2023 by American Journal of Neuroradiology.)

Objective/aim: To investigate the effect of cerebral microbleeds (CMBs) on the functional and safety outcomes of endovascular thrombectomy (EVT) in patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO)., Methods: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines for systematic review and meta-analysis. We included observational studies that recruited AIS-LVO patients, used susceptibility-sensitive magnetic resonance imaging (MRI) to detect CMBs, and examined the association between them and predefined outcome events. The extracted data included study and population characteristics, risk of bias domains, and outcome measures. The outcomes of interest included functional independence, revascularization success, procedural and hemorrhagic adverse events. We conducted a meta-analysis using the Mantel-Haenszel method and calculated the risk ratios., Results: Four studies with a total of 1,514 patients were included. A significant reduction in the likelihood of achieving a favorable functional outcome was observed in patients with CMBs (Risk ratio (RR) 0.69, 95% confidence interval (CI): 0.52 to 0.91, P=0.01). No significant differences were observed between the CMBs and no CMBs groups in terms of successful revascularization, mortality, intracranial hemorrhage (ICH), subarachnoid hemorrhage (SAH), and parenchymal hematoma., Conclusions: The presence of CMBs significantly reduced the likelihood of achieving functional independence post-EVT in AIS-LVO patients. However, CMBs did not impact the rates of successful revascularization, mortality, or the occurrence of various hemorrhagic events. Future research should explore the mechanisms of this association and strategies to mitigate its impact., Competing Interests: Declaration of Competing Interest The Authors declare that they did not receive any financial and personal relationships with other people or organizations that could inappropriately influence (bias) this work., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Endovascular thrombectomy (EVT) is the standard treatment of acute ischemic stroke (AIS) due to large vessel occlusion (LVO). Although > 70% of patients in the trials assessing EVT for AIS-LVO had successful recanalization, only a third ultimately achieved favorable outcomes. A "no-reflow" phenomenon due to distal microcirculation disruption might contribute to such suboptimal outcomes. Combining intra-arterial (IA) tissue plasminogen activator (tPA) and EVT to reduce the distal microthrombi burden was investigated in a few studies. We present a pooled-data meta-analysis of the existing evidence of this combinatorial treatment., Methods: We followed the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) recommendations. We aimed to include all original studies investigating EVT plus IA tPA in AIS-LVO patients. Using R software, we calculated pooled odds ratios (ORs) with corresponding 95% confidence intervals (CI). A fixed-effects model was adopted to evaluate pooled data., Results: Five studies satisfied the inclusion criteria. Successful recanalization was comparable between the IA tPA and control groups at 82.9% and 82.32% respectively. The 90-day functional independence was similar between both groups (OR= 1.25; 95% CI= 0.92-1.70; P= 0.154). Symptomatic intracranial hemorrhage (sICH) was also comparable between both groups (OR= 0.66; 95% CI= 0.34-1.26; P= 0.304)., Conclusion: Our current meta-analysis does not show significant differences between EVT alone and EVT plus IA tPA in terms of functional independence or sICH. However, with the limited number of studies and included patients, more randomized controlled trials (RCTs) are needed to further investigate the benefits and safety of combined EVT and IA tPA., Competing Interests: Declaration of Competing Interest The Authors declare that they did not receive any financial and personal relationships with other people or organizations that could inappropriately influence (bias) this work., (Copyright © 2023. Published by Elsevier Inc.)

Nucleic acid-based detection of RNA viruses requires an annealing procedure to obtain RNA/probe or RNA/primer complexes for unwinding stable structures of folded viral RNA. In this study, we designed a protein-enzyme-free nano-construction, named four-armed DNA machine (4DNM), that requires neither an amplification stage nor a high-temperature annealing step for SARS-CoV-2 detection. It uses a binary deoxyribozyme (BiDz) sensor incorporated in a DNA nanostructure equipped with a total of four RNA-binding arms. Additional arms were found to improve the limit of detection at least 10-fold. The sensor distinguished SARS-CoV-2 from other respiratory viruses and correctly identified five positive and six negative clinical samples verified by quantitative polymerase chain reaction (RT-qPCR). The strategy reported here can be used for the detection of long natural RNA and can become a basis for a point-of-care or home diagnostic test., (© 2022 Wiley-VCH GmbH.)

Collateral status has prognostic and treatment implications in acute ischemic stroke (AIS) patients. Unlike CTA, grading collaterals on MRA is not well studied. We aimed to evaluate the accuracy of assessing collaterals on pretreatment MRA in AIS patients against DSA. AIS patients with anterior circulation proximal arterial occlusion with baseline MRA and subsequent endovascular treatment were included. MRA collaterals were evaluated by two neuroradiologists independently using the Tan and Maas scoring systems. DSA collaterals were evaluated by using the American Society of Interventional and Therapeutic Neuroradiology grading system and were used as the reference for comparative analysis against MRA. A total of 104 patients met the inclusion criteria (59 female, age (mean ± SD): 70.8 ± 18.1). The inter-rater agreement ( k ) for collateral scoring was 0.49, 95% CI 0.37-0.61 for the Tan score and 0.44, 95% CI 0.26-0.62 for the Maas score. Total number (%) of sufficient vs. insufficient collaterals based on DSA was 49 (47%) and 55 (53%) respectively. Using the Tan score, 45% of patients with sufficient collaterals and 64% with insufficient collaterals were correctly identified in comparison to DSA, resulting in a poor agreement (0.09, 95% CI 0.1-0.28). Using the Maas score, only 4% of patients with sufficient collaterals and 93% with insufficient collaterals were correctly identified against DSA, resulting in poor agreement (0.03, 95% CI 0.06-0.13). Pretreatment MRA in AIS patients has limited concordance with DSA when grading collaterals using the Tan and Maas scoring systems.

Background: The modified Rankin Scale (mRS) is the most common endpoint in acute stroke trials, but its power is limited when analyzed dichotomously and its indication of effect size is challenging to interpret when analyzed ordinally. To address these issues, the utility-weighted-mRS (UW-mRS) has been developed as a patient-centered, linear scale. However, appropriate data visualizations of UW-mRS results are needed, as current stacked bar chart displays do not convey crucial utility-weighting information., Design/methods: Two UW-mRS display formats were devised: (1) Utility Staircase charts, and (2) choropleth-stacked-bar-charts (CSBCs). In Utility Staircase displays, mRS segment height reflects the utility value of each mRS level. In CSBCs, mRS segment color intensity reflects the utility of each mRS level. Utility Staircase and CSBC figures were generated for 15 randomized comparisons of acute ischemic/hemorrhagic stroke therapies, including fibrinolysis, endovascular reperfusion, blood pressure moderation, and hemicraniectomy. Display accuracy in showing utility outcomes was assessed with the Tufte-lie-factor and ease-of-use assessed by formal ratings completed by a panel of 4 neurologists and emergency physicians and one nurse-coordinator., Results: The Utility Staircase and CSBC displays rapidly conveyed patient-centered valuation of trial outcome distributions not available in conventional ordinal stacked bar charts. Tufte-lie-factor (LF) scores indicated "substantial distortion" of utility-valued outcomes for 93% (14/15) of conventional stacked bar charts, vs. "no distortion" for all Utility Staircase and CSBC displays. Clinician ratings on the Figural Display Questionnaire indicated that utility information encoded in row height (Utility Staircase display) was more readily assimilated than that conveyed in segment hue intensity (CSBC), both superior to conventional stacked bar charts., Conclusions: Utility Staircase displays are an efficient graphical format for conveying utility weighted-modified Rankin Scale primary endpoint results of acute stroke trials, and choropleth-stacked-bar-charts a good alternative. Both are more accurate in depicting quantitative, health-related quality of life results and preferred by clinician users for utility results visualization, compared with conventional stacked bar charts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tokunbah, Sung, Chatfield, Gaines, Nour, Starkman and Saver.)