Complex Metabolism of the Novel Neurosteroid, Ganaxolone, in Humans: A Unique Challenge for Metabolites in Safety Testing Assessment.

The human pharmacokinetics, metabolism, and excretion of [14C]-ganaxolone (GNX) were characterized in healthy male subjects (n = 8) following a single 300-mg (150 µCi) oral dose. GNX exhibited a short half-life of 4 hours in plasma, whereas total radioactivity had a half-life of 413 hours indicating extensive metabolism to long-lived metabolites. Identification of the major GNX circulating metabolites required extensive isolation and purification for liquid chromatography-tandem mass spectrometry analysis, together with in vitro studies, NMR spectroscopy, and synthetic chemistry support. This revealed that the major routes of GNX metabolism involved hydroxylation at the 16α-hydroxy position, stereoselective reduction of the 20-ketone to afford the corresponding 20α-hydroxysterol, and sulfation of the 3α-hydroxy group. This latter reaction yielded an unstable tertiary sulfate, which eliminated the elements of H2SO4 to introduce a double bond in the A ring. A combination of these pathways, together with oxidation of the 3ß-methyl substituent to a carboxylic acid and sulfation at the 20α position, led to the major circulating metabolites in plasma, termed M2 and M17. These studies, which led to the complete or partial identification of no less than 59 metabolites of GNX, demonstrated the high complexity of the metabolic fate of this drug in humans and demonstrated that the major circulating products in plasma can result from multiple sequential processes that may not be easily replicated in animals or with animal or human in vitro systems. SIGNIFICANCE STATEMENT: Studies on the metabolism of [14C]-ganaxolone in humans revealed a complex array of products that circulated in plasma, the two major components of which were formed via an unexpected multi-step pathway. Complete structural characterization of these (disproportionate) human metabolites required extensive in vitro studies, along with contemporary mass spectrometry, NMR spectroscopy, and synthetic chemistry efforts, which served to underscore the limitations of traditional animal studies in predicting major circulating metabolites in man.

Telemedicine for Acute Monocular Visual Loss: A Retrospective Large Telestroke Network Experience.

Introduction: Central retinal artery occlusion (CRAO) is an under-recognized stroke subtype that may benefit from hyperacute reperfusion therapies. We aimed to evaluate the ability of telestroke activations to provide CRAO diagnosis and thrombolysis. Methods: This retrospective observational study investigates all encounters conducted for acute visual loss between 2010 and 2021 in our multicentric Mayo Clinic Telestroke Network. Demographics, time from visual loss to telestroke evaluation, ocular examination, diagnostic, and therapeutic recommendations were collected for CRAO subjects. Results: Out of 9,511, 49 encounters (0.51%) were conducted for an acute ocular complaint. Five patients had possible CRAO, and 4 presented within 4.5 h from symptom onset (range 1.5-5 h). None received thrombolytic therapy. All telestroke physicians recommended ophthalmology consultation. Conclusion: Current telestroke assessment of acute visual loss is suboptimal and patients eligible for acute reperfusion therapies may not be offered treatment. Teleophthalmologic evaluations and advanced ophthalmic diagnostic tools should complement telestroke systems.

Emergent use of ticagrelor during endovascular reperfusion in large arterial occlusions.

OBJECTIVE: Given many emerging indications for endovascular interventions in ischemic strokes, a safe and effective adjuvant antiplatelet regimen for acute revascularization has become a subject of interest. Ticagrelor is a direct oral P2Y12 inhibitor that may achieve rapid platelet suppression than standard oral therapies. We report our experience of Ticagrelor use in revascularization of acute large arterial steno-occlusive disease, describing procedural post-procedure thrombotic events, major hemorrhages, and other clinical outcomes. METHODS: This was a single-center retrospective case series of large steno-occlusive disease requiring endovascular reperfusion with emergent adjuvant Ticagrelor, defined as 30 min of the procedure from skin puncture to closure of the arteriotomy. Major outcomes investigated were thromboembolism in the target artery, and symptomatic intracranial or extracranial major hemorrhages. Additional analyses were performed with respect to timing of the administration and use of rescue GPIIb/IIIa inhibitors if any. RESULTS: 73 consecutive patients were identified, presenting with severe ischemic stroke (median NIHSS 16) of large artery origin. 67% required stent placement (45% cervical carotid, 22% intracranial artery), 9.5% angioplasty and 23% mechanical thrombectomy only. Two experienced symptomatic in-stent occlusion, and 7 experienced major hemorrhages (9.5%) including 3 fatal symptomatic intracranial hemorrhages (4.1%). Among 19 subjects (26%) who received pretreatment with Ticagrelor, there were fewer GPIIb/IIIa administration, angioplasty and stenting, without yielding benefit in functional outcome or mortality. GPIIb/IIIa was administered as rescue therapy in 45 subjects (62%), which was found associated with increased bleeding compared to patients receiving Ticagrelor only, in whom no bleeding complications were recorded (16% vs. 0%; p = 0.03). CONCLUSION: We report our findings on Ticagrelor as an adjuvant antiplatelet therapy in ischemic stroke of large arterial origin requiring emergent revascularization. Effectiveness, safety, need for additional rescue treatment, and comparison to other commonly used oral antiplatelets should be investigated in future prospective studies.

Reliability of Field Assessment Stroke Triage for Emergency Destination Scale Use by Paramedics: Mobile Stroke Unit First-Year Experience.

Background and Purpose: Field Assessment Stroke Triage for Emergency Destination (FAST-ED) scale is a helpful tool to triage patients with stroke in the field. However, data on its reliability in the prehospital setting are lacking. We aim to test the reliability of FAST-ED scale when used by paramedics in a mobile stroke unit covering a metropolitan area. Methods: As part of standard operating mobile stroke unit procedures, paramedics initially evaluated patients. If the event characterized a stroke alert, the FAST-ED score was determined by the paramedic upon patient contact (in-person) and then independently by a vascular neurologist (VN) immediately after paramedic evaluation (remotely/telemedicine). This allowed testing of the interrater agreement of the FAST-ED scoring performance between on-site prehospital providers and remotely located VN. Results: Of a total of 238 patients transported in the first 15 months of the mobile stroke unit's activity, 173 were included in this study. Median age was 63 (interquartile range, 55.5­75) years and 52.6% were females. A final diagnosis of ischemic stroke was made in 71 (41%), transient ischemic attack in 26 (15%), intracranial hemorrhage in 15 (9%), whereas 61 (35%) patients were stroke mimics. The FAST-ED scores matched perfectly among paramedics and VN in 97 (56%) instances, while there was 0 to 1-point difference in 158 (91.3%), 0 to 2-point difference in 171 (98.8%), and 3 or more point difference in 2 (1.1%) patients. The intraclass correlation between VN and paramedic FAST-ED scores showed excellent reliability, intraclass correlation coefficient 0.94 (95% CI, 0.92­0.96; P<0.001). When VN recorded FAST-ED score ≥3, paramedics also scored FAST-ED≥3 in majority of instances (63/71 patients; 87.5%). A large vessel occlusion was identified in 16 (9.2%) patients; 13 occlusions were identified with a FAST-ED≥3 while 3 were missed. All of the latter patients had National Institutes of Health Stroke Scale score ≤5. Conclusions: We demonstrate excellent reliability of FAST-ED scale performed by paramedics when compared with VN, indicating that it can be accurately performed by paramedics in the prehospital setting.

Vascular Spinal Cord Disorders.

Vascular disorders of the spinal cord are uncommon yet under-recognized causes of myelopathy. Etiologies can be predominantly categorized into clinical and radiographic presentations of arterial ischemia, venous congestion/ischemia, hematomyelia, and extraparenchymal hemorrhage. While vascular myelopathies often produce significant morbidity, recent advances in the understanding and recognition of these disorders should continue to expedite diagnosis and proper management, and ideally improve patient outcomes. This article comprehensively reviews relevant spinal cord vascular anatomy, clinical features, radiographic findings, treatment, and prognosis of vascular disorders of the spinal cord.

Stroke Thrombolysis in Patients Taking Ticagrelor -Two Successful Cases and a Review of the Literature.

BACKGROUND: Ticagrelor is a novel antiplatelet agent that is frequently used for secondary prevention in coronary artery disease and has emerging evidence in stroke after the recent results of SOCRATES and THALES trials. The use of intravenous thrombolysis with alteplase in acute ischemic stroke (AIS) patients on ticagrelor is a topic of debate as the safety profile of ticagrelor in this setting is not well established. METHODS: We identified consecutive AIS patients taking ticagrelor who received intravenous alteplase at a comprehensive stroke center from January 2016 to December 2019. We then performed a literature search to capture all known published cases of intravenous thrombolysis in stroke patients on ticagrelor. RESULTS: Of the 3896 patients who were treated for AIS at our local comprehensive stroke center during this time period, two patients received intravenous alteplase while on ticagrelor. Both patients had posterior circulation acute strokes and were successfully treated with intravenous alteplase without a systemic or intracranial bleeding event. Only five other cases of intravenous thrombolysis in AIS patients on ticagrelor have been reported in the literature. Among these cases, four of the five cases had a hemorrhagic complication. CONCLUSION: Despite prior reports of hemorrhagic complications with use of IV alteplase in setting of pre-treatment with ticagrelor, we report the safe use of intravenous thrombolysis in two cases presenting with acute ischemic stroke. Until safety is established in large studies, decision for thrombolysis should be made on case-by-case basis.

Safety of Ticagrelor in Moderate and Severe Acute Ischemic Stroke: A Single-Center Retrospective Review.

OBJECTIVES: Ticagrelor may be superior to aspirin after minor ischemic stroke or TIA, particularly in patients with symptomatic atherosclerotic disease. However, there may be an increased risk of intracerebral hemorrhage in patients with moderate to severe ischemic stroke, and ticagrelor has not been studied in this patient population. Therefore, we sought to evaluate the safety of ticagrelor after moderate or severe ischemic stroke. MATERIALS AND METHODS: Retrospective chart review of all patients admitted with acute ischemic stroke and NIHSS 6 or greater who were discharged on ticagrelor between January 2016 and December 2019. Patients who underwent angioplasty, stenting or carotid revascularization during the hospitalization were excluded. RESULTS: Of 183 patients discharged on ticagrelor, 61 patients were included. Median age was 61 (IQR 52-68); 33 (54%) patients were men. Median NIHSS was 11 (IQR 8-15). Fourteen (23%) patients received IV alteplase and 35 (57%) patients received mechanical thrombectomy. Stroke mechanism was large artery atherosclerosis in 53 (87%) of patients, of which 40 (71%) were deemed intracranial atherosclerosis. Final infarct volume was greater than 10 mL in 32 (52%) patients. Follow-up information was available for 53 (87%) patients; median length of follow-up was 3 (IQR 2-6) months. Six (10%) patients experienced recurrent ischemic stroke. No patients experienced symptomatic intracerebral hemorrhage after initiation of ticagrelor. One (2%) patient experienced major bleeding. CONCLUSIONS: This study provides preliminary evidence supporting the potential safety of ticagrelor following moderate or severe acute ischemic stroke. These findings support the need for future prospective studies.

Absorption, distribution, metabolism, and excretion of cenerimod, a selective S1P1 receptor modulator in healthy subjects.

Cenerimod is a sphingosine-1-phosphate 1 receptor modulator under development for treatment of systemic lupus erythematosus.This single-centre, open-label, single-dose study investigated the mass balance and excretion routes and aimed at identifying and quantifying cenerimod metabolites in plasma, urine, and faeces after oral administration of 2 mg/100 µCi (3.7 MBq) of 14C-cenerimod.Total mean cumulative recovery was 84% of the administered dose (58-100% in faeces and 4.6-12% in urine). In a 0-504 h cross-subject area under the curve plasma pool, cenerimod and two metabolites were detected accounting for 78, 6.0, and 4.9% of total radioactivity, respectively, i.e. no major metabolite was identified in plasma. Cenerimod was only detected in faeces and accounted for 17% of the radioactivity excreted in this matrix. The metabolite M32 was detected in both urine and faeces and represented 23% and 66% of radioactivity excreted in these matrices, respectively. Other metabolites of unknown structure were detected in small amounts. Overall, M32 and cenerimod accounted for 52% and 13%, respectively, of the total radioactivity recovered.Among the excreted metabolites, only the non-enzymatically formed M32 represented more than 25% of total drug-related material. Therefore, no pharmacokinetic drug-drug interaction studies are foreseen.

Causes of Death in Status Epilepticus.

OBJECTIVES: To determine the causes of death in patients with status epilepticus. To analyze the relative contributions of seizure etiology, seizure refractoriness, use of mechanical ventilation, anesthetic drugs for seizure control, and medical complications to in-hospital and 90-day mortality, hospital length of stay, and discharge disposition. DESIGN: Retrospective cohort. SETTING: Single-center neuroscience ICU. PARTICIPANTS: Patients with status epilepticus were identified by retrospective search of electronic database from January 1, 2011, to December 31, 2016. INTERVENTIONS: Review of electronic medical records. MEASUREMENTS AND MAIN RESULTS: Demographics, clinical characteristics, treatments, and outcomes were collected. Univariable and multivariable logistic regression analysis were used to determine whether the use of anesthetic drugs, mechanical ventilation, Status Epilepticus Severity Score, refractoriness of seizures, etiology of seizures, or medical complications were associated with in-hospital, 90-day mortality or discharge disposition. Among 244 patients with status epilepticus (mean age was 64 yr [interquartile range, 42-76], 55% male, median Status Epilepticus Severity Score 3 [interquartile range, 2-4]), 24 received anesthetic drug infusions for seizure control. In-hospital and 90-day mortality rates were 9.2% and 19.2%, respectively. Death was preceded by withdrawal of life-sustaining treatment in 19 patients (86.3%) and cardiac arrest in three (13.7%). Only Status Epilepticus Severity Score was associated with in-hospital and 90-day mortality, whereas the use of anesthetic drugs for seizure control, mechanical ventilation, medical complications, etiology, and refractoriness of seizures were not. Hospital length of stay was longer in patients with medical complications (p = 0.0091), refractory seizures (p = 0.0077), and in those who required anesthetic drugs for seizure control (p = 0.0035). Patients who had refractory seizures were less likely to be discharged home (odds ratio, 0.295; CI, 0.143-0.608; p = 0.0009). CONCLUSIONS: In this cohort, death primarily resulted from the underlying neurologic disease and withdrawal of life-sustaining treatment and not from our treatment choices. Use of anesthetic drugs, medical complications, and mechanical ventilation were not associated with in-hospital and 90-day mortality.

Rethinking Prehospital Stroke Notification: Assessing Utility of Emergency Medical Services Impression and Cincinnati Prehospital Stroke Scale.

BACKGROUND AND PURPOSE: Although prehospital stroke notification has improved stroke treatment, incorporation of these systems into existing infrastructure has resulted in new challenges. The goal of our study was to design an effective prehospital notification system that allows for early and accurate identification of patients presenting with acute stroke. METHODS: We conducted a retrospective single-center cohort study of patients presenting with suspicion of acute stroke from 2014 to 2015. Data recorded included patient demographics, time of symptom onset, Cincinnati Prehospital Stroke Scale (CPSS) score, Glasgow Coma Scale score, National Institutes of Health Stroke Scale (NIHSS) score, emergency medical services (EMS) impression, acute stroke pager activation, acute intervention, and discharge diagnosis. Univariate logistic regression was performed with discharge diagnosis of stroke as the end point. RESULTS: A total of 130 patients were included in the analysis; 96 patients were discharged with a diagnosis of stroke or transient ischemic attack. Both NIHSS and the presence of face, arm and speech abnormalities on CPSS were significantly higher in patients with stroke (P < .05). EMS correctly recognized stroke in 77.1% of cases but falsely identified stroke in 85.3% of negative cases. CPSS identified 75% of acute stroke cases, but specificity was poor at only 20.6%. All patients receiving intervention had acute stroke pager activation in Emergency Department. CONCLUSIONS: Prehospital stroke notification systems utilizing EMS impressions and stroke screening tools are sensitive but lack appropriate specificity required for modern acute stroke systems of care. Better solutions must be explored so that prehospital notification can keep pace with advances in acute stroke treatment.

Brachiocephalic Arterial Occlusive Disease Presenting as Limb-Shaking Transient Ischemic Attacks.

Limb-shaking transient ischemic attacks (LSTIAs) are a phenomenon that occurs due to transient hypoperfusion to a cerebral motor territory with a chronically outstripped autoregulatory vascular reserve. First described in 1962 by Miller Fisher, the pathogenesis and the global understanding of this presentation have undergone a significant advancement throughout the years. Typically, patients will present with this syndrome of transient hypoperfusion in the context of extracranial carotid intrinsic vessel stenosis or by intracranial vascular stenosis to select motor pathways. We present within this case report a novel mechanism by which LSTIAs may emerge. Through this knowledge, clinicians may need to consider expansion of their diagnostic breadth to include proximal vasculature luminal integrity.

Pharmacokinetics and metabolism of [14C]-tozadenant (SYN-115), a novel A2a receptor antagonist ligand, in healthy volunteers.

1. This phase-I study (NCT02240290) was designed to investigate the human absorption, disposition and mass balance of 14C-tozadenant, a novel A2a receptor antagonist in clinical development for Parkinson s disease. 2. Six healthy male subjects received a single oral dose of tozadenant (240 mg containing 81.47 KBq of [14C]-tozadenant). Blood, urine and feces were collected over 14 days. Radioactivity was determined by liquid scintillation counting or accelerator mass spectrometry (AMS). Tozadenant and metabolites were characterized using HPLC-MS/MS and HPLC-AMS with fraction collection. 3. At 4 h, the Cmax of tozadenant was 1.74 µg/mL and AUC(0-t) 35.0 h µg/mL, t1/2 15 h, Vz/F 1.82 L/kg and CL/F 1.40 mL/min/kg. For total [14C] radioactivity, the Cmax was 2.29 µg eq/mL at 5 h post-dose and AUC(0-t) 43.9 h µg eq/mL. Unchanged tozadenant amounted to 93% of the radiocarbon AUC(0-48h). At 312 h post-dose, cumulative urinary and fecal excretion of radiocarbon reached 30.5% and 55.1% of the dose, respectively. Unchanged tozadenant reached 11% in urine and 12% of the dose in feces. Tozadenant was excreted as metabolites, including di-and mono-hydroxylated metabolites, N/O dealkylated metabolites, hydrated metabolites. 4. The only identified species circulating in plasma was unchanged tozadenant. Tozadenant was primarily excreted in urine and feces in the form of metabolites.

External validation of preoperative and postoperative nomograms for prediction of cancer-specific survival, overall survival and recurrence after robot-assisted radical cystectomy for urothelial carcinoma of the bladder.

OBJECTIVE: To externally validate currently available bladder cancer nomograms for prediction of all-cause survival (ACS), cancer-specific survival (CSS), other-cause mortality (OCM) and progression-free survival (PFS). PATIENTS AND METHODS: Retrospective analysis of a prospectively maintained database of 282 patients who underwent robot-assisted radical cystectomy (RARC) at a single institution was performed. The Bladder Cancer Research Consortium (BCRC), International Bladder Cancer Nomogram Consortium (IBCNC) and Lughezzani nomograms were used for external validation, and evaluation for accuracy at predicting oncological outcomes. The 2- and 5-year oncological outcomes were compared, and nomogram performance was evaluated through measurement of the concordance (c-index) between nomogram-derived predicted oncological outcomes and observed oncological outcomes. RESULTS: The median (range) patient age was 70 (36-90) years. At a mean follow-up of 20 months, local or distant disease recurrence developed in 30% of patients. With an overall mortality rate of 33%, 17% died from bladder cancer. The actuarial 2- and 5-year PFS after RARC was 62% (95% confidence interval [CI] 54-68) and 55% (95% CI 46-63), respectively. The actuarial 2- and 5-year ACS was 66% (95% CI 59-72) and 47% (95% CI 37-55), respectively, and the 2- and 5-year CSS was 81% (95% CI 74-86) and 67% (95% CI 57-76), respectively. The PFS c-index for IBCNC was 0.70 at 5 years, and for BCRC was 0.77 at both the 2 and 5 years. The accuracy of ACS and CSS prediction was evaluated using the BCRC and Lughezzani nomograms. Using the BCRC nomogram, c-indices of for 2- and 5-year ACS were each 0.73 and c-indices for 2- and 5-year CSS were 0.70 each. The performance of Lughezzani nomogram for 5-year ACS, cancer-specific mortality and OCM were 0.73, 0.72 and 0.40, respectively. The BCRC nomogram prediction of advanced pathological stage and lymph node metastasis was modest, with c-indices of 0.66 and 0.61, respectively. CONCLUSIONS: Bladder cancer nomograms available from the current open RC literature adequately predict ACS, CSS and PFS after RARC. However, prediction of advanced tumour stage and lymph node metastasis was modest and the Lughezzani nomogram failed to predict OCM.

Artificial intelligence to enhance prehospital stroke diagnosis and triage: a perspective.

As health systems organize to deliver the highest quality stroke care to their patients, there is increasing emphasis being placed on prehospital stroke recognition, accurate diagnosis, and efficient triage to improve outcomes after stroke. Emergency medical services (EMS) personnel currently rely heavily on dispatch accuracy, stroke screening tools, bypass protocols and prehospital notification to care for patients with suspected stroke, but novel tools including mobile stroke units and telemedicine-enabled ambulances are already changing the landscape of prehospital stroke care. Herein, the authors provide our perspective on the current state of prehospital stroke diagnosis and triage including several of these emerging trends. Then, we provide commentary to highlight potential artificial intelligence (AI) applications to improve stroke detection, improve accurate and timely dispatch, enhance EMS training and performance, and develop novel stroke diagnostic tools for prehospital use.

Donation after circulatory death: A transplant cardiologist's take on neuroprognostication.

Donation after circulatory death (DCD) is becoming increasingly utilized in heart transplantation and has the potential to further expand the donor pool. As transplant cardiologists gain more familiarity with DCD donor selection, there are many issues that lack consensus including how we incorporate the neurologic examination, how we measure functional warm ischemic time (fWIT), and what fWIT thresholds are acceptable. DCD donor selection calls for prognostication tools to help determine how quickly a donor may expire, and in current practice there is no standardization in how we make these predictions. Current scoring systems help to determine which donor may expire within a specified time window either require the temporary disconnection of ventilatory support or do not incorporate any neurologic examination or imaging. Moreover, the specified time windows differ from other DCD solid organ transplantation without standardization or strong scientific justification for these thresholds. In this perspective, we highlight the challenges faced by transplant cardiologists as they navigate the muddy waters of neuroprognostication in DCD cardiac donation. Given these difficulties, this is also a call to action for the creation of a more standardized approach to improve the DCD donor selection process for appropriate resource allocation and organ utilization.

Prehospital stroke scales outperform National Institutes of Health Stroke Scale in predicting large vessel occlusion in a large academic telestroke network.

INTRODUCTION: Prehospital telestroke evaluations may improve stroke triage compared to paramedic-applied large vessel occlusion scales, but ambulance-based video National Institutes of Health Stroke Scale assessments are challenging. The accuracy of telestroke-administered large vessel occlusion scales has not been investigated, so we sought to evaluate this further. METHODS: This retrospective study included all in-hospital telestroke encounters in a large academic telestroke network from 2019 to 2020. We retrospectively calculated seven large vessel occlusion scales using the in-hospital telestroke National Institutes of Health Stroke Scale (Rapid Arterial oCclusion Evaluation, Cincinnati Stroke Triage Assessment Tool, Field Assessment Stroke Triage for Emergency Destination, 3-Item Stroke Scale, Prehospital Acute Stroke Severity, Vision-Aphasia-Neglect, and Gaze-Face-Arm-Speech-Time). Diagnostic performance was assessed via sensitivity, specificity, negative predictive value, positive predictive value, positive likelihood ratio, negative likelihood ratio, and accuracy using established scale thresholds. These results were compared to the National Institutes of Health Stroke Scale at thresholds of 6, 8, and 10. The area under curve was calculated using c-statistics by treating scales as continuous variables. RESULTS: A total of 625 patients were included; 111 (17.8%) patients had an anterior large vessel occlusion, 118 (18.9%) patients had any large vessel occlusion, and 182 (29.1%) patients had stroke mimic diagnosis. The mean age (SD) was 67.9 (15.9), 48.3% were female, and 93.4% were white. The Mean National Institutes of Health Stroke Scale (SD) was 14.9 (8.4) for patients with anterior large vessel occlusion, 4.7 (5.0) for patients with non-large vessel occlusion ischemic stroke, and 4.4 (5.8) for stroke mimic (p < 0.001). Compared to the National Institutes of Health Stroke Scale, Field Assessment Stroke Triage for Emergency Destination, and Rapid Arterial oCclusion Evaluation scales demonstrated higher accuracy and area under curve for large vessel occlusion detection. DISCUSSION: Both the Field Assessment Stroke Triage for Emergency Destination and Rapid Arterial oCclusion Evaluation scales outperformed the National Institutes of Health Stroke Scale for large vessel occlusion detection in patients evaluated by in-hospital telestroke. These scales may be valid alternatives to the National Institutes of Health Stroke Scale examination in this setting.

Disposition and Mass Balance of Etrasimod in Healthy Subjects and In Vitro Determination of the Enzymes Responsible for Its Oxidative Metabolism.

Etrasimod (APD334) is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator (S1P1,4,5 ) in development for treatment of various immune-mediated inflammatory disorders. The disposition and mass balance of a single 2-mg [14 C]etrasimod dose were evaluated in 8 healthy males. An in vitro study was also conducted to identify etrasimod's oxidative metabolizing enzymes. Peak concentrations of etrasimod and total radioactivity in plasma and whole blood were typically reached 4-7 hours postdose. Etrasimod constituted 49.3% of total radioactivity plasma exposure, with multiple minor/trace metabolites making up the remainder. Etrasimod was slowly cleared mainly via biotransformation, predominantly by oxidative metabolism, with unchanged etrasimod recovered in feces accounting for only 11.2% of the dose and none in urine. The mean apparent terminal half-lives of etrasimod and total radioactivity in plasma were 37.8 and 89.0 hours, respectively. Mean cumulative recovery of radioactivity in excreta over 336 hours was 86.9% of the dose, mostly in feces. The prevalent metabolites eliminated in feces were M3 (hydroxy-etrasimod) and M36 (oxy-etrasimod sulfate), accounting for 22.1% and 18.9% of the dose, respectively. From in vitro reaction phenotyping, the predominant enzymes involved in the oxidation of etrasimod were CYP2C8, CYP2C9, and CYP3A4, with minor contributions from CYP2C19 and CYP2J2.

Telestroke's Role Through the COVID-19 Pandemic and Beyond.

Purpose of review: The goal of this paper is to discuss the role and utilization of telestroke services through the COVID-19 pandemic and to suggest future directions to sustain and increase patients' access to stroke expertise. Recent findings: Telestroke is an innovative and effective tool that has been shown to improve access, quality of care, and outcomes of patients with acute stroke syndromes in resource-limited areas for the last two decades. The COVID-19 pandemic posed a significant challenge and strained healthcare systems worldwide, but it created novel and unique opportunities to expand and increase the utilization of telehealth and telestroke services to deliver personalized healthcare across the continuum of stroke care outside of traditional settings. This rapid and widespread increase in telestroke use was facilitated by the removal of many legislative and regulatory barriers which have limited patients' access to stroke expertise for many years. Summary: As the public health emergency ends, there exists a unique opportunity to optimize and expand upon the pandemic-related rapid growth of telestroke care. Optimal utilization of telehealth and telestroke services will depend on maintaining and improving required infrastructure, laws, and regulations, particularly those governing reimbursement and licensing.

Improving the Telemedicine Evaluation of Patients With Acute Vision Loss: A Call to Eyes.

Acute vision loss related to cerebral or retinal ischemia is a time-sensitive emergency with potential treatment options including IV or intra-arterial thrombolysis and mechanical thrombectomy. However, patients either present in a delayed fashion or present to an emergency department that lacks the subspecialty expertise to recognize and treat these conditions in a timely fashion. Moreover, health care systems in the United States are becoming increasingly reliant on telestroke and teleneurology services for acute neurologic care, making the accurate diagnosis of acute vision loss even more challenging due to critical limitations to the remote video evaluation, including the inability to perform routine ophthalmoscopy. The COVID-19 pandemic has led to a greater reliance on telemedicine services and helped to accelerate the development of novel tools and care pathways to improve remote ophthalmologic evaluation, but these tools have yet to be adapted for use in the remote evaluation of acute vision loss. Permanent vision loss can be disabling for patients, and efforts must be made to increase and improve early diagnosis and management. Herein, the authors outline the importance of improving acute ophthalmologic diagnosis, outline key limitations and barriers to the current video-based teleneurology assessments, highlight opportunities to leverage new tools to enhance the remote assessment of vision loss, and propose new avenues to improve access to emergent ophthalmology subspecialty.

Telemedicine-enabled ambulances and mobile stroke units for prehospital stroke management.

The recognition and management of stroke in the prehospital setting has become increasingly important to improve patient outcomes. Several strategies to advance prehospital stroke care have been developed, including the mobile stroke unit and the telemedicine-enabled ambulance-or "mini-MSU." These strategies both incorporate ambulance-based audio-visual telemedicine evaluation with a vascular neurologist to facilitate faster treatment but differ in several areas including upfront and recurring costs, scalability or growth potential, ability to integrate into existing emergency medical services systems, and interoperability across multiple specialties or conditions. While both the mobile stroke unit and mini-mobile stroke unit model are valid approaches to improve stroke care, the authors aim to compare these models based on costs, scalability, integration, and interoperability in order to guide our prehospital leaders to find the best solutions for their communities.