Acute Therapies Research Articles

Allogeneic Donor-Derived Anti-CD19 CAR T Cell Is a Promising Therapy for Relapsed/Refractory B-ALL After Allogeneic Hematopoietic Stem-Cell Transplantation

IntroductionCurrently, effective and safe salvage therapies are limited among patients with relapsed acute lymphoblastic leukemia after allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Anti-CD19 chimeric antigen receptor T (CAR T) cell is a promising treatment. Patients and MethodsWe studied 11 patients with B-cell acute lymphoblastic leukemia that relapsed after allo-HSCT between September 2017 and October 2019. Patients were treated with a dose of single-infusion donor-derived anti-CD19 CAR T cells. ResultsEight patients (72.7%) experienced morphologic remissions. Seven (63.6%) experienced minimal residual disease–negative remission. The ongoing complete remission (CR) duration of 2 patients reached 22 months. The median overall survival was 9 months (range, 2-22 months). Only one patient with grade 1 acute graft-versus-host disease was observed. Two patients (18.2%) developed grade 3/4 cytokine release syndrome. ConclusionThis prospective study showed allogeneic donor-derived anti-CD19 CAR T-cell therapy is an effective and safe salvage regimen for patients with relapsed/refractory B-cell acute lymphoblastic leukemia after allo-HSCT. Further randomized and multicenter investigations are needed to evaluate their potential role in relapsed acute lymphoblastic leukemia therapies after allo-HSCT.

Daily Intermittent Fasting in Mice Enhances Morphine Induced Anti‐Nociception while Mitigating Multiple Side Effects

The opioid epidemic has continued to plague the United States with high levels of abuse and poor quality of life for chronic pain patients requiring continuous use of opioids. Many potential solutions have been proposed to mitigate this epidemic including new medications to reduce the abuse and side effect profiles of opioids; however, new medications are plagued by low efficacy, abuse potential, and toxicities. These limitations suggest that non‐pharmacological interventions could be more efficacious with low side effect profiles. Intermittent fasting (IF) is a time restriction diet which has recently grown in popularity over the past decade in the prevention and mitigation of a variety of pathological states. Numerous animal and human studies have shown the benefits of IF in these disease states, but not in opioid treatment paradigms. We thus subjected male and female CD1 mice to 18‐hour fasting intervals followed by 6‐hour feed periods with standard chow for 1 week. Mice which underwent this diet displayed an enhanced anti‐nociceptive response to systemic morphine both in efficacy and duration using thermal tail flick and post‐operative paw incision pain models. While showing enhanced anti‐nociception, IF mice also demonstrated a reduction in the development of anti‐nociceptive tolerance using the thermal tail flick assay paired with daily systemic morphine treatment. We also found a reduction in the development of opioid induced constipation using both fecal mass and fecal pellet count in IF mice. Seeking a mechanism for our behavioral findings, we performed 35S‐GTPγS assays to assess the functionality of mu opioid receptors within the spinal cord and periaqueductal grey (PAG) tissues from IF mice with and without chronic morphine treatment. The resulting DAMGO concentration‐response curves demonstrated an increased efficacy of mu opioid receptors within the spinal cord in IF mice and an absence of the development of tolerance within the PAG in IF mice, suggesting site‐specific receptor mechanisms for the behavioral effects we observed. These data suggest that a daily IF diet may improve the therapeutic index of acute and chronic opioid therapies for pain patients in the clinic, both in improved analgesia and reduced tolerance and constipation.

No Evidence of the "Weekend Effect" in the Northern New South Wales Telestroke Network.

Background: Admission outside normal business hours has been associated with prolonged door-to-treatment times and poorer patient outcomes, the so called “weekend effect. ” This is the first examination of the weekend effect in a telestroke service that uses multi-modal computed tomography.Aims: To examine differences in workflow and triage between in-hours and out-of-hours calls to a telestroke service.Methods: All patients assessed using the Northern New South Wales (N-NSW) telestroke service from April 2013 to January 2019 were eligible for inclusion (674 in total; 539 with complete data). The primary outcomes measured were differences between in-hours and out-of-hours in door-to-call-to-decision-to-needle times, differences in the proportion of patients confirmed to have strokes or of patients selected for reperfusion therapies or patients with a modified Rankin Score (mRS ≤ 2) at 90 days.Results: There were no significant differences between in-hours and out-of-hours in any of the measured times, nor in the proportions of patients confirmed to have strokes (67.6 and 69.6%, respectively, p = 0.93); selected for reperfusion therapies (22.7 and 22.6%, respectively, p = 0.56); or independent at 3 months (34.8 and 33.6%, respectively, p = 0.770). There were significant differences in times between individual hospitals, and patient presentation more than 4.5 h after symptom onset was associated with slower times (21 minute delay in door-to-call, p = 0.002 and 22 min delay in door-to-image, p = 0.001).Conclusions: The weekend effect is not evident in the Northern NSW telestroke network experience, though this study did identify some opportunities for improvement in the delivery of acute stroke therapies.

Mechanical Thrombectomy for Patients with In-Hospital Ischemic Stroke: A Case-Control Study

Patients with in-hospital acute ischemic stroke (AIS) have, in general, worse outcomes compared to those presenting from the community, partly attributed to the numerous contraindications to intravenous thrombolysis. We aimed to identify and analyze a group of patients with in-hospital AIS who remain suitable candidates for acute endovascular therapies. A retrospective 6-year data analysis was conducted in patients evaluated through the in-hospital stroke alert protocol in a single tertiary care university hospital to identify those with in-hospital AIS due to acute intracranial large vessel occlusion (ILVO). Feasibility and safety of mechanical thrombectomy for in-hospital AIS was assessed in a case-control study comparing inpatients to those presenting from the community. From 1460 in-hospital stroke alert activations, 11% had a final diagnosis of AIS (n = 167). One hundred and two patients with in-hospital AIS had emergent intracranial vessel imaging and were included in our cohort. Acute ILVO was identified in 27 patients within this cohort. Patients were younger in the ILVO group and had more severe neurologic deficit on presentation. Compared to a matched (1:2) control group of patients presenting from the community, inpatients who underwent mechanical thrombectomy achieved equivalent technical success, safety, and clinical outcomes. The incidence of acute ILVO in patients with in-hospital AIS who underwent emergent vessel imaging is similar to the reported incidence of ILVO in patients presenting with community-onset AIS. Among patients with in-hospital AIS secondary to ILVO, mechanical thrombectomy is a feasible and safe therapy associated with favorable outcomes.

Care Among Migraine Patients in a Commercially Insured Population.

IntroductionMigraine management is characterized by the poor use of preventive therapy and the overuse of acute medications. An analysis of current treatment patterns in migraineurs is needed to improve care in this patient population. The aim of this study was to describe treatment patterns and healthcare utilization of newly diagnosed migraine patients.MethodsThis was a retrospective observation study of newly diagnosed migraine patients (no indication of migraine in the past year) identified in the IBM MarketScan Commercial Claims and Encounters database from 1 January 2010 to 30 June 2014. The final study population comprised persons aged 18–64 years at index (new diagnosis of migraine) with 12 months of continuous enrollment in an insurance plan with medical and pharmacy benefits pre-index and post-index. Treatment patterns and healthcare resource utilization were assessed during the post-index period (at least 12-months).ResultsOf the 1,588,666 migraine patients identified in the database as potentially eligible to participate in the study, 284,719 (17.9%) met the final inclusion criteria. Patients generally used acute and preventive therapies to manage migraine attacks, with most patients using preventive therapy (59.1%). However, 67.9% of those using preventive therapy discontinued the current therapy, with a median time to discontinuation of 5 months. Most of the patients who discontinued preventative therapy also used an acute treatment to manage migraine attacks after discontinuation (77.6%), generally in the year following discontinuation (68.4%). Patients on acute therapies were found to use triptans excessively (1.6%) and other non-migraine-specific acute medications for treatment (7.1%). Acute patients were also at risk of opioid dependence (12.0%) and commonly received opioids or barbiturates as first-line therapy (34.1%).ConclusionNewly diagnosed migraine patients are not being properly treated, as indicated by their excessive use of acute therapies and short time on preventive treatment before discontinuation of that treatment. Further study of the reasons why patients discontinue preventive therapy (adverse events, no response, etc.) and continue to excessively use acute treatments once their treatment regimen has been established is needed.

Abstract WP203: National Institute of Neurological Disorders and Stroke Common Data Elements: Public Review and Updates to the Stroke Recommendations

Objective: The National Institute of Neurological Disorders and Stroke (NINDS) initiated the Common Data Element (CDE) project to provide standardized clinical research data collection formats that increase the efficiency and effectiveness of studies and reduce start-up time, as well as improve data quality and facilitate and accelerate data sharing. In 2010, Stroke-specific CDEs were posted on the NINDS CDE website. The Stroke Oversight Committee (OC) reviewed Core CDEs in 2015; and in 2018, recommended that Stroke CDEs undergo a comprehensive review and update to Version 2.0. Background: In August 2018, a Stroke V2.0 Working Group (WG) consisting of over 50 worldwide subject matter experts was convened by NINDS. The WG was asked to review all current Stroke CDEs and subarachnoid hemorrhage and unruptured cerebral aneurysms (SAH) CDEs (developed in 2017) for harmonization and inclusion within Stroke V2.0. Methods: The Stroke V2.0 WG divided into eight domain-specific subgroups: Biospecimens, Biomarkers, and Laboratory Tests; Hospital Course and Acute Therapies; Imaging; Long Term Therapies; Medical History and Prior Health Status; Outcomes and Endpoints; Stroke Presentation and Vital Signs; and Stroke Types and Subtypes. Subgroups met regularly to review, revise and add to the existing Stroke CDEs based on developments in stroke research. Following an internal WG review, a public review of the draft updates will be held. The WG will consider public feedback before V2.0 is finalized. The Stroke OC plans to review the project status at the 2020 International Stroke Conference. Results: The Stroke V2.0 CDE recommendations will include updated and new template case report forms, data dictionaries, instrument informational documents and guideline documents. The updates will reflect the current state of science, streamline CDE recommendations, and incorporate SAH CDEs. Stroke V2.0 CDEs will be available on the NINDS CDE website in 2020. Conclusions: The NINDS CDEs are periodically revised as research progresses. Through the update of the Stroke CDEs to V2.0, the initiative strives to maintain the utility of CDEs as a valuable clinical research resource. NINDS encourages use of CDEs to standardize research data collection across studies.

Abstract 5: CT Perfusion is Not a Treatment Effect Modifier for Mechanical Thrombectomy in the 0-8-Hour-Window: A Pre-Planned Analysis of the RESILIENT Trial

Background: CT perfusion has been increasingly used as a selection tool in acute reperfusion therapies. However, it remains unknown whether its use is associated with a higher treatment benefit in patients undergoing thrombectomy. We sought to evaluate the interaction between imaging selection modalities and treatment effect in the RESILIENT Trial. Methods: RESILIENT was a randomized, prospective, multicenter, controlled trial evaluating the safety, efficacy, and cost-effectiveness of thrombectomy versus medical treatment alone in Brazil. A total of 221 patient were enrolled. The trial showed a strong benefit of thrombectomy (90-day mRS ordinal shift, OR 2.28 95%CI [1.41-3.70]; p=0.001). Key imaging selection criteria included ASPECTS ≥6 on non-contrast CT (NCCT) and the exclusion of malignant collateral profile on CT angiography. The use of automated CT perfusion software (RAPID, IschemaView) was optional but was made available in some centers with the pre-specified plan to compare imaging selection modalities. The primary end-point was the common odds ratio (cOR) of mRs at 90 days (shift analysis) and the main secondary endpoint was the rate of functional independence (mRS 0-2) at 90 days. Ordinal logistic and binary regression analyses with imaging selection modality (NCCT versus CTP) as an interaction term were performed with adjustments for potential confounders including age, baseline NIHSS score, occlusion site, IV tPA use and ASPECTS. A p value < 0.05 was considered statistically significant. Results: CTP was performed in 41% of the thrombectomy group and 45% in the control group. There was no significant difference in the treatment effect size for patients selected on the basis of NCCT and CTA only versus those submitted to CTP in terms of overall functional disability (ordinal mRS shift: aOR: 2.87, 95%CI [1.47-5.61] vs. 2.10, 95%CI [1.01-4.36]; p=0.390) or functional independence (mRS 0-2: aOR: 3.16, 95%CI [1.32-7.57] vs. 2.54 95%CI [0.86-7.49], p=0.40) at 90 days. Conclusion: In a randomized clinical trial of thrombectomy within 8 hours of stroke onset, there was no evidence of difference in the treatment effect size across patients selected with NCCT and CTA alone versus automated CT perfusion software.

Abstract WP75: Comparison of Automated CT Perfusion Software for Prediction of Final Infarct Volume

Introduction: CT Perfusion (CTP) has been increasingly used in patient selection for acute reperfusion therapies. Perfusion software allow for automated and faster processing using standardized approaches. We aim to compare the perfusion parameters and final infarct volume (FIV) predictability of two commercially available CTP packages (RAPID and Viz.ai). Methods: Retrospective analysis of a mechanical thrombectomy database of mechanical thrombectomy between 9/ 2018- 6/ 2019. Patients without a technically adequate baseline CTP were excluded. Ischemic core was defined as CBF<30%. Patients with (1) complete post-treatment reperfusion (mTICI 2c-3) and (2) absence of parenchymal hematoma that could confound FIV calculation were used to derive the correlations between baseline core and FIV. FIV was measured on MRI (n=150) and CT (n=14). Results: A total of 164 patients were included (mean age, 66±13.14 years; baseline NIHSS, 14.93±6.73; median time from CTP to reperfusion; median 86.5 IQR [61.25-111.75] min). The median baseline rCBF<30% lesion was 4.5 [0-21]cc and 10.4 [0-36]cc on Rapid and Viz.ai, respectively. There was a strong correlation across all baseline perfusion parameters: rCBF<30%: R=0.813; Tmax>6: R=0.879, Tmax>8: R=0.866, Tmax>10: R=0.852. In addition, there was a highagreement rate for binary values for qualification for the DAWN (core≤21 cc: 88.9%; ≤31cc: 82.4%; ≤51cc: 89.1%), DEFUSE-3 (93%), and EXTEND (91) trials. A total of 148 patients were fully reperfused (mTICI2c-3). Their median FIV was 23.72 [11.0-78.2] cc. There was only a marginal correlation between rCBF<30% and FIV which not significantly different across the two platforms (RAPID: R=0.456; Viz.ai R=0.437, p<0.001). Conclusion: The RAPID and Viz-AI software have a strong correlation in terms of the overall baseline parameters and reperfusion treatment eligibility. In fully reperfused patients, the prediction of FIV was only marginal with both softwares.

Incidence, underlying conditions, and outcomes of patients receiving acute renal replacement therapies in tertiary cardiac intensive care units: An analysis from the Critical Care Cardiology Trials Network Registry

The prevalence of renal disease in cardiac intensive care units (CICUs) is increasing, but little is known about the utilization, concurrent therapies, and outcomes of patients requiring acute renal replacement therapy (RRT) in this specialized environment. In the Critical Care Cardiology Trials Network, 16 centers submitted data on CICU admissions including acute RRT (defined as continuous renal replacement therapy and/or acute intermittent dialysis). Among 2,985 admissions, 178 (6.0%; interhospital range 1.0%-16.0%) received acute RRT. Patients receiving RRT, versus not, were more commonly admitted for cardiogenic shock (15.7% vs 4.2%, P < .01), cardiac arrest (9.6% vs 3.7%, P < .01), and acute general medical diagnoses (10.7% vs 5.8%, P < .01), whereas acute coronary syndromes (16.9% vs 32.1%, P < .01) were less frequent. Variables independently associated with acute RRT included diabetes, heart failure, liver disease, severe valvular disease, shock, cardiac arrest, hypertension, and younger age. In patients receiving acute RRT, versus not, advanced therapies including mechanical ventilation (55.6% vs 18.0%), vasoactive support (73.0% vs 35.2%), invasive hemodynamic monitoring (59.6% vs 29.2%), and mechanical circulatory support (27.5% vs 8.4%) were more common. Acute RRT was associated with higher in-hospital mortality (42.1% vs 9.3%, adjusted odds ratio 3.74, 95% CI, 2.52-5.53) and longer median length of stay (10.0 vs 5.3 days, P < .01). In conclusion, acute RRT in contemporary CICUs was associated with the provision of other advanced therapies and lower survival. These data underscore the risks associated with the provision of renal support in patients with primary cardiovascular problems and the need to develop standardized indications and potential futility measures in this specialized population.

Rationale and design for studying organisation of care for intra-arterial thrombectomy in the Netherlands: simulation modelling study

IntroductionThe introduction of intra-arterial thrombectomy (IAT) challenges acute stroke care organisations to provide fast access to acute stroke therapies. Parameters of pathway performance include distances to primary and comprehensive stroke...

Community Knowledge and Awareness of Stroke in New Zealand

Introduction: Community knowledge and stroke awareness is crucial for primary prevention of stroke and timely access to stroke treatments including acute reperfusion therapies. We conducted a national telephone survey to quantify the level of community stroke awareness. Methods: A random sample of 400 adults in New Zealand (NZ), stratified by the 4 main ethnic groups, was surveyed. Eligible participants answered stroke awareness questions using both unprompted (open-ended) and prompted questions (using a list). Proportional odds logistic regression models were used to identify factors associated with stroke awareness. Results: Only 1.5% of participants named stroke as a major cause of death. The stroke signs and symptoms most frequently identified from a list were sudden speech difficulty (94%) and sudden 1-sided weakness (92%). Without prompting, 78% of participants correctly identified at least 1 risk factor, 62% identified at least 2, and 35% identified 3 or more. When prompted with the list, scores increased 10-fold compared with unprompted responses. Ethnic disparities were observed, with Pacific peoples having the lowest level of awareness among the 4 ethnic groups. Higher education level, higher income, and personal experience of stroke were predictive of greater awareness (P ≤ .05). Conclusions: Stroke was not recognized as a major cause of death. Although identification of stroke risk factors was high with prompting, awareness was low without prompting, particularly among those with lower education and income. Nationwide, culturally tailored public awareness campaigns are necessary to improve knowledge of stroke risk factors, recognition of stroke in the community and appropriate actions to take in cases of suspected stroke.

Case Fatality Decline from 2009 to 2013 among Medicare Beneficiaries with Ischemic Stroke

ObjectivesThis study aimed to examine the temporal trend of 30-day and 1-year mortality among U.S. Medicare beneficiaries who were hospitalized for ischemic stroke, with special focus on the mortality among subgroup of patients in relation to acute reperfusion therapies including intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT). MethodsWe evaluated Medicare fee-for-service beneficiaries age 65 years or older who were hospitalized for ischemic stroke between 2009 and 2013. Multivariable Cox proportional hazards models were generated to analyze the trend of adjusted mortality. ResultsA total of 1,070,574 patients were included in the study. The 30-day mortality did not change among patients who were not treated with IVT or EVT. It decreased by 13% among patients treated with IVT but not EVT (HR = .87, 95% CI .82-.92), 25% among patients treated with EVT but not IVT (HR = .75, 95% CI .59-.95), and 37% among patients treated with both IVT and EVT (HR = .63, 95% CI .52-.77). One-year mortality decreased by 19% among patients who were not treated with IVT nor EVT (HR = .81, 95% CI .80-.83), 22% among those treated with IVT but not EVT (HR = .78, 95% CI .75-.81), 33% among those treated with EVT but not IVT (HR = .67, 95% CI .55-.81), and 38% among those treated with both IVT and EVT (HR = .62, 95% CI .53-.73). ConclusionsFrom 2009 to 2013, the 30-day stroke case fatality decreased only among the patients received reperfusion therapy. The 1-year mortality declined among all the stroke patients, with the greatest decline among those treated with both IVT and EVT.

Acute Transverse and Flaccid Myelitis in Children.

The etiologies of myelitis in children are broad, and our understanding of inflammatory myelopathies in the pediatric population continues to evolve. Acute flaccid myelitis (AFM), increasingly linked to enterovirus infections, has risen in incidence over recent years. As with other infectious myelopathies, AFM can be challenging to distinguish from inflammatory causes of acute transverse myelitis (ATM) at initial presentation. This review outlines an approach to the treatment of children presenting with myelopathy of suspected inflammatory etiology, with attention to how management may differ in the specific case of acute flaccid myelitis. Although high-quality evidence is limited, intravenous corticosteroids, intravenous immunoglobulin, and plasma exchange have important roles in the acute management of ATM. Spinal cord injury in AFM, though similar to ATM in clinical presentation, is largely mediated by direct infection as opposed to a primary inflammatory process, and treatment with corticosteroids may worsen outcomes. Awareness of the distinguishing clinical features of AFM and the underlying inflammatory conditions that commonly manifest with ATM is essential to judicious selection of appropriate acute (and potentially chronic) therapies in children presenting with myelitis.

Recent Advances in Mono- and Combined Stem Cell Therapies of Stroke in Animal Models and Humans.

Following the failure of acute neuroprotection therapies, major efforts are currently made worldwide to promote neurological recovery and brain plasticity in the subacute and post-acute phases of stroke. Currently, there is hope that stroke recovery might be promoted by cell-based therapies. The field of stem cell therapy for cerebral ischemia has made significant progress in the last five years. A variety of stem cells have been tested in animal models and humans including adipose stem cells, human umbilical cord blood-derived mesenchymal stem cells, human amnion epithelial cells, human placenta amniotic membrane-derived mesenchymal stem cells, adult human pluripotent-like olfactory stem cells, human bone marrow endothelial progenitor cells, electrically-stimulated human neuronal progenitor cells, or induced pluripotent stem cells (iPSCs) of human origin. Combination therapies in animal models include a mix of two or more therapeutic factors consisting of bone marrow stromal cells, exercise and thyroid hormones, endothelial progenitor cells overexpressing the chemokine CXCL12. Mechanisms underlying the beneficial effects of transplanted cells include the “bystander” effects, paracrine mechanisms, or extracellular vesicles-mediated restorative effects. Mitochondria transfer also appears to be a powerful strategy for regenerative processes. Studies in humans are currently limited to a small number of studies using autologous stem cells mainly aimed to assess tolerability and side-effects of human stem cells in the clinic.

Azithromycin Affords Neuroprotection in Rat Undergone Transient Focal Cerebral Ischemia.

Repurposing existing drugs represents a promising approach for successful development of acute stroke therapies. In this context, the macrolide antibiotic azithromycin has been shown to exert neuroprotection in mice due to its immunomodulatory properties. Here, we have demonstrated that acute administration of a single dose of azithromycin upon reperfusion produces a dose-dependent (ED50 = 1.40 mg/kg; 95% CI = 0.48–4.03) reduction of ischemic brain damage measured 22 h after transient (2 h) middle cerebral artery occlusion (MCAo) in adult male rats. Neuroprotection by azithromycin (150 mg/kg, i.p., upon reperfusion) was associated with a significant elevation of signal transducer and activator of transcription 3 (STAT3) phosphorylation in astrocytes and neurons of the peri-ischemic motor cortex as detected after 2 and 22 h of reperfusion. By contrast, in the core region of the striatum, drug administration resulted in a dramatic elevation of STAT3 phosphorylation only after 22 h of reperfusion, being the signal mainly ascribed to infiltrating leukocytes displaying an M2 phenotype. These early molecular events were associated with a long-lasting neuroprotection, since a single dose of azithromycin reduced brain infarct damage and neurological deficit measured up to 7 days of reperfusion. These data, together with the evidence that azithromycin was effective in a clinically relevant time-window (i.e., when administered after 4.5 h of MCAo), provide robust preclinical evidence to support the importance of developing azithromycin as an effective acute therapy for ischemic stroke.

Management of Maternal Stroke and Mitigating Risk.

Pregnancy places women at a higher risk for hemorrhagic and ischemic strokes. This review discusses the pathophysiological mechanisms underlying this increased risk, management considerations for pregnant patients, and ways to decrease the risk of stroke in this patient population. Rates of ischemic and hemorrhagic pregnancy-associated stroke have increased over the past 20years, particularly events associated with hypertensive disorders of pregnancy. There is a growing body of evidence supporting the use of acute reperfusion therapies in ischemic pregnancy-associated stroke including tissue plasminogen activator (tPA) and endovascular thrombectomy. While the unique physiology of pregnancy places women at a higher risk of stroke, acute ischemic stroke management in pregnant patients should closely mirror the management of non-pregnant patients. Secondary stroke prevention agents should be selected with consideration of the pregnancy.

Acute Respiratory Distress Syndrome Novel Therapies.

Acute respiratory distress syndrome (ARDS) was first described in 1967. Since then, several landmark studies have been published that have greatly influenced the way we diagnose and treat patients with ARDS. Despite extensive research and advancements in ventilator strategies, moderate-severe ARDS has been associated with high mortality rates. Current treatment remains primarily supportive with lung-protective ventilation strategies. Pharmacological therapies that reduce the severity of lung injury in vivo and in vitro have not yet translated into effective clinical treatment options. Currently, the mortality rate of severe ARDS remains in the range of 30% to 40%. To review, the mainstay of ARDS management includes mechanical ventilation with low tidal volumes to decrease barotrauma, prone ventilation, conservative fluid management, and neuromuscular blockade. ARDS survivors tend to have long-term and potentially permanent neuromuscular, cognitive, and psychological symptoms, affecting patient's quality of life posthospitalization. These long-term effects are likely secondary to prolonged hospitalizations, prolonged mechanical ventilation, utilization of prone strategies, utilization of paralytic drugs, and occasionally steroids. Therefore, several novel therapies outside the realm of advanced ventilation and prone positioning methods are being studied. In this article, we discuss a few of these novel therapies including prophylactic aspirin, inhaled nitric oxide, mesenchymal stem cells, and intravenous β-agonists. Steroids and extracorporeal membrane oxygenation have been discussed in a previous article.

Mobile stroke units and urgent decision making

Improving systems of care to deliver acute stroke therapies faster is one of the best ways to optimize patient outcomes. Every minute saved in the time between stroke onset and restoration of cerebral blood flow reduces disability. This talk will discuss a range of interventions to reduce treatment delays in the pre-hospital and emergency department setting. Mobile Stroke Units (ambulances equipped with specialized stroke clinicians and a CT scanner) are one potential tool to reduce the time from stroke onset to treatment initiation. Mobile stroke units can also definitively differentiate intracerebral hemorrhage from large vessel occlusion ischemic stroke and non-large vessel occlusion ischemic stroke and therefore determine the optimal hospital destination for the individual patient. Bypassing a patient with large vessel occlusion directly to an endovascular-capable hospital dramatically reduces the delay to treatment, often by 1-2 hours, and this directly translates into reduced patient disability. For non-large vessel ischemic stroke a mobile stroke unit can initiate thrombolysis considerably earlier than in the emergency department, again potentially reducing disability. Even without a mobile stroke unit, paramedic clinical assessment using severity-based triage scores and algorithms can improve the proportion of patients transported direct to an endovascular-capable hospital. Pre-notification of the receiving hospital allows activation of the stroke team and transport direct to the CT scanner on the ambulance stretcher reduces in-hospital door to needle time.

Recent Advances in Pharmacotherapy for Episodic Migraine.

In 2018, three calcitonin gene-related peptide (CGRP) pathway monoclonal antibodies, erenumab, fremanezumab and galcanezumab, were approved in various parts of the world, including Europe and the US, and another, eptinezumab, is pending, for the prevention of migraine. In this article, episodic migraine treatment is reviewed, although these medicines are approved and are just as effective for chronic migraine. These new medicines usher a new phase in the preventive management of migraine with migraine-specific treatments. Data from phase III trials of CGRP pathway monoclonal antibodies have shown they are efficacious, with adverse effect rates comparable to placebo. The combination of clear efficacy and excellent tolerability will be welcome in an area where poor adherence to current preventives is common. Rimegepant, ubrogepant and lasmiditan are migraine-specific acute therapies yet to be approved by regulators. Phase III data for the respective CGRP receptor antagonists, the gepants, and the serotonin 5-HT1F receptor agonist, the ditan, have been positive and free of cardiovascular adverse effects. These medicines are not vasoconstrictors. When approved, they could meet the acute therapy demand of patients with cardiovascular risk factors where triptans are contraindicated. Beyond this, gepants will see the most disruptive development in migraine management in generations with medicines that can have both acute and preventive effects, the latter evidenced by data from the discontinued drug telcagepant and the early-phase drug atogepant. Moreover, one can expect no risk of medication overuse syndromes with gepants since the more patients take, the less migraines they have. During the next years, as experience with monoclonal antibodies grows in clinical practice, we can expect an evolution in migraine management to take shape. Clinicians will be able to offer treatment patients want rather than trying to fit migraineurs into therapeutic boxes for their management. Despite pessimistic susurrations of a largely addlepated form, many patients, and physicians, will welcome new options, and the challenges of new treatment paradigms, with optimism.

Differences in treatment response between migraine with aura and migraine without aura: lessons from clinical practice and RCTs

Migraine is a major public health problem afflicting approximately 10% of the general population and is a leading cause of disability worldwide, yet our understanding of the basis mechanisms of migraine remains incomplete. About a third of migraine patients have attacks with aura, consisting of transient neurological symptoms that precede or accompany headache, or occur without headache. For patients, aura symptoms are alarming and may be transiently disabling. For clinicians and scientists, aura represents an intriguing neurophysiological event that may provide important insight into basic mechanisms of migraine. Several observations point toward important differences between migraine with and without aura. Compared with migraine without aura, migraine with aura has different heritability, greater association with different conditions including stroke, different alterations of brain structure and function as revealed by imaging studies. A number of studies also indicate that migraine with aura may respond differently to acute and preventive therapies as compared to migraine without aura. The purpose of this review is to provide an overview of these differences in treatment responses, and to discuss the possibility of different therapeutic strategies for migraine with vs. without aura.