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While the rupture rate of cerebral aneurysms is only 1% per year, ruptured aneurysms are associated with significant morbidity and mortality, while aneurysm treatments have their own associated risk of morbidity and mortality. Conventional markers for aneurysm rupture include patient-specific and aneurysm-specific characteristics, with the development of scoring systems to better assess rupture risk. These scores, however, rely heavily on aneurysm size, and their accuracy in assessing risk in smaller aneurysms is limited. While the individual risk of rupture of small aneurysms is low, due to their sheer number, the largest proportion of ruptured aneurysms are small aneurysms. Conventional imaging techniques are valuable in characterizing aneurysm morphology; however, advanced imaging techniques assessing the presence of inflammatory changes within the aneurysm wall, hemodynamic characteristics of blood flow within aneurysm sacs, and imaging visualization of irregular aneurysm wall motion have been used to further determine aneurysm instability that otherwise cannot be characterized by conventional imaging techniques. The current manuscript reviews conventional imaging techniques and their value and limitations in cerebral aneurysm characterization, and evaluates the applications, value and limitations of advanced aneurysm imaging and post-processing techniques including intracranial vessel wall MRA, 4D-flow, 4D-CTA, and computational fluid dynamic simulations.

Background: Quantitative End-Tidal CO2 (PETCO2) measurement during cardiac arrest is recommended for monitoring the CPR quality to detect ROSC. While low ETC02 can reflect suboptimal CPR quality and increases in ETC02 are often associated with ROSC the significance of high values of PETCO2 without ROSC remain unclear. Objectives: To describe the population of OHCA victims with high PETCO2 (>50 mm Hg) during ongoing resuscitation including demographics, rhythm characteristics, occurrence of ROSC, the later occurrence of field termination of resuscitation and the presumed etiology. Methods: An observational analysis of adult OHCAs with available PETCO2 data occurring between Oct 2010 and Nov 2014 at two sites involved in the Save Hearts in Arizona Registry and Education (SHARE) quality improvement program. CPR and PETCO2 data were recorded using ZOLL E and X Series EMS monitors. PETCO2 is reported as the mean value for each minute. The cardiac rhythm and the presence of ROSC were determined for each minute using EMS provider reports, vital signs, ECG, and accelerometer data. The first recorded minute of PETCO2 and minutes with ROSC were excluded. Results: Study population included 654 OHCAs with PETCO2 data, 96 cases (58% male, age median 65 (IQR 54-75)) with at least 1 min of high PETCO2 in the absence of ROSC were identified. Of these, 31 (32%) had ROSC at least once during their resuscitation. Cases were of presumed cardiac etiology in 81 (84%), while 12% and 4% had presumed respiratory and other etiologies, respectively. A total of 322 minutes of PETCO2 >50 mm Hg in the absence of ROSC were identified. The mean PETC02 value was 67 (IQR 54-75). Of these 296 minutes (92%) occurred during PEA. Despite high PETCO2, resuscitation was terminated in the field in 21 (22%) patients. Only one subject survived to hospital discharge. Conclusions: In this observational study, high PETCO2 was frequently found during resuscitation without ROSC and PEA was the most common cardiac rhythm. Further study is warranted to determine the significance and possible reasons for this finding.

Background: Previous studies have described modest correlation between end-tidal CO 2 (ETCO 2 ) and CPR quality during resuscitation of cardiac arrest patients, but it is unclear whether ETCO 2 alone can indicate CPR quality. The present study investigated whether ETCO 2 adequately identifies the quality of CPR provided during out-of-hospital cardiac resuscitation. Methods: ETCO 2 was monitored with side-stream CO 2 (Philips/Respironics) and CPR quality measured with an accelerometer-based system (E Series, ZOLL Medical) during the treatment of consecutive adult OHCA patients with presumed cardiac etiology by 2 EMS agencies in the Arizona SHARE QI Program between 10/08-06/13. Minute-by-minute ETCO 2 and CPR quality were extracted. ETCO 2 values were log transformation to achieve approximate normality. Linear mixed effect models were fitted to use (transformed) ETCO 2 level to predict four CPR variables: chest compression (CC) depth, CC rate, CC release velocity (CCRV), and ventilation rate (VR). A random intercept for each case was included and a spatial power covariance structure assumed for measurements over time. Results: 230 subjects (median age 69 yrs, 69% male) with 1581 minutes of data were studied. Transformed ETCO 2 was significant for CC depth (p< 0.0001), CCRV (p=0.003) and VR (p<0.0001), but only explained 3.7%, 2.7%, and 10.0% of the total variance for these variables, respectively. Transformed ETCO 2 was not a significant predictor for CC rate (p=0.89). The Figure illustrates the overlap in CC depth over quartiles of ETCO 2 , demonstrating that any specific ETCO 2 level could be found over a wide range of CC depths. Conclusion: In this secondary analysis, ETCO 2 was not an independent indicator of CC rate but was a weak predictor for CC depth, CCRV and VR. These findings suggest that ETCO 2 may be not be an adequate substitute for CPR quality monitoring. Future studies should investigate how ETCO 2 and CPR quality monitoring can be used in conjunction to optimize CPR.

Background: Higher chest compression release velocity (CCRV) is associated with better outcomes after OHCA. Patient age and gender have been associated with variations in chest wall compliance and compressibility which may impact outcomes. Hypothesis: To evaluate the association between CCRV and OHCA patient age, weight, and gender. Methods: Observational study of prospectively collected OHCA quality improvement data in two suburban EMS agencies in Arizona between 10/1/2008 and 12/31/2016. Patient age and weight were categorized into quartiles for the analysis. CCRV was summarized at each level of the categorical variable by median and inter-quartile range (IQR), and was then compared between different levels by the Kruskal-Wallis test. Results: During the study period, 2,661 OHCA cases were treated. After exclusion criteria, 1,140 cases remained for analysis. Median duration of compressions was 8.70 minutes. Mean CCRV was negatively correlated with age and positively correlated with weight (Table). Male patients exhibited a greater mean CCRV compared to female patients [344.4 mm/s (IQR 307.3-384.6) vs. 331.5 (285.3-385.5), p=0.0133]. Conclusion: Patient characteristics including younger age, male gender, and increased weight were associated with a higher CCRV during OHCA resuscitation.

Background: Extended care facilities (ECFs) house unique patient populations with increased risk of out of hospital cardiac arrest (OHCA) and with unique, generally medically trained first responders initiating care prior to arrival of emergency medical services (EMS). However, little is known about bystander cardiopulmonary resuscitation (CPR) and resuscitation outcomes in this population. Our aim is to assess rate of CPR delivery prior to EMS arrival in cases of OHCA among residents ECFs across the state of Arizona. Methods: Cases of OHCA between 2016-2018, cared for by participating Arizona EMS agencies, were included if OHCA occurred at an ECF, age 18+, and was of presumed cardiac etiology. Association between survival status at discharge and bystander CPR was examined first by Chi-squared test then by logistic regression, which adjusted for important risk factors and potential confounders including: age, gender, witnessed arrest, shockable initial rhythm, and return of spontaneous circulation (ROSC) in EMS care. Results: There were 1,046 cases included in this study after excluding 32 cases with DNR and 11 with unknown bystander CPR status. Median patient age was 74 (interquartile range 64, 83). The overall rate of CPR prior to EMS arrival was 78.4% (95% CI, 75.8%, 80.9%). Survival to hospital discharge and survival with favorable neurologic outcome were not different between nursing home patients who received CPR prior to EMS arrival and those who did not [6.2% vs. 4.4% (p = 0.34) and 3.1% vs. 1.8% (p = 0.29)]. There was no statistically significant difference in the adjusted analysis. Conclusions: In this study population CPR was commonly delivered prior to EMS arrival. However, delivery of CPR prior to EMS arrival was not associated with survival to hospital discharge or favorable neurologic outcome. The lack of positive association between CPR prior to arrival and survival to hospital discharge may be related to comorbid factors present in ECF patients or differences in the time between collapse and initiation of CPR. Further study is needed to identify factors that might improve survival in this unique population.

Abstract Objective To determine the potential efficacy of ubrogepant for acute treatment of migraine based on historical experience with triptans. Background Although triptans have improved migraine treatment, their efficacy and tolerability may limit their utility in some individuals. Ubrogepant is a small‐molecule, oral calcitonin gene–related peptide receptor antagonist approved by the Food and Drug Administration for acute treatment of migraine in adults. Methods This post hoc analysis of pooled data from the pivotal trials ACHIEVE I and II, identically designed, randomized, double‐blind, phase 3, single‐attack trials of ubrogepant in adults with a history of migraine with/without aura, examined the efficacy and tolerability of ubrogepant 50 mg versus placebo based on participants’ historical experience with triptans: triptan responder, triptan‐insufficient responder, and triptan naïve. Co‐primary efficacy endpoints were pain freedom and absence of most bothersome migraine‐associated symptom (MBS) 2 h post initial dose. Adverse events (AEs) within historical triptan experience subgroups were evaluated. Results In the pooled analysis population ( n = 1799), 682 (placebo, n = 350; ubrogepant 50 mg, n = 332), 451 (placebo, n = 223; ubrogepant, n = 228), and 666 (placebo, n = 339; ubrogepant, n = 327) participants were triptan responders, triptan‐insufficient responders, and triptan‐naïve, respectively. Response rates on co‐primary efficacy endpoints were higher for ubrogepant versus placebo across all groups. Treatment‐by‐subgroup interaction p values based on odds ratios for pain freedom ( p = 0.290) and absence of MBS ( p = 0.705) indicated no significant impact of historical triptan experience on ubrogepant efficacy. AE incidence for ubrogepant did not differ appreciably across historical triptan experience subgroups. Conclusions Ubrogepant efficacy and tolerability did not differ for the acute treatment of migraine in participants classified as triptan responders, triptan‐insufficient responders, and triptan‐naïve based on their historical experience with triptans.

Background The full utility of an acute treatment requires examination of the entire time course of effect during a migraine attack. Here the time course of effect of ubrogepant is evaluated. Methods ACHIEVE-I and -II were double-blind, single-attack, Phase 3 trials. Adults with migraine were randomised 1:1:1 to placebo or ubrogepant (50mg or 100mg, ACHIEVE-I; 25 mg or 50 mg, ACHIEVE-II). Pain freedom, absence of most bothersome symptom, and pain relief were assessed at various timepoints. Samples were collected for pharmacokinetic analysis. Data were pooled for this post-hoc analysis. Results Participants’ (n = 912 placebo, n = 887 ubrogepant 50 mg, pooled analysis population) mean age was 41 years, with a majority female and white. Pain relief separated from placebo by 1 h (43% versus 37% [OR, 95% CI: 1.30, 1.0–1.59]), absence of most bothersome symptom by 1.5 h (28% versus 22% [1.42, 1.14–1.77]), and pain freedom by 2 h (20% vs. 13% [1.72, 1.33–2.22]). Efficacy was sustained from 2–24 h (pain relief: 1.71, 1.1–2.6; pain freedom: 1.71, 1.3–2.3) and remained separated at 48 h (pain relief: 1.7, 1.1–2.6; pain freedom: 1.31, 1.0–1.7). Pharmacokinetic analysis demonstrated maximum plasma concentrations were achieved at 1 h, with pharmacologically active concentrations reached within 11 min and remaining above the EC 90 for nearly 12 h. Conclusions Evaluation of the time course of effect of ubrogepant showed pain relief as the most sensitive and earliest measure of clinical effect, followed by absence of most bothersome symptom, and pain freedom. Efficacy was demonstrated out to 48 h, providing evidence of the long-lasting effect of ubrogepant. This evaluation supports the role of examining the entire time course of effect to understand fully the utility of an acute treatment for migraine. Trial registration: ACHIEVE I (ClinicalTrials.gov, NCT02828020) and ACHIEVE II (ClinicalTrials.gov, NCT02867709)

Abstract Purpose: NOTCH signaling is associated with tumorigenesis, mutagenesis, and immune tolerance in non–small cell lung cancer (NSCLC), indicating its association with the clinical benefit of immune checkpoint inhibitors (ICI). We hypothesized that NOTCH mutation in NSCLC might be a robust predictor of immunotherapeutic efficacy. Experimental Design: Multiple-dimensional data including genomic, transcriptomic, and clinical data from cohorts of NSCLC internal and public cohorts involving immunotherapeutic patients were analyzed. Polymorphism Phenotyping v2 (PolyPhen-2) system was performed to determine deleterious NOTCH mutation (del-NOTCHmut). Further investigation on molecular mechanism was performed in The Cancer Genome Atlas (TCGA) data via CIBERSORT and gene set enrichment analysis. Results: Our 3DMed cohort (n = 58) and other four cohorts (Rizvi, POPLAR/OAK, Van Allen, and MSKCC; n = 1,499) uncovered marked correlation between NOTCH1/2/3 mutation and better ICI outcomes in EGFR/ALKWT population, including objective response rate (2.20-fold, P = 0.001), progression-free survival [HR, 0.61; 95% confidence interval (CI), 0.46–0.81; P = 0.001], and overall survival (HR, 0.56; 95% CI, 0.32–0.96; P = 0.035). Del-NOTCHmut exhibited better predictive function than non-deleterious NOTCH mutation, potentially via greater transcription of genes related to DNA damage response and immune activation. Del-NOTCHmut was not linked with prognosis in TCGA cohorts and chemotherapeutic response, but was independently associated with immunotherapeutic benefit, delineating the predictive, but not prognostic, utility of del-NOTCHmut. Conclusions: This work distinguishes del-NOTCHmut as a potential predictor to favorable ICI response in NSCLC, highlighting the importance of genomic profiling in immunotherapy. More importantly, our results unravel a possibility of personalized combination immunotherapy as adding NOTCH inhibitor to ICI regimen in NSCLC, for the optimization of ICI treatment in clinical practice.