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Background/Aims: The Pediatric Research Equity Act and Best Pharmaceuticals for Children Act are intended to promote the conduct of clinical trials that generate pediatric-specific evidence about drug safety and efficacy. This study assesses the quality of evidence generated through Pediatric Research Equity Act–mandated and Best Pharmaceuticals for Children Act–incentivized clinical trials of hematology/oncology drugs and characterizes subsequent changes in pediatric drug utilization rates. Methods: Trial characteristics (blinding, randomization, and comparator group) were determined for clinical trials that supported pediatric label changes. Using data from OptumLabs ® Data Warehouse, a de-identified administrative claims database, we calculated pediatric utilization rates for each drug. We calculated monthly utilization rates from January 2003 (or from the first month in which data were available) to December 2018. Results: We identified 11 hematology/oncology drugs that underwent pediatric label changes under the Pediatric Research Equity Act Pediatric Research Equity Act and/or Best Pharmaceuticals for Children Act, and we identified 15 trials supporting these changes. Of these trials, 36% (5/14) were randomized, 31% (4/13) were blinded, and 36% (5/14) used a comparator group. A median of 49 children (interquartile range 29.5) received the drug under investigation across these trials. Pediatric label changes were not associated with subsequent changes in pediatric drug utilization. Although some drugs saw increased pediatric use after gaining new pediatric indications, this pattern was not consistently observed. In addition, there was no evidence to suggest that drugs were utilized less frequently after they failed to receive pediatric indications. Conclusions: Clinical trials of hematology/oncology drugs conducted under the Pediatric Research Equity Act Pediatric Research Equity Act and Best Pharmaceuticals for Children Act generally have low methodological rigor, and the resulting label changes are not consistently associated with changes in pediatric utilization. Alternative regulatory strategies and study designs may be necessary to maximize the impact of newly generated knowledge on drug utilization.

Background: Previous observational studies have demonstrated that outcomes after OHCA can be significantly improved with therapies such as mild therapeutic hypothermia and percutaneous coronary intervention (PCI). However, the optimal candidate and timing for PCI in OHCA remains unknown. This study aimed to assess the impact of emergent PCI on survival and neurological outcome after OHCA. Methods: This is a prospective observational study from a statewide OHCA database in Arizona. Patients included were greater than 18 years old who received CPR and were admitted to one of 34 recognized cardiac receiving centers. Patients who did not achieve ROSC, died within 2 hours of hospital arrival, and DNAR patients were excluded since the likelihood of PCI impacting outcome in these patients is questionable. An in-hospital post-arrest database, including PCI (Y/N), was linked with an Utstein-style OHCA database. Univariate and multivariate logistic regression were utilized to assess the association between PCI and survival to hospital discharge and neurological outcome. Results: During this study period (1-1-2011-12-31-2013), there were a total of 6,543 adult OHCA patients. After exclusions, 782 patients with suspected cardiac etiology OHCA were analyzed. The median age of patients was 64.0 years (Q1:54.0, Q3:73.0) and 70.2% were male. Among them 458 (58.6%) and 238 (30.4%) patients underwent the emergency coronary angiogram (CAG), and Primary PCI, respectively. Among PCI patients, the rate of survival to hospital discharge was 75.2%, vs. 60.4% for those without PCI (p<0.001) and good cerebral outcome (CPC 1-2) was found in 67.6%, vs. 44.3% of those without PCI (p<0.001). After adjusting for age, gender, initial rhythm, bystander CPR, and hypothermia, the Odds Ratio was 1.2 (95% CI:0.8-1.8) for survival and 2.8 (95% CI:1.5-5.1) for good neurologic outcome (CPC 1-2) among PCI patients. Conclusion: This study shows an association with emergent PCI and good neurologic outcome after OHCA. Further study is necessary to determine a potential causal relationship between PCI and outcome.

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: Abnormal breathing, or “gasping,” frequently occurs during cardiac arrest and has been associated with increased survival. During 9-1-1 calls, early recognition of gasping may allow dispatchers to identify OHCA and to start CPR instructions promptly. Objective: To characterize lay rescuers’ descriptions of abnormal breathing during OHCA. Methods: 9-1-1 audio recordings of 4,279 confirmed OHCAs (10/10-7/14) in Arizona were reviewed by program personnel. Terms used by lay rescuers to describe victims’ breathing were recorded in a structured database. Results: Abnormal breathing (as opposed to “not breathing”) was described in 542/4279 (13%) calls. There were 623 verbal descriptions. A total of 50 different terms were used. However, the top 8 accounted for 83% and the remaining 42 descriptions (“Other”) comprised only 17% of all terms used. “Gasping” was the most commonly used term (30%; 187/623), followed by “snoring” (15%; 95/623; Figure). Conclusion: Lay rescuers used a wide variety of terms to describe abnormal breathing in documented OHCA. However, 8 terms accounted for 83% of descriptions. Familiarizing 9-1-1 telecommunicators with the most commonly used terms may improve the accuracy of recognition and hasten the identification of OHCA.

OBJECTIVE : To evaluate the impact of cardiocerebral resuscitation (CCR), an alternative emergency medical services (EMS) protocol, on out-of-hospital cardiac arrest (OOHCA) survival in the state of Arizona. CCR, emphasizes 200 preshock chest compressions, a single defibrillator shock (when indicated) followed immediately by 200 postshock chest compressions, early intravenous epinephrine and delayed endotracheal intubation. METHODS : The Save Hearts in Arizona Registry and Education (SHARE) program collected Utstein style data from 38 different fire departments (FDs) servicing approximately 70% of Arizona’s population. 2671 consecutive OOHCAs, of which 1847 were adult and presumed cardiac etiology were enrolled between October, 2004 and December, 2006. The CCR protocol was implemented in 11/38 (29%) FDs and the remaining FDs 27/38 (72%) utilized standard ACLS. The primary end-point was survival to hospital discharge of all cardiac arrests and for the subgroup with witnessed arrest and ventricular fibrillation (VF) on EMS arrival. Outcomes were obtained from the Office of Vital Statistics as well as local hospitals and were compared using chi square testing; alpha = 0.05. RESULTS: 457/1847 (24.7%) patients were treated by CCR FDs and 1390/1847 (75.3%) were treated by ACLS FDs. Overall survival in the CCR group was significantly better than in the ACLS group (9.2% (42/457) vs. 3.5% (49/1390), p < 0.001). Similarly, survival for witnessed VF arrests was significantly better in the CCR group than the ACLS group (29.3% (29/99) vs. 11.1% (30/271), p < 0.001). Odds ratios were adjusted for age, gender, location, bystander CPR performed, % witnessed, % VF and EMS dispatch to arrival time. The odds of overall survival was 2.7 times higher in the CCR group compared to the overall ACLS group (95% CI 1.7,4.4), and 3.0 times higher in the CCR subgroup of witnessed VF (95% CI 1.6,5.6). CONCLUSION: Survival of patients with OOHCA in Arizona was significantly better in fire departments utilizing the cardiocerebral resuscitation protocol than in fire departments utilizing ACLS. Implementing the cardiocerebral resuscitation protocol on a large scale is feasible and saves lives.

Background: Bystander CPR (BCPR) increases survival from OHCA yet is provided in a minority of cases. The AHA has promulgated guidelines on the provision of pre-arrival Telephone CPR (TCPR) instructions and measurement to increase the proportion of BCPR; however, the impact of those guidelines on survival is unknown. Objective: To describe the impact of a comprehensive bundle of 9-1-1 TCPR protocol, training, data collection, and feedback on BCPR and survival from OHCA across the state of Arizona. Methods: 9-1-1 audio recordings of confirmed OHCAs and suspected OHCAs (10/2010-6/2013) in 7 large 9-1-1 centers were reviewed using a standardized time-stamp methodology linked with EMS and hospital process and outcome data. There were 2343 pre-implementation cases (P1) and 2291 cases post-implementation of a bundle of care (P2) that included staff training and guideline-based protocol changes, data collection and feedback to providers. Univariate and multivariable analyses were used to assess outcomes between P1 and P2. Results: There were 2532 OHCAs [1232 P1, 1300 P2; 64% male, median age 62 (IQR: 47-74)]. 83% of cases were identified in P1 compared with 89% in P2 (p<0.001). The rate of telephone-assisted BCPR went from 44% in P1 to 62% in P2 (p<0.001). Time to beginning TCPR instructions decreased from a median of 144 sec (P1) to 126 in P2 (p<0.001). Time to first chest compression also decreased (P1: 178; P2: 155; p<0.001). Outcome data are currently available for 64% of confirmed OHCAs (1630 patient outcomes with 1619 neuro outcomes). Survival was significantly higher in P2 (11.2%) compared to P1 (7.9%; p=0.023), as was good neuro outcome (CPC-1 or 2: 7.7% P2 vs. 4.8% P1 p=0.018). After adjusting for witnessed arrest, shockable rhythms, age, and sex, both survival and good neuro outcome were still significantly higher in P2 vs. P1 [adjusted odds ratios: survival = 1.5 (95% 1.1-2.1); good neuro outcome = 1.7 (95% 1.1-2.6)]. Conclusion: The implementation of a comprehensive statewide TCPR bundle was associated with significant improvements in the rates of telephone-assisted BCPR, survival and good neurologic outcome after OHCA.

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.

Abstract Introduction: A test that detects cancer signal across multiple cancer types and predicts signal (tissue) origin (SO) could aid in more efficient diagnostic workup and shorten time to cancer diagnosis in individuals with signs and symptoms.Methods: The Circulating Cell-free Genome Atlas (CCGA; NCT02889978) study is a prospective, longitudinal, multicenter, case-control study to develop and validate a multi-cancer detection test. The 2nd CCGA substudy utilized a targeted methylation-based cell-free DNA assay and machine learning algorithm and included assessment of test performance (sensitivity and SO prediction accuracy) in a subgroup of participants with clinically presenting cancers (CPCs) that were undiagnosed prior to blood draw. Specificity was assessed in the noncancer group and subgroups with confounding (nonmalignant) conditions (CCs; eg, cirrhosis) and noncancer participants enrolled in hematology clinics (HCs).Results: Specificity was 99.5% (95% confidence interval: 98.2-99.9%; 396/398), 93.8% (71.7-99.7%; 15/16), and 99.3% (96.0-100.0%; 136/137) for the noncancer group, CCs subgroup, and HCs subgroup, respectively. Overall sensitivity among those with CPCs was 66.4% (62.2-70.3%; 344/518). Sensitivity of cancer signal detection increased with increasing clinical stage (Table). SO prediction accuracy was 91.7% (88.3-94.3%; 300/327) among CPC participants with cancers detected, excluding those with multiple or unknown primaries. The test demonstrated prognostic value as detected cancer participants had worse survival probability than those not detected. Conclusions: This multi-cancer detection test detected cancer signals and predicted SO in individuals with CPCs with high specificity. These findings support further clinical development of this multi-cancer detection test that could accelerate the diagnostic resolution of symptomatic cancers. Table. Sensitivity by Clinical Stage Across Cancer Type in Clinically Presenting CancersClinical StagePositive Test/Total Cancer; Sensitivity (95% CI)All*344/518; 66.4% (62.2-70.3%)I33/122; 27.0% (20.0-35.5%)II60/102; 58.8% (49.1-67.9%)III103/121; 85.1% (77.7-90.4%)IV136/147; 92.5% (87.1-95.8%)Not expected to be staged9/21; 42.9% (24.5-63.5%)Non-informative2/4; 50.0% (15.0-85.0%)CI, confidence interval.*One participant who had a positive test result had multiple primaries with clinical stage I and not-expected-to-be-staged. Citation Format: Alan H. Bryce, Minetta C. Liu, Michael V. Seiden, David D. Thiel, Donald Richards, Carlos Becerra, Kathryn N. Kurtzman, Xiaoji Chen, Tony Wu, Quan Zhang, Jingjing Gao, Nan Zhang, Earl Hubbell, Arash Jamshidi, Eric T. Fung, Eric A. Klein. Performance of a cell-free DNA-based multi-cancer detection test as a tool for diagnostic resolution of symptomatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB058.