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L9 is a potent human monoclonal antibody (mAb) that preferentially binds two adjacent NVDP minor repeats and cross-reacts with NANP major repeats of the Plasmodium falciparum circumsporozoite protein (PfCSP) on malaria-infective sporozoites. Understanding this mAb's ontogeny and mechanisms of binding PfCSP will facilitate vaccine development. Here, we isolate mAbs clonally related to L9 and show that this B cell lineage has baseline NVDP affinity and evolves to acquire NANP reactivity. Pairing the L9 kappa light chain (L9κ) with clonally related heavy chains results in chimeric mAbs that cross-link two NVDPs, cross-react with NANP, and more potently neutralize sporozoites in vivo compared with their original light chain. Structural analyses reveal that the chimeric mAbs bound minor repeats in a type-1 β-turn seen in other repeat-specific antibodies. These data highlight the importance of L9κ in binding NVDP on PfCSP to neutralize sporozoites and suggest that PfCSP-based immunogens might be improved by presenting ≥2 NVDPs., Competing Interests: Declaration of interests R.A.S., J.R.F., and L.T.W. have submitted US Provisional Patent Application No. 62/842590, filed May 3, 2019, describing mAb L9. All other authors declare no competing interests., (Copyright © 2022. Published by Elsevier Inc.)

Study Objective: While often prioritized in the resuscitation of patients with out-of-hospital cardiac arrest, the optimal timing of advanced airway insertion is unknown. We evaluated the association between the timing of advanced airway (laryngeal tube and endotracheal intubation) insertion attempt and survival to hospital discharge in adult out-of-hospital cardiac arrest., Methods: We performed a secondary analysis of the Pragmatic Airway Resuscitation Trial (PART), a clinical trial comparing the effects of laryngeal tube and endotracheal intubation on outcomes after adult out-of-hospital cardiac arrest. We stratified the cohort by randomized airway strategy (laryngeal tube or endotracheal intubation). Within each subset, we defined a time-dependent propensity score using patients, arrest, and emergency medical services systems characteristics. Using the propensity score, we matched each patient receiving an initial attempt of laryngeal tube or endotracheal intubation with a patient at risk of receiving laryngeal tube or endotracheal intubation attempt within the same minute., Results: Of 2,146 eligible patients, 1,091 (50.8%) and 1,055 (49.2%) were assigned to initial laryngeal tube and endotracheal intubation strategies, respectively. In the propensity score-matched cohort, timing of laryngeal tube insertion attempt was not associated with survival to hospital discharge: 0 to lesser than 5 minutes (risk ratio [RR]=1.35, 95% confidence interval [CI] 0.53 to 3.44); 5 to lesser than10 minutes (RR=1.07, 95% CI 0.66 to 1.73); 10 to lesser than 15 minutes (RR=1.17, 95% CI 0.60 to 2.31); or 15 to lesser than 20 minutes (RR=2.09, 95% CI 0.35 to 12.47) after advanced life support arrival. Timing of endotracheal intubation attempt was also not associated with survival: 0 to lesser than 5 minutes (RR=0.50, 95% CI 0.05 to 4.87); 5 to lesser than10 minutes (RR=1.20, 95% CI 0.51 to 2.81); 10 to lesser than15 minutes (RR=1.03, 95% CI 0.49 to 2.14); 15 to lesser than 20 minutes (RR=0.85, 95% CI 0.30 to 2.42); or more than/equal to 20 minutes (RR=0.71, 95% CI 0.07 to 7.14)., Conclusion: In the PART, timing of advanced airway insertion attempt was not associated with survival to hospital discharge., (Copyright © 2021 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: Previous studies have shown racial disparities in outcomes after out-of-hospital cardiac arrest. Although several treatment factors may account for these differences, there is limited information regarding differences in CPR quality and its effect on survival in underrepresented racial populations., Methods: We conducted a secondary analysis of data from patients enrolled in the Pragmatic Airway Resuscitation Trial (PART). We calculated compliance rates with AHA 2015 high quality CPR metrics as well as compliance to intended CPR strategy (30:2 or continuous chest compression) based on the protocol in place for the first responding EMS agency. The primary analysis used general estimating equations logistic regression to examine differences between black and white patients based on EMS-assessed race after adjustment for potential confounders. Sensitivity analyses examined differences using alternate race definitions., Results: There were 3004 patients enrolled in PART of which 1734 had > 2 minutes of recorded CPR data and an EMS-assessed race (1003 white, 555 black, 176 other). Black patients had higher adjusted odds of compression rate compliance (OR: 1.36, 95% CI: 1.02-1.81) and lower adjusted odds of intended CPR strategy compliance (OR: 0.78, 95% CI: 0.63-0.98) compared to white patients. Of 974 transported to the hospital, there was no difference in compliance metric estimates based on ED-reported race., Conclusion: Compression rate compliance was higher in black patients however compliance with intended strategy was lower based on EMS-assessed race. The remaining metrics showed no difference suggesting that CPR quality differences are not important contributors to the observed outcome disparities by race., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Repeat antigens, such as the Plasmodium falciparum circumsporozoite protein (PfCSP), use both sequence degeneracy and structural diversity to evade the immune response. A few PfCSP-directed antibodies have been identified that are effective at preventing malaria infection, including CIS43, but how these repeat-targeting antibodies might be improved has been unclear. Here, we engineered a humanized mouse model in which B cells expressed inferred human germline CIS43 (iGL-CIS43) B cell receptors and used both vaccination and bioinformatic analysis to obtain variant CIS43 antibodies with improved protective capacity. One such antibody, iGL-CIS43.D3, was significantly more potent than the current best-in-class PfCSP-directed antibody. We found that vaccination with a junctional epitope peptide was more effective than full-length PfCSP at recruiting iGL-CIS43 B cells to germinal centers. Structure-function analysis revealed multiple somatic hypermutations that combinatorically improved protection. This mouse model can thus be used to understand vaccine immunogens and to develop highly potent anti-malarial antibodies., Competing Interests: Declaration of interests S.K., P.T., R.R., M.R., P.D.K., R.A.S. and F.D.B. have submitted a US Provisional Patent Application describing improved CIS43 antibodies (filed November 5, 2021). B.J.F., R.A.S., A.H.I., and N.K.K. hold patents on CIS43 (International Application No. PCT/US2018/017826; US Patent Application No. 16/485,354; issued June 1, 2021). L.T.W., R.A.S., and J.R.F. have submitted a US Provisional Patent Application describing mAb L9 (62/842,590; filed May 3, 2019). The remaining authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Combinations of monoclonal antibodies (mAbs) against different epitopes on the same antigen synergistically neutralize many viruses. However, there are limited studies assessing whether combining human mAbs against distinct regions of the Plasmodium falciparum (Pf) circumsporozoite protein (CSP) enhances in vivo protection against malaria compared to each mAb alone or whether passive transfer of PfCSP mAbs would improve protection following vaccination against PfCSP. Here, we isolated a panel of human mAbs against the subdominant C-terminal domain of PfCSP (C-CSP) from a volunteer immunized with radiation-attenuated Pf sporozoites. These C-CSP-specific mAbs had limited binding to sporozoites in vitro that was increased by combination with neutralizing human "repeat" mAbs against the NPDP/NVDP/NANP tetrapeptides in the central repeat region of PfCSP. Nevertheless, passive transfer of repeat- and C-CSP-specific mAb combinations did not provide enhanced protection against in vivo sporozoite challenge compared to repeat mAbs alone. Furthermore, combining potent repeat-specific mAbs (CIS43, L9, and 317) that respectively target the three tetrapeptides (NPDP/NVDP/NANP) did not provide additional protection against in vivo sporozoite challenge. However, administration of either CIS43, L9, or 317 (but not C-CSP-specific mAbs) to mice that had been immunized with R21, a PfCSP-based virus-like particle vaccine that induces polyclonal antibodies against the repeat region and C-CSP, provided enhanced protection against sporozoite challenge when compared to vaccine or mAbs alone. Collectively, this study shows that while combining mAbs against the repeat and C-terminal regions of PfCSP provide no additional protection in vivo, repeat mAbs do provide increased protection when combined with vaccine-induced polyclonal antibodies. These data should inform the implementation of PfCSP human mAbs alone or following vaccination to prevent malaria infection., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: R.A.S., J.F., L.T.W., and R.V. have submitted U.S. Provisional Patent Application No. 62/842,590, filed 3 May 2019, describing mAb L9. All other authors have declared that no competing interests exist.

Rare and potent monoclonal antibodies (mAbs) against the Plasmodium falciparum (Pf) circumsporozoite protein (CSP) on infective sporozoites (SPZ) preferentially bind the PfCSP junctional tetrapeptide NPDP or NVDP minor repeats while cross-reacting with NANP central repeats in vitro. The extent to which each of these epitopes is required for protection in vivo is unknown. Here, we assessed whether junction-, minor repeat- and central repeat-preferring human mAbs (CIS43, L9 and 317 respectively) bound and protected against in vivo challenge with transgenic P. berghei (Pb) SPZ expressing either PfCSP with the junction and minor repeats knocked out (KO), or PbCSP with the junction and minor repeats knocked in (KI). In vivo protection studies showed that the junction and minor repeats are necessary and sufficient for CIS43 and L9 to neutralize KO and KI SPZ, respectively. In contrast, 317 required major repeats for in vivo protection. These data establish that human mAbs can prevent malaria infection by targeting three different protective epitopes (NPDP, NVDP, NANP) in the PfCSP repeat region. This report will inform vaccine development and the use of mAbs to passively prevent malaria., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: R.A.S., J.F., and L.T.W. have submitted U.S. Provisional Patent Application No. 62/842,590, filed 3 May 2019, describing L9. R.A.S, N.K.K. and A.H.I. hold a patent (International Application No. PCT/US2018/017826) describing CIS43 and related mAbs. Y. F-G., B.A., N.K.H, C.M and F.Z. have declared that no competing interests exist.

Background: Out-of-hospital cardiac arrest (OHCA) data debriefing and clinical research often require the retrospective analysis of large datasets containing defibrillator files from different vendors and clinical annotations by the emergency medical services., Aim: To introduce and evaluate a methodology to automatically extract cardiopulmonary resuscitation (CPR) quality data in a uniform and systematic way from OHCA datasets from multiple heterogeneous sources., Methods: A dataset of 2236 OHCA cases from multiple defibrillator models and manufacturers was analyzed. Chest compressions were automatically identified using the thoracic impedance and compression depth signals. Device event time-stamps and clinical annotations were used to set the start and end of the analysis interval, and to identify periods with spontaneous circulation. A manual audit of the automatic annotations was conducted and used as gold standard. Chest compression fraction (CCF), rate (CCR) and interruption ratio were computed as CPR quality variables. The unsigned error between the automated procedure and the gold standard was calculated., Results: Full-episode median errors below 2% in CCF, 1 min -1 in CCR, and 1.5% in interruption ratio, were measured for all signals and devices. The proportion of cases with large errors (>10% in CCF and interruption ratio, and >10 min -1 in CCR) was below 10%. Errors were lower for shorter sub-intervals of interest, like the airway insertion interval., Conclusions: An automated methodology was validated to accurately compute CPR metrics in large and heterogeneous OHCA datasets. Automated processing of defibrillator files and the associated clinical annotations enables the aggregation and analysis of CPR data from multiple sources., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Additional interventions are needed to reduce the morbidity and mortality caused by malaria., Methods: We conducted a two-part, phase 1 clinical trial to assess the safety and pharmacokinetics of CIS43LS, an antimalarial monoclonal antibody with an extended half-life, and its efficacy against infection with Plasmodium falciparum . Part A of the trial assessed the safety, initial side-effect profile, and pharmacokinetics of CIS43LS in healthy adults who had never had malaria. Participants received CIS43LS subcutaneously or intravenously at one of three escalating dose levels. A subgroup of participants from Part A continued to Part B, and some received a second CIS43LS infusion. Additional participants were enrolled in Part B and received CIS43LS intravenously. To assess the protective efficacy of CIS43LS, some participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying P. falciparum sporozoites 4 to 36 weeks after administration of CIS43LS., Results: A total of 25 participants received CIS43LS at a dose of 5 mg per kilogram of body weight, 20 mg per kilogram, or 40 mg per kilogram, and 4 of the 25 participants received a second dose (20 mg per kilogram regardless of initial dose). No safety concerns were identified. We observed dose-dependent increases in CIS43LS serum concentrations, with a half-life of 56 days. None of the 9 participants who received CIS43LS, as compared with 5 of 6 control participants who did not receive CIS43LS, had parasitemia according to polymerase-chain-reaction testing through 21 days after controlled human malaria infection. Two participants who received 40 mg per kilogram of CIS43LS and underwent controlled human malaria infection approximately 36 weeks later had no parasitemia, with serum concentrations of CIS43LS of 46 and 57 μg per milliliter at the time of controlled human malaria infection., Conclusions: Among adults who had never had malaria infection or vaccination, administration of the long-acting monoclonal antibody CIS43LS prevented malaria after controlled infection. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 612 ClinicalTrials.gov number, NCT04206332.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: A large, randomized trial showed no significant difference in survival to discharge between cardiopulmonary resuscitation (CPR) strategies of 30 compressions with pause for 2 ventilations per cycle (30:2) and continuous chest compression with asynchronous ventilations (CCC). Data from the same trial suggested that adherence to the intended CPR strategy was associated with significantly greater survival. We sought to determine the adherence rate with intended strategy and then explore the association of adherence with survival to discharge in the Resuscitation Outcomes Consortium (ROC)., Methods: This secondary analysis of data from the ROC included three interventional trials and a prospective registry. We modified an automated software algorithm that classified care as 30:2 or CCC before intubation based on compression segment length (defined as the elapsed time from start of compressions to subsequent pause of ≥2 s), number of pauses per minute ≥2 s in length and chest compression fraction. Intended CPR strategy for individual agencies was based on study randomization (during trial phase) or local standard of care (during registry phase). We defined CPR delivered as adherent when its classification matched the intended strategy. We characterized adherence with intended strategy across trial and registry periods. We examined its association with survival to hospital discharge using multivariate logistic regression after adjustment for Utstein and other potential confounders. Effect modification with intended strategy was assessed through a multiplicative interaction term., Results: Included were 26,810 adults with out of hospital cardiac arrest, of which 10,942 had an intended strategy of 30:2 and 15,868 an intended strategy of CCC. The automated algorithm classified 12,276 cases as CCC, 7037 as 30:2 and left 7497 as unclassified. Adherence to intended strategy was 54.4%; this differed by intended strategy (58.6% for CCC vs 48.3% for 30:2). Overall adherence was less during the registry phase as compared to during the trial phase(s). The association between adherence and survival was modified by treatment arm (CCC OR: 0.72, 95% CI: 0.64-0.81 vs 30:2 OR: 1.05, 95% CI: 0.90-1.22; interaction p-value<0.01) after adjustment for known confounders., Conclusion: For intended strategy CCC, survival was significantly lower, OR (95%CI) = 0.72 (0.64, 0.81), when adhered to while for intended strategy 30:2, survival was higher, OR (95%CI) = 1.05 (0.90, 1.22), when adhered to. Intended strategy of 30:2 had lower adherence rates than CCC possibly a result of being a more difficult strategy to administer., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Immunoglobulin (Ig)A antibodies play a critical role in protection against mucosal pathogens. However, the role of serum IgA in immunity to nonmucosal pathogens, such as Plasmodium falciparum , is poorly characterized, despite being the second most abundant isotype in blood after IgG. Here, we investigated the circulating IgA response in humans to P. falciparum sporozoites that are injected into the skin by mosquitoes and migrate to the liver via the bloodstream to initiate malaria infection. We found that circulating IgA was induced in three independent sporozoite-exposed cohorts: individuals living in an endemic region in Mali, malaria-naïve individuals immunized intravenously with three large doses of irradiated sporozoites, and malaria-naïve individuals exposed to a single controlled mosquito bite infection. Mechanistically, we found evidence in an animal model that IgA responses were induced by sporozoites at dermal inoculation sites. From malaria-resistant individuals, we isolated several IgA monoclonal antibodies that reduced liver parasite burden in mice. One antibody, MAD2-6, bound to a conserved epitope in the amino terminus of the P. falciparum circumsporozoite protein, the dominant protein on the sporozoite surface. Crystal structures of this antibody revealed a unique mode of binding whereby two Fabs simultaneously bound either side of the target peptide. This study reveals a role for circulating IgA in malaria and identifies the amino terminus of the circumsporozoite protein as a target of functional antibodies., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Chest compression (CC) quality is associated with improved out-of-hospital cardiopulmonary arrest (OHCA) outcomes. Airway management efforts may adversely influence CC quality. We sought to compare the effects of initial laryngeal tube (LT) and initial endotracheal intubation (ETI) airway management strategies upon chest compression fraction (CCF), rate and interruptions in the Pragmatic Airway Resuscitation Trial (PART)., Methods: We analyzed CPR process files collected from adult OHCA enrolled in PART. We used automated signal processing techniques and a graphical user interface to calculate CC quality measures and defined interruptions as pauses in chest compressions longer than 3 s. We determined CC fraction, rate and interruptions (number and total duration) for the entire resuscitation and compared differences between LT and ETI using t-tests. We repeated the analysis stratified by time before, during and after airway insertion as well as by successive 3-min time segments. We also compared CC quality between single vs. multiple airway insertion attempts, as well as between bag-valve-mask (BVM-only) vs. ETI or LT., Results: Of 3004 patients enrolled in PART, CPR process data were available for 1996 (1001 LT, 995 ETI). Mean CPR analysis duration were: LT 22.6 ± 10.8 min vs. ETI 25.3 ± 11.3 min (p < 0.001). Mean CC fraction (LT 88% vs. ETI 87%, p = 0.05) and rate (LT 114 vs. ETI 114 compressions per minute (cpm), p = 0.59) were similar between LT and ETI. Median number of CC interruptions were: LT 11 vs. ETI 12 (p = 0.001). Total CC interruption duration was lower for LT than ETI (LT 160 vs. ETI 181 s, p = 0.002); this difference was larger before airway insertion (LT 56 vs. ETI 78 s, p < 0.001). There were no differences in CC quality when stratified by 3-min time epochs., Conclusion: In the PART trial, compared with ETI, LT was associated with shorter total CC interruption duration but not other CC quality measures. CC quality may be associated with OHCA airway management., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The most advanced malaria vaccine, RTS,S, includes the central repeat and C-terminal domains of the Plasmodium falciparum circumsporozoite protein (PfCSP). We have recently isolated human antibodies that target the junctional region between the N-terminal and repeat domains that are not included in RTS,S. Due to the fact that these antibodies protect against malaria challenge in mice, their epitopes could be effective vaccine targets. Here, we developed immunogens displaying PfCSP junctional epitopes by genetic fusion to either the N-terminus or B domain loop of the E2 protein from chikungunya (CHIK) alphavirus and produced CHIK virus-like particles (CHIK-VLPs). The structural integrity of these junctional-epitope-CHIK-VLP immunogens was confirmed by negative-stain electron microscopy. Immunization of these CHIK-VLP immunogens reduced parasite liver load by up to 95% in a mouse model of malaria infection and elicited better protection than when displayed on keyhole limpet hemocyanin, a commonly used immunogenic carrier. Protection correlated with PfCSP serum titer. Of note, different junctional sequences elicited qualitatively different reactivities to overlapping PfCSP peptides. Overall, these results show that the junctional epitopes of PfCSP can induce protective responses when displayed on CHIK-VLP immunogens and provide a basis for the development of a next generation malaria vaccine to expand the breadth of anti-PfCSP immunity.

Background: High-quality chest compressions are associated with improved outcomes after cardiac arrest. Defibrillators record important information about chest compressions during cardiopulmonary resuscitation (CPR) and can be used in quality-improvement programs. Defibrillator review software can automatically annotate files and measure chest compression metrics. However, evidence is limited regarding the accuracy of such measurements., Objective: To compare chest compression fraction (CCF) and rate measurements made with software annotation vs. manual annotation vs. limited manual annotation of defibrillator files recorded during out-of-hospital cardiac arrest (OHCA) CPR., Methods: This was a retrospective, observational study of 100 patients who had CPR for OHCA. We assessed chest compression bioimpedance waveforms from the time of initial CPR until defibrillator removal. A reviewer revised software annotations in two ways: completely manual annotations and limited manual annotations, which marked the beginning and end of CPR and ROSC, but not chest compressions. Measurements were compared for CCF and rate using intraclass correlation coefficient (ICC) analysis., Results: Case mean rate showed no significant difference between the methods (108.1-108.6 compressions per minute) and ICC was excellent (>0.90). The case mean (±SD) CCF for software, manual, and limited manual annotation was 0.64 ± 0.19, 0.86 ± 0.07, and 0.81 ± 0.10, respectively. The ICC for manual vs. limited manual annotation of CCF was 0.69 while for individual minute epochs it was 0.83., Conclusion: Software annotation performed very well for chest compression rate. For CCF, the difference between manual and software annotation measurements was clinically important, while manual vs. limited manual annotation were similar with an ICC that was good-to-excellent., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Studies examining gender-based differences in outcomes of patients experiencing out-of-hospital cardiac arrest have demonstrated that, despite a higher likelihood of return of spontaneous circulation, women do not have higher survival., Methods: Patients successfully resuscitated from out-of-hospital cardiac arrest enrolled in the CCC trial (Trial of Continuous or Interrupted Chest Compressions during CPR) were included. Hierarchical multivariable logistic regression models were constructed to evaluate the association between gender and survival after adjustment for age, gender, cardiac arrest rhythm, witnessed status, bystander cardiopulmonary resuscitation, episode location, epinephrine dose, emergency medical services response time, and duration of resuscitation. Do not resuscitate (DNR) and withdrawal of life-sustaining therapy (WLST) order status were used to assess whether differences in postresuscitation outcomes were modified by baseline prognosis. The analysis was replicated among ALPS trial (Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest) participants., Results: Among 4875 successfully resuscitated patients, 1825 (37.4%) were women and 3050 (62.6%) were men. Women were older (67.5 versus 65.3 years), received less bystander cardiopulmonary resuscitation (49.1% versus 54.9%), and had a lower proportion of cardiac arrests that were witnessed (55.1% versus 64.5%) or had shockable rhythm (24.3% versus 44.6%, P <0.001 for all). A significantly higher proportion of women received DNR orders (35.7% versus 32.1%, P =0.009) and had WLST (32.8% versus 29.8%, P =0.03). Discharge survival was significantly lower in women (22.5% versus 36.3%, P <0.001; adjusted odds ratio, 0.78 [95% CI, 0.66-0.93]; P =0.005). The association between gender and survival to discharge was modified by DNR and WLST order status such that women had significantly reduced survival to discharge among patients who were not designated DNR (31.3% versus 49.9%, P =0.005; adjusted odds ratio, 0.74 [95% CI, 0.60-0.91]) or did not have WLST (32.3% versus 50.7%, P =0.002; adjusted odds ratio, 0.73 [95% CI, 0.60-0.89]). In contrast, no gender difference in survival was noted among patients receiving a DNR order (6.7% versus 7.4%, P =0.90) or had WLST (2.8% versus 2.4%, P =0.93). Consistent patterns of association between gender and postresuscitation outcomes were observed in the secondary cohort., Conclusions: Among patients resuscitated after experiencing out-of-hospital cardiac arrest, discharge survival was significantly lower in women than in men, especially among patients considered to have a favorable prognosis.

The diversity of circulating human B cells is unknown. We use single-cell RNA sequencing (RNA-seq) to examine the diversity of both antigen-specific and total B cells in healthy subjects and malaria-exposed individuals. This reveals two B cell lineages: a classical lineage of activated and resting memory B cells and an alternative lineage, which includes previously described atypical B cells. Although atypical B cells have previously been associated with disease states, the alternative lineage is common in healthy controls, as well as malaria-exposed individuals. We further track Plasmodium-specific B cells after malaria vaccination in naive volunteers. We find that alternative lineage cells are primed after the initial immunization and respond to booster doses. However, alternative lineage cells develop an atypical phenotype with repeated boosts. The data highlight that atypical cells are part of a wider alternative lineage of B cells that are a normal component of healthy immune responses., Competing Interests: Declaration of interests S.C., N.K., B.K.L.S., and S.L.H. are salaried employees of Sanaria, the developer and owner of PfSPZ Vaccine and the investigational new drug (IND) application sponsor of the clinical trials. S.L.H. and B.K.L.S. have a financial interest in Sanaria. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

CIS43 is a potent neutralizing human mAb that targets a highly conserved "junctional" epitope in the Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP). Enhancing the durability of CIS43 in vivo will be important for clinical translation. Here, 2 approaches were used to improve the durability of CIS43 in vivo while maintaining potent neutralization. First, the Fc domain was modified with the LS mutations (CIS43LS) to increase CIS43 binding affinity for the neonatal Fc receptor (FcRn). CIS43LS and CIS43 showed comparable in vivo protective efficacy. CIS43LS had 9- to 13-fold increased binding affinity for human (6.2 nM versus 54.2 nM) and rhesus (25.1 nM versus 325.8 nM) FcRn at endosomal pH 6.0 compared with CIS43. Importantly, the half-life of CIS43LS in rhesus macaques increased from 22 days to 39 days compared with CIS43. The second approach for sustaining antibody levels of CIS43 in vivo is through adeno-associated virus (AAV) expression. Mice administered once with AAV-expressing CIS43 had sustained antibody levels of approximately 300 μg/mL and mediated protection against sequential malaria challenges up to 36 weeks. Based on these data, CIS43LS has advanced to phase I clinical trials, and AAV delivery provides a potential next-generation approach for malaria prevention.

Objective: While emphasized in clinical practice, the association between advanced airway insertion first-pass success (FPS) and patient outcomes is incompletely understood. We sought to determine the association of airway insertion FPS with adult out-of-hospital cardiac arrest (OHCA) outcomes in the Pragmatic Airway Resuscitation Trial (PART)., Methods: We performed a secondary analysis of PART, a multicenter clinical trial comparing LT and ETI upon adult OHCA outcomes. We defined FPS as successful LT insertion or ETI on the first attempt as reported by EMS personnel. We examined the outcomes return of spontaneous circulation (ROSC), 72-h survival, hospital survival, and hospital survival with favorable neurologic status (Modified Rankin Scale ≤3). Using multivariable GEE (generalized estimating equations), we determined the association between FPS and OHCA outcomes, adjusting for age, sex, witnessed arrest, bystander CPR, initial rhythm, and initial airway type., Results: Of 3004 patients enrolled in the trial, 1423 received LT, 1227 received ETI, 354 received bag-valve-mask ventilation only. FPS was: LT 86.2% and ETI 46.7%. FPS was associated with increased ROSC (aOR 1.23; 95%CI: 1.07-1.41)), but not 72-h survival (1.22; 0.94-1.58), hospital survival (0.90; 0.68-1.19) or hospital survival with favorable neurologic status (0.66; 0.37-1.19)., Conclusion: In adult OHCA, airway insertion FPS was associated with increased ROSC but not other OHCA outcomes. The influence of airway insertion FPS upon OHCA outcomes is unclear., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: An artefact-free electrocardiogram (ECG) is essential during cardiac arrest to decide therapy such as defibrillation. Mechanical cardiopulmonary resuscitation (CPR) devices cause movement artefacts that alter the ECG. This study analyzes the effectiveness of mechanical CPR artefact suppression filters to restore clinically relevant ECG information., Approach: In total, 495 10 s ECGs were used, of which 165 were in ventricular fibrillation (VF), 165 in organized rhythms (OR) and 165 contained mechanical CPR artefacts recorded during asystole. CPR artefacts and rhythms were mixed at controlled signal-to-noise ratios (SNRs), ranging from -20 dB to 10 dB. Mechanical artefacts were removed using least mean squares (LMS), recursive least squares (RLS) and Kalman filters. Performance was evaluated by comparing the clean and the restored ECGs in terms of restored SNR, correlation-based similarity measures, and clinically relevant features: QRS detection performance for OR, and dominant frequency, mean amplitude and waveform irregularity for VF. For each filter, a shock/no-shock support vector machine algorithm based on multiresolution analysis of the restored ECG was designed, and evaluated in terms of sensitivity (Se) and specificity (Sp)., Main Results: The RLS filter produced the largest correlation coefficient (0.80), the largest average increase in SNR (9.5 dB), and the best QRS detection performance. The LMS filter best restored VF with errors of 10.3% in dominant frequency, 18.1% in amplitude and 11.8% in waveform irregularity. The Se/Sp of the diagnosis of the restored ECG were 95.1/94.5% using the RLS filter and 97.0/91.4% using the LMS filter., Significance: Suitable filter configurations to restore ECG waveforms during mechanical CPR have been determined, allowing reliable clinical decisions without interrupting mechanical CPR therapy.

Discovering potent human monoclonal antibodies (mAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on sporozoites (SPZ) and elucidating their mechanisms of neutralization will facilitate translation for passive prophylaxis and aid next-generation vaccine development. Here, we isolated a neutralizing human mAb, L9 that preferentially bound NVDP minor repeats of PfCSP with high affinity while cross-reacting with NANP major repeats. L9 was more potent than six published neutralizing human PfCSP mAbs at mediating protection against mosquito bite challenge in mice. Isothermal titration calorimetry and multiphoton microscopy showed that L9 and the other most protective mAbs bound PfCSP with two binding events and mediated protection by killing SPZ in the liver and by preventing their egress from sinusoids and traversal of hepatocytes. This study defines the subdominant PfCSP minor repeats as neutralizing epitopes, identifies an in vitro biophysical correlate of SPZ neutralization, and demonstrates that the liver is an important site for antibodies to prevent malaria., Competing Interests: Declaration of Interests R.A.S., J.R.F., L.T.W., and R.V. have submitted US Provisional Patent Application 62/842,590, filed 3 May 2019, describing mAb L9. All other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Generating sufficient antibody to block infection is a key challenge for vaccines against malaria. Here, we show that antibody titers to a key target, the repeat region of the Plasmodium falciparum circumsporozoite protein (PfCSP), plateaued after two immunizations in a clinical trial of the radiation-attenuated sporozoite vaccine. To understand the mechanisms limiting vaccine responsiveness, we developed immunoglobulin (Ig)-knockin mice with elevated numbers of PfCSP-binding B cells. We determined that recall responses were inhibited by antibody feedback, potentially via epitope masking of the immunodominant PfCSP repeat region. Importantly, the amount of antibody that prevents boosting is below the amount of antibody required for protection. Finally, while antibody feedback limited responses to the PfCSP repeat region in vaccinated volunteers, potentially protective subdominant responses to PfCSP C-terminal regions expanded with subsequent boosts. These data suggest that antibody feedback drives the diversification of immune responses and that vaccination for malaria will require targeting multiple antigens., Competing Interests: Declaration of Interests S.C., N.K., B.K.L.S., and S.L.H. are salaried employees of Sanaria Inc., the developer and owner of PfSPZ Vaccine and the investigational new drug (IND) application sponsor of the clinical trials. S.L.H. and B.K.L.S. have a financial interest in Sanaria Inc. All other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Importance: Traumatic brain injury (TBI) is the leading cause of death and disability due to trauma. Early administration of tranexamic acid may benefit patients with TBI., Objective: To determine whether tranexamic acid treatment initiated in the out-of-hospital setting within 2 hours of injury improves neurologic outcome in patients with moderate or severe TBI., Design, Setting, and Participants: Multicenter, double-blinded, randomized clinical trial at 20 trauma centers and 39 emergency medical services agencies in the US and Canada from May 2015 to November 2017. Eligible participants (N = 1280) included out-of-hospital patients with TBI aged 15 years or older with Glasgow Coma Scale score of 12 or less and systolic blood pressure of 90 mm Hg or higher., Interventions: Three interventions were evaluated, with treatment initiated within 2 hours of TBI: out-of-hospital tranexamic acid (1 g) bolus and in-hospital tranexamic acid (1 g) 8-hour infusion (bolus maintenance group; n = 312), out-of-hospital tranexamic acid (2 g) bolus and in-hospital placebo 8-hour infusion (bolus only group; n = 345), and out-of-hospital placebo bolus and in-hospital placebo 8-hour infusion (placebo group; n = 309)., Main Outcomes and Measures: The primary outcome was favorable neurologic function at 6 months (Glasgow Outcome Scale-Extended score >4 [moderate disability or good recovery]) in the combined tranexamic acid group vs the placebo group. Asymmetric significance thresholds were set at 0.1 for benefit and 0.025 for harm. There were 18 secondary end points, of which 5 are reported in this article: 28-day mortality, 6-month Disability Rating Scale score (range, 0 [no disability] to 30 [death]), progression of intracranial hemorrhage, incidence of seizures, and incidence of thromboembolic events., Results: Among 1063 participants, a study drug was not administered to 96 randomized participants and 1 participant was excluded, resulting in 966 participants in the analysis population (mean age, 42 years; 255 [74%] male participants; mean Glasgow Coma Scale score, 8). Of these participants, 819 (84.8%) were available for primary outcome analysis at 6-month follow-up. The primary outcome occurred in 65% of patients in the tranexamic acid groups vs 62% in the placebo group (difference, 3.5%; [90% 1-sided confidence limit for benefit, -0.9%]; P = .16; [97.5% 1-sided confidence limit for harm, 10.2%]; P = .84). There was no statistically significant difference in 28-day mortality between the tranexamic acid groups vs the placebo group (14% vs 17%; difference, -2.9% [95% CI, -7.9% to 2.1%]; P = .26), 6-month Disability Rating Scale score (6.8 vs 7.6; difference, -0.9 [95% CI, -2.5 to 0.7]; P = .29), or progression of intracranial hemorrhage (16% vs 20%; difference, -5.4% [95% CI, -12.8% to 2.1%]; P = .16)., Conclusions and Relevance: Among patients with moderate to severe TBI, out-of-hospital tranexamic acid administration within 2 hours of injury compared with placebo did not significantly improve 6-month neurologic outcome as measured by the Glasgow Outcome Scale-Extended., Trial Registration: ClinicalTrials.gov Identifier: NCT01990768.

Feedback on chest compressions and ventilations during cardiopulmonary resuscitation (CPR) is important to improve survival from out-of-hospital cardiac arrest (OHCA). The thoracic impedance signal acquired by monitor-defibrillators during treatment can be used to provide feedback on ventilations, but chest compression components prevent accurate detection of ventilations. This study introduces the first method for accurate ventilation detection using the impedance while chest compressions are concurrently delivered by a mechanical CPR device. A total of 423 OHCA patients treated with mechanical CPR were included, 761 analysis intervals were selected which in total comprised 5 884 minutes and contained 34 864 ventilations. Ground truth ventilations were determined using the expired CO 2 channel. The method uses adaptive signal processing to obtain the impedance ventilation waveform. Then, 14 features were calculated from the ventilation waveform and fed to a random forest (RF) classifier to discriminate false positive detections from actual ventilations. The RF feature importance was used to determine the best feature subset for the classifier. The method was trained and tested using stratified 10-fold cross validation (CV) partitions. The training/test process was repeated 20 times to statistically characterize the results. The best ventilation detector had a median (interdecile range, IDR) F 1 -score of 96.32 (96.26-96.37). When used to provide feedback in 1-min intervals, the median (IDR) error and relative error in ventilation rate were 0.002 (-0.334-0.572) min -1 and 0.05 (-3.71-9.08)%, respectively. An accurate ventilation detector during mechanical CPR was demonstrated. The algorithm could be introduced in current equipment for feedback on ventilation rate and quality, and it could contribute to improve OHCA survival rates.

Objective: We evaluated the effect of chest compression fraction (CCF) on survival to hospital discharge and return of spontaneous circulation (ROSC) in out-of-hospital cardiac arrest (OHCA) patients with non-shockable rhythms., Methods: This is a retrospective analysis (completed in 2016) of a prospective cohort study which included OHCA patients from ten U.S. and Canadian sites (Resuscitation Outcomes Consortium Epistry and PRIMED study (2007-2011)). We included all OHCA victims of presumed cardiac aetiology, not witnessed by emergency medical services (EMS), without automated external defibrillator shock prior to EMS arrival, receiving > 1 min of CPR with CPR process measures available, and initial non-shockable rhythm. We measured CCF using the first 5 min of electronic CPR records., Results: Demographics of 12,928 adult patients were: mean age 68; male 59.9%; public location 8.5%; bystander witnessed 35.2%; bystander CPR 39.3%; median interval from 911 to defibrillator turned on 10 min:04 s; initial rhythm asystole 64.8%, PEA 26.0%, other non-shockable 9.2%; compression rate 80-120/min (69.1%); median CCF 74%; ROSC 25.6%; survival to hospital discharge 2.4%. Adjusted odds ratio (OR); 95% confidence intervals (95%CI) of survival for each CCF category were: 0-40% (2.00; 1.16, 3.32); 41-60% (0.83; 0.54, 1.24); 61-80% (1.02; 0.77, 1.35); and 81-100% (reference group). Adjusted (OR; 95%CI) of ROSC for each CCF category were: 0-40% (1.02; 0.79, 1.30); 41-60% (0.83; 0.72, 0.95); 61-80% (0.85; 0.77, 0.94); and 81-100% (reference group)., Conclusions: We observed an incremental benefit from higher CCF on the incidence of ROSC, but not survival, among non-shockable OHCA patients with CCF higher than 40%., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: While emergency medical services (EMS) often use endotracheal intubation (ETI) or supraglottic airways (SGA), some patients receive only bag-valve-mask (BVM) ventilation during out-of-hospital cardiac arrests (OHCA). Our objective was to compare patient characteristics and outcomes for BVM ventilation to advanced airway management (AAM) in adults with OHCA., Methods: Using data from the Pragmatic Airway Resuscitation Trial, we identified patients receiving AAM (ETI or a SGA), BVM ventilation only (BVM-only), and BVM ventilation as a rescue after at least one failed attempt at advanced airway placement (BVM-rescue). The outcomes were return of spontaneous circulation (ROSC), 72-hour survival, survival to hospital discharge, neurologically intact survival (Modified Rankin Scale ≤ 3), and the presence of aspiration on a chest radiograph. Comparisons were made using generalized mixed-effects models while adjusting for age, sex, initial rhythm, EMS-witnessed status, bystander cardiopulmonary resuscitation, response time, study cluster, and advanced life support first on scene., Results: Of 3,004 patients enrolled, there were 282 BVM-only, 2,129 AAM, and 156 BVM-rescue patients with complete covariates. Shockable initial rhythms (34% vs. 18.6%) and EMS-witnessed arrests (21.6% vs. 11.3%) were more likely in BVM-only than AAM but similar between BVM-rescue and AAM. Compared to AAM, BVM-only patients had similar ROSC (odds ratio [OR] = 1.29, 95% confidence interval [CI] = 0.96 to 1.73), but higher 72-hour survival (OR = 1.96, 95% CI = 1.42 to 2.69), survival to discharge (OR = 4.47, 95% CI = 3.03 to 6.59), and neurologically intact survival (OR = 7.05, 95% CI = 4.40 to 11.3). Compared to AAM, BVM-rescue patients had similar ROSC (OR = 0.73, 95% CI = 0.47 to 1.12) and 72-hour survival (OR = 1.08, 95% CI = 0.66 to 1.77) but higher survival to discharge (OR = 2.15, 95% CI = 1.17 to 3.95) and neurologically intact survival (OR = 2.64, 95% CI = 1.20 to 5.81). Aspiration incidence was similar., Conclusions: Bag-valve-mask-only ventilation is associated with improved OHCA outcomes. Despite similar rates of ROSC and 72-hour survival, BVM-rescue ventilation was associated with improved survival to discharge and neurologically intact survival compared to successful AAM., (© 2020 by the Society for Academic Emergency Medicine.)

Background: Adrenaline is an important component in the resuscitation of individuals experiencing out-of-hospital cardiac arrest (OHCA). The 2018 Advanced Cardiac Life Support (ACLS) algorithm gives the option of either intravenous (IV) or intraosseous (IO) routes for adrenaline administration during cardiac arrest. However, the optimal route during prehospital resuscitation remains controversial. This study aims to investigate whether IV and IO routes lead to different outcomes in OHCA patients who received prehospital adrenaline., Methods: This retrospective analysis included adult patients with OHCA of presumed cardiac origin who had Emergency Medical Services (EMS) CPR, received adrenaline, and were enrolled in the Resuscitation Outcomes Consortium (ROC) Cardiac Epistry version 3 database between 2011 and 2015. We divided the study population into IV and IO groups based on the administration route. Logistic regression analysis was performed to evaluate the association between adrenaline delivery routes and prehospital return of spontaneous circulation (ROSC), survival to hospital discharge, and favorable neurological outcome., Results: Of the 35,733 patients included, 27,758 (77.7%) had adrenaline administered via IV access and 7975 (22.3%) via IO access. With the IO group as a reference in the logistic regression model, the adjusted odds ratios of the IV group for prehospital ROSC, survival and favorable neurological outcome were 1.367 (95%CI, 1.276-1.464), 1.468 (95%CI, 1.264-1.705) and 1.849 (95%CI, 1.526-2.240), respectively. Similar results were found in the propensity score matched population and subgroup analysis., Conclusion: Compared with the IO approach, the IV approach appears to be the optimal route for adrenaline administration in advanced life support for OHCA during prehospital resuscitation., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Bystander cardiopulmonary resuscitation (B-CPR) delivery and survival after out-of-hospital cardiac arrest vary at the neighborhood level, with lower survival seen in predominantly black neighborhoods. Although the Hispanic population is the fastest-growing minority population in the United States, few studies have assessed whether the proportion of Hispanic residents in a neighborhood is associated with B-CPR delivery and survival from out-of-hospital cardiac arrest. We assessed whether B-CPR rates and survival vary by neighborhood-level ethnicity. We hypothesized that neighborhoods with a higher proportion of Hispanic residents have lower B-CPR rates and lower survival., Methods: We conducted a retrospective cohort study using data from the Resuscitation Outcomes Consortium Epistry at US sites. Neighborhoods were classified by census tract based on percentage of Hispanic residents: <25%, 25% to 50%, 51% to 75%, or >75%. We independently modeled the likelihood of receipt of B-CPR and survival by neighborhood-level ethnicity controlling for site and patient-level confounding characteristics., Results: From 2011 to 2015, the Resuscitation Outcomes Consortium collected 27 481 US arrest events; after excluding pediatric arrests, emergency medical services-witnessed arrests, or arrests occurring in a healthcare or institutional facility, 18 927 were included. B-CPR was administered in 37% of events. In neighborhoods with <25% Hispanic residents, B-CPR was administered in 39% of events, whereas it was administered in 27% of events in neighborhoods with >75% Hispanic residents. Compared with <25% Hispanic neighborhoods in a multivariable analysis, out-of-hospital cardiac arrest in predominantly Hispanic neighborhoods had lower B-CPR rates (51% to 75% Hispanic: odds ratio, 0.79 [CI, 0.65-0.95], P =0.014; >75% Hispanic: odds ratio, 0.72 [CI, 0.55-0.96], P =0.025) and lower survival rates (global P value 0.029; >75% Hispanic: odds ratio, 0.56 [CI, 0.34-0.93], P =0.023)., Conclusions: Individuals with out-of-hospital cardiac arrest in predominantly Hispanic neighborhoods were less likely to receive B-CPR and had lower likelihood of survival. These findings suggest a need to understand the underlying disparities in cardiopulmonary resuscitationdelivery and an unmet cardiopulmonary resuscitationtraining need in Hispanic communities.

Background: Automated detection of return of spontaneous circulation (ROSC) is still an unsolved problem during cardiac arrest. Current guidelines recommend the use of capnography, but most automatic methods are based on the analysis of the ECG and thoracic impedance (TI) signals. This study analysed the added value of EtCO 2 for discriminating pulsed (PR) and pulseless (PEA) rhythms and its potential to detect ROSC., Materials and Methods: A total of 426 out-of-hospital cardiac arrest cases, 117 with ROSC and 309 without ROSC, were analysed. First, EtCO 2 values were compared for ROSC and no ROSC cases. Second, 5098 artefact free 3-s long segments were automatically extracted and labelled as PR (3639) or PEA (1459) using the instant of ROSC annotated by the clinician on scene as gold standard. Machine learning classifiers were designed using features obtained from the ECG, TI and the EtCO 2 value. Third, the cases were retrospectively analysed using the classifier to discriminate cases with and without ROSC., Results: EtCO 2 values increased significantly from 41 mmHg 3-min before ROSC to 57 mmHg 1-min after ROSC, and EtCO 2 was significantly larger for PR than for PEA, 46 mmHg/20 mmHg (p < 0.05). Adding EtCO 2 to the machine learning models increased their area under the curve (AUC) by over 2 percentage points. The combination of ECG, TI and EtCO 2 had an AUC for the detection of pulse of 0.92. Finally, the retrospective analysis showed a sensitivity and specificity of 96.6% and 94.5% for the detection of ROSC and no-ROSC cases, respectively., Conclusion: Adding EtCO 2 improves the performance of automatic algorithms for pulse detection based on ECG and TI. These algorithms can be used to identify pulse on site, and to retrospectively identify cases with ROSC., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aim of Study: To determine the association between bioimpedence-detected ventilation and out-of-hospital cardiac arrest (OHCA) outcomes., Methods: This is a retrospective, observational study of 560 OHCA patients from the Dallas-Fort Worth site enrolled in the Resuscitation Outcomes Consortium Trial of Continuous or Interrupted Chest Compressions During CPR from 4/2012 to 7/2015. We measured bioimpedance ventilation (lung inflation) waveforms in the pause between chest compression segments (Physio-Control LIFEPAK 12 and 15, Redmond, WA) recorded through defibrillation pads. We included cases ≥18 years with presumed cardiac cause of arrest assigned to interrupted 30:2 chest compressions with bag-valve-mask ventilation and ≥2 min of recorded cardiopulmonary resuscitation. We compared outcomes in two a priori pre-specified groups: patients with ventilation waveforms in <50% of pauses (Group 1) versus those with waveforms in ≥50% of pauses (Group 2)., Results: Mean duration of 30:2 CPR was 13 ± 7 min with a total of 7762 pauses in chest compressions. Group 1 (N = 424) had a median 11 pauses and 3 ventilations per patient vs. Group 2 (N = 136) with a median 12 pauses and 8 ventilations per patient, which was associated with improved return of spontaneous circulation (ROSC) at any time (35% vs. 23%, p < 0.005), prehospital ROSC (19.8% vs. 8.7%, p < 0.0009), emergency department ROSC (33% vs. 21%, p < 0.005), and survival to hospital discharge (10.3% vs. 4.0%, p = 0.008)., Conclusions: This novel study shows that ventilation with lung inflation occurs infrequently during 30:2 CPR. Ventilation in ≥50% of pauses was associated with significantly improved rates of ROSC and survival., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aim: To examine outcomes associated with intraosseous access route attempt for delivery of medications during out-of-hospital cardiac arrest (OHCA) resuscitation., Methods: Using data from the Continuous Chest Compression trial, we examined rates of survival to hospital discharge, sustained return of spontaneous circulation (ROSC), and survival with favorable neurological function among patients with intraosseous and intravenous access attempts after adjusting for age, sex, initial rhythm, bystander cardiopulmonary resuscitation, public location, witnessed status, EMS response and trial randomization cluster., Results: Among 19,731 patients, intraosseous access was attempted in 3068 patients and intravenous access in 16,663 patients respectively. Patients in whom intraosseous access was attempted were younger, more often female, and had marginally faster times to initial access and to initial drug administration. Unadjusted outcomes were significantly lower in patients with attempted intraosseous access compared with intravenous access: (4.6% vs. 5.7%, p = 0.01) for survival to discharge, (17.9% vs. 23.5%, p < 0.001) for sustained ROSC and (2.8% vs. 4.2%, p < 0.001) for survival with favorable neurological function. After adjustment, there were no differences in hospital survival (OR, 0.88, 95% CI 0.72-1.09, p = 0.24) or survival with favorable neurological function (OR, 0.87, 95% CI 0.67-1.12, p = 0.29) in patients with intraosseous access attempt (vs. intravenous access). However, intraosseous access continued to associate with lower rates of sustained ROSC (OR, 0.80, 95% CI 0.71 - 0.89, p < 0.001)., Conclusions: Among patients with OHCA, intraosseous access attempt was associated with worse ROSC rates but no difference in survival. Further studies are necessary to elucidate the optimal access route among OHCA patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Devices that measure ventilation in the pre-hospital setting are deficient especially during early cardiopulmonary resuscitation (CPR) before placement of an advanced airway. Consequently, evidence is limited regarding the role of ventilation during early CPR and its effect on outcomes., Objective: To develop software that automatically identifies ventilation waveforms recorded by defibrillators based on changes in transthoracic impedance during standard CPR., Methods: This was an observational, retrospective analysis of non-traumatic pre-hospital cardiac arrest patients who received 30:2 CPR by emergency medical service rescuers. Data was collected from 550 cases recorded by the bioimpedance channel of defibrillators. Two expert clinicians independently assessed all episodes from the time of initial CPR until placement of an advanced airway, defined acceptable ventilation waveforms, and annotated the pauses between compressions with ventilation waveforms. We then developed software that incorporated the expert criteria and automatically annotated pauses with acceptable ventilations., Results: A total of 7396 pauses were analyzed, mean(SD) duration of 30:2 CPR was 13 (8) min, with 13 (10) pauses/patient, and mean pause duration of 6 (3) s. Reviewer 1 and reviewer 2 identified 2375 and 2249 pauses with any acceptable ventilation, respectively, with an inter-rater reliability of 0.94. The novel software program reproduced expert annotation with excellent agreement (>0.8) and high accuracy, both sensitivity and specificity above 90%, compared to two reviewers. The software presented a substantial agreement with the reviewers (κ > 0.73) for ventilation counts in the pauses., Conclusion: We developed a novel and reliable strategy that enables investigation of ventilation quality during standard CPR using thoracic bioimpedance. This strategy would allow a timely and reliable automatic annotation of large scale resuscitation datasets., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background Targeted temperature management (TTM) for out-of-hospital cardiac arrest is associated with improved functional survival and is a class I recommendation in resuscitation guidelines. However, patterns of utilization of TTM and adherence to recommended TTM guidelines in contemporary practice are unknown. Methods and Results In a multicenter, prospective cohort of consecutive adults with non-traumatic out-of-hospital cardiac arrest in the Resuscitation Outcomes Consortium in 2012 to 2015, we identified all adults (≥18 years) who were potential candidates for TTM. Of 37 898 out-of-hospital cardiac arrest patients at 186 hospitals across 10 Resuscitation Outcomes Consortium sites, 8313 survived for ≥4 hours after hospital arrival, of which, 2878 (34.6%) received TTM. Mean age was 61.5 years and 36.3% were women. Median hospital rate of TTM use was 27% (interquartile range [IQR]: 14%, 45%), with an over 2-fold difference across sites after accounting for differences in presentation characteristics (median odds ratio, 2.10 [1.83-2.26]). Notably, TTM utilization decreased during the study period (57.5% [2012] to 26.5% [2015], P<0.001) including among shockable out-of-hospital cardiac arrest (73.4% to 46.3%, P<0.001). When administered, the median rate of deviation from one or more recommended practices was 60% (IQR: 40%, 78%). The median rate for delayed onset of TTM was 13% (IQR: 0%, 25%), varying by 70% for identical patients across 2 randomly chosen hospitals (median odds ratio 1.70 [1.39-1.97]). Similarly, the median rate for TTM <24 hours was 20% (IQR: 0%, 34%) and for achieved temperature <32°C was 18% (IQR: 0%, 39%), with marked variation across sites (median odds ratios of 1.44 [1.18-1.64] and 1.98 [1.62-2.31], respectively). Conclusions There has been a substantial decline in the utilization of TTM with significant variation in its real-world implementation. Further standardization of contemporary post-resuscitation practices, like TTM, is critical to ensure that their potential survival benefit is realized.

Importance: Emergency medical services (EMS) deliver essential initial care for patients with out-of-hospital cardiac arrest (OHCA), but the extent to which patient outcomes vary between different EMS agencies is not fully understood., Objective: To quantify variation in patient outcomes after OHCA across EMS agencies., Design, Setting, and Participants: This observational cohort study was conducted in the Resuscitation Outcomes Consortium (ROC) Epistry, a prospective multicenter OHCA registry at 10 sites in North America. Any adult with OHCA treated by an EMS from April 2011 through June 2015 was included. Data analysis occurred from May 2017 to March 2018., Exposure: Treating EMS agency., Main Outcomes and Measures: The primary outcome was survival to hospital discharge. Secondary outcomes were return of spontaneous circulation at emergency department arrival and favorable functional outcome at hospital discharge (defined as a modified Rankin scale score ≤3). Multivariable hierarchical logistic regression models were used to adjust confounders and clustering of patients within EMS agencies, and calculated median odds ratios (MORs) were used to quantify the extent of residual variation in outcomes between EMS agencies., Results: We identified 43 656 patients with OHCA treated by 112 EMS agencies. At EMS agency level, we observed large variations in survival to hospital discharge (range, 0%-28.9%; unadjusted MOR, 1.43 [95% CI, 1.34-1.54]), return of spontaneous circulation on emergency department arrival (range, 9.0%-57.1%; unadjusted MOR, 1.53 [95% CI, 1.43-1.65]), and favorable functional outcome (range, 0%-20.4%; unadjusted MOR, 1.54 [95% CI, 1.40-1.73]). This variation persisted despite adjustment for patient-level and EMS agency-level factors known to be associated with outcomes (adjusted MOR for survival 1.56 [95% CI 1.44-1.73]; adjusted MOR for return of spontaneous circulation at emergency department arrival, 1.50 [95% CI, 1.41-1.62]; adjusted MOR for functionally favorable survival, 1.53 [95% CI, 1.37-1.78]). After restricting analysis to those who survived more than 60 minutes after hospital arrival and including hospital treatment characteristics, the variation persisted (adjusted MOR for survival, 1.49 [95% CI, 1.36-1.69]; adjusted MOR for functionally favorable survival, 1.34 [95% CI, 1.20-1.59])., Conclusions and Relevance: We found substantial variations in patient outcomes after OHCA between a large group of EMS agencies in North America that were not explained by documented patient-level and EMS agency-level variables.

Importance: Emergency medical services (EMS) commonly perform endotracheal intubation (ETI) or insertion of supraglottic airways, such as the laryngeal tube (LT), on patients with out-of-hospital cardiac arrest (OHCA). The optimal method for OHCA advanced airway management is unknown., Objective: To compare the effectiveness of a strategy of initial LT insertion vs initial ETI in adults with OHCA., Design, Setting, and Participants: Multicenter pragmatic cluster-crossover clinical trial involving EMS agencies from the Resuscitation Outcomes Consortium. The trial included 3004 adults with OHCA and anticipated need for advanced airway management who were enrolled from December 1, 2015, to November 4, 2017. The final date of follow-up was November 10, 2017., Interventions: Twenty-seven EMS agencies were randomized in 13 clusters to initial airway management strategy with LT (n = 1505 patients) or ETI (n = 1499 patients), with crossover to the alternate strategy at 3- to 5-month intervals., Main Outcomes and Measures: The primary outcome was 72-hour survival. Secondary outcomes included return of spontaneous circulation, survival to hospital discharge, favorable neurological status at hospital discharge (Modified Rankin Scale score ≤3), and key adverse events., Results: Among 3004 enrolled patients (median [interquartile range] age, 64 [53-76] years, 1829 [60.9%] men), 3000 were included in the primary analysis. Rates of initial airway success were 90.3% with LT and 51.6% with ETI. Seventy-two hour survival was 18.3% in the LT group vs 15.4% in the ETI group (adjusted difference, 2.9% [95% CI, 0.2%-5.6%]; P = .04). Secondary outcomes in the LT group vs ETI group were return of spontaneous circulation (27.9% vs 24.3%; adjusted difference, 3.6% [95% CI, 0.3%-6.8%]; P = .03); hospital survival (10.8% vs 8.1%; adjusted difference, 2.7% [95% CI, 0.6%-4.8%]; P = .01); and favorable neurological status at discharge (7.1% vs 5.0%; adjusted difference, 2.1% [95% CI, 0.3%-3.8%]; P = .02). There were no significant differences in oropharyngeal or hypopharyngeal injury (0.2% vs 0.3%), airway swelling (1.1% vs 1.0%), or pneumonia or pneumonitis (26.1% vs 22.3%)., Conclusions and Relevance: Among adults with OHCA, a strategy of initial LT insertion was associated with significantly greater 72-hour survival compared with a strategy of initial ETI. These findings suggest that LT insertion may be considered as an initial airway management strategy in patients with OHCA, but limitations of the pragmatic design, practice setting, and ETI performance characteristics suggest that further research is warranted., Trial Registration: ClinicalTrials.gov Identifier: NCT02419573.

Background: Bystander cardiopulmonary resuscitation (BCPR) improves survival from out-of-hospital cardiac arrest (OHCA), yet BCPR rates remain low. It is unknown whether BCPR delivery disparities exist based on victim gender. We measured BCPR rates by gender in private and public environments, hypothesizing that females would be less likely than males to receive BCPR in public settings, with an associated difference in survival to hospital discharge., Methods and Results: We analyzed data from adult, nontraumatic OHCA events within the Resuscitation Outcomes Consortium registry (2011-2015). Using logistic regression, we modeled the likelihood of receiving BCPR by gender, including patient-level variables, stratified by location. A cohort of 19 331 OHCAs was assessed. Mean age was 64±17 years, and 63% (12 225/19 331) were male. Overall, 37% of OHCA victims received bystander CPR. In public locations, 39% (272/694) of females and 45% (1170/2600) of males received BCPR ( P<0.01), whereas in private settings, 35% (2198/6328) of females and 36% (3364/9449) of males received BCPR ( P=NS). Among public OHCAs, males had significantly increased odds of receiving BCPR compared with females (odds ratio, 1.27; 95% CI, 1.05-1.53; P=0.01); this was not the case in the private setting (odds ratio, 0.93; 95% CI, 0.87-1.01; P=NS). Controlling for site, age, and race, BCPR was significantly associated with survival to hospital discharge (odds ratio, 1.69; 95% CI, 1.54-1.85; P<0.01); in this model, males had 29% increased odds of survival compared with females (odds ratio, 1.29; 95% CI, 1.17-1.42; P<0.01)., Conclusions: Males had an increased likelihood of receiving BCPR compared with females in public. BCPR improved survival to discharge, with greater survival among males compared with females.

Background: Survival following out-of-hospital cardiac arrest (OHCA) with shockable rhythms can be improved with early defibrillation. Although shockable OHCA accounts for only ≈25% of overall arrests, ≈60% of public OHCAs are shockable, offering the possibility of restoring thousands of individuals to full recovery with early defibrillation by bystanders. We sought to determine the association of bystander automated external defibrillator use with survival and functional outcomes in shockable observed public OHCA., Methods: From 2011 to 2015, the Resuscitation Outcomes Consortium prospectively collected detailed information on all cardiac arrests at 9 regional centers. The exposures were shock administration by a bystander-applied automated external defibrillator in comparison with initial defibrillation by emergency medical services. The primary outcome measure was discharge with normal or near-normal (favorable) functional status defined as a modified Rankin Score ≤2. Survival to hospital discharge was the secondary outcome measure., Results: Among 49 555 OHCAs, 4115 (8.3%) observed public OHCAs were analyzed, of which 2500 (60.8%) were shockable. A bystander shock was applied in 18.8% of the shockable arrests. Patients shocked by a bystander were significantly more likely to survive to discharge (66.5% versus 43.0%) and be discharged with favorable functional outcome (57.1% versus 32.7%) than patients initially shocked by emergency medical services. After adjusting for known predictors of outcome, the odds ratio associated with a bystander shock was 2.62 (95% confidence interval, 2.07-3.31) for survival to hospital discharge and 2.73 (95% confidence interval, 2.17-3.44) for discharge with favorable functional outcome. The benefit of bystander shock increased progressively as emergency medical services response time became longer., Conclusions: Bystander automated external defibrillator use before emergency medical services arrival in shockable observed public OHCA was associated with better survival and functional outcomes. Continued emphasis on public automated external defibrillator utilization programs may further improve outcomes of OHCA., (© 2018 American Heart Association, Inc.)

Background: Previous studies have demonstrated that earlier epinephrine administration is associated with improved survival from out-of-hospital cardiac arrest (OHCA) with shockable initial rhythms. However, the effect of epinephrine timing on patients with nonshockable initial rhythms is unclear. The objective of this study was to measure the association between time to epinephrine administration and survival in adults and children with emergency medical services (EMS)-treated OHCA with nonshockable initial rhythms., Methods: We performed a secondary analysis of OHCAs prospectively identified by the Resuscitation Outcomes Consortium network from June 4, 2011, to June 30, 2015. We included patients of all ages with an EMS-treated OHCA and an initial nonshockable rhythm. We excluded those with return of spontaneous circulation in <10 minutes. We conducted a subgroup analysis involving patients <18 years of age. The primary exposure was time (minutes) from arrival of the first EMS agency to the first dose of epinephrine. Secondary exposure was time to epinephrine dichotomized as early (<10 minutes) or late (≥10 minutes). The primary outcome was survival to hospital discharge. We adjusted for Utstein covariates and Resuscitation Outcomes Consortium study site., Results: From 55 568 EMS-treated OHCAs, 32 101 patients with initial nonshockable rhythms were included. There were 12 238 in the early group, 14 517 in the late group, and 5346 not treated with epinephrine. After adjusting for potential confounders, each minute from EMS arrival to epinephrine administration was associated with a 4% decrease in odds of survival for adults, odds ratio=0.96 (95% confidence interval, 0.95-0.98). A subgroup analysis (n=13 290) examining neurological outcomes showed a similar association (adjusted odds ratio, 0.94 per minute; 95% confidence interval, 0.89-0.98). When epinephrine was given late in comparison with early, odds of survival were 18% lower (odds ratio, 0.82; 95% confidence interval, 0.68-0.98). In a pediatric analysis (n=595), odds of survival were 9% lower (odds ratio, 0.91; 95% confidence interval, 0.81-1.01) for each minute delay in epinephrine., Conclusions: Among OHCAs with nonshockable initial rhythms, the majority of patients were administered epinephrine >10 minutes after EMS arrival. Each minute delay in epinephrine administration was associated with decreased survival and unfavorable neurological outcomes. EMS agencies should consider strategies to reduce epinephrine administration times in patients with initial nonshockable rhythms., (© 2018 American Heart Association, Inc.)

Development of a highly effective vaccine or antibodies for the prevention and ultimately elimination of malaria is urgently needed. Here we report the isolation of a number of human monoclonal antibodies directed against the Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) from several subjects immunized with an attenuated Pf whole-sporozoite (SPZ) vaccine (Sanaria PfSPZ Vaccine). Passive transfer of one of these antibodies, monoclonal antibody CIS43, conferred high-level, sterile protection in two different mouse models of malaria infection. The affinity and stoichiometry of CIS43 binding to PfCSP indicate that there are two sequential multivalent binding events encompassing the repeat domain. The first binding event is to a unique 'junctional' epitope positioned between the N terminus and the central repeat domain of PfCSP. Moreover, CIS43 prevented proteolytic cleavage of PfCSP on PfSPZ. Analysis of crystal structures of the CIS43 antigen-binding fragment in complex with the junctional epitope determined the molecular interactions of binding, revealed the epitope's conformational flexibility and defined Asn-Pro-Asn (NPN) as the structural repeat motif. The demonstration that CIS43 is highly effective for passive prevention of malaria has potential application for use in travelers, military personnel and elimination campaigns and identifies a new and conserved site of vulnerability on PfCSP for next-generation rational vaccine design.

Aim: To evaluate the performance of a state-of-the-art cardiopulmonary resuscitation (CPR) artefact suppression method by assessing to what extent the filtered electrocardiogram (ECG) can be correctly diagnosed by emergency medicine doctors., Methods: A total of 819 ECG segments were used. Each segment contained two consecutive 10 s intervals, an artefact free interval and an interval corrupted by CPR artefacts. Each ECG segment was digitally processed to remove CPR artefacts using an adaptive filter. Each ECG segment was split into artefact-free and filtered intervals, randomly reordered for dissociation, and independently offered to four reviewers for rhythm annotation. The rhythm annotations of the artefact-free intervals were considered as the gold standard against which the rhythm annotations of the filtered intervals were evaluated. For the filtered intervals, the rater agreement (κ, Kappa score) with the gold standard, the sensitivity and the specificity were computed individually for each reviewer, and jointly through the majority decision of the pool of reviewers (DPR). These results were also compared to those obtained using a commercial shock advisory algorithm (SAA)., Results: The agreement between each reviewer and the gold standard was moderate ranging between κ = 0.41-0.64. The sensitivities and specificities ranged between 64.3-95.0%, and 70.0-95.9%, respectively. The agreement for the DPR was substantial with κ = 0.64 (0.62-0.66), a sensitivity of 90.6%, and a specificity of 85.6%. For the SAA, the agreement was fair with κ = 0.33 (0.31-0.35), a sensitivity of 90.3%, and a specificity of 66.4%., Conclusion: Clinicians outperformed the SAA, but specificities remained below the specifications recommended by the American Heart Association. Visual assessment of the filtered ECG by clinicians is not reliable enough, and varies greatly among clinicians. Results considerably improve by considering the consensus decision of a pool of clinicians., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The Utstein style for drowning (USFD) was published in 2003 with the aim of improving drowning research. To support a revision of the USFD, the current study aimed to generate an inventory of the use of the USFD parameters and compare the findings of the publications that have used the USFD., Methods: A search in Pubmed, Embase, the Cochrane Library, Web of Science and Scopus was performed to identify studies that used the USFD and were published between 01-10-2003 and 22-03-2015. We also searched in Pubmed, Embase, the Cochrane Library, Web of Science, and Scopus for all publications that cited the two publications containing the original ILCOR advisory statement introducing and recommending the USFD. In total we identified 14 publications by groups that explicitly used elements of the USFD for collecting and reporting their data., Results: Of the 22 core and 19 supplemental USFD parameters, 6-19 core (27-86%) and 1-12 (5-63%) supplemental parameters were used; two parameters (5%) have not been used in any publication. Associations with outcome were reported for nine core (41%) and five supplemental (26%) USFD parameters. The USFD publications also identified non-USFD parameters related to outcome: initial cardiac rhythm, time points and intervals during resuscitation, intubation at the drowning scene, first hospital core temperature, serum glucose and potassium, the use of inotropic/vasoactive agents and the Paediatric Index of Mortality 2-score., Conclusions: Fourteen USFD based drowning publications have been identified. These publications provide valuable information about the process and quality of drowning resuscitation and confirm that the USFD is helpful for a structured comparison of the outcome of drowning resuscitation.

Background: Out-of-hospital cardiac arrest (OHCA) commonly presents with nonshockable rhythms (asystole and pulseless electric activity). It is unknown whether antiarrhythmic drugs are safe and effective when nonshockable rhythms evolve to shockable rhythms (ventricular fibrillation/pulseless ventricular tachycardia [VF/VT]) during resuscitation., Methods: Adults with nontraumatic OHCA, vascular access, and VF/VT anytime after ≥1 shock(s) were prospectively randomized, double-blind, to receive amiodarone, lidocaine, or placebo by paramedics. Patients presenting with initial shock-refractory VF/VT were previously reported. The current study was a prespecified analysis in a separate cohort that initially presented with nonshockable OHCA and was randomized on subsequently developing shock-refractory VF/VT. The primary outcome was survival to hospital discharge. Secondary outcomes included discharge functional status and adverse drug-related effects., Results: Of 37 889 patients with OHCA, 3026 with initial VF/VT and 1063 with initial nonshockable-turned-shockable rhythms were treatment-eligible, were randomized, and received their assigned drug. Baseline characteristics among patients with nonshockable-turned-shockable rhythms were balanced across treatment arms, except that recipients of a placebo included fewer men and were less likely to receive bystander cardiopulmonary resuscitation. Active-drug recipients in this cohort required fewer shocks, supplemental doses of their assigned drug, and ancillary antiarrhythmic drugs than recipients of a placebo ( P <0.05). In all, 16 (4.1%) amiodarone, 11 (3.1%) lidocaine, and 6 (1.9%) placebo-treated patients survived to hospital discharge ( P =0.24). No significant interaction between treatment assignment and discharge survival occurred with the initiating OHCA rhythm (asystole, pulseless electric activity, or VF/VT). Survival in each of these categories was consistently higher with active drugs, although the trends were not statistically significant. Adjusted absolute differences (95% confidence interval) in survival from nonshockable-turned-shockable arrhythmias with amiodarone versus placebo were 2.3% (-0.3, 4.8), P =0.08, and for lidocaine versus placebo 1.2% (-1.1, 3.6), P =0.30. More than 50% of these survivors were functionally independent or required minimal assistance. Drug-related adverse effects were infrequent., Conclusions: Outcome from nonshockable-turned-shockable OHCA is poor but not invariably fatal. Although not statistically significant, point estimates for survival were greater after amiodarone or lidocaine than placebo, without increased risk of adverse effects or disability and consistent with previously observed favorable trends from treatment of initial shock-refractory VF/VT with these drugs. Together the findings may signal a clinical benefit that invites further investigation., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01401647., (© 2017 American Heart Association, Inc.)

Background: Utstein-style guidelines use an established consensus process, endorsed by the international resuscitation community, to facilitate and structure resuscitation research and publication. The first "Guidelines for Uniform Reporting of Data From Drowning" were published over a decade ago. During the intervening years, resuscitation science has advanced considerably, thus making revision of the guidelines timely. In particular, measurement of cardiopulmonary resuscitation elements and neurological outcomes reporting have advanced substantially. The purpose of this report is to provide updated guidelines for reporting data from studies of resuscitation from drowning., Methods: An international group with scientific expertise in the fields of drowning research, resuscitation research, emergency medical services, public health, and development of guidelines met in Potsdam, Germany, to determine the data that should be reported in scientific articles on the subject of resuscitation from drowning. At the Utstein-style meeting, participants discussed data elements in detail, defined the data, determined data priority, and decided how data should be reported, including scoring methods and category details., Results: The template for reporting data from drowning research was revised extensively, with new emphasis on measurement of quality of resuscitation, neurological outcomes, and deletion of data that have proved to be less relevant or difficult to capture., Conclusions: The report describes the consensus process, rationale for selecting data elements to be reported, definitions and priority of data, and scoring methods. These guidelines are intended to improve the clarity of scientific communication and the comparability of scientific investigations., (Copyright © 2017 European Resuscitation Council, American Heart Association, Inc. Published by Elsevier B.V. All rights reserved.)

Review: The American Heart Association set goals in 2010 to train 20 million people annually in cardiopulmonary resuscitation and to double bystander response by 2020. These ambitious goals are difficult to achieve without new approaches., Methods: The main objective is to evaluate a new approach to cardiopulmonary resuscitation instruction using a self-instructional kiosk to teach Hands-Only CPR to people at a busy international airport. This is a prospective, observational study evaluating a new approach to teach Hands-Only CPR to the public from July 2013 to February 2016. The American Heart Association developed a Hands-Only CPR Kiosk for this project. We assessed the number of participants who viewed the instructional video and practiced chest compressions as well as the quality metrics of the chest compressions., Results: In a 32-month period, there were 23478 visits to the Hands-Only CPR Kiosk and 9006 test sessions; of those practice sessions, 26.2% achieved correct chest compression rate, 60.2% achieved correct chest compression depth, and 63.5% had the correct hand position., Conclusions: There is noticeable public interest in learning Hands-Only CPR by using an airport kiosk and an airport is an opportune place to engage a layperson in learning Hands-Only CPR. The average quality of Hands-Only CPR by the public needs improvement and adding kiosks to other locations in the airport could reach more people and could be replicated in other major airports in the United States., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose of Review: Affirmation of the importance of precision in fundamentals of resuscitation practices with improving neurologically intact survival from sudden cardiac arrest, correlated with both measurements of resuscitation metrics generically and recently further refined metric parameters specifically., Recent Findings: Quality of baseline cardiopulmonary resuscitation (CPR) in historic intervention trials may not be 'high quality' as once assumed. Optimal chest compression rates are within the narrow spectrum of 106-108/min for adults. Optimal ventilation rates remain within the 8-10/min range., Summary: Although traditional CPR teaching of 'hard and fast' chest compressions has promoted a relatively easy to remember directive, the reality is that laypersons and medical professionals alike may unwittingly provide markedly suboptimal chest compression depths and rates. Prior resuscitation studies that focused upon airway adjuncts, defibrillation strategies, and/or pharmaceutical interventions that did not simultaneously gauge the underlying CPR chest compression rates, chest compression fraction of time, and ventilation rates should be cautiously interpreted in light of discovery that assumption of 'high-quality CPR' without measurement of the metrics of such is likely a faulty assumption.

Purpose of Review: To discuss the evolution of the technique of cardiopulmonary resuscitation (CPR), including presenting important research that has made substantial improvements in patient outcome., Recent Findings: The last half century has seen the arising of guidelines for performing CPR increasingly based on good scientific evidence. Improvements in the technique, including teaching citizens 'compressions only CPR', have simplified the process of rescue while improving survival., Summary: Numerous scientific studies and the better understanding of physiology have contributed to enhanced outcomes while creating community-based systems of care.

Purpose of Review: To evaluate the past and present literature on ventilation during out of hospital cardiac arrest, highlighting research that has informed current guidelines., Recent Findings: Previous studies have studied what are optimal compression-to-ventilation ratios, ventilation rates, and methods of ventilation. Continuous chest compression cardiopulmonary resuscitation (CPR) has not shown to provide a significant survival benefit over the traditional 30 : 2 CPR. The optimal ventilation rate is recommended at 8 to 10 breaths per minute. Methods such as capnography and thoracic impedance are being used to evaluate ventilation in research studies., Summary: Future out of hospital cardiac arrest studies are still exploring how to optimize the delivery of ventilation during the initial stages of resuscitation. More prospective studies focusing on ventilation are needed to inform guidelines.

Background: Bystander cardiopulmonary resuscitation (CPR) is associated with increased survival from cardiac arrest, yet bystander CPR rates are low in many communities. The overall prevalence of CPR training in the United States and associated individual-level disparities are unknown. We sought to measure the national prevalence of CPR training and hypothesized that older age and lower socioeconomic status would be independently associated with a lower likelihood of CPR training., Methods and Results: We administered a cross-sectional telephone survey to a nationally representative adult sample. We assessed the demographics of individuals trained in CPR within 2 years (currently trained) and those who had been trained in CPR at some point in time (ever trained). The association of CPR training and demographic variables were tested using survey weighted logistic regression. Between September 2015 and November 2015, 9022 individuals completed the survey; 18% reported being currently trained in CPR, and 65% reported training at some point previously. For each year of increased age, the likelihood of being currently CPR trained or ever trained decreased (currently trained: odds ratio, 0.98; 95% CI, 0.97-0.99; P <0.01; ever trained: OR, 0.99; 95% CI, 0.98-0.99; P =0.04). Furthermore, there was a greater then 4-fold difference in odds of being currently CPR trained from the 30-39 to 70-79 year old age groups (95% CI, 0.10-0.23). Factors associated with a lower likelihood of CPR training were lesser educational attainment and lower household income ( P <0.01 for each of these variables)., Conclusions: A minority of respondents reported current training in CPR. Older age, lesser education, and lower income were associated with reduced likelihood of CPR training. These findings illustrate important gaps in US CPR education and suggest the need to develop tailored CPR training efforts to address this variability., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Introduction: The Universal Termination of Resuscitation (TOR) Guideline accurately identifies potential out-of-hospital cardiac arrest (OHCA) survivors. However, implementation is inconsistent with some Emergency Medical Service (EMS) agencies using absence of return of spontaneous circulation (ROSC) as sole criterion for termination., Objective: To compare the performance of the Universal TOR Guideline with the single criterion of no prehospital ROSC. Second, to determine factors associated with survival for patients transported without a ROSC. Lastly, to compare the impact of time to ROSC as a marker of futility to the Universal TOR Guideline., Design: Retrospective, observational cohort study., Participants: Non-traumatic, adult (≥18 years) OHCA patients of presumed cardiac etiology treated by EMS providers., Setting: ROC-PRIMED and ROC-Epistry post ROC-PRIMED databases between 2007 and 2011., Outcomes: Primary outcome was survival to hospital discharge and the secondary outcome was functional survival. We used multivariable regression to evaluate factors associated with survival in patients transported without a ROSC., Results: 36,543 treated OHCAs occurred of which 9467 (26%) were transported to hospital without a ROSC. Patients transported without a ROSC who met the Universal TOR Guideline for transport had a survival of 3.0% (95% CI 2.5-3.4%) compared to 0.7% (95% CI 0.4-0.9%) in patients who met the Universal TOR Guideline for termination. The Universal TOR Guideline identified 99% of survivors requiring continued resuscitation and transportation to hospital including early identification of survivors who sustained a ROSC after extended durations of CPR., Conclusion: Using absence of ROSC as a sole predictor of futility misses potential survivors. The Universal TOR Guideline remains a strong predictor of survival., Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the writing and content of the paper., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Antiarrhythmic drugs are used commonly in out-of-hospital cardiac arrest for shock-refractory ventricular fibrillation or pulseless ventricular tachycardia, but without proven survival benefit., Methods: In this randomized, double-blind trial, we compared parenteral amiodarone, lidocaine, and saline placebo, along with standard care, in adults who had nontraumatic out-of-hospital cardiac arrest, shock-refractory ventricular fibrillation or pulseless ventricular tachycardia after at least one shock, and vascular access. Paramedics enrolled patients at 10 North American sites. The primary outcome was survival to hospital discharge; the secondary outcome was favorable neurologic function at discharge. The per-protocol (primary analysis) population included all randomly assigned participants who met eligibility criteria and received any dose of a trial drug and whose initial cardiac-arrest rhythm of ventricular fibrillation or pulseless ventricular tachycardia was refractory to shock., Results: In the per-protocol population, 3026 patients were randomly assigned to amiodarone (974), lidocaine (993), or placebo (1059); of those, 24.4%, 23.7%, and 21.0%, respectively, survived to hospital discharge. The difference in survival rate for amiodarone versus placebo was 3.2 percentage points (95% confidence interval [CI], -0.4 to 7.0; P=0.08); for lidocaine versus placebo, 2.6 percentage points (95% CI, -1.0 to 6.3; P=0.16); and for amiodarone versus lidocaine, 0.7 percentage points (95% CI, -3.2 to 4.7; P=0.70). Neurologic outcome at discharge was similar in the three groups. There was heterogeneity of treatment effect with respect to whether the arrest was witnessed (P=0.05); active drugs were associated with a survival rate that was significantly higher than the rate with placebo among patients with bystander-witnessed arrest but not among those with unwitnessed arrest. More amiodarone recipients required temporary cardiac pacing than did recipients of lidocaine or placebo., Conclusions: Overall, neither amiodarone nor lidocaine resulted in a significantly higher rate of survival or favorable neurologic outcome than the rate with placebo among patients with out-of-hospital cardiac arrest due to initial shock-refractory ventricular fibrillation or pulseless ventricular tachycardia. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT01401647.).