A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease

Live-attenuated RNA virus vaccines are efficacious but subject to reversion to virulence. Among RNA viruses, replication fidelity is recognized as a key determinant of virulence and escape from antiviral therapy; increased fidelity is attenuating for some viruses. Coronavirus replication fidelity is approximately 20-fold greater than that of other RNA viruses and is mediated by a 3′-5′ exonuclease activity (ExoN) that likely functions in RNA proofreading. In this study, we demonstrate that engineered inactivation of SARS-CoV ExoN activity results in a stable mutator phenotype with profoundly decreased fidelity in vivo and attenuation of pathogenesis in young, aged, and immunocompromised mouse models of human SARS. The ExoN inactivation genotype and mutator phenotype are stable and do not revert to virulence, even after serial passage or long-term persistent infection in vivo. Our approach represents a strategy with potential for broad applications for the stable attenuation of coronaviruses and possibly other RNA viruses

Practice characteristics of Emergency Department extracorporeal cardiopulmonary resuscitation (eCPR) programs in the United States: The current state of the art of Emergency Department extracorporeal membrane oxygenation (ED ECMO).

PURPOSE: To characterize the current scope and practices of centers performing extracorporeal cardiopulmonary resuscitation (eCPR) on the undifferentiated patient with cardiac arrest in the emergency department. METHODS: We contacted all US centers in January 2016 that had submitted adult eCPR cases to the Extracorporeal Life Support Organization (ELSO) registry and surveyed them, querying for programs that had performed eCPR in the Emergency Department (ED ECMO). Our objective was to characterize the following domains of ED ECMO practice: program characteristics, patient selection, devices and techniques, and personnel. RESULTS: Among 99 centers queried, 70 responded. Among these, 36 centers performed ED ECMO. Nearly 93% of programs are based at academic/teaching hospitals. 65% of programs are less than 5 years old, and 60% of programs perform ≤3 cases per year. Most programs (90%) had inpatient eCPR or salvage ECMO programs prior to starting ED ECMO programs. The majority of programs do not have formal inclusion and exclusion criteria. Most programs preferentially obtain vascular access via the percutaneous route (70%) and many (40%) use mechanical CPR during cannulation. The most commonly used console is the Maquet Rotaflow(®). Cannulation is most often performed by cardiothoracic (CT) surgery, and nearly all programs (\u3e85%) involve CT surgeons, perfusionists, and pharmacists. CONCLUSIONS: Over a third of centers that submitted adult eCPR cases to ELSO have performed ED ECMO. These programs are largely based at academic hospitals, new, and have low volumes. They do not have many formal inclusion or exclusion criteria, and devices and techniques are variable

Collaborative SCA Survival Project: Cardiac Arrest Survival is a Mess

Systems diagnoses have been effectively used to understand many complex organizational systems within healthcare, government, military, and global corporate enterprises. Systems methodologies have been effectively used to change the direction and improve the outcomes of complex organizational systems. We feel that framing cardiac arrest survival as a systems problem and applying a systems methodology is innovative, practical, and essential if we are to make significant and sustainable impact

Are Thiel-embalmed Cadavers Effective Tools in Educating Medical Students to Perform Knee Arthrocentesis?

INTRODUCTION: The purposes of this study are to determine whether Thiel-embalmed cadavers are an effective educational tool in teaching medical students to perform knee arthrocentesis, to compare the use of Thiel-embalmed cadavers to formalin-embalmed cadavers in arthrocentesis education, and to determine whether the use of Thiel-embalmed cadavers is potentially generalizable to the instruction of other orthopedic procedures. METHODS: Sixty-eight third-year medical students participated in the study. The participants first completed a pre-survey to assess their prior experience with arthrocentesis procedures and Thiel-embalmed cadavers. Participants then attended an instructional session where the knee arthrocentesis procedure was demonstrated on a Thiel-embalmed cadaver. Participants then individually performed the simulated knee arthrocentesis procedure twice: once on a Thiel-embalmed cadaver and once on a formalin-embalmed cadaver. Success of each attempt was determined through the visualization of aspirated joint fluid. Following the laboratory session, each participant completed a post-survey to determine whether the session improved their perceived confidence in performing knee arthrocentesis, if they preferred the use of Thiel-embalmed cadavers or formalin-embalmed cadavers as a teaching tool, and if they believed simulated practice using Thiel-embalmed cadavers would be effective for learning other orthopedic procedural skills. RESULTS: Sixty-eight students participated in the laboratory session and successfully completed both pre- and post-course surveys. 96% of participants reported that they felt confident performing knee arthrocentesis under physician supervision following their participation in the laboratory session (versus 15% of participants in the pre-survey). 96% of participants reported that the Thiel-embalmed cadavers provided a more realistic teaching model than formalin-embalmed cadavers for learning knee arthrocentesis. 100% of participants believed the incorporation of simulated practice using Thiel-embalmed cadavers is an effective method in teaching students to perform knee arthrocentesis. 100% of participants reported that they would participate in future sessions using Thiel-embalmed cadavers to learn and practice other orthopedic procedural techniques. DISCUSSION: This study used a moderate sample size of third-year medical students to provide data regarding the suitability of using Thiel cadavers in arthrocentesis education. Results indicate that Thiel cadavers are effective tools in teaching medical students to perform knee arthrocentesis, that students preferred the Thiel cadavers to the formalin cadavers, and that the use of Thiel cadavers is a safe, engaging, and high-quality teaching modality for demonstrating proper arthrocentesis procedural technique to medical students. Since this study looked specifically at teaching knee arthrocentesis to medical students, it is uncertain whether the benefits of Thiel cadavers are generalizable to the education of other orthopedic procedures and subject groups such as residents, fellows, and practicing physicians. Further studies should be performed to assess whether Thiel cadavers are beneficial in teaching other orthopaedic procedures and if these benefits extend to other subject groups

Time to intra-arrest therapeutic hypothermia in out-of-hospital cardiac arrest patients and its association with neurologic outcome: a propensity matched sub-analysis of the PRINCESS trial

© 2020, The Author(s). Purpose: To study the association between early initiation of intra-arrest therapeutic hypothermia and neurologic outcome in out-of-hospital cardiac arrest. Methods: A prespecified sub-analysis of the PRINCESS trial (NCT01400373) that randomized 677 bystander-witnessed cardiac arrests to transnasal evaporative intra-arrest cooling initiated by emergency medical services or cooling started after hospital arrival. Early cooling (intervention) was defined as intra-arrest cooling initiated \u3c 20 min from collapse (i.e., ≤ median time to cooling in PRINCESS). Propensity score matching established comparable control patients. Primary outcome was favorable neurologic outcome, Cerebral Performance Category (CPC) 1–2 at 90 days. Complete recovery (CPC 1) was among secondary outcomes. Results: In total, 300 patients were analyzed and the proportion with CPC 1–2 at 90 days was 35/150 (23.3%) in the intervention group versus 24/150 (16%) in the control group, odds ratio (OR) 1.92, 95% confidence interval (CI) 0.95–3.85, p =.07. In patients with shockable rhythm, CPC 1–2 was 29/57 (50.9%) versus 17/57 (29.8%), OR 3.25, 95%, CI 1.06–9.97, p =.04. The proportion with CPC 1 at 90 days was 31/150 (20.7%) in the intervention group and 17/150 (11.3%) in controls, OR 2.27, 95% CI 1.12–4.62, p =.02. In patients with shockable rhythms, the proportion with CPC 1 was 27/57 (47.4%) versus 12/57 (21.1%), OR 5.33, 95% CI 1.55–18.3, p =.008. Conclusions: In the whole study population, intra-arrest cooling initiated \u3c 20 min from collapse compared to cooling initiated at hospital was not associated with improved favorable neurologic outcome. In the subgroup with shockable rhythms, early cooling was associated with improved favorable outcome and complete recovery

Persistently Altered Brain Mitochondrial Bioenergetics After Apparently Successful Resuscitation From Cardiac Arrest

Background Although advances in cardiopulmonary resuscitation have improved survival from cardiac arrest (CA), neurologic injury persists and impaired mitochondrial bioenergetics may be critical for targeted neuroresuscitation. The authors sought to determine if excellent cardiopulmonary resuscitation and postresuscitation care and good traditional survival rates result in persistently disordered cerebral mitochondrial bioenergetics in a porcine pediatric model of asphyxia‐associated ventricular fibrillation CA. Methods and Results After 7 minutes of asphyxia, followed by ventricular fibrillation, 5 female 1‐month‐old swine (4 sham) received blood pressure–targeted care: titration of compression depth to systolic blood pressure of 90 mm Hg and vasopressor administration to a coronary perfusion pressure \u3e20 mm Hg. All animals received protocol‐based vasopressor support after return of spontaneous circulation for 4 hours before they were killed. The primary outcome was integrated mitochondrial electron transport system (ETS) function. CA animals displayed significantly decreased maximal, coupled oxidative phosphorylating respiration (OXPHOSCI+CII) in cortex (PPPPCI PCII PCIPCII PCI+CII), as well as a 30% reduction in citrate synthase activity (P\u3c0.04). Conclusions Mitochondria in both the cortex and hippocampus displayed significant alterations in respiratory function after CA despite excellent cardiopulmonary resuscitation and postresuscitation care in asphyxia‐associated ventricular fibrillation CA. Analysis of integrated ETS function identifies mitochondrial bioenergetic failure as a target for goal‐directed neuroresuscitation after CA. IACUC Protocol: IAC 13‐001023

Invasive Electrical Impedance Tomography for Blood Vessel Detection

We present a novel method for localization of large blood vessels using a bioimpedance based needle positioning system on an array of ten monopolar needle electrodes. The purpose of the study is to develop a portable, low cost tool for rapid vascular access for cooling and controlled reperfusion of cardiac arrest patients. Preliminary results show that localization of blood vessels is feasible with this method, but larger studies are necessary to improve the technology

Quantitative estimation of nerve fiber engagement by vagus nerve stimulation using physiological markers

Background Cervical vagus nerve stimulation (VNS) is a rapidly emerging bioelectronic treatment for brain, metabolic, cardiovascular and immune disorders. Its desired and off-target effects are mediated by different nerve fiber populations and knowledge of their engagement could guide calibration and monitoring of VNS therapies. Objective /Hypothesis: Stimulus-evoked compound action potentials (eCAPs) directly provide fiber engagement information but are currently not feasible in humans. A method to estimate fiber engagement through common, noninvasive physiological readouts could be used instead of eCAP measurements. Methods In anesthetized rats, we recorded eCAPs while registering acute physiological response markers to VNS: cervical electromyography (EMG), changes in heart rate (ΔHR) and breathing interval (ΔBI). Quantitative models were established to capture the relationship between A-, B- and C-fiber type activation and those markers, and to quantitatively estimate fiber activation from physiological markers and stimulation parameters. Results In bivariate analyses, we found that EMG correlates with A-fiber, ΔHR with B-fiber and ΔBI with C-fiber activation, in agreement with known physiological functions of the vagus. We compiled multivariate models for quantitative estimation of fiber engagement from these markers and stimulation parameters. Finally, we compiled frequency gain models that allow estimation of fiber engagement at a wide range of VNS frequencies. Our models, after calibration in humans, could provide noninvasive estimation of fiber engagement in current and future therapeutic applications of VNS

Video-Only Cardiopulmonary Resuscitation Education for High-Risk Families Before Hospital Discharge: A Multicenter Pragmatic Trial

BACKGROUND: Cardiopulmonary resuscitation (CPR) training rates in the United States are low, highlighting the need to develop CPR educational approaches that are simpler, with broader dissemination potential. The minimum training required to ensure long-term skill retention remains poorly characterized. We compared CPR skill retention among laypersons randomized to training with video-only (VO; no manikin) with those trained with a video self-instruction kit (VSI; with manikin). We hypothesized that VO training would be noninferior to the VSI approach with respect to chest compression (CC) rate. METHODS AND RESULTS: We performed a prospective, cluster randomized trial of CPR education for family members of patients with high-risk cardiac conditions on hospital cardiac units, using a multicenter pragmatic design. Eight hospitals were randomized to offer either VO or VSI training before discharge using volunteer trainers. CPR skills were assessed 6 months post training. Mean CC rate among those trained with VO compared with those trained with VSI was assessed with a noninferiority margin set at 8 CC per min; as a secondary outcome, mean differences in CC depth were assessed. From February 2012 to May 2015, 1464 subjects were enrolled and 522 subjects completed a skills assessment. The mean CC rates were 87.7 (VO) CC per min and 89.3 (VSI) CC per min; we concluded noninferiority for VO based on a mean difference of -1.6 (90% confidence interval, -5.2 to 2.1). The mean CC depth was 40.2 mm (VO) and 45.8 mm (VSI) with a mean difference of -5.6 (95% confidence interval, -7.6 to -3.7). Results were similar after multivariate regression adjustment. CONCLUSIONS: In this large, prospective trial of CPR skill retention, VO training yielded a noninferior difference in CC rate compared with VSI training. CC depth was greater in the VSI group. These findings suggest a potential trade-off in efforts for broad dissemination of basic CPR skills; VO training might allow for greater scalability and dissemination, but with a potential reduction in CC depth. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01514656

Public-Access Defibrillation and Survival After Out-of-Hospital Cardiac Arrest

Background The rate of survival after out-of-hospital cardiac arrest is low. It is not known whether this rate will increase if laypersons are trained to attempt defibrillation with the use of automated external defibrillators (AEDs). Methods We conducted a prospective, community-based, multicenter clinical trial in which we randomly assigned community units (e.g., shopping malls and apartment complexes) to a structured and monitored emergency-response system involving lay volunteers trained in cardiopulmonary resuscitation (CPR) alone or in CPR and the use of AEDs. The primary outcome was survival to hospital discharge. Results More than 19,000 volunteer responders from 993 community units in 24 North American regions participated. The two study groups had similar unit and volunteer characteristics. Patients with treated out-of-hospital cardiac arrest in the two groups were similar in age (mean, 69.8 years), proportion of men (67 percent), rate of cardiac arrest in a public location (70 percent), and rate of witnessed cardiac arrest (72 percent). No inappropriate shocks were delivered. There were more survivors to hospital discharge in the units assigned to have volunteers trained in CPR plus the use of AEDs (30 survivors among 128 arrests) than there were in the units assigned to have volunteers trained only in CPR (15 among 107; P=0.03; relative risk, 2.0; 95 percent confidence interval, 1.07 to 3.77); there were only 2 survivors in residential complexes. Functional status at hospital discharge did not differ between the two groups. Conclusions Training and equipping volunteers to attempt early defibrillation within a structured response system can increase the number of survivors to hospital discharge after out-of-hospital cardiac arrest in public locations. Trained laypersons can use AEDs safely and effectively