Survey of a protocol to increase appropriate implementation of dispatcher-assisted cardiopulmonary resuscitation for out-of-hospital cardiac arrest.

BACKGROUND: Dispatcher-assisted cardiopulmonary resuscitation (DA-CPR) attempts to improve the management of out-of-hospital cardiac arrest by laypersons who are unable to recognize cardiac arrest and are unfamiliar with CPR. Therefore, we investigated the sensitivity and specificity of our new DA-CPR protocol for achieving implementation of bystander CPR in out-of-hospital cardiac arrest victims not already receiving bystander CPR. METHODS AND RESULTS: Since 2007, we have applied a new DA-CPR protocol that uses supplementary key words. Fire departments prospectively collected baseline data on DA-CPR from January 2009 to December 2011. DA-CPR was attempted in 2747 patients; of these, 417 (15.2%) did not experience cardiac arrest. The sensitivity and specificity of the 2007 protocol versus estimated values of the previous standard protocol were 72.9% versus 50.3% and 99.6% versus 99.8%, respectively. We identified key words that may be useful for detecting out-of-hospital cardiac arrest. Multiple logistic regression analysis revealed that the occurrence of cardiac arrest after an emergency call (odds ratio, 16.85) and placing an emergency call away from the scene of the arrest (odds ratio, 11.04) were potentially associated with failure to provide DA-CPR. Furthermore, at-home cardiac arrest (odds ratio, 1.61) and family members as bystanders (odds ratio, 1.55) were associated with bystander noncompliance with DA-CPR. No complications were reported in the 417 patients who received DA-CPR but did not have cardiac arrest. CONCLUSIONS: Our 2007 protocol is safe and highly specific and may be more sensitive than the standard protocol. Understanding the factors associated with failure of bystanders to provide DA-CPR and implementing public education are necessary to increase the benefit of DA-CPR.

Misplaced links in the chain of survival due to an incorrect manual for the emergency call at public facilities.

BACKGROUND: The incidence of delayed emergency calls and the outcome of out-of-hospital cardiac arrest (OHCA) may differ among public facilities when emergency calls are placed by institutional staff. The purpose of this study was to identify the actions prescribed in the rules and/or manuals of public facilities and to clarify whether the incidence of delayed emergency call placement and the outcome of OHCA differ among these facilities. METHODS: We performed a questionnaire-based survey regarding emergency calls in public facilities in our community and analyzed our regional Utstein-based OHCA database. RESULTS: Our questionnaire survey disclosed that the most common actions prescribed in the manuals or rules applied in care facilities and educational institutions are to report the situation when a cardiac arrest occurs and to follow the directions of a custodian or supervisor. The international web search disclosed that these actions are rarely prescribed in medical emergency manuals in other countries. Most of these manuals simply say that staff should make an emergency call immediately upon detecting a serious illness or medical emergency. Analysis of the Utstein-based database from our community revealed that the time interval between collapse and emergency call placement is prolonged and the outcome of cardiac arrest poor in care facilities. A prompt emergency call and cardiopulmonary resuscitation (CPR) after arrest are associated with improved 1-year survival following OHCA. Contrary to accepted wisdom, staff who recognize a cardiac arrest may consult their supervisor and then continue CPR until they receive instructions from him or her. CONCLUSIONS: Manuals or rules for making emergency calls in our public facilities may contain incorrect information, and emergency calls may be delayed owing to correctable human factors. Such manuals should be checked and revised.

Does the number of rescuers affect the survival rate from out-of-hospital cardiac arrests? Two or more rescuers are not always better than one.

REVIEW: An increased number of rescuers may improve the survival rate from out-of-hospital cardiac arrests (OHCAs). The majority of OHCAs occur at home and are handled by family members. MATERIALS AND METHODS: Data from 5078 OHCAs that were witnessed by citizens and unwitnessed by citizens or emergency medical technicians from January 2004 to March 2010 were prospectively collected. The number of rescuers was identified in 4338 OHCAs and was classified into two (single rescuer (N=2468) and multiple rescuers (N=1870)) or three (single rescuer, two rescuers (N=887) and three or more rescuers (N=983)) groups. The backgrounds, characteristics and outcomes of OHCAs were compared between the two groups and among the three groups. RESULTS: When all OHCAs were collectively analysed, an increased number of rescuers was associated with better outcomes (one-year survival and one-year survival with favourable neurological outcomes were 3.1% and 1.9% for single rescuers, 4.1% and 2.0% for two rescuers, and 6.0% and 4.6% for three or more rescuers, respectively (p=0.0006 and p<0.0001)). A multiple logistic regression analysis showed that the presence of multiple rescuers is an independent factor that is associated with one-year survival (odds ratio (95% confidence interval): 1.539 (1.088-2.183)). When only OHCAs that occurred at home were analysed (N=2902), the OHCAs that were handled by multiple rescuers were associated with higher incidences of bystander CPR but were not associated with better outcomes. CONCLUSIONS: In summary, an increased number of rescuers improves the outcomes of OHCAs. However, this beneficial effect is absent in OHCAs that occur at home.

Muscle creatine kinase/SV40 hybrid promoter for muscle-targeted long-term transgene expression.

Gene therapy for congenital protein deficiencies requires lifelong expression of a deficient protein. Current gene therapy approaches preferentially employ the strong cytomegalovirus (CMV) promoter/enhancer or its derivative CAG promoter; however, these promoters provide only temporary transgene expression. To create a promoter that enables long-lasting expression in muscle, hybrid promoters were constructed by coupling the muscle creatine kinase (MCK) enhancer to various strong promoters for enhancement of tissue specificity and improved transcriptional activity. A hybrid promoter containing the MCK enhancer and the simian virus 40 promoter (MCK/SV40 promoter) yielded long-term (>6 months) expression of a human secretory alkaline phosphatase (huSEAP) reporter gene following electrotransfer of the plasmid into mice, whereas expression using a conventional CMV or CAG promoter faded away within a few weeks. To explore the mechanism behind the sustained expression obtained with the MCK/SV40 promoter, mice were immunized with a LacZ expression plasmid driven by MCK/SV40 or a conventional promoter. Minimal cellular and humoral responses to LacZ were observed in MCK/SV40 promoter-treated animals, and mouse SEAP gene expression in vivo was successfully maintained by both the MCK/SV40 and conventional promoters. These results suggest that the lower immunogenicity of the MCK/SV40 promoter contributed to long-lasting gene expression in mice. Therefore, the MCK/SV40 promoter may provide the basis for development of an effective transgene expression cassette for treatment of congenital protein deficiencies in which therapeutic proteins are recognized as foreign by the host immune system.

Activator protein 1-mediated transcriptional regulation strategy sustains long-term expression of a xenogeneic gene product in vivo: an implication for gene therapy targeting congenital protein deficiencies.

Maintenance of high-level transgene expression is the main challenge in current gene therapy. Although the cytomegalovirus (CMV) promoter/enhancer or its derivative the CAG promoter has been harnessed in current gene therapy vectors, transgene expression by these vectors is often transient and remains at suboptimal levels due to undefined mechanisms, possibly including the shortage of transcriptional machinery. To overcome this drawback, we designed a novel transcriptional control system, designated here as transcription factor-supercharging promoter system, in which transgene expression is regulated by the positive feedback circuit consisting of cis- and trans-acting elements of gene expression machinery. Among combinations of these elements, a plasmid composed of a target gene expression cassette driven by the chimeric CMV promoter containing repetitive 12-O-tetradecanoylphorbol-13-acetate-responsive elements as cis-acting elements (CMV-TTT) and expression cassettes for c-Fos and c-Jun genes as trans-acting elements facilitated high and long-term (>10 months) expression of a transgene after its intramuscular electroporation-mediated delivery in mice. Since human secretory alkaline phosphatase was used as a reporter, it was suggested that the immune evasion mechanism elicited by the CMV-TTT and/or c-Fos/ c-Jun expression also contributed to the sustained expression in mice. Our strategy may open a new avenue for a gene therapy that involves lifelong supplementation of a deficient protein that could be targeted by the host's immune system.

Multivalent DNA vaccine protects mice against pulmonary infection caused by Pseudomonas aeruginosa.

For efficacious vaccine development against Pseudomonas aeruginosa (P. aeruginosa), the immunogenicity of multivalent DNA vaccine was evaluated. Three different plasmids each targeting a fusion of outer membrane proteins (OprF/OprI), a protein regulating type III secretion system (PcrV), or an appendage (PilA) were prepared and mice were immunized with single (monovalent) or a combination of these plasmids (multivalent) via intramuscular electroporation (imEPT) or gene gun. Immunization with multivalent DNA vaccine via imEPT induced the most potent protection against lethal pneumonia. Although the serum levels of IgG binding to whole bacteria cells were comparable between groups, the strongest immune protection was associated with the serum levels of Th1-dominated multivalent IgG, the bronchoalveolar levels of macrophage inflammatory protein 2 (MIP-2) and IFN-gamma, and the number of neutrophils and macrophages in the bronchoalveolar lavage following intranasal challenge. These results implied the possible clinical application of multivalent DNA vaccine against P. aeruginosa.