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

Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian children in the second year of life

Rotavirus gastroenteritis is one of the leading causes of diarrhea in Indian children less than 2 years of age. The 116E rotavirus strain was developed as part of the Indo-US Vaccine Action Program and has undergone efficacy trials. This paper reports the efficacy and additional safety data in children up to 2 years of age. In a double-blind placebo controlled multicenter trial, 6799 infants aged 6-7 weeks were randomized to receive three doses of an oral human-bovine natural reassortant vaccine (116E) or placebo at ages 6, 10, and 14 weeks. The primary outcome was severe (≥11 on the Vesikari scale) rotavirus gastroenteritis. Efficacy outcomes and adverse events were ascertained through active surveillance. We randomly assigned 4532 and 2267 subjects to receive vaccine and placebo, respectively, with over 96% subjects receiving all three doses of the vaccine or placebo. The per protocol analyses included 4354 subjects in the vaccine and 2187 subjects in the placebo group. The overall incidence of severe RVGE per 100 person years was 1.3 in the vaccine group and 2.9 in the placebo recipients. Vaccine efficacy against severe rotavirus gastroenteritis in children up to 2 years of age was 55.1% (95% CI 39.9 to 66.4; p<0.0001); vaccine efficacy in the second year of life of 48.9% (95% CI 17.4 to 68.4; p=0.0056) was only marginally less than in the first year of life [56.3% (95% CI 36.7 to 69.9; p<0.0001)]. The number of infants needed to be immunized to prevent one episode of severe RVGE in the first 2 years of life was 40 (95% CI 28.0 to 63.0) and for RVGE of any severity, it was 21 (95% CI 16.0 to 32.0). Serious adverse events were observed at the same rates in the two groups. None of the eight intussusception events occurred within 30 days of a vaccine dose and all were reported only after the third dose. The sustained efficacy of the 116E in the second year of life is reassuring

The adaptive designs CONSORT extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design

Abstract: Adaptive designs (ADs) allow pre-planned changes to an ongoing trial without compromising the validity of conclusions and it is essential to distinguish pre-planned from unplanned changes that may also occur. The reporting of ADs in randomised trials is inconsistent and needs improving. Incompletely reported AD randomised trials are difficult to reproduce and are hard to interpret and synthesise. This consequently hampers their ability to inform practice as well as future research and contributes to research waste. Better transparency and adequate reporting will enable the potential benefits of ADs to be realised. This extension to the Consolidated Standards Of Reporting Trials (CONSORT) 2010 statement was developed to enhance the reporting of randomised AD clinical trials. We developed an Adaptive designs CONSORT Extension (ACE) guideline through a two-stage Delphi process with input from multidisciplinary key stakeholders in clinical trials research in the public and private sectors from 21 countries, followed by a consensus meeting. Members of the CONSORT Group were involved during the development process. The paper presents the ACE checklists for AD randomised trial reports and abstracts, as well as an explanation with examples to aid the application of the guideline. The ACE checklist comprises seven new items, nine modified items, six unchanged items for which additional explanatory text clarifies further considerations for ADs, and 20 unchanged items not requiring further explanatory text. The ACE abstract checklist has one new item, one modified item, one unchanged item with additional explanatory text for ADs, and 15 unchanged items not requiring further explanatory text. The intention is to enhance transparency and improve reporting of AD randomised trials to improve the interpretability of their results and reproducibility of their methods, results and inference. We also hope indirectly to facilitate the much-needed knowledge transfer of innovative trial designs to maximise their potential benefits. In order to encourage its wide dissemination this article is freely accessible on the BMJ and Trials journal websites.“To maximise the benefit to society, you need to not just do research but do it well” Douglas G Altma

The adaptive designs CONSORT extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design.

Adaptive designs (ADs) allow pre-planned changes to an ongoing trial without compromising the validity of conclusions and it is essential to distinguish pre-planned from unplanned changes that may also occur. The reporting of ADs in randomised trials is inconsistent and needs improving. Incompletely reported AD randomised trials are difficult to reproduce and are hard to interpret and synthesise. This consequently hampers their ability to inform practice as well as future research and contributes to research waste. Better transparency and adequate reporting will enable the potential benefits of ADs to be realised.This extension to the Consolidated Standards Of Reporting Trials (CONSORT) 2010 statement was developed to enhance the reporting of randomised AD clinical trials. We developed an Adaptive designs CONSORT Extension (ACE) guideline through a two-stage Delphi process with input from multidisciplinary key stakeholders in clinical trials research in the public and private sectors from 21 countries, followed by a consensus meeting. Members of the CONSORT Group were involved during the development process.The paper presents the ACE checklists for AD randomised trial reports and abstracts, as well as an explanation with examples to aid the application of the guideline. The ACE checklist comprises seven new items, nine modified items, six unchanged items for which additional explanatory text clarifies further considerations for ADs, and 20 unchanged items not requiring further explanatory text. The ACE abstract checklist has one new item, one modified item, one unchanged item with additional explanatory text for ADs, and 15 unchanged items not requiring further explanatory text.The intention is to enhance transparency and improve reporting of AD randomised trials to improve the interpretability of their results and reproducibility of their methods, results and inference. We also hope indirectly to facilitate the much-needed knowledge transfer of innovative trial designs to maximise their potential benefits. In order to encourage its wide dissemination this article is freely accessible on the BMJ and Trials journal websites."To maximise the benefit to society, you need to not just do research but do it well" Douglas G Altman

The adaptive designs CONSORT extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design.

Adaptive designs (ADs) allow pre-planned changes to an ongoing trial without compromising the validity of conclusions and it is essential to distinguish pre-planned from unplanned changes that may also occur. The reporting of ADs in randomised trials is inconsistent and needs improving. Incompletely reported AD randomised trials are difficult to reproduce and are hard to interpret and synthesise. This consequently hampers their ability to inform practice as well as future research and contributes to research waste. Better transparency and adequate reporting will enable the potential benefits of ADs to be realised.This extension to the Consolidated Standards Of Reporting Trials (CONSORT) 2010 statement was developed to enhance the reporting of randomised AD clinical trials. We developed an Adaptive designs CONSORT Extension (ACE) guideline through a two-stage Delphi process with input from multidisciplinary key stakeholders in clinical trials research in the public and private sectors from 21 countries, followed by a consensus meeting. Members of the CONSORT Group were involved during the development process.The paper presents the ACE checklists for AD randomised trial reports and abstracts, as well as an explanation with examples to aid the application of the guideline. The ACE checklist comprises seven new items, nine modified items, six unchanged items for which additional explanatory text clarifies further considerations for ADs, and 20 unchanged items not requiring further explanatory text. The ACE abstract checklist has one new item, one modified item, one unchanged item with additional explanatory text for ADs, and 15 unchanged items not requiring further explanatory text.The intention is to enhance transparency and improve reporting of AD randomised trials to improve the interpretability of their results and reproducibility of their methods, results and inference. We also hope indirectly to facilitate the much-needed knowledge transfer of innovative trial designs to maximise their potential benefits. In order to encourage its wide dissemination this article is freely accessible on the BMJ and Trials journal websites."To maximise the benefit to society, you need to not just do research but do it well" Douglas G Altman

Treatment with IL-7 Prevents the Decline of Circulating CD4+ T Cells during the Acute Phase of SIV Infection in Rhesus Macaques

Although treatment with interleukin-7 (IL-7) was shown to transiently expand the naïve and memory T-cell pools in patients with chronic HIV-1 infection receiving antiretroviral therapy (ART), it is uncertain whether a full immunologic reconstitution can be achieved. Moreover, the effects of IL-7 have never been evaluated during acute HIV-1 (or SIV) infection, a critical phase of the disease in which the most dramatic depletion of CD4+ T cells is believed to occur. In the present study, recombinant, fully glycosylated simian IL-7 (50 µg/kg, s.c., once weekly for 7 weeks) was administered to 6 rhesus macaques throughout the acute phase of infection with a pathogenic SIV strain (mac251); 6 animals were infected at the same time and served as untreated controls. Treatment with IL-7 did not cause clinically detectable side effects and, despite the absence of concomitant ART, did not induce significant increases in the levels of SIV replication except at the earliest time point tested (day 4 post-infection). Strikingly, animals treated with IL-7 were protected from the dramatic decline of circulating naïve and memory CD4+ T cells that occurred in untreated animals. Treatment with IL-7 induced only transient T-cell proliferation, but it was associated with sustained increase in the expression of the anti-apoptotic protein Bcl-2 on both CD4+ and CD8+ T cells, persistent expansion of all circulating CD8+ T-cell subsets, and development of earlier and stronger SIV Tat-specific T-cell responses. However, the beneficial effects of IL-7 were not sustained after treatment interruption. These data demonstrate that IL-7 administration is effective in protecting the CD4+ T-cell pool during the acute phase of SIV infection in macaques, providing a rationale for the clinical evaluation of this cytokine in patients with acute HIV-1 infection

COMPASS identifies T-cell subsets correlated with clinical outcomes.

Advances in flow cytometry and other single-cell technologies have enabled high-dimensional, high-throughput measurements of individual cells as well as the interrogation of cell population heterogeneity. However, in many instances, computational tools to analyze the wealth of data generated by these technologies are lacking. Here, we present a computational framework for unbiased combinatorial polyfunctionality analysis of antigen-specific T-cell subsets (COMPASS). COMPASS uses a Bayesian hierarchical framework to model all observed cell subsets and select those most likely to have antigen-specific responses. Cell-subset responses are quantified by posterior probabilities, and human subject-level responses are quantified by two summary statistics that describe the quality of an individual's polyfunctional response and can be correlated directly with clinical outcome. Using three clinical data sets of cytokine production, we demonstrate how COMPASS improves characterization of antigen-specific T cells and reveals cellular 'correlates of protection/immunity' in the RV144 HIV vaccine efficacy trial that are missed by other methods. COMPASS is available as open-source software

A call for transparent reporting to optimize the predictive value of preclinical research

The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress