Prevention of Immune Cell Apoptosis as Potential Therapeutic Strategy for Severe Infections

Lymphocyte apoptosis prevention may improve survival

Health evaluation of a pronghorn antelope population in Oregon

During 1996 and 1997, the U.S. Fish and Wildlife Service conducted a study to determine the cause(s) of population decline and low survival of pronghorn antelope (Antilocapra americana) fawns on Hart Mountain National Antelope Refuge (HMNAR) located in southeastern Oregon (USA). As part of that study, blood, fecal, and tissue samples from 104 neonatal fawns, 40 adult does, and nine adult male pronghorns were collected to conduct a health evaluation of the population. Physiological parameters related to nutrition and/or disease were studied. No abnormalities were found in the complete blood cell counts of adults (n = 40) or fawns (n = 44 to 67). Serum total protein and blood urea nitrogen (BUN) levels were lower compared to other pronghorn populations. Does had mean BUN values significantly lower (P < 0.001) in December 1996 than March 1997. Serum copper (Cu) levels in does (range 0.39 to 0.74 ppm) were considered marginal when compared to domestic animals and other wild ungulates. Fawns had low (0.28 ppm) Cu levels at birth and reached the does' marginal values in about 3 days. Whole blood, serum and liver selenium (Se) levels were considered marginal to low in most segments of the pronghorn population. However, serum levels of vitamin E (range 1.98 to 3.27 μg/ml), as determined from the does captured in March, were apparently sufficient to offset any signs of Se deficiency. No clinical signs of Cu or Se deficiency were observed. Fifty-five of 87 dead fawns were necropsied. Trauma, due to predation by coyotes (Canis latrans), accounted for 62% of the mortality during mid-May to mid-July of each year. Other causes included predation by golden eagles (Aquila chrysaetos) (4%), dystocia (2%), septicemic pasteurellosis (4%), starvation (5%), and unknown (23%). Adult females were tested for serum neutralizing antibodies to Brucella spp. (n = 20, negative), Leptospira interrogans (n = 20, negative), bluetongue virus (n = 20, 35% positive), epizootic hemorrhagic disease virus (n = 20, 30% positive), respiratory syncytial virus (n = 18, negative), parainfluenza virus type 3 (n = 18, 67% positive), infectious bovine rhinotracheitis (n = 18, negative), and bovine viral diarrhea (n = 18, negative). Considering the parameters examined, we found no apparent predisposing factors to mortality including those killed by coyotes, but some nutritional parameters suggest that pronghorns on HMNAR exist on a diet low in protein and Se and marginal in Cu. The effect these factors have on the population is not known

Effective Post-Exposure Treatment of Ebola Infection

Ebola viruses are highly lethal human pathogens that have received considerable attention in recent years due to an increasing re-emergence in Central Africa and a potential for use as a biological weapon. There is no vaccine or treatment licensed for human use. In the past, however, important advances have been made in developing preventive vaccines that are protective in animal models. In this regard, we showed that a single injection of a live-attenuated recombinant vesicular stomatitis virus vector expressing the Ebola virus glycoprotein completely protected rodents and nonhuman primates from lethal Ebola challenge. In contrast, progress in developing therapeutic interventions against Ebola virus infections has been much slower and there is clearly an urgent need to develop effective post-exposure strategies to respond to future outbreaks and acts of bioterrorism, as well as to treat laboratory exposures. Here we tested the efficacy of the vesicular stomatitis virus-based Ebola vaccine vector in post-exposure treatment in three relevant animal models. In the guinea pig and mouse models it was possible to protect 50% and 100% of the animals, respectively, following treatment as late as 24 h after lethal challenge. More important, four out of eight rhesus macaques were protected if treated 20 to 30 min following an otherwise uniformly lethal infection. Currently, this approach provides the most effective post-exposure treatment strategy for Ebola infections and is particularly suited for use in accidentally exposed individuals and in the control of secondary transmission during naturally occurring outbreaks or deliberate release

More than words: The influence of affective content and linguistic style matches in online reviews on conversion rates

Customers increasingly rely on other consumers' reviews to make purchase decisions online. New insights into the customer review phenomenon can be derived from studying the semantic content and style properties of verbatim customer reviews to examine their influence on online retail sites' conversion rates. The authors employ text mining to extract changes in affective content and linguistic style properties of customer book reviews on Amazon.com. A dynamic panel data model reveals that the influence of positive affective content on conversion rates is asymmetrical, such that greater increases in positive affective content in customer reviews have a smaller effect on subsequent increases in conversion rate. No such tapering-off effect occurs for changes in negative affective content in reviews. Furthermore, positive changes in affective cues and increasing congruence with the product interest group's typical linguistic style directly and conjointly increase conversion rates. These findings suggest that managers should identify and promote the most influential reviews in a given product category, provide instructions to stimulate reviewers to write powerful reviews, and adapt the style of their own editorial reviews to the relevant product category

A simple statistical test of taxonomic or functional homogeneity using replicated microbiome sequencing samples

One important question in microbiome analysis is how to assess the homogeneity of the microbial composition in a given environment, with respect to a given analysis method. Do different microbial samples taken from the same environment follow the same taxonomic distribution of organisms, or the same distribution of functions? Here we provide a non-parametric statistical “triangulation test” to address this type of question. The test requires that multiple replicates are available for each of the biological samples, and it is based on three-way computational comparisons of samples. To illustrate the application of the test, we collected three biological samples taken from different locations in one piece of human stool, each represented by three replicates, and analyzed them using MEGAN. (Despite its name, the triangulation test does not require that the number of biological samples or replicates be three.) The triangulation test rejects the null hypothesis that the three biological samples exhibit the same distribution of taxa or function (error probability ≤0.05), indicating that the microbial composition of the investigated human stool is not homogenous on a macroscopic scale, suggesting that pooling material from multiple locations is a reasonable practice. We provide an implementation of the test in our open source program MEGAN Community Edition

The “Outcome Reporting in Brief Intervention Trials: Alcohol” (ORBITAL) core outcome set:International consensus on outcomes to measure in efficacy and effectiveness Trials of alcohol brief interventions

Objective: The purpose of this study was to report the “Outcome Reporting in Brief Intervention Trials: Alcohol” (ORBITAL) recommended core outcome set (COS) to improve efficacy and effectiveness trials/evaluations for alcohol brief interventions (ABIs). Method: A systematic review identified 2,641 outcomes in 401 ABI articles measured by 1,560 different approaches. These outcomes were classified into outcome categories, and 150 participants from 19 countries participated in a two-round e-Delphi outcome prioritization exercise. This process prioritized 15 of 93 outcome categories for discussion at a consensus meeting of key stakeholders to decide the COS. A psychometric evaluation determined how to measure the outcomes. Results: Ten outcomes were voted into the COS at the consensus meeting: (a) typical frequency, (b) typical quantity, (c) frequency of heavy episodic drinking, (d) combined consumption measure summarizing alcohol use, (e) hazardous or harmful drinking (average consumption), (f) standard drinks consumed in the past week (recent, current consumption), (g) alcohol-related consequences, (h) alcohol-related injury, (i) use of emergency health care services (impact of alcohol use), and (j) quality of life. Conclusions: The ORBITAL COS is an international consensus standard for future ABI trials and evaluations. It can improve the synthesis of new findings, reduce redundant/selective reporting (i.e., reporting only some, usually significant outcomes), improve between-study comparisons, and enhance the relevance of trial and evaluation findings to decision makers. The COS is the recommended minimum and does not exclude other, additional outcomes

Assessing changes in vascular permeability in a hamster model of viral hemorrhagic fever

<p>Abstract</p> <p>Background</p> <p>A number of RNA viruses cause viral hemorrhagic fever (VHF), in which proinflammatory mediators released from infected cells induce increased permeability of the endothelial lining of blood vessels, leading to loss of plasma volume, hypotension, multi-organ failure, shock and death. The optimal treatment of VHF should therefore include both the use of antiviral drugs to inhibit viral replication and measures to prevent or correct changes in vascular function. Although rodent models have been used to evaluate treatments for increased vascular permeability (VP) in bacterial sepsis, such studies have not been performed for VHF.</p> <p>Results</p> <p>Here, we use an established model of Pichinde virus infection of hamsters to demonstrate how changes in VP can be detected by intravenous infusion of Evans blue dye (EBD), and compare those measurements to changes in hematocrit, serum albumin concentration and serum levels of proinflammatory mediators. We show that EBD injected into sick animals in the late stage of infection is rapidly sequestered in the viscera, while in healthy animals it remains within the plasma, causing the skin to turn a marked blue color. This test could be used in live animals to detect increased VP and to assess the ability of antiviral drugs and vasoactive compounds to prevent its onset. Finally, we describe a multiplexed assay to measure levels of serum factors during the course of Pichinde arenavirus infection and demonstrate that viremia and subsequent increase in white blood cell counts precede the elaboration of inflammatory mediators, which is followed by increased VP and death.</p> <p>Conclusions</p> <p>This level of model characterization is essential to the evaluation of novel interventions designed to control the effects of virus-induced hypercytokinemia on host vascular function in VHF, which could lead to improved survival.</p

The 'Outcome Reporting in Brief Intervention Trials: Alcohol' (ORBITAL) framework: protocol to determine a core outcome set for efficacy and effectiveness trials of alcohol screening and brief intervention

Background: The evidence base to assess the efficacy and effectiveness of alcohol brief interventions (ABI) is weakened by variation in the outcomes measured and by inconsistent reporting. The 'Outcome Reporting in Brief Intervention Trials: Alcohol' (ORBITAL) project aims to develop a core outcome set (COS) and reporting guidance for its use in future trials of ABI in a range of settings. Methods/design: An international Special Interest Group was convened through INEBRIA (International Network on Brief Interventions for Alcohol and Other Drugs) to inform the development of a COS for trials of ABI. ORBITAL will incorporate a systematic review to map outcomes used in efficacy and effectiveness trials of ABI and their measurement properties, using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) criteria. This will support a multi-round Delphi study to prioritise outcomes. Delphi panellists will be drawn from a range of settings and stakeholder groups, and the Delphi study will also be used to determine if a single COS is relevant for all settings. A consensus meeting with key stakeholder representation will determine the final COS and associated guidance for its use in trials of ABI. Discussion: ORBITAL will develop a COS for alcohol screening and brief intervention trials, with outcomes stratified into domains and guidance on outcome measurement instruments. The standardisation of ABI outcomes and their measurement will support the ongoing development of ABI studies and a systematic synthesis of emerging research findings. We will track the extent to which the COS delivers on this promise through an exploration of the use of the guidance in the decade following COS publication.We would like to thank and acknowledge the funding from Alcohol Research UK (Research Innovation Grant Number: R2016/04) and the INEBRIA ORBITAL SIG for feedback and useful commentary at the INEBRIA 2016 conference workshop on the topic

Developing a core outcome set for the health outcomes for children and adults with congenital oesophageal atresia and/or tracheo-oesophageal fistula: OCELOT task group study protocol

Introduction: Heterogeneity in reported outcomes of infants with oesophageal atresia (OA) with or without tracheo-oesophageal fistula (TOF) prevents effective data pooling. Core outcome sets (COS) have been developed for many conditions to standardise outcome reporting, facilitate meta-analysis and improve the relevance of research for patients and families. Our aim is to develop an internationally-agreed, comprehensive COS for OA-TOF, relevant from birth through to transition and adulthood. Methods and analysis: A long list of outcomes will be generated using (1) a systematic review of existing studies on OA-TOF and (2) qualitative research with children (patients), adults (patients) and families involving focus groups, semistructured interviews and self-reported outcome activity packs. A two-phase Delphi survey will then be completed by four key stakeholder groups: (1) patients (paediatric and adult); (2) families; (3) healthcare professionals; and (4) researchers. Phase I will include stakeholders individually rating the importance and relevance of each long-listed outcome using a 9-point Likert scale, with the option to suggest additional outcomes not already included. During phase II, stakeholders will review summarised results from phase I relative to their own initial score and then will be asked to rescore the outcome based on this information. Responses from phase II will be summarised using descriptive statistics and a predefined definition of consensus for inclusion or exclusion of outcomes. Following the Delphi process, stakeholder experts will be invited to review data at a consensus meeting and agree on a COS for OA-TOF. Ethics and dissemination: Ethical approval was sought through the Health Research Authority via the Integrated Research Application System, registration no. 297026. However, approval was deemed not to be required, so study sponsorship and oversight were provided by Alder Hey Children’s NHS Foundation Trust. The study has been prospectively registered with the COMET Initiative. The study will be published in an open access forum