Ebola virus replication leading to viral load as a predictor of disease severity and transmission

Le virus Ebola (EBOV) est l'agent étiologique de la maladie à virus Ebola (MVE), une maladie à progression fulgurante qui peut atteindre des taux de mortalité allant jusqu'à 90%. Malgré le fait que ce virus ait été découvert en 1976, ce n'est pas avant 2014 que le public fut exposé à ses effets dévastateurs, alors que l'épidémie de 2014-2016 qui a frappé l'Afrique de l'Ouest ne soit déclarée une urgence de santé publique à portée internationale, et où plus de 28 000 individus seront touchés principalement en Guinée, au Sierra Leone, et au Libéria, mais également aux États-Unis et en Europe. Une des raisons principales qui fait en sorte que notre compréhension du virus n'évolue pas aussi rapidement que pour d'autres agents pathogènes est qu'EBOV doit être manipulé dans le plus haut niveau de sécurité biologique, c'est-à-dire un laboratoire de niveau de confinement 4. Ce type de laboratoire est rare, et le fait de devoir contenir le virus à l'intérieur de celui-ci complexifie le nombre d'expériences pouvant y être effectué. De plus, aucune intervention prophylactique ou thérapeutique n'a été disponible pendant plus de 40 ans. La majorité des travaux effectués ont donc continuellement cherché à pallier à ce manque. Ainsi, un important travail a été effectué afin de comprendre la nature des réponses immunitaires suite à l'infection, puisque cette dernière peut mieux diriger le développement de mesures efficaces. Cependant, peu d'études se sont penchées sur la caractérisation des propriétés virales basiques, tels que les déterminants viraux associés avec la pathogénèse et la transmission du virus. Dans cette thèse, le rôle spécifique de la charge virale, résultant de la réplication du virus Ebola, est évalué dans un contexte de sévérité de la maladie et de transmission. Dans un premier temps, un état général des connaissances quant à EBOV et son cycle de vie est présenté, ainsi que de la manière dont le virus se comporte chez l'humain et dans les modèles animaux. Dans le premier chapitre de cette thèse, l'association entre la charge virale et l'issue suite à la maladie est décrite dans un contexte d'une épidémie naturelle chez l'humain. Dans un contexte de diagnostic, la virémie de patients qui se sont présentés à un centre de traitement Ebola a été évaluée, mais de plus amples analyses ont révélées que ceux qui se présentaient avec une virémie moindre étaient plus susceptible de se rétablir, une mesure indirecte de la sévérité de la maladie. Dans le second chapitre, un nouveau modèle de transmission chez le furet est décrit, où la transmission résultant d'un contact direct ou indirect a été évaluée simultanément. Alors que les mâles en contact direct avec un furet infecté ont développé et succombé à la MVE dans un laps de temps correspondant à une infection par leur compagnon de cage en phase terminale, aucune femelle n'a développer la MVE ou possédait une charge virale détectable. Cependant, tous les animaux contacts directs et indirects ont expérimenté une séroconversion à EBOV, suggérant que dans ce modèle une transmission par contact indirect est fréquente, mais résulte en une maladie clinique moins sévère. Finalement, dans le dernier chapitre de cette thèse, le rôle de la charge virale et de la voie d'infection est évalué dans un modèle de primates non-humains. Dans une série d'expériences indépendantes, une infection intraoesophagienne ou par exposition du visage des animaux à des aérosols n'a pas résulté en une infection clinique ou une virémie. Cependant, les animaux en contact direct avec ceux infecté par aérosol ont tous développé des anticorps spécifiques contre EBOV. Des expériences additionnelles utilisant un modèle d'infection intramusculaire ou intratrachéale suggèrent que la charge virale détermine la transmission d'EBOV dans un contexte d'infection intramusculaire, puisque le seul animal ayant transmis avec succès EBOV à son compagnon de cage était celui démontrant les plus hauts niveaux de virémie et sécrétion virale. Cette transmission est facilitée dans un modèle d'infection intratrachéale, puisqu'elle a été observée de manière consistante entre les animaux infectés et contacts. En effet, la charge virale mesurée dans les sécrétions mucosales des animaux infectés était plus élevée que celle de l'animal ayant transmis EBOV lors de l'infection intramusculaire, suggérant que dans ce modèle d'infection, la charge virale sécrétée est associée avec la transmission d'EBOV.Ebola virus (EBOV) is the etiological agent responsible for Ebola virus disease (EVD), a rapidly progressing infection which has historically reached case fatality rates of up to 90%. Although the virus was first identified in 1976, it was not until 2014 that the general public was exposed to its devastating impacts, as the 2014-2016 West African Ebola outbreak was declared a public health emergency of international concern and affected over 28,000 individuals, mostly in Guinea, Sierra Leone, and Liberia, but also in the United States and Europe. One of the main reasons that hinders our ability to characterize this disease extensively and rapidly is that handling this virus requires the highest level of biosafety containment available, namely biosafety level 4. These facilities are scarce world-wide, and the need to maintain high confinement usually limits the size and volume of the experiments that can be safely performed within. Given that for over 40 years, no medical countermeasures were available, a large proportion of available biosafety level 4 (BSL-4) resources was dedicated to solving this pressing issue. As such, a large amount of important work has focused on understanding the immune responses to infection, as they can better direct the development of efficacious countermeasures. Conversely, little has been done to characterize basic viral properties, such as viral determinants associated with pathogenicity and transmission of this virus. In this thesis, the role of viral loads specifically, as a result of virus replication, is evaluated with regards to pathogenicity and transmission. In the first section of this document, the current state of knowledge related to EBOV and its life cycle is presented, as well as what is currently known about how the virus behaves in both humans and animal models. In the first chapter of this thesis, the association between viral load and outcome is described from a human outbreak perspective. In the context of diagnostics, viremia of individuals who presented at an Ebola management center was assessed, but a follow-up analysis revealed that individuals who presented for care with a lower viremia better associated with recovery -- an indirect measure of disease severity. In the second chapter, a novel ferret model for transmission is described, where transmission resulting from direct and indirect contact could be evaluated simultaneously. While male direct contact animals developed and succumbed to clinical EVD in a timeframe consistent with infection by their terminally-ill challenged cagemate, no female contact animals became viremic or symptomatic. Interestingly, all direct and indirect contact animals seroconverted against EBOV, suggesting that in this model indirect transmission is frequent but results in a less-severe disease. Finally, in the final chapter of this thesis, the role of viral loads, as well as route of infection, was evaluated thoroughly in non-human primates. In a series of independent experiments, intraesophageal and facial aerosol exposure did not result in clinical EVD or viremia, but interestingly, all contact animals from the latter challenge seroconverted. Additional intramuscular or intratracheal challenge studies suggest that viral loads determine transmission of EBOV in an intramuscular challenge, as only the animal exhibiting the highest viral load was able o transmit EBOV to its contact cagemate. This transmission was found to be facilitated when using an intratracheal route of infection, as transmission was observed consistently from an infected to a naïve cagemate. Interestingly, viral loads as a result of shedding were found to be higher than those of the transmitting animal from the intramuscular challenge, suggesting that in this model, viral load as a result from shedding associate with transmission

Parameters Characterization and Cognitive-Behavioral Effects of Transcranial Pulsed Current Stimulation

Neuromodulation is being recognized as “technology impacting on the neural interface” And noninvasive brain stimulation (NIBS) is becoming an interesting alternative for this interface. Transcranial pulsed current stimulation (tPCS) is emerging as an option in the field of neuromodulation as a technique that employs weak, pulsed current at different frequency ranges, inducing electrical fields that reach cortical and subcortical structures; however, little is known about its properties and mechanistic effects on electrical brain activity and how it can modulate its oscillatory patterns. Moreover, there is not clear understanding in how tPCS can affect cognition and behavior or its neurophysiological correlates as indexed by autonomic responses. This research looked at the mechanisms behind tPCS in four randomized clinical trials; the main aim of each experiment was to evaluate the effects of tPCS in quantitative electroencephalography (qEEG) and cognitive-behavioral testing by exploring different parameters of stimulation. Based in the findings obtained per experiment, tPCS can be defined as a safe and tolerable technique that modulates the power spectrum of qEEG signals by means of applied randomized frequencies in a pre-defined range, tPCS also facilitates connectivity in the area of influence by the electrical field and this has an impact on optimization of performance by decreasing reaction times (RT) in attention switching task and by facilitating wide-ranging network processing as in the case of arithmetic functioning. This work also delivered an insight about the potential that tPCS has for future clinical applications.The Labuschagne-Foundation Spaulding Neurmodulation Cente

Engineering data compendium. Human perception and performance. User's guide

The concept underlying the Engineering Data Compendium was the product of a research and development program (Integrated Perceptual Information for Designers project) aimed at facilitating the application of basic research findings in human performance to the design and military crew systems. The principal objective was to develop a workable strategy for: (1) identifying and distilling information of potential value to system design from the existing research literature, and (2) presenting this technical information in a way that would aid its accessibility, interpretability, and applicability by systems designers. The present four volumes of the Engineering Data Compendium represent the first implementation of this strategy. This is the first volume, the User's Guide, containing a description of the program and instructions for its use

Special oils for halal and safe cosmetics

Three types of non conventional oils were extracted, analyzed and tested for toxicity. Date palm kernel oil (DPKO), mango kernel oil (MKO) and Ramputan seed oil (RSO). Oil content for tow cultivars of dates Deglect Noor and Moshkan was 9.67% and 7.30%, respectively. The three varieties of mango were found to contain about 10% oil in average. The red yellow types of Ramputan were found to have 11 and 14% oil, respectively. The phenolic compounds in DPKO, MKO and RSO were 0.98, 0.88 and 0.78 mg/ml Gallic acid equivalent, respectively. Oils were analyzed for their fatty acid composition and they are rich in oleic acid C18:1 and showed the presence of (dodecanoic acid) lauric acid C12:0, which reported to appear some antimicrobial activities. All extracted oils, DPKO, MKO and RSO showed no toxic effect using prime shrimp bioassay. Since these oils are stable, melt at skin temperature, have good lubricity and are great source of essential fatty acids; they could be used as highly moisturizing, cleansing and nourishing oils because of high oleic acid content. They are ideal for use in such halal cosmetics such as Science, Engineering and Technology 75 skin care and massage, hair-care, soap and shampoo products

Bronx Community College of the City University of New York Catalog 1992-94 Gateway to Success

Course catalog for Bronx Community College for 1992-94

Digital imaging technology assessment: Digital document storage project

An ongoing technical assessment and requirements definition project is examining the potential role of digital imaging technology at NASA's STI facility. The focus is on the basic components of imaging technology in today's marketplace as well as the components anticipated in the near future. Presented is a requirement specification for a prototype project, an initial examination of current image processing at the STI facility, and an initial summary of image processing projects at other sites. Operational imaging systems incorporate scanners, optical storage, high resolution monitors, processing nodes, magnetic storage, jukeboxes, specialized boards, optical character recognition gear, pixel addressable printers, communications, and complex software processes