66 research outputs found

    Initial Considerations Before Designing a Promoter Construct.

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    Before designing a synthetic promoter, it can be helpful to think about its final application. Is the study purely an in vitro exercise in monitoring short-term promoter activity from an episomal vector, or does the promoter eventually need to be permanently active and be integrated into the genome or perhaps even to function in vivo? The final application will have a bearing on promoter design and vector of choice from the start of the study. In this chapter I highlight some of the vector attributes to consider and features that should be thought about

    A Canadian Critical Care Trials Group project in collaboration with the international forum for acute care trialists - Collaborative H1N1 Adjuvant Treatment pilot trial (CHAT): study protocol and design of a randomized controlled trial

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    <p>Abstract</p> <p>Background</p> <p>Swine origin influenza A/H1N1 infection (H1N1) emerged in early 2009 and rapidly spread to humans. For most infected individuals, symptoms were mild and self-limited; however, a small number developed a more severe clinical syndrome characterized by profound respiratory failure with hospital mortality ranging from 10 to 30%. While supportive care and neuraminidase inhibitors are the main treatment for influenza, data from observational and interventional studies suggest that the course of influenza can be favorably influenced by agents not classically considered as influenza treatments. Multiple observational studies have suggested that HMGCoA reductase inhibitors (statins) can exert a class effect in attenuating inflammation. The Collaborative H1N1 Adjuvant Treatment (CHAT) Pilot Trial sought to investigate the feasibility of conducting a trial during a global pandemic in critically ill patients with H1N1 with the goal of informing the design of a larger trial powered to determine impact of statins on important outcomes.</p> <p>Methods/Design</p> <p>A multi-national, pilot randomized controlled trial (RCT) of once daily enteral rosuvastatin versus matched placebo administered for 14 days for the treatment of critically ill patients with suspected, probable or confirmed H1N1 infection. We propose to randomize 80 critically ill adults with a moderate to high index of suspicion for H1N1 infection who require mechanical ventilation and have received antiviral therapy for ≤ 72 hours. Site investigators, research coordinators and clinical pharmacists will be blinded to treatment assignment. Only research pharmacy staff will be aware of treatment assignment. We propose several approaches to informed consent including a priori consent from the substitute decision maker (SDM), waived and deferred consent. The primary outcome of the CHAT trial is the proportion of eligible patients enrolled in the study. Secondary outcomes will evaluate adherence to medication administration regimens, the proportion of primary and secondary endpoints collected, the number of patients receiving open-label statins, consent withdrawals and the effect of approved consent models on recruitment rates.</p> <p>Discussion</p> <p>Several aspects of study design including the need to include central randomization, preserve allocation concealment, ensure study blinding compare to a matched placebo and the use novel consent models pose challenges to investigators conducting pandemic research. Moreover, study implementation requires that trial design be pragmatic and initiated in a short time period amidst uncertainty regarding the scope and duration of the pandemic.</p> <p>Trial Registration Number</p> <p><a href="http://www.controlled-trials.com/ISRCTN45190901">ISRCTN45190901</a></p

    Likely Correlation between Sources of Information and Acceptability of A/H1N1 Swine-Origin Influenza Virus Vaccine in Marseille, France

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    BACKGROUND: In France, there was a reluctance to accept vaccination against the A/H1N1 pandemic influenza virus despite government recommendation and investment in the vaccine programme. METHODS AND FINDINGS: We examined the willingness of different populations to accept A/H1N1 vaccination (i) in a French hospital among 3315 employees immunized either by in-house medical personnel or mobile teams of MDs and (ii) in a shelter housing 250 homeless persons. Google was used to assess the volume of enquiries concerning incidence of influenza. We analyzed the information on vaccination provided by Google, the website of the major French newspapers, and PubMed. Two trust Surveys were used to assess public opinion on the trustworthiness of people in different professions. Paramedics were significantly more reluctant to accept immunisation than qualified medical staff. Acceptance was significantly increased when recommended directly by MDs. Anecdotal cases of directly observed severe infections were followed by enhanced acceptance of paramedical staff. Scientific literature was significantly more in favour of vaccination than Google and French newspaper websites. In the case of the newspaper websites, information correlated with their recognised political reputations, although they would presumably claim independence from political bias. The Trust Surveys showed that politicians were highly dis-trusted in contrast with doctors and pharmacists who were considered much more trustworthy. CONCLUSIONS: The low uptake of the vaccine could reflect failure to convey high quality medical information and advice relating to the benefits of being vaccinated. We believe that the media and internet contributed to this problem by raising concerns within the general population and that failure to involve GPs in the control programme may have been a mistake. GPs are highly regarded by the public and can provide face-to-face professional advice and information. The top-down strategy of vaccine programme management and information delivered by the Ministry of Health could have aggravated the problem, because the general population does not always trust politicians

    Hemagglutinin from the H5N1 Virus Activates Janus Kinase 3 to Dysregulate Innate Immunity

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    Highly pathogenic avian influenza viruses (HPAIVs) cause severe disease in humans. There are no effective vaccines or antiviral therapies currently available to control fatal outbreaks due in part to the lack of understanding of virus-mediated immunopathology. In our study, we used hemagglutinin (HA) of H5N1 virus to investigate the related signaling pathways and their relationship to dysregulated innate immune reaction. We found the HA of H5N1 avian influenza triggered an abnormal innate immune signalling in the pulmonary epithelial cells, through an unusual process involving activation of Janus kinase 3 (JAK3) that is exclusively associated with γc chain and is essential for signaling via all γc cytokine receptors. By using a selective JAK3 inhibitor and JAK3 knockout mice, we have, for the first time, demonstrated the ability to target active JAK3 to counteract injury to the lungs and protect immunocytes from acute hypercytokinemia -induced destruction following the challenge of H5N1 HA in vitro and in vivo. On the basis of the present data, it appears that the efficacy of selective JAK3 inhibition is likely based on its ability to block multiple cytokines and protect against a superinflammatory response to pathogen-associated molecular patterns (PAMPs) attack. Our findings highlight the potential value of selective JAK3 inhibitor in treating the fatal immunopathology caused by H5N1 challenge

    Processus bidimensionnels et modele autoregressif vectoriel ; application a la modelisation des textures

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    Cet article propose l'utilisation d'un modèle vectoriel pour l'identification des processus à 2 indices ; les principaux résultats concernant l'estimation linéaire vectorielle sont présentés : nous analysons, en particulier, les relations entre la factorisation des matrices de corrélation et différentes normalisations de l'algorithme de Robinson. Nous montrons que certains polynomes à 2 variables orthogonaux sur le cercle unité sont obtenus en utilisant un algorithme récursif d'estimation des processus vectoriels ; ces polynomes sont associés au filtre bidimensionnel récursif le plus général (filtre demi-plan asymétrique) ; cette méthode est ensuite utilisée pour la modélisation des Textures

    Quelques proprietes importantes du modele autoregressif vectoriel

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    Dans cet article nous étudions les méthodes d'estimation des moindres carrés et du maximum de vraisemblance pour le modèle autorégressif vectoriel. Plusieurs résultats nouveaux sont présentés ; nous montrons, en particulier, que comme dans le cas scalaire, les deux méthodes conduisent au même ensemble de paramètres estimés. Nous démontrons ensuite une propriété intéressante de la formulation des moindres carrés et du maximum de vraisemblance : l'estimation du modèle autorégressif vectoriel est réalisée en minimisant l'erreur de prédiction pour chacune des composantes du signal vectoriel. Plusieurs formes canoniques du modèle autorégressif vectoriel sont proposées, et nous étudions en détail, les propriétés algébriques et les propriétés de stabilité des algorithmes normalisés correspondants. Nous présentons, ensuite, plusieurs critères de reconnaissance qui se déduisent des méthodes d'estimation précédentes
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