Síndrome de Mowat-Wilson

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Safety of human immunisation with a live-attenuated Mycobacterium tuberculosis vaccine: a randomised, double-blind, controlled phase I trial.

BACKGROUND: Tuberculosis remains one of the world's deadliest transmissible diseases despite widespread use of the BCG vaccine. MTBVAC is a new live tuberculosis vaccine based on genetically attenuated Mycobacterium tuberculosis that expresses most antigens present in human isolates of M tuberculosis. We aimed to compare the safety of MTBVAC with BCG in healthy adult volunteers. METHODS: We did this single-centre, randomised, double-blind, controlled phase 1 study at the Centre Hospitalier Universitaire Vaudois (CHUV; Lausanne, Switzerland). Volunteers were eligible for inclusion if they were aged 18-45 years, clinically healthy, HIV-negative and tuberculosis-negative, and had no history of active tuberculosis, chemoprophylaxis for tuberculosis, or BCG vaccination. Volunteers fulfilling the inclusion criteria were randomly assigned to three cohorts in a dose-escalation manner. Randomisation was done centrally by the CHUV Pharmacy and treatments were masked from the study team and volunteers. As participants were recruited within each cohort, they were randomly assigned 3:1 to receive MTBVAC or BCG. Of the participants allocated MTBVAC, those in the first cohort received 5 × 10(3) colony forming units (CFU) MTBVAC, those in the second cohort received 5 × 10(4) CFU MTBVAC, and those in the third cohort received 5 × 10(5) CFU MTBVAC. In all cohorts, participants assigned to receive BCG were given 5 × 10(5) CFU BCG. Each participant received a single intradermal injection of their assigned vaccine in 0·1 mL sterile water in their non-dominant arm. The primary outcome was safety in all vaccinated participants. Secondary outcomes included whole blood cell-mediated immune response to live MTBVAC and BCG, and interferon γ release assays (IGRA) of peripheral blood mononuclear cells. This trial is registered with ClinicalTrials.gov, number NCT02013245. FINDINGS: Between Jan 23, 2013, and Nov 6, 2013, we enrolled 36 volunteers into three cohorts, each of which consisted of nine participants who received MTBVAC and three who received BCG. 34 volunteers completed the trial. The safety of vaccination with MTBVAC at all doses was similar to that of BCG, and vaccination did not induce any serious adverse events. All individuals were IGRA negative at the end of follow-up (day 210). After whole blood stimulation with live MTBVAC or BCG, MTBVAC was at least as immunogenic as BCG. At the same dose as BCG (5×10(5) CFU), although no statistical significance could be achieved, there were more responders in the MTBVAC group than in the BCG group, with a greater frequency of polyfunctional CD4+ central memory T cells. INTERPRETATION: To our knowledge, MTBVAC is the first live-attenuated M tuberculosis vaccine to reach clinical assessment, showing similar safety to BCG. MTBVAC seemed to be at least as immunogenic as BCG, but the study was not powered to investigate this outcome. Further plans to use more immunogenicity endpoints in a larger number of volunteers (adults and adolescents) are underway, with the aim to thoroughly characterise and potentially distinguish immunogenicity between MTBVAC and BCG in tuberculosis-endemic countries. Combined with an excellent safety profile, these data support advanced clinical development in high-burden tuberculosis endemic countries. FUNDING: Biofabri and Bill & Melinda Gates Foundation through the TuBerculosis Vaccine Initiative (TBVI)

Reconfiguring tissue banking consent through enrichment of a restricted debate

Tissue banks are thought to be an essential resource for medical research in the post-genomic age. Collections of tissue, usually removed in the course of diagnostic or therapeutic procedures, enable laboratory-based epidemiological studies to be carried out, linking abnormalities in the tissue to disease aetiology, prognosis and treatment responsiveness. There are, however, a number of technical, regulatory and ethical concerns that challenge those wishing to engage in tissue banking research. It is becoming increasingly apparent that tissue banking research is not without risk of harms, even though there is no direct physical risk to donors. This is because, in order to be most useful, banked specimens need to be linked to personal information about tissue donors and this poses the risk of inadvertent disclosure of personal─ particularly genetic─ information to those who might exploit such information (eg. insurance companies and employers). Furthermore, the long-term storage of specimens, and the impossibility of predicting all potential types of research programs for which they might be useful, raises the possibility that future projects will be carried out that are unacceptable to some (past) tissue donors. The ethical principles of autonomy and respect for persons demand that research subjects be informed of such risks and of the nature of the research, and that they participate willingly. On the other hand, there is a desire for science to progress unhindered by stringent consent requirements. For these reasons, a debate has emerged in the academic (bioethical and biomedical) literature and in the legal (law reform) sphere over what would constitute adequate consent. Despite an extensive discourse, it is still unclear whether it is permissible to carry out research on archival tissue that was originally taken for diagnostic purposes and whether project-specific (as opposed to open-ended) consent is required for research on tissue collected today. This lack of clarity is of concern to researchers, ethics committees and research subjects, all of whom recognise the importance of tissue banking research, yet fear that current consent procedures may be ethically or legally inadequate. Thus it is important that the consent dilemma be resolved as quickly and definitively as possible. Ongoing controversy and regulatory ambiguity are appropriate when morally contentious issues are at stake, and their existence does not, on its own, signal any flaws in the discourse process. There are, however, two reasons to suspect that the current 'consent to tissue banking' debate, as portrayed in the academic literature and law reform documentation, is problematic. Firstly, the debate appears to be mired in an intractable conflict between those who want to maximise personal autonomy through stringent consent requirements, and those who want the scientific endeavour to progress in a manner that is unconstrained by what are viewed as arduous consent procedures. Secondly, the possible practical options (consent models) being generated by the debate are all limited because they are underpinned by a restricted notion of consent as an individualistic, legalistic and static activity, without consideration of any alternative conceptualisations of consent. Through a thematic analysis of the current 'consent to tissue banking' debate in the academic and law reform literature (Section 3), this thesis shows that debate is essentially occurring between those who see individual autonomy (and stringent consent) as being of primary importance, and those who see unimpeded, market-driven scientific progress as the more important social good, which should not be impeded by unnecessarily stringent consent. Thematic analysis also confirms the existence of the two problems described above, and a failure of those engaged in the debate to reflect on, and challenge, the value-level assumptions underpinning their arguments and those of their opponents. It is argued that this lack of reflection accounts for the two problems: • Firstly, it precludes recognition of the cause of─ and, therefore, ways of resolving─ the intractable conflict at the centre of the debate. Value-level reflection shows that this is a result of the logical and moral conflict within western liberalism, between two modernist goods: individual freedom and scientific progress. • Secondly, it precludes the generation of varied conceptions of consent. Value-level reflection shows that the current range of consent models is restricted to procedures which are individualistic, abstract, static and legalistic, since they are underpinned by western liberal notions of autonomy and scientific progress. This recognition paves the way to consideration of alternative notions of autonomy, scientific progress and, therefore, consent, such as those derived from communitarian and feminist systems of values. A conceptually enriched model of tissue banking consent is then developed (Section 4). This model incorporates dominant (liberal) conceptions of autonomy and scientific progress as well as alternative notions of autonomy and scientific progress espoused by communitarian and feminist systems of values. It is argued that this conceptually-enriched model provides a practical solution to the two problems associated with the standard 'consent to tissue banking' debate. In relation to the philosophically intractable conflict─ or what is termed the 'modernist dilemma'─ between those privileging autonomy and those privileging scientific progress, it shows how the two apparently conflicting 'modernist' goods can both be accommodated at a practical level, thus making the 'consent to tissue banking' debate more tractable and fruitful. In relation to the restricted range of consent models being generated by the current debate, it provides new insights into the ways in which consent might be obtained such that a broader range of community values can be accommodated. More specifically, it stimulates the construction of a model that 1) involves communities, as opposed to merely individuals, in all stages of the scientific process; 2) is flexible and able to adapt consent procedures to specific contexts, rather than predefining procedures in abstract terms; and 3) is transactional and relational rather than static and legalistic. This outcome has interesting philosophical as well as practical implications. It shows that despite apparently unresolved, and possibly irresolvable, normative-level conflicts between the two modernist elements of western liberalism (autonomy and scientific progress), and between liberal, feminist and communitarian systems of values, a multi-perspectival, inclusive, model-building approach provides a practical solution that circumvents these normative-level conflicts

Influence of product placement in children's movies on children's snack choices

Background Media exposure affects health, including obesity risk. Children's movies often contain food placements—frequently unhealthy foods. However, it is not known if these cues influence children's food choices or consumption after viewing. We explored whether children's snack choices or consumption differs based on: 1) recent exposure to movies with high versus low product placement of unhealthy foods; and 2) children's weight status. Methods Children ages 9–11 were assigned to watch a high (“Alvin and the Chipmunks,” n = 54) or low (“Stuart Little,” n = 60) product-placement movie. After viewing, participants selected a snack choice from each of five categories, several of which were specifically featured in “Alvin.” Uneaten snacks from each participant were weighed upon completion. Snack choice and amount consumed by movie were compared by t-tests, and differences in snack choices by movie were tested with logistic regression. Results Participants consumed an average of 800.8 kcal; mean kcal eaten did not vary by movie watched. Participants who watched the high product-placement movie had 3.1 times the odds (95% CI 1.3–7.2) of choosing cheese balls (most featured snack) compared to participants who watched the low product-placement movie. Children who were overweight or obese consumed a mean of 857 kcal (95% CI: 789–925) compared to 783 kcal (95% CI: 742–823, p = 0.09) for children who were underweight or healthy weight. Children's weight status did not significantly affect their choice of snack. Conclusions Branding and obesogenic messaging in children's movies influenced some choices that children made about snack foods immediately following viewing, especially food with greatest exposure time in the film, but did not affect total calories consumed. Future studies should examine how the accumulation of these messages affects children's long-term food choices

Black Hole, Jet, and Disk: The Universal Engine

In this paper I review the results of our ongoing project to investigate the coupling between accretion disk and radio jet in galactic nuclei and stellar mass black holes. We find a good correlation between the UV bump luminosity and the radio luminosities of AGN, which improves upon the usual [OIII]/radio correlations. Taking mass and energy conservation in the jet/disk system into account we can successfully model the correlation for radio-loud and radio-weak quasars. We find that jets are comparable in power to the accretion disk luminosity, and the difference between radio-loud and radio-weak may correspond to two natural stages of the relativistic electron distribution -- assuming that radio weak quasars have jets as well. The distribution of flat- and steep-spectrum sources is explained by bulk Lorentz factors gamma_j ~ 5-10. The absence of radio-loud quasars below a critical optical luminosity coincides with the FR I/FR II break and could be explained by a powerdependent, ``closing'' torus. This points towards a different type of obscuring torus in radio-loud host galaxies which might be a consequence of past mergers (e.g. by the temporary formation of a binary black-hole). Interaction of the jet with the closing torus might in principle also help to make a jet radio-loud. Turning to stellar-mass black holes we find that galactic jet sources can be described with the same coupled jet/disk model as AGN which is suggestive of some kind of universal coupling between jet and accretion disk around compact objects.Comment: to appear in ``Jets from Stars and Galactic Nuclei'', Springer Lecture Notes, plain TeX, 16 pages, also at http://www.astro.umd.edu/~hfalcke/publications.htm

Multiwavelength studies of MHD waves in the solar chromosphere: An overview of recent results

The chromosphere is a thin layer of the solar atmosphere that bridges the relatively cool photosphere and the intensely heated transition region and corona. Compressible and incompressible waves propagating through the chromosphere can supply significant amounts of energy to the interface region and corona. In recent years an abundance of high-resolution observations from state-of-the-art facilities have provided new and exciting ways of disentangling the characteristics of oscillatory phenomena propagating through the dynamic chromosphere. Coupled with rapid advancements in magnetohydrodynamic wave theory, we are now in an ideal position to thoroughly investigate the role waves play in supplying energy to sustain chromospheric and coronal heating. Here, we review the recent progress made in characterising, categorising and interpreting oscillations manifesting in the solar chromosphere, with an impetus placed on their intrinsic energetics.Comment: 48 pages, 25 figures, accepted into Space Science Review

PROFESSORES DO PISA: A ESPERANÇA E A REALIZAÇÃO DA EDUCAÇÃO

RESUMO: As atividades do Programme for International Student Assessment (PISA) e os seus efeitos são diversos, sendo possível dizer que o PISA cria e forma uma fundamentação específica (HACKING, 1992) para discutir, falar e pensar sobre a educação. Neste estudo sobre as atividades do PISA, são analisadas as ideias sobre os professores, as atividades que realizam, e como estas são conceitualizadas no interior de uma narrativa própria ao PISA. Os resultados mostram que os professores são apresentados como sendo importantes e cruciais para a transformação e para o desenvolvimento da educação. Os professores também são representados como sendo essenciais para reduzir as "disparidades no desempenho" dos alunos medidas pelo teste PISA. Ademais, os "bons" professores e o ensino "eficaz" são descritos como os professores e as estratégias que conduzem a tal redução. Consequentemente, os principais relatórios do PISA enfatizam uma imagem dos professores como os atores que desenvolvem a educação e o ensino, e não como executantes de políticas determinadas pelo Estado. Deste modo, os professores são considerados como indicadores da eficácia dos sistemas de educação e importantes para elevar os padrões de desempenho, sendo assim considerados como a esperança e a realização da educação

Blended versus face-to-face: comparing student performance in a therapeutics class

Therapeutics is a very complex subject for every pharmacy student, since it requires the application of knowledge from several other disciplines. The study of therapeutics is often done in case-based learning in order to promote reflective thinking and give a scenario as real as possible. The objective of this study was to compare student performance between faceto-face (n = 54) and blended learning (n = 56) approaches to the teaching of therapeutics. They can confirm that there are statistically significant differences (p < 0.05) between the final exam scores from both groups, being that the b learning group achieved higher scores. Blended learning seems to be an effective way to teach therapeutics, following pre established teaching methods, and above all, does not negatively affect student performance. It also provides new learning environments and strategies, and promotes the development of new skills such as learning and collaborating online, which may be relevant in a networked knowledge society.info:eu-repo/semantics/publishedVersio

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation