Points to consider for prioritizing clinical genetic testing services: a European consensus process oriented at accountability for reasonableness.

Given the cost constraints of the European health-care systems, criteria are needed to decide which genetic services to fund from the public budgets, if not all can be covered. To ensure that high-priority services are available equitably within and across the European countries, a shared set of prioritization criteria would be desirable. A decision process following the accountability for reasonableness framework was undertaken, including a multidisciplinary EuroGentest/PPPC-ESHG workshop to develop shared prioritization criteria. Resources are currently too limited to fund all the beneficial genetic testing services available in the next decade. Ethically and economically reflected prioritization criteria are needed. Prioritization should be based on considerations of medical benefit, health need and costs. Medical benefit includes evidence of benefit in terms of clinical benefit, benefit of information for important life decisions, benefit for other people apart from the person tested and the patient-specific likelihood of being affected by the condition tested for. It may be subject to a finite time window. Health need includes the severity of the condition tested for and its progression at the time of testing. Further discussion and better evidence is needed before clearly defined recommendations can be made or a prioritization algorithm proposed. To our knowledge, this is the first time a clinical society has initiated a decision process about health-care prioritization on a European level, following the principles of accountability for reasonableness. We provide points to consider to stimulate this debate across the EU and to serve as a reference for improving patient management.

Itinéraires : les guides de voyage en Suisse de la fin du XVIIIe siècle à 1914 : contribution à une histoire culturelle du tourisme

Menée dans une approche d'histoire culturelle, cette thèse de doctorat prend pour objet un corpus de guides de voyage en Suisse entre la fin du XVIIIe et le début du XXe siècle. Centrée sur les guides, ces livres qui entretiennent plus que d'autres des liens étroits avec le monde physique, elle a deux grands axes. Le premier est une lecture interdisciplinaire des guides de voyage, qui mêle littérature, bibliographie matérielle, histoire et histoire de l'art. Elle a cherché à comprendre les raisons et logiques du genre, en s'attachant particulièrement à ses fonctions et à ses formes (tant structurelles que textuelles et iconographiques). Cette partie de l'étude est importante, car elle n'a encore jamais été menée. Elle s'articule en deux volets : un volet théorique qui s'intéresse à l'histoire et à la forme des guides de voyage ; et une étude de cas qui s'attache à la lecture plus rapprochée de 6 guides : ceux de Thomas Martyr (1788, 1790 & 1794), Heinrich August Ottokar Reichard (1793 & 1802) et Johann Gottfried Ebel (1793, 1805, 1810-11 & 1817-18) pour la fin du XVIIIe siècle et le tournant du XIXe, et ceux de John Murray (1838 & 1886), Adolphe Joanne (1841, 1865, 1874, 1882 & 1908) et Karl Baedeker (1844, 1852, 1859, 1869, 1876, 1883, 1893, 1901 & 1913) pour le XIXe et la Belle Epoque. Le second axe de cette recherche est une réflexion sur les manières de mettre en scène l'espace dans un texte. En étudiant les itinéraires de voyage en Suisse (mais jusqu'au début du XXe siècle, « la Suisse »est pour les guides de voyage indifféremment un pays et une région supranationale : «les Alpes »), quatre types de mises en forme ont pu être identifiés : le voyage en boucle (linéaire, il part d'un point A pour y revenir), le voyage en marguerite (linéaire avec excursions), le voyage éclaté de l'ordre alphabétique, et enfin le voyage par «routes », fragments d'espace que l'on combine comme les pièces d'un puzzle, créant son chemin au fur et à mesure de sa progression. Ce faisant, on peut affirmer que les guides de voyage modernes (dont la forme se fixe dans les années 1830-1840 avec les premiers Murray, Baedeker et Joanne) se sont construits -malgré tout ce que l'on a pu dire sur la normativité prescriptive du tourisme -autour d'une liberté de plus en plus grande accordée aux voyageurs. Chacune de ces formes et chacun de ces types ayant une histoire et des conditions de possibilités, c'est en s'appuyant sur celles-ci que l'on peut mieux comprendre non seulement l'évolution du voyage et de ses pratiques, mais aussi la constitution de la forme littéraire qui l'a accompagné et permis. Ce faisant, des jalons pour une histoire culturelle du tourisme ont aussi été posés, histoire culturelle que j'appelle maintenant de mes voeux : il est quand même surprenant que, dans le pays de tourisme qu'est la Suisse, quand on s'est jusqu'à présent attaché à l'histoire du tourisme, on n'ait parlé qu'économie, société, infrastructures, loisirs ou santé, voire, plus récemment, écologie et bien-être. Redonner son creuset culturel à ce phénomène, c'est aussi retrouver une part du nôtre, car ces mémoires s'entremêlent indissociablement.

Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group.

Currently, the most widely used criteria for assessing response to therapy in high-grade gliomas are based on two-dimensional tumor measurements on computed tomography (CT) or magnetic resonance imaging (MRI), in conjunction with clinical assessment and corticosteroid dose (the Macdonald Criteria). It is increasingly apparent that there are significant limitations to these criteria, which only address the contrast-enhancing component of the tumor. For example, chemoradiotherapy for newly diagnosed glioblastomas results in transient increase in tumor enhancement (pseudoprogression) in 20% to 30% of patients, which is difficult to differentiate from true tumor progression. Antiangiogenic agents produce high radiographic response rates, as defined by a rapid decrease in contrast enhancement on CT/MRI that occurs within days of initiation of treatment and that is partly a result of reduced vascular permeability to contrast agents rather than a true antitumor effect. In addition, a subset of patients treated with antiangiogenic agents develop tumor recurrence characterized by an increase in the nonenhancing component depicted on T2-weighted/fluid-attenuated inversion recovery sequences. The recognition that contrast enhancement is nonspecific and may not always be a true surrogate of tumor response and the need to account for the nonenhancing component of the tumor mandate that new criteria be developed and validated to permit accurate assessment of the efficacy of novel therapies. The Response Assessment in Neuro-Oncology Working Group is an international effort to develop new standardized response criteria for clinical trials in brain tumors. In this proposal, we present the recommendations for updated response criteria for high-grade gliomas.

Methadone maintenance treatment and St. John's Wort - a case report.

St. John's wort, a popular over-the-counter drug for treatment of depression, might reduce concentrations of drugs such as cyclosporin and indinavir and lead to drug resistance and treatment failure. No studies as yet have examined its influence on methadone plasma levels. The trough methadone plasma levels were measured in four patients (2 males, median age: 31 years; range 19 - 40 years) in methadone maintenance treatment just before the introduction of St. John's wort (900 mg/d) and after a median period of 31-day treatment (range 14 - 47). The study was proposed to addict patients about to start an antidepressant therapy. Introduction of St. John's wort resulted in a strong reduction of (R,S)-methadone concentration-to-dose ratios in the four median patients included, with a median decrease to 47 % of the original concentration (range: 19 % - 60 % of the original concentration). Two patients reported symptoms that suggested a withdrawal syndrome. Thus, prescription of St. John's wort might decrease methadone blood levels and induce withdrawal symptoms which, if not correctly identified and handled (by changing the antidepressant or by increasing the methadone dose), might cause unnecessary discomfort to the patient, lead to resumption of illicit drug uses, or be a risk factor for discontinuation of the methadone or antidepressant treatment.

La force motrice hydraulique au service du développement économique helvétique : L'exemple du réseau d'eau sous pression à Lausanne 1868-1914

The success story of hydroelectricity long influenced and dominated Swiss scholarly literature devoted to the history of technology. This means of conducting power, which emerged at the end of the 19th century and is still dominating today, has attracted much more attention than technologies that have been shadowed by its success. In spite of their important contribution to Swiss economic development, the distribution networks of pressurized water have been neglected by scholars. This article contributes to close this historiographic gap by analyzing the introduction of pressurized water distribution in 1876 in Lausanne, in the context of the building of the first Swiss cable funicular between Lausanne and Ouchy. This article shows how pressurized water distribution transformed socio-economic practices in the urban areas in which it was adopted. Indeed, this innovation, which allowed the use of distant hydraulic resources, enabled the rationalization of industrial and artisanal production as well as improved the density of the urban industrial base. By facilitating the introduction of electric lighting, pressurized water networks played a key role in the early development, and further successes, of the Swiss hydroelectric industry.

Effect of immune pressure on hepatitis C virus evolution: insights from a single-source outbreak.

The host's immune response to hepatitis C virus (HCV) can result in the selection of characteristic mutations (adaptations) that enable the virus to escape this response. The ability of the virus to mutate at these sites is dependent on the incoming virus, the fitness cost incurred by the mutation, and the benefit to the virus in escaping the response. Studies examining viral adaptation in chronic HCV infection have shown that these characteristic immune escape mutations can be observed at the population level as human leukocyte antigen (HLA)-specific viral polymorphisms. We examined 63 individuals with chronic HCV infection who were infected from a single HCV genotype 1b source. Our aim was to determine the extent to which the host's immune pressure affects HCV diversity and the ways in which the sequence of the incoming virus, including preexisting escape mutations, can influence subsequent mutations in recipients and infection outcomes. Conclusion: HCV sequences from these individuals revealed 29 significant associations between specific HLA types within the new hosts and variations within their viruses, which likely represent new viral adaptations. These associations did not overlap with previously reported adaptations for genotypes 1a and 3a and possibly reflected a combination of constraint due to the incoming virus and genetic distance between the strains. However, these sites accounted for only a portion of the sites in which viral diversity was observed in the new hosts. Furthermore, preexisting viral adaptations in the incoming (source) virus likely influenced the outcomes in the new hosts.

Impaired activation of protein kinase C-zeta by insulin and phosphatidylinositol-3,4,5-(PO4)3 in cultured preadipocyte-derived adipocytes and myotubes of obese subjects.

Insulin resistance in obesity is partly due to diminished glucose transport in myocytes and adipocytes, but underlying mechanisms are uncertain. Insulin-stimulated glucose transport requires activation of phosphatidylinositol (PI) 3-kinase (3K), operating downstream of insulin receptor substrate-1. PI3K stimulates glucose transport through increases in PI-3,4,5-(PO(4))(3) (PIP(3)), which activates atypical protein kinase C (aPKC) and protein kinase B (PKB/Akt). However, previous studies suggest that activation of aPKC, but not PKB, is impaired in intact muscles and cultured myocytes of obese subjects. Presently, we examined insulin activation of glucose transport and signaling factors in cultured adipocytes derived from preadipocytes harvested during elective liposuction in lean and obese women. Relative to adipocytes of lean women, insulin-stimulated [(3)H]2-deoxyglucose uptake and activation of insulin receptor substrate-1/PI3K and aPKCs, but not PKB, were diminished in adipocytes of obese women. Additionally, the direct activation of aPKCs by PIP(3) in vitro was diminished in aPKCs isolated from adipocytes of obese women. Similar impairment in aPKC activation by PIP(3) was observed in cultured myocytes of obese glucose-intolerant subjects. These findings suggest the presence of defects in PI3K and aPKC activation that persist in cultured cells and limit insulin-stimulated glucose transport in adipocytes and myocytes of obese subjects.

The hotel industry and its importance in the technical and economic development of a region : the Lake Geneva case (1852-1914)

The historiography dedicated to tourism has emphasised how some socio-economic evolutions such as urbanisation, mechanisation of transport or the advent of leisure time in society have supported pleasure trips and therefore the development of the hotel industry. On the contrary, the research has too often neglected or at least minimised the impact of the hotel sector on a region's development. This contribution seeks to fill this gap by analysing the Geneva Lake region, one of the most important birthplaces of the European tourism. In this space not much touched by the first industrial revolution, the hotel business has in fact played the role of an economic motor, stimulating investment and employment. This dynamism provoked a domino effect on several other sectors of the economy (industry, bulding sector, banking). To please their customers, the hoteliers have not only given impulses on housing modernisation, but also to the revitalisation of transport, energy and communication networks. The necessity to remain on the state-of-the-art of technical issues, with the concern of competitiveness, has called forth an acceleration of the technology transfer and stimulated the constitution of technical know-how.