The impact of fibrosis and steatosis on early viral kinetics in HCV genotype 1-infected patients treated with Peg-IFN-alfa-2a and ribavirin.

Summary.  Hepatitis C viral (HCV) kinetics after initiation of interferon-based therapy provide valuable insights for understanding virus pathogenesis, evaluating treatment antiviral effectiveness and predicting treatment outcome. Adverse effects of liver fibrosis and steatosis on sustained virological response have been frequently reported, yet their impacts on the early viral kinetics remain unclear. In this study, associations between histology status and early viral kinetics were assessed in 149 HCV genotype 1-infected patients treated with pegylated interferon alfa-2a and ribavirin (DITTO trial). In multivariate analyses adjusted for critical factors such as IL28B genotype and baseline viral load, presence of significant fibrosis (Ishak stage > 2) was found to independently reduce the odds of achieving an initial reduction (calculated from day 0 to day 4) in HCV RNA of ≥2 logIU/mL (adjusted OR 0.03, P = 0.004) but was not associated with the second-phase slope of viral decline (calculated from day 8 to day 29). On the contrary, presence of liver steatosis was an independent risk factor for not having a rapid second-phase slope, that is, ≥0.3 logIU/mL/week (adjusted OR 0.22, P = 0.012) but was not associated with the first-phase decline. Viral kinetic modelling theory suggests that significant fibrosis primarily impairs the treatment antiviral effectiveness in blocking viral production by infected cells, whereas the presence of steatosis is associated with a lower net loss of infected cells. Further studies will be necessary to identify the biological mechanisms underlain by these findings.

Cytochrome P450 1A2 activity and inducibility: impact of smoking, smoking cessation and genetic polymorphisms

Aims: Cytochrome P4501A2 (CYP1A2) is involved in the metabolism of severaldrugs (clozapine, olanzapine, theopylline, caffeine, etc) and is induced by smoking.This can result in decreased plasma levels of drugs metabolized by thisisoenzyme, causing a decrease in therapeutic response. After quitting smoking,increased plasma levels can lead to adverse effects of the concerned drugs, such asconfusion and seizures, described under clozapine treatment. The present studyaimed to examine the variation of CYP1A2 activity in a large group of smokersbefore and after smoking cessation. Moreover, we aimed to determine whethergenetic polymorphisms of CYP1A2 gene could influence the inducibility ofCYP1A2. Methods: CYP1A2 activity was determined by the paraxanthine/caffeineratio in 194 smokers and in 118 of them being abstinent during a 4-weekperiod. Participants were genotyped for CYP1A2*1F (rs762551), *1D(rs35694136) and *1C (rs2069514) polymorphisms. Results: Smokers had higherCYP1A2 activity (1.55-fold; p < 0.0001). Individual change of CYP1A2 activityafter smoking cessation ranged from 1.0-fold (no change) to 7.3-fold decreasedactivity. In five participants with low initial CYP1A2 activity, an increase wasobserved after smoking cessation. During smoking, CYP1A2*1F (p = 0.005), CYP1A2*1D (p = 0.014), the number of cigarettes/day (p = 0.012), contraceptives use(p < 0.001) and - 163A/- 2467T/- 3860G haplotype (p = 0.002) influencedCYP1A2 activity, while after quitting smoking, CYP1A2*1F (p = 0.017) and contraceptives(p = 0.05) did. No influence of CYP1A2 polymorphisms on the inducibilityof CYP1A2 was observed. Conclusion: Higher CYP1A2 activity wasmeasured in smokers, but with a large interindividual variability of its inductionby smoking. Careful clinical management with the help of therapeutic drug monitoringis therefore needed for patients receiving drugs which are metabolized byCYP1A2, who stop or start smoking. Unidentified genetic variations in theCYP1A2 gene and/or in other genes controlling CYP1A2 activity and other environmentalfactors could be responsible of the observed differences in CYP1A2enzymatic activity and inducibility.

Réduction de la consommation de sel: opportunité, impact et stratégies. [Population reduction of salt consumption: opportunities, impact and strategies].

A national survey showed that Swiss people eat high quantity of salt (9.1 g per day on average). The Swiss Federal Office of Public Health (FOPH) has launched a strategy to reduce salt intake in the population in order to decrease cardiovascular morbidity and mortality, mainly via blood pressure reduction. The most effective public health measures are to reduce the salt content of processed food rich in salt because they do not need to change consumers' eating behaviours. The FOPH has chosen to collaborate with the food industry on a voluntary basis. Regular population-based surveys will be needed to monitor the impact of current measures on salt consumption, hypertension prevalence as well as cardiovascular morbidity and mortality in the years to come.

Soutien informatique dans la gestion de la douleur aiguë aux urgences: acceptation par les soignants et impact sur les connaissances des Recommandations de Pratiques Cliniques (RPC)

Dans une étude précédente, nous avons démontré qu'un soutieninformatique rappelant les Recommandations de Pratiques Cliniques(RPC) améliore la gestion de la douleur aiguë aux urgences à moyenterme (JEUR 2009;22:A88). Par contre, son acceptation par lessoignants et son impact sur leurs connaissances des RPC sontinconnus. But de l'étude: mesurer l'impact du logiciel en termesd'acceptation et connaissance des RPC par l'équipe soignante.Méthode: analyse de 2 questionnaires remplis par les médecins etinfirmiers: le 1er administré en pré-, post-déploiement et 6 mois plustard (phases P1, P2 et P3) qui a évalué: a) l'appréciation subjective desconnaissances des RPC par échelle de Lickert à 5 niveaux; b) lesconnaissances objectives des RPC à l'aide de 7 questions théoriques(score max. 7 points); le 2ème administré en P2 et P3, l'utilité perçue dulogiciel (échelle à 4 niveaux). Analyses statistiques par test de chi2outest exact de Fisher; p bilatéral <0.05 significatif. Résultats: la proportiondes soignants estimant avoir une bonne connaissance des RPC apassé de 48% (45/94) en P1, à 73% (83/114) puis 84% (104/124) en P2et P3, respectivement (p <0.0001). Score des connaissances: cftableau. Entre P2 et P3, l'appréciation globale de l'utilité du logiciel s'estaméliorée: la proportion des avis favorables a passé de 59% (47/79) à82% (96/117) (p = 0.001). Conclusion: ce logiciel a été bien accepté et apermis une amélioration significative des connaissances des RPC parles soignants.

Impact of family structure on long-term survivors of osteosarcoma

Rapport de synthèse : But du travail : le pronostic des patients atteints d'ostéosarcome s'est considérablement amélioré grâce à l'utilisation de thérapies combinées performantes. Cependant, ces traitements agressifs sont grevés de complications chroniques. Notre travail a consisté à l'évaluation du status fonctionnel, psychologique et familial chez des patients survivants au long cours d'ostéosarcome traités au centre pluridisciplinaire d'oncologie. Patients et méthodes: 15 survivants au long cours d'ostéosarcome ont été évalués à la recherche de séquelles physiques et psychologiques. Pour l'évaluation fonctionnelle, nous avons utilisé la méthode de Enneking. L'évaluation psychologique a été basée sur un test d'évaluation globale (GHQ-28), sur un test de cohésion familiale (FAST test) et sur une échelle d'évaluation de symptômes post-traumatiques. Résultats: sur le plan fonctionnel, seuls 5 patients présentaient des séquelles graves et 10 des handicaps modérés. 4 patients souffraient de symptômes dépressifs. 6 patients ont décrit uns structure familiale déséquilibrée dont 3 des 4 patients avec des symptômes dépressifs, les 4 patients avec symptômes post-traumatiques et 5 des 7 patients avec une mauvaise acceptation émotionnelle. Conclusions: la plupart des patients souffrant d'ostéosarcome présentent une bonne récupération fonctionnelle. Seule une minorité reste sévèrement handicapée. Un tiers des patients souffre de symptômes dépressifs et de stress post-traumatique. Une mauvaise acceptation émotionnelle est fortement liée à une structure familiale déséquilibrée. La situation psychologique et familiale des patients atteints d'ostéosarcome doit donc être rapidement prise en compte afin d'améliorer leur évolution au long cours.

The impact of pre- and post-natal contexts on immunity, glucocorticoids and oxidative stress resistance in wild and domesticated grey partridges

Genetic background, prenatal and post-natal early-life conditions influence the development of interconnected physiological systems and thereby shape the phenotype. Certain combinations of genotypes and pre- and post-natal conditions may provide higher fitness in a specific environmental context. Here, we investigated how grey partridges Perdix perdix of two strains (wild and domesticated) cope physiologically with pre- and post-natal predictable vs. unpredictable food supply. Food unpredictability occurs frequently in wild environments and requires physiological and behavioural adjustments. Well-orchestrated and efficient physiological systems are presumably more vital in a wild environment as compared to captivity. We thus predicted that wild-strain grey partridges have a stronger immunity, glucocorticoid (GC) stress response and oxidative stress resistance (OSR) than domesticated birds, which have undergone adaptations to captivity. We also predicted that wild-strain birds react more strongly to environmental stimuli and, when faced with harsh prenatal conditions, are better able to prepare their offspring for similarly poor post-natal conditions than birds of domesticated origin. We found that wild-strain offspring were physiologically better prepared for stressful situations as compared to the domesticated strain. They had a high GC stress response and a high OSR when kept under predictable food supply. Wild-strain parents reacted to prenatal unpredictable food supply by lowering their offspring's GC stress response, which potentially lowered GC-induced oxidative pressure. No such pattern was evident in the domesticated birds. Irrespective of strain and prenatal feeding scheme, post-natal unpredictable food supply boosted immune indices, and GC stress response was negatively related to antibody response in females and to mitochondrial superoxide production. Wild-strain grey partridge showed fitness-relevant physiological advantages and appeared to prepare their offspring for the prospective environment. Negative relationships between GC stress response, immunity and oxidative indices imply a pivotal role of an organism's oxidative balance and support the importance of considering multiple physiological systems simultaneously.

Impact of a telenursing service on satisfaction and health outcomes of children with inflammatory rheumatic diseases and their families: a crossover randomized trial study protocol.

BACKGROUND: Pediatric rheumatic diseases have a significant impact on children's quality of life and family functioning. Disease control and management of the symptoms are important to minimize disability and pain. Specialist clinical nurses play a key role in supporting medical teams, recognizing poor disease control and the need for treatment changes, providing a resource to patients on treatment options and access to additional support and advice, and identifying best practices to achieve optimal outcomes for patients and their families. This highlights the importance of investigating follow-up telenursing (TN) consultations with experienced, specialist clinical nurses in rheumatology to provide this support to children and their families. METHODS/DESIGN: This randomized crossover, experimental longitudinal study will compare the effects of standard care against a novel telenursing consultation on children's and family outcomes. It will examine children below 16 years old, recently diagnosed with inflammatory rheumatic diseases, who attend the pediatric rheumatology outpatient clinic of a tertiary referral hospital in western Switzerland, and one of their parents. The telenursing consultation, at least once a month, by a qualified, experienced, specialist nurse in pediatric rheumatology will consist of providing affective support, health information, and aid to decision-making. Cox's Interaction Model of Client Health Behavior serves as the theoretical framework for this study. The primary outcome measure is satisfaction and this will be assessed using mixed methods (quantitative and qualitative data). Secondary outcome measures include disease activity, quality of life, adherence to treatment, use of the telenursing service, and cost. We plan to enroll 56 children. DISCUSSION: The telenursing consultation is designed to support parents and children/adolescents during the course of the disease with regular follow-up. This project is novel because it is based on a theoretical standardized intervention, yet it allows for individualized care. We expect this trial to confirm the importance of support by a clinical specialist nurse in improving outcomes for children and adolescents with inflammatory rheumatisms. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT01511341 (December 1st, 2012).

The impact of information on decision-making in palliative care

Résumé Ce travail vise à clarifier les résultats contradictoires de la littérature concernant les besoins des patients d'être informés et de participer à la prise de décision. La littérature insiste sur le contenu de l'information comme base de la prise de décision, bien qu'il existe des preuves que d'autres contenus sont importants pour les patients. La thèse essaie en outre d'identifier des possibilités de mieux répondre aux préférences d'information et de participation des patients. Les travaux ont porté en particulier sur les soins palliatifs. Une analyse de la littérature donne un aperçu sur les soins palliatifs, sur l'information des patients et sur leur participation à la prise de décisions thérapeutiques. Cette analyse résume les résultats d'études précédentes et propose un: modèle théorique d'information, de prise de décision et de relation entre ces deux domaines. Dans le cadre de ce travail, deux études empiriques ont utilisé des questionnaires écrits adressés à des personnes privées et à des professionnels de la santé, couvrant la Suisse et le Royaume Uni, pour identifier d'éventuelles différences entre ces deux pays. Les enquêtes ont été focalisées sur des patients souffrant de cancer du poumon. Les instruments utilisés pour ces études proviennent de la littérature afin de les rendre comparables. Le taux de réponse aux questionnaires était de 30-40%. La majorité des participants aux enquêtes estime que les patients devraient: - collaborer à la prise de décision quant à leur traitement - recevoir autant d'information que possible, positive aussi bien que négative - recevoir toutes les informations mentionnées dans le questionnaire (concernant la maladie, le diagnostic et les traitements), tenant compte de la diversité des priorités des patients - être soutenus par des professionnels de la santé, leur famille, leurs amis et/ou les personnes souffrant de la même maladie En plus, les participants aux enquêtes ont identifié divers contenus de l'information aux patients souffrant d'une maladie grave. Ces contenus comprennent entre autres: - L'aide à la prise de décision concernant le traitement - la possibilité de maintenir le contrôle de la situation - la construction d'une relation entre le patient et le soignant - l'encouragement à faire des projets d'avenir - l'influence de l'état émotionnel - l'aide à la compréhension de la maladie et de son impact - les sources potentielles d'états confusionnels et d'états anxieux La plupart des contenus proposés sont positifs. Les résultats suggèrent la coexistence possible de différents contenus à un moment donné ainsi que leur changement au cours du temps. Un modèle est ensuite développé et commenté pour présenter le diagnostic d'une maladie grave. Ce modèle est basé sur la littérature et intègre les résultats des études empiriques réalisées dans le cadre de ce travail. Ce travail analyse également les sources préférées d'information et de soutien, facteurs qui peuvent influencer ou faire obstacle aux préférences d'information et de participation. Les deux groupes de participants considèrent les médecins spécialistes comme la meilleure source d'information. En ce qui concerne le soutien, les points de vue divergent entre les personnes privées et les professionnels de la santé: généralement, les rôles de soutien semblent peu définis parmi les professionnels. Les barrières à l'information adéquate du patient apparaissent fréquemment liées aux caractéristiques des professionnels et aux problèmes d'organisation. Des progrès dans ce domaine contribueraient à améliorer les soins fournis aux patients. Finalement, les limites des études empiriques sont discutées. Celles-ci comprennent, entre autres, la représentativité restreinte des participants et les objections de certains groupes de participants à quelques détails des questionnaires. Summary The present thesis follows a call from the current body of literature to better understand patient needs for information and for participation in decision-making, as previous research findings had been contradictory. Information so far seems to have been considered essentially as a means to making treatment decisions, despite certain evidence that it may have a number of other values to patients. Furthermore, the thesis aims to identify ways to optimise meeting patient preferences for information and participation in treatment decisions. The current field of interest is palliative care. An extensive literature review depicts the background of current concepts of palliative care, patient information and patient involvement into treatment decisions. It also draws together results from previous studies and develops a theoretical model of information, decision-making, and the relationship between them. This is followed by two empirical studies collecting data from members of the general public and health care professionals by means of postal questionnaires. The professional study covers both Switzerland and the United Kingdom in order to identify possible differences between countries. Both studies focus on newly diagnosed lung cancer patients. The instruments used were taken from the literature to make them comparable. The response rate in both surveys was 30-40%, as expected -sufficient to allow stastical tests to be performed. A third study, addressed to lung cancer patients themselves, turned out to require too much time within the frame available. A majority of both study populations thought that patients should: - have a collaborative role in treatment-related decision-making -receive as much information as possible, good or bad - receive all types of information mentioned in the questionnaire (about illness, tests, and treatment), although priorities varied across the study populations - be supported by health professionals, family members, friends and/or others with the same illness Furthermore they identified various 'meanings' information may have to patients with a serious illness. These included: - being an aid in treatment-related decision-making - allowing control to be maintained over the situation - helping the patient-professional relationship to be constructed - allowing plans to be made - being positive for the patient's emotional state - helping the illness and its impact to be understood - being a source of anxiety - being a potential source of confusion to the patient Meanings were mostly positive. It was suggested that different meanings could co-exist at a given time and that they might change over time. A model of coping with the disclosure of a serious diagnosis is then developped. This model is based on existing models of coping with threatening events, as takeñ from the literature [ref. 77, 78], and integrates findings from the empirical studies. The thesis then analyses the remaining aspects apparent from the two surveys. These range from the identification of preferred information and support providers to factors influencing or impeding information and participation preferences. Specialist doctors were identified by both study populations as the best information providers whilst with regard to support provision views differed between the general public and health professionals. A need for better definition of supportive roles among health care workers seemed apparent. Barriers to information provision often seem related to health professional characteristics or organisational difficulties, and improvements in the latter field could well help optimising patient care. Finally, limitations of the studies are discussed, including questions of representativness of certain results and difficulties with or objections against questionnaire details by some groups of respondents.

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Decreased binding of peptides-MHC class I (pMHC) multimeric complexes to CD8 affects their binding avidity for the TCR but does not significantly impact on pMHC/TCR dissociation rate.

The CD8 coreceptor plays a crucial role in both T cell development in the thymus and in the activation of mature T cells in response to Ag-specific stimulation. In this study we used soluble peptides-MHC class I (pMHC) multimeric complexes bearing mutations in the CD8 binding site that impair their binding to the MHC, together with altered peptide ligands, to assess the impact of CD8 on pMHC binding to the TCR. Our data support a model in which CD8 promotes the binding of TCR to pMHC. However, once the pMHC/TCR complex is formed, the TCR dominates the pMHC/TCR dissociation rates. As a consequence of these molecular interactions, under physiologic conditions CD8 plays a key role in complex formation, resulting in the enhancement of CD8 T cell functions whose specificity, however, is determined by the TCR.

Paediatric cardiac CT examinations: impact of the iterative reconstruction method ASIR on image quality--preliminary findings.

BACKGROUND: Radiation dose exposure is of particular concern in children due to the possible harmful effects of ionizing radiation. The adaptive statistical iterative reconstruction (ASIR) method is a promising new technique that reduces image noise and produces better overall image quality compared with routine-dose contrast-enhanced methods. OBJECTIVE: To assess the benefits of ASIR on the diagnostic image quality in paediatric cardiac CT examinations. MATERIALS AND METHODS: Four paediatric radiologists based at two major hospitals evaluated ten low-dose paediatric cardiac examinations (80 kVp, CTDI(vol) 4.8-7.9 mGy, DLP 37.1-178.9 mGy·cm). The average age of the cohort studied was 2.6 years (range 1 day to 7 years). Acquisitions were performed on a 64-MDCT scanner. All images were reconstructed at various ASIR percentages (0-100%). For each examination, radiologists scored 19 anatomical structures using the relative visual grading analysis method. To estimate the potential for dose reduction, acquisitions were also performed on a Catphan phantom and a paediatric phantom. RESULTS: The best image quality for all clinical images was obtained with 20% and 40% ASIR (p < 0.001) whereas with ASIR above 50%, image quality significantly decreased (p < 0.001). With 100% ASIR, a strong noise-free appearance of the structures reduced image conspicuity. A potential for dose reduction of about 36% is predicted for a 2- to 3-year-old child when using 40% ASIR rather than the standard filtered back-projection method. CONCLUSION: Reconstruction including 20% to 40% ASIR slightly improved the conspicuity of various paediatric cardiac structures in newborns and children with respect to conventional reconstruction (filtered back-projection) alone.