Diagnostics VIH tardifs en 2009 en Suisse: motivation a un dépistage systématique du VIH [Late diagnoses of HIV infection in 2009 in Switzerland: towards a universal HIV testing?]

Individuals who are unaware of their HIV infection constitute a fragile and a critical population both from a personal and from a community-based point of view: if the infection is diagnosed too late, the outcome can be complicated by AIDS-defining diseases, whose prognosis may remain unfavourable even after the initiation of a potent antiretroviral therapy. These patients contribute to the virus spreading into the community, owing to a high viral load. It is now necessary to recognise the limits of a risk behaviour and disease-driven HIV screening policy. Since 2006, the American guidelines recommend a routine HIV testing for all patients age 13 to 64 years unless they specifically refuse the test (opt-out). In Switzerland, the recommendations remain so far risk-centred.

Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial.

BACKGROUND: The outcome of diffuse large B-cell lymphoma has been substantially improved by the addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy regimens. We aimed to assess, in patients aged 18-59 years, the potential survival benefit provided by a dose-intensive immunochemotherapy regimen plus rituximab compared with standard treatment plus rituximab. METHODS: We did an open-label randomised trial comparing dose-intensive rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) with subsequent consolidation versus standard rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (R-CHOP). Random assignment was done with a computer-assisted randomisation-allocation sequence with a block size of four. Patients were aged 18-59 years with untreated diffuse large B-cell lymphoma and an age-adjusted international prognostic index equal to 1. Our primary endpoint was event-free survival. Our analyses of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00140595. FINDINGS: One patient withdrew consent before treatment and 54 did not complete treatment. After a median follow-up of 44 months, our 3-year estimate of event-free survival was 81% (95% CI 75-86) in the R-ACVBP group and 67% (59-73) in the R-CHOP group (hazard ratio [HR] 0·56, 95% CI 0·38-0·83; p=0·0035). 3-year estimates of progression-free survival (87% [95% CI, 81-91] vs 73% [66-79]; HR 0·48 [0·30-0·76]; p=0·0015) and overall survival (92% [87-95] vs 84% [77-89]; HR 0·44 [0·28-0·81]; p=0·0071) were also increased in the R-ACVBP group. 82 (42%) of 196 patients in the R-ACVBP group experienced a serious adverse event compared with 28 (15%) of 183 in the R-CHOP group. Grade 3-4 haematological toxic effects were more common in the R-ACVBP group, with a higher proportion of patients experiencing a febrile neutropenic episode (38% [75 of 196] vs 9% [16 of 183]). INTERPRETATION: Compared with standard R-CHOP, intensified immunochemotherapy with R-ACVBP significantly improves survival of patients aged 18-59 years with diffuse large B-cell lymphoma with low-intermediate risk according to the International Prognostic Index. Haematological toxic effects of the intensive regimen were raised but manageable. FUNDING: Groupe d'Etudes des Lymphomes de l'Adulte and Amgen.

Predictors of mortality from pump failure and sudden cardiac death in patients with systolic heart failure and left ventricular dyssynchrony: results of the CARE-HF trial.

BACKGROUND: Determining a specific death cause may facilitate individualized therapy in patients with heart failure (HF). Cardiac resynchronization therapy (CRT) decreased mortality in the Cardiac Resynchronization in Heart Failure trial by reducing pump failure and sudden cardiac death (SCD). This study analyzes predictors of specific causes of death. METHODS AND RESULTS: Univariate and multivariate analyses used 8 baseline and 3-month post-randomization variables to predict pump failure and SCD (categorized as "definite," "probable," and "possible"). Of 255 deaths, 197 were cardiovascular. There were 71 SCDs with a risk reduction by CRT of 0.47 (95% confidence interval 0.29-0.76; P = .002) with similar reductions in SCD classified as definite, probable, and possible. Univariate SCD predictors were 3-month HF status (mitral regurgitation [MR] severity, plasma brain natriuretic peptide [BNP], end-diastolic volume, and systolic blood pressure), whereas randomization to CRT decreased risk. Multivariate SCD predictors were randomization to CRT 0.56 (0.53-0.96, P = .035) and 3-month MR severity 1.82 (1.77-2.60, P = .0012). Univariate pump failure death predictors related to baseline HF state (quality of life score, interventricular mechanical delay, end-diastolic volume, plasma BNP, MR severity, and systolic pressure), whereas randomization to CRT and nonischemic cardiomyopathy decreased risk; multivariate predictors of pump failure death were baseline plasma BNP and systolic pressure and randomization to CRT. CONCLUSION: CRT decreased SCD in patients with systolic HF and ventricular dyssynchrony. SCD risk was increased with increased severity of MR (including the 3-month value for MR as a time-dependent covariate) and reduced by randomization to CRT. HF death was increased related to the level of systolic blood pressure, log BNP, and randomization to CRT. These results emphasize the importance and interdependence of HF severity to mortality from pump failure and SCD.

La spéciation écologique racontée au travers de l'étude de l'évolution des poissons-clowns et de quelques autres

Ecological speciation and its hallmark, adaptive radiation is a process from which most of the current biodiversity derives. As ecological opportunity allows species to colonise unoccupied niches, natural selection drives adaptive phenotypical change. In this thesis, I begin by describing how this evolutionary process acted on the evolution of the clownfishes. During its infancy, this iconic group of coral reef fishes developed a mutualism with sea anemone species. I show how this event triggered the evolutionary radiation of the group, generating species that now inhabit diverse habitats of the coral reefs. Following the appearance of the mutualism, the diversification of the clownfish was catalysed by hybridisation events which shuffled genes, allowing hybrids to reach new fitness optima. While the clownfishes appeared in the region of the coral triangle, a lineage colonised the eastern shores of Africa. I reconstructed the geographic history of the group and showed that this event lead to the rapid appearance of new species, replicating the evolutionary patterns of the original radiation. To better grasp the mechanisms of ecological speciation, I conducted analyses at the population level and identified similar evolutionary patterns than found at the clade level. I discuss how such result suggests a continuity bridging micro- and macroevolution, which so far only been theorised. In parallel to this study case, I question whether biotic and abiotic interactions can promote or restrain ecological speciation. Indeed, I show how the ecological setting of species can drastically impact on their diversification dynamics. Moreover, tradeoffs can occur between specialisation made on different ecological axes allowing species cohabitation. Overall, I show in this work that regardless of the few simple rules that explain the mechanism of ecological speciation, the unavoidable interactions with the ever changing ecological context lead diversification events to give always a different outcome. It is thus primordial to account for the ecological settings of species when discussing their evolutionary dynamics. LA SPÉCIATION ÉCOLOGIQUE RACONTÉE AU TRAVERS DE L'ÉTUDE DE L'ÉVOLUTION DES POISSONS-CLOWNS ET DE QUELQUES AUTRES Le phénomène de spéciation écologique est à l'origine de la majeure partie de la biodiversité que l'on rencontre aujourd'hui. Au fil des opportunités qu'elles rencontrent, les espèces colonisent l'espace écologique laissant la sélection naturelle forger leur phénotype moyen. Malgré l'omniprésence de ce phénomène dans la nature, beaucoup de questions qui lui sont relatives restent à élucider. C'est afin de mieux comprendre ce mécanisme que j'étudie les poissons-clowns, célèbres habitants des récifs coralliens. Dans ce travail, je démontré que le développement du comportement mutualiste liant les poissons-clowns aux anémones de mer fut l'événement qui déclencha leur diversification. Suite à ce premier événement, j'illustre comment l'hybridation entre lignées primordiales a remodelé la diversité génétique du groupe et catalysé leur radiation évolutive. Je poursuis en reconstruisant l'expansion géographique des poissons-clowns au cours du temps depuis le triangle de corail, leur lieu d'origine, jusqu'aux côtes d'Afrique de l'Ouest. Afin d'affiner ces analyses générales sur le groupe, je continue en étudiant plus finement des populations d'une seule espèce de poisson-clown. Cette fine résolution me permet de comprendre plus précisément quels sont les facteurs écologiques qui permettent aux poissons-clowns de se différencier. Les résultats de ces analyses suggèrent qu'il est important de comprendre les liens entre le contexte écologique et la diversification des espèces. J'étudie cette question dans la seconde partie de ce travail en montrant que l'hétérogénéité du paysage ou les liens entretenus avec un partenaire mutualiste influencent fortement la dynamique évolutive des espèces. Finalement, j'illustre les compromis que chaque espèce réalise en se spécialisant ou non dans ses interactions avec l'environnent. Plus généralement, je souligne dans ce travail l'influence du contexte écologique sur le résultat de la spéciation écologique. Ce sont ces interactions entre les organismes et leur environnent qui sont à l'origine de l'incroyable diversité de la vie. Il est donc primordial de les prendre en compte lors de l'étude de l'évolution des espèces.

An international registry on autoinflammatory diseases: the Eurofever experience.

OBJECTIVE: To report on the demographic data from the first 18 months of enrollment to an international registry on autoinflammatory diseases in the context of the Eurofever project. METHODS: A web-based registry collecting baseline and clinical information on autoinflammatory diseases and related conditions is available in the member area of the PRINTO web-site. Anonymised data were collected with standardised forms. RESULTS: 1880 (M:F=916:964) individuals from 67 centers in 31 countries have been entered in the Eurofever registry. Most of the patients (1388; 74%), reside in western Europe, 294 (16%) in the eastern and southern Mediterranean region (Turkey, Israel, North Africa), 106 (6%) in eastern Europe, 54 in Asia, 27 in South America and 11 in Australia. In total 1049 patients with a clinical diagnosis of a monogenic autoinflammatory diseases have been enrolled; genetic analysis was performed in 993 patients (95%): 703 patients have genetically confirmed disease and 197 patients are heterozygous carriers of mutations in genes that are mutated in patients with recessively inherited autoinflammatory diseases. The median diagnosis delay was 7.3 years (range 0.3-76), with a clear reduction in patients born after the identification of the first gene associated with autoinflammatory diseases in 1997. CONCLUSIONS: A shared online registry for patients with autoinflammatory diseases is available and enrollment is ongoing. Currently, there are data available for analysis on clinical presentation, disease course, and response to treatment, and to perform large scale comparative studies between different conditions.

Geological observation in southeastern Zanskar and adjacent Lahul area (northern Himalaya).

The paper deals with the stratigraphic and structural setting of the sedimentary sequence cropping out in southeastern Zanskar and adjacent Lahul areas. The Tibetan Zone succession of southeastern Zanskar consists of about 6000 m of sediments, Late Precambrian~ ?Eocene in age, arranged in two superposed slabs (Pugh tal Unit, below, and Zangla Unit, above) tectonically resting upon the High Himalayan Crystalline. The Pughtal sequence, mostly terrigenous with carbonate units in the Cambrian, Silurian and Carboniferous, is about 2500 m thick. It was deposited from ?Late Precambrian to Carboniferous or ?Early Permian. The Permian Panjal Traps constitute the "sole" of the Zangla Unit, whose sedimentary sequence, about 3000 m thick, mainly carbonatic, spans from Late Permian (Kuling Formation) to Middle Jurassic (Kioto Limestone) in eastern Zanskar. In the Zangla area Late Jurassic/Cretaceous formations (Spiti Shales, Giumal Sandstone, Chikkim Limestone) are also present. Towards northwest, the sequence ranges up to Paleocene (Spanboth Formation) and ?Eocene (Chulung La Slates). Au nord de la Haute Chaine, dans la partie septentrionale de I'Himalaya, la marge continentale indienne a vu plus de 6000 m de sediments se deposer depuis I'Infracambrien jusqu'a I'Eocene. Lors de l'orogenese himalayenne, ces sediments ont ete decolles de leur substratum originel, dMormes et metamorphises de maniere differenciee suivant leur position. Ils reposent en contact tectonique sur la nappe cristalline du Haut-Himalaya. L'unite inferieure ou unite de Pughtal consiste, la ou elle est complete, en plus de 2500 m de sediments en partie detritiques terrigenes mais marque par l'edification de plates-formes carbonatees au Cambrien, Silurien et Carbonifere. Dans cette unite on releve deux grandes sequences sedimentaires separees par l'evenement epirogenique et magmatique tardi-Cambrien (500 rna), contrecoup de l'orogenese pan-africaine. Un niveau massif de vo1canites basaltiques permiennes ~ les Panjal Traps ~ forme la base ou sole de I'unite superieure (nappe de Zangla). Cette unite, plissee de maniere disharmonique, recouvre progressivement vers l'ouest des niveaux de plus en plus anciens de l'unite inferieure, niveaux eux-memes replisses en grands plis couches kilometriques a vergence nord. Dans la partie occidentale (Ringdom) l'unite superieure repose directement sur la nappe cristalline. Cette unite montre une serie sedimentaire avec des carbonates de plate-forme bien developpes au Trias superieur et au Lias puis des sediments surtout pelagiques et en partie detritiques terrigenes au Jurassique superieur et au Cretace. Des la fin du Cretace et jusqu'au Paleocene superieur s'edifie a nouveau une plate-forme peu profonde. La serie se termine par des couches continentales attribuees a l'Eocene. L'evolution geodynamique durant Ie Paleozoique et Ie Mesozoique est analysee. II en ressort que la sedimentation, a partir de I'Ordovicien, est regJee plus par des grands cycles eustatiques que par des mouvements tectoniques ou epirogeniques regionaux (les orogeneses caledoniennes, hercyniennes et cretacees des auteurs).

An Ion Transport-Independent Role for the Cation-Chloride Cotransporter KCC2 in Dendritic Spinogenesis In Vivo.

The neuron-specific K-Cl cotransporter, KCC2, is highly expressed in the vicinity of excitatory synapses in pyramidal neurons, and recent in vitro data suggest that this protein plays a role in the development of dendritic spines. The in vivo relevance of these observations is, however, unknown. Using in utero electroporation combined with post hoc iontophoretic injection of Lucifer Yellow, we show that premature expression of KCC2 induces a highly significant and permanent increase in dendritic spine density of layer 2/3 pyramidal neurons in the somatosensory cortex. Whole-cell recordings revealed that this increased spine density is correlated with an enhanced spontaneous excitatory activity in KCC2-transfected neurons. Precocious expression of the N-terminal deleted form of KCC2, which lacks the chloride transporter function, also increased spine density. In contrast, no effect on spine density was observed following in utero electroporation of a point mutant of KCC2 (KCC2-C568A) where both the cotransporter function and the interaction with the cytoskeleton are disrupted. Transfection of the C-terminal domain of KCC2, a region involved in the interaction with the dendritic cytoskeleton, also increased spine density. Collectively, these results demonstrate a role for KCC2 in excitatory synaptogenesis in vivo through a mechanism that is independent of its ion transport function.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Différences induites par la définition des périodes diurnes et nocturnes sur la pression artérielle et le dipping lors d'une mesure ambulatoire de la pression artérielle [Effects of nighttime and daytime interval definition on blood pressure and dipping in patients referred for ambulatory blood pressure measurement].

Ambulatory blood pressure monitoring (ABPM) has become indispensable for the diagnosis and control of hypertension. However, no consensus exists on how daytime and nighttime periods should be defined. OBJECTIVE: To compare daytime and nighttime blood pressure (BP) defined by an actigraph and by body position with BP resulting from arbitrary daytime and nighttime periods. PATIENTS AND METHOD: ABPM, sleeping periods and body position were recorded simultaneously using an actigraph (SenseWear Armband(®)) in patients referred for ABPM. BP results obtained with the actigraph (sleep and position) were compared to the results obtained with fixed daytime (7a.m.-10p.m.) and nighttime (10p.m.-7a.m.) periods. RESULTS: Data from 103 participants were available. More than half of them were taking antihypertensive drugs. Nocturnal BP was lower (systolic BP: 2.08±4.50mmHg; diastolic BP: 1.84±2.99mmHg, P<0.05) and dipping was more marked (systolic BP: 1.54±3.76%; diastolic BP: 2.27±3.48%, P<0.05) when nighttime was defined with the actigraph. Standing BP was higher (systolic BP 1.07±2.81mmHg; diastolic BP: 1.34±2.50mmHg) than daytime BP defined by a fixed period. CONCLUSION: Diurnal BP, nocturnal BP and dipping are influenced by the definition of daytime and nighttime periods. Studies evaluating the prognostic value of each method are needed to clarify which definition should be used.

Stress ulcer prophylaxis in non-critically ill patients: a prospective evaluation of current practice in a general surgery department.

RATIONALE, AIMS AND OBJECTIVES: There is little evidence regarding the benefit of stress ulcer prophylaxis (SUP) outside a critical care setting. Overprescription of SUP is not devoid of risks. This prospective study aimed to evaluate the use of proton pump inhibitors (PPIs) for SUP in a general surgery department. METHOD: Data collection was performed prospectively during an 8-week period on patients hospitalized in a general surgery department (58 beds) by pharmacists. Patients with a PPI prescription for the treatment of ulcers, gastro-oesophageal reflux disease, oesophagitis or epigastric pain were excluded. Patients admitted twice during the study period were not reincluded. The American Society of Health-System Pharmacists guidelines on SUP were used to assess the appropriateness of de novo PPI prescriptions. RESULTS: Among 255 patients in the study, 138 (54%) received a prophylaxis with PPI, of which 86 (62%) were de novo PPI prescriptions. A total of 129 patients (94%) received esomeprazole (according to the hospital drug policy). The most frequent dosage was at 40 mg once daily. Use of PPI for SUP was evaluated in 67 patients. A total of 53 patients (79%) had no risk factors for SUP. Twelve and two patients had one or two risk factors, respectively. At discharge, PPI prophylaxis was continued in 33% of patients with a de novo PPI prescription. CONCLUSIONS: This study highlights the overuse of PPIs in non-intensive care unit patients and the inappropriate continuation of PPI prescriptions at discharge. Treatment recommendations for SUP are needed to restrict PPI use for justified indications.

Personalized drug administrations using Support Vector Machine

The decision-making process regarding drug dose, regularly used in everyday medical practice, is critical to patients' health and recovery. It is a challenging process, especially for a drug with narrow therapeutic ranges, in which a medical doctor decides the quantity (dose amount) and frequency (dose interval) on the basis of a set of available patient features and doctor's clinical experience (a priori adaptation). Computer support in drug dose administration makes the prescription procedure faster, more accurate, objective, and less expensive, with a tendency to reduce the number of invasive procedures. This paper presents an advanced integrated Drug Administration Decision Support System (DADSS) to help clinicians/patients with the dose computing. Based on a support vector machine (SVM) algorithm, enhanced with the random sample consensus technique, this system is able to predict the drug concentration values and computes the ideal dose amount and dose interval for a new patient. With an extension to combine the SVM method and the explicit analytical model, the advanced integrated DADSS system is able to compute drug concentration-to-time curves for a patient under different conditions. A feedback loop is enabled to update the curve with a new measured concentration value to make it more personalized (a posteriori adaptation).

Comorbidity and nutritional indices as predictors of morbidity after transurethral procedures: A prospective cohort study.

INTRODUCTION: Preoperative scores are widely used predictors of complications after major surgery. These scores, however, are not widely used in transurethral procedures. The aim of this study was to assess the value of the Charlson Comorbidity Index (CCI), the age-adjusted CCI, the American Society of Anesthesiologist score (ASA) and the Nutritional Risk Score (NRS) in predicting early morbidity after transurethral urological procedures. METHODS: Consecutive patients undergoing transurethral resection of the bladder or the prostate were prospectively enrolled. The scores were calculated preoperatively; 30-day complications were prospectively recorded according to the Dindo-Clavien classification. Univariate logistic regression was performed to investigate the value of each score and of other factors (i.e., age, sex, body mass index, anemia, smoking habit, type of operation and anaesthesia) as predictors of complications. A multivariate model was then calculated using these predictors. RESULTS: Overall, 197 patients were included. The mean age was 72 (standard deviation ± 10). In total, 26.9% patients had at least 1 complication. Using univariate analysis, we found that each score significantly predicted complications. In multivariate analysis, only the ASA (odds ration [OR] 2.11; 95% confidence interval [CI] 1.01-4.43) and the NRS (OR 2.42; 95% CI 1.56-3.74) remained independent predictors. The best model incorporated ASA, NRS and gender, and predicted morbidity with an area under the curve of 76%. Our study's main limitations are population heterogeneity and limited sample size. CONCLUSION: The ASA and the NRS are important and independent determinants of early morbidity after transurethral procedures. The use of these indices may assist clinicians in the decision-making process to balance the possible benefits of transurethral procedures with the potential risks.