Clinical utility of a molecular test in adjuvant treatment decision making in women with endocrine-sensitive early stage breast cancer: a retrospective, single center one year experience

Background. Molecular tests for breast cancer (BC) risk assessment are reimbursed by health insurances in Switzerland since the beginning of year 2015. The main current role of these tests is to help oncologists to decide about the usefulness of adjuvant chemotherapy in patients with early stage endocrine-sensitive and human epidermal growth factor receptor 2 (HER2)-negative BC. These gene expression signatures aim at predicting the risk of recurrence in this subgroup. One of them (OncotypeDx/OT) also predicts distant metastases rate with or without the addition of cytotoxic chemotherapy to endocrine therapy. The clinical utility of these tests -in addition to existing so-called "clinico-pathological" prognostic and predictive criteria (e.g. stage, grade, biomarkers status)-is still debated. We report a single center one year experience of the use of one molecular test (OT) in clinical decision making. Methods. We extracted from the CHUV Breast Cancer Center data base the total number of BC cases with estrogen-receptor positive (ER+), HER2-negative early breast cancer (node negative (pN0) disease or micrometastases in up to 3 lymph nodes) operated between September 2014 and August 2015. For the cases from this group in which a molecular test had been decided by the tumor board, we collected the clinicopathologic parameters, the initial tumor board decision, and the final adjuvant systemic therapy decision. Results. A molecular test (OT) was done in 12.2% of patients with ER + HER2 negative early BC. The median age was 57.4 years and the median invasive tumor size was 1.7 cm. These patients were classified by ODX testing (Recurrence Score) into low-, intermediate-, and high risk groups, respectively in 27.2%, 63.6% and 9% of cases. Treatment recommendations changed in 18.2%, predominantly from chemotherapyendocrine therapy to endocrine treatment alone. Of 8 patients originally recommended chemotherapy, 25% were recommended endocrine treatment alone after receiving the Recurrence Score result. Conclusions. Though reimbursed by health insurances since January 2015, molecular tests are used moderately in our institution as per the decision of the multidisciplinary tumor board. It's mainly used to obtain a complementary confirmation supporting the decision of no chemotherapy. The OncotypeDx Recurrence Score results were in the intermediate group in 66% of the 9 tested cases but contributed to avoid chemotherapy in 2 patients during the last 12 months.

Ability of physicians to diagnose influenza and usefulness of a rapid influenza antigen test in febrile returning travelers: A randomized controlled trial.

BACKGROUND: Fever is a frequent cause of medical consultation among returning travelers. The objectives of this study were to assess whether physicians were able to identify patients with influenza and whether the use of an influenza rapid diagnostic test (iRDT) modified the clinical management of such patients. METHODS: Randomized controlled trial conducted at 2 different Swiss hospitals between December 2008 and November 2012. Inclusion criteria were 1) age ≥18 years, 2) documented fever of ≥38 °C or anamnestic fever + cough or sore throat within the last 4 days, 3) illness occurring within 14 days after returning from a trip abroad, 4) no definitive alternative diagnosis. Physicians were asked to estimate the likelihood of influenza on clinical grounds, and a single nasopharyngeal swab was taken. Thereafter patients were randomized into 2 groups: i) patients with iRDT (BD Directigen A + B) performed on the nasopharyngeal swab, ii) patients receiving usual care. A quantitative PCR to detect influenza was done on all nasopharyngeal swabs after the recruitment period. Clinical management was evaluated on the basis of cost of medical care, number of X-rays requested and prescription of anti-infective drugs. RESULTS: 100 eligible patients were referred to the investigators. 93 patients had a naso-pharyngeal swab for a PCR and 28 (30%) swabs were positive for influenza. The median probability of influenza estimated by the physician was 70% for the PCR positive cases and 30% for the PCR negative cases (p < 0.001). The sensitivity of the iRDT was only 20%, and specificity 100%. Mean medical cost for the patients managed with iRDT and without iRDT were USD 581 (95%CI 454-707) and USD 661 (95%CI 522-800) respectively. 14/60 (23%) of the patients managed with iRDT were prescribed antibiotics versus 13/33 (39%) in the control group (p = 0.15). No patient received antiviral treatment. CONCLUSION: Influenza was a frequent cause of fever among these febrile returning travelers. Based on their clinical assessment, physicians had a higher level of suspicion for influenza in PCR positive cases. The iRDT used in this study showed a disappointingly low sensitivity and can therefore not be recommended for the management of these patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00821626.

Predicting richness and composition in mountain insect communities at high resolution: a new test of the SESAM framework

Aim The aim of this study was to test different modelling approaches, including a new framework, for predicting the spatial distribution of richness and composition of two insect groups. Location The western Swiss Alps. Methods We compared two community modelling approaches: the classical method of stacking binary prediction obtained fromindividual species distribution models (binary stacked species distribution models, bS-SDMs), and various implementations of a recent framework (spatially explicit species assemblage modelling, SESAM) based on four steps that integrate the different drivers of the assembly process in a unique modelling procedure. We used: (1) five methods to create bS-SDM predictions; (2) two approaches for predicting species richness, by summing individual SDM probabilities or by modelling the number of species (i.e. richness) directly; and (3) five different biotic rules based either on ranking probabilities from SDMs or on community co-occurrence patterns. Combining these various options resulted in 47 implementations for each taxon. Results Species richness of the two taxonomic groups was predicted with good accuracy overall, and in most cases bS-SDM did not produce a biased prediction exceeding the actual number of species in each unit. In the prediction of community composition bS-SDM often also yielded the best evaluation score. In the case of poor performance of bS-SDM (i.e. when bS-SDM overestimated the prediction of richness) the SESAM framework improved predictions of species composition. Main conclusions Our results differed from previous findings using community-level models. First, we show that overprediction of richness by bS-SDM is not a general rule, thus highlighting the relevance of producing good individual SDMs to capture the ecological filters that are important for the assembly process. Second, we confirm the potential of SESAM when richness is overpredicted by bS-SDM; limiting the number of species for each unit and applying biotic rules (here using the ranking of SDM probabilities) can improve predictions of species composition

Evaluation of a new serological test for the detection of anti-Coxiella and anti-Rickettsia antibodies.

Coxiella burnetii and members of the genus Rickettsia are obligate intracellular bacteria. Since cultivation of these organisms requires dedicated techniques, their diagnosis usually relies on serological or molecular biology methods. Immunofluorescence is considered the gold standard to detect antibody-reactivity towards these organisms. Here, we assessed the performance of a new automated epifluorescence immunoassay (InoDiag) to detect IgM and IgG against C. burnetii, Rickettsia typhi and Rickettsia conorii. Samples were tested with the InoDiag assay. A total of 213 sera were tested, of which 63 samples from Q fever, 20 from spotted fever rickettsiosis, 6 from murine typhus and 124 controls. InoDiag results were compared to micro-immunofluorescence. For acute Q fever, the sensitivity of phase 2 IgG was only of 30% with a cutoff of 1 arbitrary unit (AU). In patients with acute Q fever with positive IF IgM, sensitivity reached 83% with the same cutoff. Sensitivity for chronic Q fever was 100% whereas sensitivity for past Q fever was 65%. Sensitivity for spotted Mediterranean fever and murine typhus were 91% and 100%, respectively. Both assays exhibited a good specificity in control groups, ranging from 79% in sera from patients with unrelated diseases or EBV positivity to 100% in sera from healthy patients. In conclusion, the InoDiag assay exhibits an excellent performance for the diagnosis of chronic Q fever but a very low IgG sensitivity for acute Q fever likely due to low reactivity of phase 2 antigens present on the glass slide. This defect is partially compensated by the detection of IgM. Because it exhibits a good negative predictive value, the InoDiag assay is valuable to rule out a chronic Q fever. For the diagnosis of rickettsial diseases, the sensitivity of the InoDiag method is similar to conventional immunofluorescence.

Application of intravoxel incoherent motion perfusion imaging to shoulder muscles after a lift-off test of varying duration.

Intravoxel incoherent motion (IVIM) MRI is a method to extract microvascular blood flow information out of diffusion-weighted images acquired at multiple b-values. We hypothesized that IVIM can identify the muscles selectively involved in a specific task, by measuring changes in activity-induced local muscular perfusion after exercise. We tested this hypothesis using a widely used clinical maneuver, the lift-off test, which is known to assess specifically the subscapularis muscle functional integrity. Twelve shoulders from six healthy male volunteers were imaged at 3 T, at rest, as well as after a lift-off test hold against resistance for 30 s, 1 and 2 min respectively, in three independent sessions. IVIM parameters, consisting of perfusion fraction (f), diffusion coefficient (D), pseudo-diffusion coefficient D* and blood flow-related fD*, were estimated within outlined muscles of the rotator cuff and the deltoid bundles. The mean values at rest and after the lift-off tests were compared in each muscle using a one-way ANOVA. A statistically significant increase in fD* was measured in the subscapularis, after a lift-off test of any duration, as well as in D. A fD* increase was the most marked (30 s, +103%; 1 min, +130%; 2 min, +156%) and was gradual with the duration of the test (in 10(-3) mm(2) /s: rest, 1.41 ± 0.50; 30 s, 2.86 ± 1.17; 1 min, 3.23 ± 1.22; 2 min, 3.60 ± 1.21). A significant increase in fD* and D was also visible in the posterior bundle of the deltoid. No significant change was consistently visible in the other investigated muscles of the rotator cuff and the other bundles of the deltoid. In conclusion, IVIM fD* allows the demonstration of a task-related microvascular perfusion increase after a specific task and suggests a direct relationship between microvascular perfusion and the duration of the effort. It is a promising method to investigate non-invasively skeletal muscle physiology and clinical perfusion-related muscular disorders.

Balayage visuel des sujets effectuant l'auto-évaluation de l'échelle ELADEB

Introduction Les Echelles Lausannoises d'Auto-Evaluation des Difficultés et des Besoins ELADEB, est un outil utilisé en réhabilitation psychiatrique permettant de dresser le profil des problèmes rencontrés par les patients psychiatriques dans les principaux domaines de la vie quotidienne, ainsi que le besoin d'aide supplémentaire à celle déjà existante. Cet outil a déjà été validé dans une étude1 portant sur 94 patients et recueille un intérêt grandissant. Afin de compléter les données de validation recueillies lors de la première étude, nous présentons ici une seconde étude visant à comprendre d'avantage cet outil en le couplant à l'Eye tracker qui permet une étude du regard et ainsi observer des phénomènes visuels des sujets qui pratiquent l'auto-évaluation des difficultés et des besoins d'aide. Objectifs Cette étude pilote et exploratrice a pour but de mesurer l'exploration visuelle des cartes lors de l'évaluation d'ELADEB au travers des trois variables suivantes d'oculométrie récoltées au travers de l'outil de mesure de l'Eye tracker : (1) la variation de la taille pupillaire (pixels), (2) le rapport des nombres de points de fixation/temps, et (3) de la durée totale du temps de traitement de l'information de la carte (ms). Hypothèses. Le traitement visuel des cartes sélectionnées comme problèmes versus non problèmes sera différent chez tout le monde d'une part au niveau de : (1) la variation pupillaire, (2) du nombre de points de fixation de l'oeil/temps ainsi que (3) de la durée totale du traitement de l'information de la carte en fonction de notre compréhension. On peut poser l'hypothèse que l'émotion sera différente selon que la personne rencontre un problème ou non et ainsi, on peut s'attendre à ce que les cartes sélectionnées comme problèmes soient associées à une réaction émotionnelle plus importante que les autres, ce qui nous permettrait d'observer une corrélation entre le balayage visuel et ELADEB. Méthodes Cette étude exploratoire porte sur un échantillon de 10 sujets passant un test d'évaluation des difficultés et des besoins ELADEB, couplé à un appareil d'Eye tracking. Les critères d'inclusion des sujets sont : (1) hommes entre 30 et 40 ans, (2) dépourvu de symptômes psychotiques ou de psychoses. Les critères d'exclusion des sujets sont : (1) consommation d'alcool ou de drogues, (2) troubles psycho-organiques, (3) retard mental, (4) difficulté de compréhension de la langue française, (5) état de décompensation aiguë empêchant la réalisation de l'étude. Trois instruments sont utilisés comme supports d'analyses pour cette étude : (1) ELADEB, (2) l'Eye tracking et (3) le Gaze tracker. Le dispositif (2) d'Eye tracking se présente sous forme de lunettes particulières à porter par le sujet et qui permet de suivre les mouvements de l'oeil. L'une des caméras suit et enregistre les mouvements oculaires du sujet et permet de « voir en temps réel ce que voit le sujet et où il regarde » tandis que la seconde caméra scrute et analyse sa pupille. Les données sont ensuite répertoriées par le logiciel de mesures (3) « Gaze tracker », qui les analyse avec, à la fois une évaluation quantitative des points de fixation2 en se basant sur leurs nombres et leurs durées, ainsi qu'une mesure de la variation pupillaire fournie en pixels par le logiciel. Résultat(s) escompté(s) Il s'agit d'une étude exploratoire dans laquelle on espère retrouver les variations moyennes intra-sujets selon les hypothèses carte problème versus non problèmes. On peut s'attendre à trouver une retraduction des mesures de l'échelle ELADEB au travers de l'Eye tracking, ce qui concorderait avec les hypothèses énoncées et ajouterait encore d'avantage de validation à ELADEB au travers d'un outil pointu de mesure physiologique.

Altered Sleep Homeostasis in Rev-erbα Knockout Mice.

STUDY OBJECTIVES: The nuclear receptor REV-ERBα is a potent, constitutive transcriptional repressor critical for the regulation of key circadian and metabolic genes. Recently, REV-ERBα's involvement in learning, neurogenesis, mood, and dopamine turnover was demonstrated suggesting a specific role in central nervous system functioning. We have previously shown that the brain expression of several core clock genes, including Rev-erbα, is modulated by sleep loss. We here test the consequences of a loss of REV-ERBα on the homeostatic regulation of sleep. METHODS: EEG/EMG signals were recorded in Rev-erbα knockout (KO) mice and their wild type (WT) littermates during baseline, sleep deprivation, and recovery. Cortical gene expression measurements after sleep deprivation were contrasted to baseline. RESULTS: Although baseline sleep/wake duration was remarkably similar, KO mice showed an advance of the sleep/wake distribution relative to the light-dark cycle. After sleep onset in baseline and after sleep deprivation, both EEG delta power (1-4 Hz) and sleep consolidation were reduced in KO mice indicating a slower increase of homeostatic sleep need during wakefulness. This slower increase might relate to the smaller increase in theta and gamma power observed in the waking EEG prior to sleep onset under both conditions. Indeed, the increased theta activity during wakefulness predicted delta power in subsequent NREM sleep. Lack of Rev-erbα increased Bmal1, Npas2, Clock, and Fabp7 expression, confirming the direct regulation of these genes by REV-ERBα also in the brain. CONCLUSIONS: Our results add further proof to the notion that clock genes are involved in sleep homeostasis. Because accumulating evidence directly links REV-ERBα to dopamine signaling the altered homeostatic regulation of sleep reported here are discussed in that context.

PEC1/AtABCG32 transport function in cuticle biosynthesis

Most aerial parts of the plants are covered by a hydrophobic coating called cuticle. The cuticle is formed of cutin, a complex mixture of esterified fatty acids that are embedded and associated with waxes. The cuticle often appears as a superposition of layers of different composition: The cuticle proper formed of cutin and a mixture of waxes and underneath, the cuticle layer containing cutin, intracuticular waxes and polysaccharides of the cell wall. In addition to its involvement in plant development by preventing organ fusions, the cuticle acts as a barrier to prevent water loss and protect plants against environmental aggressions such as excessive radiation or pathogens attacks. PEC1/AtABCG32 is an ABC transporter from the PDR family involved in cutin biosynthesis. Characterization of the peci mutant in Arabidopsis thaliana showed that PEC1 plays a significant role in the diffusion barrier formation in leaves and petals. The cuticles of leaves and flowers of peci are permeable and the cuticular layer rather than the cuticular proper was altered in the petals, underlining the importance of this particular layer in the maintenance of the diffusion barrier. Chemical analysis on the flower cutin monomer composition of ped mutant revealed a decrease in hydroxylated cutin monomers, suggesting a function of PEC1 in the incorporation of these monomers in the polymer cutin. However, the exact nature of the substrates of PEC1 remained elusive. PEC1 homologues in barley and rice, respectively HvABCG31/EIBI1 and OsABCG31, are also implicated in cuticle biosynthesis. Interestingly, the rice mutant displays more severe phenotypes such as dwarfism and spreading necrosis conducting to the seedling death. In this work, we further characterized osabcg31 mutant and hairpin-RNAi downregulated OsABCG31 plant lines showing reduced growth and cuticle permeability. Our analysis showed a decrease in hydroxylated cutin monomers and severe disruptions in the cuticle, which explain the permeability. Further insights into the function of the cuticle in rice resistance/susceptibility to Pathogens were obtained after inoculation with Magnaporthe oryzae, the fungus responsible for the rice blast disease. Osabcg31 as well as the transgenic lines downregulating OsABCG31 showed increased resistance to the fungus. However, only later steps of infection are reduced . and no impact is obseived on the germination or penetration stages, suggesting that the cuticle disruption per se is not responsible for the resistance. We further investigated the cause of the resistance by analyzing the expression of defense related gene in osabcg31 prior to infection. We found that osabcg31 constitutively express defense related genes, which may explain the resistance, the dwarfism and the cell death. osabcg31 is thus a tool to study the connection between cuticle, plant development and defense signaling networks in rice. The transport function of PEC1 family members is still unknown. In order to link cutin biosynthesis and transport activity, we combined ped mutation with mutations in cutin synthesis related genes. Here, we show that PEC1 acts independently from GPAT4 and GPAT8 pathway and partially overlaps with GPAT6 biosynthesis pathway that leads to the production of hydroxylated C16 cutin precursor 2-Mono(10,16-dihydroxyhexadecanoylJglycerol (2-MHG). In addition, we noticed that despite a comparable cutin monomer composition, ped mutant leaves cuticle are permeable while that of gpat6 mutant are not. This finding raises the possibility of PEC1 being required for the incorporation of C16 hydroxylated monomers and their structural arrangement rather than their direct transport towards the cuticle. A careful investigation of the cuticle permeability, cutin composition and ultrastructure during leave development in Wt plants and ped mutants revealed a possible different regulation of several pathways of cutin biosynthesis and showed the importance of PEC1 function early during leave cuticle maturation. In order to elucidate the transport activity of PEC1, we successfully expressed PEC1 in Nicotiana benthamiana plant system for direct transport experiments. This system will be used to test the PEC 1-dependent transport of potential substrates such as sn-2-monoacylglycerol loaded with a hydroxylated C16 fatty acid. -- Toutes les parties aériennes des plantes sont recouvertes d'une couche hydrophobe appelée «cuticule». Cette cuticule est composée de cutine, un polymère d'acides gras estérifiés, et de cires. La cuticule apparaît souvent sous forme de couches superposées: une première couche extérieure appelée «cuticle proper» formée de cutine et d'un mélange de cires, et une deuxième couche, la «cuticle layer», formée de cutine associée à des cires intracuticulaires et des polysaccharides pariétaux. La cuticule joue le rôle de barrière prévenant contre la perte d'eau et les agressions environnementales. AtABCG32/PEC1 est un transporteur ABC de la famille des PDR impliqué dans la synthèse de la cutine. L'étude du mutant peci d'Arabidopsis thaliana a révélé une fonction de PEC1 dans la formation de la barrière de diffusion. La cuticule des feuilles et fleurs de peci est perméable. Des altérations de la «cuticle layer» ont été démontrées, soulignant son importance dans le maintien de la barrière. L'analyse de la composition de la cutine de peci a montré une réduction spécifique en monomères hydroxylés, suggérant un rôle de PEC1 dans leur incorporation dans la cuticule. Cependant, la nature exacte des substrats de PEC1 n'a pas été identifiée. PEC1 possède deux homologues chez l'orge et le riz, respectivement HvABCG31 et OsABCG31, et qui sont impliqués dans la biosynthèse de la cuticule. Chez le riz, des phénotypes plus sévères ont été observés tels que nanisme et nécroses conduisant à la mort des jeunes plants. Dans cette étude, nous avons continué la caractérisation de osabcg31 ainsi que des lignées de riz sous exprimant le gène OsABCG31 et présentant une cuticule perméable tout en ayant une meilleure croissance. Notre étude a démontré une réduction des monomères hydroxylés de cutine et une désorganisation de la structure de la cuticule, aggravée dans le mutant osabcg31. Ce résultat explique la perméabilité observée. Des mformations P|us approfondies sur l'implication de la cuticule dans la résistance aux pathogènes ont été obtenues après inoculation du mutant osabcg31 et les lignées sous- exprimant OsABCG31 avec une souche virulente de Magnaporthe Oryzae, le champignon responsable de la pyriculariose du riz. Les différentes lignées testées ont démontré une résistance au pathogène. Cependant, seules les étapes tardives de l'infection sont réduites et aucun impact n'est observé sur la germination des spores ou la pénétration du champignon, suggérant que les modifications de la cuticule ne sont pas directement à l'origine de la résistance. L'analyse de l'expression de gènes impliqués dans la résistance à Magnaporthe.oryzae a mis en évidence l'expression constitutive de ces gènes en l'absence de tout contact avec le pathogène. Ceci explique la résistance, le nanisme et la mort cellulaire observés. Ainsi, osabcg31 représente un outil efficace pour l'étude intégrée des systèmes de régulation de la défense, de développement des plantes et la cuticule. La nature des substrats transportés par PEC1/AtABCG32 reste inconnue. Dans le but d'établir une liaison entre biosynthèse de cutine et transport des précurseurs par PEC1, la mutation peci a été combinée avec des mutants impliqués dans différentes voies de biosynthèse. Cette étude a démontré une fonction indépendante de PEC1 de la voie de biosynthèse impliquant les enzymes GPAT4 et GPAT8, et une fonction partiellement indépendante de la voie impliquant GPAT6 qui mène à la production de précurseurs sn-2- monoacylglycerol chargés en acides gras en C16 (2-MHG). De plus, malgré un profil similaire en monomères de cutine, gpat6 conserve une cuticule imperméable alors que celle de PEC1 est perméable. Ceci suggère que PEC1 est nécessaire à l'incorporation des monomères en C16 et leur arrangement structurel plutôt que simplement à leur transport direct. L'étude approfondie de la perméabilité cuticulaire, de la structure ainsi que de la composition en cutine pendant le développement des feuilles de peci et la plante sauvage a révélé l'existence de différentes régulations des voies de biosynthèses des monomères et a démontré l'importance de PEC1 dans les premières étapes de la mise en place de la cuticule. Pour identifier les substrats transportés, l'expression de PEC1 chez le système hétérologue Nicotiana benthamiana a été conduite avec succès. Ce système sera utilisé pour tester le transport de substrats potentiels tels que le sn-2-monoacylglycerol chargé en acide gras en C16.

On the Use of a Test to Exhaustion Specific to Tennis (TEST) with Ball Hitting by Elite Players

PURPOSE: We aimed to a) introduce a new Test to Exhaustion Specific to Tennis (TEST) and compare performance (test duration) and physiological responses to those obtained during the 20-m multistage shuttle test (MSST), and b) determine to which extent those variables correlate with performance level (tennis competitive ranking) for both test procedures. METHODS: Twenty-seven junior players (8 males, 19 females) members of the national teams of the French Tennis Federation completed MSST and TEST, including elements of the game (ball hitting, intermittent activity, lateral displacement), in a randomized order. Cardiorespiratory responses were compared at submaximal (respiratory compensation point) and maximal loads between the two tests. RESULTS: At the respiratory compensation point oxygen uptake (50.1 +/- 4.7 vs. 47.5 +/- 4.3 mL.min-1.kg-1, p = 0.02), but not minute ventilation and heart rate, was higher for TEST compared to MSST. However, load increment and physiological responses at exhaustion did not differ between the two tests. Players' ranking correlated negatively with oxygen uptake measured at submaximal and maximal loads for both TEST (r = -0.41; p = 0.01 and -0.55; p = 0.004) and MSST (r = -0.38; P = 0.05 and -0.51; p = 0.1). CONCLUSION: Using TEST provides a tennis-specific assessment of aerobic fitness and may be used to prescribe aerobic exercise in a context more appropriate to the game than MSST. Results also indicate that VO2 values both at submaximal and maximal load reached during TEST and MSST are moderate predictors of players competitive ranking.