Caractérisation virologique des virus VIH-1 isolés en primo-infection en France

L épidémiologie moléculaire des virus VIH-1 en France est caractérisée par une augmentation constante de la diversité virologique et de la fréquence des virus de sous-types non-B chez les patients en primo-infection. Entre 1997 et 2007, 28.4% des 591 patients suivis étaient infectés par des virus de sous-types non-B. De plus, 49 patients (8.3%) étaient infectés par des souches de sous-types différents sur les gènes pol et env, témoignant d évènements de recombinaisons entre ces gènes. Ces virus recombinants étaient isolés à la fois chez des patients originaires d Afrique sub-saharienne (28.3%) et des sujets caucasiens (6.3%). Ces résultats témoignent des échanges de souches virales entre les populations d'origine africaine et caucasienne, contribuant encore à augmenter la diversité virologique dans ces deux populations. Parmi 131 virus de sous-types non-B, 12.2% étaient classés comme ayant un tropisme CXCR4 par méthode génotypique, mais seulement 0.8% par méthode phénotypique, indiquant d une part la faible proportion de virus non-B de tropisme CXCR4 en primo-infection en France, et d autre part le manque de spécificité des méthodes génotypiques de détermination du tropisme pour ces sous-types, rendant nécessaire la mise au point d autres algorithmes spécifiques pour ces virus.L analyse de 987 virus isolés dans la cohorte entre 1999 et 2010 a mis en évidence que 12.7% d entre eux étaient regroupés en "clusters" de transmission. Les patients en primo-infection contribuent donc de façon significative à la propagation de l épidémie de VIH en France, particulièrement les hommes homo/bi-sexuels, avec une fréquence augmentant au cours de la période récente (2006-2010).La comparaison des quasi-espèces virales circulant concomitamment chez 8 patients en primo-infection ( receveurs ) et leurs 8 partenaires sexuels respectifs ( donneurs ) a révélé dans tous les cas la transmission d un virus unique, présent de façon minoritaire parmi les sous-populations virales du donneur. La transmission virale muqueuse implique donc une sélection génétique drastique.High genetic diversity is a major characteristics of HIV-1. In France, although subtype B strains are still predominant, the proportion of non-B viruses isolated in patients at the time of primary HIV-1 (PHI) infection increases over time. Between 1997 and 2007, 28.4% of patients were infected with non-B subtypes strains. Forty-nine viruses showed different phylogenies between the pol and env genes, indicating that recombinations have occurred in 8.3% of cases. These recombinants were isolated both in patients from Sub-Saharan Africa (28.3%) and in white subjects (6.3%).The phenotypic analysis of viral tropism of 131 non-B strains showed a very low (0.8%) proportion of CXCR4-tropic strains (X4 strains) at the time of PHI. Compared to phenotypic tests, genotypic predictions can overestimate (12.2% versus 0.8%) the proportion of X4 strains in non-B subtypes.The phylogenetic analysis of 987 strains isolated in 1999-2010 showed that 12.7% of PHI cosegregated into 56 transmission chains. PHIs are a significant source of onward transmission, especially in men having sex with men, with increasing frequency during the recent years (10.2% in 1999-2006 versus 15.2% in 2006-2010, p=0.02).The comparison of the viral quasispecies isolated in plasma and PBMC samples from 8 patients at the time of PHI ("recipients") and their transmitting partners ("donors") suggested that a severe genetic bottleneck occurrs during HIV-1 heterosexual and homosexual transmission. Indeed, we observed in all cases the transmission of a single variant, which was derived from an infrequent variant population within the blood of the donor. The proportion of X4 quasispecies in donors were higher in case of X4 versus CCR5-tropic viral transmission, suggesting that X4 transmission may be associated with a threshold of X4 circulating quasispecies in donors.PARIS5-Bibliotheque electronique (751069902) / SudocSudocFranceF

Cognitive Flexibility Or Flexibilities? New Insights From A Classroom Study

The definition of cognitive flexibility remains debated in the literature. Some refer to flexibility as a general shifting ability. Others argue that it is a context-dependent skill. For others, flexibility is a dimensional construct including reactive flexibility and spontaneous flexibility. To help decide between these views, we analyzed the performances of first-graders across four flexibility tasks. Two tasks focused on reactive flexibility (rule-shifting and verbally-cued-shifting), and two targeted spontaneous flexibility (role-shifting and divergent thinking). Three additional executive tasks investigated the contribution of inhibition, working memory, and processing speed. Significant — though moderate — positive correlations emerged between all but one of the pairs of flexibility tasks. Besides, executive functions were not found to systematically correlate with any measure of flexibility. Furthermore, confirmatory factorial analyses failed to identify a unique or bi-dimensional structure of flexibility. Taken together, these results did not provide evidence for a domain-general ability. Implications and future directions are discussed

Cognitive Flexibility Or Flexibilities? New Insights From A Classroom Study

International audienceThere is an ongoing debate in the scientific community regarding the nature of cognitive flexibility. It is either seen as a general ability, a task-dependent skill, or a dimensional construct composed of reactive flexibility and spontaneous flexibility. To develop the discussion, we compared first-graders’ performance on four cognitive flexibility tasks. Two tasks focused on reactive flexibility (rule-switching and verbally-cued-switching), and two targeted spontaneous flexibility (role-shifting and divergent thinking). We also used three tests of executive functions (cognitive inhibition, working memory, and processing speed) to evaluate their link with cognitive flexibility. Significant positive correlations emerged between all but one of the flexibility tasks, regardless of whether they targeted a reactive or spontaneous use of flexibility. Similarly, confirmatory factorial analyses did not provide evidence for the dimensional structure of cognitive flexibility. These results suggest that different flexibility tasks may tap into distinct aspects of a task-dependent ability, rather than a generalized competence

Une ou des flexibilité(s) cognitive(s) ? Une étude corrélationnelle en milieu scolaire

International audienceÊtre capable de s’adapter efficacement à un changement dans une situation, préjuge-t-il de la capacité à s’adapter dans une autre ? Ces dernières années, la conception selon laquelle la flexibilité cognitive serait une compétence exécutive générale(e.g., Diamond, 2013), a été remise en question.Des recherches ont montré que l’expression de la flexibilité dépend de facteurs contextuels, cognitifs et expérientiels (e.g., Blaye & Maintenant, 2008 ; Deák & Whiseheart, 2015). Par ailleurs, les travaux menés en neuropsychologie ont permis de différencier deux formes de flexibilité : la flexibilité adaptative et la flexibilité spontanée (e.g., Eslinger & Grattan, 1993), Dans le but d'investiguer le caractère unitaire de la flexibilité cognitive, , nous avons invité XX enfants scolarisés en cours préparatoire à résoudre différentes épreuves de flexibilité. Deux épreuves de flexibilité adaptative (task-switching), dont une d’adaptation à un changement de règle (Four Dimension Changes Card Sorting, 4DCCS) et l’autre d’inférence flexible pour comprendre des mots nouveaux (Four Flexible Induction of Meaning Animates, 4FIM-An) ; ainsi que deux épreuves de flexibilité spontanée dont une épreuve de pensée divergente (Alternative Uses Test, AUT) et (ii) une tâche originale de flexibilité conceptuelle. En outre, les enfants ont été soumis à trois mesures exécutives : la mémoire de travail (BREV) ; l’inhibition cognitive verbale (NEPSY-II) et la vitesse de traitement (NEPSY-II). Les performances scolaires en vocabulaire réceptif sont retenues pour mesurer la compréhension verbale des enfants. L’analyse des performances individuelles aux quatre tâches de flexibilité (en cours de traitement) permettra d’appréhender la nature unitaire ou non de la flexibilité

Une ou des flexibilité(s) cognitive(s) ? Une étude corrélationnelle en milieu scolaire

International audienceÊtre capable de s’adapter efficacement à un changement dans une situation, préjuge-t-il de la capacité à s’adapter dans une autre ? Ces dernières années, la conception selon laquelle la flexibilité cognitive serait une compétence exécutive générale(e.g., Diamond, 2013), a été remise en question.Des recherches ont montré que l’expression de la flexibilité dépend de facteurs contextuels, cognitifs et expérientiels (e.g., Blaye & Maintenant, 2008 ; Deák & Whiseheart, 2015). Par ailleurs, les travaux menés en neuropsychologie ont permis de différencier deux formes de flexibilité : la flexibilité adaptative et la flexibilité spontanée (e.g., Eslinger & Grattan, 1993), Dans le but d'investiguer le caractère unitaire de la flexibilité cognitive, , nous avons invité XX enfants scolarisés en cours préparatoire à résoudre différentes épreuves de flexibilité. Deux épreuves de flexibilité adaptative (task-switching), dont une d’adaptation à un changement de règle (Four Dimension Changes Card Sorting, 4DCCS) et l’autre d’inférence flexible pour comprendre des mots nouveaux (Four Flexible Induction of Meaning Animates, 4FIM-An) ; ainsi que deux épreuves de flexibilité spontanée dont une épreuve de pensée divergente (Alternative Uses Test, AUT) et (ii) une tâche originale de flexibilité conceptuelle. En outre, les enfants ont été soumis à trois mesures exécutives : la mémoire de travail (BREV) ; l’inhibition cognitive verbale (NEPSY-II) et la vitesse de traitement (NEPSY-II). Les performances scolaires en vocabulaire réceptif sont retenues pour mesurer la compréhension verbale des enfants. L’analyse des performances individuelles aux quatre tâches de flexibilité (en cours de traitement) permettra d’appréhender la nature unitaire ou non de la flexibilité

Cognitive Flexibility Or Flexibilities? Insights From A Classroom Study.

There is an ongoing debate in the scientific community regarding the nature of cognitive flexibility. It is either seen as a general executive process (set shifting), as a dimensional construct composed of reactive flexibility and spontaneous flexibility, or as a task-dependent skill. To help decide between these views, we analyzed the performances of 86 first-graders across four Cognitive Flexibility tasks. Two tasks focused on reactive flexibility (rule-shifting and predicate-shifting), and two tasks targeted spontaneous flexibility (role-shifting and divergent thinking). We also assessed children’s performance on three Executive Functions tasks (cognitive inhibition, verbal working memory, and visuomotor processing speed) to investigate the extent to which they correlate with cognitive flexibility. Significant — though moderate — positive correlations emerged among five out of the six pairs of cognitive flexibility tasks, regardless of whether they involved a reactive or spontaneous use of cognitive flexibility. Besides, none of the executive functions tasks systematically correlated with the four measures of cognitive flexibility. On the other hand, Confirmatory Factorial Analyses did not state whether cognitive flexibility is a unifactorial or bi-factorial construct. Overall, our results suggest that cognitive flexibility performance may reflect the recruitment of several task-dependent transversal processes. Implications with regard to the three postulates as well as future directions are discussed

Patient-specific dosimetric workflow with a reduced number of time-points for 177Lu treatments

International audienceAim/Introduction: Patients with unresectable neuroendocrine tumors can be treated by internal radiation therapy administrating 7.4 GBq of Lu177-labeled somatostatin analog. Image-based absorbed dose estimation to organs requires several time-points acquisitions but their number is limited by clinical and logistical constraints. The goal of this work was to propose an adaptive dosimetric workflow for estimating absorbed doses from a reduced number of acquisitionacquisitionMaterials and Methods: Thirteen patients with neuroendocrine tumors received four injections of 7.4 GBq of 177Lu-DOTATATE except one patient because of haematological toxicity. Three SPECT/CT acquisitions were performed after the first cycle at 1h, 24h and 96h or 144h and a single acquisition after three latter cycles at 24h for estimating absorbed doses by kidneys, liver and intrahepatic tumors, spleen and bone marrow. Monte Carlo simulations were used to estimate dose rates for each acquisition to take into account self- and cross- doses. These dose rates were then integrated at the organ level (ODR). Time dose rate curves (TDC) were fitted with a tri-exponential function to respect the patients' physiology. For cycles with less than three acquisitions, three methods were proposed and evaluated. If the acquisition at 24h of cycle 1 was missing, the ODR was approximated by the next first ODR at 24h scaled according to the injected activities at each cycle. When only one acquisition was available, two cases were distinguished. Absorbed doses were estimated from the TDC of a previous cycle for the samepatient scaled to the ODR available. Otherwise, TDC of other patients were scaled to the ODR and their integrals were averaged to obtain absorbed doses as proposed by Jackson and al. (1) with time activity curvesResults: Estimated errors when the ODR at 24h was replaced was inferior to 15.9% except for one patient. With only one acquisition, the lowest error was obtained for acquisitions at 96h or 144h with two methods: less than 11% for liver and spleen and less than 20% for kidneys. Thesemethods are being tested for bone marrow dose estimation. Absorbed doses estimated with this workflow were: 2⼟.50.9 Gy (left kidney), 2.7⼟1.2 Gy (right kidney), 2.8⼟1.7 Gy (liver) and 3.4⼟1.6 Gy (spleen) all cycles taken together. Conclusion: The proposed workflow allows the estimation of organ doses from a reduced number of acquisitions for patients treated with 177Lu. References: (1) Jackson and al. JNM 202

Patient-specific dosimetry adapted to variable number of SPECT/CT time-points per cycle for 177^{177}Lu-DOTATATE therapy

International audienceBackground: The number of SPECT/CT time-points is important for accurate patient dose estimation in peptide receptor radionuclide therapy. However, it may be limited by the patient's health and logistical reasons. Here, an image-based dosimetric workflow adapted to the number of SPECT/CT acquisitions available throughout the treatment cycles was proposed, taking into account patient-specific pharmacokinetics and usable in clinic for all organs at risk.Methods: Thirteen patients with neuroendocrine tumors were treated with four injections of 7.4 GBq of 177 Lu-DOTATATE. Three SPECT/CT images were acquired during the first cycle (1H, 24H and 96H or 144H post-injection) and a single acquisition (24H) for following cycles. Absorbed doses were estimated for kidneys (LK and RK), liver (L), spleen (S), and three surrogates of bone marrow (L2 to L4, L1 to L5 and T9 to L5) that were compared. 3D dose rate distributions were computed with Monte Carlo simulations. Voxel dose rates were averaged at the organ level. The obtained Time Dose-Rate Curves (TDRC) were fitted with a tri-exponential model and time-integrated. This method modeled patient-specific uptake and clearance phases observed at cycle 1. Obtained fitting parameters were reused for the following cycles, scaled to the measure organ dose rate at 24H. An alternative methodology was proposed when some acquisitions were missing based on population average TDRC (named STP-Inter). Seven other patients with three SPECT/CT acquisitions at cycles 1 and 4 were included to estimate the uncertainty of the proposed methods.Results: Absorbed doses (in Gy) per cycle available were: 3.1 ± 1.1 (LK), 3.4 ± 1.5 (RK), 4.5 ± 2.8 (L), 4.6 ± 1.8 (S), 0.3 ± 0.2 (bone marrow). There was a significant difference between bone marrow surrogates (L2 to L4 and L1 to L5, Wilcoxon's test: p value < 0.05), and while depicting very doses, all three surrogates were significantly different than dose in background (p value < 0.01). At cycle 1, if the acquisition at 24H is missing and approximated, medians of percentages of dose difference (PDD) compared to the initial tri-exponential function were inferior to 3.3% for all organs. For cycles with one acquisition, the median errors were smaller with a late time-point. For STP-Inter, medians of PDD were inferior to 7.7% for all volumes, but it was shown to depend on the homogeneity of TDRC