Clinical trial simulation to evaluate power to compare the antiviral effectiveness of two hepatitis C protease inhibitors using nonlinear mixed effect models: a viral kinetic approach.

International audienceBACKGROUND: Models of hepatitis C virus (HCV) kinetics are increasingly used to estimate and to compare in vivo drug's antiviral effectiveness of new potent anti-HCV agents. Viral kinetic parameters can be estimated using non-linear mixed effect models (NLMEM). Here we aimed to evaluate the performance of this approach to precisely estimate the parameters and to evaluate the type I errors and the power of the Wald test to compare the antiviral effectiveness between two treatment groups when data are sparse and/or a large proportion of viral load (VL) are below the limit of detection (BLD). METHODS: We performed a clinical trial simulation assuming two treatment groups with different levels of antiviral effectiveness. We evaluated the precision and the accuracy of parameter estimates obtained on 500 replication of this trial using the stochastic approximation expectation-approximation algorithm which appropriately handles BLD data. Next we evaluated the type I error and the power of the Wald test to assess a difference of antiviral effectiveness between the two groups. Standard error of the parameters and Wald test property were evaluated according to the number of patients, the number of samples per patient and the expected difference in antiviral effectiveness. RESULTS: NLMEM provided precise and accurate estimates for both the fixed effects and the inter-individual variance parameters even with sparse data and large proportion of BLD data. However Wald test with small number of patients and lack of information due to BLD resulted in an inflation of the type I error as compared to the results obtained when no limit of detection of VL was considered. The corrected power of the test was very high and largely outperformed what can be obtained with empirical comparison of the mean VL decline using Wilcoxon test. CONCLUSION: This simulation study shows the benefit of viral kinetic models analyzed with NLMEM over empirical approaches used in most clinical studies. When designing a viral kinetic study, our results indicate that the enrollment of a large number of patients is to be preferred to small population sample with frequent assessments of VL

Green Currents for Meromorphic Maps of Compact K\"ahler Manifolds

We consider the dynamics of meromorphic maps of compact K\"ahler manifolds. In this work, our goal is to locate the non-nef locus of invariant classes and provide necessary and sufficient conditions for existence of Green currents in codimension one.Comment: Statement of Theorem 1.5 is slightly improved. Proposition 5.2 and Theorem 5.3 are adde

Increase of precuneus metabolism correlates with reduction of PTSD symptoms after EMDR therapy in military veterans: an 18F-FDG PET study during virtual reality exposure to war

International audienc

Learning Stochastic Majority Votes by Minimizing a PAC-Bayes Generalization Bound

We investigate a stochastic counterpart of majority votes over finite ensembles of classifiers, and study its generalization properties. While our approach holds for arbitrary distributions, we instantiate it with Dirichlet distributions: this allows for a closed-form and differentiable expression for the expected risk, which then turns the generalization bound into a tractable training objective.The resulting stochastic majority vote learning algorithm achieves state-of-the-art accuracy and benefits from (non-vacuous) tight generalization bounds, in a series of numerical experiments when compared to competing algorithms which also minimize PAC-Bayes objectives -- both with uninformed (data-independent) and informed (data-dependent) priors

Weighted pluricomplex energy

We study the complex Monge-Ampre operator on the classes of finite pluricomplex energy $\mathcal{E}_\chi (\Omega)$ in the general case ($\chi(0)=0$ i.e. the total Monge-Ampre mass may be infinite). We establish an interpretation of these classes in terms of the speed of decrease of the capacity of sublevel sets and give a complete description of the range of the operator $(dd^c \cdot)^n$ on the classes $\mathcal{E}\chi(\Omega).$Comment: Contrary to what we claimed in the previous version, in Theorem 5.1 we generalize some Theorem of Urban Cegrell but we do not give a new proof. To appear in Potenial Analysi

Clinical characteristics and brain PET findings in 3 cases of dissociative amnesia : Disproportionate retrograde devicit and posterior middle temporal gyrus hypometabolism

Background Precipitated by psychological stress, dissociative amnesia occurs in the absence of identifiable brain damage. Its clinical characteristics and functional neural basis are still a matter of controversy. Methods In the present paper, we report 3 cases of retrograde autobiographical amnesia, characterized by an acute onset concomitant with emotional/neurological precipitants. We present 2 cases of dissociative amnesia with fugue (cases 1 and 2), and one case of focal dissociative amnesia after a minor head trauma (case 3). The individual case histories and neuropsychological characteristics are reported, as well as the whole-brain voxel-based 18FDG-PET metabolic findings obtained at group-level in comparison to 15 healthy subjects. Results All patients suffered from autobiographical memory loss, in the absence of structural lesion. They had no significant impairment of anterograde memory or of executive function. Impairment of autobiographical memory was complete for two of the three patients, with loss of personal identity (cases 1 and 2). A clinical recovery was found for the two patients in whom follow-up was available (cases 2 and 3). Voxel-based group analysis highlighted a metabolic impairment of the right posterior middle temporal gyrus. 18FDG-PET was repeated in case 3, and showed a complete functional brain recovery. Conclusion The situation of dissociative amnesia with disproportionate retrograde amnesia is clinically heterogeneous between individuals. Our findings may suggest that impairment of high-level integration of visual and/or emotional information processing involving dysfunction of the right posterior middle temporal gyrus could reduce triggering of multi-modal visual memory traces, thus impeding reactivation of aversive memories

Post-critical set and non existence of preserved meromorphic two-forms

We present a family of birational transformations in $CP_2$ depending on two, or three, parameters which does not, generically, preserve meromorphic two-forms. With the introduction of the orbit of the critical set (vanishing condition of the Jacobian), also called ``post-critical set'', we get some new structures, some "non-analytic" two-form which reduce to meromorphic two-forms for particular subvarieties in the parameter space. On these subvarieties, the iterates of the critical set have a polynomial growth in the \emph{degrees of the parameters}, while one has an exponential growth out of these subspaces. The analysis of our birational transformation in $CP_2$ is first carried out using Diller-Favre criterion in order to find the complexity reduction of the mapping. The integrable cases are found. The identification between the complexity growth and the topological entropy is, one more time, verified. We perform plots of the post-critical set, as well as calculations of Lyapunov exponents for many orbits, confirming that generically no meromorphic two-form can be preserved for this mapping. These birational transformations in $CP_2$, which, generically, do not preserve any meromorphic two-form, are extremely similar to other birational transformations we previously studied, which do preserve meromorphic two-forms. We note that these two sets of birational transformations exhibit totally similar results as far as topological complexity is concerned, but drastically different results as far as a more ``probabilistic'' approach of dynamical systems is concerned (Lyapunov exponents). With these examples we see that the existence of a preserved meromorphic two-form explains most of the (numerical) discrepancy between the topological and probabilistic approach of dynamical systems.Comment: 34 pages, 7 figure

FDG-PET hyperactivity pattern in anti-NMDAr encephalitis.

FDG-PET can show anteroposterior glucose metabolism gradient in anti-NMDAr encephalitis, but there are also suggestions that basal ganglia are involved. We examined FDG-PET scans in 5 consecutive episodes of serologically proven anti-NMDAr encephalitis, compared with healthy controls. We confirmed the anteroposterior metabolic gradient and found a significant FDG uptake increase in the caudate nuclei in episodes of varying intensity and delay from the onset of the symptoms. FDG-PET can be useful in the work-up of suspected anti-NMDAr encephalitis disclosing a characteristic cortical and sub-cortical metabolism pattern

Predictive value of dorso-lateral prefrontal connectivity for rTMS response in treatment-resistant depression: A brain perfusion SPECT study

Background: Previous clinical trials have suggested that repetitive transcranial magnetic stimulation (rTMS) has a significant antidepressant effect in patients with treatment resistant depression (TRD). However, results remain heterogeneous with many patients without effective response. / Objective: The aim of this SPECT study was to determine before treatment the predictive value of the connectivity of the stimulated area on further rTMS response in patients with TRD. / Methods: Fifty-eight TRD patients performed a brain perfusion SPECT before high frequency rTMS of the left dorsolateral prefrontal cortex (DLPFC). A voxel based-analysis was achieved to compare connectivity of the left DLPFC in responders and non-responders using inter-regional correlations (p < 0.005, corrected for cluster volume). A multiple logistic regression model was thereafter used with the goal of establishing a predictive score. / Results: Before rTMS, responders exhibited increased SPECT connectivity between the left DLPFC and the right cerebellum in comparison to non-responders, independently of age, gender, severity of depression, and severity of treatment resistance. The area under the curve for the combination of these two SPECT clusters to predict rTMS response was 0.756 (p < 0.005). / Conclusions: SPECT connectivity of the left DLPFC predicts rTMS response before treatment