Combined Analysis of Phase I and Phase II Data to Enhance the Power of Pharmacogenetic Tests

International audienceWe show through a simulation study how the joint analysis of data from phase I and phase II studies enhances the power of pharmacogenetic tests in pharmacokinetic (PK) studies. PK profiles were simulated under different designs along with 176 genetic markers. The null scenarios assumed no genetic effect, while under the alternative scenarios, drug clearance was associated to 6 genetic markers randomly sampled in each simulated dataset. We compared penalised regression Lasso and stepwise procedures to detect the associations between empirical Bayes estimates of clearance, estimated by nonlinear mixed effects models, and genetic variants. Combining data from phase I and phase II studies, even sparse, increases the power to identify the associations between genetics and PK due to the larger sample size. Design optimisation brings a further improvement, and we highlight a direct relationship between η-shrinkage and loss of genetic signal

Rethinking Weight Decay For Efficient Neural Network Pruning

Introduced in the late 80's for generalization purposes, pruning has now become a staple to compress deep neural networks. Despite many innovations brought in the last decades, pruning approaches still face core issues that hinder their performance or scalability. Drawing inspiration from early work in the field, and especially the use of weight-decay to achieve sparsity, we introduce Selective Weight Decay (SWD), which realizes efficient continuous pruning throughout training. Our approach, theoretically-grounded on Lagrangian Smoothing, is versatile and can be applied to multiple tasks, networks and pruning structures. We show that SWD compares favorably to state-of-the-art approaches in terms of performance/parameters ratio on the CIFAR-10, Cora and ImageNet ILSVRC2012 datasets.Comment: 16 pages, 14 figures, submitted at ICML 2021, update : added new results, rewrit

Microglial Involvement in Neuroplastic Changes Following Focal Brain Ischemia in Rats

The pathogenesis of ischemic stroke is a complex sequence of events including inflammatory reaction, for which the microglia appears to be a major cellular contributor. However, whether post-ischemic activation of microglial cells has beneficial or detrimental effects remains to be elucidated, in particular on long term brain plasticity events. The objective of our study was to determine, through modulation of post-stroke inflammatory response, to what extent microglial cells are involved in some specific events of neuronal plasticity, neurite outgrowth and synaptogenesis. Since microglia is a source of neurotrophic factors, the identification of the brain-derived neurophic factor (BDNF) as possible molecular actor involved in these events was also attempted. As a means of down-regulating the microglial response induced by ischemia, 3-aminobenzamide (3-AB, 90 mg/kg, i.p.) was used to inhibit the poly(ADP-ribose) polymerase-1 (PARP-1). Indeed, PARP-1 contributes to the activation of the transcription factor NF-kB, which is essential to the upregulation of proinflammatory genes, in particular responsible for microglial activation/proliferation. Experiments were conducted in rats subjected to photothrombotic ischemia which leads to a strong and early microglial cells activation/proliferation followed by an infiltration of macrophages within the cortical lesion, events evaluated at serial time points up to 1 month post-ictus by immunostaining for OX-42 and ED-1. Our most striking finding was that the decrease in acute microglial activation induced by 3-AB was associated with a long term down-regulation of two neuronal plasticity proteins expression, synaptophysin (marker of synaptogenesis) and GAP-43 (marker of neuritogenesis) as well as to a significant decrease in tissue BDNF production. Thus, our data argue in favour of a supportive role for microglia in brain neuroplasticity stimulation possibly through BDNF production, suggesting that a targeted protection of microglial cells could represent an innovative approach to potentiate post-stroke neuroregeneration

Cytoprotective Efficacy and Mechanisms of the Liposoluble Iron Chelator 2,2Ј-Dipyridyl in the Rat Photothrombotic Ischemic Stroke Model

ABSTRACT We examined the efficacy of the liposoluble iron chelator 2,2Ј-dipyridyl (DP) in reducing histological damage in rats submitted to cerebral ischemia and the mechanisms involved in the potential cytoprotection. For this purpose, DP (20 mg/kg, i.p.) was administered 15 min before and 1 h after induction of cortical photothrombotic vascular occlusion in rat. Histological studies were performed to assess infarct volume (at days 1 and 3 postischemia) and astromicroglial activation (at day 3 postischemia). Damage to endothelial and neuronal cells was evaluated at day 1 postischemia by quantitative measurements of Evans Blue extravasation and N-acetylaspartate levels, respectively. Cerebral blood flow was recorded in the ischemic core by laser-Doppler flowmetry within the 15 min to 2 h period after photothrombosis. At 4-h postischemia, radical oxygen species (ROS) production was evaluated by measuring brain glutathione concentrations. The cortical expression of the proteins heme oxygenase-1 (HO-1) and hypoxia-inducible factor-1␣ (HIF-1␣) was analyzed by Western blotting at day 1 postischemia. Infarct volume and ischemic damage to endothelial and neuronal cells were significantly reduced by DP treatment. This cytoprotection was associated with a reduction in ROS production, perfusion deficits, and astrocytic activation. DP treatment also resulted in significant changes in HO-1 (ϩ100%) and HIF-1␣ (Ϫ50%) protein expression at the level of the ischemic core. These results report the efficacy of the liposoluble iron chelator DP in reducing histological damage induced by permanent focal ischemia

A PKC-Dependent Recruitment of MMP-2 Controls Semaphorin-3A Growth-Promoting Effect in Cortical Dendrites

There is increasing evidence for a crucial role of proteases and metalloproteinases during axon growth and guidance. In this context, we recently described a functional link between the chemoattractive Sema3C and Matrix metalloproteinase 3 (MMP3). Here, we provide data demonstrating the involvement of MMP-2 to trigger the growth-promoting effect of Sema3A in cortical dendrites. The in situ analysis of MMP-2 expression and activity is consistent with a functional growth assay demonstrating in vitro that the pharmacological inhibition of MMP-2 reduces the growth of cortical dendrites in response to Sema3A. Hence, our results suggest that the selective recruitment and activation of MMP-2 in response to Sema3A requires a PKC alpha dependent mechanism. Altogether, we provide a second set of data supporting MMPs as effectors of the growth-promoting effects of semaphorins, and we identify the potential signalling pathway involved

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Comparison of nonlinear mixed effects models and non-compartmental approaches in detecting pharmacogenetic covariates: Approaches to detect pharmacogenetic covariates

International audienceGenetic data is now collected in many clinical trials, especially in population pharmacokinetic studies. There is no consensus on methods to test the association between pharmacokinetics and genetic covariates. We performed a simulation study inspired by real clinical trials, using the PK of a compound under development having a nonlinear bioavailability along with genotypes for 176 Single Nucleotide Polymorphisms (SNPs). Scenarios included 78 subjects extensively sampled (16 observations per subject) to simulate a phase I study, or 384 subjects with the same rich design. Under the alternative hypothesis (H 1), 6 SNPs were drawn randomly to affect the log-clearance under an additive linear model. For each scenario 200 PK data sets were simulated under the null hypothesis (no gene effect) and H1. We compared 16 combinations of four association tests, a stepwise procedure and three penalised regressions (ridge regression, Lasso, HyperLasso), applied to four pharmacokinetic phenotypes, two observed concentrations, area under the curve estimated by noncompartmental analysis and model-based clearance. The different combinations were compared in terms of true and false positives and probability to detect the genetic effects. In presence of nonlinearity and/or variability in bioavailability, model-based phenotype allowed a higher probability to detect the SNPs than other phenotypes. In a realistic setting with a limited number of subjects, all methods showed a low ability to detect genetic effects. Ridge regression had the best probability to detect SNPs, but also a higher number of false positives. No association test showed a much higher power than the others

A discrete element thermo-mechanical modelling of diffuse damage induced by thermal expansion mismatch of two-phase materials

International audienceAt the macroscopic scale, brittle media such as rocks, concretes or ceramics can be seen as homogeneous continua. However, at the microscopic scale, these materials involve sophisticated microstructures that mix several phases. Generally, these microstructures are composed of a large amount of inclusions embedded in a brittle matrix that ensures the cohesion of the material. These materials generally exhibit complex mechanical behaviors resulting from the interactions between the different phases of the microstructure. As a result, the macroscopic behavior of these media may be predicted considering an accurate knowledge of their microstructures. This paper proposes a model to study the impact of diffuse damage resulting from thermal expansion mismatch between the mixed phases. This type of damage (which is not catastrophic for the integrity of two-phase materials) may appear when heterogeneous materials are subjected to thermal cycles. This phenomenon involves a high amount of discontinuities and can not be tackled easily with the Finite Element Method (FEM). The Discrete Element Method (DEM) naturally accounts for discontinuities and is therefore a good alternative to the continuum approaches. However, the difficulty with DEM is to perform quantitative simulations because the mechanical quantities are not described in terms of the classical continuum theory. This study describes the approach used here to tackle this fundamental difficulty. The results given by the * Corresponding author proposed approach are finally compared to experimental observations