Sensitivity analysis of a branching process evolving on a network with application in epidemiology

We perform an analytical sensitivity analysis for a model of a continuous-time branching process evolving on a fixed network. This allows us to determine the relative importance of the model parameters to the growth of the population on the network. We then apply our results to the early stages of an influenza-like epidemic spreading among a set of cities connected by air routes in the United States. We also consider vaccination and analyze the sensitivity of the total size of the epidemic with respect to the fraction of vaccinated people. Our analysis shows that the epidemic growth is more sensitive with respect to transmission rates within cities than travel rates between cities. More generally, we highlight the fact that branching processes offer a powerful stochastic modeling tool with analytical formulas for sensitivity which are easy to use in practice.Comment: 17 pages (30 with SI), Journal of Complex Networks, Feb 201

Expression of Mutated Poliovirus Receptors in Human Neuroblastoma Cells Persistently Infected with Poliovirus

AbstractPoliovirus (PV) is able to establish persistent infections in human neuroblastoma IMR-32 cells [Colbère-Garapin et al. (1989) Proc. Natl. Acad. Sci. USA 86, 7590]. During persistent infection, PV mutants are selected that display substitutions of residues in regions of the capsid known to interact with the PV receptor (PVR), a glycoprotein of the immunoglobulin superfamily. The mechanism of persistent infection in IMR-32 cells may therefore involve the selection of mutant PVRs. To test this hypothesis, the sequences of the PVR mRNAs in uninfected IMR-32 cells and in two independent IMR-32 cell cultures persistently infected with the Mahoney strain of PV type 1 (PV1/Mahoney) were determined. The PVR mRNA population of uninfected cells was homogeneous, and no mutation was repeatedly found, whereas that of persistently infected cells displayed missense mutations. Particular mutations were repeatedly detected, and all of them mapped to the N-terminal domain of PVR (domain 1), which interacts directly with PV. These mutations generated several types of PVR variants with the following substitutions: Ala67→Thr alone, Ala67→Thr associated with Gly39→Ser, and Arg104→Gln. Functional analysis of PVR in murine LM cells, stably expressing each of the PVR forms, showed that the PVR forms selected during persistent infection conferred on LM cells partial resistance to PV1/Mahoney-induced lysis. Although adsorption onto PVR seemed to be independent of the PVR form, an analysis of the conformational changes of the capsid during the early steps of the PV cycle provided evidence that the Ser39/Thr67 and Gln104 substitutions almost halved the conversion of 160S infectious particles into 135S A particles associated with the PV–PVR interaction. Altogether, these findings indicate that during persistent infection, specific mutations were selected in the domain 1 of PVR and that these mutations increased the resistance of cells to PV-induced lysis. These results are discussed in view of the position of the mutations on PVR

Impact of grain boundary and surface diffusion on predicted fission gas bubble behavior and release in UO2_2 fuel

In this work, we quantify the impact of grain boundary (GB) and surface diffusion on fission gas bubble evolution and fission gas release in UO$_2$ nuclear fuel using simulations with a hybrid phase field/cluster dynamics model. We begin with a comprehensive literature review of uranium vacancy and xenon atom diffusivity in UO$_2$ through the bulk, along GBs, and along surfaces. In our model we represent fast GB and surface diffusion using a heterogeneous diffusivity that is a function of the order parameters that represent bubbles and grains. We find that the GB diffusivity directly impacts the rate of gas release via GB transport, and that the GB diffusivity is likely below 10$^4$ times the lower value from Olander and van Uffelen (2001). We also find that the surface diffusivity impacts bubble coalescence and mobility, and that the bubble surface diffusivity is likely below $10^{-4}$ times the value from Zhou and Olander (1984).Comment: 34 pages, 11 figures, submitted at Journal of Nuclear Materials (Under Review

Identification of effective elastic modulus using modal analysis : application to canine cancellous bone

Mechanical properties of cancellous bone play a role in osteoporosis and fracture induction, bone tumor microenvironment, fracture healing and implant fixation. Most characterization methods used to identify cancellous bone Young modulus are compressive tests, which are known to comprise significant limitations especially when they are performed on small size specimens. We hypothesized that modal analysis of straight beams could be proposed as an alternative methodology to obtain effective elastic properties. Theoretical key-points were provided to determine the elastic modulus from natural frequencies and mode shapes. In a first step, the methodology was validated using a synthetic bone model as control. Then, water-jet cutting allowed collecting fourteen regular beam-like specimens in specific zones of canine distal femurs. X-ray microtomography confirmed the preservation of tissue microarchitecture and homogeneity. The first natural frequency in clamped-free boundary conditions was used to obtain mean values of Young modulus, which ranged from 210 MPa to 280 MPa depending on the specimen’s collection site. This was in good agreement with literature data obtained with uniaxial compressive tests. Experimental tests were rapid and reproducible, non-destructive and did not depend on scale factor. Therefore, beam modal analysis can be a compelling methodology for exploring mechanical properties of fragile and scarce biological tissues

Perinatal health monitoring through a European lens: eight lessons from the Euro-Peristat report on 2015 births

International audienceNo abstract availabl

BMJ Med

OBJECTIVE: To evaluate the efficacy of covid-19 convalescent plasma to treat patients admitted to hospital for moderate covid-19 disease with or without underlying immunodeficiency (CORIPLASM trial). DESIGN: Open label, randomised clinical trial. SETTING: CORIMUNO-19 cohort (publicly supported platform of open label, randomised controlled trials of immune modulatory drugs in patients admitted to hospital with moderate or severe covid-19 disease) based on 19 university and general hospitals across France, from 16 April 2020 to 21 April 2021. PARTICIPANTS: 120 adults (n=60 in the covid-19 convalescent plasma group, n=60 in the usual care group) admitted to hospital with a positive SARS-CoV2 test result, duration of symptoms 40. MAIN OUTCOME MEASURES: Primary outcomes were proportion of patients with a WHO Clinical Progression Scale score of ≥6 on the 10 point scale on day 4 (higher values indicate a worse outcome), and survival without assisted ventilation or additional immunomodulatory treatment by day 14. Secondary outcomes were changes in WHO Clinical Progression Scale scores, overall survival, time to discharge, and time to end of dependence on oxygen supply. Predefined subgroups analyses included immunosuppression status, duration of symptoms before randomisation, and use of steroids. RESULTS: 120 patients were recruited and assigned to covid-19 convalescent plasma (n=60) or usual care (n=60), including 22 (covid-19 convalescent plasma) and 27 (usual care) patients who were immunocompromised. 13 (22%) patients who received convalescent plasma had a WHO Clinical Progression Scale score of ≥6 at day 4 versus eight (13%) patients who received usual care (adjusted odds ratio 1.88, 95% credible interval 0.71 to 5.24). By day 14, 19 (31.6%) patients in the convalescent plasma group and 20 (33.3%) patients in the usual care group needed ventilation, additional immunomodulatory treatment, or had died. For cumulative incidence of death, three (5%) patients in the convalescent plasma group and eight (13%) in the usual care group died by day 14 (adjusted hazard ratio 0.40, 95% confidence interval 0.10 to 1.53), and seven (12%) patients in the convalescent plasma group and 12 (20%) in the usual care group by day 28 (adjusted hazard ratio 0.51, 0.20 to 1.32). In a subgroup analysis performed in patients who were immunocompromised, transfusion of covid-19 convalescent plasma was associated with mortality (hazard ratio 0.39, 95% confidence interval 0.14 to 1.10). CONCLUSIONS: In this study, covid-19 convalescent plasma did not improve early outcomes in patients with moderate covid-19 disease. The efficacy of convalescent plasma in patients who are immunocompromised should be investigated further. TRIAL REGISTRATION: ClinicalTrials.gov NCT04345991

Socioeconomic inequalities in stillbirth rates in Europe: measuring the gap using routine data from the Euro-Peristat Project

Background Previous studies have shown that socioeconomic position is inversely associated with stillbirth risk, but the impact on national rates in Europe is not known. We aimed to assess the magnitude of social inequalities in stillbirth rates in European countries using indicators generated from routine monitoring systems. Methods Aggregated data on the number of stillbirths and live births for the year 2010 were collected for three socioeconomic indicators (mothers’ educational level, mothers’ and fathers’ occupational group) from 29 European countries participating in the Euro-Peristat project. Educational categories were coded using the International Standard Classification of Education (ISCED) and analysed as: primary/lower secondary, upper secondary and postsecondary. Parents’ occupations were grouped using International Standard Classification of Occupations (ISCO-08) major groups and then coded into 4 categories: No occupation or student, Skilled/ unskilled workers, Technicians/clerical/service occupations and Managers/professionals. We calculated risk ratios (RR) for stillbirth by each occupational group as well as the percentage population attributable risks using the most advantaged category as the reference (post-secondary education and professional/managerial occupations). Results Data on stillbirth rates by mothers’ education were available in 19 countries and by mothers’ and fathers’ occupations in 13 countries. In countries with these data, the median RR of stillbirth for women with primary and lower secondary education compared to women with postsecondary education was 1.9 (interquartile range (IQR): 1.5 to 2.4) and 1.4 (IQR: 1.2 to 1.6), respectively. For mothers’ occupations, the median RR comparing outcomes among manual workers with managers and professionals was 1.6 (IQR: 1.0–2.1) whereas for fathers’ occupations, the median RR was 1.4 (IQR: 1.2–1.8). When applied to the entire set of countries with data about mothers’ education, 1606 out of 6337 stillbirths (25 %) would not have occurred if stillbirth rates for all women were the same as for women with post-secondary education in their country. Conclusions Data on stillbirths and socioeconomic status from routine systems showed widespread and consistent socioeconomic inequalities in stillbirth rates in Europe. Further research is needed to better understand differences between countries in the magnitude of the socioeconomic gradient

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

Optimisation du blindage contre les neutrons pour le démonstrateur de SuperNEMO et analyse de la double désintégration β du néodyme-150 vers les états excités du samarium-150 avec le détecteur NEMO 3

The NEMO detector series is designed to search for the neutrinoless double β decay, which would prove that the neutrino is a Majorana particle (i.e. identical to its own antiparticle) and has a nonzero mass. After an introduction to neutrino physics and a description of both the NEMO 3 and SuperNEMO detectors, this thesis is articulated in two independent parts.The first provides an investigation of the neutron background in order to optimize the shielding for the first SuperNEMO module. The outcome of the study recommends the addition of borated polyethylene to the NEMO 3 shielding (on both sides of the iron shielding) to obtain a negligible background, coming from neutrons in the energy window of the two-electron channel where the neutrinoless double β decay of selenium-82 is expected, for the duration of five years for which data will be taken with this first module. In the second part, the neodymium foil located in the NEMO 3 detector is deeply analyzed to obtain an indication of the standard double β decay of neodymium-150 to the 0+1 excited state of samarium-150. The measured half-life, with a significance of 3.7σ, is: T1/2 (150 Nd 0+ →0+1 ) = [7.12 ± 1.28 (stat.) ± 0.91 (syst.)] × 10E19 yearsLa série de détecteurs NEMO est conçue pour la recherche de la double désintégration β sans émission de neutrino qui prouverait que le neutrino est une particule de Majorana (i.e. identique à son antiparticule) et massif. Après avoir présenté l’état des lieux en physique des neutrinos et les détecteurs NEMO 3 et SuperNEMO, cette thèse s’articule en deux parties indépendantes. La première concerne l’étude du bruit de fond provenant des neutrons pour optimiser le blindage destiné au premier module de SuperNEMO. La conclusion de cette étude montre que l’ajout de plaques de polyéthylène boré par rapport au blindage de NEMO 3 (de part et d’autre du blindage en fer) permet d’obtenir un bruit de fond négligeable provenant des neutrons, dans la fenêtre en énergie du canal deux électrons où la double désintégration β sans émission de neutrino du sélénium-82 est attendue, en cinq ans de prise de données de ce premier module. La seconde partie, via l’analyse des données du détecteur NEMO 3, permet une indication de la désintégration double β standard du néodyme-150 vers l’état excité 0+1 du samarium-150. La feuille de néodyme qui est placée dans le détecteur est analysée en détail pour obtenir cette indication à 3, 7σ avec une demi-vie mesurée de : T1/2 (150 Nd0+ →0+1 ) = [7, 12 ± 1, 28 (stat.) ± 0, 91 (syst.)] × 10E19 an

In vitro pharmacological model of Hutchinson-Gilford progeria syndrome using patient-specific induced pluripotent stem cells

La progéria est une maladie génétique rare caractérisée par un vieillissement global, prématuré et accéléré entrainant le décès des enfants atteints aux alentours de l’âge de 13 ans. La compréhension des mécanismes moléculaires à l’origine de ce syndrome ont récemment permis de démarrer deux protocoles d’essai clinique, avec un objectif commun : ralentir la progression de la maladie en bloquant la maturation de la protéine mutée. Cependant, l’identification de nouvelles voies thérapeutiques reste encore, pour cette pathologie, un défi à relever. L’objectif de ce travail de thèse a consisté à utiliser le potentiel unique des cellules souches induites à la pluripotence (iPSCs) pour explorer les mécanismes cellulaires et moléculaires de ce syndrome, identifier de nouvelles cibles thérapeutiques et proposer des pistes innovantes de traitement.La première étape de cette thèse s’est consacrée à la dérivation et la caractérisation des lignées d’iPSCs à partir de cellules de patients atteints par ce syndrome. De manière surprenante,cette étude a mis en évidence une préservation des neurones générés à partir d’iPSCs de patients progeria. L’étude des mécanismes moléculaires à l’origine de cette protection neuronale a par la suite permis d’identifier l’implication d’un microARN, miR-9, capable de réguler l’expression de la progérine et de protéger les neurones de ce vieillissement accéléré. La seconde partie de ces travaux de thèse s’est attachée à explorer le potentiel de ces cellules pour étudier l’efficacité des composés proposés aux patients dans le cadre des différents essais cliniques réalisés ces dernières années. Bien que l’ensemble des molécules testées améliore de façon significative les défauts de structuration de l’enveloppe nucléaire, nos travaux soulignent un certain nombre de différences fonctionnelles tant au niveau de leurs effets sur la prolifération cellulaire que sur la différentiation ostéogénique ou encore le métabolisme énergétique. Enfin, sur la base de ce travail de modélisation pathologique, la dernière partie de ce projet de thèse a eu pour objectif de développer et réaliser un criblage à haut contenu de plus de vingt mille petites molécules pouvant réguler le processus de maturation de la prélamine A. Au cours de cette étude, onze composés à fort potentiel thérapeutique ont été identifiés, dont trois appartenant à la même famille chimique, les mono-aminopyrimidines, ouvrant de nouvelles perspectives thérapeutiques dans la progéria.Progeria is a rare genetic disease characterized by a global, premature and accelerated aging, leading to patient death at average 13 years old. The understanding of the molecular mechanism of this syndrome has recently opened the possibility to start two clinical trials, with one common objective: slow down the disease progression blocking the maturation of the mutated protein. However, the identification of new therapeutic pathway is still a challenge to rise for this pathology. The objective of this PhD thesis has consisted to use the unique potential of induced pluripotent stem cells (iPSCs) to explore cellular and molecular mechanisms of this syndrome, identify new therapautical target and propose innovative trails of treatment. The first step of this thesis was focused on the derivation and the characterization of the iPSCs lines from patient's cells affected by this syndrome. In a surprising manner, this study has highlighted a preservation of neurons generated from progeria patients. The study of the molecular mechanisms led to the identification of the microRNA miR-9 involvement. This latter regulates progerin expression, protecting neurons from accelerated aging. The second part of this work has endeavored to explore the potential of progeria iPSCs to study the efficiency of chemical compounds proposed to patients in the different clinical trials realized these last years. Although the set of tested molecules significantly improved nuclear architecture, differences in proliferation or in osteogenic differentiation or in metabolic energetic have been detected. Finally, on the basis of this pathological modeling work, the last part of this thesis praject was to develop and realize a high content screening of more than twenty thousand small molecules to select drugs which block the maturation process of prelamin A. Eleven molecules with a high therapeutical potential have been identified, with three belonging to the same chemical family, the mono-aminopyrimidins, opening new therapeutical perspectives in progeria