Normalization in MALDI-TOF imaging datasets of proteins: practical considerations

Normalization is critically important for the proper interpretation of matrix-assisted laser desorption/ionization (MALDI) imaging datasets. The effects of the commonly used normalization techniques based on total ion count (TIC) or vector norm normalization are significant, and they are frequently beneficial. In certain cases, however, these normalization algorithms may produce misleading results and possibly lead to wrong conclusions, e.g. regarding to potential biomarker distributions. This is typical for tissues in which signals of prominent abundance are present in confined areas, such as insulin in the pancreas or β-amyloid peptides in the brain. In this work, we investigated whether normalization can be improved if dominant signals are excluded from the calculation. Because manual interaction with the data (e.g., defining the abundant signals) is not desired for routine analysis, we investigated two alternatives: normalization on the spectra noise level or on the median of signal intensities in the spectrum. Normalization on the median and the noise level was found to be significantly more robust against artifact generation compared to normalization on the TIC. Therefore, we propose to include these normalization methods in the standard “toolbox” of MALDI imaging for reliable results under conditions of automation

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Narrow resonances in the continuum of the unbound nucleus 15^{15}F

The structure of the unbound $^{15}$F nucleus is investigated using the inverse kinematics resonant scattering of a radioactive $^{14}$O beam impinging on a CH$_2$ target. The analysis of $^{1}$H($^{14}$O,p)$^{14}$O and $^{1}$H($^{14}$O,2p)$^{13}$N reactions allowed the confirmation of the previously observed narrow $1/2^{-}$ resonance, near the two-proton decay threshold, and the identification of two new narrow 5/2$^{-}$ and 3/2$^{-}$ resonances. The newly observed levels decay by 1p emission to the ground of $^{14}$O, and by sequential 2p emission to the ground state (g.s.) of $^{13}$N via the $1^-$ resonance of $^{14}$O. Gamow shell model (GSM) analysis of the experimental data suggests that the wave functions of the 5/2$^{-}$ and 3/2$^{-}$ resonances may be collectivized by the continuum coupling to nearby 2p- and 1p- decay channels. The observed excitation function $^{1}$H($^{14}$O,p)$^{14}$O and resonance spectrum in $^{15}$F are well reproduced in the unified framework of the GSM

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Two scale description of local mechanisms : application to reinforced concrete

Dans le contexte du développement durable, la fissuration des structures en béton armé est devenue un sujet d'étude central. Deux niveaux d'analyse de la durabilité d'un ouvrage apparaissent : l'échelle de la structure et l'échelle de la fissure. A l'échelle de la structure, les modèles à éléments finis basés sur la mécanique de l'endommagement peuvent être utilisés. Cependant, l'utilisation de ces modèles nécessite l'introduction d'une longueur caractéristique afin de prévenir la dépendance au maillage. Or l'introduction de cette longueur caractéristique empêche l'étude fine de la fissuration. A l'échelle de la fissure, la discontinuité peut être décrite de manière explicite à l'aide d'un modèle à éléments discrets. Grâce à ces modèles, les principaux mécanismes de dégradation du béton sont reproduits. Mais, l'étude d'ouvrages industriels en béton n'est pas possible à cause de la finesse de maillage nécessaire à l'étude de la fissuration. Dans ce travail, une méthode de couplage non-intrusive est proposée. A l'échelle globale, un modèle à éléments finis basé sur la mécanique de l'endommagement est utilisé. Les zones d'intérêt -- c'est-à-dire les zones de concentration d'endommagement -- sont analysées à l'échelle locale à l'aide d'un modèle à éléments discrets. Les résultats numériques obtenus à l'aide de la stratégie proposée sont comparés à des résultats expérimentaux afin de valider la méthode. Plusieurs cas tests sont étudiés afin de montrer les capacités de l'approche à modéliser la propagation des fissures pour une structure en béton sous chargement. Des problèmes spécifiques au béton comme l'effet d'échelle, l'impact des armatures ou l'effet 3D sont adressés.In the context of sustainable development, the study of cracking of large concrete structures has become of primary importance. Two levels of analysis appear: the structure scale and the crack scale. At the structural level, non-linear finite element analyses based on continuum damage mechanics can be carried out. Nevertheless, the use of such models requires the introduction of a characteristic length to prevent the occurrence of spurious mesh dependency in case of strain softening. This characteristic length tends to smooth the discontinuity and thus makes the study of the cracks harder. At the crack level, an explicit description of the crack can be achieved using discrete element methods. This way, the main failure mechanisms of quasi-brittle materials are recovered. But the mesh density required for such modeling is nevertheless prohibitive to treat a whole industrial structure. A non-intrusive technique is proposed, allowing the use of finite element models at a global scale and a decoupled local analysis of some interesting areas, i.e. around cracks, for which a discrete element model is used. Numerical results obtained from the proposed strategy are compared with experimental results and show the applicability of the approach. Several test cases are studied proving the capability of the approach to model the cracks propagation of loaded concrete structures. Specific concrete problems such as scale effect, 3D effect or rebars impact are addressed

Comportement à rupture des structures : description à deux échelles des mécanismes locaux appliquée aux matériaux fragiles renforcés

In the context of sustainable development, the study of cracking of large concrete structures has become of primary importance. Two levels of analysis appear: the structure scale and the crack scale. At the structural level, non-linear finite element analyses based on continuum damage mechanics can be carried out. Nevertheless, the use of such models requires the introduction of a characteristic length to prevent the occurrence of spurious mesh dependency in case of strain softening. This characteristic length tends to smooth the discontinuity and thus makes the study of the cracks harder. At the crack level, an explicit description of the crack can be achieved using discrete element methods. This way, the main failure mechanisms of quasi-brittle materials are recovered. But the mesh density required for such modeling is nevertheless prohibitive to treat a whole industrial structure. A non-intrusive technique is proposed, allowing the use of finite element models at a global scale and a decoupled local analysis of some interesting areas, i.e. around cracks, for which a discrete element model is used. Numerical results obtained from the proposed strategy are compared with experimental results and show the applicability of the approach. Several test cases are studied proving the capability of the approach to model the cracks propagation of loaded concrete structures. Specific concrete problems such as scale effect, 3D effect or rebars impact are addressed.Dans le contexte du développement durable, la fissuration des structures en béton armé est devenue un sujet d'étude central. Deux niveaux d'analyse de la durabilité d'un ouvrage apparaissent : l'échelle de la structure et l'échelle de la fissure. A l'échelle de la structure, les modèles à éléments finis basés sur la mécanique de l'endommagement peuvent être utilisés. Cependant, l'utilisation de ces modèles nécessite l'introduction d'une longueur caractéristique afin de prévenir la dépendance au maillage. Or l'introduction de cette longueur caractéristique empêche l'étude fine de la fissuration. A l'échelle de la fissure, la discontinuité peut être décrite de manière explicite à l'aide d'un modèle à éléments discrets. Grâce à ces modèles, les principaux mécanismes de dégradation du béton sont reproduits. Mais, l'étude d'ouvrages industriels en béton n'est pas possible à cause de la finesse de maillage nécessaire à l'étude de la fissuration. Dans ce travail, une méthode de couplage non-intrusive est proposée. A l'échelle globale, un modèle à éléments finis basé sur la mécanique de l'endommagement est utilisé. Les zones d'intérêt -- c'est-à-dire les zones de concentration d'endommagement -- sont analysées à l'échelle locale à l'aide d'un modèle à éléments discrets. Les résultats numériques obtenus à l'aide de la stratégie proposée sont comparés à des résultats expérimentaux afin de valider la méthode. Plusieurs cas tests sont étudiés afin de montrer les capacités de l'approche à modéliser la propagation des fissures pour une structure en béton sous chargement. Des problèmes spécifiques au béton comme l'effet d'échelle, l'impact des armatures ou l'effet 3D sont adressés

Beam-Particle modeling of discontinuous crack growth in concrete

International audienc

Modeling anisotropic damage using a reconstruction by rational covariants of the elasticity tensor obtained by Discrete Element tests

When submitted to mechanical loading, quasi-brittle materials such as concrete are degraded. This degradation leads to a decrease in stiffness and a loss of isotropy. In the literature, different anisotropic damage models account for those phenomena. However, anisotropic damage models usually require complex experimental identification procedures.This study aims at deriving a 2D anisotropic damage model from discrete beam-particle simulations. This work is the continuation of previous studies [1, 2].A virtual beam-particle [3] unit cell is loaded with multi-axial proportional and non-proportional loadings until failure. Those simulations explicitly represent micro-cracking and describe its impact on the effective elasticity tensor. During the loadings, there are two phases of failure: diffuse nucleation of micro-cracks, which then coalesce as macro-cracks. We construct a dataset of effective elasticity tensors using the measurements during each loading.The formulation of the anisotropic damage state model is done in two parts. We start by defining a damage variable and then model the effective elasticity tensor from this damage variable using the dataset. To achieve those objectives, we analyze the dataset under the light of two mathematical tools. The first is the (exact) distance to a symmetry class (here, to orthotropy). Using this tool, we show that most of the effective elasticity tensors in the dataset are indeed not isotropic. An anisotropic damage model is therefore required to represent the impact of micro-cracking on the elastic properties. We also show that most tensors are close to being orthotropic, so we next assume that the elasticity tensor is at most orthotropic. The second mathematical tool is the harmonic decomposition of an elasticity tensor coupled with a reconstruction by rational covariants. It decomposes any elasticity tensors into two invariants (shear and bulk modulus), a 2nd-order tensor covariant and a 4th-order tensor covariant. Both covariants are harmonic, i.e., traceless and totally symmetric. This decomposition enables us to introduce a damage variable to recover exactly the bulk modulus and the 2nd-order covariant from the damage variable and initial elastic properties. Then, we propose different models to express the shear modulus and the 4th-order harmonic tensor from damage. Thanks to the orthogonality property of harmonic decomposition terms, the models for each part are independent. This procedure enables us to obtain a satisfying state model requiring the introduction of only one parameter up to high levels of damage.The damage yield surface associated with the beam-particle is analyzed in the second step. We show that a Drucker-Prager criterion fits the discrete model yield surface. Finally, we propose an evolution model based on invariants of the damage variable.To summarize, we propose a 2D anisotropic state model that accurately represents the impact of micro-cracking on the effective elastic properties up to a high level of damage. We also propose a damage evolution model. A similar methodology could be applied in the 3D case in future studies. Another perspective is adding the effect of crack closure (with contact and friction). References [1] Delaplace, A., & Desmorat, R. (2008). Discrete 3D model as complimentary numerical testing for anisotropic damage. International Journal of Fracture, 148(2), 115–128. https://doi.org/10.1007/s10704-008-9183-9 [2] Oliver-Leblond, C., Desmorat, R., & Kolev, B. (2021). Continuous anisotropic damage as a twin modelling of discrete bi-dimensional fracture. European Journal of Mechanics - A/Solids, 89, 104285. https://doi.org/10.1016/j.euromechsol.2021.104285 [3] Vassaux, M., Richard, B., Ragueneau, F., Millard, A., & Delaplace, A. (2015). Lattice models applied to cyclic behavior description of quasi-brittle materials: Advantages of implicit integration. International Journal for Numerical and Analytical Methods in Geomechanics, 39(7), 775–798. https://doi.org/10.1002/nag.234

Anisotropic Damage Model Based on a Decomposition of the Elasticity Tensor in Terms of Covariants

Anisotropic damage models usually require complex experimental identification procedure. To avoid this issue, this study aims at deriving an anisotropic damage model from micromechanical simulations. In particular, we will focus on the determination of a relevant second order damage variable. In the first part, a particular-lattice model is used to generate a dataset of elasticity tensors. Such discrete models provide an explicit representation of cracking and its impact on the mechanical behavior. It is used to represent the behavior of a unit cell of a heterogeneous quasi-brittle material. The cell is submitted to a range of mechanical proportional and non-proportional loadings: tension, bi-tension, shear, ... During those loadings, two phases can be highlighted: diffuse micro-cracking appears first, then micro-cracks coalesce into a macro-crack. At each load step of each loading, the elasticity tensor is measured by means of periodic elastic loadings. Those measures provide the evolution of the elasticity tensor during a damaging loading. Then, the harmonic decomposition of 2D elasticity tensor is used to analyze those evolutions. It enables to describe the elasticity tensors by two invariants, one second order and one fourth order covariant tensors. Additionally, distances to isotropy and orthotropy are calculated. The analysis of the distance to isotropy shows that an anisotropic damage model is necessary. Moreover, the analysis of the distance to orthotropy shows that an orthotropic damage model is sufficient. In the second part, we seek to reconstruct the elasticity tensor of a cracked cell from the elasticity tensor of the undamaged cell and a second order tensor. The reconstruction is based on the harmonic decomposition and assumes that the elasticity tensor is orthotropic. The dilation tensor d=tr_12(E) is chosen as the second order variable. This choice leads to an exact reconstruction of the dilatation part. However, models are required to reconstruct isotropic and harmonic parts. Thanks to the orthogonality of the terms of the harmonic decomposition, reconstruction of both parts are independent. Different models, based on various assumptions, are proposed and compared. While building those models, we try to limit the number of parameters as much as possible. Then, the evolutions of elasticity tensors are reconstructed from the models and are compared to the exact measures. The results show that effective elasticity tensors can be satisfactorily reconstructed from a second order variable with few or no parameters. Finally, a damage variable is deduced from the second order tensor variable. In conclusion, a second order damage variable has been obtained from a micromechanical model. This variable enables to retrieve the elasticity tensor using a reconstruction formula based on the harmonic decomposition. A future study will aim at deriving an evolution law for the damage variable. It will lead to the complete formulation of an anisotropic damage model in the framework of thermodynamics of irreversible process. Moreover, the framework laid in this study will also be used to study the transition from diffuse micro-cracking to localized macro-crack