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Background Few data regarding post-induction management following first-line anti-epidermal growth factor receptor (EGFR)-based doublet regimens in patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC) are available. Methods This multicenter, retrospective study aimed at evaluating clinicians' attitude, and the safety and effectiveness of post-induction strategies in consecutive patients affected by left-sided RAS/BRAF wild-type mCRC treated with doublet chemotherapy plus anti-EGFR as first-line regimen, who did not experience disease progression within 6 months from induction initiation, at 21 Italian and 1 Spanish Institutions. The measured clinical outcomes were: progression-free survival (PFS), overall survival (OS), adverse events, and objective response rate (ORR). Results At the data cutoff, among 686 consecutive patients with left-sided RAS/BRAF wild-type mCRC treated with doublet plus anti-EGFR as first-line regimen from March 2012 to October 2020, 355 eligible patients have been included in the present analysis. Among these, 118 (33.2%), 66 (18.6%), and 11 (3.1%) received a maintenance with 5-fluorouracil/leucovorin (5FU/LV)+anti-EGFR, anti-EGFR, and 5FU/LV, respectively, while 160 (45.1%) patients continued induction treatment (non-maintenance) until disease progression, unacceptable toxicity, patient decision, or completion of planned treatment. The median period of follow-up for the overall population was 33.7 months (95%CI = 28.9-35.6). The median PFS values of the 5FU/LV+anti-EGFR, anti-EGFR, 5FU/LV, and non-maintenance cohorts were 16.0 (95%CI = 14.3-17.7, 86 events), 13.0 (95%CI = 11.4-14.5, 56 events), 14.0 (95%CI = 8.1-20.0, 8 events), and 10.1 months (95%CI = 9.0-11.2, 136 events), respectively (p < 0.001). The median OS values were 39.6 (95%CI = 31.5-47.7, 43 events), 36.1 (95%CI = 31.6-40.7, 36 events), 39.5 (95%CI = 28.2-50.8, 4 events), and 25.1 months (95%CI = 22.6-27.6, 99 events), respectively (p < 0.001). After adjusting for key covariates, a statistically significant improvement in PFS in favor of 5FU/LV+anti-EGFR (HR = 0.59, 95%CI = 0.44-0.77, p < 0.001) and anti-EGFR (HR = 0.71, 95%CI = 0.51-0.98, p = 0.039) compared to the non-maintenance cohort was found. Compared to the non-maintenance cohort, OS was improved by 5FU/LV+anti-EGFR (HR = 0.55, 95%CI = 0.38-0.81, p = 0.002) and, with marginal significance, by anti-EGFR (HR = 0.67, 95%CI = 0.51-0.98, p = 0.051). No difference was found in ORR. Any grade non-hematological and hematological events were generally higher in the non-maintenance compared to the maintenance cohorts. Conclusion Among the treatment strategies following an anti-EGFR-based doublet first-line induction regimen in patients affected by left-sided RAS/BRAF wild-type mCRC treated in a "real-life" setting, 5FU/LV+anti-EGFR resulted the most adopted, effective, and relatively safe regimen.

En el presente trabajo analizo una serie de notas y apuntes escritos por Juan José Saer durante uno de sus viajes de regreso a la Argentina, en los meses de septiembre y octubre de 1982. La composición de la libreta precede de inmediato el íncipit de Glosa, razón por la cual intento trazar posibles conexiones entre las anotaciones y la escritura de la novela. Parte del trabajo está dedicada a una revisión crítica de la reciente discusión acerca de la intimidad, sobre los géneros literarios a ella ligados, sobre la necesidad de considerar como “íntimos” los apuntes de Saer y sobre aquellos procedimientos que los distancian de las retóricas características de las escrituras íntimas.

Motivation The advancements of single-cell sequencing methods have paved the way for the characterization of cellular states at unprecedented resolution, revolutionizing the investigation on complex biological systems. Yet, single-cell sequencing experiments are hindered by several technical issues, which cause output data to be noisy, impacting the reliability of downstream analyses. Therefore, a growing number of data science methods has been proposed to recover lost or corrupted information from single-cell sequencing data. To date, however, no quantitative benchmarks have been proposed to evaluate such methods. Results We present a comprehensive analysis of the state-of-the-art computational approaches for denoising and imputation of single-cell transcriptomic data, comparing their performance in different experimental scenarios. In detail, we compared 19 denoising and imputation methods, on both simulated and real-world datasets, with respect to several performance metrics related to imputation of dropout events, recovery of true expression profiles, characterization of cell similarity, identification of differentially expressed genes and computation time. The effectiveness and scalability of all methods were assessed with regard to distinct sequencing protocols, sample size and different levels of biological variability and technical noise. As a result, we identify a subset of versatile approaches exhibiting solid performances on most tests and show that certain algorithmic families prove effective on specific tasks but inefficient on others. Finally, most methods appear to benefit from the introduction of appropriate assumptions on noise distribution of biological processes.

The interaction between the natural ambient winds found in the atmospheric boundary layer (ABL) and buoyant flames is crucial in broad applications in the scientific and engineering fields. Unlike the buoyancy-driven pool fires in still air that have been studied extensively, the complexity of physics changes significantly in wind presence. This study aims at analysing the characteristics of boundary-layer turbulence in the presence of large fires. The eddy dissipation concept, finite volume discrete ordinate method, and one k-equation model are used for combustion, thermal radiation, and sub-grid scale closure using the Large-Eddy Simulation (LES), respectively. A numerical model on simple cases is validated first to assess its capability to reproduce available experimental observations for a purely buoyant fire in still air. A forced-flow boundary layer combustion in a small chamber with a smooth inflow is further considered. In general, good agreement between the simulation results and available experimental data was achieved for temperature and velocity profiles. The unsteady inflow condition used to consider incoming atmospheric turbulence is generated through a precursor simulation. The wind interaction with the line fire changes the atmospheric boundary layer profile affecting the heat transfer ahead of the flame, thereby creating counter-rotating structures downstream. It is shown that the buoyancy-dominated flow due to the flame reaction induced local pressure variation and perturbed shear flow near the ground, thereby altering the wind speed through which the plume rises. Richardson number was also used as a dominant non-dimensional group to analyse the variation of enhanced flow vertical velocity with distance from the fire source. Thus, it is understood that the pronounced longitudinal shear spreading at the surface affects the behaviour of short term or puff releases, suggesting the shedding of small eddies during the combustion process.

The evaluation of the aerodynamic admittance is a fundamental step in the calculation of the buffeting response of flexible structures immersed in turbulent flows such as long-span bridges and slender towers. As it is well-known, bluff sections immersed in turbulent flows often exhibit a complex aerodynamic behavior, which can be greatly affected by the turbulence intensity and the integral length scales of the impinging turbulence. In this paper, computational fluid dynamics is used for the evaluation of the admittance functions of a 6:1 rectangular cylinder. Firstly, the incoming turbulence is synthetically generated. Then the aerodynamic admittance functions are evaluated considering five different inflow conditions using Large Eddy Simulations. The use of synthetic inflows allows to easily separate the role played by each characteristic of the inflow turbulence, so allowing to separately study the effect of the turbulence intensity and the length scales.

A geometrically nonlinear Generalized Beam Theory is formulated and the results in the framework of buckling analyses are discussed. The geometrically nonlinear model is recovered reusing the model available in the linear context. This generalization to the nonlinear context is obtained exploiting the corotational based method called Implicit Corotational Method, starting from a mixed energy description of the continuum in terms of nonlinear Biot stress/strain tensors and using convenient assumptions for the linear stress/strain tensors. Once obtained, the nonlinear model has been implemented using a flexibility based finite element. The results of buckling analyses for different and complex beam cross-section geometries, emphasizing distortional and local buckling behaviors, are presented and comparisons with finite element shell models made.

The flow field around the rectangular cylinder with aspect ratio 5:1 has been widely investigated in recent literature as a prototype of reattached flow around elongated bluff bodies like bridge decks and high rise buildings. Due to the technical importance of such flows, many research works have been proposed aiming at studying the accuracy of available simulation techniques in reproducing the flow organization. When Large Eddy Simulations (LES) are considered, to the authors’ knowledge, the proposed contributions focused on perfectly smooth inlet conditions which, indeed, represent more an exception than a rule in Computational Wind Engineering. In the present paper, LES are performed aiming at reproducing the modifications occurring in the flow when turbulent inflow conditions are adopted. In order to synthetically produce the unsteady inlet condition, a divergence-free and spatially correlated fluctuations field is generated by means of the Modified Discretizing and Synthesizing Random Flow Generator technique. The obtained synthetic fluctuations are imposed in the computational domain by modifying the velocity-pressure coupling algorithm in order to avoid nonphysical pressure fluctuations. Two configurations, corresponding to mild and strong incoming turbulence levels, are investigated highlighting the role played by the spanwise domain size. Results are compared to experimental data showing good agreement between experiments and numerical simulations.

In this paper, the flow around a rectangular cylinder with aspect ratio 5:1 is studied at three attack angles by means of both LES and URANS simulations. Despite its geometric simplicity, such a rectangular shape is characterized by many aerodynamic phenomena typical of reattached flows around bluff bodies and has been recently widely studied as a prototype of flows encountered around shapes of technical interest like, for example, bridge deck sections. The present study is aimed at providing insight in the modifications occurring in the flow at small incidence angles, by comparing the accuracy of the two aforementioned simulation strategies in reproducing them. Some recurring biases observed in URANS simulations are illustrated and their origin discussed. Results are presented in terms of flow bulk parameters and pressure distributions and systematic comparison with available experimental data is provided. Finally, the effects of small incidence angles on along span flow correlations are investigated and Covariance Proper Transformation is used in order to further characterize the flow dynamic behavior.

Crop rotation is a common practice aimed at enhancing both plant disease suppression and crop productivity under open field condition. The objective of the present study was to evaluate the effects of tomato-wheat rotation on Fusarium wilt suppression and shoot growth on tomato in comparison to tomato monoculture. The following factors were determined and integrated through a transdisciplinary approach: (i) soil chemical parameters; (ii) abundance, composition, richness and diversity of soil fungal and bacterial communities; (iii) soil biochemical and enzymatic indicators; (iv) abundance of Fusarium oxysporum isolates in rhizosphere under tomato cultivation and evaluation of the pathogenicity of the isolates; (v) suppressive response of the bulk soil samples against a selected pathogenic strain of Fusarium oxysporum f. sp. lycopersici on tomato; and (vi) tomato shoot growth. The integrated approach included soil amplicon sequencing by metabarcoding analyses carried out by Illumina MiSeq platform in association with the standard procedure for soil analyses. In addition, the pathogenicity of F. oxysporum from the tomato rhizosphere and the suppressive response of the soil bulk to Fusarium wilt were performed by bioassays under greenhouse condition. The results showed that, if durum wheat was rotated with cherry tomato for at least four consecutive years, it had the following beneficial effects: (i) increased suppressive response of the bulk soil samples against F. oxysporum f. sp. lycopersici, (ii) decreased abundance of the F. oxysporum isolates in tomato rhizosphere, (iii) decreased pathogenicity of the F. oxysporum isolates, and (iv) increased tomato shoot growth. The increased abundance of certain microbial groups belonging to potential biocontrol agents against fusaria-related wilt including Bacillales (Bacillus and Paenibacillus), Pseudomonadales (Pseudomonas), Streptomycetales (Streptomyces), Eurotiales (Aspergillus and Penicillium) and Mortierellales (Mortierella), as well as the highest tomato shoot growth, coincided with the end of the second wheat rotation cycle. There were significant Spearman cross-correlations and two-way ANOVA interactions among the microbiome variables with the (i) soil chemical parameters, (ii) abundance and pathogenicity of the F. oxysporum isolates in tomato rhizosphere, (iii) soil suppression to Fusarium wilt, and (iv) tomato shoot growth. The results indicate that a soil managed under tomato-wheat rotation displays increased suppressive response against Fusarium wilt and improved shoot growth in tomato plants by changing the microbial composition and chemical parameters of the soil.

We perform Computational Fluid Dynamics (CFD) analyses of a low-rise building immersed in a turbulent boundary layer. The Silsoe 6 m cube is chosen as the main case study aiming at representing the key features of the typical wind conditions experienced by low-rise buildings. The turbulent inflow condition is generated by employing a precursor technique. A sensitivity study is conducted to investigate the effects of eight subgrid-scale (SGS) models on the flow around the cube. The incoming turbulence intensity and mesh sizing for each of the SGS models are also explored. The results in terms of time-averaged pressure fields for relatively well-resolved simulations are well compliant with available experimental data and insensitive to the selection of the SGS model. We demonstrate that, while the effect of the aforementioned factors has a limited impact on the first-order statistics of the pressure coefficients, their influence becomes much more pronounced when analysing higher-order statistics (i.e. variance, skewness and kurtosis) and extreme values. The extent of their relative importance depends on the location of the point under investigation and the quantity of interest. The current study provides guidelines on the choice of factors which can strongly affect the results obtained employing CFD simulations when the local peak pressures are of interest, for example, as in the case of cladding design.

The application of unsteady inflow conditions represents an important aspect when scale resolving turbulence models are adopted in Computational Fluid Dynamics (CFD) analyses. In such context, with reference to Wind Engineering applications, the main concern is often represented by the generation of a synthetic velocity field representative of the turbulent fluctuations impinging on the studied body. Once such synthetic field has been generated, it is applied at the inflow patch. Unfortunately, such operation is not trivial: undesired pressure fluctuations are often generated due to the incompatibility between the applied inflow condition and the flow field found inside the computational domain. In this paper, a procedure able to guarantee a correct application of synthetically generated velocity fields to CFD simulations is described. The procedure, which relies on a variational background, is simple and can be readily implemented in existing codes. Numerical results confirm that, by adopting the proposed corrections, pressure fluctuations are strongly reduced, so confirming the soundness of the proposed approach. An OpenFoam implementation of the method is available for download at https://site.unibo.it/cwe-lamc/en .

In this article, the accuracy of standard computational fluid dynamics techniques and turbulence models in predicting the critical flutter speed of streamlined and bluff deck sections is investigated. It is well known that such numerical tools can provide inaccurate prediction of the flow field around bluff bodies which reflects in biases in their aeroelastic behavior. Aiming at systematically study the effects of such inaccuracies, in this article, six deck sections are analyzed by numerically extracting flutter derivatives and calculating the critical flutter speed for a set of representative test structures. It is shown that the flutter onset velocity is mainly underestimated but cases showing opposite behavior are identified and discussed. Two simulation strategies are adopted: the differences in the flutter mechanism between such two approaches are taken as an indicator of possible strong inaccuracies.

The numerical approximation of 2D elasticity problems is considered, in the framework of the small strain theory and in connection with the mixed Hellinger–Reissner variational formulation. A low-order Virtual Element Method (VEM) with a priori symmetric stresses is proposed. Several numerical tests are provided, along with a rigorous stability and convergence analysis.

The need for studying tailored composts, as new feedstocks become available with time, increases the in-depth studies of suppressive composts derived from green sources and agro-wastes recycling. The composition, diversity and variability of microbiomes within a collection of 10 composts were investigated by amplicon sequencing and bioinformatics analyses. The observed differences in microbiome structure were related to the different compost origin. The multi-suppressive properties of composts from agricultural residues, agro-industrial co/by-products, and plant green-waste showed the most complex microbiome structure, which included either biocontrol agents associated with the control of Rhizoctonia damping-off in bean and Verticillium wilt in eggplant or microbial consortia for controlling Pythium damping-off in cucumber and zucchini and Phytophthora root rot in tomato and azalea. In contrast, the pathogen-specific property of composts from municipal solid waste and co-composted cow manure household waste showed a microbiome that overall included biocontrol agents against Fusarium wilt in tomato, melon and basil. The highest correlations between physicochemical properties, disease suppression, and the microbiome have allowed to make a helpful matrix to know how relationships among these variables of composts could be established and quantified for predicting their suppressive properties basing on the physicochemical properties and the microbiome.