Luigi Martinelli

There is limited real-world evidence on the use and positioning of inhaled long-acting muscarinic antagonists (LAMAs) for treating severe asthma. We aimed to assess the differences in clinicians’ perspectives on prescribing LAMA for severe asthma across Europe. Within the Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) network, we conducted a multi-country survey of 470 respiratory clinicians in 2023-24. Most participants were pneumonologists (83%). 68% reported using specific criteria for prescribing LAMA for severe asthma, primarily fixed bronchial obstruction (68%), frequent asthma exacerbations (65%), and a history of smoking (53%). Improved quality of life, lung function improvement, and reduction of asthma exacerbations were the three expected outcomes of LAMA treatment that showed the largest agreement across clinicians (85–95%). As compared to non-severe asthma specialists (about 50% of the sample), severe asthma specialists were more likely to report always prescribing LAMA before biologics (54 vs. 41%) and before oral corticosteroids (OCS) (51 vs. 40%). Approximately 90% of participants prioritised tapering or discontinuing OCS before stopping LAMA. Overall, participants in Northern (n = 73) and Western Europe (n = 71) appeared less prone to prescribe LAMA and less confident in their benefits compared to those from Eastern (n = 88) and Southern Europe (n = 238). In particular, most participants from Latvia (91%) and Lithuania (67%) reported that LAMAs are not reimbursed for severe asthma in their countries. Most participants who expressed their opinion favoured triple therapy (n = 236) over single inhaler therapy (n = 91). Our findings show that barriers and heterogeneous approaches still limit LAMA prescription for severe asthma in Europe, potentially leading to the underuse of this treatment option. Establishing a clear role for LAMA within a precision medicine framework is crucial; this aspect is not yet firmly supported by current international recommendations. Long-acting muscarinic antagonists (LAMA) are approved for treating severe asthma, but the best responder profile is unclear. Our survey documents heterogeneous perspectives and barriers to LAMA use across Europe, examining the background of different prescription behaviours. The findings highlight the need for international recommendations to specify which patient profiles are most likely to benefit from LAMA treatment and to clarify LAMA positioning within the step-up and step-down approach to asthma management.

<bold>Background:</bold> Tiotropium is a long-acting muscarinic antagonist (LAMA) approved for severe asthma (SA). <bold>Aims:</bold> We aimed at describing clinicians’ views on LAMA prescription for severe asthma patients. <bold>Methods:</bold> Within the Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) network, we surveyed 470 respiratory clinicians in 2023-24. <bold>Results:</bold> Most participants were pneumologists (83%), and half of them self-qualified as SA specialists. In general, the clinicians in Northern (n=73) and Western Europe (n=71) were less confident in the benefits of LAMA treatment compared to those from Eastern (n=88) and Southern Europe (n=238). Many clinicians from Latvia (91%) and Lithuania (67%) reported that LAMA are not reimbursed for SA in their countries. Most clinicians (71%) report using specific criteria for prescribing LAMA, primarily fixed bronchial obstruction (67%), frequent asthma exacerbations (65%), and a history of smoking (54%). Improved quality of life, lung function improvement, and reduction of asthma exacerbations were the three expected outcomes of LAMA treatment showing the largest agreement (85-95%). As compared to non-SA specialists, SA specialists were more likely to report always prescribing LAMA before biologics (54 vs 41%) and before oral corticosteroids (OCS) (51 vs 40%). Approximately 90% of clinicians prioritized tapering or discontinuing OCS before stopping LAMA. <bold>Conclusions:</bold> The results highlight the heterogeneity in LAMA use across Europe. They may help consolidate LAMA positioning within a precision medicine approach – an aspect not yet firmly supported by current international guidelines and recommendations.

We explore the dynamics of the three-dimensional compressible Taylor--Green vortex from the perspective of kinetic theory by directly solving the six-dimensional Boltzmann equation. This work studies the connections between molecular-scale information encoded in the high-dimensional distribution function (e.g., molecular entropy measures) and macroscopic turbulent flow characteristics. We present high-order direct numerical simulations at Mach numbers of $0.5$ to $1.25$ and Reynolds numbers of $400$ to $1600$ performed using up to $137{\times}10^{9}$ degrees of freedom. The results indicate that the Kullback--Leibler divergence of the distribution function $f$ and its local equilibrium state $M[f]$ (i.e., the relative entropy functional $\langle f \log (f/M[f]) \rangle$) is strongly related to the macroscopic viscous dissipation rate, with the relative entropy value matching the sum of the solenoidal and dilatational dissipation rates very closely across a range of Mach and Reynolds numbers. Furthermore, we present the behavior of subgrid-scale quantities under spatial averaging/filtering operations performed directly on the particle distribution function, which shows notable similarities between the subgrid-scale dissipation and subgrid-scale relative entropy. These observations imply that information encoded in the distribution function, particularly certain measures of its deviation from equilibrium, may be useful for closure-modeling for compressible turbulence.

Background: Non-cholera Vibrio species are rare waterborne pathogens that can cause severe infections. Among these, few cases of Vibrio metschnikovii infections have been reported, especially in the gastrointestinal tract, with no cardiac tissue involvement as a result. Following the PRISMA checklist, we conducted a literature review, and thirteen articles for twenty-two cases overall were included: seven cases of sepsis (in three cases, the echocardiographic results were negative), seven cases of pneumonia, two skin infections, eleven cases of diarrhoea, and a gastroenteritis outbreak. This report documents the expanding clinical spectrum and the role played by V. metschnikovii in infective endocarditis. Case report: A 28-year-old male patient was referred to the cardiac surgery unit for urgent mitral valve replacement due to suspicion of infective endocarditis. Microbiological tests yielded negative results. Following recovery and discharge with antimicrobial therapy for 6 weeks, the patient experienced prosthesis detachment, necessitating re-hospitalisation for an emergency valve replacement. Vibrio metschnikovii was identified on the prosthesis valve through PCR and successfully treated with ciprofloxacin. However, a spontaneous rupture of the ascending thoracic aorta led to a neurological injury. Discussion: This case represents the first case of valve infection caused by Vibrio metschnikovii, characterised by diagnostic and therapeutic challenges and the involvement of the great vessels. Also considered in this case, for a disease with a median age of 58 years (11–83) and a male-to-female ratio of 2.2, were one male neonate and six cases for whom neither sex nor age was indicated. Excluding gastrointestinal cases, the septic forms are associated with high morbidity, although the single case described involved a young and healthy subject. Risk factors for the pathogen or predisposing/pathological conditions for endocarditis did not emerge. The routes and the time of infection could not be determined, deepening the possibility of occupational exposure via the patient’s position as a boat worker. Poor sensitivity to third-generation cephalosporins has been reported in the literature: the absence of an antibiogram does not allow for a comparison, although resolution was achieved with ciprofloxacin. Conclusion: The rising global incidence of non-cholera Vibrio infections, driven by environmental changes, calls for urgent research into the factors behind their pathogenicity and infection routes. Diagnostic complexities have emerged together with clinical severity.

Asthma and obesity are both chronic diseases. Obesity is a common comorbidity and a risk factor of severe asthma, associated with increased asthma exacerbation risk, poorer asthma control and reduced quality of life. However, the responsible mechanisms are poorly understood. The aim of this study was to detect parameters associated with obesity in patients with severe asthma in order to check different pattern of inflammation in obese asthmatics. Baseline data from the Severe Asthma Network in Italy (SANI) registry were analysed in 1922 patients with severe asthma. Demographic, clinical and functional features were compared, according to body mass index (BMI). The prevalence of overweight and obesity among severe asthma patients was 34,8 and 20,3, respectively. Females were more prevalent in the obese cluster (p < 0.001). Asthma onset age in overweight and obese patients was higher than in normal population (p < 0.001). Obese subjects reported less frequently chronic rhinosinusitis with nasal polyposis (CRSwNP) and more frequently impaired sleep quality, cardiovascular disease, and type-2 diabetes (p < 0.001). Severe asthma patients with obesity had lower predicted FVC values (89.0 ± 19.2 vs 93.5 ± 20.2; p 0.002) and higher FEV1/FVC ratio (69.9 ± 11.5 vs 66.9 ± 12.4; p < 0.001) than patients without obesity. Obese asthmatics had lower blood eosinophilic count, and fractional exhaled nitric oxide (FeNO) levels than non-obese asthmatics. Asthma control test (ACT) was significantly poorer in obese patients (17, IQR 12-21) than other subgroups. Regarding treatment, overweight and obese patients were more likely to receive a GINA-Step 5 therapy (p 0.023), with more than 20 of obese asthmatics having frequent exacerbations requiring oral corticosteroid (OCS). Patients with severe asthma and obesity presented different characteristics that support the existence of distinct asthma phenotype in obese patients. Trial registration: Trial registry: ClinicalTrials.gov. ID: NCT06625216. Retrospectively registered October 3, 2024.

<bold>Aim:</bold> Neutrophilic asthma is a phenotype of asthma with frequent symptoms and hospital admissions. The present study aims to provide a real-life assessment of the economic cost of neutrophilic asthma in patients from the general adult population in Italy. <bold>Methods:</bold> A prevalence-based cost-of-illness study was conducted on adult subjects with current asthma and low blood neutrophils (<5000 cells/mm^-3; n = 168, mean age 43.1 years, female 46.4%) or high blood neutrophils (≥5000 cells/mm⁻³; n = 56, mean age 41.6 years, female 50.0%). These patients were identified in the Gene Environment Interactions in Respiratory Diseases (2008-2010) survey in Verona, Italy. The costs attributable to poor control of asthma (emergency department visits, hospital admissions, loss of productivity and leisure time) were calculated from the societal perspective following the bottom-up approach based on 2013 rates, wages, and prices (obtained from official Italian sources). The mean annual cost per patient [and 95% confidence interval (95%CI)] was estimated separately by neutrophil level using a two-part model (first part: logistic regression; second part: gamma regression) with robust standard errors. <bold>Results:</bold> The mean annual cost attributable to poor control of asthma was 156 (95%CI: 86-225) and 400 (95%CI: 82-719) euro per patient with low or high blood neutrophils, respectively. Conditional on reporting any cost, these costs were estimated to be 1,005 (95%CI: 735-1,275) and 2,241 (95%CI: 981-3,501) euro, respectively. <bold>Conclusion:</bold> In the general population the economic cost of asthma is high and increases significantly with the level of blood neutrophils.

The use of limiting methods for high-order numerical approximations of hyperbolic conservation laws generally requires defining an admissible region/bounds for the solution. In this work, we present a novel approach for computing solution bounds and limiting for the Euler equations through the kinetic representation provided by the Boltzmann equation, which allows for extending limiters designed for linear advection directly to the Euler equations. Given an arbitrary set of solution values to compute bounds over (e.g., numerical stencil) and a desired linear advection limiter, the proposed approach yields an analytic expression for the admissible region of particle distribution function values, which may be numerically integrated to yield a set of bounds for the density, momentum, and total energy. These solution bounds are shown to preserve positivity of density/pressure/internal energy and, when paired with a limiting technique, can robustly resolve strong discontinuities while recovering high-order accuracy in smooth regions without any ad hoc corrections (e.g., relaxing the bounds). This approach is demonstrated in the context of an explicit unstructured high-order discontinuous Galerkin/flux reconstruction scheme for a variety of difficult problems in gas dynamics, including cases with extreme shocks and shock-vortex interactions. Furthermore, this work presents a foundation for limiting techniques for more complex macroscopic governing equations that can be derived from an underlying kinetic representation for which admissible solution bounds are not well-understood.

This work explores the feasibility of performing three-dimensional molecular gas dynamics simulations of hypersonic flows such as re-entry vehicles through directly solving the six-dimensional nonlinear Boltzmann equation closed with the BGK (Bhatnagar-Gross-Krook) collision model. Through the combination of high-order unstructured spatial discretizations and conservative discrete velocity models as well as their efficient implementation on large-scale GPU computing architectures, we demonstrate the ability to simulate unsteady and non-equilibrium three-dimensional high-speed flows at a feasible computational cost through a unified numerical framework. We present the results of high-order simulations of the Apollo capsule at realistic re-entry conditions from the AS-202 mission flight path, including the steady non-equilibrium flow in the high-altitude regime at a Mach number of 22.7 and a Reynolds number of 43,000 as well as the unsteady turbulent flow in the low-altitude regime at a Mach number of 8 and a Reynolds number of 550,000. The results show the validity of the approach over the entire range of a typical re-entry trajectory from the rarefied to the continuum limit, the ability to directly resolve strong shocks profiles without numerical shock capturing techniques, and the ability of resolving small-scale unsteady flow structures in the inertial range.

The influence and validity of wall boundary conditions for non-equilibrium fluid flows described by the Boltzmann equation remains an open problem. The substantial computational cost of directly solving the Boltzmann equation has limited the extent of numerical validation studies to simple, often two-dimensional, flow problems. Recent algorithmic advancements for the Boltzmann–Bhatnagar–Gross–Krook equation introduced by the authors [Dzanic et al., J. Comput. Phys. 486, 112146 (2023)], consisting of a highly efficient high-order spatial discretization augmented with a discretely conservative velocity model, have made it feasible to accurately simulate unsteady three-dimensional flow problems across both the rarefied and continuum regimes. This work presents a comprehensive evaluation and validation of wall boundary conditions across a variety of flow regimes, primarily for the purpose of exploring their effects on momentum transfer in the low Mach limit. Results are presented for a range of steady and unsteady wall-bounded flow problems across both the rarefied and continuum regimes, from canonical two-dimensional laminar flows to unsteady three-dimensional transitional and turbulent flows, the latter of which are the first instances of wall-bounded turbulent flows computed by directly solving the Boltzmann equation. We show that approximations of the molecular gas dynamics equations can accurately predict both non-equilibrium phenomena and complex hydrodynamic flow instabilities and show how spatial and velocity domain resolution affect the accuracy. The results indicate that an accurate approximation of particle transport (i.e., high spatial resolution) is significantly more important than particle collision (i.e., high velocity domain resolution) for predicting flow instabilities and momentum transfer consistent with that predicted by the hydrodynamic equations and that these effects can be computed accurately even with very few degrees of freedom in the velocity domain. These findings suggest that highly accurate spatial schemes (e.g., high-order schemes) are a promising approach for solving molecular gas dynamics for complex flows and that the direct solution of the Boltzmann equation can be performed at a reasonable cost when compared to hydrodynamic simulations at the same level of resolution.

Cette thèse a pour objet la notion de résolution catégorique des singularités développée par Kuznetsov. On s'y intéresse dans deux exemples concrets; à chacun est consacré un chapitre de ce manuscrit. Le premier chapitre concerne l'étude catégorique des variétés dont le lieu singulier est un point double ordinaire isolé. Ces variétés admettent une résolution catégorique faiblement crépante : on montre qu'un objet sphérique en engendre le noyau. On applique ce résultat au cas particulier d'une cubique de dimension quatre avec un point double ordinaire; motivés par le comportement de sa composante de Kuznetsov, on propose deux définitions de catégorie nodale. Le deuxième chapitre porte sur certains espaces de modules de faisceaux sur une surface K3. Plus précisément, pour tout n > 2 on fixe le vecteur de Mukai (2,0,2-2n) et on s'occupe de l'espace de modules M qui lui est associé : M est singulier, n'admet pas de résolution crépante, et O'Grady en a construit une résolution explicite des singularités. On étudie en détail cette résolution, et on donne une description globale de son diviseur exceptionnel : c'est l'étape préliminaire nécessaire dans la recherche d'une résolution catégorique faiblement crépante de M.

This work explores the capability of simulating complex fluid flows by directly solving the Boltzmann equation. Due to the high-dimensionality of the governing equation, the substantial computational cost of solving the Boltzmann equation has generally limited its application to simpler, two-dimensional flow problems. Utilizing a combination of high-order spatial discretizations and discretely-conservative velocity models along with their highly-efficient implementation on massively-parallel GPU computing architectures, we demonstrate the current ability of directly solving the Boltzmann equation augmented with the BGK collision model for complex, three-dimensional flows. Numerical results are presented for a variety of these problems including rarefied microchannels, transitional and turbulent flows, and high-speed atmospheric re-entry vehicles, showcasing the ability of the approach in accurately predicting complex nonlinear flow phenomena and non-equilibrium effects.

The influence and validity of wall boundary conditions for non-equilibrium fluid flows described by the Boltzmann equation remains an open problem. The substantial computational cost of directly solving the Boltzmann equation has limited the extent of numerical validation studies to simple, often two-dimensional, flow problems. Recent algorithmic advancements for the Boltzmann--BGK equation introduced by the authors, consisting of a high-order spatial discretization augmented with a discretely-conservative velocity model, have made it feasible to accurately simulate unsteady three-dimensional flow problems across both the rarefied and continuum regimes. This work presents a comprehensive evaluation and validation of wall boundary conditions across a variety of flow regimes, primarily for the purpose of exploring their effects on momentum transfer in the low Mach limit. Results are presented for a range of steady and unsteady wall-bounded flow problems across both the rarefied and continuum regimes, from canonical two-dimensional laminar flows to unsteady three-dimensional transitional and turbulent flows, the latter of which are the first instances of wall-bounded turbulent flows computed by directly solving the Boltzmann equation. We show that approximations of the molecular gas dynamics equations can accurately predict both non-equilibrium phenomena and complex hydrodynamic flow instabilities and show how spatial and velocity domain resolution affect the accuracy. The results indicate that an accurate approximation of particle transport (i.e. high spatial resolution) is significantly more important than particle collision (i.e. high velocity domain resolution) for predicting flow instabilities and momentum transfer consistent with that predicted by the hydrodynamic equations and that these effects can be computed accurately even with very few degrees of freedom in the velocity domain.

The discontinuous Galerkin method and related flavors of high-order spectral element methods provide many well-known benefits for the spatial discretization of partial differential equations such as the Navier–Stokes equations. However, practical problems of engineering relevance such as large-eddy simulation of turbulent flows over complex geometries are computationally intractable by standard explicit time integration methods, necessitating the use of implicit methods. The efficient solution of the nonlinear algebraic systems arising from implicit time integration methods applied to DG discretizations of nonlinear PDEs is challenging; standard linearization methods result in very stiff block-sparse systems with prohibitive computational and memory requirements. This paper presents a low-memory, computationally efficient, implicit solution method that combines a framework of nonlinear polynomial multigrid, adaptive explicit Runge–Kutta smoothers, implicit Jacobian-free coarse level smoothers, nonlinear Krylov subspace acceleration and adaptive time stepping using feedback control of the nonlinear solver convergence rate.

Abstract In this paper we study derived categories of nodal singularities. We show that for all nodal singularities there is a categorical resolution whose kernel is generated by a 2 or 3-spherical object, depending on the dimension. We apply this result to the case of nodal cubic fourfolds, where we describe the kernel generator of the categorical resolution as an object in the bounded derived category of the associated degree six K3 surface. This paper originated from one of the problem sessions at the Interactive Workshop and Hausdorff School “Hyperkähler Geometry”, Bonn, September 6–10, 2021.

In this work, we present a positivity-preserving high-order flux reconstruction method for the polyatomic Boltzmann--BGK equation augmented with a discrete velocity model that ensures the scheme is discretely conservative. Through modeling the internal degrees of freedom, the approach is further extended to polyatomic molecules and can encompass arbitrary constitutive laws. The approach is validated on a series of large-scale complex numerical experiments, ranging from shock-dominated flows computed on unstructured grids to direct numerical simulation of three-dimensional compressible turbulent flows, the latter of which is the first instance of such a flow computed by directly solving the Boltzmann equation. The results show the ability of the scheme to directly resolve shock structures without any ad hoc numerical shock capturing method and correctly approximate turbulent flow phenomena in a consistent manner with the hydrodynamic equations.