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Transient early blood eosinophil increases do not affect dupilumab's long-term efficacy in patients with moderate-to-severe asthma
No full textBackground: Transient increases in blood eosinophil count (BEC) have been observed in dupilumab clinical trials but are rarely associated with clinical symptoms.
Objective: We assessed the effect of early increases in BEC on long-term treatment outcomes.
Methods: Patients aged ≥12 years with moderate-to-severe type 2 asthma from the phase 3 QUEST study (NCT02414854; 52 weeks) who enrolled onto the TRAVERSE open-label extension study (NCT02134028; 96 weeks) were stratified by BEC: with or without ≥2-fold BEC increase any time by week 12 of QUEST, or presence or absence of increased BEC any time during QUEST (defined as <500 cells/μL at baseline but ≥500 cells/μL at any time during QUEST). End points included annualized severe exacerbation rate and change from parent study baseline in prebronchodilator forced expiratory volume in 1 second (FEV1), 5-item Asthma Control Questionnaire, and type 2 inflammatory biomarkers.
Results: A total of 36.6% of dupilumab-treated patients versus 21.7% of placebo-receiving patients experienced a ≥2-fold BEC change by week 12, while 31.3% versus 28.0% experienced increased BEC any time during QUEST. Dupilumab versus placebo reduced annualized severe exacerbation rate, improved prebronchodilator FEV1 and questionnaire scores, and reduced biomarkers across subgroups at week 52 of QUEST. Improvements were maintained in all subgroups through week 96 of TRAVERSE.
Conclusions: Dupilumab reduced asthma exacerbations and improved lung function and asthma control up to 148 weeks in patients with uncontrolled moderate-to-severe type 2 asthma irrespective of early transient increases in BEC. Overall safety was consistent with the known dupilumab safety profile
Kinematic guidance using virtual reference point for underactuated marine vehicles with sideslip compensation
No full textPath following for underwater vehicles remains a significant challenge due to underactuation in the sway and heave directions. Most existing approaches rely on line-of-sight guidance to address this issue. In this paper, we explore an alternative approach using kinematic guidance, based on virtual reference point guidance, wherein a fictitious point offset from the vehicle’s center of rotation is used to reformulate the kinematic control problem and mitigate underactuation constraints. While this concept has been explored to some extent, previous works have largely overlooked the impact of the vehicle’s attitude. To address this limitation, we propose a solution that simultaneously accounts for the vehicle’s attitude while minimizing cross-track error by defining the error dynamics in the body reference frame, which enables direct control of yaw and sway through yaw rate actuation. A model predictive controller is designed to optimize both attitude stabilization and trajectory tracking performance and is enhanced with an adaptive extended Kalman filter-like observer to estimate the sideslip caused by sea currents and external disturbances. The proposed controller is evaluated under the influence of sea currents and modeling uncertainties, and compared to an existing method from the literature, demonstrating its effectiveness in maintaining path-following accuracy while stabilizing the attitude in the presences of the sea currents
GY971 mitigates inflammation by reducing neutrophil recruitment in cystic fibrosis Ex Vivo and In Vivo models
No full textBackground: There is a prominent need for anti-inflammatory agents for people with CF (pwCF), even in the era of CFTR modulators. ETI (Elexacaftor/Tezacaftor/Ivacaftor) reduces but does not eliminate pulmonary inflammation, that chronically damages CF pulmonary tissues and favors recurrent pulmonary exacerbations. Furthermore, although known anti-inflammatory drugs are beneficial to pwCF, their side effects are limiting the clinical use. To address this issue, we developed a new synthetic furocoumarin molecule named GY971, able to reduce the excessive accumulation of neutrophils in the bronchial lumen, by targeting the nuclear transcription factor NF-kB.
Methods: To assess its efficacy, GY971 was tested in human primary bronchial and nasal epithelial cells obtained ex vivo from different pwCF carrying the F508del mutation and infected with Pseudomonas aeruginosa. Moreover, GY971 was also administered in a zebrafish model infected with Pseudomonas aeruginosa in vivo.
Results: GY971 reduced neutrophil chemotaxis mediators both in CF bronchial epithelial cell lines and in CF primary bronchial and nasal epithelial cells ex vivo. The expression of key inflammatory proteins involved in CF lung disease, including IL-8, IL-1beta, TNF-alpha and IL-6, was significantly reduced using nanomolar concentrations of GY971. Importantly, GY971 does not interfere with the ETI-mediated rescue of CFTR protein and showed no cytotoxic effects. Lastly, in vivo testing with a zebrafish model confirmed its effectiveness: GY971 decreased neutrophil recruitment in treated larvae across different concentrations, supporting earlier results from murine studies.
Conclusions: GY971 appears to be a promising molecule for the future development of combinatorial anti-inflammatory treatments together with ETI
Variations on the capacitary inradius
No full textWe discuss some properties of the capacitary inradius for an open set. This is an extension of the classical concept of inradius (i.e. the radius of a largest inscribed ball), which takes into account capacitary effects. Its introduction dates back to the pioneering works of Vladimir Maz’ya. We present some variants of this object and their mutual relations, as well as their connections with Poincaré inequalities. We also show that, under a mild regularity assumption on the boundary of the sets, the capacitary inradius is equivalent to the classical inradius. This comes with an explicit estimate and it permits to get a Buser–type inequality for a large class of open sets, whose boundaries may have power-like cusps of arbitrary order. Finally, we present a couple of open problems
A potential bottom-up cascade on the abundance of invasive Atlantic blue crab Callinectes sapidus in northwestern Adriatic lagoons
No full textThe introduction of the Atlantic blue crab (Callinectes sapidus) in the Mediterranean Sea dates back to the 1900s; however, the species has recently spread in the region resulting in negative impacts on the structure and functions of invaded ecosystems and local fisheries. This study investigated the covariation between spatiotemporal dynamics of the Atlantic blue crab fishery landings (catch-per-unit-area; CPUE) and environmental explanatory variables (i.e., salinity, water temperature, nitrate and chlorophyll-a used as a proxy of primary productivity) over a four-year period (2020–2023) in four key lagoonal ecosystems of the North Adriatic Sea. Our results showed that the marked increase in Atlantic blue crab CPUE in all studied lagoons since 2020 was strongly related with local primary productivity which likely supports a greater abundance of food resources for the suspension feeding Manila clam (Ruditapes philippinarum), a key prey for blue crabs and one of the most important fisheries in the region. Conversely, salinity and water temperature, two key parameters regulating blue crab biology, i.e., mating and subsequent larval spawning, did not significantly influence CPUE in the studied lagoons. These results suggest that primary production in the lagoons, which directly influences food availability (e.g., Manila clams) for the Atlantic blue crab, is the primary factor driving its apparent invasion success in the study area. Our results provide new insights into understanding the environmental factors that promote its invasion and spread, allowing for targeted control measures such as managed fisheries and water quality
Foraging Habit Determines the Amount of Microplastics Ingested in Five Fish Species from a Northern Adriatic Lagoon
No full textIn this study we documented differences in the accumulation of microplastics (MP) in the gastrointestinal tract (GIT) of 5 commercially important lagoon fish species, also considering the concentration of MP in the water column and sediment of a lagoon in the Po River Delta (Northern Adriatic Sea). Two sampling campaigns were carried out in 2021 (spring and autumn), and a total of 201 fish were examined. MP contents in fish species varied widely, with ingestion frequencies ranging from 16% (Atherina. boyeri) to 92% (Chelon ramada). Polyethylene and polypropylene were the polymer types identified in GIT through μ-Raman spectroscopy. There were more fibers than fragments both in the water column and in sediments, but different relative proportions were found in the contents of the GIT of visually-oriented planktivorous and chemically-oriented benthivorous fish. In the detritivorous Chelon ramada a higher concentration of MP (with fibers in greater proportion) was found in comparison to planktivorous and benthivorous fish, probably as a consequence of their passive foraging. Our results indicate that the quantity of MP ingested seems to be more a function of the foraging habits of the species considered, rather than MP availability in the environmen
A general Boltzmann-BGK model for gas mixtures: hydrodynamic limits and convergence results
No full textThis thesis, in the frame of kinetic theory of gas mixtures, develops a general framework which integrates the Boltzmann and the BGK descriptions of the collision operators within one model, with the aim of combining the accuracy of the Boltzmann integral with the greater analytical and computational tractability of the BGK operator. Hence, the proposed model allows for each binary interaction to be described by either operators.
After having proved the consistency properties, namely the correct conservation laws, uniqueness of equilibrium distribution and H-theorem, the dimensionless form of the model is introduced, enabling the analysis of different hydrodynamic regimes.
In the classical collision dominated regime, in which all collisions are equally dominant in the evolution, we consider a Chapman-Enskog expansion in terms of a suitable Knudsen number and derive Euler and Navier-Stokes equations in the hydrodynamic limit. In order to provide a closure for the Navier-Stokes equations, we derive explicit first-order corrections for the species velocities, while the complexity of the Boltzmann linearized operator prevents a closed-form computation of the first order corrections of the pressure tensor and heat flux. Nevertheless, the computations involve linear systems which admit unique solutions, ensuring a constructive closure of the Navier–Stokes equations. Since in real mixtures the number of species is typically small, the coefficient matrix can easily be inverted using standard numerical tools.
We then analyze binary mixtures in which intra-species collisions are described by Boltzmann operators and inter-species ones by BGK terms, focusing on two relevant hydrodynamic regimes. In the first one, both intra-species interactions play a dominant role, allowing to obtain the Navier-Stokes equations for macroscopic fields of both species, with source terms on the right-hand side, representative of the slow collisional dynamics. In the second one, the dominant role is played by the intra-species interactions of the heavier species only, allowing for fluid equations of Navier-Stokes type for such species, while the lightest one retains a kinetic description.
Finally, exponential convergence of the species distribution functions towards the species Maxwellian distribution is proved, with explicit dependence of the convergence rate on the collision frequencies and mixture parameters.Questa tesi, nel contesto della teoria cinetica per miscele di gas, sviluppa un modello generale che integra le descrizioni degli operatori di collisione di Boltzmann e BGK in un unico modello, con l’obiettivo di combinare l’accuratezza dell’integrale di Boltzmann con la maggiore maneggevolezza analitica e computazionale dell’operatore BGK. Il modello proposto consente quindi di descrivere ogni interazione binaria tramite uno dei due operatori.
Dopo aver dimostrato le principali proprietà di consistenza— le corrette leggi di conservazione, l’unicità degli equilibri collisionali e il teorema H—viene introdotta un’opportuna adimensionalizzazione del modello, che permette l’analisi di diversi regimi idrodinamici. Nel regime dominato dalle collisioni, in cui ogni interazione è ugualmente dominate, applichiamo l’espansione di Chapman–Enskog in termini di un opportuno numero di Knudsen e deriviamo le equazioni di Eulero e di Navier–Stokes in tale limite idrodinamico. Per ottenere una chiusura delle equazioni di Navier–Stokes, si ricavano le correzioni del primo ordine delle velocità di ogni specie; tuttavia, la complessità analitica dell’operatore linearizzato di Boltzmann impedisce di trovare una forma chiusa delle correzioni al primo ordine del tensore pressione e del vettore flusso di calore. Ciononostante, i calcoli richiedono la risoluzione di sistemi lineari che ammettono un’unica soluzione, garantendo così una chiusura costruttiva delle equazioni di Navier–Stokes. Poiché nelle miscele reali le specie coinvolte sono poche, la matrice dei coefficienti può essere invertita agevolmente con metodi numerici standard. Analizziamo poi miscele binarie in cui le collisioni intra-specie sono descritte mediante integrali di tipo Boltzmann, mentre quelle inter-specie tramite operatori BGK, focalizzandoci su due regimi idrodinamici di particolare interesse. Nel primo, le interazioni intra-specie svolgono entrambe un ruolo dominante, permettendo di ottenere le equazioni di Navier–Stokes per i campi macroscopici di ciascuna specie, con termini sorgente, rappresentativi della dinamica collisionale inter-specie più lenta. Nel secondo regime, il ruolo dominante è svolto dalle collisioni intra-specie della sola specie più pesante, il che permette di derivare equazioni di tipo Navier–Stokes per tale specie, mentre la specie più leggera mantiene una descrizione cinetica. Infine, dimostriamo la convergenza esponenziale delle funzioni di distribuzione alle maxwelliane, con una dipendenza esplicita dei tassi di convergenza dalle frequenze di collisione e dai parametri macroscopici della miscela
Stable improvement of older outpatients with acute coronary syndrome after one year of exercise-based secondary prevention program. Insights from the ITER registry
No full textPurpose: Among cardiovascular diseases, acute coronary syndrome (ACS) is the leading cause of morbidity and mortality. Cardiac rehabilitation and secondary prevention programs are highly recommended for the long-term management of patients, and physical activity has been recognized as core part of such interventions. However, despite the documented benefits, older patients diagnosed with acute coronary syndrome (ACS) are less likely to attend traditional center-based programs limiting the efficacy of the intervention. Therefore, more comprehensive and sustainable intervention strategies are advocated. In light of these considerations, the aim of the study was to examine functional changes of older patients with ACS involved in a hybrid center- and home-based secondary prevention program during the first year of intervention after the acute event.
Methods: A subsample of 254 consecutive patients (mean age 75 years) with ACS extracted from the ITER registry (NCT05817305) was analyzed. The intervention was composed of 6 individual on-site sessions including functional evaluation and continuous motivational reinforcement to reach exercise goals and stably maintain an active lifestyle. The home-based exercise prescription was based on the results of the validated 1km-Treadmill Walking Test. Main outcomes were changes in self-reported weekly physical activity, average walking speed (WS) registered during the test and estimated cardiorespiratory fitness (VO2peak) assessed during each visit.
Results: Physical activity levels significantly increased and were maintained during the follow-up period (median MET-h/week 3.0, 12.0, and 9.0 at baseline, 6-, and 12 months, respectively; p<0.0001). These results were associated with increasing mean WS (2.9, 3.9, 4.1 km/h, respectively, p<0.0001), and VO2peak (16.9, 20.0, 20.5 mL/kg/min, respectively, p<0.0001).
Conclusions: The proposed intervention demonstrated a stable adherence to physically active lifestyle, along with improved walking speed and estimated VO2peak in older patients with ACS. Results therefore highlight the importance of exercise testing and training and provide important information for the development of more efficient and patient-centered exercise-based secondary prevention programs
Strategia industriale e crescita economica regionale in Cina
No full textL'esperienza di crescita e sviluppo industriale cinese è unica in termini di dimensioni,
velocità e portata del processo cambiamento strutturale, nonché in termini di impatto sul resto del mondo. Il cambiamento strutturale degli ultimi quarant'anni è stato pianificato e governato attraverso la promozione di interventi di policy mirati proprio alla struttura dell'economia cinese, alle sue industrie, alle sue aziende e ai suoi territori. Uno dei tratti distintivi dell’approccio cinese alla promozione dei processi di crescita e cambiamento strutturale è l’attenzione alla dimensione regionale, spaziale delle politiche pubbliche e alla geografia della produzione. Il processo di apertura e cambiamento della Cina inizia con la
creazione di quattro zone economiche speciali (ZES) inizialmente volte a sperimentare e introdurre nel paese diverse modalità di produzione. Lo stesso tipo di strumento verrà utilizzato nel tempo per perseguire obiettivi molto diversi, dalla crescita high-tech alla strategia “go-global”. Accanto alle ZES anche la promozione di cluster industriali specializzati ha caratterizzato la crescita delle regioni che hanno trainato lo sviluppo industriale cinese. Infine, negli anni recenti proprio la crescita regionale, volutamente disuguale nelle fasi iniziali del processo di sviluppo industriale, ha mutato le priorità di governo verso una strategia di maggiore riequilibrio territoriale. In maniera crescente oltre al tema della disuguaglianza nei tassi di crescita delle regioni cinesi negli anni recenti i programmi di policy cinesi e il dibattito attorno ad essi evidenzia un interesse al riequilibrio anche nelle dimensioni della resilienza e della sostenibilità sociale
Seismic damage analysis for historic buildings: the case of Palazzo Gulinelli in Ferrara
No full textThe seismic risk assessment of historic heritage is a challenge for seismic engineering, due to the historical and cultural value of these buildings and the transformations they have undergone over time. Structures in historic centres, often built in aggregate and using traditional construction techniques, require in-depth knowledge of materials, structural connections, construction technologies, and the historical building context.
This contribution deals with the case of the Renaissance buildings owned by the University of Ferrara, located along Via Savonarola, which were damaged during the 2012 Emilia seismic sequence. These buildings, currently unusable, are the focus of a complex process involving surveys, investigations, analyses, and seismic retrofitting techniques.
This study proposes a methodology of analysis relative to some local critical mechanisms. In particular, the proposed approach integrates damage surveys, materials characterization, and classification of the main failure mechanisms activated during the earthquake, relating the modes to the specific construction features of Renaissance architecture. The methodology is based on rapid surveys, simplified modelling and vulnerability analysis, with the aim of providing practical tools for the prevention and mitigation of seismic risk