Università degli Studi di Perugia

Background In patients with heart failure with reduced ejection fraction (HFrEF), treatment with sacubitril–valsartan (S/V) may reverse left ventricular remodeling (rLVR). Whether this effect is superior to that induced by other renin–angiotensin system (RAS) inhibitors is not well known. Methods HFrEF patients treated with S/V (n = 795) were compared, by propensity score matching, with a historical cohort of 831 HFrEF patients (non-S/V group) treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (RAS inhibitors). All patients were also treated with beta-blockers and shared the same protocol with repeat echocardiogram 8–12 months after starting therapy. The difference-in-difference (DiD) analysis was used to evaluate the impact of S/V on CR indices between the two groups. Results After propensity score matching, compared to non-S/V group (n = 354), S/V group (n = 354) showed a relative greater reduction in end-diastolic and end-systolic volume index (ESVI), and greater increase in ejection fraction (DiD estimator = + 5.42 mL/m², P = 0.0005; + 4.68 mL/m², P = 0.0009, and + 1.76%, P = 0.002, respectively). Reverse LVR (reduction in ESVI ≥ 15% from baseline) was more prevalent in S/V than in non-S/V group (34% vs 26%, P = 0.017), while adverse LVR (aLVR, increase in ESVI at follow-up ≥ 15%) was more frequent in non-S/V than in S/V (16% vs 7%, P < 0.001). The beneficial effect of S/V on CR over other RAS inhibitors was appreciable across a wide range of patient’s age and baseline end-diastolic volume index, but it tended to attenuate in more dilated left ventricles (P for interaction = NS for both). Conclusion In HFrEF patients treated with beta-blockers, sacubitril/valsartan is associated with a relative greater benefit in LV reverse remodeling indices than other RAS inhibitors. Graphical abstract

PURPOSE ARTO (ClinicalTrials.gov identifier: NCT03449719 ) is a multicenter, phase II randomized clinical trial testing the benefit of adding stereotactic body radiation therapy (SBRT) to abiraterone acetate and prednisone (AAP) in patients with oligometastatic castrate-resistant prostate cancer (CRPC). MATERIALS AND METHODS All patients were affected by oligometastatic CRPC as defined as three or less nonvisceral metastatic lesions. Patients were randomly assigned 1:1 to receive either AAP alone (control arm) or AAP with concomitant SBRT to all the sites of disease (experimental arm). Primary end point was the rate of biochemical response (BR), defined as a prostate-specific antigen (PSA) decrease ≥50% from baseline measured at 6 months from treatment start. Complete BR (CBR), defined as PSA < 0.2 ng/mL at 6 months from treatment, and progression-free survival (PFS) were secondary end points. RESULTS One hundred and fifty-seven patients were enrolled between January 2019 and September 2022. BR was detected in 79.6% of patients (92% v 68.3% in the experimental v control arm, respectively), with an odds ratio (OR) of 5.34 (95% CI, 2.05 to 13.88; P = .001) in favor of the experimental arm. CBR was detected in 38.8% of patients (56% v 23.2% in the experimental v control arm, respectively), with an OR of 4.22 (95% CI, 2.12 to 8.38; P < .001). SBRT yielded a significant PFS improvement, with a hazard ratio for progression of 0.35 (95% CI, 0.21 to 0.57; P < .001) in the experimental versus control arm. CONCLUSION The trial reached its primary end point of biochemical control and PFS, suggesting a clinical advantage for SBRT in addition to first-line AAP treatment in patients with metastatic castration-resistant prostate cancer.

Objective Assessment of circulating autoantibodies represents one of the earliest diagnostic procedures in patients with suspected connective tissue disease (CTD), providing important information for disease diagnosis, identification and prediction of potential clinical manifestations. The purpose of this study was to evaluate the ability of multiparametric assay to correctly classify patients with multiple CTDs and healthy controls (HC), independent of clinical features, and to evaluate whether serological status could identify clusters of patients with similar clinical features. Methods Patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjogren’s syndrome (SjS), undifferentiated connective tissue disease (UCTD), idiopathic inflammatory myopathies (IIM) and HC were enrolled. Serum was tested for 29 autoantibodies. An XGBoost model, exclusively based on autoantibody titres was built and classification accuracy was evaluated. A hierarchical clustering model was subsequently developed and clinical/laboratory features compared among clusters. Results 908 subjects were enrolled. The classification model showed a mean accuracy of 60.84±4.05% and a mean area under the receiver operator characteristic curve of 88.99±2.50%, with significant discrepancies among groups. Cluster analysis identified four clusters (CL). CL1 included patients with typical features of SLE. CL2 included most patients with SjS, along with some SLE and UCTD patients with SjS-like features. CL4 included anti-Jo1 patients only. CL3 was the largest and most heterogeneous, including all the remaining subjects, overall characterised by low titre or lower-prevalence autoantibodies. Conclusion Extended multiparametric autoantibody assay allowed an accurate classification of CTD patients, independently of clinical features. Clustering according to autoantibody titres is able to identify clusters of CTD subjects with similar clinical features, independently of their final diagnosis.

The NE‐dipping Anghiari normal fault (AF), bounding to the west the Sansepolcro basin in the Upper Tiber Valley (northern Apennines), is thought to be a synthetic splay of the Altotiberina (ATF) low‐angle normal fault (LANF), an active ENE‐dipping extensional detachment whose seismogenic behavior is debated. In order to assess the Anghiari fault capability to break the surface during strong earthquakes and be the source of historical earthquakes, we acquired high resolution topographic data, performed field survey and geophysical investigations (Seismic reflection, Ground Penetrating Radar (GPR), Electrical Resistivity Tomography (ERT)) and dug three paleoseismological trenches across different fault sections of the Anghiari fault. The acquired data reveal for the first time the Late Pleistocene to historical activity of the A nghiari fault, constraining the age of seven paleo‐earthquakes over the last 25 ka, the youngest of which is comparable with one of the poorly constrained historical earthquakes of the Sansepolcro basin. The yielded slip rate is > 0.2 mm/yr averaged over the last 25 ka and the recurrence interval is about 2500‐3200 years. An analysis of the anisotropy of the magnetic susceptibility performed in one of the paleoseismological trenches revealed an extensional stress field, continuously acting during the sedimentation of the entire trenched stratigraphy. Our results confirm the ability of the Anghiari fault to slip in surface faulting earthquakes and if the Anghiari fault does sole at depth into the Altotiberina low‐angle normal fault, suggests that this LANF could also be seismogenic and generate M>6.

Heart failure (HF) is a progressive condition with a clinical picture resulting from reduced cardiac output (CO) and/or elevated left ventricular (LV) filling pressures (LVFP). The original Diamond-Forrester classification, based on haemodynamic data reflecting CO and pulmonary congestion, was introduced to grade severity, manage, and risk stratify advanced HF patients, providing evidence that survival progressively worsened for those classified as warm/dry, cold/dry, warm/wet, and cold/wet. Invasive haemodynamic evaluation in critically ill patients has been replaced by non-invasive haemodynamic phenotype profiling using echocardiography. Decreased CO is not infrequent among ambulatory HF patients with reduced ejection fraction, ranging from 23 to 45%. The Diamond-Forrester classification may be used in combination with the evaluation of natriuretic peptides (NPs) in ambulatory HF patients to pursue the goal of early identification of those at high risk of adverse events and personalise therapy to antagonise neurohormonal systems, reduce congestion, and preserve tissue/renal perfusion. The most benefit of the Guideline-directed medical treatment is to be expected in stable patients with the warm/dry profile, who more often respond with LV reverse remodelling, while more selective individualised treatments guided by echocardiography and NPs are necessary for patients with persisting congestion and/or tissue/renal hypoperfusion (cold/dry, warm/wet, and cold/wet phenotypes) to achieve stabilization and to avoid further neurohormonal activation, as a result of inappropriate use of vasodilating or negative chronotropic drugs, thus pursuing the therapeutic objectives. Therefore, tracking the haemodynamic status over time by clinical, imaging, and laboratory indicators helps implement therapy by individualising drug regimens and interventions according to patients' phenotypes even in an ambulatory setting.

Daytime Radiative Cooling (DRC) is a highly effective passive cooling technique that holds great potential for enhancing energy efficiency and promoting decarbonization. Several Daytime Radiative Coolers (DRCs) are reported in the literature to highly reflect shortwave radiation and emit thermal radiation, either specifically in the Atmospheric Window (AW) wavelengths (8–13 µm) (Selective DRCs) or in both AW and non‐AW wavelengths (Broadband DRCs). This review presents the advancements in the six key categories of DRCs identified in the literature based on their design characteristics: i) multilayer DRCs, ii) metamaterial DRCs, iii) randomly distributed particle DRC structures, iv) porous DRCs, v) colored DRCs, and vi) adaptive DRCs. The review discusses their main attributes in terms of their demonstrated thermo‐optical performance. Research gaps include the need for real‐life studies to investigate scaling up DRCs in the built environment and their effects on indoor thermal comfort and air temperature reduction. Finally, an eight‐step feedback‐loop scheme is proposed to establish efficient design and implementation protocols for DRC materials in the built environment.

Navigation is a critical task for the operations of both manned and unmanned aircraft systems. Current positioning systems rely primarily on satellite systems such as the Global Positioning System (GPS) or alternative sensor fusion algorithms, which typically require vision sensing and processing. Due to the possibility of temporary GPS outages and/or GPS jamming, it is critical for aircraft sensing systems to predict the position as well as the ground velocity of the aircraft in the absence of GPS signals. This work proposes two state estimation algorithms for predicting the position and ground velocity of aircraft. These methods do not require vision sensors or aircraft dynamic model information, thus providing a portable approach applicable to any aircraft. The proposed methods consider infrequent GPS position updates. Although not completely GPS free, these algorithms do not require GPS velocity measurements and can predict the aircraft position in between the position updates. The proposed methods use the information filter and unscented information filter; they are first validated using unmanned aircraft flight data and later applied to flight data from a high-speed manned military trainer jet. The results indicate the effectiveness of this approach for model-free position and ground velocity estimation.

Additive manufacturing technology like laser powder bed fusion represents a valid alternative for the production of ferromagnetic cores. In this study, two grades of steel were considered, with standard (3.0 wt%) and high (6.5 wt%) Si content. The study is aimed at optimizing the process parameters in order to obtain components suitable for magnetic applications. Moreover, the effect of post-production annealing heat treatment on the microstructure evolution is investigated. The investigation included microstructural analysis by optical microscope, dynamic scanning calorimetry analysis and electro-magnetic measurements on samples with optimized geometry. Results shows that both types of steel can be produced free from defects. Even if the magnetic behaviour of FeSi6.5 samples by AM do not fully reproduces that obtained on electrical steels manufactured by standard process, it appears quite promising. In this framework the optimization of post-production processes represents a promising challenge to meet market demands. Graphical abstract

AtopyReg® is a multicenter, prospective, observational, non-profit cohort study on moderate-to-severe atopic dermatitis in adults promoted in 2018 by the Italian Society of Dermatology and Venereology (SIDeMaST). We aimed to describe baseline demographics, disease characteristics, comorbidities, and therapeutic data of adult patients affected by moderate-to-severe atopic dermatitis. Patients were selected based on the following inclusion criteria: age ≥ 18 years; Eczema Area and Severity Index score ≥ 16 or localization in visible or sensitive areas (face, neck, hands, or genitalia), or a Numeric Rating Scale itch score ≥ 7 or a Numeric Rating Scale sleep loss score ≥ 7, or a Dermatology Life Quality Index score ≥ 10. Demographic and clinical data at baseline were recorded and analyzed. A total of 1170 patients (male 51.1%; mean age: 44.7 years; range 18–90 years) were enrolled by 12 Italian Dermatology Units between January 2019 and November 2022. Skin lesions were eczematous in 83.2% of patients, the most involved site were the flexures (53.9%), face (50.9%), and neck (48.0%). Mean Eczema Area and Severity Index score was 22.3, mean Dermatology Life Quality Index value was 17.6, mean Patient Oriented Eczema Measure score was 13.1, and mean Numeric Rating Scale itch and sleep loss scores were 7.6 and 5.9, respectively. Previous systemic therapies were corticosteroids in 77.7% of patients, antihistamines in 50.3% of patients, and cyclosporine A in 42.6% of patients. This baseline data analysis deriving from AtopyReg® provides real-life evidence on patients with moderate-to-severe atopic dermatitis in Italy confirming the high burden of atopic dermatitis with a significant impact on patients’ quality of life.

Glyoxalase 2 (Glo2) is the second enzyme in the glyoxalase system, and while its cytoplasmic function is well-established, its subcellular localization in the nucleus and potential role there remain unexplored. This study investigates nuclear localization and function of Glo2 in human breast cancer (MCF7) and normal fibroblast-derived (HDF) cells. Glo2 was present in both cytoplasm and nucleus of MCF7 and HDF cells. Interestingly, Glo2 expression levels were significantly higher in MCF7 compared to HDF, especially when considering the nuclear Glo2. Western-blot analysis revealed the monomeric 29 KDa Glo2 form and a 47 KDa Glo2 form suggesting complex formation with other proteins in the cytoplasm of MCF7 and HDF cells. Interestingly, at the nuclear level only the tumor cells showed the 47 KDa Glo2 form. Sequential salt extraction indicated a potential association of Glo2 with non-histone proteins. Intriguingly, nuclear Glo2 positively correlated with cell cycle proliferative phase (G2/M), more markedly in MCF7. Furthermore, higher levels of S-glutathionylation of nuclear proteins were observed in MCF7 compared to HDFs, and “in vitro” addition of Glo2 to nuclear extracts increased S-glutathionylation levels, significantly in MCF7. Finally, inhibiting Glo2 increased doxorubicin cytotoxicity in MCF7. Overall, these results indicate that nuclear Glo2 may play a role in in promoting cancer cell survival and targeting Glo2 could be a promising strategy to improve the efficacy of some anticancer therapies in breast cancer.

The formation of Brønsted acid aggregates in the course of asymmetric organocatalytic reactions is often overlooked in mechanistic studies, even though it might have a deep impact on the stereo-controlling factors of the transformations. In this work, we shed light on the influence of the catalyst structure and reaction conditions on the spontaneity of the aggregation process for popular chiral organocatalysts derived from phosphoric acids using high-level quantum mechanical calculations. Our study encompasses small and sterically unhindered chiral phosphoric acids as well as large and “confined” imidodiphosphates and imidodiphosphorimidates. These systems have recently proven particularly effective in promoting a large number of highly relevant asymmetric transformations. While cooperative catalytic effects of sterically less hindered chiral phosphoric acid catalysts are well appreciated in literature, it is found that the formation of catalyst dimers in solution is possible for both standard and confined catalysts. The spontaneity of the aggregation process depends on reaction conditions like solvent polarity, polarizability, temperature, the nature of the interaction with the substrate, as well as the catalyst architecture. Finally, it is shown that, at low temperatures (153 K), the aggregation process can profoundly influence the reaction kinetics and selectivity.

The aim of this chapter is to describe the different conditions leading to a tracheal injury with a focus on those occurring in the clinical setting of thyroid surgery. Tracheal injury can be classified as traumatic or iatrogenic occurring during surgery, endotracheal intubation, or bronchoscopy. Tracheal damage is a rare complication of thyroidectomy and is more frequently observed in advanced thyroid cancer invading the airways. Respiratory distress, mediastinitis and sepsis are the most critical consequences. Early diagnosis and appropriate treatment are of paramount importance to prevent a fatal outcome or severe clinical sequelae. Two options for management can be considered: operative or non-operative. The choice of the most appropriate treatment is determined by the patient’s respiratory condition and the local extent of the injury. Non-operative management may be a safe option in patients with uncomplicated ventilation, superficial or sufficiently covered tears, moderate and non-progressive subcutaneous emphysema. A nonoperative approach includes tracheal bridging with ventilation tube, stent placement, or endoluminal repair. Surgical repair is the option of choice in those patients with larger injuries which require mechanical ventilation.

Background The issue of sex differences in stroke has gained concern in the past few years. However, multicenter studies are still required in this field. This study explores sex variation in a large number of patients and compares stroke characteristics among women in different age groups and across different countries. Methods This multicenter retrospective cross-sectional study aimed to compare sexes regarding risk factors, stroke severity, quality of services, and stroke outcome. Moreover, conventional risk factors in women according to age groups and among different countries were studied. Results Eighteen thousand six hundred fifty-nine patients from 9 countries spanning 4 continents were studied. The number of women was significantly lower than men, with older age, more prevalence of AF, hypertension, and dyslipidemia. Ischemic stroke was more severe in women, with worse outcomes among women ( p : < 0.0001), although the time to treatment was shorter. Bridging that was more frequent in women ( p :0.002). Analyzing only women: ischemic stroke was more frequent among the older, while hemorrhage and TIA prevailed in the younger and stroke of undetermined etiology. Comparison between countries showed differences in age, risk factors, type of stroke, and management. Conclusion We observed sex differences in risk factors, stroke severity, and outcome in our population. However, access to revascularization was in favor of women.

In this paper, we consider the affine variety codes obtained evaluating the polynomials by=akxk+…+a1x+a0\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$by=a_kx^k+\ldots +a_1x+a_0$$\end{document}, b,ai∈Fqr\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$b,a_i\in {\mathbb {F}}_{q^r}$$\end{document}, at the affine Fqr\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${{\mathbb {F}}}_{q^r}$$\end{document}-rational points of the Norm-Trace curve. In particular, we investigate the weight distribution and the set of minimal codewords. Our approach, which uses tools of algebraic geometry, is based on the study of the absolute irreducibility of certain algebraic varieties.

The tremendous importance of dirhodium paddlewheel com‐plexes for asymmetric catalysis is largely the result of anempirical optimization of the chiral ligand sphere aboutthe bimetallic core. Only recently, a H(C)Rhtriple resonance 103Rh NMR experiment provided the long‐awaited opportunity to examine – with previously incon‐ceivable accuracy – how variation of the ligands impacts onthe electronic structure of such catalysts. The recorded ef‐fects are dramatic: formal replacement of one out ofeight O‐atoms in a dirhodium tetracarboxylate by an N‐atom results in a shielding of thecorresponding Rh‐site of no less than 1000 ppm. The cur‐rent paper provides the framework that allowsthis and related experimental observations made with a setof 19 representative rhodium complexes to be interpreted.In line with symmetry considerations, it is shown that theshielding tensor responds only to the donor ability of theequatorial ligands along the perpendicular principal axis.Axial ligands, in contrast, have no direct effect on shield‐ing but exert an electronic cis‐effect that onto the neighboring equatorial sites. Furthermore, charge redistribution within the core as well as the electronic trans‐effect of ligands ofdifferent donor strengths is reflected in the 103 Rh NMR shifts.

The aromatic amino acid L-tryptophan (Trp) is essentially metabolized along the host and microbial pathways. While much is known about the role played by downstream metabolites of each pathways in intestinal homeostasis, their role in lung immune homeostasis is underappreciated. Here we have examined the role played by the Trp hydroxylase/5-hydroxytryptamine (5-HT) pathway in calibrating host and microbial Trp metabolism during Aspergillus fumigatus pneumonia. We found that 5-HT produced by mast cells essentially contributed to pathogen clearance and immune homeostasis in infection by promoting the host protective indoleamine-2,3-dioxygenase 1/kynurenine pathway and limiting the microbial activation of the indole/aryl hydrocarbon receptor pathway. This occurred via regulation of lung and intestinal microbiota and signaling pathways. 5-HT was deficient in the sputa of patients with Cystic fibrosis, while 5-HT supplementation restored the dysregulated Trp partitioning in murine disease. These findings suggest that 5-HT, by bridging host-microbiota Trp partitioning, may have clinical effects beyond its mood regulatory function in respiratory pathologies with an inflammatory component.

This paper assesses the performance of European Union countries in achieving sustainable development using an assessment framework based on the 2030 Agenda. Through the application of the Spatial Sustainability Assessment Model, which integrates multi-criteria analysis with the geographical tool QuantumGIS, European countries are classified according to the four basic dimensions of sustainability (social, economic, environmental , and institutional) organized into various sub-dimensions, with reference to the year 2020. The results show that Northern countries have better overall sustainability performance in all dimensions except the environment. In contrast, Eastern European and Mediterranean countries perform worse, showing major weaknesses, especially in the economic and institutional dimensions, with a gap between the countries that joined the Union after 2004 and the other states. An in-depth analysis was conducted to highlight the reasons behind these difficulties in order to give useful indications to public decision-makers, as a tool for planning, on future choices.