Search

Abstract Multiple myeloma (MM) is a plasma cell (PC) disorder characterized by skeletal involvement at the time of diagnosis. Recently, cell-free DNA (cfDNA) has been proven to recapitulate the heterogeneity of bone marrow (BM) disease. Our aim was to evaluate the prognostic role of cfDNA at diagnosis according to disease distribution, and to investigate the role of the MM microenvironment inflammatory state in supplying the release of cfDNA. A total of 162 newly diagnosed MM patients were screened using 18F-FDG PET/CT and assessed by ultra low-pass whole genome sequencing (ULP-WGS). High cfDNA tumor fraction (ctDNA) levels were correlated with different tumor mass markers, and patients with high ctDNA levels at diagnosis were more likely to present with metabolically active paraskeletal (PS) and extramedullary (EM) lesions. Moreover, we demonstrated that microenvironment cancer-associated fibroblast (CAFs)-mediated inflammation might correlate with high ctDNA levels. Indeed, a high cfDNA TF level at diagnosis predicted a poorer prognosis, independent of R-ISS III and 1q amplification; the inclusion of >12% ctDNA in the current R-ISS risk score enables a better identification of high-risk patients. ctDNA can be a reliable and less invasive marker for disease characterization, and can refine patient risk.

Abstract Psoriasis is a chronic, immune-mediated, inflammatory skin disease, associated with multiple comorbidities and psychological and psychiatric disorders. The quality of life of patients with this disease is severely compromised, especially in moderate-to-severe plaque psoriasis. Secukinumab, a fully humanized monoclonal antibody, was the first anti-interleukin (IL)-17 biologic approved for treating psoriasis. Secukinumab demonstrated long-lasting efficacy and a good safety profile in individuals with plaque psoriasis, and it is associated with an improvement in health-related quality of life. While there is evidence that early treatment with systemic therapy can affect disease progression and improve long-term outcomes in other autoimmune diseases, evidence is limited in psoriasis, especially in real-world settings. This review provides an overview of studies describing the effectiveness of secukinumab in the treatment of psoriasis summarizing the literature and focusing on real-world evidence and early intervention.

Abstract In this paper, we investigate the effectiveness of shape completion neural networks as clinical aids in maxillofacial surgery planning. We present a pipeline to apply shape completion networks to automatically reconstruct complete eumorphic 3D meshes starting from a partial input mesh, easily obtained from CT data routinely acquired for surgery planning. Most of the existing works introduced solutions to aid the design of implants for cranioplasty, i.e. all the defects are located in the neurocranium. In this work, we focus on reconstructing defects localized on both neurocranium and splanchnocranium. To this end, we introduce a new dataset, specifically designed for this task, derived from publicly available CT scans and subjected to a comprehensive pre-processing procedure. All the scans in the dataset have been manually cleaned and aligned to a common reference system. In addition, we devised a pre-processing stage to automatically extract point clouds from the scans and enrich them with virtual defects. We experimentally compare several state-of-the-art point cloud completion networks and identify the two most promising models. Finally, expert surgeons evaluated the best-performing network on a clinical case. Our results show how casting the creation of personalized implants as a problem of shape completion is a promising approach for automatizing this complex task.

Introduction: Tildrakizumab, a humanized monoclonal antibody targeting the p19 subunit of interleukin-23 (IL-23), has shown promise in the management of moderate-to-severe plaque psoriasis, offering potential improvements in clinical outcomes and quality of life. Objectives: The study aimed to identify patient characteristics that indicate the initiation of a 200-mg dosage of tildrakizumab in a real-world setting, focusing on factors that enhance treatment efficacy and safety. Methods: This prospective study included 54 adult patients with moderate-to-severe plaque psoriasis treated with tildrakizumab 200 mg from March 2023 to March 2024 across 13 Italian Dermatology Units. Data collected included demographics, disease duration, comorbidities, and previous treatments. PASI, BSA, and DLQI scores were recorded at baseline, week 4, 16, and 28. Safety was assessed through adverse event reporting. Univariate analysis was performed to identify baseline characteristics significantly associated with achieving PASI ≤ 5 at week 16. Results: Significant reductions in PASI scores were observed at week 4 (9 ± 6.9, p 30) had higher odds (OR = 4.333, p < 0.05) of achieving PASI ≤ 5. Longer disease duration and starting with a 100 mg dose also correlated with better outcomes. The safety profile was favorable, with minimal adverse events reported. Conclusions: Tildrakizumab 200 mg is effective and safe for moderate-to-severe psoriasis, particularly in obese patients. These findings support its use as a long-term treatment option.

Abstract The complexity of Multiple Myeloma (MM) is driven by several genomic aberrations, interacting with disease-related and/or -unrelated factors and conditioning patients’ clinical outcome. Patient’s prognosis is hardly predictable, as commonly employed MM risk models do not precisely partition high- from low-risk patients, preventing the reliable recognition of early relapsing/refractory patients. By a dimensionality reduction approach, here we dissect the genomic landscape of a large cohort of newly diagnosed MM patients, modelling all the possible interactions between any MM chromosomal alterations. We highlight the presence of a distinguished cluster of patients in the low-dimensionality space, with unfavorable clinical behavior, whose biology was driven by the co-occurrence of chromosomes 1q CN gain and 13 CN loss. Presence or absence of these alterations define MM patients overexpressing either CCND2 or CCND1, fostering the implementation of biology-based patients’ classification models to describe the different MM clinical behaviors.

The design of patient-specific implants for cranioplasty surgery is time-consuming and challenging. Hence, the 2021 AutoImplant II challenge, consisting of the SkullBreak and SkullFix datasets, was organized to foster research on computer vision techniques pursuing automation of the cranial implant design task. Data-driven methods working on Computed Tomography (CT) emerged as a promising procedure for the realization of such a task. The best performing approaches turned out to rely on ensembles of Convolutional Neural Networks (CNN) architectures that either process each CT slice separately or the entire voxelized volume through computationally demanding three-dimensional convolutions. More recently, few methods were designed to deal with different data representations, for instance point clouds, to perform skull completion. Similarly, we investigate a novel solution for implant generation that deploys a conditioned occupancy network. Starting from the partial point cloud, we directly reconstruct the completed voxel grid by evaluating the learned occupancy function in the given space resolution. Our approach can generate high-quality implants achieving qualitative and quantitative results comparable to state-of-the-art methods on the SkullBreak and SkullFix datasets while requiring significantly less computational resources. The model trained on the SkullBreak dataset successfully generalize to real craniotomies provided in the MUG500+ dataset.

The impact of daratumumab on CD34+ hematopoietic stem cell (HSC) mobilization has recently been a matter of concern. To address this issue, we compared CD34+ HSC-related outcomes in patients with multiple myeloma treated with daratumumab-based quadruplets (N = 44) and bortezomib/thalidomide/dexamethasone (N = 50) before cyclophosphamide-based mobilization. Plerixafor was more often required in the daratumumab group (52% vs. 20%, p = 0.002) and, despite a lower total yield, retained its efficacy in boosting HSC harvesting (+90% vs. +79%, p = 0.463). As a result, the same proportion of patients reached their planned collection goal in the two groups, suggesting its potential to overcome the interference of daratumumab on HSC mobilization. No clinically significant differences were observed in the immediate post-autologous HSC transplant interval in the two groups.

A 74-year-old man with advanced heart failure was admitted to the hospital with a diagnosis of colorectal cancer, and he underwent surgery. To maintain stable hemodynamics, the Impella CP device was used. The patient was weaned from the device shortly after surgery, and he had an uneventful postoperative course. This case may pave the way for non-procrastinating surgery in patients with poorly stable hemodynamics.

Background: Existing data on the impact of sex differences on transvenous lead extraction (TLE) outcomes in cardiac device patients are limited. Objective: The purpose of this study was to evaluate the safety and efficacy of mechanical TLE in female patients. Methods: A retrospective evaluation was performed on 3051 TLE patients (group 1: female; group 2: male) from a single tertiary referral center. All individuals received treatment using single sheath mechanical dilation and various venous approaches as required. Results: Our analysis included 3051 patients (group 1: 750; group 2: 2301), with a total of 5515 leads handled with removal. Female patients were younger, had a higher left ventricular ejection fraction, and lower prevalences of coronary artery disease and diabetes mellitus. Infection was more common in male patients, whereas lead malfunction or abandonment were more frequent in female patients. Radiologic success was lower in female patients (95.8% vs 97.5%; P = .003), but there was no significant difference in clinical success between groups (97.2% vs 97.5%; P = .872). However, major complications (1.33% vs 0.60%; P

Artificial Intelligence (AI) applications and Machine Learning (ML) methods have gained much attention in recent years for their ability to automatically detect patterns in data without being explicitly taught rules. Specific features characterise the ECGs of patients with Brugada Syndrome (BrS); however, there is still ambiguity regarding the correct diagnosis of BrS and its differentiation from other pathologies.This work presents an application of Echo State Networks (ESN) in the Recurrent Neural Networks (RNN) class for diagnosing BrS from the ECG time series.12-lead ECGs were obtained from patients with a definite clinical diagnosis of spontaneous BrS Type 1 pattern (Group A), patients who underwent provocative pharmacological testing to induce BrS type 1 pattern, which resulted in positive (Group B) or negative (Group C), and control subjects (Group D). One extracted beat in the V2 lead was used as input, and the dataset was used to train and evaluate the ESN model using a double cross-validation approach. ESN performance was compared with that of 4 cardiologists trained in electrophysiology.The model performance was assessed in the dataset, with a correct global diagnosis observed in 91.5 % of cases compared to clinicians (88.0 %). High specificity (94.5 %), sensitivity (87.0 %) and AUC (94.7 %) for BrS recognition by ESN were observed in Groups A + B vs. C + D.Our results show that this ML model can discriminate Type 1 BrS ECGs with high accuracy comparable to expert clinicians. Future availability of larger datasets may improve the model performance and increase the potential of the ESN as a clinical support system tool for daily clinical practice.

Clonal hematopoiesis of indeterminate potential (CHIP) refers to the phenomenon where a hematopoietic stem cell acquires fitness-increasing mutation(s), resulting in its clonal expansion. CHIP is frequently observed in multiple myeloma (MM) patients, and it is associated with a worse outcome. High-throughput amplicon-based single-cell DNA sequencing was performed on circulating CD34+ cells collected from twelve MM patients before autologous stem cell transplantation (ASCT). Moreover, in four MM patients, longitudinal samples either before or post-ASCT were collected. Single-cell sequencing and data analysis were assessed using the MissionBio Tapestri® platform, with a targeted panel of 20 leukemia-associated genes. We detected CHIP pathogenic mutations in 6/12 patients (50%) at the time of transplant. The most frequently mutated genes were TET2, EZH2, KIT, DNMT3A, and ASXL1. In two patients, we observed co-occurring mutations involving an epigenetic modifier (i.e., DNMT3A) and/or a gene involved in splicing machinery (i.e., SF3B1) and/or a tyrosine kinase receptor (i.e., KIT) in the same clone. Longitudinal analysis of paired samples revealed a positive selection of mutant high-fitness clones over time, regardless of their affinity with a major or minor sub-clone. Copy number analysis of the panel of all genes did not show any numerical alterations present in stem cell compartment. Moreover, we observed a tendency of CHIP-positive patients to achieve a suboptimal response to therapy compared to those without. A sub-clone dynamic of high-fitness mutations over time was confirmed.

Abstract Nanofibrous mats provide substantial delamination hindering in composite laminates, especially if the polymer (as rubbers) can directly toughen the composite resin. Here, the well-known Nylon 66 nanofibers were impregnated with Nitrile Butadiene Rubber (NBR) for producing rubber/thermoplastic membranes for hampering the delamination of epoxy Carbon Fiber Reinforced Polymers (CFRPs). The starting polyamide mats were electrospun using two different solvent systems, and their effect on the mat's thermal and mechanical properties was investigated, as well as the laminate Mode I delamination resistance via Double Cantilever Beam (DCB) tests. Plain Nylon 66 mats electrospun from formic acid/chloroform perform better than the ones obtained from a solvent system containing trifluoroacetic acid, showing up to + 64% vs + 53% in interlaminar fracture toughness (GI), respectively. The effect of NBR coating benefits both nanofiber types, significantly raising the GI. The best results are obtained when interleaving medium-thickness and lightweight mats (20 µm, 9–10 g/m2) with 70–80 wt% of loaded rubber, achieving up to + 180% in GI. The work demonstrates the ability of NBR at improving the delamination hindering of common polyamide nonwovens, paving the way to the use of NBR-coated Nylon 66 nanofibers as effective interleaves for GI enhancement and overall composite safety improvement.

Abstract Background Radiofrequency ablation has been shown to be a safe and effective treatment for scar-related ventricular arrhythmias (VA). Recent preliminary studies have shown that real time integration of late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) images with electroanatomical map (EAM) data may lead to increased procedure efficacy, efficiency, and safety. Methods VOYAGE is a prospective, randomized, multicenter controlled open label study designed to compare in terms of efficacy, efficiency, and safety a CMR aided/guided workflow to standard EAM-guided ventricular tachycardia (VT) ablation. Patients with an ICD or with ICD implantation expected within 1 month, with scar related VT, suitable for CMR and multidetector computed tomography (MDCT) will be randomized to a CMR-guided or CMR-aided approach, whereas subjects unsuitable for imaging or with image quality deemed not sufficient for postprocessing will be allocated to standard of care ablation. Primary endpoint is defined as VT recurrences (sustained or requiring appropriate ICD intervention) during 12 months follow-up, excluding the first month of blanking period. Secondary endpoints will include procedural efficiency, safety, impact on quality of life and comparison between CMR-guided and CMR-aided approaches. Patients will be evaluated at 1, 6 and 12 months. Discussion The clinical impact of real time CMR-guided/aided ablation approaches has not been thoroughly assessed yet. This study aims at defining whether such workflow results in more effective, efficient, and safer procedures. If proven to be of benefit, results from this study could be applied in large scale interventional practice. Trial registrationClinicalTrials.gov, NCT04694079, registered on January 1, 2021.

Corrected transposition of the great arteries (c-TGA) is a congenital abnormality characterized by atrioventricular (AV) and ventriculoarterial discordance, associated with early and late-onset conduction disturbances. We report the case of a c-TGA patient affected by congenital complete AV block, with right ventricular lead malfunction with prolonged dwell time and two abandoned leads. He underwent leadless VDD pacemaker implantation at an unusual site (i.e. the anterior wall of subpulmonic left ventricle), with an optimal electrical performance, a good AV synchrony, and QRS narrowing. Leadless VDD pacing is safe and feasible in patients affected by corrected transposition of the great arteries, even with an unusual implant site such as the anterior wall of subpulmonic left ventricle. [ABSTRACT FROM AUTHOR]

Human cancer arises from a population of cells that have acquired a wide range of genetic alterations, most of which are targets of therapeutic treatments or are used as prognostic factors for patient’s risk stratification. Among these, copy number alterations (CNAs) are quite frequent. Currently, several molecular biology technologies, such as microarrays, NGS and single-cell approaches are used to define the genomic profile of tumor samples. Output data need to be analyzed with bioinformatic approaches and particularly by employing computational algorithms.Molecular biology tools estimate the baseline region by comparing either the mean probe signals, or the number of reads to the reference genome. However, when tumors display complex karyotypes, this type of approach could fail the baseline region estimation and consequently cause errors in the CNAs call. To overcome this issue, we designed an R-package, BoBafit, able to check and, eventually, to adjust the baseline region, according to both the tumor-specific alterations’ context and the sample-specific clustered genomic lesions.Several databases have been chosen to set up and validate the designed package, thus demonstrating the potential of BoBafit to adjust copy number (CN) data from different tumors and analysis techniques.Relevantly, the analysis highlighted that up to 25% of samples need a baseline region adjustment and a redefinition of CNAs calls, thus causing a change in the prognostic risk classification of the patients.We support the implementation of BoBafit within CN analysis bioinformatics pipelines to ensure a correct patient’s stratification in risk categories, regardless of the tumor type.

IntroductionMinimal residual disease (MRD) is commonly assessed in bone marrow (BM) aspirate. However, sample quality can impair the MRD measurement, leading to underestimated residual cells and to false negative results. To define a reliable and reproducible method for the assessment of BM hemodilution, several flow cytometry (FC) strategies for hemodilution evaluation have been compared.MethodsFor each BM sample, cells populations with a well-known distribution in BM and peripheral blood - e.g., mast cells (MC), immature (IG) and mature granulocytes (N) – have been studied by FC and quantified alongside the BM differential count.ResultsThe frequencies of cells’ populations were correlated to the IG/N ratio, highlighting a mild correlation with MCs and erythroblasts (R=0.25 and R=0.38 respectively, with p-value=0.0006 and 0.0000052), whereas no significant correlation was found with B or T-cells. The mild correlation between IG/N, erythroblasts and MCs supported the combined use of these parameters to evaluate BM hemodilution, hence the optimization of the ALLgorithMM. Once validated, the ALLgorithMM was employed to evaluate the dilution status of BM samples in the context of MRD assessment. Overall, we found that 32% of FC and 52% of Next Generation Sequencing (NGS) analyses were MRD negative in samples resulted hemodiluted (HD) or at least mildly hemodiluted (mHD).ConclusionsThe high frequency of MRD-negative results in both HD and mHD samples implies the presence of possible false negative MRD measurements, impairing the correct assessment of patients’ response to therapy and highlighs the importance to evaluate BM hemodilution.

In PVC compounds, hydrogen chloride plays a fundamental role in ·H and ·OH radical trapping, lowering the flame energy during combustion. Furthermore, it yields actual Lewis acids promoting the cross-linking of the polyene sequences from PVC degradation and bringing a char layer, protecting PVC items from flames. Therefore, PVC is inherently flame-retarded. However, plasticized PVC requires flame retardants and smoke suppressants to enhance fire performance. Low-smoke acidity PVC compounds have been developed to reduce the HCl emission during combustion and, therefore, the acidity of the smoke. They contain potent acid scavengers capable of acting at high temperatures. They react with hydrogen chloride in the condensed phase, making it unavailable in the gas and even in the condensed phase, compromising the reaction to fire and enhancing the smoke produced during the combustion. The effect of the sequestration of hydrogen chloride in PVC compounds for cables by potent acid scavengers is studied in this paper through measurements of oxygen index, heat release, and smoke production. It is noteworthy that the potent acid scavengers strongly affect parameters such as the oxygen index, the fire growth rate in cone calorimetry, the specific (total) heat capacity, and the specific heat of combustion of fuel gases in micro combustion calorimetry. In some formulations, acid scavengers reduce the oxygen index below the values of the formulations without flame retardants and double their fire growth rate. In fact, they neutralize the action of antimony trioxide and Lewis acid precursors commonly used as flame retardants and smoke suppressants in PVC items, making them prone to ignite, release smoke, and spread flame. A new generation of flame retardants and smoke suppressants is needed to keep together the low-smoke acidity and the fire performance in PVC items.

Epicardial access is often crucial for successful ventricular tachycardia (VT) ablation, but it is often burdened by significant procedural risk. Intentional coronary vein exit and intrapericardial CO 2 insufflation (EpiCO 2) can facilitate subxiphoid pericardial access. This prospective study aimed to assess procedural feasibility, safety, and impact of the introduction of intrapericardial CO 2 insufflation for epicardial access in a referral center for VT ablation. All consecutive patients treated with epicardial VT ablation between November 2022 and January 2024 with the EpiCO 2 technique at Pisa University Hospital were prospectively enrolled and compared in terms of feasibility, efficiency, and safety with a local retrospective cohort of patients treated with subxiphoid dry puncture between July 2018 and October 2022. Twenty-two consecutive patients (90.9% male; mean age, 54.3 years) underwent VT ablation with EpiCO 2 during the study period. Epicardial access was achieved in all patients; median time from coronary sinus (CS) cannulation to epicardial access was 33 minutes. Intentional vein exit was successful in all cases, whereas CO 2 insufflation was not feasible in 1 patient. There were no major complications and no significant bleeding. Since EpiCO 2 introduction, epicardial approach utilization increased from 17.8% to 40% of all VT procedures. Comparison with 20 standard dry approach epicardial ablations showed no significant differences in terms of total procedural duration (322.5 [interquartile range, 296.75–363.75] minutes vs 359 [interquartile range, 323–409] minutes; P =.08). In our single-center experience, EpiCO 2 was feasible and safe and led to significant increase in procedural volume without affecting total procedural time compared with standard dry puncture. [ABSTRACT FROM AUTHOR]

Abstract Introduction Severe pneumonia caused by multidrug-resistant Acinetobacter baumannii (MDR-AB) remains a difficult-to-treat infection. Considering the poor lung penetration of most antibiotics, the choice of the better antibiotic regimen is debated. Methods We performed a prospective, observational, multicenter study conducted from January 2017 to June 2020. All consecutive hospitalized patients with severe pneumonia due to MDR-AB were included in the study. The primary endpoint of the study was to evaluate risk factors associated with survival or death at 30 days from pneumonia onset. A propensity score for receiving therapy with fosfomycin was added to the model. Results During the study period, 180 cases of hospital-acquired pneumonia, including ventilator-associated pneumonia, caused by MDR-AB strains were observed. Cox regression analysis of factors associated with 30-day mortality, after propensity score, showed that septic shock, and secondary bacteremia were associated with death, while a fosfomycin-containing regimen was associated with 30-day survival. Antibiotic combinations with fosfomycin in definitive therapy for 44 patients were: fosfomycin + colistin in 11 (25%) patients followed by fosfomycin + carbapenem + tigecycline in 8 (18.2%), fosfomycin + colistin + tigecycline in 7 (15.9%), fosfomycin + rifampin in 7 (15.9%), fosfomycin + tigecycline in 6 (13.6%), fosfomycin + carbapenem in 3 (6.8%), and fosfomycin + aminoglycoside in 2 (4.5%). Conclusions This real-life clinical experience concerning the therapeutic approach to severe pneumonia caused by MDR-AB provides useful suggestions to clinicians, showing the use of different antibiotic regimens with a predominant role for fosfomycin. Further randomized clinical trials are necessary to confirm or exclude these observations.

Catalysts are used for producing the vast majority of chemical products. Usually, catalytic membranes are inorganic. However, when dealing with reactions conducted at low temperatures, such as in the production of fine chemicals, polymeric catalytic membranes are preferred due to a more competitive cost and easier tunability compared to inorganic ones. In the present work, nanofibrous mats made of poly(ethylene oxide), PEO, and poly(ethylene glycol) diacrylate, PEGDA, blends with the Au/Pd catalyst are proposed as catalytic membranes for water phase and low-temperature reactions. While PEO is a water-soluble polymer, its blending with PEGDA can be exploited to make the overall PEO/PEGDA blend nanofibers water-resistant upon photo-crosslinking. Thus, after the optimization of the blend solution (PEO molecular weight, PEO/PEGDA ratio, photoinitiator amount), electrospinning process, and UV irradiation time, the resulting nanofibrous mat is able to maintain the nanostructure in water. The addition of the Au6/Pd1 catalyst (supported on TiO2) in the PEO/PEGDA blend allows the production of a catalytic nanofibrous membrane. The reduction of 4-nitrophenol (4-NP) to 4-aminophenol (4-AP), taken as a water phase model reaction, demonstrates the potential usage of PEO-based membranes in catalysis.

Abstract In this research, we propose an advanced system for the cleaning of wax-based coatings applied on indoor bronzes. To this aim we developed a new kind of eco-friendly gel based on PHB (poly-3-hydroxybutyrate) used as thickening agent, biodiesel (BD) and dimethyl carbonate (DMC). BD is a mixture of methyl esters obtained from palm oil, which acts as cleaning agent while DMC was added as additional solvent to partially solubilize PHB and forming a gelly phase. For the first time a PHB-based gel obtained by mixing two solvents with different proprieties was proposed, expanding the range of possible formulations, that can be used according to the specific restoration purpose. After the preliminary characterization of chemical and physical properties of the gel, an ad hoc analytical protocol was implemented to evaluate both the cleaning efficiency and the release of residues on the treated surfaces. Standard samples were prepared following ancient recipes and submitted to spectroscopic and chromatographic analysis before and after the cleaning procedures. Finally, the performances of PHB-DMC/BD gel were assessed on a real case of study presenting a wax-based coating: the Pulpito della passione attributed to Donatello and dated back to 1460. In situ analysis demonstrated the high cleaning efficiency of the proposed systems also for the removal of aged coatings.

The improvement of the fracture toughness of adhesive joints is a key factor in many structural applications. The ability of nylon electrospun nanofibrous mat to act as an adhesive carrier and reinforcing web in adhesive bonding has been demonstrated by the Authors in previous works. It has been shown that the impregnation method developed and refined during the previous studies allow generating high-quality pre-preg nanomats out of a 2k unfilled epoxy resin. By applying this methodology, in the present work, rubbery nanofibrous mats have been adopted for the first time to reinforce and increase the fracture toughness of adhesive joints. Rubbery nanofibers were produced by electrospinning of nitrile butadiene rubber (NBR) and poly(ε-caprolactone) (PCL). The addition of the semi-crystalline polymer (PCL) is exploited to maintain the nanofibrous morphology, which the rubber alone (NBR) would not be able to ensure due to its low glass transition temperature (Tg). The nanofibers thus obtained have been integrated into a two-component high strength epoxy resin for structural applications. S235 steel adherends for Double Cantilever Beam (DCB) tests have been manufactured and sandblasted to improve adhesion. An optimization of the sandblasting parameters (distance, pressure, angle and time) has been carried out evaluating the shear strength and the fracture surfaces on S235 steel Single Lap Joints (SLJ). Finally, DCB tests have been performed to compare the mode I fracture toughness with and without the rubbery electrospun nanomats.

Rubbery electrospun nanofibers represent a smart way for hindering delamination and enhancing damping capacity in Carbon Fiber Reinforced Polymer (CFRP) laminates, which are two of the most serious drawbacks hampering their use. Nitrile Butadiene Rubber / Poly(ε-caprolactone) (NBR/PCL) blend nanofibers, with 20‐40-60%wt of not crosslinked NBR, were interleaved in epoxy-based CFRPs to evaluate their effect on the final composite performance. CFRPs with rubbery mats show a significant increase of the energy release rate in Mode I, both at initiation and propagation stages (+480% and +340%, respectively), thanks to NBR/PCL blend ability to promote high matrix toughening of the fragile epoxy resin. In Mode II a maximum improvement of about 30% was achieved. The presence of highly damping NBR component widens the composite energy dissipation window below room temperature, enhancing the CFRP damping. Similar results were obtained with two different epoxy resins, and the effect of the layering sequence was also discussed. NBR percentage in nanofibers and nanofibrous mats amount may strongly affect the CFRP maximum operating temperature. Nanofibers can be positioned, during lamination, in the critical regions where interlaminar stresses are mostly concentrated due to geometric discontinuities providing a flexible approach to localized modification of laminates.

Energy depletion caused by ischemic brain insults may result in persistent neuronal depolarization accompanied by hyper-stimulation of ionotropic glutamate receptors and excitotoxic phenomena, possibly leading to cell death. The use of glutamate receptor antagonists, such as the AMPARs antagonist Perampanel (PER), might be a pharmacological approach to counteract the excessive over-activation of glutamate receptors providing neuroprotective effects. Using electrophysiological and molecular analyses, we investigated the effect of PER against in vitro ischemia obtained by oxygen and glucose deprivation (OGD) in rat slices of two brain structures particularly sensitive to ischemic insults, the nucleus striatum and the hippocampus. We found that in these regions PER was able to avoid the OGD-induced neuronal suffering, at low doses not reducing basal excitatory synaptic transmission and not altering long-term potentiation (LTP) induction. Furthermore, in both the analysed regions, PER blocked a pathological form of LTP, namely ischemic LTP (iLTP). Finally, we hypothesized that the protective effect of PER against OGD was due to its capability to normalize the altered synaptic localization and function of AMPAR subunits, occuring after an ischemic insult. Taken together these findings support the idea that PER is a drug potentially effective to counteract ischemic damage.

The pathogenesis of Parkinson’s disease (PD) is thought to rely on a complex interaction between the patient’s genetic background and a variety of largely unknown environmental factors. In this scenario, the investigation of the genetic bases underlying familial PD could unveil key molecular pathways to be targeted by new disease-modifying therapies, still currently unavailable. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are responsible for the majority of inherited familial PD cases and can also be found in sporadic PD, but the pathophysiological functions of LRRK2 have not yet been fully elucidated. Here, we will review the evidence obtained in transgenic LRRK2 experimental models, characterized by altered striatal synaptic transmission, mitochondrial dysfunction, and α-synuclein aggregation. Interestingly, the processes triggered by mutant LRRK2 might represent early pathological phenomena in the pathogenesis of PD, anticipating the typical neurodegenerative features characterizing the late phases of the disease. A comprehensive view of LRRK2 neuronal pathophysiology will support the possible clinical application of pharmacological compounds targeting this protein, with potential therapeutic implications for patients suffering from both familial and sporadic PD.

The paper presents a simple method for producing rubbery nanofibers without additional crosslinking required. Electrospinning's fast solvent evaporation is able to induce in liquid NBR/PCL pairs thermoplastic elastomeric (TPE) structure that holds stable over time without any further processing. The slight relative solubility of the polymers pair promotes a homogeneous blend formation with low Tg regions of blended NBR/PCL, avoiding phase separation. Such nanofibers show also a PCL-like crystal phase that is surprisingly higher than plain PCL nanofibrous counterpart and seemingly promoted by NBR/PCL interaction at molecular scale. The obtained nanofibrous-TPE morphology is reproducible, stable with time up to at least two years and is detected in a wide range of blend compositions (up to 80%wt NBR). Such a morphology reflects in good mechanical properties, which are analysed with a fitting model taking into account nanofibrous structure. Its impressive fitting ability helps interpretation of tensile tests behavior, carried out via normalization of force data with respect to sample mass, highlighting the contribution of liquid rubber in improving both elastic modulus and properties at failure. Such rubbery nanofibers represent a cost-effective powerful tool for the production of advanced self-damping composite materials with improved overall mechanical properties. Keywords: Nitrile butadiene rubber, Polycaprolactone, Electrospinning, Rubber nanofiber, Thermal properties, Tensile test

This article deals with the increasing criminalisation and confinement of youth from poorer districts and primary migrants, carried out that much more often for those who refuse to resign themselves to their position as having “fallen through the cracks”. It is based on some twenty years of field work and multiple ethnographies stemming from stays – mainly in Burkina Faso, Belgium and Malta. The text is subdivided into three parts. The first, more contextual, provides some key elements allowing us to document the confinement of the poor. The second stresses the effects of the processes of criminalization and confinement for those primarily concerned, but also on a societal scale. In concluding the work, the third part questions the tensions and connivances between neo-liberal and security logics. It thus proposes taking another look at the acts young people at risk and primary migrants were convicted of from the joint angle of belonging to a neo-liberal project and resistance to the ostracizations inherent in its inegalitarian functioning.

Among genetic abnormalities identified in Parkinson's disease (PD), mutations of the leucine-rich repeat kinase2 (LRRK2) gene, such as the G2019S missense mutation linked to enhanced kinase activity, are the most common. While the complex role of LRRK2 has not been fully elucidated, evidence that mutated kinase activity affects synaptic transmission has been reported. Thus, our aim was to explore possible early alterations of neurotransmission produced by the G2019S LRRK2 mutation in PD. We performed electrophysiological patch-clamp recordings of striatal spiny projection neurons (SPNs) in the G2019S-Lrrk2 knock-in (KI) mouse model of PD, in D1994S kinase-dead (KD), Lrrk2 knock-out (KO) and wild-type (WT) mice. In G2019S Lrrk2 KI mice, basal spontaneous glutamatergic transmission, synaptic facilitation, and NMDA/AMPA ratios were unchanged, whereas the stimulation of dopamine (DA) D2 receptor by quinpirole reduced the spontaneous and evoked excitatory postsynaptic currents (EPSC). Quinpirole reduced the EPSC amplitude of SPNs in KI but not in KD, KO and WT mice, suggesting that the enhanced LRRK2 kinase activity induced by the G2019S mutation is associated with the observed functional alteration of SPNs synaptic transmission. The effect of quinpirole was mediated by a phospholipase C (PLC)-dependent release of endocannabinoid, with subsequent activation of presynaptic cannabinoid receptor 1 and reduced release of glutamate. The key role of DA D2 receptor in reducing glutamatergic output in our LRRK2 genetic model of PD further supports the use of DA agonists in the treatment of early PD patients with LRRK2 mutations to counteract the disease progression.

Abstract Background The cardiovascular disease risk was assessed in metabolically healthy obese (MHO) children, obese children with metabolic disorders (MUO), and to a control group of normal-weight children using carotid intima-media thickness (CIMT). Methods Participants were 204 obese children (114 M, 90 F), including 162 MUO (74 M, 88 F) and 42 MHO (24 M, 18 F), and 99 gender- and age-matched controls (45 M, 54 F). Glucose, triglycerides, total cholesterol, high-density and low-density lipoprotein cholesterol, and other serum values were determined in peripheral blood. Anthropometric parameters, blood pressure, and a carotid Doppler ultrasound scan were also acquired. The mean CIMT of obese subjects and controls was compared by analysis of variance. Abnormality of even one of the metabolic parameters assessed involved assignation to the MUO group. Mean CIMT was compared in MHO and MUO children. Results Mean CIMT in control children was 402.97 ± 53.18 μm (left carotid artery) and 377.85 ± 52.47 μm (right carotid artery). In MHO and MUO patients CIMT was respectively 453.29 ± 62.04 and 460.17 ± 92.22 μm (left carotid artery) and 446.36 ± 49.21 and 456.30 ± 85.7 μm (right carotid artery). The mean CIMT was not significantly different in MUO and MHO children, whereas it showed a significant difference between both groups of obese children and controls (p

During multiple sclerosis (MS), a close link has been demonstrated to occur between inflammation and neuro-axonal degeneration, leading to the hypothesis that immune mechanisms may promote neurodegeneration, leading to irreversible disease progression. Energy deficits and inflammation-driven mitochondrial dysfunction seem to be involved in this process. In this work we investigated, by the use of striatal electrophysiological field-potential recordings, if the inflammatory process associated with experimental autoimmune encephalomyelitis (EAE) is able to influence neuronal vulnerability to the blockade of mitochondrial complex IV, a crucial component for mitochondrial activity responsible of about 90% of total cellular oxygen consumption. We showed that during the acute relapsing phase of EAE, neuronal susceptibility to mitochondrial complex IV inhibition is markedly enhanced. This detrimental effect was counteracted by the pharmacological inhibition of microglia, of nitric oxide (NO) synthesis and its intracellular pathway (involving soluble guanylyl cyclase, sGC, and protein kinase G, PKG). The obtained results suggest that mitochondrial complex IV exerts an important role in maintaining neuronal energetic homeostasis during EAE. The pathological processes associated with experimental MS, and in particular the activation of microglia and of the NO pathway, lead to an increased neuronal vulnerability to mitochondrial complex IV inhibition, representing promising pharmacological targets.

The business model concept is a common topic investigated in different fields of research. To participate to the debate around such concept in the accounting field, the objective of this paper is showing whether and how the voluntary disclosure of the non-mandatory IASB (2010) macro-components, that we consider the key elements of a business model of financial entities, increases the value relevance of accounting amounts. Analyzing a sample of 124 European financial entities over the period 2010–2013, the paper shows that the value relevance of accounting amounts of entities that provide a wide disclosure of their business model is higher than the one of entities that provide a limited disclosure of their business model. These findings not only shed lights about the importance of disclosing information relating to the business model to improve the usefulness of accounting amounts for investors’ strategies, but also have implication for regulators and standard setters that from results could learn the opportunity to make the disclosure of IASB (2010) compulsory for all the IAS/IFRS compliant entities.