Platelet-lysate-Expanded Mesenchymal Stromal Cells as a Salvage Therapy for Severe Resistant Graft-versus-Host Disease in a Pediatric Population

Despite advances in graft-versus-host-disease (GVHD) treatment, it is estimated that overall survival (OS) at 2 years for hematopoietic cell transplantation (HCT) recipients who experience steroid-resistant GVHD is 10%. Among recent therapeutic approaches for GVHD treatment, mesenchymal stromal cells (MSCs) hold a key position. We describe a multicenter experience of 11 pediatric patients diagnosed with acute or chronic GVHD (aGVHD, cGVHD) treated for compassionate use with GMP-grade unrelated HLA-disparate donors' bone marrow-derived MSCs, expanded in platelet-lysate (PL)-containing medium. Eleven patients (aged 4-15 years) received intravenous (i.v.) MSCs for aGVHD or cGVHD, which was resistant to multiple lines of immunosuppression. The median dose was 1.2 × 10 6 /kg (range: 0.7-3.7 × 10 6 /kg). No acute side effects were observed, and no late side effects were reported at a median follow-up of 8 months (range: 4-18 months). Overall response was obtained in 71.4% of patients, with complete response in 23.8% of cases. None of our patients presented GVHD progression upon MSC administration, but 4 patients presented GVHD recurrence 2 to 5 months after infusion. Two patients developed chronic limited GVHD. This study underlines the safety of PL-expanded MSC use in children. MSC efficacy seems to be greater in aGVHD than in cGVHD, even after failure of multiple lines of immunosuppression

Quantitative MRI Harmonization to Maximize Clinical Impact: The RIN-Neuroimaging Network

Neuroimaging studies often lack reproducibility, one of the cardinal features of the scientific method. Multisite collaboration initiatives increase sample size and limit methodological flexibility, therefore providing the foundation for increased statistical power and generalizable results. However, multisite collaborative initiatives are inherently limited by hardware, software, and pulse and sequence design heterogeneities of both clinical and preclinical MRI scanners and the lack of benchmark for acquisition protocols, data analysis, and data sharing. We present the overarching vision that yielded to the constitution of RIN-Neuroimaging Network, a national consortium dedicated to identifying disease and subject-specific in-vivo neuroimaging biomarkers of diverse neurological and neuropsychiatric conditions. This ambitious goal needs efforts toward increasing the diagnostic and prognostic power of advanced MRI data. To this aim, 23 Italian Scientific Institutes of Hospitalization and Care (IRCCS), with technological and clinical specialization in the neurological and neuroimaging field, have gathered together. Each IRCCS is equipped with high- or ultra-high field MRI scanners (i.e., ≥3T) for clinical or preclinical research or has established expertise in MRI data analysis and infrastructure. The actions of this Network were defined across several work packages (WP). A clinical work package (WP1) defined the guidelines for a minimum standard clinical qualitative MRI assessment for the main neurological diseases. Two neuroimaging technical work packages (WP2 and WP3, for clinical and preclinical scanners) established Standard Operative Procedures for quality controls on phantoms as well as advanced harmonized quantitative MRI protocols for studying the brain of healthy human participants and wild type mice. Under FAIR principles, a web-based e-infrastructure to store and share data across sites was also implemented (WP4). Finally, the RIN translated all these efforts into a large-scale multimodal data collection in patients and animal models with dementia (i.e., case study). The RIN-Neuroimaging Network can maximize the impact of public investments in research and clinical practice acquiring data across institutes and pathologies with high-quality and highly-consistent acquisition protocols, optimizing the analysis pipeline and data sharing procedures

Differential diagnosis of neurodegenerative dementias with the explainable MRI based machine learning algorithm MUQUBIA

Biomarker-based differential diagnosis of the most common forms of dementia is becoming increasingly important. Machine learning (ML) may be able to address this challenge. The aim of this study was to develop and interpret a ML algorithm capable of differentiating Alzheimer's dementia, frontotemporal dementia, dementia with Lewy bodies and cognitively normal control subjects based on sociodemographic, clinical, and magnetic resonance imaging (MRI) variables. 506 subjects from 5 databases were included. MRI images were processed with FreeSurfer, LPA, and TRACULA to obtain brain volumes and thicknesses, white matter lesions and diffusion metrics. MRI metrics were used in conjunction with clinical and demographic data to perform differential diagnosis based on a Support Vector Machine model called MUQUBIA (Multimodal Quantification of Brain whIte matter biomArkers). Age, gender, Clinical Dementia Rating (CDR) Dementia Staging Instrument, and 19 imaging features formed the best set of discriminative features. The predictive model performed with an overall Area Under the Curve of 98%, high overall precision (88%), recall (88%), and F1 scores (88%) in the test group, and good Label Ranking Average Precision score (0.95) in a subset of neuropathologically assessed patients. The results of MUQUBIA were explained by the SHapley Additive exPlanations (SHAP) method. The MUQUBIA algorithm successfully classified various dementias with good performance using cost-effective clinical and MRI information, and with independent validation, has the potential to assist physicians in their clinical diagnosis

Design challenges and innovative solutions in mixed-signal high voltage integrated circuits: case studies for automotive applications

Integrated Circuits (ICs) are playing a starring role in the automotive market, especially since legal and safety requirements have been introduced to rule vehicles emissions and operation. In addition to that the development of dedicated ICs for automotive applications is pushed not only by the harsh environment and the challenging safety requirements typical of the automotive applications, but also by the increase of the complexity of the electronic equipment within the car, and the need to minimize the lead time of automotive products. In the thesis hot topics typical of electronic systems for automotive applications are introduced, the relative study of the state of the art is presented and the limitations of currently available solutions are highlighted. Finally innovative solutions designed and developed to overcome the limitations of the state of the art are described and particular emphasis is given to performance, quality and safety aspects. The thesis reports the design and validation of battery management systems, high voltage output drivers for sensor-based ICs and motor drives, showing how to fulfill in an effective way the performance, quality and safety targets according to the guidelines and constraints of the latest automotive standards, like ISO26262 and AEC-Q100. The designed ICs have been simulated and manufactured, including layout drawings, in HVCMOS 350nm technology from AMS. The effectiveness and robustness of the proposed circuits has been validated on silicon and corresponded measurement results have been reported

Study, modeling and design of a flyback and boost DC-DC converter in HV-CMOS 350 nm technology for automotive applications

L`attività di tirocinio ha riguardato lo studio, la modellizzazione ed il progetto dagli schematici di un Flyback DD-DC converter in tecnologia CMOS High Voltage 0.35µm, in grado di operare correttamente in tutte le possibili situazioni che si possono creare in un autoveicolo. La tesi, che rispecchia le fasi del lavoro svolto si articola nei seguenti 4 capitoli: Primo capitolo: Stato dell`arte dei regolatori DC-DC e dei vari metodi di controllo presenti in letteratura. Secondo capitolo: Studio delle caratteristiche che si vogliono ottenere dal regolatore e modellizzazione dello stesso con particolare enfasi sulle soluzioni adottabili ed adottate per ottenerle. Terzo capitolo: Descrizione dettagliata degli schematici che compongono il regolatore, partendo dal concept fino ad arrivare al design completo degli schematici. Inoltre sono qui riportate tutte le simulazioni effettuate per controllare il corretto funzionamento del regolatore e per valutarne i parametri di merito. Quarto capitolo: Conclusioni e sviluppi futuri del chip

A high voltage high power high frequency boost/flyback DC-DC converter for automotive applications

This work aims to present an High Voltage High Power and High Frequency CMOS DC-DC converter able to work in both Flyback and Boost configurations, designed for automotive applications. The system, implemented in Austriamicrosystems 0.35um HVCMOS technology, is able to manage input voltages from 2.5V up to 36V and generates a programmable output voltage from 6 to 36V with an output current up to 900mA. To improve EMC/EMI system performances, dithering of switching frequency and slope controlling of the gate driver have been implemented

Canalicular adenoma immunoprofile: a case report.

OBJECTIVES: To report a case of canalicular adenoma (CA) and discuss the use of immunohistochemistry to better address the diagnosis given some unusual characteristics in this patient. BACKGROUND: CA is an uncommon benign neoplasm that can develop in minor salivary gland duct tissues throughout the oral cavity. At histology, it shares several features with other salivary tumors. Immunohistochemistry can be useful in the differential diagnosis. MATERIALS AND METHODS: The clinical presentation consisted in a nodule on the left upper lip of an 85-year-old man. The patient's main complaint was upper denture instability secondary to soft tissue changes. The nodule was excised under local anesthesia and underwent histological and immunohistochemical examination to rule out any malignancy. RESULTS: Histological findings, cytokeratin positivity and the absence of any reactivity to specific markers of myoepithelial differentiation confirmed the epithelial nature of the lesion. CONCLUSION: The histological diagnosis of benign salivary tumors such as CA can be confirmed by immunohistochemistry

Evaluating erosion performance of cold-sprayed coatings by Design of Experiments

Solid Particle Erosion (SPE) occurs when solid particles dragged by fluid means impinge on the surface of pneumatic or hydraulic systems resulting in loss of their mass. Multiple potential solutions to the problem have been investigated, including the modification of the machinery design and the use of filtration systems. From the perspective of materials engineering, the alleviation of SPE in metals has been widely encountered with the fabrication of coatings [1], using methods such as laser cladding, plasma spray, high-velocity oxyfuel and cold spray (CS) [2]. CS is a low-temperature particle deposition process in which microscale powder particles are accelerated to a high velocity (300 to 1200 m/s) through a De-Laval nozzle dragged by a high-pressure propelling gas (commonly nitrogen or helium) toward a target substrate [3]. The advantages of this powerful technique over other thermal spray processes include minimizing potential phase changes, preserving the original feedstock properties, and preventing coating defects, such as surface oxides and other inclusions. Amongst nickel-based superalloys, Inconel 718 (IN718) is commonly used in applications where stability at elevated temperatures, high long-time creep strength, and corrosion resistance in aggressive environments are required [3]. The complex nature of the SPE mechanism involves several variables related to the erodent properties (e.g., feed rate, velocity, size, hardness, impingement angle) and variables related to the intrinsic properties of the coating materials. As a result, identifying a standard method for predicting the erosion performance of coatings is extremely difficult. To this end, one of the most widely adopted techniques to assess the effect of control variables on coating erosion resistance is the Design of Experiments (DoE) [4], [5]. To date, few empirical studies have investigated the erosion performance of cold spray coatings through experimental design [6], which is a major innovative aspect of this study. The authors adopted a general full factorial design to investigate the SPE resistance of cold sprayed IN718-Ni composite coatings. The coatings were deposited onto substrates via high-pressure CS using nitrogen as the propulsive gas, with inlet pressure at 3.0 MPa and gas temperature at 1000 °C. The effect of the impingement angle (°), the erodent size (µm) and the erodent feed rate (g/min) on the erosion rate (mg/min) of the coating was investigated. Empirical results showed that the erodent feed rate and the impingement angle produced a statistically significant effect on the erosion rate, as well as the interaction between erodent size and impingement angle. Furthermore, a mathematical model relating such variables with the erosion rate was identified by stepwise regression analysis. This model effectively allows predicting the erosion performance of real components deposited with IN718-Ni coating under working conditions and properly designing the in-service conditions of new cold-sprayed components. The set of parameters optimizing the erosion rate was accordingly derived by performing an optimization, and then validated. Finally, the worn surfaces of the coatings were observed by SEM in order to understand the erosion mechanism