2,763 research outputs found

    Anti-calcitonin gene-related peptide monoclonal antibodies for the treatment of vestibular migraine: A prospective observational cohort study

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    Background: Vestibular migraine is considered the most common cause of recurrent vertigo for which specific treatments are missing. Monoclonal antibodies against calcitonin gene-related peptide,, are effective in preventing migraine. Since CGRP is also detected in human cochlear and vestibular organs it may also play a role in vestibular physiology. Methods: This is a prospective observational cohort study, aiming at evaluating the efficacy of erenumab, fremanezumab or galcanezumab for the treatment of fifty vestibular migraine patients. We assessed mean monthly days with headache and dizziness/vestibular symptoms, pain intensity and migraine-related clinical burden occurring for 18 months. Results: Response to treatment was excellent as 45 (90%) patients had at least a 50% reduction in vertigo frequency, 43 (86%) had at least a 50% reduction in headache frequency, and 40 (80%) a MIDAS reduction of at least 50%. Overall, 39 (78%) patients had a concomitant reduction of all three parameters. Mean monthly days with dizziness/vestibular symptoms showed an overall significant decrease from a mean of 10.3 ± 1.9 at baseline to 0.8 ± 0.3 days, difference 9.5 (CI 95% 3.6, 15.4; p < 0.001) after twelve months. Conclusion: We show that anti-CGRP mAbs may be effective in the treatment of Vestibular Migraine. Their use should be encouraged early in the disease course to allow for a better symptom control and quality of life improvement

    A Substrate-induced Switch in the Reaction Mechanism of a Thermophilic Esterase KINETIC EVIDENCES AND STRUCTURAL BASIS

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    The reaction mechanism of the esterase 2 (EST2) from Alicyclobacillus acidocaldarius was studied at the kinetic and structural level to shed light on the mechanism of activity and substrate specificity increase previously observed in its double mutant M211S/R215L. In particular, the values of kinetic constants (k1, k(-1), k2, and k3) along with activation energies (E1, E(-1), E2, and E3) were measured for wild type and mutant enzyme. The previously suggested substrate-induced switch in the reaction mechanism from kcat=k3 with a short acyl chain substrate (p-nitrophenyl hexanoate) to kcat=k2 with a long acyl chain substrate (p-nitrophenyl dodecanoate) was validated. The inhibition afforded by an irreversible inhibitor (1-hexadecanesulfonyl chloride), structurally related to p-nitrophenyl dodecanoate, was studied by kinetic analysis. Moreover the three-dimensional structure of the double mutant bound to this inhibitor was determined, providing essential information on the enzyme mechanism. In fact, structural analysis explained the observed substrate-induced switch because of an inversion in the binding mode of the long acyl chain derivatives with respect to the acyl- and alcohol-binding sites

    Liquid Metals Heat-Pipe solution for hypersonic air-intake leading edge: Conceptual design, numerical analysis and verification

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    Embedded propulsion systems will allow future hypersonic aircraft to reach amazing levels of performance. However, their peculiar small-radius air-intake leading edges pose serious challenges from the aerothermodynamic, design, integration, and manufacturing standpoints. This paper discloses the methodology developed in the framework of the H2020 STRATOFLY project and specifically tailored to support the conceptual and preliminary design phases of future high-speed transportation systems. The methodology implements an incremental approach which includes multifidelity design, modelling and simulation techniques. The specific application to the MR3, a Mach 8 waverider configuration with an embedded dorsal mounted propulsive subsystem, is reported. Different alternative solutions have been thoroughly analysed, including five liquid metals as fluids (Mercury, Cesium, Potassium, Sodium and Lithium) and relative wick and case materials (Steel, Titanium, Nickel, Inconel® and Tungsten) and three leading-edges materials (CMC, Tungsten with low emissivity painting and Tungsten with high emissivity painting). The analysis of the heat transfer limits (the capillary, entrainment, viscosity, chocking and boiling limits) carried out for all five fluids and relative compatible materials, together with a more accurate FEM analysis, suggest the adoption of a Nickel- Potassium liquid metal heat pipe completely integrated in a platelet air-intake leading edge made of CMC material. Ultimately, the effectiveness of the adopted solution throughout all mission phases has been verified with a detailed numerical model, built upon an electrical analogy

    Cooling system of STRATOFLY hypersonic vehicle: conceptual design, numerical analysis and verification

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    This paper describes the thermal design processes of STRATOFLY hypersonic vehicle cooling system showing either the methodology and the supporting FEM numerical simulations. It focuses on two different regions that are both subjected to severe overheating: air-intake leading edges and the combustion chamber. Final remarks on structure survivability are presented

    Thermal Protection System preliminary design of STRATOFLY high-speed propelled vehicle

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    This paper discloses the methodology and the preliminary results achieved in the framework of the H2020 STRATOFLY Project on the design of the Thermal Protection System of the MR3 vehicle. The results of the aero-thermal assessment performed throughout the trajectory clearly indicate the air-intake leading edges as the most critical area, thus dedicated Thermal Protection System alternatives have been explored. Specifically, solutions coupling high-temperature materials (mainly CMC and tungsten with different emissivity paints) with Liquid Metals Heat Pipe arrangements are modelled. Eventually, the effectiveness of the designed solutions is verified with detailed numerical simulation. The design which includes the air-intake main structure made of CMC material and integrating Nickel - Potassium heat pipe results to be the most promising solution to withstand the high thermal loads experienced by STRATOFLY MR3 throughout its Mach 8 long-haul route

    Aero-thermal design of STRATOFLY MR3 hypersonic vehicle

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    Civil hypersonic flights are one of the key technological challenges of next generation. The EC-funded STRATOFLY (Stratospheric Flying Opportunities for High-Speed Propulsion Concepts) project has the objective of assessing the potential of this type of high-speed transport vehicle to reach TRL6 by 2035, with respect to key technological, societal and economical aspects, namely thermal and structural integrity, low-emissions combined propulsion cycles, subsystems design and integration including smart energy management, environmental aspects impacting climate change, noise emissions and social acceptance, and economic viability accounting for safety and human factors. This paper presents the aerothermal design of the new STRATOFLY MR3 hypersonic vehicle

    An evaluation of morphological and functional multi-parametric MRI sequences in classifying non-muscle and muscle invasive bladder cancer

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    Objectives: Our goal is to determine the ability of multi-parametric magnetic resonance imaging (mpMRI) to differentiate muscle invasive bladder cancer (MIBC) from non-muscle invasive bladder cancer (NMIBC). Methods: Patients underwent mpMRI before tumour resection. Four MRI sets, i.e. T2-weighted (T2W) + perfusion-weighted imaging (PWI), T2W plus diffusion-weighted imaging (DWI), T2W + DWI + PWI, and T2W + DWI + PWI + dif-fusion tensor imaging (DTI) were interpreted qualitatively by two radiologists, blinded to histology results. PWI, DWI and DTI were also analysed quantitatively. Accuracy was determined using histopathology as the reference standard. Results: A total of 82 tumours were analysed. Ninety-six percent of T1-labeled tumours by the T2W + DWI + PWI image set were confirmed to be NMIBC at histopathology. Overall accuracy of the complete mpMRI protocol was 94% in differentiating NMIBC from MIBC. PWI, DWI and DTI quantitative parameters were shown to be significantly different in cancerous versus non-cancerous areas within the bladder wall in T2-labelled lesions. Conclusions: MpMRI with DWI and DTI appears a reliable staging tool for bladder cancer. If our data are validated, then mpMRI could precede cystoscopic resection to allow a faster recognition of MIBC and accelerated treatment pathways. Key Points: • A critical step in BCa staging is to differentiate NMIBC from MIBC. • Morphological and functional sequences are reliable techniques in differentiating NMIBC from MIBC. • Diffusion tensor imaging could be an additional tool in BCa staging

    Early cementation and accommodation space dictate the evolution of an overstepping barrier system during the Holocene

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    The morphology and stratigraphic features of a well-preserved drowned barrier system, located on the western coast of Sardinia (Mediterranean Sea), are presented here. The barriers were mapped using a multibeam echosounder. The Digital Terrain Model of the seabed revealed five sub-parallel barriers in a depth range of 18\u201337 m, with a distance of ~ 300 m between each single barrier. Direct inspection by scuba diving, revealed that the barriers consist of beachrocks, topped by seagrass meadows growing on a biogenic hardground. The inner-most barrier is limited landward by a steep cliff, 10 m high, bordering the back-barrier area. About 200 km of seismic lines were collected along the barrier system using a 0.4\u20131.0 kJ sparker source and a 3.5 kHz Chirp Subbottom profiler. The seismic data, calibrated with vibrocores, allowed us to recognize the subaerial topographic surface of the last glacial maximum as well as several seismic units interpreted as the Pliocene marine sediments, the pre-Holocene deposits and the Holocene barrier\u2013lagoon complex composed of shoreface, barrier, lagoonal/deltaic and beach deposits. Despite the relatively high seabed gradient (0.3\ub0\u20130.4\ub0) and the relatively low rate of sea-level rise (10\u201315 mm y 12 1), the barriers were well preserved due to the early diagenetic processes which led to a rapid cementation with the formation of beachrocks, and the subsequent overstepping with the rise of the sea level. The development of the overstepping barrier system is strictly related to the antecedent subaerial topography which is, in turn, related to the tectonic setting of the area. The Pliocene seismic unit was lowered by a direct fault at the entrance of the gulf forming a depression filled by sediments. The overstepping barrier system developed following the increase of the seabed gradient and was limited landward by the above-mentioned depression which increased the accommodation space. Following the sea-level rise and the barrier formation, this depression was filled by lagoonal sediments, washover fans and sediments coming from the rivers. The age model of barrier evolution, based on previous sea-level-rise curves during the Holocene, supported by radiocarbon data, highlighted that the whole system evolved over a time period of 1 ka; while the time elapsed from this formation to the drowning of single barriers was estimated to be in the order of magnitude of centuries. Scenarios of short-term evolution of modern barrier\u2013lagoon systems of the adjacent coastal sector, under conditions of accelerated sea-level rise, according to Church et al. (2013) (2013 IPCC report) and Rahmstorf (2007) projections, were elaborated. The study of this ancient analogue suggests that the processes of adaptation of coastal systems to the rising sea level would require times evaluable from centuries to millennia

    Multiparametric MRI of the bladder: inter-observer agreement and accuracy with the Vesical Imaging-Reporting and Data System (VI-RADS) at a single reference center

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    Objectives: To evaluate accuracy and inter-observer variability using Vesical Imaging-Reporting and Data System (VI-RADS) for discrimination between non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). Methods: Between September 2017 and July 2018, 78 patients referred for suspected bladder cancer underwent multiparametric MRI of the bladder (mpMRI) prior to transurethral resection of bladder tumor (TURBT). All mpMRI were reviewed by two radiologists, who scored each lesion according to VI-RADS. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for each VI-RADS cutoff. Receiver operating characteristics curves were used to evaluate the performance of mpMRI. The Ƙ statistics was used to estimate inter-reader agreement. Results: Seventy-five patients were included in the final analysis, 53 with NMIBC and 22 with MIBC. Sensitivity and specificity were 91% and 89% for reader 1 and 82% and 85% for reader 2 respectively when the cutoff VI-RADS &gt; 2 was used to define MIBC. At the same cutoff, PPV and NPV were 77% and 96% for reader 1 and 69% and 92% for reader 2. When the cutoff VI-RADS &gt; 3 was used, sensitivity and specificity were 82% and 94% for reader 1 and 77% and 89% for reader 2. Corresponding PPV and NPV were 86% and 93% for reader 1 and 74% and 91% for reader 2. Area under curve was 0.926 and 0.873 for reader 1 and 2 respectively. Inter-reader agreement was good for the overall score (Ƙ = 0.731). Conclusions: VI-RADS is accurate in differentiating MIBC from NMIBC. Inter-reader agreement is overall good. Key Points: • Traditionally, the local staging of bladder cancer relies on transurethral resection of bladder tumor. • However, transurethral resection of bladder tumor carries a significant risk of understaging a cancer; therefore, more accurate, faster, and non-invasive staging techniques are needed to improve outcomes. • Multiparametric MRI has proved to be the best imaging modality for local staging; therefore, its use in suitable patients has the potential to expedite radical treatment when necessary and non-invasive diagnosis in patients with poor fitness

    Diagnosi molecolare di sindrome di Brugada in un giovane atleta mediante il sequenziamento di un pannello multigenico con tecniche di nuova generazione

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    Mutations in genes driving the molecular pathways that regulate myocardial functions can predispose to many independent cardiopathies and also to sudden cardiac death (SCD) even in asymptomatic subjects. The overlapping clinical signs or symptoms or even silent phenotypes make it difficult to diagnose these diseases, therefore the risk of undiagnosed disease could be high especially in young adults and athletes, which may then incur in SCD. We describe the case of a clinical asymptomatic eight-year-old child, practicing soccer game, who underwent a screening medical examination to undertake the path of an increasing physical activity to become a competitive athlete, where abnormal signs at ECG indicated a suspicion of an arrhythmogenic heart disease. Molecular screening analysis, to discriminate among the various predisposing gene alterations, was performed using a 75 gene-panel for arrhythmias customized in our laboratory. The child resulted carrier of a loss-of-function mutation in the SCN5A gene (c.1126C>T). About 25% of Brugada patients carry mutations in this gene coding for the cardiac sodium channel. The loss-of-function mutations in SCN5A gene induce alterations of sodium ion conduction in cardiomyocytes, compatible with the Brugada Syndrome. This case report highlights the importance of the implementation of a rapid, sensitive and wide molecular screening to shed light on possible genetic alterations present also in asymptomatic athletes with negative family history, which may often remain undiagnosed, thus exposed to high risk of sudden death
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