Aim
This study aimed to investigate the role of resistance‐associated substitutions (RASs) to direct‐acting‐antivirals (DAAs) in HCV genotype 3 (GT3).
Methods
Within the Italian VIRONET‐C network, a ...total of 539 GT3‐infected patients (417 DAA‐naïve and 135 DAA‐failures, of them, 13 at both baseline and failure) were analysed. Sanger sequencing of NS3/NS5A/NS5B was performed following home‐made protocols.
Results
The majority of patients were male (79.4%), 91.4% were injection drug users, 49.3% were cirrhotic and 13.9% were HIV co‐infected. Phylogenetic analysis classified sequences as GT3a‐b‐g‐h (98%‐0.4%‐0.2%‐1.2%) respectively.
Overall, 135 patients failed a DAA regimen: sofosbuvir (SOF)/daclatasvir (DCV) or velpatasvir (VEL)±ribavirin (RBV) (N = 91/15) and glecaprevir (G)/pibrentasvir (P) (N = 9). Moreover, 14.8% of patients were treated with suboptimal regimens for GT3: 3D ± RBV (Paritaprevir/r + Ombitasvir+Dasabuvir, N = 15), SOF + Simeprevir (SIM) (N = 1) or SOF/Ledipasvir (LDV) ± RBV (N = 4).
RAS prevalence was 15.8% in DAA‐naïve patients. At failure, 81.5% patients showed at least one RAS: 11/25 (44.0%) in NS3, 109/135 (80.7%) in NS5A, 7/111 (6.3%) in NS5B SOF‐failures. In NS5A‐failures, Y93H RAS was the most prevalent (68.5% vs 5.1% DAA‐naïve, P < .001) followed by A30K (12.7% vs 2.8% in DAA‐naïve, P < .001). Analysing baseline samples, a higher prevalence of NS5A‐RASs was observed before treatment in DAA‐failures (5/13, 38.5%) vs DAA‐naïves (61/393, 15.5%, P = .04). Regarding 228 DAA‐naïve patients with an available outcome, 93.9% achieved a SVR. Interestingly, patients with baseline Y93H and/or A30K had SVR rate of 72.2% vs 95.7% for patients without NS5A‐RASs (P = .002).
Conclusions
In this real‐life GT3 cohort, the majority of failures harboured resistant variants carrying NS5A‐RASs, the most frequent being Y93H. The presence of natural NS5A‐RASs before treatment was associated with failure. Further analyses are needed to confirm this observation, particularly for the new current regimens.
An improved algorithm to generate skeletal mechanisms from the original detailed chemical kinetic mechanisms is proposed. The new algorithm builds on the computational singular perturbation (CSP) ...framework, by adding an additional layer of automation based on the tangential stretching rate (TSR) and the species’ participation index to TSR. The main advantage of the new approach is that it does not require the specification of a set of target species. Instead, the target species set is dynamic and automatically identified through the simplification algorithm, which defines the system’s state variables that the skeletal mechanism is required to accurately predict. In this way, the new procedure pursues an optimum set of target species that leads the algorithm to include a minimal number of species/reactions that ensures the replication of global observables, such as ignition delay time, without any a-priori knowledge of the chemical pathways. The capabilities and performance of the new simplification algorithm are demonstrated in a test problem employing the 397-species detailed mechanism for C0-C2 species, augmented with polycyclic aromatic hydrocarbon (PAH) soot precursor species. The results are compared with those obtained from the standard CSP-based algorithm in terms of the ignition delay times, main species evolution and their equilibrium state. Subsequent examples also demonstrate the capabilities of the TSR-based algorithm to generate additional sub-mechanisms that, combined with the core mechanism, allow to extend its range of operating conditions and target variables.
Rotaxane molecular shuttles were studied in which a tetralactam macrocyclic ring moves between a succinamide station and a second station in which the structure is varied. Station 2 in all cases is ...an aromatic imide, which is a poor hydrogen‐bond acceptor in the neutral form, but a strong one when reduced with one or two electrons. When the charge density on the hydrogen‐bond‐accepting carbonyl groups in station 2 is reduced by changing a naphthalimide into a naphthalene diimide radical anion, the shuttling rate changes only slightly. When station 2 is a pyromellitimide radical anion, however, the shuttling rate is significantly reduced. This implies that the shuttling rate is not only determined by the initial unbinding of the ring from the first station, as previously supposed. An alternative reaction mechanism is proposed in which the ring binds to both stations in the transition state.
Shuttling via harpooning: Comparison of the shuttling kinetics in a series of imide‐based rotaxanes suggest that the mechanism involves a transition state in which the moving ring is hydrogen‐bonded to both stations (see figure).
This paper describes automated procedures for the design and deployment of artificial skin for humanoid robots. This problem is challenging under different perspectives: on the one hand, different ...robots are characterized by different shapes, thereby requiring a high degree of skin customization; on the other hand, it is necessary to define optimal criteria specifying how the skin must be placed on robot parts. This paper addresses the problem of optimally covering robot parts with tactile sensors, discussing possible solutions with reference to a specific artificial skin technology for robots, which has been developed in the past few years. Results show that it is possible to automate the majority of the required steps, with promising results in view of a future complete automation of the process.
Mesotherapy, also known as local intradermal therapy, widely used all over the world, is a technique used to inject substances into the surface layer of the skin. There are no international ...guidelines for the correct use of this technique and in many countries, it is still applied empirically without valid patient consent. The Italian society of mesotherapy has planned a study to assess the rationale and clinical applications based on current evidence.
An independent steering committee, based on the available scientific literature, has formulated a series of clinical questions. 21 experts responded by writing an evidence-based document. From this document 30 statements were obtained which were presented to 114 experts using the Delphi method.
28 statements reached a broad agreement on definition, technique, pharmacological rationale, indications and some crucial ethical aspect.
Although further studies are needed to establish the clinical role of this technique in each field of application, our statements recommend the correct application according to the needs of the individual patient in full respect of ethics.
The series of upgrades to the Large Hadron Collider, culminating in the High Luminosity Large Hadron Collider, will enable a significant expansion of the physics program of the CMS experiment. ...However, the accelerator upgrades will also make the experimental conditions more challenging, with implications for detector operations, triggering, and data analysis. The luminosity of the proton–proton collisions is expected to exceed 2–3×1034 cm−2s−1 for Run 3 (starting in 2022), and it will be at least 5×1034 cm−2s−1 when the High Luminosity Large Hadron Collider is completed for Run 4. These conditions will affect muon triggering, identification, and measurement, which are critical capabilities of the experiment. To address these challenges, additional muon detectors are being installed in the CMS endcaps, based on Gas Electron Multiplier technology. For this purpose, 161 large triple-Gas Electron Multiplier detectors have been constructed and tested. Installation of these devices began in 2019 with the GE1/1 station and will be followed by two additional stations, GE2/1 and ME0, to be installed in 2023 and 2026, respectively. The assembly and quality control of the GE1/1 detectors were distributed across several production sites around the world. We motivate and discuss the quality control procedures that were developed to standardize the performance of the detectors, and we present the final results of the production. Out of 161 detectors produced, 156 detectors passed all tests, and 144 detectors are now installed in the CMS experiment. The various visual inspections, gas tightness tests, intrinsic noise rate characterizations, and effective gas gain and response uniformity tests allowed the project to achieve this high success rate.
Shuttling rules! A bistable fullerene‐stoppered molecular shuttle equipped with two ferrocene electron donors on the macrocycle has been prepared. A controlled positional change of the ferrocene ...groups along the thread results in different spatial arrangements of the electroactive units and allows the kinetics of the electron transfer and the lifetime of the charged‐separated state to be modulated/fine‐tuned (see picture).
•The ITER Neutral Beam Test Facility in Padova, Italy: substantial progress achieved.•The realization of SPIDER, the ITER full-size negative ion source, is well advanced.•Integrated tests of Power ...Supply and preparation of SPIDER operation starting now.•Big progress on the realization of MITICA full-scale prototype of ITER HNB injector.•MITICA operation planned to start in 2021, depending on the BS and BLC delivery.
Substantial progresses have been achieved in the realization of the ITER Neutral Beam Test Facility (NBTF) hosted in Padova, Italy; the buildings, completed by the end of 2015, are being progressively filled with new systems and components. The realization of SPIDER, the ITER full-size negative ion source, is well advanced and important progress is also recorded for MITICA, the full-scale prototype of the ITER HNB injector. The paper gives an overview of the achieved results, highlighting the main challenges faced.
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