Efficacy and Drug Survival after Switching from Etanercept to the Biosimilar SB4: A Real-Life Long-Term Study

We evaluated the 3-year drug survival and efficacy of the biosimilar SB4/Benepali in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) patients, pre-viously treated with etanercept (ETA). Drug survival rate was calculated using the Kaplan\u2013Meier method and Cox proportional hazard models were developed to examine predictors of SB4 discontin-uation. 236 patients (120 RA, 80 PsA and 36 AS), aged 60.7 \ub1 13.8 years and with an ETA duration of 4.1 \ub1 3.4 years were included. The 3-year retention rate for SB4 was 94.4%, 88% and 86% in AS, RA and PsA patients, respectively, with no difference between groups. Patients without comorbid disease had higher retention rates vs. patients with comorbid disease (90% vs. 60%, p < 0.0001). Disease activity, as measured by DAS28, DAPSA and BASDAI remained stable over the 3 years. Comorbid disease (hazard ratio; HR: 4.06, p < 0.0001) and HAQ at baseline (HR: 2.42, p = 0.0024) significantly increased the risk of SB4 discontinuation, while previous ETA duration was negatively associated with SB4 discontinuation (HR: 0.97, p = 0.0064). Forty-one (17.4%) patients left the study due to the interruption of the SB4 treatment, 31 (75.6%) discontinued due to inefficacy and 10 (24.4%) due to adverse events. This real-life study confirms the similar efficacy profile of ETA with long-term retention and a good safety profile in inflammatory arthritis patients

Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3-Kinase (PI3K)-γ Inhibitors

In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved to give compounds such as 15, which is a potent and remarkably selective PI3Kγ inhibitor with ADME properties suitable for oral administration. Compound 15 was advanced into in vivo studies showing dose-dependent inhibition of LPS-induced airway neutrophilia in rats when administered orally

On the Collective Sort Problem for Distributed Tuple Spaces

In systems coordinated with a distributed set of tuple spaces, it is crucial to make agents easily retrieving the tuples they are interested in. This can be achieved by some sorting technique that can group similar tuples together in the same tuple space, so that the position of a tuple can be inferred by similarity. Accordingly, we formulate the col lective sort problem for distributed tuple spaces, where an on-line, background service of autonomous agents is in charge of moving tuples from one space to the other until reaching complete sorting, namely, each of the N tuple spaces aggregate tuples belonging to one of the N kinds available. After pointing out the requirements for effectively tackling this problem, we propose a self-organising solution inspired by ants' brood sorting. This is based on simple agents that perform partial observations and accordingly take decisions on tuple movement. Complete convergence from any initial configuration of tuples is addressed by a form of fully-adaptive simulated annealing, based on noise tuples inserted and removed by agents on a by-need basis so as to avoid situations of non-optimal sorting. The approach is evaluated by stochastic simulations, which provide evidence of full-sorting emergence, scalability, and reactiveness to external interactions

Exploring the Dynamics of Self-Organising Systems with Stochastic π-Calculus: Detecting Abnormal Behaviour in MAS

The intrinsic complexity of self-organising MASs (multi-agent systems) makes it difficult to predict global system evolutions at early stages of the design process. Simulating high-level models to analyse properties of a MAS design can anticipate detection of incorrect / wrong design choices, and allow tuning of system parameters. In this paper, we take abnormal-behaviour detection as a case study, and devise an artifact-based MAS architecture inspired by principles of the human immune systems. We use stochastic π-calculus to specify and run quantitative large-scale simulations, which allow us to verify the basic applicability of our IDS (intrusion detection system) and possibly obtain a preliminary set of its main working parameters

A self-organising solution to the collective sort problem in distributed tuple spaces

Coordination languages and models are recently moving towards the application of techniques coming from the research context of complex systems: adaptivity and self-organisation are exploited in order to tackle typical features of systems to coordinate, such as openness, dynamism and unpredictability. In this paper we focus on a paradigmatic problem we call collective sort, where autonomous agents are assigned the task of moving tuples across different tuple spaces with the goal of reaching perfect clustering: tuples of the same kind are to be collected in the same, unique tuple space. We describe a self-organising solution to this problem, where each agent moves tuples according to partial observations, still making complete sorting emerge from any initial tuple configuration

Assessing transport network resilience: empirical insights from real-world data studies.

Determining the factors that positively and negatively affect the resilience of transport networks provides valuable information that leads to a deeper understanding of the preparedness and response of networks to external disruptions. Over the past few decades, several review papers have explored various interpretations of transport network resilience and its calculation metrics. Nevertheless, only a limited number of these papers have paid attention on the utilisation of empirical data in resilience studies. This paper, through a systematic literature review, contributes to filling this gap. To this end, from a pool of 127 relevant articles, a subset of 53 articles using real-world data was selected. The paper analyses and classifies empirical findings in transport network resilience studies. In particular, it highlights and thoroughly discusses spatial patterns of resilience and relevant influencing factors that positively or negatively affect the resilience attributes of a transport network. Although it is possible to place the empirical results within the theoretical framework proposed by the literature, two main issues on target reference levels arise from the graphical representation of transport network resilience as suggested by the theory. Based on these findings, research gaps are identified and future directions for transport researchers are proposed

An efficient, fully-planar cavity backed module for smart array antennas

We present a cavity-backed patch antenna with enhanced bandwidth and good efficiency which is assembled in a multilayer fully planar structure. The single element represents a basic block that can be replicated in a modular configuration to design array antennas implementing beam scanning or more general "smart" functionalities. To do that, each element has to be provided by a phase shifter that can be directly integrated on the layer hosting the beamforming network. For this reason, particular care was taken to minimize the space occupied on this layer by the feeding and matching network, so that most of the space of the unit cell is left free. The antenna was designed using a commercial, method of moments (MoM) based software. Results are shown for a single element and for a 2x2 array; a prototype is under construction

Regular-integrand line-integral representation for the PO scattered field, suitable for an efficient numerical integration

We present a new formulation for providing an exact line integral representation for the PO radiation integral describing the scattering from an aperture in a black screen or by a flat perfectly conducting plate, illuminated by an elementary electric or magnetic dipole, which joins numerical efficiency of Asvestas to the physical appeal and ease of implementation of Rubinowicz; indeed the present formulation overcomes numerical impairments of traditional techniques preserving the physical interpretability of the result. This feature allows us to obtain an efficient tool for numerical scattering computation whose applicability range can also be extended, using typical ray heuristic approximations, to manage scattering by impenetrable or transparent impedance objects, with a well-assessed degree of confidence. Numerical examples show the effectiveness of the presented formulation

REGIOCHEMICAL CONTROL OF THE RING-OPENING OF AZIRIDINES BY MEANS OF CHELATING PROCESSES - SYNTHESIS AND RING-OPENING REACTIONS OF CIS- AND TRANS-AZIRIDINES DERIVED FROM 4-(BENZYLOXY)CYCLOHEXENE

The regiochemical outcome of the ring opening of aziridines bearing a polar remote functionality was verified in a conformationally semirigid bicyclic system in which the polar functionality (OBn) is in an homoallylic relationship to the aziridine ring. The couples of diastereoisomeric unactivated cis-3 and trans-4 and activated aziridines cis-5 and -7 and trans-6 and -8 derived from 4-(benzyloxy)-cyclohexene were prepared, and some of their opening reactions were studied. The regioselectivity observed in the opening reactions of the cis derivatives turned out to depend largely on the opening (standard, strongly acidic, or metal-assisted) reaction conditions, thus providing a nice regioalternating process. The results obtained are rationalized by admitting the incursion of chelate bidentate intermediate structures in which the proton or the metal is actively involved