going beyond BASDAI

This work was supported by a Research Grant from the InvestigatorInitiated Studies program of Merck Sharp & Dohme (Grant No. 56078). The sponsor did not interfere with the study question, analysis or interpretation of results. AS is supported by a doctoral grant from Fundação para a Ciência e Tecnologia (Foundation for Science and Technology) (SFRH/BD/108246/2015).OBJECTIVES: To compare definitions of high disease activity of the Ankylosing Spondylitis Disease Activity Score (ASDAS) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in selecting patients for treatment with biologic disease-modifying antirheumatic drugs (bDMARDs). METHODS: Patients from Rheumatic Diseases Portuguese Register (Reuma.pt) with a clinical diagnosis of axial spondyloarthritis (axSpA) were included. Four subgroups (cross-tabulation between ASDAS (≥2.1) and BASDAI (≥4) definitions of high disease activity) were compared regarding baseline characteristics and response to bDMARDs at 3 and 6 months estimated in multivariable regression models. RESULTS: Of the 594 patients included, the majority (82%) had both BASDAI≥4 and ASDAS ≥2.1. The frequency of ASDAS ≥2.1, if BASDAI<4 was much larger than the opposite (ie, ASDAS <2.1, if BASDAI≥4): 62% vs 0.8%. Compared to patients fulfilling both definitions, those with ASDAS ≥2.1 only were more likely to be male (77% vs 51%), human leucocyte antigen B27 positive (79% vs 65%) and have a higher C reactive protein (2.9 (SD 3.5) vs 2.1 (2.9)). Among bDMARD-treated patients (n=359), responses across subgroups were globally overlapping, except for the most 'stringent' outcomes. Patients captured only by ASDAS responded better compared to patients fulfilling both definitions (eg, ASDAS inactive disease at 3 months: 61% vs 25% and at 6 months: 42% vs 25%). CONCLUSION: The ASDAS definition of high disease activity is more inclusive than the BASDAI definition in selecting patients with axSpA for bDMARD treatment. The additionally 'captured' patients respond better and have higher likelihood of predictors thereof. These results support using ASDAS≥2.1 as a criterion for treatment decisions.publishersversionpublishe

Technical Design Report - TDR CYGNO-04/INITIUM

The aim of this Technical Design Report is to illustrate the technological choices foreseen to be implemented in the construction of the CYGNO-04 demonstrator, motivate them against the experiment physics goals of CYGNO-30 and demonstrate the financial sustainability of the project. CYGNO-04 represents PHASE 1 of the long term CYGNO roadmap, towards the development of large high precision tracking gaseous Time Projection Chamber (TPC) for directional Dark Matter searches and solar neutrino spectroscopy. The CYGNO project1 peculiarities reside in the optical readout of the light produced during the amplification of the primary ionization electrons in a stack of triple Gas Electron Multipliers (GEMs), thanks to the nice scintillation properties of the chosen He:CF4 gas mixture. To this aim, CYGNO is exploiting the fast progress in commercial scientific Active Pixel Sensors (APS) development for highly performing sCMOS cameras, whose high granularity and sensitivity allow to significantly boost tracking, improve particle identification and lower the energy threshold. The X-Y track project obtained from the reconstruction of the sCMOS images is combined with a PMT measurement to obtain a full 3D track reconstruction. In addition, several synergic R&Ds based on the CYGNO experimental approach are under development in the CYGNO collaboration (see Sec 2) to further enhance the light yield by means of electro luminescence after the amplification stage, to improve the tracking performances by exploiting negative ion drift operation within the INITIUM ERC Consolidator Grant, and to boost the sensitivity to O(GeV) Dark Matter masses by employing hydrogen rich target towards the development of PHASE 2 (see Sec. 1.2). While still under optimization and subject to possible significant improvements, the CYGNO experimental approach performances and capabilities demonstrated so far with prototypes allow to foresee the development of an O(30) m3 experiment by 2026 for a cost of O(10) MEUROs. A CYGNO-30 experiment would be able to give a significant contribution to the search and study of Dark Matter with masses below 10 GeV/c2 for both SI and SD coupling. In case of a Dark Matter observation claim by other experiments, the information provided by a directional detector such as CYGNO would be fundamental to positively confirm the galactic origin of the allegedly detected Dark Matter signal. CYGNO-30 could furthermore provide the first directional measurement of solar neutrinos from the pp chain, possibly extending to lower energies the Borexino measurement2. In order to reach this goal, the CYGNO project is proceeding through a staged approach. The PHASE 0 50 L detector (LIME, recently installed underground LNGS) will validate the full performances of the optical readout via APS commercial cameras and PMTs and the Montecarlo simulation of the expected backgrounds. The full CYGNO-04 demonstrator will be realized with all the technological and material choices foreseen for CYGNO-30, to demonstrate the scalability of the experimental approach and the potentialities of the large PHASE 2 detector to reach the expected physics goals. The first PHASE 1 design anticipated a 1 m3 active volume detector with two back-to-back TPCs with a central cathode and 500 mm drift length. Each 1 m2 readout area would have been composed by 9 + 9 readout modules having the LIME PHASE 0 dimensions and layout. Time (end of INITIUM project by March 2025) and current space availability at underground LNGS (only Hall F) forced the rescaling of the PHASE 1 active volume and design to a 0.4 m3, hence CYGNO-04. CYGNO-04 will keep the back-to-back double TPC layout with 500 mm drift length each, but with an 800 x 500 mm2 readout area covered by a 2 + 2 modules based on LIME design. The reduction of the detector volume has no impact on the technological objectives of PHASE 1, since the modular design with central cathode, detector materials and shieldings and auxiliary systems are independent of the total volume. The physics reach (which is a byproduct of PHASE 1 and NOT an explicit goal) will be only very partially reduced (less than a factor 2 overall) since a smaller detector volume implies also a reduced background from internal materials radioactivity. In addition, the cost reduction of CYGNO-04 of about 1⁄3 with respect to CYGNO-1 illustrated in the CDR effectively makes the overall project more financially sustainable (see CBS in the last section). In summary this document will explain: the physical motivation of the CYGNO project and the technical motivations of the downscale of the PHASE 1 to CYGNO-04, 400 liters of active volume, with respect to the demonstrator presented in the CDR; the results of R&D and the Montecarlo expectations for PHASE 0; the technical choices, procedures and the executive drawings of CYGNO-04 in the Hall F of the LNGS; safety evaluations and the interference/request to the LNGS services; Project management, WBS/WBC, WP, GANTT, ec

Both “illness and temptation of the enemy”: melancholy, the medieval patient and the writings of King Duarte of Portugal (r. 1433–38)

Recent historians have rehabilitated King Duarte of Portugal, previously maligned and neglected, as an astute ruler and philosopher. There is still a tendency, however, to view Duarte as a depressive or a hypochondriac, due to his own description of his melancholy in his advice book, the Loyal Counselor. This paper reassesses Duarte's writings, drawing on key approaches in the history of medicine, such as narrative medicine and the history of the patient. It is important to take Duarte's views on his condition seriously, placing them in the medical and theological contexts of his time and avoiding modern retrospective diagnosis. Duarte's writings can be used to explore the impact of plague, doubt and death on the life of a well-educated and conscientious late-medieval ruler

Imagiologia de raios-X com GEM de 100 µm de espessura a operar em misturas de Kr-CO2

Dissertação de Mestrado Integrado em Engenharia Física apresentada à Faculdade de Ciências e TecnologiaO crípton é o gás nobre que possui os melhores valores de resolução espacial para energias entre 14−34 keV, o que o torna um bom candidato para aplicações de imagiologia. Além disso, a escolha de Gas Electron Multipliers (GEM) com 100 μm de espessura ao invés de um GEM standard representa uma vantagem inegável; os primeiros são mais robustos a descargas, atingindo coeficientes de multiplicação semelhantes. Combinando estas duas características, é possível atingir ganhos em carga mais elevados e melhores valores de resolução espacial, o que permite obter imagens mais detalhadas no intervalo de energias 14−34 keV. Uma cascata de dois GEMs não convencionais (com o dobro da espessura de um GEM standard) fabricados no CERN foi associada a uma placa resistiva de leitura bidimensional, com uma área ativa de 10×10 cm2 . Esta montagem permite recolher informação sobre a energia e a posição de cada evento usando apenas quatro canais, simplificando a eletrónica associada, bem como a própria reconstrução das imagens. Este detetor foi operado em misturas baseadas em crípton e irradiado com uma fonte de 55Fe e com uma fonte contínua de raios-x. Sempre que possível, os resultados foram comparados com as medidas obtidas com uma mistura Ar-CO2 (70:30). Parâmetros como ganho em carga, resolução em energia, relação sinal ruído das imagens, resolução espacial e resposta em contraste foram determinados nestas condições. Para as misturas baseadas em crípton, verificou-se uma redução na resolução espacial para energias acima dos 18 keV. O valor da MTF a 10% no intervalo de energias 22−24 keV foi também avaliado, sendo 0.5876(342) lp/cm para Ar-CO2 (70:30) e cerca de 3 lp/cm para misturas de Kr-CO2.Krypton is known to have the best value of position resolution amongst the noble gases within the range 14−34 keV, which makes it a good candidate for imaging applications. Also, the choosing of 100 μm thick Gas Electron Multipliers (GEM) over the standard GEM plates presents an undeniable advantage as the former is more robust to sparking while achieving similar multiplication coefficients. By taking these factors into account, higher charge gains and lower values of position resolution can be achieved to produce cleaner imaging data in the energy range 14−34 keV. A cascade of two non-standard GEM plates (twice the thickness of a standard GEM) fabricated at CERN was coupled to a 2D resistive readout with an active area of 10×10 cm2. This setup allows event energy and interaction position information to be recorded using only four channels, simplifying the electronic system and the image reconstruction process. This detection system was operated in krypton-based mixtures and irradiated by a 55Fe and a continuous x-ray source. Whenever possible, the results were compared to the ones achieved in a Ar-CO2 (70:30) mixture. Parameters such as the charge gain, energy resolution, image signal-to-noise ratio, position resolution and contrast response were measured under the described conditions. For krypton-based mixtures, the reduction of position resolution happened for radiation energies higher than 18 keV. The Modulation Transfer Function value at 10% in the energy interval 22−24 keV was also evaluated, being 0.5876(342) lp/cm for Ar-CO2 (70:30) and around 3 lp/cm for Kr-CO2 mixtures

Entrevista: Impérios, historiografia, ciências sociais: uma entrevista com Sanjay Subrahmanyam

Esta entrevista coletiva do Grupo de Investigação “Impérios, Colonialismo e Sociedades Pós-Coloniais” do Instituto de Ciências Sociais da Universidade de Lisboa realizou-se no ics em 2016. Em primeiro lugar, procurou-se compreender o lugar do império português, e dos impérios ibéricos na investigação de Sanjay Subrahmanyam, mas também as potencialidades de internacionalização de temas relativos ao império português, bem como da própria historiografia portuguesa. A história global, as histórias conectadas, a micro-história, a etno-história, as possibilidades e os limites da comparação, e até mesmo a relação entre historiador e cidadão, e entre passado e presente, foram outros dos muitos problemas abordados.info:eu-repo/semantics/publishedVersio

NMR metabolomics to study the metabolic response of human osteoblasts to non-poled and poled poly (L-lactic) acid

Untargeted nuclear magnetic resonance (NMR) metabolomics was employed, for the first time to our knowledge, to characterize the metabolome of human osteoblast (HOb) cells and extracts in the presence of non-poled or negatively poled poly-L-lactic acid (PLLA). The metabolic response of these cells to this polymer, extensively used in bone regeneration strategies, may potentially translate into useful markers indicative of in vivo biomaterial performance. We present preliminary results of multivariate and univariate analysis of NMR spectra, which have shown the complementarity of lysed cells and extracts in terms of information on cell metabolome, and unveil that, irrespective of poling state, PLLA-grown cells seem to experience enhanced oxidative stress and activated energy metabolism, at the cost of storage lipids and glucose. Possible changes in protein and nucleic acid metabolisms were also suggested, as well as enhanced membrane biosynthesis. Therefore, the presence of PLLA seems to trigger cell catabolism and anti-oxidative protective mechanisms in HOb cells, while directing them towards cellular growth. This was not sufficient, however, to lead to a visible cell proliferation enhancement in the presence of PLLA, although a qualitative tendency for negatively poled PLLA to be more effective in sustaining cell growth than non-poled PLLA was suggested. These preliminary results indicate the potential of NMR metabolomics in enlightening cell metabolism in response to biomaterials and their properties, justifying further studies of the fine effects of poled PLLA on these and other cells of significance in tissue regeneration strategies.publishe

Portuguese recommendations for pain management by pharmocotherapy in inflammatory arthritis

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A 50 l

The nature of dark matter is still unknown and an experimental program to look for dark matter particles in our Galaxy should extend its sensitivity to light particles in the GeV mass range and exploit the directional information of the DM particle motion (Vahsen et al. in CYGNUS: feasibility of a nuclear recoil observatory with directional sensitivity to dark matter and neutrinos, arXiv:2008.1258

Directional Dark Matter Searches with CYGNO

The CYGNO project aims at developing a high resolution Time Projection Chamber with optical readout for directional dark matter searches and solar neutrino spectroscopy. Peculiar CYGNO’s features are the 3D tracking capability provided by the combination of photomultipliers and scientific CMOS camera signals, combined with a helium-fluorine-based gas mixture at atmospheric pressure amplified by gas electron multipliers structures. In this paper, the performances achieved with CYGNO prototypes and the prospects for the upcoming underground installation at Laboratori Nazionali del Gran Sasso of a 50-L detector in fall 2021 will be discussed, together with the plans for a 1-m3 experiment. The synergy with the ERC consolidator, grant project INITIUM, aimed at realising negative ion drift operation within the CYGNO 3D optical approach, will be further illustrated