Desenvolvimento de Drug Delivery Systems (DDS) com fiibras e óleo de Cannabis para aplicações orais e dérmicas

A Cannabis sativa L. constitui uma matéria-prima de excelência tanto na investigação e desenvolvimento, como à escala industrial e empresarial, devido às suas características sustentáveis, renováveis, biodegradáveis, recicláveis e rentáveis. A presença de compostos ativos como o tetrahidrocanabinol (THC) e o canabidiol (CBD), apresenta um grande potencial terapêutico que tem sido utilizado em aplicações biomédicas. Assim, o desenvolvimento de sistemas que controlem a taxa de libertação destas moléculas ativas, e que preservem as suas propriedades terapêuticas, constitui um exemplo inovador de investigação multidisciplinar na área do projeto de tratamentos específicos adaptados a diferentes necessidades. Com este propósito, o objetivo do presente trabalho é desenvolver Drug Delivery Systems (DDS) à base de biomateriais de Cannabis em três aplicações distintas: suplementos alimentares, formulações orais e sistemas dérmicos. Para alcançar este objetivo, foi realizada inicialmente uma moagem a partir de sementes de cânhamo através do processo de crio-moagem. De forma a preservar os compostos bioativos e obter uma textura suave e uniforme, foram otimizadas as condições de número de ciclos de operação (6), o tempo (10 minutos por ciclo), a temperatura (0-20ºC), e a frequência utilizada (25 Hz). Adicionalmente, foi utilizada a técnica de EDX para a sua caracterização. Posteriormente, foram obtidas fibras de Cannabis a partir dos caules através de processos de cozimento e branqueamento. A caracterização destas foi realizada em termos de microscopia ótica e microscopia eletrónica de varrimento (SEM), obtendo-se 43% das fibras compreendidas entre 10 e 20 µm. Foi também desenvolvida uma metodologia de otimização da matriz 3D de fibras de Cannabis, com função de reter e libertar controladamente as moléculas bioativas do extrato e do óleo de Cannabis, utilizando ferramentas computacionais de simulação computacional e modelação 3D. Os DDS dedicados às formulações orais foram produzidos com diferentes proporções e combinações de biomateriais, entre os quais se incluem as moléculas ativas, presentes na flor, extrato e óleo de Cannabis, e também polímeros e fibras para formação da matriz 3D de retenção e libertação controlada. Nestes incluem-se o alginato e a Carboximetilcelulose (CMC), assim como as fibras de celulose, das quais se destacam as fibras de Cannabis e de Celulose Nano Fibrilada (CNF). Efetuaram-se também estudos in vitro de estabilidade dos DDS utilizando três soluções a fim de mimetizar o pH do estômago (pH = 2), duodeno (pH = 6,6), e da corrente sanguínea (pH = 7,4). Os resultados mostraram que foram obtidos DDS estáveis e uniformes, apresentando no seu interior uma rede 3D à base de biomateriais de celulose e fibras de Cannabis, com capacidade de reter e libertar controladamente substâncias ativas de interesse. A incorporação das fibras de Cannabis nestes sistemas também promoveu um aumento da estabilidade da estrutura e conformidade do DDS, inibindo a sua degradação ao longo do tempo. Por fim, os DDS dérmicos foram desenvolvidos utilizando como base matrizes 3D de fibras de celulose branqueadas de Eucalyptus globulus e não-branqueadas de Picea abies. A fim de serem aplicados nestas estruturas, os canabinóides de duas amostras de Cannabis foram ainda incorporados, após o processo de descarboxilação, em diversos óleos de interesse, sendo posteriormente caracterizados por FTIR-ATR. A estratégia do design, desenvolvimento e otimização experimental e computacional de DDS com CBD como substância ativa, contendo combinações diversificadas de óleo de Cannabis, fibras de celulose de Cannabis, bem como extrato de Cannabis e incorporação da flor após descarboxilação, constitui numa abordagem inovadora no desenvolvimento de formulações de valor acrescentado para suplementação alimentar, na forma oral e dérmica, com elevado potencial de aplicação industrial.Cannabis sativa L. is an excellent raw material, both in research and development, at industrial and business scale, due to its sustainable, renewable, biodegradable, recyclable, and profitable characteristics. The presence of active compounds such as tetrahydrocannabinol (THC) and cannabidiol (CBD) presents a high therapeutic potential that has been used in biomedical applications. Therefore, the development of systems that control the release rate of these active molecules, and that preserve their therapeutic properties, constitutes an innovative example of multidisciplinary research in the field of specific treatments, constitutes an innovative example of multidisciplinary research in the field of the design of specific treatments adapted to different needs. For this purpose, the present work aims to develop Drug Delivery Systems (DDS) based on Cannabis biomaterials in three distinct applications: food supplements, oral formulations, and dermal systems. To achieve this goal, an extraction of Cannabis oil was initially carried out from seeds through the cryo-milling process. To preserve the bioactive compounds and obtain a smooth and uniform texture, the conditions of number of operating cycles (6), time (10 minutes per cycle), temperature (0-20ºC), and the frequency used (25 Hz) were optimized. Additionally, EDX technique was used for its characterization. Subsequently, Cannabis fibers were obtained from the stems through cooking and bleaching processes. Their characterization was performed in terms of optical microscopy and scanning electron microscopy (SEM), obtaining 42.9% of the fibers between 10 and 20 µm. A methodology for optimizing the 3D matrix of Cannabis fibers was also developed, using computational tools of computational simulation and 3D modeling approach. This 3D network retains and controllingly release the bioactive molecules of the Cannabis extract and oil. The DDS dedicated to oral formulations were produced with different proportions and combinations of biomaterials, including the active molecules present in the Cannabis flower, extract, and oil, as well as polymers and fibers for the formation of the 3D matrix for retention and controlled release. These included the alginate polymer, and carboxymethyl cellulose (CMC), as well as cellulose fibers, including Cannabis and Nano Fibrillated Cellulose (NFC). In vitro stability studies of DDS were also performed using three solutions to mimic the pH of the stomach (pH = 2), duodenum (pH = 6.6), and bloodstream (pH = 7.4). The results showed that stable and uniform DDS were obtained, presenting inside a 3D network based on cellulose biomaterials and Cannabis fibers, with the ability to retain and release active substances of interest in a controlled way. The incorporation of Cannabis fibers in these systems also promoted an increase in DDS structure and compliance, inhibiting its degradation over time. Finally, dermal DDS were developed using 3D matrixes of bleached Eucalyptus globulus and unbleached Picea abies cellulose fibers. To be applied in these structures, the cannabinoids from two samples of Cannabis flowers, after the decarboxylation process, were also incorporated into several oils of interest, being afterwards characterized by FTIR-ATR. The strategy of design, development, and experimental and computational optimization of DDS with CBD as an active molecule, containing diverse combinations of Cannabis oil, Cannabis cellulose fibers, as well as Cannabis extract and incorporation of the flower after decarboxylation, constitutes an innovative approach in the development of formulations with added value for food supplementation, in the oral and dermic form, with high potential for industrial application

A framework for modular and customizable software analysis

This paper presents a framework for the analysis of software artifacts. We revise and propose techniques that aid in the manipulation and combination of target-language specific tools, and in handling and controlling the results of such tools. We also propose to integrate under our framework techniques that are capable of performing language independent analyses. The final result of our work is an analysis environment that is modular and flexible and that allows easy and elegant implementations of complex analysis suites. We finally conduct a proof of concept for our framework by analyzing a well-known, widely used open-source software package.This work is partly funded by ERDF - European Regional Development Fund through the COMPETE Programme (operational programme for competitiveness) and by National Funds through the FCT - Fundacao para a Ciencia e a Tecnologia (Portuguese Foundation for Science and Technology) within projects FCOMP-01-0124-FEDER-010049, and FCOMP-01-0124-FEDER-022701

Measurement of the top quark pair production cross section in pppp collisions at s=7\sqrt{s}=7 TeV in dilepton final states with ATLAS

A measurement of the production cross section of top quark pairs (ttbar) in proton-proton collisions at a center-of-mass energy of 7 TeV recorded with the ATLAS detector at the Large Hadron Collider is reported. Candidate events are selected in the dilepton topology with large missing transverse energy and at least two jets. Using a data sample corresponding to an integrated luminosity of 35 pb^-1, a ttbar production cross section of 171 +/- 20(stat.) +/- 14(syst.) +8-6(lum.) pb is measured for an assumed top quark mass of 172.5 GeV. A second measurement requiring at least one jet identified as coming from a b quark yields a comparable result, demonstrating that the dilepton final states are consistent with being accompanied by b-quark jets. These measurements are in good agreement with Standard Model predictions.Peer Reviewe

Performance of the ATLAS Trigger System in 2010

Proton-proton collisions at sqrt{s} = 7 TeV and heavy ion collisions at sqrt{s_NN} = 2.76 TeV were produced by the LHC and recorded using the ATLAS experiment's trigger system in 2010. The LHC is designed with a maximum bunch crossing rate of 40 MHz and the ATLAS trigger system is designed to record approximately 200 of these per second. The trigger system selects events by rapidly identifying signatures of muon, electron, photon, tau lepton, jet, and B meson candidates, as well as using global event signatures, such as missing transverse energy. An overview of the ATLAS trigger system, the evolution of the system during 2010 and the performance of the trigger system components and selections based on the 2010 collision data are shown. A brief outline of plans for the trigger system in 2011 is presentedPeer Reviewe

Performance of Missing Transverse Momentum Reconstruction in Proton-Proton Collisions at 7 TeV with ATLAS

The measurement of missing transverse momentum in the ATLAS detector, described in this paper, makes use of the full event reconstruction and a calibration based on reconstructed physics objects. The performance of the missing transverse momentum reconstruction is evaluated using data collected in pp collisions at a centre-of-mass energy of 7 TeV in 2010. Minimum bias events and events with jets of hadrons are used from data samples corresponding to an integrated luminosity of about 0.3 inverse nb and 600 inverse nb, together with events containing a Z boson decaying to two leptons (electrons or muons) or a W boson decaying to a lepton (electron or muon) and a neutrino, from a data sample corresponding to an integrated luminosity of about 36 inverse pb. An estimate of the systematic uncertainty on the missing transverse momentum scale is presented.Peer Reviewe

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Design and evaluation of multi-band RF energy harvesting circuits and antennas for WSNs

Radio frequency (RF) energy harvesting is an emerging technology that will enable to drive the next generation of wireless sensor networks (WSNs) without the need of using batteries. In this paper, we present RF energy harvesting circuits specifically developed for GSM bands (900/1800) and a wearable dual-band antenna suitable for possible implementation within clothes for body worn applications. Besides, we address the development and experimental characterization of three different prototypes of a five-stage Dickson voltage multiplier (with match impedance circuit) responsible for harvesting the RF energy. Different printed circuit board (PCB) fabrication techniques to produce the prototypes result in different values of conversion efficiency. Therefore, we conclude that if the PCB fabrication is achieved by means of a rigorous control in the photo-positive method and chemical bath procedure applied to the PCB it allows for attaining better values for the conversion efficiency. All three prototypes (1, 2 and 3) can power supply the IRIS sensor node for RF received powers of -4 dBm, -6 dBm and -5 dBm, and conversion efficiencies of 20, 32 and 26%, respectively. © 2014 IEEE

Search for lepton flavour violation in the emu continuum with the ATLAS detector in s=7\sqrt{s}=7 TeV pppp collisions at the LHC

This paper presents a search for the t-channel exchange of an R-parity violating scalar top quark (\={t}) in the emu continuum using 2.1/fb of data collected by the ATLAS detector in sqrt(s) = 7 TeV pp collisions at the Large Hadron Collider. Data are found to be consistent with the expectation from the Standard Model backgrounds. Limits on R-parity-violating couplings at 95% C.L. are calculated as a function of the scalar top mass (m_{\={t}}). The upper limits on the production cross section for pp->emuX, through the t-channel exchange of a scalar top quark, ranges from 170 fb for m_{\={t}}=95 GeV to 30 fb for m_{\={t}}=1000 GeV.Peer Reviewe

Correction to: Comparative effectiveness and safety of non-vitamin K antagonists for atrial fibrillation in clinical practice: GLORIA-AF Registry

International audienceIn this article, the name of the GLORIA-AF investigator Anastasios Kollias was given incorrectly as Athanasios Kollias in the Acknowledgements. The original article has been corrected

Patterns of oral anticoagulant use and outcomes in Asian patients with atrial fibrillation: a post-hoc analysis from the GLORIA-AF Registry

Background: Previous studies suggested potential ethnic differences in the management and outcomes of atrial fibrillation (AF). We aim to analyse oral anticoagulant (OAC) prescription, discontinuation, and risk of adverse outcomes in Asian patients with AF, using data from a global prospective cohort study. Methods: From the GLORIA-AF Registry Phase II-III (November 2011-December 2014 for Phase II, and January 2014-December 2016 for Phase III), we analysed patients according to their self-reported ethnicity (Asian vs. non-Asian), as well as according to Asian subgroups (Chinese, Japanese, Korean and other Asian). Logistic regression was used to analyse OAC prescription, while the risk of OAC discontinuation and adverse outcomes were analysed through Cox-regression model. Our primary outcome was the composite of all-cause death and major adverse cardiovascular events (MACE). The original studies were registered with ClinicalTrials.gov, NCT01468701, NCT01671007, and NCT01937377. Findings: 34,421 patients were included (70.0 ± 10.5 years, 45.1% females, 6900 (20.0%) Asian: 3829 (55.5%) Chinese, 814 (11.8%) Japanese, 1964 (28.5%) Korean and 293 (4.2%) other Asian). Most of the Asian patients were recruited in Asia (n = 6701, 97.1%), while non-Asian patients were mainly recruited in Europe (n = 15,449, 56.1%) and North America (n = 8378, 30.4%). Compared to non-Asian individuals, prescription of OAC and non-vitamin K antagonist oral anticoagulant (NOAC) was lower in Asian patients (Odds Ratio [OR] and 95% Confidence Intervals (CI): 0.23 [0.22-0.25] and 0.66 [0.61-0.71], respectively), but higher in the Japanese subgroup. Asian ethnicity was also associated with higher risk of OAC discontinuation (Hazard Ratio [HR] and [95% CI]: 1.79 [1.67-1.92]), and lower risk of the primary composite outcome (HR [95% CI]: 0.86 [0.76-0.96]). Among the exploratory secondary outcomes, Asian ethnicity was associated with higher risks of thromboembolism and intracranial haemorrhage, and lower risk of major bleeding. Interpretation: Our results showed that Asian patients with AF showed suboptimal thromboembolic risk management and a specific risk profile of adverse outcomes; these differences may also reflect differences in country-specific factors. Ensuring integrated and appropriate treatment of these patients is crucial to improve their prognosis. Funding: The GLORIA-AF Registry was funded by Boehringer Ingelheim GmbH