Open issues in transcatheter aortic valve implantation. Part 2: procedural issues and outcomes after transcatheter aortic valve implantation.

This article provides an overview on procedure-related issues and uncertainties in outcomes after transcatheter aortic valve implantation (TAVI). The different access sites and how to select them in an individual patient are discussed. Also, the occurrence and potential predictors of aortic regurgitation (AR) after TAVI are addressed. The different methods to quantify AR are reviewed, and it appears that accurate and reproducible quantification is suboptimal. Complications such as prosthesis-patient mismatch and conduction abnormalities (and need for permanent pacemaker) are discussed, as well as cerebrovascular events, which emphasize the development of optimal anti-coagulative strategies. Finally, recent registries have shown the adoption of TAVI in the real world, but longer follow-up studies are needed to evaluate the outcome (but also prosthesis durability). Additionally, future studies are briefly discussed, which will address the use of TAVI in pure AR and lower-risk patients.

Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial

BACKGROUND Patients with muscle-invasive urothelial carcinoma of the bladder have poor survival after cystectomy. The EORTC 30994 trial aimed to compare immediate versus deferred cisplatin-based combination chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder. METHODS This intergroup, open-label, randomised, phase 3 trial recruited patients from hospitals across Europe and Canada. Eligible patients had histologically proven urothelial carcinoma of the bladder, pT3-pT4 disease or node positive (pN1-3) M0 disease after radical cystectomy and bilateral lymphadenectomy, with no evidence of any microscopic residual disease. Within 90 days of cystectomy, patients were centrally randomly assigned (1:1) by minimisation to either immediate adjuvant chemotherapy (four cycles of gemcitabine plus cisplatin, high-dose methotrexate, vinblastine, doxorubicin, and cisplatin [high-dose MVAC], or MVAC) or six cycles of deferred chemotherapy at relapse, with stratification for institution, pT category, and lymph node status according to the number of nodes dissected. Neither patients nor investigators were masked. Overall survival was the primary endpoint; all analyses were by intention to treat. The trial was closed after recruitment of 284 of the planned 660 patients. This trial is registered with ClinicalTrials.gov, number NCT00028756. FINDINGS From April 29, 2002, to Aug 14, 2008, 284 patients were randomly assigned (141 to immediate treatment and 143 to deferred treatment), and followed up until the data cutoff of Aug 21, 2013. After a median follow-up of 7·0 years (IQR 5·2-8·7), 66 (47%) of 141 patients in the immediate treatment group had died compared with 82 (57%) of 143 in the deferred treatment group. No significant improvement in overall survival was noted with immediate treatment when compared with deferred treatment (adjusted HR 0·78, 95% CI 0·56-1·08; p=0·13). Immediate treatment significantly prolonged progression-free survival compared with deferred treatment (HR 0·54, 95% CI 0·4-0·73, p<0·0001), with 5-year progression-free survival of 47·6% (95% CI 38·8-55·9) in the immediate treatment group and 31·8% (24·2-39·6) in the deferred treatment group. Grade 3-4 myelosuppression was reported in 33 (26%) of 128 patients who received treatment in the immediate chemotherapy group versus 24 (35%) of 68 patients who received treatment in the deferred chemotherapy group, neutropenia occurred in 49 (38%) versus 36 (53%) patients, respectively, and thrombocytopenia in 36 (28%) versus 26 (38%). Two patients died due to toxicity, one in each group. INTERPRETATION Our data did not show a significant improvement in overall survival with immediate versus deferred chemotherapy after radical cystectomy and bilateral lymphadenectomy for patients with muscle-invasive urothelial carcinoma. However, the trial is limited in power, and it is possible that some subgroups of patients might still benefit from immediate chemotherapy. An updated individual patient data meta-analysis and biomarker research are needed to further elucidate the potential for survival benefit in subgroups of patients. FUNDING Lilly, Canadian Cancer Society Research.

Comparative effects of teriparatide and ibandronate on spine bone mineral density (BMD) and microarchitecture (TBS) in postmenopausal women with osteoporosis: a 2-year open-label study

UNLABELLED Treatment effects over 2 years of teriparatide vs. ibandronate in postmenopausal women with osteoporosis were compared using lumbar spine bone mineral density (BMD) and trabecular bone score (TBS). Teriparatide induced larger increases in BMD and TBS compared to ibandronate, suggesting a more pronounced effect on bone microarchitecture of the bone anabolic drug. INTRODUCTION The trabecular bone score (TBS) is an index of bone microarchitecture, independent of bone mineral density (BMD), calculated from anteroposterior spine dual X-ray absorptiometry (DXA) scans. The potential role of TBS for monitoring treatment response with bone-active substances is not established. The aim of this study was to compare the effects of recombinant human 1-34 parathyroid hormone (teriparatide) and the bisphosphonate ibandronate (IBN), on lumbar spine (LS) BMD and TBS in postmenopausal women with osteoporosis. METHODS Two patient groups with matched age, body mass index (BMI), and baseline LS BMD, treated with either daily subcutaneous teriparatide (N = 65) or quarterly intravenous IBN (N = 122) during 2 years and with available LS BMD measurements at baseline and 2 years after treatment initiation were compared. RESULTS Baseline characteristics (overall mean ± SD) were similar between groups in terms of age 67.9 ± 7.4 years, body mass index 23.8 ± 3.8 kg/m(2), BMD L1-L4 0.741 ± 0.100 g/cm(2), and TBS 1.208 ± 0.100. Over 24 months, teriparatide induced a significantly larger increase in LS BMD and TBS than IBN (+7.6 % ± 6.3 vs. +2.9 % ± 3.3 and +4.3 % ± 6.6 vs. +0.3 % ± 4.1, respectively; P < 0.0001 for both). LS BMD and TBS were only weakly correlated at baseline (r (2) = 0.04) with no correlation between the changes in BMD and TBS over 24 months. CONCLUSIONS In postmenopausal women with osteoporosis, a 2-year treatment with teriparatide led to a significantly larger increase in LS BMD and TBS than IBN, suggesting that teriparatide had more pronounced effects on bone microarchitecture than IBN.

A pentasymmetric open channel blocker for Cys-loop receptor channels.

γ-Aminobutyric acid type A receptors (GABAA receptors) are chloride ion channels composed of five subunits, mediating fast synaptic and tonic inhibition in the mammalian brain. These receptors show near five-fold symmetry that is most pronounced in the second trans-membrane domain M2 lining the Cl- ion channel. To take advantage of this inherent symmetry, we screened a variety of aromatic anions with matched symmetry and found an inhibitor, pentacyanocyclopentdienyl anion (PCCP-) that exhibited all characteristics of an open channel blocker. Inhibition was strongly dependent on the membrane potential. Through mutagenesis and covalent modification, we identified the region α1V256-α1T261 in the rat recombinant GABAA receptor to be important for PCCP- action. Introduction of positive charges into M2 increased the affinity for PCCP- while PCCP- prevented the access of a positively charged molecule into M2. Interestingly, other anion selective cys-loop receptors were also inhibited by PCCP-, among them the Drosophila RDL GABAA receptor carrying an insecticide resistance mutation, suggesting that PCCP- could serve as an insecticide.

Comparative characterisation of two nitroreductases from Giardia lamblia as potential activators of nitro compounds

Giardia lamblia is a protozoan parasite that causes giardiasis, a diarrhoeal disease affecting humans and various animal species. Nitro drugs such as the nitroimidazole metronidazole and the nitrothiazolide nitazoxanide are used for treatment of giardiasis. Nitroreductases such as GlNR1 and GlNR2 may play a role in activation or inactivation of these drugs. The aim of this work is to characterise these two enzymes using functional assays. For respective analyses recombinant analogues from GlNR1 and GlNR2 were produced in Escherichia coli. E. coli expressing GlNR1 and GlNR2 alone or together were grown in the presence of nitro compounds. Furthermore, pull-down assays were performed using HA-tagged GlNR1 and GlNR2 as baits. As expected, E. coli expressing GlNR1 were more susceptible to metronidazole under aerobic and semi-aerobic and to nitazoxanide under semi-aerobic growth conditions whereas E. coli expressing GlNR2 were susceptible to neither drug. Interestingly, expression of both nitroreductases gave the same results as expression of GlNR2 alone. In functional assays, both nitroreductases had their strongest activities on the quinone menadione (vitamin K3) and FAD, but reduction of nitro compounds including the nitro drugs metronidazole and nitazoxanidewas clearly detected. Full reduction of 7-nitrocoumarin to 7-aminocoumarin was preferentially achieved with GlNR2. Pull-down assays revealed that GlNR1 and GlNR2 interacted in vivo forming a multienzyme complex. These findings suggest that both nitroreductases are multifunctional. Their main biological role may reside in the reduction of vitamin K analogues and FAD. Activation by GlNR1 or inactivation by GlNR2 of nitro drugs may be the consequence of a secondary enzymatic activity either yielding (GlNR1) or eliminating (GlNR2) toxic intermediates after reduction of these compounds. © 2015 The Authors. Published by Elsevier Ltd on behalf of Australian Society for Parasitology. This is an open access article under the CC BY-NC-ND license

The potential of female immigrants' integration into sport by intercultural clubs in Switzerland

Sport participation means a privileged access to participate in the sport system and the opportunities of actual integration into sport (Seiberth et al., 2013). The access to sport activities is often restricted for female immigrants. The function of sport participation concerning exercise offers of social associations is not a common theme in research on migration or on sports-related integration. Research on boundaries (Lamont & Molnár, 2002) suggest that gender-related and ethnic boundaries are stable behavioural and cognitive patterns leading to unequal social opportunities. The present study examined the potential of a Swiss intercultural club regarding female immigrants’ integration into sport by focussing on gender-related and ethnic boundaries. Ten interviews with female immigrants and conductress of an intercultural club plus a group discussion were held. Using qualitative content analysis and documentary method, findings reveal multifaceted, interwoven boundaries, e.g. maternal devotion, exclusive exercise offers for women, language learning devotion, religious need of headscarf. Otherwise resources to overcome boundaries are provided: Deploying competent employees; offering childcare, exercise offers suited to mothers‘ time schedule and language lessons; equitable, on integration focussed club-life. Thus, intercultural clubs might help to overcome boundaries and facilitate access to exercise for female immigrants and integrate them more successfully into sport than many sport clubs. A boundary focus and present data may open new perspectives for sport organisation and integration research. Further investigations of social associations offering exercise are advised.

Local Heat Application for the Treatment of Buruli Ulcer: Results of a Phase II Open Label Single Center Non Comparative Clinical Trial.

BACKGROUND Buruli ulcer (BU) is a necrotizing skin disease most prevalent among West African children. The causative organism, Mycobacterium ulcerans, is sensitive to temperatures above 37°C. We investigated the safety and efficacy of a local heat application device based on phase change material. METHODS In a phase II open label single center noncomparative clinical trial (ISRCTN 72102977) under GCP standards in Cameroon, laboratory confirmed BU patients received up to 8 weeks of heat treatment. We assessed efficacy based on the endpoints 'absence of clinical BU specific features' or 'wound closure' within 6 months ("primary cure"), and 'absence of clinical recurrence within 24 month' ("definite cure"). RESULTS Of 53 patients 51 (96%) had ulcerative disease. 62% were classified as World Health Organization category II, 19% each as category I and III. The average lesion size was 45 cm(2). Within 6 months after completion of heat treatment 92.4% (49 of 53, 95% confidence interval [CI], 81.8% to 98.0%) achieved cure of their primary lesion. At 24 months follow-up 83.7% (41 of 49, 95% CI, 70.3% to 92.7%) of patients with primary cure remained free of recurrence. Heat treatment was well tolerated; adverse effects were occasional mild local skin reactions. CONCLUSIONS Local thermotherapy is a highly effective, simple, cheap and safe treatment for M. ulcerans disease. It has in particular potential as home-based remedy for BU suspicious lesions at community level where laboratory confirmation is not available. CLINICAL TRIALS REGISTRATION ISRCT 72102977.

Potential REST Targets in Neural Stem Cells and Glioblastoma-Derived Stem Cells

Glioblastoma multiforme (GBM) tumors are the most common malignant primary brain tumors in adults. The current theory is that these tumors are caused by self-renewing glioblastoma-derived stem cells (GSCs). At the current time, the mechanisms that regulate self-renewal and other oncogenic properties of GSCs remain unknown. Recently, we found transcriptional repressor REST maintains self-renewal in neural stem cells (NSCs) and in GSCs. REST also regulates other oncogenic properties, such as apoptosis, invasion and proliferation. However, the mechanisms by which REST regulates these oncogenic properties are unknown. In an attempt to determine these mechanisms, we performed loss and gain-of-function experiments and genome-wide mRNA expression analysis in GSCs, and we were able to identify REST-regulated genes in GSCs. This was accomplished, after screening concordantly regulated genes in NSCs and GSCs, utilizing two RE1 databases, and setting two-fold expression as filters on the resulting genes. These results received further validation by qRT-PCR. Ingenuity Pathway Analysis (IPA) analysis further revealed the top REST target genes in GSCs were downstream targets of REST and/or involved in other cancers in other cell lines. IPA also revealed that many of the differentially-regulated genes identified in this study are involved in oncogenic properties seen in GBM, and which we believe are related to REST expression.

Open Access Influence on Argentinean Scientific Community's Publishing Patterns

Este estudio tiene como objetivo estimar la influencia del acceso abierto en los patrones de publicación de la comunidad científica argentina en diferentes campos temáticos (Medicina; Física y Astronomía; Agricultura y Ciencias biológicas y Ciencias sociales y Humanidades), a partir del análisis del modelo de acceso de las revistas elegidas para comunicar los resultados de investigación en el período 2008-2010. La producción fue recogida de la base de datos SCOPUS y los modelos de acceso de las revistas determinados a partir de la consulta a las fuentes DOAJ, e-revist@s, SCielo, Redalyc, PubMed, Romeo-Sherpa y Dulcinea. Se analizó la accesibilidad real y potencial de la producción científica nacional por las vías dorada y verde, respectivamente, así como también por suscripción a través de la Biblioteca Electrónica de Ciencia y Tecnología del Ministerio de Ciencia, Tecnología e Innovación Productiva de la Nación Argentina. Los resultados muestran que en promedio, y para el conjunto de las temáticas estudiadas, el 70 de la producción científica argentina visible en SCOPUS se publica en revistas que adhieren de una u otra forma al movimiento de acceso abierto, en una relación del 27 para la vía dorada y del 43 para las que permiten el autoarchivo por la vía verde. Entre el 16 y el 30 (según las áreas temáticas) de los artículos publicados en revistas que permiten el autoarchivo se accede vía suscripción. El porcentaje de revistas sin acceso es del orden del 30 en Ciencias Sociales y Humanidades, y alcanza cerca del 45 en el resto de las áreas. Se concluye que Argentina presenta condiciones muy favorables para liberar un alto porcentaje de la literatura científica generada en el país bajo la modalidad del acceso abierto a través de repositorios institucionales y de mandatos para el auto-archivo, contribuyendo además a incrementar la accesibilidad y la preservación a largo plazo de la producción científica y tecnológica nacional

Open Access Influence on Argentinean Scientific Community's Publishing Patterns

Este estudio tiene como objetivo estimar la influencia del acceso abierto en los patrones de publicación de la comunidad científica argentina en diferentes campos temáticos (Medicina; Física y Astronomía; Agricultura y Ciencias biológicas y Ciencias sociales y Humanidades), a partir del análisis del modelo de acceso de las revistas elegidas para comunicar los resultados de investigación en el período 2008-2010. La producción fue recogida de la base de datos SCOPUS y los modelos de acceso de las revistas determinados a partir de la consulta a las fuentes DOAJ, e-revist@s, SCielo, Redalyc, PubMed, Romeo-Sherpa y Dulcinea. Se analizó la accesibilidad real y potencial de la producción científica nacional por las vías dorada y verde, respectivamente, así como también por suscripción a través de la Biblioteca Electrónica de Ciencia y Tecnología del Ministerio de Ciencia, Tecnología e Innovación Productiva de la Nación Argentina. Los resultados muestran que en promedio, y para el conjunto de las temáticas estudiadas, el 70 de la producción científica argentina visible en SCOPUS se publica en revistas que adhieren de una u otra forma al movimiento de acceso abierto, en una relación del 27 para la vía dorada y del 43 para las que permiten el autoarchivo por la vía verde. Entre el 16 y el 30 (según las áreas temáticas) de los artículos publicados en revistas que permiten el autoarchivo se accede vía suscripción. El porcentaje de revistas sin acceso es del orden del 30 en Ciencias Sociales y Humanidades, y alcanza cerca del 45 en el resto de las áreas. Se concluye que Argentina presenta condiciones muy favorables para liberar un alto porcentaje de la literatura científica generada en el país bajo la modalidad del acceso abierto a través de repositorios institucionales y de mandatos para el auto-archivo, contribuyendo además a incrementar la accesibilidad y la preservación a largo plazo de la producción científica y tecnológica nacional

Potential impact of DOM accumulation on fCO2 and carbonate ion computations in ocean acidification experiments

Culture and mesocosm experiments are often carried out under high initial nutrient concentrations, yielding high biomass concentrations that in turn often lead to a substantial build-up of DOM. In such experiments, DOM can reach concentrations much higher than typically observed in the open ocean. To the extent that DOM includes organic acids and bases, it will contribute to the alkalinity of the seawater contained in the experimental device. Our analysis suggests that whenever substantial amounts of DOM are produced during the experiment, standard computer programmes used to compute CO2 fugacity can underestimate true fCO2 significantly when the computation is based on AT and CT. Unless the effect of DOM-alkalinity can be accounted for, this might lead to significant errors in the interpretation of the system under consideration with respect to the experimentally applied CO2 perturbation. Errors in the inferred fCO2 can misguide the development of parameterisations used in simulations with global carbon cycle models in future CO2-scenarios. Over determination of the CO2-system in experimental ocean acidification studies is proposed to safeguard against possibly large errors in estimated fCO2.

Reflectances transect from coast to open sea, Baltic Sea

In this study, retrievals of the medium resolution imaging spectrometer (MERIS) reflectances and water quality products using 4 different coastal processing algorithms freely available are assessed by comparison against sea-truthing data. The study is based on a pair-wise comparison using processor-dependent quality flags for the retrieval of valid common macro-pixels. This assessment is required in order to ensure the reliability of monitoring systems based on MERIS data, such as the Swedish coastal and lake monitoring system (http.vattenkvalitet.se). The results show that the pre-processing with the Improved Contrast between Ocean and Land (ICOL) processor, correcting for adjacency effects, improve the retrieval of spectral reflectance for all processors, Therefore, it is recommended that the ICOL processor should be applied when Baltic coastal waters are investigated. Chlorophyll was retrieved best using the FUB (Free University of Berlin) processing algorithm, although overestimations in the range 18-26.5%, dependent on the compared pairs, were obtained. At low chlorophyll concentrations (< 2.5 mg/m**3), random errors dominated in the retrievals with the MEGS (MERIS ground segment processor) processor. The lowest bias and random errors were obtained with MEGS for suspended particulate matter, for which overestimations in te range of 8-16% were found. Only the FUB retrieved CDOM (Coloured Dissolved Organic Matter) correlate with in situ values. However, a large systematic underestimation appears in the estimates that nevertheless may be corrected for by using a~local correction factor. The MEGS has the potential to be used as an operational processing algorithm for the Himmerfjärden bay and adjacent areas, but it requires further improvement of the atmospheric correction for the blue bands and better definition at relatively low chlorophyll concentrations in presence of high CDOM attenuation.

A Model-based Repository for Open Source Service and Component Integration.

Open source is a software development paradigm that has seen a huge rise in recent years. It reduces IT costs and time to market, while increasing security and reliability. However, the difficulty in integrating developments from different communities and stakeholders prevents this model from reaching its full potential. This is mainly due to the challenge of determining and locating the correct dependencies for a given software artifact. To solve this problem we propose the development of an extensible software component repository based upon models. This repository should be capable of solving the dependencies between several components and work with already existing repositories to access the needed artifacts transparently. This repository will also be easily expandable, enabling the creation of modules that support new kinds of dependencies or other existing repository technologies. The proposed solution will work with OSGi components and use OSGi itself.

Knowledge pipeline in freight pipeline industry: competence- based model for open innovation

There is growing concern over the challenges for innovation in Freight Pipeline industry. Since the early works of Chesbrough a decade ago, we have learned a lot about the content, context and process of open innovation. However, much more research is needed in Freight Pipeline Industry. The reality is that few corporations have institutionalized open innovation practices in ways that have enabled substantial growth or industry leadership. Based on this, we pursue the following question: How does a firm’s integration into knowledge networks depend on its ability to manage knowledge? A competence-based model for freight pipeline organizations is analysed, this model should be understood by any organization in order to be successful in motivating professionals who carry out innovations and play a main role in collaborative knowledge creation processes. This paper aims to explain how can open innovation achieve its potential in most Freight Pipeline Industries.

Exploration of RVC applications using an ARM multicore processor = Exploración de aplicaciones RVC empleando un procesador ARM multinúcleo

Single core capabilities have reached their maximum clock speed; new multicore architectures provide an alternative way to tackle this issue instead. The design of decoding applications running on top of these multicore platforms and their optimization to exploit all system computational power is crucial to obtain best results. Since the development at the integration level of printed circuit boards are increasingly difficult to optimize due to physical constraints and the inherent increase in power consumption, development of multiprocessor architectures is becoming the new Holy Grail. In this sense, it is crucial to develop applications that can run on the new multi-core architectures and find out distributions to maximize the potential use of the system. Today most of commercial electronic devices, available in the market, are composed of embedded systems. These devices incorporate recently multi-core processors. Task management onto multiple core/processors is not a trivial issue, and a good task/actor scheduling can yield to significant improvements in terms of efficiency gains and also processor power consumption. Scheduling of data flows between the actors that implement the applications aims to harness multi-core architectures to more types of applications, with an explicit expression of parallelism into the application. On the other hand, the recent development of the MPEG Reconfigurable Video Coding (RVC) standard allows the reconfiguration of the video decoders. RVC is a flexible standard compatible with MPEG developed codecs, making it the ideal tool to integrate into the new multimedia terminals to decode video sequences. With the new versions of the Open RVC-CAL Compiler (Orcc), a static mapping of the actors that implement the functionality of the application can be done once the application executable has been generated. This static mapping must be done for each of the different cores available on the working platform. It has been chosen an embedded system with a processor with two ARMv7 cores. This platform allows us to obtain the desired tests, get as much improvement results from the execution on a single core, and contrast both with a PC-based multiprocessor system. Las posibilidades ofrecidas por el aumento de la velocidad de la frecuencia de reloj de sistemas de un solo procesador están siendo agotadas. Las nuevas arquitecturas multiprocesador proporcionan una vía de desarrollo alternativa en este sentido. El diseño y optimización de aplicaciones de descodificación de video que se ejecuten sobre las nuevas arquitecturas permiten un mejor aprovechamiento y favorecen la obtención de mayores rendimientos. Hoy en día muchos de los dispositivos comerciales que se están lanzando al mercado están integrados por sistemas embebidos, que recientemente están basados en arquitecturas multinúcleo. El manejo de las tareas de ejecución sobre este tipo de arquitecturas no es una tarea trivial, y una buena planificación de los actores que implementan las funcionalidades puede proporcionar importantes mejoras en términos de eficiencia en el uso de la capacidad de los procesadores y, por ende, del consumo de energía. Por otro lado, el reciente desarrollo del estándar de Codificación de Video Reconfigurable (RVC), permite la reconfiguración de los descodificadores de video. RVC es un estándar flexible y compatible con anteriores codecs desarrollados por MPEG. Esto hace de RVC el estándar ideal para ser incorporado en los nuevos terminales multimedia que se están comercializando. Con el desarrollo de las nuevas versiones del compilador específico para el desarrollo de lenguaje RVC-CAL (Orcc), en el que se basa MPEG RVC, el mapeo estático, para entornos basados en multiprocesador, de los actores que integran un descodificador es posible. Se ha elegido un sistema embebido con un procesador con dos núcleos ARMv7. Esta plataforma nos permitirá llevar a cabo las pruebas de verificación y contraste de los conceptos estudiados en este trabajo, en el sentido del desarrollo de descodificadores de video basados en MPEG RVC y del estudio de la planificación y mapeo estático de los mismos.