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Aim: To analyse the clinical features, laboratory data and foetal-maternal outcomes, and follow them up on a cohort of 1000 women with obstetric antiphospholipid syndrome (OAPS). Methods: The European Registry of OAPS became a registry within the framework of the European Forum on Antiphospholipid Antibody projects and was placed on a website in June 2010. Thirty hospitals throughout Europe have collaborated to carry out this registry. Cases with obstetric complaints related to antiphospholipid antibodies (aPL) who tested positive for aPL at least twice were included prospectively and retrospectively. The seven-year survey results are reported. Results: 1000 women with 3553 episodes were included of which 2553 were historical and 1000 were latest episodes. All cases fulfilled the Sydney classification criteria. According to the laboratory categories, 292 (29.2%) were in category I, 357 (35.7%) in Era, 224 (22.4%) in IIb and 127 (12.7%) in IIc. Miscarriages were the most prevalent clinical manifestation in 386 cases (38.6%). Moreover, the presence of early preeclampsia (PE) and early foetal growth restriction (FGR) appeared in 181 (18.1%) and 161 (16.1%), respectively. In this series, 448 (44.8%) women received the recommended OAPS treatment. Patients with recommended treatment had a good live-birth rate (85%), but worse results (72.4%) were obtained in patients with any treatment (low-dose aspirin (LDA) or low-molecular-weight heparin (LMWH) not on recommended schedule, while patients with no treatment showed a poor birth rate (49.6%). Conclusion: In this series, recurrent miscarriage is the most frequent poor outcome. To avoid false-negative diagnoses, all laboratory category subsets were needed. OAPS cases have very good foetal-maternal outcomes when treated. Results suggest that we were able to improve our clinical practice to offer better treatment and outcomes to OAPS patients.

Contains fulltext : 172671.pdf (Publisher’s version ) (Closed access) Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274 patients from 167 kindreds originating from 40 countries from 5 continents. Demographic data, clinical features, immunological parameters, treatment, and outcome were recorded. The median age of the 274 patients was 22 years (range, 1-71 years); 98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years). Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients. Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%) caused by Mycobacterium tuberculosis, environmental mycobacteria, or Bacille Calmette-Guerin vaccines were less common. Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%). Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome. CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment. Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested. STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis.

We introduce an algorithm for the segmentation of a class of regime switching processes. The segmentation algorithm is a non parametric statistical method able to identify the regimes (patches) of the time series. The process is composed of consecutive patches of variable length, each patch being described by a stationary compound Poisson process, i.e. a Poisson process where each count is associated to a fluctuating signal. The parameters of the process are different in each patch and therefore the time series is non stationary. Our method is a generalization of the algorithm introduced by Bernaola-Galvan, et al., Phys. Rev. Lett., 87, 168105 (2001). We show that the new algorithm outperforms the original one for regime switching compound Poisson processes. As an application we use the algorithm to segment the time series of the inventory of market members of the London Stock Exchange and we observe that our method finds almost three times more patches than the original one., Comment: 11 pages, 11 figures

© 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license Background Continuous electronic fetal heart-rate monitoring is widely used during labour, and computerised interpretation could increase its usefulness. We aimed to establish whether the addition of decision-support software to assist in the interpretation of cardiotocographs affected the number of poor neonatal outcomes. Methods In this unmasked randomised controlled trial, we recruited women in labour aged 16 years or older having continuous electronic fetal monitoring, with a singleton or twin pregnancy, and at 35 weeks' gestation or more at 24 maternity units in the UK and Ireland. They were randomly assigned (1:1) to decision support with the INFANT system or no decision support via a computer-generated stratified block randomisation schedule. The primary outcomes were poor neonatal outcome (intrapartum stillbirth or early neonatal death excluding lethal congenital anomalies, or neonatal encephalopathy, admission to the neonatal unit within 24 h for ≥48 h with evidence of feeding difficulties, respiratory illness, or encephalopathy with evidence of compromise at birth), and developmental assessment at age 2 years in a subset of surviving children. Analyses were done by intention to treat. This trial is completed and is registered with the ISRCTN Registry, number 98680152. Findings Between Jan 6, 2010, and Aug 31, 2013, 47 062 women were randomly assigned (23 515 in the decision-support group and 23 547 in the no-decision-support group) and 46 042 were analysed (22 987 in the decision-support group and 23 055 in the no-decision-support group). We noted no difference in the incidence of poor neonatal outcome between the groups—172 (0·7%) babies in the decision-support group compared with 171 (0·7%) babies in the no-decision-support group (adjusted risk ratio 1·01, 95% CI 0·82–1·25). At 2 years, no significant differences were noted in terms of developmental assessment. Interpretation Use of computerised interpretation of cardiotocographs in women who have continuous electronic fetal monitoring in labour does not improve clinical outcomes for mothers or babies. Funding National Institute for Health Research.

We study the finite temperature transition in QCD with two flavors of dynamical fermions at a pseudoscalar pion mass of about 350 MeV. We use lattices with temporal extent of $N_t$=8, 10 and 12. For the first time in the literature a continuum limit is carried out for several observables with dynamical overlap fermions. These findings are compared with results obtained within the staggered fermion formalism at the same pion masses and extrapolated to the continuum limit. The presented results correspond to fixed topology and its effect is studied in the staggered case. Nice agreement is found between the overlap and staggered results., Comment: 12 pages, 6 figures

Order flow in equity markets is remarkably persistent in the sense that order signs (to buy or sell) are positively autocorrelated out to time lags of tens of thousands of orders, corresponding to many days. Two possible explanations are herding, corresponding to positive correlation in the behavior of different investors, or order splitting, corresponding to positive autocorrelation in the behavior of single investors. We investigate this using order flow data from the London Stock Exchange for which we have membership identifiers. By formulating models for herding and order splitting, as well as models for brokerage choice, we are able to overcome the distortion introduced by brokerage. On timescales of less than a few hours the persistence of order flow is overwhelmingly due to splitting rather than herding. We also study the properties of brokerage order flow and show that it is remarkably consistent both cross-sectionally and longitudinally., Comment: 42 pages, 15 figures

There is a need for decision support tools that integrate energy simulation into early design in the context of Australian practice. Despite the proliferation of simulation programs in the last decade, there are no ready-to-use applications that cater specifically for the Australian climate and regulations. Furthermore, the majority of existing tools focus on achieving interaction with the design domain through model-based interoperability, and largely overlook the issue of process integration. This paper proposes an energy-oriented design environment that both accommodates the Australian context and provides interactive and iterative information exchanges that facilitate feedback between domains. It then presents the structure for DEEPA, an openly customisable system that couples parametric modelling and energy simulation software as a means of developing a decision support tool to allow designers to rapidly and flexibly assess the performance of early design alternatives. Finally, it discusses the benefits of developing a dynamic and concurrent performance evaluation process that parallels the characteristics and relationships of the design process.

Effective strategies for the design of effi cient and environmentally sensitive buildings require a close collaboration between architects and engineers in the design of the building shell and environmental control systems at the outset of projects. However, it is often not practical for engineers to be involved early on in the design process. It is therefore essential that architects be able to perform preliminary energy analyses to evaluate their proposed designs prior to the major building characteristics becoming fi xed. Subsequently, a need exists for a simplifi ed energy design tool for architects. This paper discusses the limitations of existing analysis software in supporting early design explorations and proposes a framework for the development of a tool that provides decision support by permitting architects to quickly assess the performance of design alternatives.

We study spin 1/2 isoscalar and isovector, even and odd parity candidates for the $��^+(1540)$ pentaquark particle using large scale lattice QCD simulations. Previous lattice works led to inconclusive results because so far it has not been possible to unambiguously identify the known scattering spectrum and tell whether additionally a genuine pentaquark state also exists. Here we carry out this analysis using several possible wave functions (operators). Linear combinations of those have a good chance of spanning both the scattering and pentaquark states. Our operator basis is the largest in the literature, and it also includes spatially non-trivial ones with unit orbital angular momentum. The cross correlator we compute is 14$\times$14 with 60 non-vanishing elements. We can clearly distinguish the lowest scattering state(s) in both parity channels up to above the expected location of the pentaquark, but we find no trace of the latter. Based on that we conclude that there are most probably no pentaquark bound states at our quark masses, corresponding to $m_��$=400--630 MeV. However, we cannot rule out the existence of a pentaquark state at the physical quark mass corresponding to $m_��$=135 MeV or pentaquarks with a more exotic wave function., 18 pages, 2 figures

5-Hydroxytryptamine 2A (5-HT2A) serotonin receptors are important for a variety of functions including vascular smooth muscle contraction, platelet aggregation, and the modulation of perception, cognition, and emotion. In a search for 5-HT2A receptor-interacting proteins, we discovered that caveolin-1 (Cav-1), a scaffolding protein enriched in caveolae, complexes with 5-HT2A receptors in a number of cell types including C6 glioma cells, transfected HEK-293 cells, and rat brain synaptic membrane preparations. To address the functional significance of this interaction, we performed RNA interference-mediated knockdown of Cav-1 in C6 glioma cells, a cell type that endogenously expresses both 5-HT2A receptors and Cav-1. We discovered that the in vitro knockdown of Cav-1 in C6 glioma cells nearly abolished 5-HT2A receptor-mediated signal transduction as measured by calcium flux assays. RNA interference-mediated knockdown of Cav-1 also greatly attenuated endogenous Gαq-coupled P2Y purinergic receptor-mediated signaling without altering the signaling of PAR-1 thrombin receptors. Cav-1 appeared to modulate 5-HT2A signaling by facilitating the interaction of 5-HT2A receptors with Gαq. These studies provide compelling evidence for a prominent role of Cav-1 in regulating the functional activity of not only 5-HT 2A serotonin receptors but also selected Gαq-coupled receptors.

Six different sulphonamide-β- 4 N-glucosides were studied by a hydrolysing enzyme, the β- 4 N-glucosidase, prepared from rabbit blood plasma. On purification, the specific activity rises 200–250 times in preparation and 75–80 per cent of original activity can be obtained. The hydrolysis is reversible. The velocity of the enzymic reaction is influenced by the different substituents group on the NH 2 . The reaction has zero-rate in the initial stages of the hydrolysis changing to first-rate and, finally, polymolecular effects dominate on reaching the equilibrium state. The dependence of enzyme activity on substrate concentration has been examined and the k m 's for each sulphonamide-β- 4 N-glucoside have been calculated. The temperature and and pH optimum arc 40° and pH 7 respectively. The β- 4 N-glucosidase can be strongly activated by K + , Na + and Mg 2+ and slightly by Ca 2+ . The NH 4 + ion has a negligible effect but Zn 2+ and Cu 2+ inhibit. The enzyme is competitively inhibited by sulphonamide molecules liberated from β- 4 N-glucosides.

Emerging from the challenge to reduce energy consumption in buildings is a need for research and development into the more effective use of simulation as a decision-support tool. Despite significant research, persistent limitations in process and software inhibit the integration of energy simulation in early architectural design. This paper presents a green star case study to highlight the obstacles commonly encountered with current integration strategies. It then examines simulation-based design in the aerospace industry, which has overcome similar limitations. Finally, it proposes a design system based on this contrasting approach, coupling parametric modelling and energy simulation software for rapid and iterative performance assessment of early design options.

There is a growing need for parametric design software that communicates building performance feedback in early architectural exploration to support decision-making. This paper examines how the circuit of design and analysis process can be closed to provide active and concurrent feedback between architecture and services engineering domains. It presents the structure for an openly customisable design system that couples parametric modelling and energy analysis software to allow designers to assess the performance of early design iterations quickly. Finally, it discusses how user interactions with the system foster information exchanges that facilitate the sharing of design intelligence across disciplines.

We study the finite temperature transition in QCD with two flavors of dynamical fermions at a pseudoscalar pion mass of about 350 MeV. We use lattices with temporal extent of $N_t$=8, 10 and 12. For the first time in the literature a continuum limit is carried out for several observables with dynamical overlap fermions. These findings are compared with results obtained within the staggered fermion formalism at the same pion masses and extrapolated to the continuum limit. The presented results correspond to fixed topology and its effect is studied in the staggered case. Nice agreement is found between the overlap and staggered results.

We present an empirical study of the intertwined behaviour of members in a financial market. Exploiting a database where the broker that initiates an order book event can be identified, we decompose the correlation and response functions into contributions coming from different market participants and study how their behaviour is interconnected. We find evidence that (1) brokers are very heterogeneous in liquidity provision -- some are consistently liquidity providers while others are consistently liquidity takers. (2) The behaviour of brokers is strongly conditioned on the actions of {\it other} brokers. In contrast brokers are only weakly influenced by the impact of their own previous orders. (3) The total impact of market orders is the result of a subtle compensation between the same broker pushing the price in one direction and the liquidity provision of other brokers pushing it in the opposite direction. These results enforce the picture of market dynamics being the result of the competition between heterogeneous participants interacting to form a complicated market ecology., 22 pages, 5+9 figures

Motor neuron–specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease., Target ALS; European Union (European Union); Horizon 2020; European Research Council (ERC), European Union's Seventh Framework Programme (FP7/2007-2013); AFM Telethon; NIH; National Institute of Neurological Disorders and Stroke; NIH/NINDS; United Kingdom, Medical Research Council; Suna and İnan Kıraç Foundation; Legacy Heritage Fund; Bruno and Ilse Frick Foundation for Research on ALS; Teva Pharmaceutical Industries Ltd. as part of the Israeli National Network of Excellence in Neuroscience (NNE); Minna-James-Heineman Stiftung through Minerva; Israel Science Foundation; ALS-Therapy Alliance; Motor Neuron Disease Association (United Kingdom); Thierry Latran Foundation for ALS research; ERA-Net for Research Programmes on Rare Diseases (FP7); IsrALS, Yeda-Sela, Yeda-CEO, Israel Ministry of Trade and Industry; Y. Leon Benoziyo Institute for Molecular Medicine; Kekst Family Institute for Medical Genetics; David and Fela Shapell Family Center for Genetic Disorders Research; Crown Human Genome Center; Nathan, Shirley, Philip and Charlene Vener New Scientist Fund; Julius and Ray Charlestein Foundation; Fraida Foundation; Wolfson Family Charitable Trust; Adelis Foundation; Merck (United Kingdom); ALS Canada Tim E. Noel Postdoctoral Fellowship; Project5 for ALS; Robert Packard Center for ALS Research; University of Missouri Spinal Cord Injury/Disease Research Program; Hope Center for Neurological Disorders; ALS Association ; Biogen; ALS Finding a Cure; Angel Fund; ALS-One; Cellucci Fund; Motor Neurone Disease Association; National Institute for Health Research (NIHR) Biomedical Research Centre

Background— Fractional flow reserve (FFR) measurement of intermediate coronary stenoses is recommended by guidelines when demonstration of ischemia by noninvasive testing is unavailable. The study aims to evaluate the penetration of this recommendation into current thinking about revascularization strategies for stable coronary artery disease. Methods and Results— International Survey on Interventional Strategy was conducted via a web-based platform. First, participants’ experiences in interventional cardiology were queried. Second, 5 complete angiograms were provided, presenting only focal intermediate stenoses. FFR and quantitative coronary angiography values were known; however, remained undisclosed. Determination of stenosis significance was asked for each lesion. In cases of uncertainty, the most appropriate adjunctive invasive diagnostic method among quantitative coronary angiography, intravascular ultrasound, optical coherence tomography, or FFR needed to be selected. International Survey on Interventional Strategy was taken by 495 participants who provided 4421 lesion evaluations. In 3158 (71%) decisions, participants relied solely on angiographic appearance that was discordant in 47% with the known FFR, using 0.80 as cutoff value. The use of FFR and imaging modalities was requested in 21% and 8%, respectively. Comparing 4 groups of participants according to the experience in FFR, angiogram-based decisions were less frequent with increasing experience (77% versus 72% versus 69% versus 67%, respectively; P P P Conclusions— The findings confirm that, even when all potential external constraints are virtually eliminated, visual estimation continues to dominate the treatment decisions for intermediate stenoses, indicative of a worrisome disconnect between recommendations and current practice.

We introduce an algorithm for the segmentation of a class of regime switching processes. The segmentation algorithm is a non parametric statistical method able to identify the regimes (patches) of a time series. The process is composed of consecutive patches of variable length. In each patch the process is described by a stationary compound Poisson process, i.e. a Poisson process where each count is associated with a fluctuating signal. The parameters of the process are different in each patch and therefore the time series is non-stationary. Our method is a generalization of the algorithm introduced by Bernaola-Galván, et al. [Phys. Rev. Lett. 87, 168105 (2001)]. We show that the new algorithm outperforms the original one for regime switching models of compound Poisson processes. As an application we use the algorithm to segment the time series of the inventory of market members of the London Stock Exchange and we observe that our method finds almost three times more patches than the original one. © 2010 EDP Sciences, Società Italiana di Fisica, Springer-Verlag.