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  • Open Access
    Authors: 
    Morad Aaboud; Alexander Kupco; Stefan Schmitt; Ahmed Bassalat; Matej Melo; Marjorie Shapiro; Grigore Tarna; Till Eifert; Maximiliano Sioli; Nello Bruscino; +816 more
    Publisher: American Physical Society (APS)
    Project: NSERC

    A measurement of the associated production of a top-quark pair (tt) with a vector boson (W, Z) in proton-proton collisions at a center-of-mass energy of 13 TeV is presented, using 36.1 fb-1 of integrated luminosity collected by the ATLAS detector at the Large Hadron Collider. Events are selected in channels with two same- or opposite-sign leptons (electrons or muons), three leptons or four leptons, and each channel is further divided into multiple regions to maximize the sensitivity of the measurement. The ttZ and ttW production cross sections are simultaneously measured using a combined fit to all regions. The best-fit values of the production cross sections are σttZ=0.95±0.08stat±0.10syst pb and σttW=0.87±0.13stat±0.14syst pb in agreement with the Standard Model predictions. The measurement of the ttZ cross section is used to set constraints on effective field theory operators which modify the ttZ vertex.

  • Open Access
    Authors: 
    Gregory J. Dore; Brian Conway; Yan Luo; Ewa Janczewska; Brygida Knysz; Y. Liu; Adrian Streinu-Cercel; Florin Alexandru Caruntu; Manuela Curescu; Richard Skoien; +16 more
    Publisher: Elsevier BV

    Background & AimsTelaprevir plus pegylated interferon/ribavirin (TPV+PegIFN/RBV) remains a therapeutic option for chronic hepatitis C virus (HCV) genotype (GT) 1 infection in many regions. We conducted two open-label, phase IIIb trials comparing safety and efficacy of all-oral ombitasvir/paritaprevir/ritonavir and dasabuvir±ribavirin (OBV/PTV/r+DSV±RBV) and TPV+PegIFN/RBV.MethodsTreatment-naïve (MALACHITE-I) or PegIFN/RBV-experienced (MALACHITE-II) non-cirrhotic, chronic HCV GT1-infected patients were randomized to OBV/PTV/r+DSV+weight-based RBV, OBV/PTV/r+DSV (treatment-naïve, GT1b-infected patients only), or 12weeks of TPV+PegIFN+weight-based RBV and 12–36 additional weeks of PegIFN/RBV. The primary endpoint was sustained virologic response 12weeks post-treatment (SVR12). Patient-reported outcome questionnaires evaluated mental and physical health during the studies.ResultsThree hundred eleven treatment-naïve and 148 treatment-experienced patients were randomized and dosed. Among treatment-naïve patients, SVR12 rates were 97% (67/69) and 82% (28/34), respectively, in OBV/PTV/r+DSV+RBV and TPV+PegIFN/RBV-treated GT1a-infected patients; SVR12 rates were 99% (83/84), 98% (81/83), and 78% (32/41) in OBV/PTV/r+DSV+RBV, OBV/PTV/r+DSV, and TPV+PegIFN/RBV-treated GT1b-infected patients. Among treatment-experienced patients, SVR12 rates were 99% (100/101) and 66% (31/47) with OBV/PTV/r+DSV+RBV and TPV+PegIFN/RBV. Mental and physical health were generally better with OBV/PTV/r+DSV±RBV than TPV+PegIFN/RBV. Rates of discontinuation due to adverse events (0–1% and 8–11%, respectively, p<0.05) and rates of hemoglobin decline to <10g/dl (0–4% and 34–47%, respectively, p<0.05) were lower for OBV/PTV/r+DSV±RBV than TPV+PegIFN/RBV.ConclusionsAmong non-cirrhotic, HCV GT1-infected patients, SVR12 rates were 97–99% with 12week, multi-targeted OBV/PTV/r+DSV±RBV regimens and 66–82% with 24–48 total weeks of TPV+PegIFN/RBV. OBV/PTV/r+DSV±RBV was associated with a generally better mental and physical health, more favorable tolerability, and lower rates of treatment discontinuation due to adverse events.

  • Publication . Article . Other literature type . 2013
    Open Access English
    Authors: 
    Maimoona A. Zariwala; Heon Yung Gee; Małgorzata Kurkowiak; Dalal A. Al-Mutairi; Margaret W. Leigh; Toby W. Hurd; Rim Hjeij; Sharon D. Dell; Moumita Chaki; Gerard W. Dougherty; +48 more
    Countries: Croatia, France, Germany
    Project: WT , NIH | Novel genetics, pathobiol... (5R01DK068306-13), NIH | Colorado Clinical and Tra... (3UL1TR000154-05S1), NIH | Pathogenesis of PCD Lung ... (5R01HL071798-04), NIH | Identifying all Meckel-li... (1RC4DK090917-01), NIH | Genetic Disorder of Mucoc... (5U54HL096458-14)

    Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally, ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function. © 2013 The American Society of Human Genetics.

  • Publication . Article . Conference object . Preprint . 2017 . Embargo End Date: 01 Jan 2017
    Open Access
    Authors: 
    Ron Weiss; Jan Chorowski; Navdeep Jaitly; Yonghui Wu; Zhifeng Chen;
    Publisher: arXiv

    We present a recurrent encoder-decoder deep neural network architecture that directly translates speech in one language into text in another. The model does not explicitly transcribe the speech into text in the source language, nor does it require supervision from the ground truth source language transcription during training. We apply a slightly modified sequence-to-sequence with attention architecture that has previously been used for speech recognition and show that it can be repurposed for this more complex task, illustrating the power of attention-based models. A single model trained end-to-end obtains state-of-the-art performance on the Fisher Callhome Spanish-English speech translation task, outperforming a cascade of independently trained sequence-to-sequence speech recognition and machine translation models by 1.8 BLEU points on the Fisher test set. In addition, we find that making use of the training data in both languages by multi-task training sequence-to-sequence speech translation and recognition models with a shared encoder network can improve performance by a further 1.4 BLEU points. Comment: 5 pages, 1 figure. Interspeech 2017

  • Open Access
    Authors: 
    Roy Fleischmann; Eduardo Mysler; Louis Bessette; Charles Peterfy; Patrick Durez; Yoshiya Tanaka; Jerzy Swierkot; N. Khan; X. Bu; Y. Li; +1 more
    Publisher: BMJ

    Background:In the SELECT-COMPARE study, the Janus kinase inhibitor, upadacitinib (UPA), demonstrated significant improvements in the signs and symptoms of rheumatoid arthritis (RA) when administered at 15 mg once daily (QD) on background methotrexate (MTX) compared with adalimumab (ADA) plus MTX at Week 12 that were maintained through 72 weeks in patients with prior inadequate response to MTX.1Objectives:To assess the long-term safety and efficacy of UPA vs ADA over 3 years in the ongoing long-term extension (LTE).Methods:Patients receiving background MTX were randomized 2:2:1 to UPA 15 mg QD, placebo (PBO), or ADA 40 mg every other week. Between Weeks 14-26, rescue was mandated for either lack of response (<20% improvement in tender or swollen joint counts: Weeks 14, 18, 22) or failure to achieve a targeted disease outcome (CDAI low disease activity: Week 26). Patients who completed the 48-week double-blind period could enter an LTE for up to 10 years total. This analysis describes patients through 3 years of treatment. Treatment-emergent adverse events (TEAEs) per 100 patient years (PY), including events of special interest (AESI), were summarized up to 3 years based on exposure to UPA and to ADA. Efficacy was analyzed by original randomized groups. Patients who were rescued or prematurely discontinued study drug were categorized as non-responders for visits after rescue or discontinuation. Descriptive analyses were performed without formal statistical comparisons.Results:In total, 651, 651, and 327 patients were randomized at baseline to receive UPA, PBO, and ADA, respectively. Between Weeks 14-26, 252 (39%) patients were rescued from UPA to ADA, 159 (49%) were rescued from ADA to UPA, and all PBO patients were switched to UPA by Week 26.1 A higher proportion of patients randomized to UPA completed 3 years without rescue compared to those randomized to ADA (47% vs 36%, respectively). UPA was generally well-tolerated as assessed by the rates of TEAEs, including serious AEs, AEs leading to discontinuation of study drug, and AESIs, including serious and opportunistic infections, malignancies, adjudicated major adverse cardiac events or venous thromboembolism; Figure 1). Consistent with previous analyses, the event rates of AESIs were generally comparable between the UPA and ADA groups, while herpes zoster, lymphopenia, hepatic disorder, and CPK elevation were reported at higher rates with UPA. Consistent with earlier time points, greater proportions of patients randomized to UPA achieved low disease activity and remission at 3 years based on CDAI, as well as DAS28(CRP) ≤3.2 or <2.6, compared with patients randomized to ADA (Table 1).Conclusion:The safety profile of UPA was consistent with the results reported previously and with the integrated Phase 3 safety analysis.1,2 Higher levels of clinical response continued to be observed with UPA vs ADA through 3 years of treatment.References:[1]Fleischmann R, et al. Ann Rheum Dis 2020;79:323.[2]Cohen SB, et al. Ann Rheum Dis 2020; doi: 10.1136/annrheumdis-2020-218510.Table 1.Efficacy Endpoints at 3 Years (NRI)Endpoints, % (95% CI)UPA 15 mg QDN=651*ADA 40 mg EOWN=327*CDAI ≤1039 (36, 43)29 (24, 34)CDAI ≤2.824 (21, 28)17 (12, 21)DAS28(CRP) ≤3.237 (33, 41)26 (21, 31)DAS28(CRP) <2.632 (29, 36)22 (17, 26)ADA, adalimumab; CI, confidence interval; DAS28(CRP), Disease Activity Score for 28-joints C-Reactive Protein; CDAI, clinical disease activity index; EOW, every other week; NRI, non-responder imputation; QD, once daily; UPA, upadacitinib.*Patients who were rescued prior to/at Week 26 were considered non-responders. 252/651 and 159/327 patients were rescued of those randomized to UPA and ADA, respectively.Acknowledgements:AbbVie and the authors thank the patients, trial sites, and investigators who participated in this clinical trial. AbbVie, Inc was the trial sponsor, contributed to trial design, data collection, analysis & interpretation, and to writing, reviewing, and approval of final version. No honoraria or payments were made for authorship. The authors thank Dr. Tim Shaw of AbbVie Inc. for his support with the interpretation of the data. Medical writing support was provided by Ramona Vladea, PhD, of AbbVie, Inc.Disclosure of Interests:Roy Fleischmann Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, GSK, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, and UCB, Grant/research support from: AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech, Janssen, Novartis, Pfizer Inc, Regeneron, Roche, Sanofi-Aventis and UCB, Eduardo Mysler Consultant of: AbbVie, AstraZeneca, Lilly, Pfizer, Roche, BMS, Sandoz, GSK, Janssen, Grant/research support from: AbbVie, AstraZeneca, Lilly, Pfizer, Roche, BMS, Sandoz, GSK, Janssen, Louis Bessette Consultant of: Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Eli Lilly, Novartis, Gilead, Grant/research support from: Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Eli Lilly, Novartis, Gilead, Charles Peterfy Shareholder of: Spire Sciences, Inc, Speakers bureau: Amgen, Bristol-Myers Squibb, Consultant of: Aclaris, Centrexion, Daiichi Sankyo, EMD, Serono, Five Prime, Flexion Therapeutics, Genentech, Gilead, GlaxoSmithKline, Istresso, Eli Lilly, Myriad Genetics, Novartis, Roche, SetPoint, Sorrento, UCB, Employee of: Spire Sciences, Inc, Patrick Durez Speakers bureau: BMS, Sanofi, Eli Lilly, Celltrion, Yoshiya Tanaka Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Teijin, Consultant of: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Teijin, Grant/research support from: Asahi-kasei, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Ono, Jerzy Swierkot Speakers bureau: AbbVie, Sandoz, Pfizer, Roche, BMS, UCB, MSD, Accord, Janssen, Consultant of: AbbVie, Sandoz, Pfizer, Roche, BMS, UCB, MSD, Accord, Janssen, Grant/research support from: AbbVie, Sandoz, Pfizer, Roche, BMS, UCB, MSD, Accord, Janssen, Nasser Khan Shareholder of: AbbVie, Employee of: AbbVie, Xianwei Bu Shareholder of: AbbVie, Employee of: AbbVie, Yihan Li Shareholder of: AbbVie, Employee of: AbbVie, In-Ho Song Shareholder of: AbbVie, Employee of: AbbVie.

  • Open Access
    Authors: 
    Jingyin Huang; Michael Pawliuk; Marcin Sabok; Daniel T. Wise;
    Publisher: Wiley
    Project: NSERC

    We study the problem of extending partial isomorphisms for hypertournaments, which are relational structures generalizing tournaments. This is a generalized version of an old question of Herwig and Lascar. We show that the generalized problem has a negative answer, and we provide a positive answer in a special case. As a corollary, we show that the extension property holds for tournaments in case the partial isomorphisms have pairwise disjoint ranges and pairwise disjoint domains.

  • Open Access
    Authors: 
    Marta Białecka-Pikul; Marta Szpak; Julian Zubek; Małgorzata Stępień-Nycz; Anna Kołodziejczyk; Sandra Bosacki; Bruce D. Homer;
    Publisher: Wiley
    Country: Poland

    Abstract Introduction Although much is known about theory of mind (ToM) development during childhood, data on how these skills develop in adolescence is scarce. This cavity is due in part to the limited knowledge about measures of advanced theory of mind. Methods The study examined the relation among six common story-based tasks designed to measure advanced ToM in two age groups of Polish adolescents: early (13-year-olds; 78 girls) and late (16-year-olds; 143 girls) adolescents. Results Factor models for individual tasks were constructed, followed by an examination of the underlying structure that explained the variability of factor scores. Only in half of the tasks, the results revealed an age-related increase in advanced ToM. Contrary to expectation, results showed a lack of correlations among story-based advanced ToM tasks in the two adolescent groups. Conclusions The results suggest a lack of coherence among advanced story-based ToM tasks and the need for further development of reliable and valid advanced ToM measures which are sensitive enough to show increasingly complex social reasoning abilities in adolescence.

  • Open Access
    Authors: 
    Jürgen Dengler; Thomas J. Matthews; Manuel J. Steinbauer; Sebastian Wolfrum; Steffen Boch; Alessandro Chiarucci; Timo Conradi; Iwona Dembicz; Corrado Marcenò; Itziar García-Mijangos; +35 more
    Publisher: Wiley
    Countries: Italy, Belgium, Italy, Portugal, Italy, Germany, Spain, Poland, Norway, Switzerland ...

    Aim Species-area relationships (SARs) are fundamental scaling laws in ecology although their shape is still disputed. At larger areas, power laws best represent SARs. Yet, it remains unclear whether SARs follow other shapes at finer spatial grains in continuous vegetation. We asked which function describes SARs best at small grains and explored how sampling methodology or the environment influence SAR shape. Location Palaearctic grasslands and other non-forested habitats. Taxa Vascular plants, bryophytes and lichens. Methods We used the GrassPlot database, containing standardized vegetation-plot data from vascular plants, bryophytes and lichens spanning a wide range of grassland types throughout the Palaearctic and including 2,057 nested-plot series with at least seven grain sizes ranging from 1 cm(2) to 1,024 m(2). Using nonlinear regression, we assessed the appropriateness of different SAR functions (power, power quadratic, power breakpoint, logarithmic, Michaelis-Menten). Based on AICc, we tested whether the ranking of functions differed among taxonomic groups, methodological settings, biomes or vegetation types. Results The power function was the most suitable function across the studied taxonomic groups. The superiority of this function increased from lichens to bryophytes to vascular plants to all three taxonomic groups together. The sampling method was highly influential as rooted presence sampling decreased the performance of the power function. By contrast, biome and vegetation type had practically no influence on the superiority of the power law. Main conclusions We conclude that SARs of sessile organisms at smaller spatial grains are best approximated by a power function. This coincides with several other comprehensive studies of SARs at different grain sizes and for different taxa, thus supporting the general appropriateness of the power function for modelling species diversity over a wide range of grain sizes. The poor performance of the Michaelis-Menten function demonstrates that richness within plant communities generally does not approach any saturation, thus calling into question the concept of minimal area. We thank all vegetation scientists who carefully collected multi‐ scale plant diversity data from Palaearctic Grasslands available in GrassPlot. The Eurasian Dry Grassland Group (EDGG) and the International Association for Vegetation Science (IAVS) sup‐ ported the EDGG Field Workshops, which generated a core part of the GrassPlot data. The Bavarian Research Alliance (grant BayIntAn_UBT_2017_58) and the Bayreuth Center of Ecology and Environmental Research (BayCEER) funded the initial GrassPlot workshop during which the database was established and the cur‐ rent paper was initiated. A.N. acknowledges support by the Center for International Scientific Studies and Collaboration (CISSC), Iran. C.M., I.B., I.G.‐M and J.A.C. were funded by the Basque Government (IT936‐16). D.V. carried out the research supported by a grant of the State Fund For Fundamental Research Ф83/53427. G.F. carried out the research in the frame of the MIUR initiative ‘Department of excellence' (Law 232/2016). I.D. was supported by the Polish National Science Centre (grant DEC‐2013/09/N/NZ8/03234). J.Do. was supported by the Czech Science Foundation (GA 17‐19376S). M.J. was supported by grant by Slovak Academy of Sciences (VEGA 02/0095/19). W.U. ac‐ knowledges support from the Polish National Science Centre (grant 2017/27/B/NZ8/00316).

  • Open Access English
    Authors: 
    Emmanuel Sorbets; Kim Fox; Yedid Elbez; Nicolas Danchin; Paul Dorian; Roberto Ferrari; Ian Ford; Nicola Greenlaw; Paul R. Kalra; Zofia Parma; +6 more
    Countries: Italy, United Kingdom

    Abstract Aims Over the last decades, the profile of chronic coronary syndrome has changed substantially. We aimed to determine characteristics and management of patients with chronic coronary syndrome in the contemporary era, as well as outcomes and their determinants. Methods and results Data from 32 703 patients (45 countries) with chronic coronary syndrome enrolled in the prospective observational CLARIFY registry (November 2009 to June 2010) with a 5-year follow-up, were analysed. The primary outcome [cardiovascular death or non-fatal myocardial infarction (MI)] 5-year rate was 8.0% [95% confidence interval (CI) 7.7–8.3] overall [male 8.1% (7.8–8.5); female 7.6% (7.0–8.3)]. A cox proportional hazards model showed that the main independent predictors of the primary outcome were prior hospitalization for heart failure, current smoking, atrial fibrillation, living in Central/South America, prior MI, prior stroke, diabetes, current angina, and peripheral artery disease. There was an interaction between angina and prior MI (P = 0.0016); among patients with prior MI, angina was associated with a higher primary event rate [11.8% (95% CI 10.9–12.9) vs. 8.2% (95% CI 7.8–8.7) in patients with no angina, P &lt; 0.001], whereas among patients without prior MI, event rates were similar for patients with [6.3% (95% CI 5.4–7.3)] or without angina [6.4% (95% CI 5.9–7.0)], P &gt; 0.99. Prescription rates of evidence-based secondary prevention therapies were high. Conclusion This description of the spectrum of chronic coronary syndrome patients shows that, despite high rates of prescription of evidence-based therapies, patients with both angina and prior MI are an easily identifiable high-risk group who may deserve intensive treatment. Clinical registry ISRCTN43070564

  • Open Access
    Authors: 
    Hatef Darabi; Karen McCue; Jonathan Beesley; Kyriaki Michailidou; Silje Nord; Siddhartha Kar; Keith Humphreys; Deborah J. Thompson; Maya Ghoussaini; Manjeet K. Bolla; +119 more
    Countries: Netherlands, United Kingdom

    Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer. This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.ajhg.2015.05.002.

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The following results are related to Canada. Are you interested to view more results? Visit OpenAIRE - Explore.
6,297 Research products, page 1 of 630
  • Open Access
    Authors: 
    Morad Aaboud; Alexander Kupco; Stefan Schmitt; Ahmed Bassalat; Matej Melo; Marjorie Shapiro; Grigore Tarna; Till Eifert; Maximiliano Sioli; Nello Bruscino; +816 more
    Publisher: American Physical Society (APS)
    Project: NSERC

    A measurement of the associated production of a top-quark pair (tt) with a vector boson (W, Z) in proton-proton collisions at a center-of-mass energy of 13 TeV is presented, using 36.1 fb-1 of integrated luminosity collected by the ATLAS detector at the Large Hadron Collider. Events are selected in channels with two same- or opposite-sign leptons (electrons or muons), three leptons or four leptons, and each channel is further divided into multiple regions to maximize the sensitivity of the measurement. The ttZ and ttW production cross sections are simultaneously measured using a combined fit to all regions. The best-fit values of the production cross sections are σttZ=0.95±0.08stat±0.10syst pb and σttW=0.87±0.13stat±0.14syst pb in agreement with the Standard Model predictions. The measurement of the ttZ cross section is used to set constraints on effective field theory operators which modify the ttZ vertex.

  • Open Access
    Authors: 
    Gregory J. Dore; Brian Conway; Yan Luo; Ewa Janczewska; Brygida Knysz; Y. Liu; Adrian Streinu-Cercel; Florin Alexandru Caruntu; Manuela Curescu; Richard Skoien; +16 more
    Publisher: Elsevier BV

    Background & AimsTelaprevir plus pegylated interferon/ribavirin (TPV+PegIFN/RBV) remains a therapeutic option for chronic hepatitis C virus (HCV) genotype (GT) 1 infection in many regions. We conducted two open-label, phase IIIb trials comparing safety and efficacy of all-oral ombitasvir/paritaprevir/ritonavir and dasabuvir±ribavirin (OBV/PTV/r+DSV±RBV) and TPV+PegIFN/RBV.MethodsTreatment-naïve (MALACHITE-I) or PegIFN/RBV-experienced (MALACHITE-II) non-cirrhotic, chronic HCV GT1-infected patients were randomized to OBV/PTV/r+DSV+weight-based RBV, OBV/PTV/r+DSV (treatment-naïve, GT1b-infected patients only), or 12weeks of TPV+PegIFN+weight-based RBV and 12–36 additional weeks of PegIFN/RBV. The primary endpoint was sustained virologic response 12weeks post-treatment (SVR12). Patient-reported outcome questionnaires evaluated mental and physical health during the studies.ResultsThree hundred eleven treatment-naïve and 148 treatment-experienced patients were randomized and dosed. Among treatment-naïve patients, SVR12 rates were 97% (67/69) and 82% (28/34), respectively, in OBV/PTV/r+DSV+RBV and TPV+PegIFN/RBV-treated GT1a-infected patients; SVR12 rates were 99% (83/84), 98% (81/83), and 78% (32/41) in OBV/PTV/r+DSV+RBV, OBV/PTV/r+DSV, and TPV+PegIFN/RBV-treated GT1b-infected patients. Among treatment-experienced patients, SVR12 rates were 99% (100/101) and 66% (31/47) with OBV/PTV/r+DSV+RBV and TPV+PegIFN/RBV. Mental and physical health were generally better with OBV/PTV/r+DSV±RBV than TPV+PegIFN/RBV. Rates of discontinuation due to adverse events (0–1% and 8–11%, respectively, p<0.05) and rates of hemoglobin decline to <10g/dl (0–4% and 34–47%, respectively, p<0.05) were lower for OBV/PTV/r+DSV±RBV than TPV+PegIFN/RBV.ConclusionsAmong non-cirrhotic, HCV GT1-infected patients, SVR12 rates were 97–99% with 12week, multi-targeted OBV/PTV/r+DSV±RBV regimens and 66–82% with 24–48 total weeks of TPV+PegIFN/RBV. OBV/PTV/r+DSV±RBV was associated with a generally better mental and physical health, more favorable tolerability, and lower rates of treatment discontinuation due to adverse events.

  • Publication . Article . Other literature type . 2013
    Open Access English
    Authors: 
    Maimoona A. Zariwala; Heon Yung Gee; Małgorzata Kurkowiak; Dalal A. Al-Mutairi; Margaret W. Leigh; Toby W. Hurd; Rim Hjeij; Sharon D. Dell; Moumita Chaki; Gerard W. Dougherty; +48 more
    Countries: Croatia, France, Germany
    Project: WT , NIH | Novel genetics, pathobiol... (5R01DK068306-13), NIH | Colorado Clinical and Tra... (3UL1TR000154-05S1), NIH | Pathogenesis of PCD Lung ... (5R01HL071798-04), NIH | Identifying all Meckel-li... (1RC4DK090917-01), NIH | Genetic Disorder of Mucoc... (5U54HL096458-14)

    Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally, ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function. © 2013 The American Society of Human Genetics.

  • Publication . Article . Conference object . Preprint . 2017 . Embargo End Date: 01 Jan 2017
    Open Access
    Authors: 
    Ron Weiss; Jan Chorowski; Navdeep Jaitly; Yonghui Wu; Zhifeng Chen;
    Publisher: arXiv

    We present a recurrent encoder-decoder deep neural network architecture that directly translates speech in one language into text in another. The model does not explicitly transcribe the speech into text in the source language, nor does it require supervision from the ground truth source language transcription during training. We apply a slightly modified sequence-to-sequence with attention architecture that has previously been used for speech recognition and show that it can be repurposed for this more complex task, illustrating the power of attention-based models. A single model trained end-to-end obtains state-of-the-art performance on the Fisher Callhome Spanish-English speech translation task, outperforming a cascade of independently trained sequence-to-sequence speech recognition and machine translation models by 1.8 BLEU points on the Fisher test set. In addition, we find that making use of the training data in both languages by multi-task training sequence-to-sequence speech translation and recognition models with a shared encoder network can improve performance by a further 1.4 BLEU points. Comment: 5 pages, 1 figure. Interspeech 2017

  • Open Access
    Authors: 
    Roy Fleischmann; Eduardo Mysler; Louis Bessette; Charles Peterfy; Patrick Durez; Yoshiya Tanaka; Jerzy Swierkot; N. Khan; X. Bu; Y. Li; +1 more
    Publisher: BMJ

    Background:In the SELECT-COMPARE study, the Janus kinase inhibitor, upadacitinib (UPA), demonstrated significant improvements in the signs and symptoms of rheumatoid arthritis (RA) when administered at 15 mg once daily (QD) on background methotrexate (MTX) compared with adalimumab (ADA) plus MTX at Week 12 that were maintained through 72 weeks in patients with prior inadequate response to MTX.1Objectives:To assess the long-term safety and efficacy of UPA vs ADA over 3 years in the ongoing long-term extension (LTE).Methods:Patients receiving background MTX were randomized 2:2:1 to UPA 15 mg QD, placebo (PBO), or ADA 40 mg every other week. Between Weeks 14-26, rescue was mandated for either lack of response (<20% improvement in tender or swollen joint counts: Weeks 14, 18, 22) or failure to achieve a targeted disease outcome (CDAI low disease activity: Week 26). Patients who completed the 48-week double-blind period could enter an LTE for up to 10 years total. This analysis describes patients through 3 years of treatment. Treatment-emergent adverse events (TEAEs) per 100 patient years (PY), including events of special interest (AESI), were summarized up to 3 years based on exposure to UPA and to ADA. Efficacy was analyzed by original randomized groups. Patients who were rescued or prematurely discontinued study drug were categorized as non-responders for visits after rescue or discontinuation. Descriptive analyses were performed without formal statistical comparisons.Results:In total, 651, 651, and 327 patients were randomized at baseline to receive UPA, PBO, and ADA, respectively. Between Weeks 14-26, 252 (39%) patients were rescued from UPA to ADA, 159 (49%) were rescued from ADA to UPA, and all PBO patients were switched to UPA by Week 26.1 A higher proportion of patients randomized to UPA completed 3 years without rescue compared to those randomized to ADA (47% vs 36%, respectively). UPA was generally well-tolerated as assessed by the rates of TEAEs, including serious AEs, AEs leading to discontinuation of study drug, and AESIs, including serious and opportunistic infections, malignancies, adjudicated major adverse cardiac events or venous thromboembolism; Figure 1). Consistent with previous analyses, the event rates of AESIs were generally comparable between the UPA and ADA groups, while herpes zoster, lymphopenia, hepatic disorder, and CPK elevation were reported at higher rates with UPA. Consistent with earlier time points, greater proportions of patients randomized to UPA achieved low disease activity and remission at 3 years based on CDAI, as well as DAS28(CRP) ≤3.2 or <2.6, compared with patients randomized to ADA (Table 1).Conclusion:The safety profile of UPA was consistent with the results reported previously and with the integrated Phase 3 safety analysis.1,2 Higher levels of clinical response continued to be observed with UPA vs ADA through 3 years of treatment.References:[1]Fleischmann R, et al. Ann Rheum Dis 2020;79:323.[2]Cohen SB, et al. Ann Rheum Dis 2020; doi: 10.1136/annrheumdis-2020-218510.Table 1.Efficacy Endpoints at 3 Years (NRI)Endpoints, % (95% CI)UPA 15 mg QDN=651*ADA 40 mg EOWN=327*CDAI ≤1039 (36, 43)29 (24, 34)CDAI ≤2.824 (21, 28)17 (12, 21)DAS28(CRP) ≤3.237 (33, 41)26 (21, 31)DAS28(CRP) <2.632 (29, 36)22 (17, 26)ADA, adalimumab; CI, confidence interval; DAS28(CRP), Disease Activity Score for 28-joints C-Reactive Protein; CDAI, clinical disease activity index; EOW, every other week; NRI, non-responder imputation; QD, once daily; UPA, upadacitinib.*Patients who were rescued prior to/at Week 26 were considered non-responders. 252/651 and 159/327 patients were rescued of those randomized to UPA and ADA, respectively.Acknowledgements:AbbVie and the authors thank the patients, trial sites, and investigators who participated in this clinical trial. AbbVie, Inc was the trial sponsor, contributed to trial design, data collection, analysis & interpretation, and to writing, reviewing, and approval of final version. No honoraria or payments were made for authorship. The authors thank Dr. Tim Shaw of AbbVie Inc. for his support with the interpretation of the data. Medical writing support was provided by Ramona Vladea, PhD, of AbbVie, Inc.Disclosure of Interests:Roy Fleischmann Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, GSK, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, and UCB, Grant/research support from: AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech, Janssen, Novartis, Pfizer Inc, Regeneron, Roche, Sanofi-Aventis and UCB, Eduardo Mysler Consultant of: AbbVie, AstraZeneca, Lilly, Pfizer, Roche, BMS, Sandoz, GSK, Janssen, Grant/research support from: AbbVie, AstraZeneca, Lilly, Pfizer, Roche, BMS, Sandoz, GSK, Janssen, Louis Bessette Consultant of: Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Eli Lilly, Novartis, Gilead, Grant/research support from: Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Eli Lilly, Novartis, Gilead, Charles Peterfy Shareholder of: Spire Sciences, Inc, Speakers bureau: Amgen, Bristol-Myers Squibb, Consultant of: Aclaris, Centrexion, Daiichi Sankyo, EMD, Serono, Five Prime, Flexion Therapeutics, Genentech, Gilead, GlaxoSmithKline, Istresso, Eli Lilly, Myriad Genetics, Novartis, Roche, SetPoint, Sorrento, UCB, Employee of: Spire Sciences, Inc, Patrick Durez Speakers bureau: BMS, Sanofi, Eli Lilly, Celltrion, Yoshiya Tanaka Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Teijin, Consultant of: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Teijin, Grant/research support from: Asahi-kasei, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Ono, Jerzy Swierkot Speakers bureau: AbbVie, Sandoz, Pfizer, Roche, BMS, UCB, MSD, Accord, Janssen, Consultant of: AbbVie, Sandoz, Pfizer, Roche, BMS, UCB, MSD, Accord, Janssen, Grant/research support from: AbbVie, Sandoz, Pfizer, Roche, BMS, UCB, MSD, Accord, Janssen, Nasser Khan Shareholder of: AbbVie, Employee of: AbbVie, Xianwei Bu Shareholder of: AbbVie, Employee of: AbbVie, Yihan Li Shareholder of: AbbVie, Employee of: AbbVie, In-Ho Song Shareholder of: AbbVie, Employee of: AbbVie.

  • Open Access
    Authors: 
    Jingyin Huang; Michael Pawliuk; Marcin Sabok; Daniel T. Wise;
    Publisher: Wiley
    Project: NSERC

    We study the problem of extending partial isomorphisms for hypertournaments, which are relational structures generalizing tournaments. This is a generalized version of an old question of Herwig and Lascar. We show that the generalized problem has a negative answer, and we provide a positive answer in a special case. As a corollary, we show that the extension property holds for tournaments in case the partial isomorphisms have pairwise disjoint ranges and pairwise disjoint domains.

  • Open Access
    Authors: 
    Marta Białecka-Pikul; Marta Szpak; Julian Zubek; Małgorzata Stępień-Nycz; Anna Kołodziejczyk; Sandra Bosacki; Bruce D. Homer;
    Publisher: Wiley
    Country: Poland

    Abstract Introduction Although much is known about theory of mind (ToM) development during childhood, data on how these skills develop in adolescence is scarce. This cavity is due in part to the limited knowledge about measures of advanced theory of mind. Methods The study examined the relation among six common story-based tasks designed to measure advanced ToM in two age groups of Polish adolescents: early (13-year-olds; 78 girls) and late (16-year-olds; 143 girls) adolescents. Results Factor models for individual tasks were constructed, followed by an examination of the underlying structure that explained the variability of factor scores. Only in half of the tasks, the results revealed an age-related increase in advanced ToM. Contrary to expectation, results showed a lack of correlations among story-based advanced ToM tasks in the two adolescent groups. Conclusions The results suggest a lack of coherence among advanced story-based ToM tasks and the need for further development of reliable and valid advanced ToM measures which are sensitive enough to show increasingly complex social reasoning abilities in adolescence.

  • Open Access
    Authors: 
    Jürgen Dengler; Thomas J. Matthews; Manuel J. Steinbauer; Sebastian Wolfrum; Steffen Boch; Alessandro Chiarucci; Timo Conradi; Iwona Dembicz; Corrado Marcenò; Itziar García-Mijangos; +35 more
    Publisher: Wiley
    Countries: Italy, Belgium, Italy, Portugal, Italy, Germany, Spain, Poland, Norway, Switzerland ...

    Aim Species-area relationships (SARs) are fundamental scaling laws in ecology although their shape is still disputed. At larger areas, power laws best represent SARs. Yet, it remains unclear whether SARs follow other shapes at finer spatial grains in continuous vegetation. We asked which function describes SARs best at small grains and explored how sampling methodology or the environment influence SAR shape. Location Palaearctic grasslands and other non-forested habitats. Taxa Vascular plants, bryophytes and lichens. Methods We used the GrassPlot database, containing standardized vegetation-plot data from vascular plants, bryophytes and lichens spanning a wide range of grassland types throughout the Palaearctic and including 2,057 nested-plot series with at least seven grain sizes ranging from 1 cm(2) to 1,024 m(2). Using nonlinear regression, we assessed the appropriateness of different SAR functions (power, power quadratic, power breakpoint, logarithmic, Michaelis-Menten). Based on AICc, we tested whether the ranking of functions differed among taxonomic groups, methodological settings, biomes or vegetation types. Results The power function was the most suitable function across the studied taxonomic groups. The superiority of this function increased from lichens to bryophytes to vascular plants to all three taxonomic groups together. The sampling method was highly influential as rooted presence sampling decreased the performance of the power function. By contrast, biome and vegetation type had practically no influence on the superiority of the power law. Main conclusions We conclude that SARs of sessile organisms at smaller spatial grains are best approximated by a power function. This coincides with several other comprehensive studies of SARs at different grain sizes and for different taxa, thus supporting the general appropriateness of the power function for modelling species diversity over a wide range of grain sizes. The poor performance of the Michaelis-Menten function demonstrates that richness within plant communities generally does not approach any saturation, thus calling into question the concept of minimal area. We thank all vegetation scientists who carefully collected multi‐ scale plant diversity data from Palaearctic Grasslands available in GrassPlot. The Eurasian Dry Grassland Group (EDGG) and the International Association for Vegetation Science (IAVS) sup‐ ported the EDGG Field Workshops, which generated a core part of the GrassPlot data. The Bavarian Research Alliance (grant BayIntAn_UBT_2017_58) and the Bayreuth Center of Ecology and Environmental Research (BayCEER) funded the initial GrassPlot workshop during which the database was established and the cur‐ rent paper was initiated. A.N. acknowledges support by the Center for International Scientific Studies and Collaboration (CISSC), Iran. C.M., I.B., I.G.‐M and J.A.C. were funded by the Basque Government (IT936‐16). D.V. carried out the research supported by a grant of the State Fund For Fundamental Research Ф83/53427. G.F. carried out the research in the frame of the MIUR initiative ‘Department of excellence' (Law 232/2016). I.D. was supported by the Polish National Science Centre (grant DEC‐2013/09/N/NZ8/03234). J.Do. was supported by the Czech Science Foundation (GA 17‐19376S). M.J. was supported by grant by Slovak Academy of Sciences (VEGA 02/0095/19). W.U. ac‐ knowledges support from the Polish National Science Centre (grant 2017/27/B/NZ8/00316).

  • Open Access English
    Authors: 
    Emmanuel Sorbets; Kim Fox; Yedid Elbez; Nicolas Danchin; Paul Dorian; Roberto Ferrari; Ian Ford; Nicola Greenlaw; Paul R. Kalra; Zofia Parma; +6 more
    Countries: Italy, United Kingdom

    Abstract Aims Over the last decades, the profile of chronic coronary syndrome has changed substantially. We aimed to determine characteristics and management of patients with chronic coronary syndrome in the contemporary era, as well as outcomes and their determinants. Methods and results Data from 32 703 patients (45 countries) with chronic coronary syndrome enrolled in the prospective observational CLARIFY registry (November 2009 to June 2010) with a 5-year follow-up, were analysed. The primary outcome [cardiovascular death or non-fatal myocardial infarction (MI)] 5-year rate was 8.0% [95% confidence interval (CI) 7.7–8.3] overall [male 8.1% (7.8–8.5); female 7.6% (7.0–8.3)]. A cox proportional hazards model showed that the main independent predictors of the primary outcome were prior hospitalization for heart failure, current smoking, atrial fibrillation, living in Central/South America, prior MI, prior stroke, diabetes, current angina, and peripheral artery disease. There was an interaction between angina and prior MI (P = 0.0016); among patients with prior MI, angina was associated with a higher primary event rate [11.8% (95% CI 10.9–12.9) vs. 8.2% (95% CI 7.8–8.7) in patients with no angina, P &lt; 0.001], whereas among patients without prior MI, event rates were similar for patients with [6.3% (95% CI 5.4–7.3)] or without angina [6.4% (95% CI 5.9–7.0)], P &gt; 0.99. Prescription rates of evidence-based secondary prevention therapies were high. Conclusion This description of the spectrum of chronic coronary syndrome patients shows that, despite high rates of prescription of evidence-based therapies, patients with both angina and prior MI are an easily identifiable high-risk group who may deserve intensive treatment. Clinical registry ISRCTN43070564

  • Open Access
    Authors: 
    Hatef Darabi; Karen McCue; Jonathan Beesley; Kyriaki Michailidou; Silje Nord; Siddhartha Kar; Keith Humphreys; Deborah J. Thompson; Maya Ghoussaini; Manjeet K. Bolla; +119 more
    Countries: Netherlands, United Kingdom

    Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer. This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.ajhg.2015.05.002.