Showing papers by "University at Buffalo published in 2014"
Alistair R. R. Forrest, Hideya Kawaji, Michael Rehli1, J Kenneth Baillie2 +277 more•Institutions (63)
TL;DR: For example, the authors mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body.
Abstract: Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body We find that few genes are truly 'housekeeping', whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved Promoter-based expression analysis reveals key transcription factors defining cell states and links them to binding-site motifs The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research
1,715 citations
TL;DR: The National Kidney Foundation-KDOQI guideline for evaluation, classification, and stratification of chronic kidney disease (CKD) was published in 2002 as mentioned in this paper, but concerns and criticisms arose as new evidence became available since the publication of the original guidelines.
1,165 citations
TL;DR: The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival.
Abstract: Background Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer. Methods Using a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topote can at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important. Results Groups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan–paclitaxel was not superior to cisplatin–paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevaciz umab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P = 0.004 in a one-sided test) and higher response rates (48% vs. 36%, P = 0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%). Conclusions The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival. (Funded by the National Cancer Institute; GOG 240 ClinicalTrials.gov number, NCT00803062.)
1,029 citations
TL;DR: This paper proposes a basic idea for the MRSE based on secure inner product computation, and gives two significantly improved MRSE schemes to achieve various stringent privacy requirements in two different threat models and further extends these two schemes to support more search semantics.
Abstract: With the advent of cloud computing, data owners are motivated to outsource their complex data management systems from local sites to the commercial public cloud for great flexibility and economic savings. But for protecting data privacy, sensitive data have to be encrypted before outsourcing, which obsoletes traditional data utilization based on plaintext keyword search. Thus, enabling an encrypted cloud data search service is of paramount importance. Considering the large number of data users and documents in the cloud, it is necessary to allow multiple keywords in the search request and return documents in the order of their relevance to these keywords. Related works on searchable encryption focus on single keyword search or Boolean keyword search, and rarely sort the search results. In this paper, for the first time, we define and solve the challenging problem of privacy-preserving multi-keyword ranked search over encrypted data in cloud computing (MRSE). We establish a set of strict privacy requirements for such a secure cloud data utilization system. Among various multi-keyword semantics, we choose the efficient similarity measure of "coordinate matching," i.e., as many matches as possible, to capture the relevance of data documents to the search query. We further use "inner product similarity" to quantitatively evaluate such similarity measure. We first propose a basic idea for the MRSE based on secure inner product computation, and then give two significantly improved MRSE schemes to achieve various stringent privacy requirements in two different threat models. To improve search experience of the data search service, we further extend these two schemes to support more search semantics. Thorough analysis investigating privacy and efficiency guarantees of proposed schemes is given. Experiments on the real-world data set further show proposed schemes indeed introduce low overhead on computation and communication.
979 citations
TL;DR: The challenges related to patients and pathogens that contribute to inadequate antibiotic dosing are explored and how to implement a process for individualised antibiotic therapy that increases the accuracy of dosing and optimises care for critically ill patients is discussed.
Abstract: Infections in critically ill patients are associated with persistently poor clinical outcomes. These patients have severely altered and variable antibiotic pharmacokinetics and are infected by less susceptible pathogens. Antibiotic dosing that does not account for these features is likely to result in suboptimum outcomes. In this Review, we explore the challenges related to patients and pathogens that contribute to inadequate antibiotic dosing and discuss how to implement a process for individualised antibiotic therapy that increases the accuracy of dosing and optimises care for critically ill patients. To improve antibiotic dosing, any physiological changes in patients that could alter antibiotic concentrations should first be established; such changes include altered fluid status, changes in serum albumin concentrations and renal and hepatic function, and microvascular failure. Second, antibiotic susceptibility of pathogens should be confirmed with microbiological techniques. Data for bacterial susceptibility could then be combined with measured data for antibiotic concentrations (when available) in clinical dosing software, which uses pharmacokinetic/pharmacodynamic derived models from critically ill patients to predict accurately the dosing needs for individual patients. Individualisation of dosing could optimise antibiotic exposure and maximise effectiveness.
707 citations
Washington University in St. Louis1, Medical University of South Carolina2, Emory University3, State University of New York System4, Oregon Health & Science University5, University of Florida6, University at Buffalo7, University of Alabama at Birmingham8, Houston Methodist Hospital9, Barrow Neurological Institute10, University of Texas Southwestern Medical Center11, Medical College of Wisconsin12, Mayo Clinic13
TL;DR: The findings lend support to the use of aggressive medical management rather than PTAS with the Wingspan system in high-risk patients with atherosclerotic intracranial arterial stenosis.
614 citations
26 May 2014
TL;DR: In this paper, a description of the software algorithms developed for the CMS tracker both for reconstructing charged-particle trajectories in proton-proton interactions and for using the resulting tracks to estimate the positions of the LHC luminous region and individual primary-interaction vertices is provided.
Abstract: A description is provided of the software algorithms developed for the CMS tracker both for reconstructing charged-particle trajectories in proton-proton interactions and for using the resulting tracks to estimate the positions of the LHC luminous region and individual primary-interaction vertices. Despite the very hostile environment at the LHC, the performance obtained with these algorithms is found to be excellent. For tt events under typical 2011 pileup conditions, the average track-reconstruction efficiency for promptly-produced charged particles with transverse momenta of p_T > 0.9GeV is 94% for pseudorapidities of |η| < 0.9 and 85% for 0.9 < |η| < 2.5. The inefficiency is caused mainly by hadrons that undergo nuclear interactions in the tracker material. For isolated muons, the corresponding efficiencies are essentially 100%. For isolated muons of p_T = 100GeV emitted at |η| < 1.4, the resolutions are approximately 2.8% in p_T, and respectively, 10μm and 30μm in the transverse and longitudinal impact parameters. The position resolution achieved for reconstructed primary vertices that correspond to interesting pp collisions is 10–12μm in each of the three spatial dimensions. The tracking and vertexing software is fast and flexible, and easily adaptable to other functions, such as fast tracking for the trigger, or dedicated tracking for electrons that takes into account bremsstrahlung.
559 citations
University of Adelaide1, University of Exeter2, University of Colorado Boulder3, University at Buffalo4, University of Coimbra5, Technion – Israel Institute of Technology6, Delft University of Technology7, University of Amsterdam8, Urbana University9, Australian National University10, University of Newcastle11, California State University, Fresno12, Polytechnic University of Milan13, Cornell University14
TL;DR: Future EA-based applications to real-world problems require a fundamental shift of focus towards improving problem formulations, understanding general theoretic frameworks for problem decompositions, major advances in EA computational efficiency, and most importantly aiding real decision-making in complex, uncertain application contexts.
Abstract: The development and application of evolutionary algorithms (EAs) and other metaheuristics for the optimisation of water resources systems has been an active research field for over two decades. Research to date has emphasized algorithmic improvements and individual applications in specific areas (e.g. model calibration, water distribution systems, groundwater management, river-basin planning and management, etc.). However, there has been limited synthesis between shared problem traits, common EA challenges, and needed advances across major applications. This paper clarifies the current status and future research directions for better solving key water resources problems using EAs. Advances in understanding fitness landscape properties and their effects on algorithm performance are critical. Future EA-based applications to real-world problems require a fundamental shift of focus towards improving problem formulations, understanding general theoretic frameworks for problem decompositions, major advances in EA computational efficiency, and most importantly aiding real decision-making in complex, uncertain application contexts.
516 citations
TL;DR: In this paper, the authors presented the results of a project with the European Research Council and EPLANET (European Union) with the objective of supporting the development of a research network in the field of nuclear energy.
Abstract: Austrian Federal Ministry of Science and Research and the Austrian Science Fund; the Belgian Fonds de la Recherche Scientifique and Fonds voor Wetenschappelijk Onderzoek; the Brazilian Funding Agencies (CNPq, CAPES, FAPERJ, and FAPESP); the Bulgarian Ministry of Education and Science; CERN; the Chinese Academy of Sciences, Ministry of Science and Technology, and National Natural Science Foundation of China; the Colombian Funding Agency (COLCIENCIAS); the Croatian Ministry of Science, Education and Sport, and the Croatian Science Foundation; the Research Promotion Foundation, Cyprus; the Ministry of Education and Research, Recurrent Financing Contract No. SF0690030s09 and European Regional Development Fund, Estonia; the Academy of Finland, Finnish Ministry of Education and Culture, and Helsinki Institute of Physics; the Institut National de Physique Nucleaire et de Physique des Particules/CNRS and Commissariat a l’Energie Atomique et aux Energies Alternatives/CEA, France; the Bundesministerium fur Bildung und Forschung, Deutsche Forschungsgemeinschaft, and Helmholtz-Gemeinschaft Deutscher Forschungszentren, Germany; the General Secretariat for Research and Technology, Greece; the National Scientific Research Foundation and National Innovation Office, Hungary; the Department of Atomic Energy and the Department of Science and Technology, India; the Institute for Studies in Theoretical Physics and Mathematics, Iran; the Science Foundation, Ireland; the Istituto Nazionale di Fisica Nucleare, Italy; the Korean Ministry of Education, Science and Technology and the World Class University program of NRF, Republic of Korea; the Lithuanian Academy of Sciences; the Mexican Funding Agencies (CINVESTAV, CONACYT, SEP, and UASLP-FAI); the Ministry of Business, Innovation and Employment, New Zealand; the Pakistan Atomic Energy Commission; the Ministry of Science and Higher Education and the National Science Centre, Poland; the Fundacao para a Ciencia e a Tecnologia, Portugal; JINR, Dubna, the Ministry of Education and Science of the Russian Federation, the Federal Agency of Atomic Energy of the Russian Federation, Russian Academy of Sciences, and the Russian Foundation for Basic Research; the Ministry of Education, Science and Technological Development of Serbia; the Secretaria de Estado de Investigacion, Desarrollo e Innovacion and Programa Consolider-Ingenio 2010, Spain; the Swiss Funding Agencies (ETH Board, ETH Zurich, PSI, SNF, UniZH, Canton Zurich, and SER); the National Science Council, Taipei; the Thailand Center of Excellence in Physics, the Institute for the Promotion of Teaching Science and Technology of Thailand, Special Task Force for Activating Research and the National Science and Technology Development Agency of Thailand; the Scientific and Technical Research Council of Turkey and the Turkish Atomic Energy Authority; the Science and Technology Facilities Council, United Kingdom; the U.S. Department of Energy and the U.S. National Science Foundation.Individuals have received support from the Marie-Curie program and the European Research Council and EPLANET (European Union); the Leventis Foundation; the A. P. Sloan Foundation; the Alexander von Humboldt Foundation; the Belgian Federal Science Policy Office; the Fonds pour la Formation a la Recherche dans l’Industrie et dans l’Agriculture (FRIA-Belgium); the Agentschap voor Innovatie door Wetenschap en Technologie (IWT-Belgium); the Ministry of Education, Youth and Sports (MEYS) of the Czech Republic; the Council of Science and Industrial Research, India; the Compagnia di San Paolo (Torino); the HOMING PLUS programme of Foundation for Polish Science, cofinanced by EU, Regional Development Fund; and the Thalis and Aristeia programmes cofinanced by EU-ESF and the Greek NSRF.
512 citations
TL;DR: Children who have FASD are more prevalent among first graders in this Midwestern city than predicted by previous, popular estimates.
Abstract: OBJECTIVES: To determine the prevalence and characteristics of fetal alcohol spectrum disorders (FASD) among first grade students (6- to 7-year-olds) in a representative Midwestern US community. METHODS: From a consented sample of 70.5% of all first graders enrolled in public and private schools, an oversample of small children (≤25th percentile on height, weight, and head circumference) and randomly selected control candidates were examined for physical growth, development, dysmorphology, cognition, and behavior. The children’s mothers were interviewed for maternal risk. RESULTS: Total dysmorphology scores differentiate significantly fetal alcohol syndrome (FAS) and partial FAS (PFAS) from one another and from unexposed controls. Alcohol-related neurodevelopmental disorder (ARND) is not as clearly differentiated from controls. Children who had FASD performed, on average, significantly worse on 7 cognitive and behavioral tests and measures. The most predictive maternal risk variables in this community are late recognition of pregnancy, quantity of alcoholic drinks consumed 3 months before pregnancy, and quantity of drinking reported for the index child’s father. From the final multidisciplinary case findings, 3 techniques were used to estimate prevalence. FAS in this community likely ranges from 6 to 9 per 1000 children (midpoint, 7.5), PFAS from 11 to 17 per 1000 children (midpoint, 14), and the total rate of FASD is estimated at 24 to 48 per 1000 children, or 2.4% to 4.8% (midpoint, 3.6%). CONCLUSIONS: Children who have FASD are more prevalent among first graders in this Midwestern city than predicted by previous, popular estimates.
495 citations
Vardan Khachatryan1, Robin Erbacher2, C. A. Carrillo Montoya3, Chang-Seong Moon4 +2123 more•Institutions (138)
TL;DR: In this paper, the diphoton decay mode of the recently discovered Higgs boson and measurement of some of its properties are reported using the entire dataset collected by the CMS experiment in proton-proton collisions during the 2011 and 2012 LHC running periods.
Abstract: Observation of the diphoton decay mode of the recently discovered Higgs boson and measurement of some of its properties are reported. The analysis uses the entire dataset collected by the CMS experiment in proton-proton collisions during the 2011 and 2012 LHC running periods. The data samples correspond to integrated luminosities of 5.1 inverse femtobarns at sqrt(s) = 7 TeV and 19.7 inverse femtobarns at 8 TeV. A clear signal is observed in the diphoton channel at a mass close to 125 GeV with a local significance of 5.7 sigma, where a significance of 5.2 sigma is expected for the standard model Higgs boson. The mass is measured to be 124.70 +/- 0.34 GeV = 124.70 +/- 0.31 (stat) +/- 0.15 (syst) GeV, and the best-fit signal strength relative to the standard model prediction is 1.14 +0.26/-0.23 = 1.14 +/- 0.21 (stat) +0.09/-0.05 (syst) +0.13/-0.09 (theo). Additional measurements include the signal strength modifiers associated with different production mechanisms, and hypothesis tests between spin-0 and spin-2 models.
TL;DR: The method yielded the best quantitative results for automatic detection of IDC regions in WSI in terms of F-measure and balanced accuracy and suggest that at least some of the tissue classification mistakes were less due to any fundamental problems associated with the approach, than the inherent limitations in obtaining a very highly granular annotation of the diseased area of interest by an expert pathologist.
Abstract: This paper presents a deep learning approach for automatic detection and visual analysis of invasive ductal carcinoma (IDC) tissue regions in whole slide images (WSI) of breast cancer (BCa). Deep learning approaches are learn-from-data methods involving computational modeling of the learning process. This approach is similar to how human brain works using dierent interpretation levels or layers of most representative and useful features resulting into a hierarchical learned representation. These methods have been shown to outpace traditional approaches of most challenging problems in several areas such as speech recognition and object detection. Invasive breast cancer detection is a time consuming and challenging task primarily because it involves a pathologist scanning large swathes of benign regions to ultimately identify the areas of malignancy. Precise delineation of IDC in WSI is crucial to the subsequent estimation of grading tumor aggressiveness and predicting patient outcome. DL approaches are particularly adept at handling these types of problems, especially if a large number of samples are available for training, which would also ensure the generalizability of the learned features and classier. The DL framework in this paper extends a number of convolutional neural networks (CNN) for visual semantic analysis of tumor regions for diagnosis support. The CNN is trained over a large amount of image patches (tissue regions) from WSI to learn a hierarchical part-based representation. The method was evaluated over a WSI dataset from 162 patients diagnosed with IDC. 113 slides were selected for training and 49 slides were held out for independent testing. Ground truth for quantitative evaluation was provided via expert delineation of the region of cancer by an expert pathologist on the digitized slides. The experimental evaluation was designed to measure classier accuracy in detecting IDC tissue regions in WSI. Our method yielded the best quantitative results for automatic detection of IDC regions in WSI in terms of F-measure and balanced accuracy (71.80%, 84.23%), in comparison with an approach using handcrafted image features (color, texture and edges, nuclear textural and architecture), and a machine learning classier for invasive tumor classication using a Random Forest. The best performing handcrafted features were fuzzy color histogram (67.53%, 78.74%) and RGB histogram (66.64%, 77.24%). Our results also suggest that at least some of the tissue classication mistakes (false positives and false negatives) were less due to any fundamental problems associated with the approach, than the inherent limitations in obtaining a very highly granular annotation of the diseased area of interest by an expert pathologist.
TL;DR: It is suggested that increased whole-body protein breakdown is an early event in development of PDAC, and elevated plasma levels of branched-chain amino acids (BCAAs) are associated with a greater than twofold increased risk of future pancreatic cancer diagnosis.
Abstract: Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months. PDAC has been linked with obesity and glucose intolerance, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from individuals with pancreatic cancer (cases) and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched-chain amino acids (BCAAs) are associated with a greater than twofold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years before diagnosis, when occult disease is probably present. We show that plasma BCAAs are also elevated in mice with early-stage pancreatic cancers driven by mutant Kras expression but not in mice with Kras-driven tumors in other tissues, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early-stage disease. Together, these findings suggest that increased whole-body protein breakdown is an early event in development of PDAC.
TL;DR: The results show that, in order to prevent the deep-level defects from being effective recombination centers, the equilibrium carrier concentrations should be controlled so that the Fermi energy is about 0.3 eV away from the band edges.
Abstract: Inorganic–organic hybrid perovskites are a new family of solar cell materials, which have recently been used to make solar cells with efficiency approaching 20%. Here, we report the unique defect chemistry of the prototype material, CH3NH3PbI3, based on first-principles calculation. We found that both the Pb cations and I anions in this material exhibit strong covalency as characterized by the formation of Pb dimers and I trimers with strong covalent bonds at some of the intrinsic defects. The Pb dimers and I trimers are only stabilized in a particular charge state with significantly lowered energy, which leads to deep charge-state transition levels within the band gap, in contradiction to a recent proposal that this system has only shallow intrinsic defects. Our results show that, in order to prevent the deep-level defects from being effective recombination centers, the equilibrium carrier concentrations should be controlled so that the Fermi energy is about 0.3 eV away from the band edges. Beyond this r...
TL;DR: In this article, the authors investigate the use of social media by 188 501(c)(3) advocacy organizations and identify new organizational practices and forms of communication heretofore unseen in the literature.
Abstract: How are nonprofit organizations utilizing social media to engage in advocacy work? We address this question by investigating the social media use of 188 501(c)(3) advocacy organizations. After briefly examining the types of social media technologies employed, we turn to an in-depth examination of the organizations’ use of Twitter. This in-depth message-level analysis is twofold: A content analysis that examines the prevalence of previously identified communicative and advocacy constructs in nonprofits’ social media messages; and an inductive analysis that explores the unique features and dynamics of social media-based advocacy and identifies new organizational practices and forms of communication heretofore unseen in the literature.
18 Jun 2014
TL;DR: This paper proposes to resolve conflicts among multiple sources of heterogeneous data types by using an optimization framework where truths and source reliability are defined as two sets of unknown variables and the objective is to minimize the overall weighted deviation between the truths and the multi-source observations.
Abstract: In many applications, one can obtain descriptions about the same objects or events from a variety of sources. As a result, this will inevitably lead to data or information conflicts. One important problem is to identify the true information (i.e., the truths) among conflicting sources of data. It is intuitive to trust reliable sources more when deriving the truths, but it is usually unknown which one is more reliable a priori. Moreover, each source possesses a variety of properties with different data types. An accurate estimation of source reliability has to be made by modeling multiple properties in a unified model. Existing conflict resolution work either does not conduct source reliability estimation, or models multiple properties separately. In this paper, we propose to resolve conflicts among multiple sources of heterogeneous data types. We model the problem using an optimization framework where truths and source reliability are defined as two sets of unknown variables. The objective is to minimize the overall weighted deviation between the truths and the multi-source observations where each source is weighted by its reliability. Different loss functions can be incorporated into this framework to recognize the characteristics of various data types, and efficient computation approaches are developed. Experiments on real-world weather, stock and flight data as well as simulated multi-source data demonstrate the necessity of jointly modeling different data types in the proposed framework.
TL;DR: The ADAPT technique is a fast, safe, simple, and effective method that has facilitated the approach to acute ischemic stroke thrombectomy by utilizing the latest generation of large bore aspiration catheters to achieve previously unparalleled angiographic outcomes.
Abstract: Background The development of new revascularization devices has improved recanalization rates and time, but not clinical outcomes. We report a prospectively collected clinical experience with a new technique utilizing a direct aspiration first pass technique with large bore aspiration catheter as the primary method for vessel recanalization. Methods 98 prospectively identified acute ischemic stroke patients with 100 occluded large cerebral vessels at six institutions were included in the study. The ADAPT technique was utilized in all patients. Procedural and clinical data were captured for analysis. Results The aspiration component of the ADAPT technique alone was successful in achieving Thrombolysis in Cerebral Infarction (TICI) 2b or 3 revascularization in 78% of cases. The additional use of stent retrievers improved the TICI 2b/3 revascularization rate to 95%. The average time from groin puncture to at least TICI 2b recanalization was 37 min. A 5MAX demonstrated similar success to a 5MAX ACE in achieving TICI 2b/3 revascularization alone (75% vs 82%, p=0.43). Patients presented with an admitting median National Institutes of Health Stroke Scale (NIHSS) score of 17.0 (12.0–21.0) and improved to a median NIHSS score at discharge of 7.3 (1.0–11.0). Ninety day functional outcomes were 40% (modified Rankin Scale (mRS) 0–2) and 20% (mRS 6). There were two procedural complications and no symptomatic intracerebral hemorrhages. Discussion The ADAPT technique is a fast, safe, simple, and effective method that has facilitated our approach to acute ischemic stroke thrombectomy by utilizing the latest generation of large bore aspiration catheters to achieve previously unparalleled angiographic outcomes.
Cincinnati Children's Hospital Medical Center1, Harvard University2, University of Pennsylvania3, Medical College of Wisconsin4, Boston Children's Hospital5, University of California, San Francisco6, University of Toronto7, Nationwide Children's Hospital8, University of Ottawa9, University at Buffalo10, University of Pittsburgh11, Emory University12
TL;DR: These CD-specific host and microbe profiles identify the ileum as the primary inductive site for all forms of CD and may direct prognostic and therapeutic approaches.
Abstract: Interactions between the host and gut microbial community likely contribute to Crohn disease (CD) pathogenesis; however, direct evidence for these interactions at the onset of disease is lacking. Here, we characterized the global pattern of ileal gene expression and the ileal microbial community in 359 treatment-naive pediatric patients with CD, patients with ulcerative colitis (UC), and control individuals. We identified core gene expression profiles and microbial communities in the affected CD ilea that are preserved in the unaffected ilea of patients with colon-only CD but not present in those with UC or control individuals; therefore, this signature is specific to CD and independent of clinical inflammation. An abnormal increase of antimicrobial dual oxidase (DUOX2) expression was detected in association with an expansion of Proteobacteria in both UC and CD, while expression of lipoprotein APOA1 gene was downregulated and associated with CD-specific alterations in Firmicutes. The increased DUOX2 and decreased APOA1 gene expression signature favored oxidative stress and Th1 polarization and was maximally altered in patients with more severe mucosal injury. A regression model that included APOA1 gene expression and microbial abundance more accurately predicted month 6 steroid-free remission than a model using clinical factors alone. These CD-specific host and microbe profiles identify the ileum as the primary inductive site for all forms of CD and may direct prognostic and therapeutic approaches.
TL;DR: Significant clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa and significant improvements in mucociliary clearance, gastrointestinal pH, and microbiome were observed, providing clinical mechanisms underlying the therapeutic benefit of ivACaftor.
Abstract: Rationale: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation.
Objectives: To evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers.
Methods: We conducted a longitudinal cohort study in 2012–2013 in G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study assessments were performed at baseline, 1, 3, and 6 months after ivacaftor initiation. Substudies evaluated mucociliary clearance, β-adrenergic sweat secretion rate, gastrointestinal pH, and sputum inflammation and microbiology
Measurements and Main Results: A total of 151 of 153 subjects were prescribed ivacaftor and 88% completed the study through 6 months. FEV1 % predicted improved from baseline to 6 months (mean absolute change, 6.7%; P < 0.001). Similarly, body mass index improved from baseline to 6 months (mean change, 0.8 kg/m2; P < 0.001). Sweat chloride decreased from baseline to 6 months (mean change, −53.8 mmol/L; 95% confidence interval, −57.7 to −49.9; P < 0.001), reflecting augmented CFTR function. There was significant improvement in hospitalization rate (P < 0.001) and Pseudomonas aeruginosa burden (P < 0.01). Significant improvements in mucociliary clearance (P < 0.001), gastrointestinal pH (P = 0.001), and microbiome were also observed, providing clinical mechanisms underlying the therapeutic benefit of ivacaftor.
Conclusions: Significant clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa. Biomarker studies substantially improve the understanding of the mechanistic consequences of CFTR modulation on pulmonary and gastrointestinal physiology.
TL;DR: An overview of the role of ABC efflux transporters in MDR and pharmacokinetic properties is provided and reliable preclinical assays and models are required for the assessment of transporter-mediated flux and potential effects on pharmacokinetics in drug development.
Abstract: Multidrug resistance (MDR) is a serious problem that hampers the success of cancer pharmacotherapy. A common mechanism is the overexpression of ATP-binding cassette (ABC) efflux transporters in cancer cells such as P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated protein 1 (MRP1/ABCC1) and breast cancer resistance protein (BCRP/ABCG2) that limit the exposure to anticancer drugs. One way to overcome MDR is to develop ABC efflux transporter inhibitors to sensitize cancer cells to chemotherapeutic drugs. The complete clinical trials thus far have showen that those tested chemosensitizers only add limited or no benefits to cancer patients. Some MDR modulators are merely toxic, and others induce unwanted drug-drug interactions. Actually, many ABC transporters are also expressed abundantly in the gastrointestinal tract, liver, kidney, brain and other normal tissues, and they largely determine drug absorption, distribution and excretion, and affect the overall pharmacokinetic properties of drugs in humans. In addition, ABC transporters such as P-gp, MRP1 and BCRP co-expressed in tumors show a broad and overlapped specificity for substrates and MDR modulators. Thus reliable preclinical assays and models are required for the assessment of transporter-mediated flux and potential effects on pharmacokinetics in drug development. In this review, we provide an overview of the role of ABC efflux transporters in MDR and pharmacokinetics. Preclinical assays for the assessment of drug transport and development of MDR modulators are also discussed.
TL;DR: A flexible and modular approach is used to target intersectionally specified populations of inhibitory interneurons in mammalian hippocampus and neurons of the ventral tegmental area defined by both genetic and wiring properties, which may expand the application of genetically encoded interventional and observational tools for intact-systems biology.
Abstract: Precisely defining the roles of specific cell types is an intriguing frontier in the study of intact biological systems and has stimulated the rapid development of genetically encoded tools for observation and control. However, targeting these tools with adequate specificity remains challenging: most cell types are best defined by the intersection of two or more features such as active promoter elements, location and connectivity. Here we have combined engineered introns with specific recombinases to achieve expression of genetically encoded tools that is conditional upon multiple cell-type features, using Boolean logical operations all governed by a single versatile vector. We used this approach to target intersectionally specified populations of inhibitory interneurons in mammalian hippocampus and neurons of the ventral tegmental area defined by both genetic and wiring properties. This flexible and modular approach may expand the application of genetically encoded interventional and observational tools for intact-systems biology.
Proceedings Article•
30 Jul 2014
TL;DR: For the long-term treatment of VTE in patients with cancer, LMWH compared with VKA reduces venous thromboembolic events but not mortality, and the quality of evidence is judged as low for mortality, major bleeding, and minor bleeding; and as moderate for recurrent VTE.
Abstract: Background
Cancer increases the risk of thromboembolic events, especially in people receiving anticoagulation treatments.
TL;DR: This work used microcrystals of photoactive yellow protein as a model system and obtained high-resolution, time-resolved difference electron density maps of excellent quality with strong features, which open the way to the study of reversible and nonreversible biological reactions on time scales as short as femtoseconds under conditions that maximize the extent of reaction initiation throughout the crystal.
Abstract: Serial femtosecond crystallography using ultrashort pulses from x-ray free electron lasers (XFELs) enables studies of the light-triggered dynamics of biomolecules. We used microcrystals of photoactive yellow protein (a bacterial blue light photoreceptor) as a model system and obtained high-resolution, time-resolved difference electron density maps of excellent quality with strong features; these allowed the determination of structures of reaction intermediates to a resolution of 1.6 angstroms. Our results open the way to the study of reversible and nonreversible biological reactions on time scales as short as femtoseconds under conditions that maximize the extent of reaction initiation throughout the crystal.
McMaster University1, Universidade Federal do Rio Grande do Sul2, University of Missouri–Kansas City3, Brock University4, University of Chile5, University of Toronto6, University of Tartu7, World Health Organization8, Pontifical Catholic University of Chile9, Oregon Health & Science University10, National Institute for Health and Care Excellence11, National Health Service12, University of Freiburg13, American University of Beirut14, University at Buffalo15
TL;DR: A comprehensive checklist of items linked to relevant resources and tools that guideline developers could consider, without the expectation that every guideline would address each item, is compiled.
Abstract: Background: Although several tools to evaluate the credibility of health care guidelines exist, guidance on practical steps for developing guidelines is lacking. We systematically compiled a comprehensive checklist of items linked to relevant resources and tools that guideline developers could consider, without the expectation that every guideline would address each item. Methods: We searched data sources, including manuals of international guideline developers, literature on guidelines for guidelines (with a focus on methodology reports from international and national agencies, and professional societies) and recent articles providing systematic guidance. We reviewed these sources in duplicate, extracted items for the checklist using a sensitive approach and developed overarching topics relevant to guidelines. In an iterative process, we reviewed items for duplication and omissions and involved experts in guideline development for revisions and suggestions for items to be added. Results: We developed a checklist with 18 topics and 146 items and a webpage to facilitate its use by guideline developers. The topics and included items cover all stages of the guideline enterprise, from the planning and formulation of guidelines, to their implementation and evaluation. The final checklist includes links to training materials as well as resources with suggested methodology for applying the items. Interpretation: The checklist will serve as a resource for guideline developers. Consideration of items on the checklist will support the development, implementation and evaluation of guidelines. We will use crowdsourcing to revise the checklist and keep it up to date.
TL;DR: This article examined the evidence for classroom management self-efficacy (CMSE) in relation to the three dimensions of burnout: emotional exhaustion, depersonalization, and (lowered) personal accomplishment.
Abstract: Like many in the human services professions, teachers are susceptible to the feelings of burnout due to their job demands, as well as interactions with students, colleagues, administrators, and parents. Many studies have identified teacher burnout as one of the crucial components influencing teacher attrition. It has been suggested that self-efficacy is a protective factor against burnout. By way of multivariate meta-analysis, we examined the evidence for classroom management self-efficacy (CMSE) in relation to the three dimensions of burnout: emotional exhaustion, depersonalization, and (lowered) personal accomplishment. Results from sixteen studies indicate that there is a significant relationship between classroom management self-efficacy and the three dimensions of burnout, suggesting that teachers with higher levels of CMSE are less likely to experience the feelings of burnout. Practical implications, as well recommendations for future research, are discussed.
Harvard University1, University of New South Wales2, University at Buffalo3, University of North Carolina at Chapel Hill4, Princeton University5, Ajou University6, Seoul National University7, Lawrence Berkeley National Laboratory8, University of California, Berkeley9, University of Cambridge10, National Institutes of Health11, Washington University in St. Louis12, Broad Institute13, Stanford University14, Massachusetts Institute of Technology15, University of Alabama at Birmingham16, Boston University17, University of California, Santa Cruz18, Tongji University19, Rutgers University20, Alexandria University21, Duke University22, University of California, Davis23, Princess Margaret Cancer Centre24, Howard Hughes Medical Institute25, Brown University26, University of Washington27, Umeå University28
TL;DR: Comparison of combinatorial patterns of histone modifications, nuclear lamina-associated domains, organization of large-scale topological domains, chromatin environment at promoters and enhancers, nucleosome positioning, and DNA replication patterns reveals many conserved features of chromatin organization among the three organisms.
Abstract: Genome function is dynamically regulated in part by chromatin, which consists of the histones, non-histone proteins and RNA molecules that package DNA. Studies in Caenorhabditis elegans and Drosophila melanogaster have contributed substantially to our understanding of molecular mechanisms of genome function in humans, and have revealed conservation of chromatin components and mechanisms. Nevertheless, the three organisms have markedly different genome sizes, chromosome architecture and gene organization. On human and fly chromosomes, for example, pericentric heterochromatin flanks single centromeres, whereas worm chromosomes have dispersed heterochromatin-like regions enriched in the distal chromosomal 'arms', and centromeres distributed along their lengths. To systematically investigate chromatin organization and associated gene regulation across species, we generated and analysed a large collection of genome-wide chromatin data sets from cell lines and developmental stages in worm, fly and human. Here we present over 800 new data sets from our ENCODE and modENCODE consortia, bringing the total to over 1,400. Comparison of combinatorial patterns of histone modifications, nuclear lamina-associated domains, organization of large-scale topological domains, chromatin environment at promoters and enhancers, nucleosome positioning, and DNA replication patterns reveals many conserved features of chromatin organization among the three organisms. We also find notable differences in the composition and locations of repressive chromatin. These data sets and analyses provide a rich resource for comparative and species-specific investigations of chromatin composition, organization and function.
Vardan Khachatryan1, Albert M. Sirunyan1, Armen Tumasyan1, Wolfgang Adam +2121 more•Institutions (139)
TL;DR: In this paper, searches for the direct electroweak production of supersymmetric charginos, neutralinos, and sleptons in a variety of signatures with leptons and W, Z, and Higgs bosons are presented.
Abstract: Searches for the direct electroweak production of supersymmetric charginos, neutralinos, and sleptons in a variety of signatures with leptons and W, Z, and Higgs bosons are presented. Results are based on a sample of proton-proton collision data collected at center-of-mass energy sqrt(s) = 8 TeV with the CMS detector in 2012, corresponding to an integrated luminosity of 19.5 inverse femtobarns. The observed event rates are in agreement with expectations from the standard model. These results probe charginos and neutralinos with masses up to 720 GeV, and sleptons up to 260 GeV, depending on the model details.
S. Chatrchyan1, Vardan Khachatryan1, Albert M. Sirunyan1, Armen Tumasyan1 +2280 more•Institutions (177)
TL;DR: In this paper, a search for a standard model Higgs boson decaying into a pair of tau leptons is performed using events recorded by the CMS experiment at the LHC in 2011 and 2012.
Abstract: A search for a standard model Higgs boson decaying into a pair of tau leptons is performed using events recorded by the CMS experiment at the LHC in 2011 and 2012. The dataset corresponds to an integrated luminosity of 4.9 inverse femtobarns at a centre-of-mass energy of 7 TeV and 19.7 inverse femtobarns at 8 TeV. Each tau lepton decays hadronically or leptonically to an electron or a muon, leading to six different final states for the tau-lepton pair, all considered in this analysis. An excess of events is observed over the expected background contributions, with a local significance larger than 3 standard deviations for m[H] values between 115 and 130 GeV. The best fit of the observed H to tau tau signal cross section for m[H] = 125 GeV is 0.78 +- 0.27 times the standard model expectation. These observations constitute evidence for the 125 GeV Higgs boson decaying to a pair of tau leptons.
TL;DR: This tutorial review discusses recent progress in developing and synthesizing doped semiconductor and metal oxide nanocrystal with LSPR, and in studying the optical properties of these plasmonic nanocrystals, and discusses their growing potential for advancing biomedical and optoelectronic applications.
Abstract: The creation and study of non-metallic nanomaterials that exhibit localized surface plasmon resonance (LSPR) interactions with light is a rapidly growing field of research. These doped nanocrystals, mainly self-doped semiconductor nanocrystals (NCs) and extrinsically-doped metal oxide NCs, have extremely high concentrations of free charge carriers, which allows them to exhibit LSPR at near infrared (NIR) wavelengths. In this tutorial review, we discuss recent progress in developing and synthesizing doped semiconductor and metal oxide nanocrystals with LSPR, and in studying the optical properties of these plasmonic nanocrystals. We go on to discuss their growing potential for advancing biomedical and optoelectronic applications.