Showing papers by "Radboud University Nijmegen published in 2008"
University of Sydney1, Icahn School of Medicine at Mount Sinai2, University of Paris3, The Heart Research Institute4, University of Queensland5, University of Oxford6, Utrecht University7, Université de Montréal8, University of Melbourne9, University of Sheffield10, Aarhus University11, St Mary's Hospital12, University of Auckland13, University of Leicester14, The George Institute for Global Health15, Radboud University Nijmegen16
TL;DR: A strategy of intensive glucose control, involving gliclazide (modified release) and other drugs as required, that lowered the glycated hemoglobin value to 6.5% yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21%relative reduction in nephropathy.
Abstract: BACKGROUND: In patients with type 2 diabetes, the effects of intensive glucose control on vascular outcomes remain uncertain. METHODS: We randomly assigned 11,140 patients with type 2 diabetes to undergo either standard glucose control or intensive glucose control, defined as the use of gliclazide (modified release) plus other drugs as required to achieve a glycated hemoglobin value of 6.5% or less. Primary end points were composites of major macrovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular events (new or worsening nephropathy or retinopathy), assessed both jointly and separately. RESULTS: After a median of 5 years of follow-up, the mean glycated hemoglobin level was lower in the intensive-control group (6.5%) than in the standard-control group (7.3%). Intensive control reduced the incidence of combined major macrovascular and microvascular events (18.1%, vs. 20.0% with standard control; hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P=0.01), as well as that of major microvascular events (9.4% vs. 10.9%; hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), primarily because of a reduction in the incidence of nephropathy (4.1% vs. 5.2%; hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P=0.006), with no significant effect on retinopathy (P=0.50). There were no significant effects of the type of glucose control on major macrovascular events (hazard ratio with intensive control, 0.94; 95% CI, 0.84 to 1.06; P=0.32), death from cardiovascular causes (hazard ratio with intensive control, 0.88; 95% CI, 0.74 to 1.04; P=0.12), or death from any cause (hazard ratio with intensive control, 0.93; 95% CI, 0.83 to 1.06; P=0.28). Severe hypoglycemia, although uncommon, was more common in the intensive-control group (2.7%, vs. 1.5% in the standard-control group; hazard ratio, 1.86; 95% CI, 1.42 to 2.40; P<0.001). CONCLUSIONS: A strategy of intensive glucose control, involving gliclazide (modified release) and other drugs as required, that lowered the glycated hemoglobin value to 6.5% yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy. (ClinicalTrials.gov number, NCT00145925.)
6,477 citations
Radboud University Nijmegen1, National Institutes of Health2, Stanford University3, University of California, Los Angeles4, University of Lausanne5, University of Alabama6, University of Paris7, University of Michigan8, University of Texas Health Science Center at San Antonio9, University of Strasbourg10, University of Manchester11, University College London12, Oregon Health & Science University13, Complutense University of Madrid14, University of Aberdeen15, Duke University16, Charité17, University at Buffalo18, Wayne State University19, University of Sydney20, University of Genoa21, University of Florida22, University of Pennsylvania23
TL;DR: These revised definitions of invasive fungal disease are intended to advance clinical and epidemiological research and may serve as a useful model for defining other infections in high-risk patients.
Abstract: BACKGROUND: Invasive fungal diseases are important causes of morbidity and mortality. Clarity and uniformity in defining these infections are important factors in improving the quality of clinical studies. A standard set of definitions strengthens the consistency and reproducibility of such studies. METHODS: After the introduction of the original European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group definitions, advances in diagnostic technology and the recognition of areas in need of improvement led to a revision of this document. The revision process started with a meeting of participants in 2003, to decide on the process and to draft the proposal. This was followed by several rounds of consultation until a final draft was approved in 2005. This was made available for 6 months to allow public comment, and then the manuscript was prepared and approved. RESULTS: The revised definitions retain the original classifications of "proven," "probable," and "possible" invasive fungal disease, but the definition of "probable" has been expanded, whereas the scope of the category "possible" has been diminished. The category of proven invasive fungal disease can apply to any patient, regardless of whether the patient is immunocompromised, whereas the probable and possible categories are proposed for immunocompromised patients only. CONCLUSIONS: These revised definitions of invasive fungal disease are intended to advance clinical and epidemiological research and may serve as a useful model for defining other infections in high-risk patients.
4,389 citations
Federal University of Bahia1, McMaster University2, University of Amsterdam3, National Institutes of Health4, Charité5, Catholic University of Cordoba6, University of Genoa7, Radboud University Nijmegen8, Transilvania University of Brașov9, Ghent University10, University of Tennessee Health Science Center11, University of Naples Federico II12, Laval University13, Universidade Federal de Minas Gerais14, University of Oslo15, University of Manchester16, Aarhus University17, Imperial College London18, Erasmus University Rotterdam19, George Washington University20, Seoul National University21, Medical University of Łódź22, Hai phong University Of Medicine and Pharmacy23, Université de Montréal24, Guangzhou Medical University25, University of South Florida26, University of California, San Diego27, University of California28, University of Chicago29, Monash University30, Teikyo University31, National and Kapodistrian University of Athens32, Nippon Medical School33, Sofia Medical University34, Leiden University35, Leiden University Medical Center36, University College London37, University of Manitoba38, University of Helsinki39, Finnish Institute of Occupational Health40, National University of Singapore41, Karolinska Institutet42, University of Minnesota43, Celal Bayar University44, University of Cape Town45, Pierre-and-Marie-Curie University46, Tunis University47, University of Ghana48, University of Wisconsin-Madison49, University of British Columbia50, Georgia Regents University51, Vilnius University52, University of Washington53, University of Dundee54, University of Poitiers55, University of Mississippi56, Federal University of São Paulo57, German Red Cross58, Jagiellonian University Medical College59, Chiba University60, American Pharmacists Association61, University of Aberdeen62, University of Nevada, Reno63, University of North Carolina at Chapel Hill64
TL;DR: The ARIA guidelines for the management of allergic rhinitis and asthma are similar in both the 1999 ARIA workshop report and the 2008 Update as discussed by the authors, but the GRADE approach is not yet available.
Abstract: Allergic rhinitis is a symptomatic disorder of the nose induced after allergen exposure by an IgE-mediated inflammation of the membranes lining the nose. It is a global health problem that causes major illness and disability worldwide. Over 600 million patients from all countries, all ethnic groups and of all ages suffer from allergic rhinitis. It affects social life, sleep, school and work and its economic impact is substantial. Risk factors for allergic rhinitis are well identified. Indoor and outdoor allergens as well as occupational agents cause rhinitis and other allergic diseases. The role of indoor and outdoor pollution is probably very important, but has yet to be fully understood both for the occurrence of the disease and its manifestations.
In 1999, during the Allergic Rhinitis and its Impact on Asthma (ARIA) WHO workshop, the expert panel proposed a new classification for allergic rhinitis which was subdivided into 'intermittent' or 'persistent' disease.
This classification is now validated. The diagnosis of allergic rhinitis is often quite easy, but in some cases it may cause problems and many patients are still under-diagnosed, often because they do not perceive the symptoms of rhinitis as a disease impairing their social life, school and work.
The management of allergic rhinitis is well established and the ARIA expert panel based its recommendations on evidence using an extensive review of the literature available up to December 1999. The statements of evidence for the development of these guidelines followed WHO rules and were based on those of Shekelle et al. A large number of papers have been published since 2000 and are extensively reviewed in the 2008 Update using the same evidence-based system. Recommendations for the management of allergic rhinitis are similar in both the ARIA workshop report and the 2008 Update. In the future, the GRADE approach will be used, but is not yet available.
Another important aspect of the ARIA guidelines was to consider co-morbidities. Both allergic rhinitis and asthma are systemic inflammatory conditions and often co-exist in the same patients. In the 2008 Update, these links have been confirmed.
The ARIA document is not intended to be a standard-of-care document for individual countries. It is provided as a basis for physicians, health care professionals and organizations involved in the treatment of allergic rhinitis and asthma in various countries to facilitate the development of relevant local standard-of-care documents for patients.
3,769 citations
TL;DR: Measurements show that mobilities higher than 200 000 cm2/V s are achievable, if extrinsic disorder is eliminated and a sharp (thresholdlike) increase in resistivity observed above approximately 200 K is unexpected but can qualitatively be understood within a model of a rippled graphene sheet in which scattering occurs on intraripple flexural phonons.
Abstract: We have studied temperature dependences of electron transport in graphene and its bilayer and found extremely low electron-phonon scattering rates that set the fundamental limit on possible charge carrier mobilities at room temperature. Our measurements show that mobilities higher than 200 000 cm2/V s are achievable, if extrinsic disorder is eliminated. A sharp (thresholdlike) increase in resistivity observed above approximately 200 K is unexpected but can qualitatively be understood within a model of a rippled graphene sheet in which scattering occurs on intraripple flexural phonons.
3,100 citations
University of Zurich1, Icahn School of Medicine at Mount Sinai2, University of North Carolina at Chapel Hill3, Monash University4, University Hospital of Lausanne5, University of California, San Diego6, Radboud University Nijmegen7, University of Buenos Aires8, Cornell University9, University of Amsterdam10, University of Alabama at Birmingham11, Johns Hopkins University School of Medicine12, University of California, San Francisco13
TL;DR: This report provides guidelines for when to initiate antiretroviral therapy, selection of appropriate initial regimens, patient monitoring, when to change therapy, and what regimens to use when changing.
Abstract: Context New trial data and drug regimens that have become available in the last 2 years warrant an update to guidelines for antiretroviral therapy (ART) in human immunodeficiency virus (HIV)–infected adults in resource-rich settings. Objective To provide current recommendations for the treatment of adult HIV infection with ART and use of laboratory-monitoring tools. Guidelines include when to start therapy and with what drugs, monitoring for response and toxic effects, special considerations in therapy, and managing antiretroviral failure. Data Sources, Study Selection, and Data Extraction Data that had been published or presented in abstract form at scientific conferences in the past 2 years were systematically searched and reviewed by an International Antiviral Society–USA panel. The panel reviewed available evidence and formed recommendations by full panel consensus. Data Synthesis Treatment is recommended for all adults with HIV infection; the strength of the recommendation and the quality of the evidence increase with decreasing CD4 cell count and the presence of certain concurrent conditions. Recommended initial regimens include 2 nucleoside reverse transcriptase inhibitors (tenofovir/emtricitabine or abacavir/lamivudine) plus a nonnucleoside reverse transcriptase inhibitor (efavirenz), a ritonavir-boosted protease inhibitor (atazanavir or darunavir), or an integrase strand transfer inhibitor (raltegravir). Alternatives in each class are recommended for patients with or at risk of certain concurrent conditions. CD4 cell count and HIV-1 RNA level should be monitored, as should engagement in care, ART adherence, HIV drug resistance, and quality-of-care indicators. Reasons for regimen switching include virologic, immunologic, or clinical failure and drug toxicity or intolerance. Confirmed treatment failure should be addressed promptly and multiple factors considered. Conclusion New recommendations for HIV patient care include offering ART to all patients regardless of CD4 cell count, changes in therapeutic options, and modifications in the timing and choice of ART in the setting of opportunistic illnesses such as cryptococcal disease and tuberculosis.
2,357 citations
TL;DR: The LHCb experiment is dedicated to precision measurements of CP violation and rare decays of B hadrons at the Large Hadron Collider (LHC) at CERN (Geneva).
Abstract: The LHCb experiment is dedicated to precision measurements of CP violation and rare decays of B hadrons at the Large Hadron Collider (LHC) at CERN (Geneva). The initial configuration and expected performance of the detector and associated systems, as established by test beam measurements and simulation studies, is described.
2,286 citations
TL;DR: In this article, the authors use density functional theory to study how graphene is doped by adsorption on metal substrates and find that weak bonding on Al, Ag, Cu, Au, and Pt, while preserving its unique electronic structure, can still shift the Fermi level with respect to the conical point by 0:5 eV.
Abstract: Making devices with graphene necessarily involves making contacts with metals. We use density functional theory to study how graphene is doped by adsorption on metal substrates and find that weak bonding on Al, Ag, Cu, Au, and Pt, while preserving its unique electronic structure, can still shift the Fermi level with respect to the conical point by 0:5 eV. At equilibrium separations, the crossover from p-type to n-type doping occurs for a metal work function of 5:4 eV, a value much larger than the graphene work function of 4.5 eV. The numerical results for the Fermi level shift in graphene are described very well by a simple analytical model which characterizes the metal solely in terms of its work function, greatly extending their applicability.
2,231 citations
TL;DR: This work reports on electron transport in quantum dot devices carved entirely from graphene, demonstrating the possibility of molecular-scale electronics based on graphene.
Abstract: The exceptional electronic properties of graphene, with its charge carriers mimicking relativistic quantum particles and its formidable potential in various applications, have ensured a rapid growth of interest in this new material. We report on electron transport in quantum dot devices carved entirely from graphene. At large sizes (>100 nanometers), they behave as conventional single-electron transistors, exhibiting periodic Coulomb blockade peaks. For quantum dots smaller than 100 nanometers, the peaks become strongly nonperiodic, indicating a major contribution of quantum confinement. Random peak spacing and its statistics are well described by the theory of chaotic neutrino billiards. Short constrictions of only a few nanometers in width remain conductive and reveal a confinement gap of up to 0.5 electron volt, demonstrating the possibility of molecular-scale electronics based on graphene.
2,032 citations
TL;DR: The emerging concept of work engagement is introduced: a positive, fulfilling, affective-motivational state of work-related well-being that is characterized by vigour, dedication, and absorption.
Abstract: This position paper introduces the emerging concept of work engagement: a positive, fulfilling, affective-motivational state of work-related well-being that is characterized by vigour, dedication, and absorption. Although there are different views of work engagement, most scholars agree that engaged employees have high levels of energy and identify strongly with their work. The most often used instrument to measure engagement is the Utrecht Work Engagement Scale, a self-report instrument that has been validated in many countries across the world. Research on engagement has investigated how engagement differs from related concepts (e.g., workaholism, organizational commitment), and has focused on the most important predictors of work engagement. These studies have revealed that engagement is a unique concept that is best predicted by job resources (e.g., autonomy, supervisory coaching, performance feedback) and personal resources (e.g., optimism, self-efficacy, self-esteem). Moreover, the first studies have shown that work engagement is predictive of job performance and client satisfaction. The paper closes with an account of what we do not know about work engagement, and offers a brief research agenda for future work.
1,580 citations
University of Oldenburg1, University of Groningen2, University of Sheffield3, OFFIS4, University of Regensburg5, Radboud University Nijmegen6, Helmholtz Centre for Environmental Research - UFZ7, Katholieke Universiteit Leuven8, Ghent University9, Wageningen University and Research Centre10, VU University Amsterdam11, Stockholm University12, Centre national de la recherche scientifique13, Autonomous University of Madrid14
TL;DR: The LEDA Traitbase is useful for large-scale analyses of functional responses of communities to environmental change, effects of community trait composition on ecosystem properties and patterns of rarity and invasiveness, as well as linkages between traits as expressions of fundamental trade-offs in plants.
Abstract: Summary 1. An international group of scientists has built an open internet data base of life-history traits of the Northwest European flora (the LEDA-Traitbase) that can be used as a data source for fundamental research on plant biodiversity and coexistence, macro-ecological patterns and plant functional responses. 2. The species-trait matrix comprises referenced information under the control of an editorial board, for ca. 3000 species of the Northwest European flora, combining existing information and additional measurements. The data base currently contains data on 26 plant traits that describe three key features of plant dynamics: persistence, regeneration and dispersal. The LEDA-Traitbase is freely available at www.leda-traitbase.org. 3. We present the structure of the data base and an overview of the trait information available. 4. Synthesis. The LEDA Traitbase is useful for large-scale analyses of functional responses of communities to environmental change, effects of community trait composition on ecosystem properties and patterns of rarity and invasiveness, as well as linkages between traits as expressions of fundamental trade-offs in plants.
1,379 citations
École Polytechnique de Montréal1, Karlsruhe Institute of Technology2, Children's Hospital Oakland Research Institute3, Radboud University Nijmegen4, University of Michigan5, Rovira i Virgili University6, ETH Zurich7, Technical University of Denmark8, Lawrence Berkeley National Laboratory9, École Polytechnique Fédérale de Lausanne10
TL;DR: Usetox as discussed by the authors is a scientific consensus model that contains only the most influential model elements and is used to calculate CFs for several thousand substances and forms the basis of the recommendations from UNEP-SETAC Life Cycle Initiative regarding characterisation of toxic impacts in life cycle assessment.
Abstract: In 2005, a comprehensive comparison of life cycle impact assessment toxicity characterisation models was initiated by the United Nations Environment Program (UNEP)–Society for Environmental Toxicology and Chemistry (SETAC) Life Cycle Initiative, directly involving the model developers of CalTOX, IMPACT 2002, USES-LCA, BETR, EDIP, WATSON and EcoSense. In this paper, we describe this model comparison process and its results—in particular the scientific consensus model developed by the model developers. The main objectives of this effort were (1) to identify specific sources of differences between the models’ results and structure, (2) to detect the indispensable model components and (3) to build a scientific consensus model from them, representing recommended practice. A chemical test set of 45 organics covering a wide range of property combinations was selected for this purpose. All models used this set. In three workshops, the model comparison participants identified key fate, exposure and effect issues via comparison of the final characterisation factors and selected intermediate outputs for fate, human exposure and toxic effects for the test set applied to all models. Through this process, we were able to reduce inter-model variation from an initial range of up to 13 orders of magnitude down to no more than two orders of magnitude for any substance. This led to the development of USEtox, a scientific consensus model that contains only the most influential model elements. These were, for example, process formulations accounting for intermittent rain, defining a closed or open system environment or nesting an urban box in a continental box. The precision of the new characterisation factors (CFs) is within a factor of 100–1,000 for human health and 10–100 for freshwater ecotoxicity of all other models compared to 12 orders of magnitude variation between the CFs of each model, respectively. The achieved reduction of inter-model variability by up to 11 orders of magnitude is a significant improvement. USEtox provides a parsimonious and transparent tool for human health and ecosystem CF estimates. Based on a referenced database, it has now been used to calculate CFs for several thousand substances and forms the basis of the recommendations from UNEP-SETAC’s Life Cycle Initiative regarding characterisation of toxic impacts in life cycle assessment. We provide both recommended and interim (not recommended and to be used with caution) characterisation factors for human health and freshwater ecotoxicity impacts. After a process of consensus building among stakeholders on a broad scale as well as several improvements regarding a wider and easier applicability of the model, USEtox will become available to practitioners for the calculation of further CFs.
TL;DR: In this article, the authors investigated in a sample of 587 telecom managers whether workaholism, burnout, and work engagement can be distinguished empirically, with existing, validated multi-dimensional questionnaires.
Abstract: The present study investigated in a sample of 587 telecom managers whether workaholism, burnout, and work engagement—the supposed antipode of burnout—can be distinguished empirically. These three concepts were measured with existing, validated multi-dimensional questionnaires. Structural equation modeling revealed that a slightly modified version of the hypothesised model that assumed three distinct yet correlated constructs—burnout, engagement, and workaholism—fitted the data best. Multiple regression analyses revealed that these three concepts retained unique hypothesised patterns of relationships with variables from five clusters representing (1) long working hours, (2) job characteristics, (3) work outcomes, (4) quality of social relationships, and (5) perceived health, respectively. In sum, our analyses provided converging evidence that workaholism, burnout, and engagement are three different kinds of employee well-being rather than three of a kind. La presente etude examine aupres d’un echantillon de 587 cadres des telecommunications la question de savoir si l’addiction au travail, le burnout et l’engagement au travail—suppose l’inverse du burnout—peuvent etre distingues empiriquement. Ces trois concepts sont mesures a partir de questionnaires multi-dimensionnels existants et valides. La modelisation d’equation structurale indique qu’une version legerement modifiee du modele teste selon lequel le burnout, l’engagement au travail et l’addiction au travail sont trois formes distinctes bien que correlees du bien-etre, rend mieux compte des resultats. Des analyses de regression multiples montrent que ces trois concepts renvoient
TL;DR: In patients with familial hypercholesterolemia, combined therapy with ezetimibe and simVastatin did not result in a significant difference in changes in intima-media thickness, as compared with simvastatin alone, despite decreases in levels of LDL cholesterol and C-reactive protein.
Abstract: The primary outcome, the mean (±SE) change in the carotid-artery intima–media thickness, was 0.0058±0.0037 mm in the simvastatin-only group and 0.0111±0.0038 mm in the simvastatin-plus-ezetimibe (combined-therapy) group (P = 0.29). Secondary outcomes (consisting of other variables regarding the intima–media thickness of the carotid and femoral arteries) did not differ significantly between the two groups. At the end of the study, the mean (±SD) LDL cholesterol level was 192.7±60.3 mg per deciliter (4.98±1.56 mmol per liter) in the simvastatin group and 141.3±52.6 mg per deciliter (3.65±1.36 mmol per liter) in the combined-therapy group (a between-group difference of 16.5%, P<0.01). The differences between the two groups in reductions in levels of triglycerides and C-reactive protein were 6.6% and 25.7%, respectively, with greater reductions in the combined-therapy group (P<0.01 for both comparisons). Side-effect and safety profiles were similar in the two groups. Conclusions In patients with familial hypercholesterolemia, combined therapy with ezetimibe and simvastatin did not result in a significant difference in changes in intima–media thickness, as compared with simvastatin alone, despite decreases in levels of LDL cholesterol and C-reactive protein. (ClinicalTrials.gov number, NCT00552097.)
Radboud University Nijmegen1, CSIRO Marine and Atmospheric Research2, Vrije Universiteit Brussel3, Commonwealth Scientific and Industrial Research Organisation4, Forest Research Institute Malaysia5, Griffith University6, University of North Carolina at Wilmington7, University of Queensland8, University of Malaya9, Plymouth Marine Laboratory10
TL;DR: In this article, the authors reviewed the literature with regard to the degree of interlinkage between mangroves and adjacent habitats, a research area which has received increasing attention in the last decade.
University of Padua1, University of Copenhagen2, Pontifical Catholic University of Chile3, University of Paris4, Erasmus University Rotterdam5, Medical University of Graz6, University of Sheffield7, University of Bern8, Hannover Medical School9, University of Murcia10, Queen Mary University of London11, Royal Stoke University Hospital12, University of Western Australia13, Royal London Hospital14, Radboud University Nijmegen15, Sapienza University of Rome16, University of Glasgow17, Charles University in Prague18, Istituto Giannina Gaslini19, Royal Alexandra Children's Hospital20, University of Leicester21, Vilnius University22, University of Amsterdam23, University of Gothenburg24, Imperial College London25
TL;DR: Large well-designed randomised controlled trials with clear descriptions of patients are needed to improve the present recommendations on the treatment of these common syndromes.
Abstract: There is poor agreement on definitions of different phenotypes of preschool wheezing disorders. The present Task Force proposes to use the terms episodic (viral) wheeze to describe children who wheeze intermittently and are well between episodes, and multiple-trigger wheeze for children who wheeze both during and outside discrete episodes. Investigations are only needed when in doubt about the diagnosis. Based on the limited evidence available, inhaled short-acting beta(2)-agonists by metered-dose inhaler/spacer combination are recommended for symptomatic relief. Educating parents regarding causative factors and treatment is useful. Exposure to tobacco smoke should be avoided; allergen avoidance may be considered when sensitisation has been established. Maintenance treatment with inhaled corticosteroids is recommended for multiple-trigger wheeze; benefits are often small. Montelukast is recommended for the treatment of episodic (viral) wheeze and can be started when symptoms of a viral cold develop. Given the large overlap in phenotypes, and the fact that patients can move from one phenotype to another, inhaled corticosteroids and montelukast may be considered on a trial basis in almost any preschool child with recurrent wheeze, but should be discontinued if there is no clear clinical benefit. Large well-designed randomised controlled trials with clear descriptions of patients are needed to improve the present recommendations on the treatment of these common syndromes.
Baylor College of Medicine1, University of Southampton2, University of Cambridge3, McGill University4, University of Florence5, University of Vermont6, Netherlands Cancer Institute7, Radboud University Nijmegen8, QIMR Berghofer Medical Research Institute9, International Agency for Research on Cancer10
TL;DR: The current state of sequence‐based genetic testing is reviewed, other standardized reporting systems used in oncology are described, and a standardized classification system for application to sequence-based results for cancer predisposition genes is proposed.
Abstract: Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic testing may detect changes that are clearly pathogenic, clearly neutral, or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based genetic testing, describe other standardized reporting systems used in oncology, and propose a standardized classification system for application to sequence-based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based genetic tests to predict cancer risk.
TL;DR: In this article, density functional calculations of electronic structure, total energy, structural distortions, and magnetism for hydrogenated single-layer, bilayer, and multilayer graphenes are performed.
Abstract: Density-functional calculations of electronic structure, total energy, structural distortions, and magnetism for hydrogenated single-layer, bilayer, and multilayer graphenes are performed. It is found that hydrogen-induced magnetism can survive only at very low concentrations of hydrogen (single-atom regime) whereas hydrogen pairs with optimized structure are usually nonmagnetic. Chemisorption energy as a function of hydrogen concentration is calculated, as well as energy barriers for hydrogen binding and release. The results confirm that graphene can be perspective material for hydrogen storage. Difference between hydrogenation of graphene, nanotubes, and bulk graphite is discussed.
University of Otago1, Utrecht University2, Radboud University Nijmegen3, University of the East4, Wayne State University5, Karolinska University Hospital6, Malmö University7, Catholic University of the Sacred Heart8, Aarhus University9, University of Copenhagen10, Duke University11, Emory University12, University of Pennsylvania13, University of Pittsburgh14, University of Helsinki15, University Medical Center Groningen16, University of London17, Imperial College London18, University of Iceland19
TL;DR: It is reported that rs10757278-G is associated with, in addition to CAD, abdominal aortic aneurysm (AAA) and intracranial aneurYSm, but not with T2D, and the role of this sequence variant is not confined to atherosclerotic diseases.
Abstract: Recently, two common sequence variants on 9p21, tagged by rs10757278-G and rs10811661-T, were reported to be associated with coronary artery disease (CAD)(1-4) and type 2 diabetes (T2D)(5-7), respectively. We proceeded to further investigate the contributions of these variants to arterial diseases and T2D. Here we report that rs10757278-G is associated with, in addition to CAD, abdominal aortic aneurysm (AAA; odds ratio (OR) 1.31, P = 1.2 x 10(-12)) and intracranial aneurysm (OR = 1.29, P = 2.5 x 10(-6)), but not with T2D. This variant is the first to be described that affects the risk of AAA and intracranial aneurysm in many populations. The association of rs10811661-T to T2D replicates in our samples, but the variant does not associate with any of the five arterial diseases examined. These findings extend our insight into the role of the sequence variant tagged by rs10757278-G and show that it is not confined to atherosclerotic diseases.
TL;DR: A review of new developments in theoretical and experimental electronic-structure investigations of half-metallic ferromagnets (HMFs) is presented in this article, where the effects of electron-magnon interaction in HMFs and their manifestations in magnetic, spectral, thermodynamic, and transport properties are considered.
Abstract: A review of new developments in theoretical and experimental electronic-structure investigations of half-metallic ferromagnets (HMFs) is presented. Being semiconductors for one spin projection and metals for another, these substances are promising magnetic materials for applications in spintronics (i.e., spin-dependent electronics). Classification of HMFs by the peculiarities of their electronic structure and chemical bonding is discussed. The effects of electron-magnon interaction in HMFs and their manifestations in magnetic, spectral, thermodynamic, and transport properties are considered. Special attention is paid to the appearance of nonquasiparticle states in the energy gap, which provide an instructive example of essentially many-body features in the electronic structure. State-of-the-art electronic calculations for correlated d-systems are discussed, and results for specific HMFs (Heusler alloys, zinc-blende structure compounds, CrO2, and Fe3O4) are reviewed.
TL;DR: The model proposed explains why it is so difficult to reduce the graphite oxide up to pure graphene, and evolution of the electronic structure ofgraphite oxide with the coverage change is investigated.
Abstract: Based on density functional calculations, optimized structures of graphite oxide are found for various coverages by oxygen and hydroxyl groups, as well as their ratio corresponding to the minimum of total energy. The model proposed describes well-known experimental results. In particular, it explains why it is so difficult to reduce the graphite oxide up to pure graphene. Evolution of the electronic structure of graphite oxide with the coverage change is investigated.
TL;DR: Human regulatory T cells can differentiate into IL-17-producing cells, when stimulated by allogeneic antigen-presenting cells, especially monocytes, in the presence of rhIL-2/rhIL-15, and data suggest that epigenetic modification underlies the phenomenon of Treg plasticity here described.
TL;DR: G-FOBT significantly underestimates the prevalence of advanced adenomas and cancer in the screening population compared with I-FO BT, and the number-to-scope to find 1 cancer was comparable between the tests.
University of Washington1, University of Geneva2, Ghent University3, Salisbury University4, University Hospital Southampton NHS Foundation Trust5, Katholieke Universiteit Leuven6, Radboud University Nijmegen7, University College London8, University of Amsterdam9, University of Manchester10, University of Bern11, University of Naples Federico II12, University of Glasgow13, Pompeu Fabra University14, Utrecht University15, University of Oxford16, Wellcome Trust Sanger Institute17, University of Chicago18, Vanderbilt University19, Cold Spring Harbor Laboratory20, Howard Hughes Medical Institute21
TL;DR: Recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease are identified.
Abstract: BACKGROUND: Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients. METHODS: We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons. RESULTS: We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P=1.1x10(-7)). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in nine children with mental retardation or autism spectrum disorder and other variable features (P=0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies. CONCLUSIONS: We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype.
TL;DR: Twenty-seven regions of the genome are identified with one or more sequence variants showing significant association with height and the strongest association was with SNPs in the ZBTB38 gene.
Abstract: Adult human height is one of the classical complex human traits. We searched for sequence variants that affect height by scanning the genomes of 25,174 Icelanders, 2,876 Dutch, 1,770 European Americans and 1,148 African Americans. We then combined these results with previously published results from the Diabetes Genetics Initiative on 3,024 Scandinavians and tested a selected subset of SNPs in 5,517 Danes. We identified 27 regions of the genome with one or more sequence variants showing significant association with height. The estimated effects per allele of these variants ranged between 0.3 and 0.6 cm and, taken together, they explain around 3.7% of the population variation in height. The genes neighboring the identified loci cluster in biological processes related to skeletal development and mitosis. Association to three previously reported loci are replicated in our analyses, and the strongest association was with SNPs in the ZBTB38 gene.
TL;DR: The energy spectrum of cosmic rays above 2.5 x 10;{18} eV, derived from 20,000 events recorded at the Pierre Auger Observatory, is described and the hypothesis of a single power law is rejected with a significance greater than 6 standard deviations.
Abstract: The energy spectrum of cosmic rays above 2.5 x 10;{18} eV, derived from 20,000 events recorded at the Pierre Auger Observatory, is described. The spectral index gamma of the particle flux, J proportional, variantE;{-gamma}, at energies between 4 x 10;{18} eV and 4 x 10;{19} eV is 2.69+/-0.02(stat)+/-0.06(syst), steepening to 4.2+/-0.4(stat)+/-0.06(syst) at higher energies. The hypothesis of a single power law is rejected with a significance greater than 6 standard deviations. The data are consistent with the prediction by Greisen and by Zatsepin and Kuz'min.
TL;DR: The incidence, pathology and clinical features of antituberculosis drug‐induced hepatotoxicity, the metabolism and mechanisms of toxicity of isoniazid, rifampicin and pyrazinamide, and risk factors and management are reviewed.
Abstract: The cornerstone of tuberculosis management is a 6-month course of isoniazid, rifampicin, pyrazinamide and ethambutol. Compliance is crucial for curing tuberculosis. Adverse effects often negatively affect the compliance, because they frequently require a change of treatment, which may have negative consequences for treatment outcome. In this paper we review the incidence, pathology and clinical features of antituberculosis drug-induced hepatotoxicity, discuss the metabolism and mechanisms of toxicity of isoniazid, rifampicin and pyrazinamide, and describe risk factors and management of antituberculosis drug-induced hepatotoxicity. The reported incidence of antituberculosis drug-induced hepatotoxicity, the most serious and potentially fatal adverse reaction, varies between 2% and 28%. Risk factors are advanced age, female sex, slow acetylator status, malnutrition, HIV and pre-existent liver disease. Still, it is difficult to predict what patient will develop hepatotoxicity during tuberculosis treatment. The exact mechanism of antituberculosis drug-induced hepatotoxicity is unknown, but toxic metabolites are suggested to play a crucial role in the development, at least in the case of isoniazid. Priorities for future studies include basic studies to elucidate the mechanism of antituberculosis drug-induced hepatotoxicity, genetic risk factor studies and the development of shorter and safer tuberculosis drug regimens.
TL;DR: It is shown that the crystal structure of indium phosphide (InP) nanowires can be controlled by using impurity dopants, and it is demonstrated that zinc decreases the activation barrier for two-dimensional nucleation growth of zinc-blende InP and therefore promotes crystallization of the InPnanowires in the zinc- Blende, instead of the commonly found wurtzite, crystal structure.
Abstract: In most superconductors, the pairing-up of electrons responsible for resistance-free conductivity is driven by vibrations of the solid's crystal lattice. But there are other superconducting materials in which the 'glue' responsible for binding electrons is thought to have a very different origin: quantum fluctuations of spin or charge. An unusually 'violent' generalization of such a pairing mechanisms, in which spin and charge instabilities combine forces, has been identified in the unconventional superconductor CeRhIn5. These intimately coupled fluctuations significantly disrupt the flow of electrons in their normal unpaired state, yet also provide the quantum-mechanical glue necessary for generating superconducting pairs. In this paper, the crystal structure and stacking fault density of semiconducting nanowires composed of the same material are controlled by doping, leading to twinning superlattices. Periodic arrays of rotational dislocations lead to crystal heterostructures in indium phosphide and gallium phosphide nanowires. Semiconducting nanowires offer the possibility of nearly unlimited complex bottom-up design1,2, which allows for new device concepts3,4. However, essential parameters that determine the electronic quality of the wires, and which have not been controlled yet for the III–V compound semiconductors, are the wire crystal structure and the stacking fault density5. In addition, a significant feature would be to have a constant spacing between rotational twins in the wires such that a twinning superlattice is formed, as this is predicted to induce a direct bandgap in normally indirect bandgap semiconductors6,7, such as silicon and gallium phosphide. Optically active versions of these technologically relevant semiconductors could have a significant impact on the electronics8 and optics9 industry. Here we show first that we can control the crystal structure of indium phosphide (InP) nanowires by using impurity dopants. We have found that zinc decreases the activation barrier for two-dimensional nucleation growth of zinc-blende InP and therefore promotes crystallization of the InP nanowires in the zinc-blende, instead of the commonly found wurtzite, crystal structure10. More importantly, we then demonstrate that we can, once we have enforced the zinc-blende crystal structure, induce twinning superlattices with long-range order in InP nanowires. We can tune the spacing of the superlattices by changing the wire diameter and the zinc concentration, and we present a model based on the distortion of the catalyst droplet in response to the evolution of the cross-sectional shape of the nanowires to quantitatively explain the formation of the periodic twinning.
TL;DR: The guidelines described herein may be helpful in the appropriate management of FAP families and, in order to improve the care of these families further, prospective controlled studies should be undertaken.
Abstract: BACKGROUND: Familial adenomatous polyposis (FAP) is a well-described inherited syndrome, which is responsible for <1% of all colorectal cancer (CRC) cases. The syndrome is characterised by the development of hundreds to thousands of adenomas in the colorectum. Almost all patients will develop CRC if they are not identified and treated at an early stage. The syndrome is inherited as an autosomal dominant trait and caused by mutations in the APC gene. Recently, a second gene has been identified that also gives rise to colonic adenomatous polyposis, although the phenotype is less severe than typical FAP. The gene is the MUTYH gene and the inheritance is autosomal recessive. In April 2006 and February 2007, a workshop was organised in Mallorca by European experts on hereditary gastrointestinal cancer aiming to establish guidelines for the clinical management of FAP and to initiate collaborative studies. Thirty-one experts from nine European countries participated in these workshops. Prior to the meeting, various participants examined the most important management issues according to the latest publications. A systematic literature search using Pubmed and reference lists of retrieved articles, and manual searches of relevant articles, was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described herein may be helpful in the appropriate management of FAP families. In order to improve the care of these families further, prospective controlled studies should be undertaken.
TL;DR: A high value for the spin wave stiffness D=2100 meV A2 and a spin-collinear domain wall creation energy E(dw)=114 meV accompanied by low magnetic anisotropy is found and possible ways of increasing the range of magnetic order and effects of edge roughness on it are discussed.
Abstract: Magnetic zigzag edges of graphene are considered as a basis for novel spintronics devices despite the fact that no true long-range magnetic order is possible in one dimension. We study the transverse and longitudinal fluctuations of magnetic moments at zigzag edges of graphene from first principles. We find a high value for the spin wave stiffness D=2100 meV A2 and a spin-collinear domain wall creation energy E(dw)=114 meV accompanied by low magnetic anisotropy. Above the crossover temperature T(x) approximately 10 K, the spin correlation length xi proportional, variantT(-1) limits the long-range magnetic order to approximately 1 nm at 300 K while below T(x), it grows exponentially with decreasing temperature. We discuss possible ways of increasing the range of magnetic order and effects of edge roughness on it.
TL;DR: In this article, the authors simulated a chemistry of imperfect graphene for a broad class of defects (Stone-Wales (SW) defects, bivacancies, nitrogen substitution impurities, and zigzag edges) by density functional calculations.
Abstract: Defects change essentially not only the electronic properties but also the chemical properties of graphene, being centers of its chemical activity. Their functionalization is a way to modify the electronic and crystal structure of graphene, which may be important for graphene-based nanoelectronics. Using hydrogen as an example, we have simulated a chemistry of imperfect graphene for a broad class of defects (Stone-Wales (SW) defects, bivacancies, nitrogen substitution impurities, and zigzag edges) by density functional calculations. We have studied also an effect of finite width of graphene nanoribbons on their chemical properties. It is shown that magnetism at graphene edges is fragile, with respect to oxidation, and, therefore, chemical protection of the graphene edges may be required for the application of graphene in spintronics. At the same time, hydrogenation of the SW defects may be a prospective way to create magnetic carbon.