Showing papers by "Boston University published in 2010"
Medical University of Vienna1, Boston University2, Arthritis Research UK3, Johns Hopkins University4, University of California, San Francisco5, Humboldt University of Berlin6, University of Toronto7, National Jewish Health8, Brigham and Women's Hospital9, Paris Descartes University10, University of Leeds11, Catholic University of the Sacred Heart12, Erasmus University Rotterdam13, University of Colorado Denver14, Leiden University15, University of California, San Diego16, University of Massachusetts Medical School17, University of Michigan18, University of Washington19, McGill University Health Centre20, University of Pittsburgh21, Ministry of Health (New Zealand)22, New York University23, University of Manchester24, University of Amsterdam25, University of Kansas26, Women's College Hospital27
TL;DR: This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features.
Abstract: Objective The 1987 American College of Rheumatology (ACR; formerly the American Rheumatism Association) classifi cation criteria for rheumatoid arthritis (RA) have been criticised for their lack of sensitivity in early disease. This work was undertaken to develop new classifi cation criteria for RA. Methods A joint working group from the ACR and the European League Against Rheumatism developed, in three phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated infl ammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/ or erosive disease—this being the appropriate current paradigm underlying the disease construct ‘RA’. Results In the new criteria set, classifi cation as ‘defi nite RA’ is based on the confi rmed presence of synovitis in at least one joint, absence of an alternative diagnosis better explaining the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in four domains: number and site of involved joints (range 0–5), serological abnormality (range 0–3), elevated acute-phase response (range 0–1) and symptom duration (two levels; range 0–1). Conclusion This new classifi cation system redefi nes the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defi ning the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimise the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct ‘RA’.
7,120 citations
Medical University of Vienna1, Boston University2, Arthritis Research UK3, Johns Hopkins University4, University of California, San Francisco5, Charité6, University of Toronto7, National Jewish Health8, Harvard University9, University of Paris10, University of Leeds11, Catholic University of the Sacred Heart12, Erasmus University Rotterdam13, University of Colorado Denver14, Leiden University15, University of California, San Diego16, University of Massachusetts Medical School17, University of Michigan18, University of Washington19, McGill University20, University of Pittsburgh21, Ministry of Health (New Zealand)22, New York University23, University of Manchester24, University of Amsterdam25
TL;DR: This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features.
Abstract: Objective The 1987 American College of Rheumatology (ACR; formerly the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticised for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. Methods A joint working group from the ACR and the European League Against Rheumatism developed, in three phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease—this being the appropriate current paradigm underlying the disease construct ‘RA’. Results In the new criteria set, classification as ‘definite RA’ is based on the confirmed presence of synovitis in at least one joint, absence of an alternative diagnosis better explaining the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in four domains: number and site of involved joints (range 0–5), serological abnormality (range 0–3), elevated acute-phase response (range 0–1) and symptom duration (two levels; range 0–1). Conclusion This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimise the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct ‘RA’.
5,964 citations
TL;DR: In this paper, the authors develop a framework for understanding the robustness of interacting networks subject to cascading failures and present exact analytical solutions for the critical fraction of nodes that, on removal, will lead to a failure cascade and to a complete fragmentation of two interdependent networks.
Abstract: Complex networks have been studied intensively for a decade, but research still focuses on the limited case of a single, non-interacting network. Modern systems are coupled together and therefore should be modelled as interdependent networks. A fundamental property of interdependent networks is that failure of nodes in one network may lead to failure of dependent nodes in other networks. This may happen recursively and can lead to a cascade of failures. In fact, a failure of a very small fraction of nodes in one network may lead to the complete fragmentation of a system of several interdependent networks. A dramatic real-world example of a cascade of failures ('concurrent malfunction') is the electrical blackout that affected much of Italy on 28 September 2003: the shutdown of power stations directly led to the failure of nodes in the Internet communication network, which in turn caused further breakdown of power stations. Here we develop a framework for understanding the robustness of interacting networks subject to such cascading failures. We present exact analytical solutions for the critical fraction of nodes that, on removal, will lead to a failure cascade and to a complete fragmentation of two interdependent networks. Surprisingly, a broader degree distribution increases the vulnerability of interdependent networks to random failure, which is opposite to how a single network behaves. Our findings highlight the need to consider interdependent network properties in designing robust networks.
3,651 citations
TL;DR: It is suggested that reporting discrimination and calibration will always be important for a prediction model and decision-analytic measures should be reported if the predictive model is to be used for clinical decisions.
Abstract: The performance of prediction models can be assessed using a variety of methods and metrics. Traditional measures for binary and survival outcomes include the Brier score to indicate overall model performance, the concordance (or c) statistic for discriminative ability (or area under the receiver operating characteristic [ROC] curve), and goodness-of-fit statistics for calibration.Several new measures have recently been proposed that can be seen as refinements of discrimination measures, including variants of the c statistic for survival, reclassification tables, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Moreover, decision-analytic measures have been proposed, including decision curves to plot the net benefit achieved by making decisions based on model predictions.We aimed to define the role of these relatively novel approaches in the evaluation of the performance of prediction models. For illustration, we present a case study of predicting the presence of residual tumor versus benign tissue in patients with testicular cancer (n = 544 for model development, n = 273 for external validation).We suggest that reporting discrimination and calibration will always be important for a prediction model. Decision-analytic measures should be reported if the predictive model is to be used for clinical decisions. Other measures of performance may be warranted in specific applications, such as reclassification metrics to gain insight into the value of adding a novel predictor to an established model.
3,473 citations
Tanya M. Teslovich1, Kiran Musunuru, Albert V. Smith2, Andrew C. Edmondson3 +215 more•Institutions (46)
TL;DR: The results identify several novel loci associated with plasma lipids that are also associated with CAD and provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
Abstract: Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
3,469 citations
TL;DR: Effect size estimates suggest that mindfulness-based therapy was moderately effective for improving anxiety and mood symptoms from pre- to posttreatment in the overall sample, and this intervention is a promising intervention for treating anxiety and Mood problems in clinical populations.
Abstract: Objective:Although mindfulness-based therapy has become a popular treatment, little is known about its efficacy. Therefore, our objective was to conduct an effect size analysis of this popular intervention for anxiety and mood symptoms in clinical samples.Method:We conducted a literature search using PubMed, PsycINFO, the Cochrane Library, and manual searches. Our meta-analysis was based on 39 studies totaling 1,140 participants receiving mindfulness-based therapy for a range of conditions, including cancer, generalized anxiety disorder, depression, and other psychiatric or medical conditions. Results:Effect size estimates suggest that mindfulness-based therapy was moderately effective for improving anxiety (Hedges’sg!0.63) and mood symptoms (Hedges’sg!0.59) from pre- to posttreatment in the overall sample. In patients with anxiety and mood disorders, this intervention was associated with effect sizes (Hedges’sg) of 0.97 and 0.95 for improving anxiety and mood symptoms, respectively. These effect sizes were robust, were unrelated to publication year or number of treatment sessions, and were maintained over follow-up.Conclusions:These results suggest that mindfulnessbased therapy is a promising intervention for treating anxiety and mood problems in clinical populations.
3,115 citations
TL;DR: The datasets and algorithms used to create the Collection 5 MODIS Global Land Cover Type product, which is substantially changed relative to Collection 4, are described, with a four-fold increase in spatial resolution and changes in the input data and classification algorithm.
2,713 citations
Elizabeth K. Speliotes1, Elizabeth K. Speliotes2, Cristen J. Willer3, Sonja I. Berndt +410 more•Institutions (86)
TL;DR: Genetic loci associated with body mass index map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor, which may provide new insights into human body weight regulation.
Abstract: Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and similar to 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
2,632 citations
TL;DR: It is shown that this approach can reprogram multiple human cell types to pluripotency with efficiencies that greatly surpass established protocols and represents a safe, efficient strategy for somatic cell reprogramming and directing cell fate that has broad applicability for basic research, disease modeling, and regenerative medicine.
2,627 citations
TL;DR: This paper showed that the most efficient spreaders are not always necessarily the most connected agents in a network, and that the position of an agent relative to the hierarchical topological organization of the network might be as important as its connectivity.
Abstract: Spreading of information, ideas or diseases can be conveniently modelled in the context of complex networks. An analysis now reveals that the most efficient spreaders are not always necessarily the most connected agents in a network. Instead, the position of an agent relative to the hierarchical topological organization of the network might be as important as its connectivity.
2,618 citations
TL;DR: Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease.
Abstract: Background Cyclophosphamide and glucocorticoids have been the cornerstone of remissioninduction therapy for severe antineutrophil cytoplasmic antibody (ANCA)−associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen. Methods We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months. Results Nine centers enrolled 197 ANCA-positive patients with either Wegener’s granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P = 0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events. Conclusions Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.)
TL;DR: It is demonstrated that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
Abstract: Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
TL;DR: The guidelines for the evaluation and treatment of androgen deficiency syndromes in adult men published previously in 2006 were updated by the Task Force of the Clinical Guidelines Subcommittee of The Endocrine Society.
Abstract: Objective: Our objective was to update the guidelines for the evaluation and treatment of androgen deficiency syndromes in adult men published previously in 2006. Participants: The Task Force was composed of a chair, selected by the Clinical Guidelines Subcommittee of The Endocrine Society, five additional experts, a methodologist, and a medical writer. The Task Force received no corporate funding or remuneration. Conclusions: We recommend making a diagnosis of androgen deficiency only in men with consistent symptoms and signs and unequivocally low serum testosterone levels. We suggest the measurement of morning total testosterone level by a reliable assay as the initial diagnostic test. We recommend confirmation of the diagnosis by repeating the measurement of morning total testosterone and, in some men in whom total testosterone is near the lower limit of normal or in whom SHBG abnormality is suspected by measurement of free or bioavailable testosterone level, using validated assays. We recommend testos...
Harvard University1, Boston University2, University of California, Davis3, Pompeu Fabra University4, Stony Brook University5, World Health Organization6, Katholieke Universiteit Leuven7, St George's Hospital8, University of Ibadan9, University of Tokyo10, The Chinese University of Hong Kong11, University of Paris12, University of Groningen13, All India Institute of Medical Sciences14, New Bulgarian University15, University of São Paulo16
TL;DR: In this paper, the authors examined joint associations of 12 childhood adversities with first onset of 20 DSM-IV disorders in World Mental Health Surveys in 21 countries and found strong associations with all classes of disorders at all life-course stages.
Abstract: Background
Although significant associations of childhood adversities with adult mental disorders are widely documented, most studies focus on single childhood adversities predicting single disorders.
Aims
To examine joint associations of 12 childhood adversities with first onset of 20 DSM–IV disorders in World Mental Health (WMH) Surveys in 21 countries.
Method
Nationally or regionally representative surveys of 51 945 adults assessed childhood adversities and lifetime DSM–IV disorders with the WHO Composite International Diagnostic Interview (CIDI).
Results
Childhood adversities were highly prevalent and interrelated. Childhood adversities associated with maladaptive family functioning (e.g. parental mental illness, child abuse, neglect) were the strongest predictors of disorders. Co-occurring childhood adversities associated with maladaptive family functioning had significant subadditive predictive associations and little specificity across disorders. Childhood adversities account for 29.8% of all disorders across countries.
Conclusions
Childhood adversities have strong associations with all classes of disorders at all life-course stages in all groups of WMH countries. Long-term associations imply the existence of as-yet undetermined mediators.
TL;DR: The multilayered effects of drug–target interactions, including the essential cellular processes that are inhibited by bactericidal antibiotics and the associated cellular response mechanisms that contribute to killing are discussed.
Abstract: Antibiotic drug-target interactions, and their respective direct effects, are generally well characterized. By contrast, the bacterial responses to antibiotic drug treatments that contribute to cell death are not as well understood and have proven to be complex as they involve many genetic and biochemical pathways. In this Review, we discuss the multilayered effects of drug-target interactions, including the essential cellular processes that are inhibited by bactericidal antibiotics and the associated cellular response mechanisms that contribute to killing. We also discuss new insights into these mechanisms that have been revealed through the study of biological networks, and describe how these insights, together with related developments in synthetic biology, could be exploited to create new antibacterial therapies.
Benjamin F. Voight1, Benjamin F. Voight2, Laura J. Scott3, Valgerdur Steinthorsdottir4 +180 more•Institutions (53)
TL;DR: By combining genome-wide association data from 8,130 individuals with type 2 diabetes and 38,987 controls of European descent and following up previously unidentified meta-analysis signals, 12 new T2D association signals are identified with combined P < 5 × 10−8.
Abstract: By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P<5x10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.
TL;DR: It is shown that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait, and indicates that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
Abstract: Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
TL;DR: Modifying factors that play roles in the development of joint OA may reduce the risk of OA and prevent subsequent pain and disability, particularly in the weight-bearing joints.
Harvard University1, McGill University2, University of Washington3, Erasmus University Rotterdam4, UCL Institute of Child Health5, University of Helsinki6, University of Cambridge7, Indiana University – Purdue University Indianapolis8, National Institutes of Health9, Wellcome Trust Sanger Institute10, Imperial College London11, Wake Forest University12, Wellcome Trust Centre for Human Genetics13, University of Oxford14, Churchill Hospital15, Tufts University16, Cedars-Sinai Medical Center17, Agency for Science, Technology and Research18, University of Miami19, Health Canada20, Public Health Agency of Canada21, University College London22, University of Aberdeen23, Broad Institute24, University of Pittsburgh25, Boston University26, King's College London27, University of Oulu28, Finnish Institute of Occupational Health29
TL;DR: In this article, a genome-wide association study of 25-hydroxyvitamin D concentrations in 33,996 individuals of European descent from 15 cohorts was conducted to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency.
TL;DR: In this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events.
Abstract: Background Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men. The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied. Methods Community-dwelling men, 65 years of age or older, with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) or a free serum testosterone level of less than 50 pg per milliliter (173 pmol per liter) were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities classification. The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group. Results A total of 209 men (mean age, 74 years) were enrolled at the time the trial was terminated. At baseline, there was a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity among the participants. During the course of the study, the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events. The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period. As compared with the placebo group, the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load. Conclusions In this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy. (ClinicalTrials.gov number, NCT00240981.)
TL;DR: Experimental spectroscopic measurements by scanning tunneling microscopy of highly strained nanobubbles that form when graphene is grown on a platinum surface open the door to both the study of charge carriers in previously inaccessible high magnetic field regimes and deliberate mechanical control over electronic structure in graphene or so-called “strain engineering.”
Abstract: Recent theoretical proposals suggest that strain can be used to engineer graphene electronic states through the creation of a pseudo-magnetic field. This effect is unique to graphene because of its massless Dirac fermion-like band structure and particular lattice symmetry (C3v). Here, we present experimental spectroscopic measurements by scanning tunneling microscopy of highly strained nanobubbles that form when graphene is grown on a platinum (111) surface. The nanobubbles exhibit Landau levels that form in the presence of strain-induced pseudo-magnetic fields greater than 300 tesla. This demonstration of enormous pseudo-magnetic fields opens the door to both the study of charge carriers in previously inaccessible high magnetic field regimes and deliberate mechanical control over electronic structure in graphene or so-called "strain engineering."
TL;DR: Obstructive sleep apnea is associated with an increased risk of incident heart failure in community-dwelling middle-aged and older men; its association with incident coronary heart disease in this sample is equivocal.
Abstract: Background— Clinic-based observational studies in men have reported that obstructive sleep apnea is associated with an increased incidence of coronary heart disease. The objective of this study was to assess the relation of obstructive sleep apnea to incident coronary heart disease and heart failure in a general community sample of adult men and women. Methods and Results— A total of 1927 men and 2495 women ≥40 years of age and free of coronary heart disease and heart failure at the time of baseline polysomnography were followed up for a median of 8.7 years in this prospective longitudinal epidemiological study. After adjustment for multiple risk factors, obstructive sleep apnea was a significant predictor of incident coronary heart disease (myocardial infarction, revascularization procedure, or coronary heart disease death) only in men ≤70 years of age (adjusted hazard ratio 1.10 [95% confidence interval 1.00 to 1.21] per 10-unit increase in apnea-hypopnea index [AHI]) but not in older men or in women of...
TL;DR: Although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD.
Abstract: Context Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD).
Objectives To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35 000 persons (8371 AD cases).
Design, Setting, and Participants In stage 1, we identified strong genetic associations (P < 10−3) in a sample of 3006 AD cases and 14 642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P<10−3. In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P<10−5. In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P<1.7×10−8. These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009.
Main Outcome Measure Presence of Alzheimer disease.
Results Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95% confidence interval [CI],1.06-1.21 per copy of the minor allele; P = 1.59×10−11) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR, 1.18; 95% CI, 1.07-1.29; P = 6.45×10−9). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P < .05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study).
Conclusions Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.
TL;DR: Preoperative cleansing of the patient's skin with chlorhexidine-alcohol is superior to cleansing with povidone-iodine for preventing surgical-site infection after clean-contaminated surgery.
Abstract: BACKGROUND Since the patient’s skin is a major source of pathogens that cause surgical-site infection, optimization of preoperative skin antisepsis may decrease postoperative infections. We hypothesized that preoperative skin cleansing with chlorhexidine–alcohol is more protective against infection than is povidone–iodine. METHODS We randomly assigned adults undergoing clean-contaminated surgery in six hospitals to preoperative skin preparation with either chlorhexidine–alcohol scrub or povidone–iodine scrub and paint. The primary outcome was any surgical-site infection within 30 days after surgery. Secondary outcomes included individual types of surgical-site infections. RESULTS A total of 849 subjects (409 in the chlorhexidine–alcohol group and 440 in the povidone–iodine group) qualified for the intention-to-treat analysis. The overall rate of surgical-site infection was significantly lower in the chlorhexidine–alcohol group than in the povidone–iodine group (9.5% vs. 16.1%; P = 0.004; relative risk, 0.59; 95% confidence interval, 0.41 to 0.85). Chlorhexidine–alcohol was significantly more protective than povidone–iodine against both superficial incisional infections (4.2% vs. 8.6%, P = 0.008) and deep incisional infections (1% vs. 3%, P = 0.05) but not against organ-space infections (4.4% vs. 4.5%). Similar results were observed in the per-protocol analysis of the 813 patients who remained in the study during the 30-day follow-up period. Adverse events were similar in the two study groups. CONCLUSIONS Preoperative cleansing of the patient’s skin with chlorhexidine–alcohol is superior to cleansing with povidone–iodine for preventing surgical-site infection after cleancontaminated surgery. (ClinicalTrials.gov number, NCT00290290.)
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TL;DR: A formal model of two-sided network externalities based in textbook economics-a mix of Katz and Shapiro network effects, price discrimination, and product differentiation is introduced, offering insights to regulators seeking to apply antitrust law to network markets.
Abstract: How can firms profitably give away free products? This paper provides a novel answer and articulates tradeoffs in a space of information product design. We introduce a formal model of two-sided network externalities based in textbook economics - a mix of Katz & Shapiro network effects, price discrimination, and product differentiation. Externality-based complements, however, exploit a different mechanism than either tying or lock-in even as they help to explain many recent strategies such as those of firms selling operating systems, Internet browsers, games, music, and video.The model presented here argues for three simple but useful results. First, even in the absence of competition, a firm can rationally invest in a product it intends to give away into perpetuity. Second, we identify distinct markets for content providers and end consumers and show that either can be a candidate for a free good. Third, product coupling across markets can increase consumer welfare even as it increases firm profits.The model also generates testable hypotheses on the size and direction of network effects while offering insights to regulators seeking to apply antitrust law to network markets.
University of North Carolina at Chapel Hill1, University of Texas Health Science Center at Houston2, University of Pavia3, University of Cambridge4, University of Milan5, Stanford University6, Kaiser Permanente7, National Institutes of Health8, University of Washington9, Wake Forest University10, Cedars-Sinai Medical Center11, Group Health Cooperative12, Lund University13, University of Michigan14, University of Helsinki15, National Institute for Health and Welfare16, Boston University17, University of Chicago18, International Agency for Research on Cancer19, Charles University in Prague20, Institut Gustave Roussy21, French Institute of Health and Medical Research22, University of Padua23, University of Glasgow24, Palacký University, Olomouc25, Trinity College, Dublin26, National and Kapodistrian University of Athens27, Newcastle University28, University of Aberdeen29, University of Turin30, Nofer Institute of Occupational Medicine31, Russian Academy32, University of Exeter33, Harvard University34, Massachusetts Institute of Technology35, Broad Institute36, VU University Amsterdam37, Erasmus University Rotterdam38, University of Virginia39, Virginia Commonwealth University40, University of Pennsylvania41, Duke University42, Tufts University43, University of Ioannina44
TL;DR: A meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium found the strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3, and three loci associated with number of cigarettes smoked per day were identified.
Abstract: Consistent but indirect evidence has implicated genetic factors in smoking behavior1,2. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], b = 1.03, standard error (s.e.) = 0.053, beta = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], b = 0.367, s. e. = 0.059, beta = 5.7 x 10(-10); and rs1028936[A], b = 0.446, s. e. = 0.074, beta = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], b = 0.333, s. e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.
TL;DR: The strong adjusted association between ischemic stroke and OAHI in community-dwelling men with mild to moderate sleep apnea suggests that this is an appropriate target for future stroke prevention trials.
Abstract: Rationale: Although obstructive sleep apnea is associated with physiological perturbations that increase risk of hypertension and are proatherogenic, it is uncertain whether sleep apnea is associated with increased stroke risk in the general population.
Objectives: To quantify the incidence of ischemic stroke with sleep apnea in a community-based sample of men and women across a wide range of sleep apnea.
Methods: Baseline polysomnography was performed between 1995 and 1998 in a longitudinal cohort study. The primary exposure was the obstructive apnea–hypopnea index (OAHI) and outcome was incident ischemic stroke.
Measurements and Main Results: A total of 5,422 participants without a history of stroke at the baseline examination and untreated for sleep apnea were followed for a median of 8.7 years. One hundred ninety-three ischemic strokes were observed. In covariate-adjusted Cox proportional hazard models, a significant positive association between ischemic stroke and OAHI was observed in men (P value for linear trend: P = 0.016). Men in the highest OAHI quartile (>19) had an adjusted hazard ratio of 2.86 (95% confidence interval, 1.1–7.4). In the mild to moderate range (OAHI, 5–25), each one-unit increase in OAHI in men was estimated to increase stroke risk by 6% (95% confidence interval, 2–10%). In women, stroke was not significantly associated with OAHI quartiles, but increased risk was observed at an OAHI greater than 25.
Conclusions: The strong adjusted association between ischemic stroke and OAHI in community-dwelling men with mild to moderate sleep apnea suggests that this is an appropriate target for future stroke prevention trials.
TL;DR: This work presents a new measure for assessing phase-amplitude CFC, defined as an adaptation of the Kullback-Leibler distance-a function that is used to infer the distance between two distributions-and calculates how much an empirical amplitude distribution-like function over phase bins deviates from the uniform distribution.
Abstract: Neuronal oscillations of different frequencies can interact in several ways. There has been particular interest in the modulation of the amplitude of high-frequency oscillations by the phase of low-frequency oscillations, since recent evidence suggests a functional role for this type of cross-frequency coupling (CFC). Phase-amplitude coupling has been reported in continuous electrophysiological signals obtained from the brain at both local and macroscopic levels. In the present work, we present a new measure for assessing phase-amplitude CFC. This measure is defined as an adaptation of the Kullback–Leibler distance—a function that is used to infer the distance between two distributions—and calculates how much an empirical amplitude distribution-like function over phase bins deviates from the uniform distribution. We show that a CFC measure defined this way is well suited for assessing the intensity of phase-amplitude coupling. We also review seven other CFC measures; we show that, by some performance benchmarks, our measure is especially attractive for this task. We also discuss some technical aspects related to the measure, such as the length of the epochs used for these analyses and the utility of surrogate control analyses. Finally, we apply the measure and a related CFC tool to actual hippocampal recordings obtained from freely moving rats and show, for the first time, that the CA3 and CA1 regions present different CFC characteristics.
TL;DR: Creation of a bioartificial lung requires engineering of viable lung architecture enabling ventilation, perfusion and gas exchange, and regenerated lungs into orthotopic position showed in vivo function.
Abstract: About 2,000 patients now await a donor lung in the United States. Worldwide, 50 million individuals are living with endstage lung disease. Creation of a bioartificial lung requires engineering of viable lung architecture enabling ventilation, perfusion and gas exchange. We decellularized lungs by detergent perfusion and yielded scaffolds with acellular vasculature, airways and alveoli. To regenerate gas exchange tissue, we seeded scaffolds with epithelial and endothelial cells. To establish function, we perfused and ventilated cellseeded constructs in a bioreactor simulating the physiologic environment of developing lung. By day 5, constructs could be perfused with blood and ventilated using physiologic pressures, and they generated gas exchange comparable to that of isolated native lungs. To show in vivo function, we transplanted regenerated lungs into orthotopic position. After transplantation, constructs were perfused by the recipient’s circulation and ventilated by means of the recipient’s airway and respiratory muscles, and they provided gas exchange in vivo for up to 6 h after extubation.
TL;DR: In this paper, it was shown that when graphite's graphene sheets are rotated out of their usual alignment, it can generate low-energy Van Hove singularities for which the position is controlled by the angle of rotation.
Abstract: When a Van Hove singularity exists near the Fermi energy of a solid’s density of states, it can cause a variety of exotic phenomena to emerge. Scanning tunnelling microscope measurements indicate that when graphite’s graphene sheets are rotated out of their usual alignment, it can generate low-energy Van Hove singularities for which the position is controlled by the angle of rotation.